FitSugar

Are Prescription Drug Ads More Harm Than Help?

FitSugar — Tue, 06 Oct 2009 03:00:43 -0700

Chances are you've seen more prescription drug commercials than you can count - Viagra, Cymbalta, Celebrex, and Yaz are just a few that I can name from memory. The ads are pervasive and influential and pharmaceutical companies know that. From 1997 to 2005, drug companies tripled their spending in television ad campaigns from $1.3 billion to $4.2 billion. In 2006 that number bumped up even further to $4.6 billion.

Though the ads do inform consumers of what's available to them, health advocates say they present drugs and symptoms in very general terms and can confuse consumers into thinking they have something they don't. A national study found that one-third of all Americans have asked for a drug they saw on a commercial and of those that asked, 82 percent were given a prescription of some sort.

To give your opinion and hear more about this issue, read more.

It's hard to say without doubt if doctors are over prescribing these drugs but it's one of the concerns that's being raised. Other concerns include patients asking self-diagnosing and ads increasing medical costs and patient risks - the advertised drugs are usually newer with higher costs and less testing, making them more risky.

I can admit to asking about Yaz after seeing the commercials over and over again. It's the top-selling birth control in the United States due in large part to its marketing campaign - a campaign that is now under question as health experts step forward with claims that the drug is unsafe.

Have you ever asked your doctor about a prescription drug because of a commercial you saw? Did you end up taking the drug?

What Do You Use For Birth Control?

FitSugar — Mon, 28 Sep 2009 04:30:19 -0700

It might seem like I have ~~sex~~ birth control on the brain. Last week I asked you about your experience or lack thereof with the female condom. Although it's most often talked about in intimate settings, birth control is in the news.

Concerns are being raised about the safety of the Yaz birth control pill, the top selling pill in the US, according to the New York Times. Women taking Yaz might have a higher chance of developing blood clots compared to other birth control pills, a claim that drug maker Bayer disputes. Investigation is ongoing, as are 74 lawsuits charging that Yaz and Yasmin, a similar product by Bayer, created health problems in women taking these pills. The lawsuits are tricky business though, since warnings about clots are presented in the pharmaceuticals' literature. Bayer strongly stands behind its product.

These new fears about the most commonly used contraceptive pill in America emphasize that avoiding pregnancy can be a difficult task, sometimes with medical consequences. I am curious about you . . .

FDA Lists Drugs Under Investigation

FitSugar — Tue, 09 Sep 2008 03:00:00 -0700

Ever been prescribed a drug by your doctor and wondered how safe or unsafe it is?

The FDA has recently begun posting a list of prescription drugs under investigation for safety problems on its site. Currently there are only about 20 meds on the list, but the FDA will continue to update it each quarter. If a medication you're currently taking is classified as under investigation, don't freak out. Continue taking your medicine as prescribed and make an appointment to talk to your doctor as the potential risks may not outweigh the benefits of taking the medicine.

For all other prescription drugs check out my new Health Guide where you'll find thousands of overviews of common medications. It's very helpful, especially if you've thrown away the little foldout pamphlet that comes with all prescriptions.

Source

Do You Share Prescription Drugs?

FitSugar — Tue, 26 Aug 2008 13:00:00 -0700

If you pass the occasional pill to your friends, you are not alone. According to a recent study published in The Journal of Women’s Health, sharing prescription drugs is common among young adults, especially 18- to 44-year-old women. The recent survey of 25,000 people found that more than one-third of the women polled shared prescription drugs with friends or took pills from their pals. The drugs included everything from allergy meds to pain pills. I'm definitely guilty of offering the occasional Allegra to friends who also take the drug, but how about you?

Source

Do You Pay Attention to Drug Interactions?

FitSugar — Mon, 28 Jul 2008 12:00:00 -0700

I'm always surprised when I read the labels on my prescription medications that they can often interact with seemingly innocent over-the-counter drugs. So I'm very careful to read the texts that come with my prescriptions, to make sure that they don't create a harmful combination with something else. Do you pay attention to the interactions spelled out on your drug labels?

Source

Top 10 Most Medicated States

FitSugar — Fri, 25 Jul 2008 03:00:00 -0700

Where you live affects many elements of your daily life, like how often you walk to your destination as opposed to drive. Based on a new study by Kaiser Family Foundation, which side of the Mason-Dixon line you live on could affect how medicated you are.

According to numbers compiled by the Kaiser Family Foundation the top ten medicated states, based on the number of retail prescriptions filled per capita annually, were in the South. Many states were considerably higher than the national average of 11.1 prescriptions filled annually. Here are the top 10 medicated states.

Public health experts believe the high prescription drug usage is related to obesity rates, which are also higher in the South. Obesity is a risk factor in many chronic diseases like type 2 diabetes and hypertension.

To see the least medicated states, read more.

To see how all 50 states and the District of Columbia fare, check out State Health Facts. Were you surprised where your state ranked? Tell me in the comments section below.

Source

Migraine headaches

FitSugar — Wed, 08 Oct 2008 17:35:00 -0700

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Migraine Surveys

About 17.1% of women and 5.6% of men suffer migraines, according to the 2007 American Migraine Prevalence and Prevention survey. Nearly a third of respondents reported 3 or more migraine attacks per month. Over half were severely impaired or needed bed rest during attacks. Although many patients met the criteria for preventive medication, only a small percentage actually received it.
About 20% of patients with migraine take potentially addictive opioid and barbiturate drugs, even though these drugs have not been approved by the Food and Drug Administration (FDA) for migraine treatment, according to a 2007 survey commissioned by the U.S. National Headache Foundation.

FDA Actions

The opioid drug fentanyl (Fentora) should not be prescribed "off-label" to patients with migraine or other severe headaches, warns the FDA, following several reports of drug-related deaths. Fentanyl is approved only for treating cancer pain.
In 2007, the FDA pulled 15 unapproved ergotamine preparations off the market because they lacked a warning label describing the risks for serious drug interactions.

Migraines in Adolescents

Many adolescents may stop having migraines, or transition to less severe types of headaches, when they reach adulthood, suggests a small 2006 study in Neurology.
Zolmitriptan (Zomig) nasal spray appears to be safe and effective for adolescent migraine, indicates a 2007 study in Pediatrics. Zolmitriptan, like all migraine drugs, is currently approved only for adults.

Sumatriptan-Naproxen Combination

A combination of the triptan drug sumatriptan (Imitrex) and the nonsteroidal anti-inflammatory drug naproxen (Aleve) works better for migraine pain relief than either drug alone, according to a 2007 study in the Journal of the American Medical Association.

Introduction

The pain from a headache does not start from inside the brain. (The brain itself can not feel pain.) Instead, headache pain begins in one or more of the following locations:

The tissues covering the brain
The structures at the base of the brain
Muscles and blood vessels around the scalp, face, and neck

Headache is generally categorized as primary or secondary.

Primary Headache. A headache is considered primary when a disease or other medical condition does not cause it.

Tension headache is the most common primary headache and accounts for 90% of all headaches. [See In-Depth Report # 11: Tension headaches.]
Neurovascular headaches are the second most common primary headaches. This type includes migraines and cluster headaches. [See In-Depth Report # 99: Cluster headaches.] Such headaches are caused by an interaction between blood vessel and nerve abnormalities.

Headaches are usually caused by muscle tension, vascular problems, or both. Migraines are vascular in origin, and may be preceded by visual disturbances, loss of peripheral vision, and fatigue. Over-the-counter pain medications can relieve most headaches.

Click the icon to see a depiction of migraine cause.

Secondary Headache. Secondary headaches are caused by other medical conditions, such as sinusitis, neck injuries or abnormalities, and stroke. About 2% of headaches are secondary headaches caused by abnormalities or infections in the nasal or sinus passages. [See "Causes of Secondary Headaches," in this report.]

It is not uncommon for someone to experience a combination of headache types.

Click the icon to see a comparison of headache symptoms.

Migraine is now recognized as a chronic illness, not simply as a headache. About 28 million people suffer from migraines annually. They are often classified by whether or not auras (seeing bright "spots" or "stars") accompany them:

Common migraines are without auras. About 75% of migraines are the common type.
Classic migraines are those with auras.

A person may experience one or the other at different times.

In general, there are four phases to a migraine (although they may not all occur in every patient): The prodrome phase, auras, the attack, and the postdrome phase.

Prodrome. The prodrome phase is a group of vague symptoms that may precede a migraine attack by several hours, or even a day or two. Prodrome symptoms include:

Sensitivity to light or sound
Changes in appetite
Fatigue and yawning
Malaise
Mood changes
Food cravings

Auras. Auras are sensory disturbances that occur before the migraine attack in 1 in 5 patients. Visually, auras are referred to as being positive or negative:

Positive auras include bright or shimmering light or shapes at the edge of their field of vision called scintillating scotoma. They can enlarge and fill the line of vision. Other positive aura experiences are zigzag lines or stars.
Negative auras are dark holes, blind spots, or tunnel vision (inability to see to the side).
Patients may have mixed positive and negative auras. This is a visual experience that is sometimes described as a fortress with sharp angles around a dark center.

Other neurologic symptoms may occur at the same time as the aura, although they are less common. They include:

Speech disturbances
Tingling, numbness, or weakness in an arm or leg
Perceptual disturbances such as space or size distortions
Confusion

Migraine Attack. If untreated, attacks usually last from 4 - 72 hours. A typical migraine attack produces the following symptoms:

Throbbing pain on one side of the head. The word migraine, in fact, is derived from the Greek word hemikrania, meaning "half of the head" because the pain of migraine often occurs on one side. Pain also sometimes spreads to affect the entire head.
Pain worsened by physical activity
Nausea, sometimes with vomiting
Visual symptoms
Facial tingling or numbness
Extreme sensitivity to light and noise
Looking pale and feeling cold

Less common symptoms include tearing and redness in one eye, swelling of the eyelid, and nasal congestion, including runny nose. (Such symptoms are more common in certain other headaches, notably cluster headaches. In one study, however, they occurred in over 40% of migraine sufferers.)

Postdrome. After a migraine attack, there is usually a postdrome phase, in which patients may feel exhausted and mentally foggy for a while.

In some cases, patients eventually experience on-going and chronic headaches. In fact, in an analysis using two different diagnostic methods, between 87 - 90% of daily chronic headaches were actually migraines. Some doctors believe that, unless otherwise demonstrated, any chronic headache consisting of episodes of disabling pain that recur regularly over years should be considered as a migraine.

Chronic migraines may occur from overuse of migraine medications (called a rebound headache) or may develop over time (called transformed migraine).

Rebound Headache. The most common cause of chronic migraine is the rebound effect, which is a cycle caused by overuse of migraine medications. The process involves the following:

Patients typically have taken pain medication for more than 3 days a week on an ongoing basis.
When the patients stop taking medication, they experience a rebound headache.
They start taking the drugs again.
Eventually the headache simply persists, and medications are no longer effective.

Medications implicated in rebound migraines include nonprescription painkillers (acetaminophen, aspirin, ibuprofen), barbiturates, sedatives, narcotics, and migraine medications, particularly those that also contain caffeine. (Heavy caffeine use can also cause this condition.)

Transformed Migraines. In some cases, migraines themselves evolve into chronic, daily headaches called transformed migraines. Such headaches resemble tension headaches but are more likely to be accompanied by gastrointestinal distress and mental or visual disturbances and, in women, to be affected by menstrual cycles. In one study, the risk for transformed migraines were associated with other factors, including allergies, asthma, hypothyroidism, hypertension, and a daily intake of caffeine.

Migraines are defined by the number and length of attacks and whether an aura is present.

Definition of Migraines without Auras (Common Migraine). To be defined as a migraine without aura, a patient should have at least five attacks that have the following characteristics:

A. Each untreated, or unsuccessfully treated, attack must last 4 - 72 hours.

B. It must have at least two of the following four characteristics:

Pain on one side of the head
Pulsing or throbbing pain
Pain severe enough to impair or prevent daily activities
Pain must be intensified by exertion, such as walking up stairs

C. During a headache at least one of the following symptoms must also be present:

Nausea, vomiting or both
Sensitivity to light and noise

In addition, other neurologic or medical conditions that might be causing this pain must be ruled out, or, if they do occur, they are not related in time to the suspected migraine.

Definition of Migraines with Auras (Classic Migraine). To be defined as a migraine with aura, the patients must have at least two attacks that have three out of four of the following events.

At least one fully reversible aura symptom suggesting the headache starts in the cerebral cortex or brain stem.
At least one aura symptom that develops gradually over more than 4 minutes ,or two or more aura symptoms that occur in succession.
No single aura symptom that lasts more than 1 hour. (There may be successive aura symptoms that extend that time, but each one should not last more than 60 minutes.)
The headache itself may begin before, at the same time, or at an interval of no more than an hour after the aura.

As with common migraines, other neurologic or medical conditions that might be causing this pain must be ruled out or if they occur, they are not related in time to the suspected migraine.

Click the icon to see a definition of a migraine.

Although migraine is considered to be a specific chronic illness, it has various presentations that occur in different individuals.

Menstrual Migraines. Migraines are often tied to a woman’s menstrual cycle. Researchers think that estrogen plays a role. About half of women with migraines report an association with menstruation. Compared to migraines that occur at other times of the month, menstrual migraines tend to be more severe, last longer, and not have auras. Triptan drugs can provide relief and may also help prevent these types of migraines.

The highest incidence of migraines typically occurs during the early follicular phase, (beginning of menstruation). A 2005 study found that women are 1.7 times more likely to have a migraine during the 2 days before menstruation begins. But, women are 2.5 times more likely to have a migraine during the first 3 days of menstruation. During this time, migraines are more likely to be severe, with symptoms that include vomiting.

Ophthalmoplegic Migraine. This very rare headache tends to occur in younger adults. The pain centers around one eye and is usually less intense than in a standard migraine. It may be accompanied by vomiting, double vision, a droopy eyelid, and paralysis of eye muscles. Attacks can last from hours to months. A computed tomography (CT) or magnetic resonance imaging (MRI) scan may be needed to rule out an aneurysm (a rupture blood vessel) in the brain.

Retinal Migraine. Symptoms of retinal migraine are short-term blind spots or total blindness in one eye that lasts less than an hour. A headache may precede or occur with the eye symptoms. Sometimes retinal migraines develop without headache. Other eye and neurologic disorders must be ruled out.

Basilar Migraine. Considered a subtype of migraine with aura, this migraine starts in the basilar artery, which forms at the base of the skull. It occurs mainly in young people. Symptoms may include vertigo (the room spins), ringing in the ears, slurred speech, unsteadiness, possibly loss of consciousness, and severe headaches.

Familial Hemiplegic Migraine. This is a very rare inherited genetic migraine disease. It can cause temporary paralysis on one side of the body, vision problems, and vertigo. These symptoms occur about 10 - 90 minutes before the headache.

Status Migrainosus. This is a serious and rare migraine. It is so severe and lasts so long that it requires hospitalization.

About 90% of people seeking help for headaches have a primary headache disorder. The balance of secondary headaches is caused by an underlying disorder that produces the headache as a symptom. Many conditions cause headaches as a symptom. Some of the most common are listed below.

Sinus Headache. Many primary headaches, including migraine, are misdiagnosed as sinus headaches. Nearly 9 in 10 patients who think they have sinus headaches actually have or probably have had a migraine. Sinus headaches occur in the front of the face, usually around the eyes, across the cheeks, or over the forehead. They are usually mild in the morning and increase during the day and are usually accompanied by fever, runny nose, congestion, and general debilitation. Sinus headaches spread over a larger area of the head than migraines, but telling the difference between these two kinds of headache is difficult, particularly if a headache is the only symptom of sinusitis. The two may even coexist in many cases. Often, the visual changes associated with migraine can rule out sinusitis, but such visual changes do not occur with all migraines. (Rarely, sinusitis can cause double vision and even vision loss, a sign of very serious infection.)

Headache Due to Neck Problems. Some headaches may be caused by abnormalities of the neck muscles resulting from prolonged poor posture (such as that caused by sitting in front of a computer keyboard or driving daily for long periods), arthritis, injuries of the upper spine, or abnormalities in the cervical spine (the spinal bones in the neck). Nerves in the neck converge in the trigeminal nerve in the face and can generate pain signals that the brain may interpret as headache. Pain is usually on one side. Even if it affects both sides of the head, it is usually more severe on one side. The quality of the headache may be similar to an aching tension headache or a mild migraine without aura.

Temporomandibular Joint Dysfunction. Temporomandibular joint dysfunction (TMJ) is caused by clenching the jaws or grinding the teeth (usually during sleep), or by abnormalities in the jaw joints themselves. The diagnosis is easy if chewing produces pain or if jaw motion is restricted or noisy. TMJ pain can occur in the ear, cheek, temples, neck, or shoulders.

Glaucoma. Acute glaucoma is caused by increased pressure in the eye and requires immediate medical attention. Throbbing pain may be felt around or behind the eyes or in the forehead. Patients have redness in the eye and may see halos or rings around lights.

Brain Tumor. Fear of having a brain tumor is common among people with headaches, but a headache is almost never the first or only sign of a tumor. Changes in personality and mental functioning, vomiting, seizures, and other symptoms are more likely to appear first. When the headache does develop, it is often worse early in the morning or may awaken sufferers during the night.

Neuralgia. Neuralgia is pain due to nerve abnormalities, which can occur in the facial area and resemble migraine or sinus headaches.

Hypertension. Although many people attribute headaches to high blood pressure, the two are rarely associated. An exception is malignant hypertension, an uncommon medical emergency, in which the blood pressure abruptly rises to extreme levels, causing damage to blood vessels in the brain, heart, and kidneys.

Strokes Caused by Blood Clots or Hemorrhages. A blood clot or hemorrhage in the brain leading to a stroke can cause a severe headache, sometimes referred to as a thunderclap headache when it is very sudden and severe. The onset of such a headache, particularly if it is associated with confusion, stupor, or other neurologic symptoms, mandates prompt medical attention. It is important to determine if a clot or bleeding is causing the stroke, since treatments are very different.

Head Injuries. It is obvious that a significant blow to the head will cause pain. Post-injury headaches, however, can reflect serious damage, ranging from skull fractures to internal bleeding.

Disorders of the Meninges. The meninges are the membranes covering the brain and the spinal cord. In very rare instances, ordinary physical strain may injure or weaken the meninges, causing a leakage of cerebrovascular fluid (the fluid that bathes the brain). This can cause severe headache and nausea, which are relieved by lying flat. The condition is very treatable. Meningitis, which is an infection or irritation of these membranes, is an uncommon but potentially serious cause of severe headache. Other symptoms include nausea and stiffness or pain in the neck.

Gynecologic Problems. Many clinicians have anecdotally linked gynecologic problems, such as ovarian cysts and menstrual disorders, to chronic headaches, and new data are emerging to support this association.

Temporal (Giant Cell) Arteritis. Certain causes of headaches are unique to the elderly, such as temporal arteritis, also called giant cell arteritis. Inflammation in arteries that carry blood to the head, neck, and sometimes the upper part of the body can cause very severe headaches. The risk for this headache is highest in people over age 70, especially among women, people of European heritage, and patients with polymyalgia rheumatica.

Miscellaneous Causes of Benign Headaches. Rapid consumption of ice cream or other very cold foods or beverages is the most common trigger of sudden headache pain. (It may be prevented by warming the food or drink for a few seconds in the front of the mouth before swallowing.) Other common benign causes of headache include eyestrain, dental problems, allergies, systemic infections, and caffeine withdrawal. Headaches may be induced by sexual activity or intense physical exertion. Leakage from spinal cord fluid is rare but can cause headaches that may be mistaken for brain tumors.

Click the icon to see an image of the sinuses.

Prognosis

For many people, migraines eventually go into remission and sometimes disappear completely, particularly as they age. Estrogen decline after menopause may be responsible for remission in some older women. One study reported that the following people with migraines (called migraineurs) have a better chance of remission if they have:

A family history of migraine with aura
Migraines that are not triggered by light
No other primary headaches

According to another study, a history of head trauma or oral contraceptive use predicted a poorer long-term outlook.

Migraine or severe headache is a risk factor for stroke in both men and women, especially before age 50. About 19% of all strokes occur in people with a history of migraine. Research indicates that migraine also increases the risk for other types of heart problems.

Migraine with aura carries a higher risk for stroke than without auras. A 2005 analysis of over 12,000 participants from an atherosclerosis risk study found that migraine with aura was significantly associated with higher risk for stroke and transient ischemic attacks. Another 2005 study suggested that people who experience migraine with aura tend to have more cardiovascular risk factors than people without migraine. These risk factors included worse cholesterol profile, higher blood pressure, early history of heart disease and stroke, and greater likelihood of using oral contraceptives.

Results from a 2005 study showed that women who have migraine with aura are at increased risk of ischemic stroke compared with those who do not have auras and those who have non-migraine headaches. Women under age 55 had the highest risk, with more than double the risk. A 2006 Women’s Health Study of women ages 45 and older found that migraine with aura also increases women’s risk for heart attack, angina, and death due to ischemic heart disease (in which blood flow is decreased due to narrowing of coronary arteries). Migraine without aura did not increase heart disease and stroke risks.

Studies suggest specific stroke risk factors for younger women with migraines, particularly those with auras. Smoking, high blood pressure, and birth control pills considerably raise one's risk 10 - 20 times.

Researchers are also studying the relationship between patent foramen ovale (PFO) and migraine. A PFO is a hole in the wall dividing the upper left and right heart chambers. About half of patients with PFO have severe migraines with aura. Researchers are investigating whether surgical repair of the PFO may help control migraines in patients with this heart condition.

Migraine and other headaches associated with aura may increase the risk for retina damage (retinopathy) among middle-aged people, suggests a 2007 study.

The negative impact of migraines on quality of life, families, and even work productivity is significant and often underrated as a serious complication. Studies indicate that people with migraines have poorer social interactions and emotional health than patients with chronic medical illnesses, including asthma, diabetes, and arthritis. Anxiety (particularly panic disorders) and major depression are also strongly associated with migraines.

A 2005 National Headache Foundation-sponsored survey of migraine sufferers reported that:

90% of people with migraines could not function normally on the day of a migraine attack
80% experienced abnormal sensitivity to light and noise
75% experienced nausea and vomiting
30% required bed rest
25% missed at least 1 day of work due to migraine in past 3 months

Effect of Pregnancy on Migraines. In one study, pregnant women with tension or migraine headaches experienced 80% fewer headaches, usually after the end of the first trimester.

Effect of Migraine on the Pregnant Woman or Fetus. Migraine headaches do not pose any added risks during pregnancy to the mother or the fetus, although women with migraines may be at higher risk for having smaller (but not premature) babies.

Causes

Until recently, the general theory on the migraine process rested solely on the idea that abnormalities of blood vessel (vascular) systems in the head were responsible for migraines. Now, however, doctors tend to believe that migraine starts with an underlying central nervous system disorder. When triggered by various stimuli, this disorder sets off a chain of neurologic and biochemical events, some of which subsequently affect the brain's vascular system. No experimental model fully explains the migraine process.

There is certainly a strong genetic component in migraine with or without auras. Researchers have located a single genetic mutation responsible for the very rare familial hemiplegic migraine, but several genes are likely to be involved in the great majority of migraine cases. Numerous chemicals, structures, nerve pathways, and other players involved in the process are under investigation.

Central Nervous Disorder. One theory that attempts to integrate many of the known events in the migraine process is as follows:

Stress or some unknown factor triggers the release of certain protein fragments called peptides (Substance P, calcitonin gene-related peptide, and others).
These peptides dilate blood vessels and produce an inflammatory response that triggers over-excitation of the nerve cells in the trigeminal pathway. [This nerve pathway runs from the brain stem to the head and face. These nerves spread to the meninges (the membrane covering of the brain).]
While the brain itself is insensitive to pain, the meninges and blood vessels around the brain are sensitive to pain. Some doctors suggest that pain occurs when blood drains from the center of the head to the blood vessels around the brain.
Auras are believed to be a response to blood flow changes that cause a rapid reduction in brain activity that reaches the cerebral cortex (the outer layer of the brain), referred to as spreading depression. This effect may be visualized as an electrical wave spreading through the brain just as a wave of water is caused by the dropping of a pebble. Some research suggests that in people with auras, the cortical spreading depression itself activates the inflammation in the trigeminal nerves that triggers pain in the meninges.

One theory of the cause of migraine is a central nervous system (CNS) disorder. The CNS consists of the brain and spinal cord. In migraine, various stimuli may cause a series of neurologic and biochemical events that affect the brain's vascular system.

Abnormal Calcium Channels. Some migraines may be due to abnormalities in the channels within cells that transport the electrical ions calcium, magnesium, sodium, and potassium. Calcium channels appear to play a particularly critical role in migraine:

Calcium channels regulate the release of serotonin, an important neurotransmitter in the migraine process. (A neurotransmitter is a chemical messenger that allows communication between nerves in the brain.)
Magnesium interacts with calcium channels, and magnesium deficiencies have been detected in the brains of patients with migraine.
Calcium channels also play a major role in cortical spreading depression, the brain event that appears to be important in migraine symptoms.

Some patients with migraines may inherit one or more factors that impair calcium channels, making them susceptible to headaches. For example, mutations in a gene that encodes calcium channels appears to be responsible for familial hemiplegic migraine.

Researchers are also investigating factors that are common to both migraines and tension-type headaches. Some research suggests that both problems may result from a continuum of abnormalities in the central nervous system (the nerves in the brain and spine). Such changes trigger a progression of symptoms starting with mild sensations, developing into tension headache, and finally, progressing in some people to a migraine.

Serotonin and Other Neurotransmitter Levels. Neurotransmitters are chemical messengers in the brain. Serotonin is a neurotransmitter (chemical messenger in the brain) that is important for sleep, well-being, and other factors that affect quality of life. Abnormalities in serotonin levels have been observed in both tension-type and migraine headache sufferers. Altered levels of other neurotransmitters, importantly dopamine and stress hormones, also occur with migraine and tension-type headaches.

Dopamine, for example, may act as a stimulant of the migraine process. Some evidence suggests that certain genetic factors make people over-sensitive to the effects of dopamine, which include nerve cell excitation. Such nerve-cell over-activity could trigger the events in the brain leading to migraine. The prodromal symptoms (mood changes, yawning, drowsiness), for example, have been associated with increased dopamine activity. Dopamine receptors are also involved in regulation of blood flow in the brain.

Reduced Magnesium Levels. Magnesium deficiencies have been observed in people with both tension-type and migraine headaches. Researchers have noted a drop in magnesium levels before or during a migraine attack. Magnesium plays a role in nerve cell function. Reduced levels could be a destabilizing factor, causing the nerves in the brain to misfire, possibly even accounting for the auras that many sufferers experience.

Nitric Oxide. Other research suggests that over-excitable neurons release nitric oxide, a small molecular messenger that may be important in triggering in most primary headaches (tension-type, cluster, and migraines). Elevated levels have been observed in blood cells of patients with tension-type headache. Some evidence suggests that the release of this molecule in blood vessels may activate nerve pathways in the brain, muscles, or elsewhere and increase pain.

Estrogen Fluctuations in Women. Tension-type headaches and migraine headaches are slightly more common in females during adolescence and adulthood. Most likely hormone fluctuations, rather than whether levels are elevated or low, trigger headaches. Some research suggests that fluctuations in estrogen levels may impact levels of serotonin and other pain-modulating substances that affect these headaches.

Inflammation in the Maxillary Nerve. Early studies suggest that some chronic tension-type and migraine headaches may be caused by inflammation in the nerve that runs behind the cheekbone (the maxillary nerve) -- not around the covering of the brain. In fact, some work using ice water for reducing swelling in areas of the gums above the last upper molars has relieved some severe migraine and tension-type headaches.

A wide range of events and conditions can alter conditions in the brain that bring on nerve excitation and trigger migraines. They include, but are not limited to:

Emotional stress
Intense physical exertion (exercise, lifting, and even bowel movements or sexual activity)
Abrupt weather changes
Bright or flickering lights
High altitude
Travel motion
Lack of sleep
Low blood sugar and fasting
Chemicals found in certain foods. More than 100 foods may potentially trigger migraine headache. Caffeine is one such trigger. Caffeine withdrawal can also trigger migraines in people who are accustomed to caffeine. Experts recommend that patients keep a headache diary to track which foods trigger migraine.

Risk Factors

About 30 million Americans suffer from migraine headaches. They affect about 17% of all women and 6% of men. In fact, 70% of all migraine sufferers are women. Migraine is more prevalent among women throughout the world and in every culture. Although the incidence of migraine is similar for boys and girls during childhood, it increases in girls after puberty. Most people with migraine have 1 - 4 attacks per month.

Hormone Fluctuations in Women. Most migraines in women develop during the hormonally active years between adolescence and menopause. Fluctuations of estrogen and progesterone, rather than their presence, appear to increase the risk for migraines and their severity in some women.

About half of women with migraines report headaches associated with their menstrual cycle, although true menstrual migraines may actually be less common. True menstrual migraines tend not to have auras and to increase in prevalence between 2 days before and 5 days after the onset of period.
The first 3 months of pregnancy can worsen migraines in some women, although one study reported that pregnancy had little effect one way or the other on severity in most women with chronic headaches.
Women whose migraines are affected by pregnancy or menstruation are also likely to have worse migraines if they take oral contraceptives or hormone replacement therapies.

General Age of Onset. More than 20% of adults with migraines report that their headaches started before age 10, and over 45% say they started before age 20. The incidence of migraine declines in both men and women after age 40.

Migraine in Children. Migraine headaches occur in all ages and can appear in children as young as 4 years of age. Migraines in children are equally prevalent in boys and girls. Studies estimate that about 4 – 10% of all children suffer from migraine. Research indicates that overweight children may be especially susceptible to headaches, although this association is most likely due to poor nutrition and lack of exercise rather than excess weight. Children who have sleep problems, especially difficulty falling asleep, may also be more prone to migraines.

A small 2006 study indicated that some adolescents with migraine may eventually grow out of their condition. By the end of the 10-year study, 38% of patients had stopped having migraines, and 20% had transitioned into less severe tension-type headache. Children with a family history of migraine were more likely to continue having migraines.

Migraine Onset in Older Adults. Although uncommon, late-life migraine occurs in about 1% of the population, usually in men. In such cases, it often occurs as migraine with visual disturbances but without headache.

Migraine headaches can be inherited. If both parents suffer from migraines, their children have a 75% chance of getting them. When only one parent gets migraines, there is a 50% chance that children will be afflicted.

Caucasians have a higher risk than either African-Americans or Asians. Worldwide, one study reported that migraines are most common in North America. They are slightly less prevalent in South America and Europe and far less common in Asia and Africa. Investigators believe that the differences are due to genetic variations, not lifestyle factors.

People with migraine have a higher incidence of other medical conditions, including:

Asthma and allergies. These conditions have also been associated with a higher risk for conversion from having periodic migraines attacks to a chronic form (transformed migraines).
H. pylori infection. People who are infected with the bacteria H. pylori, the major cause of peptic ulcers, are at higher risk for migraines.
Epilepsy. Patients with epilepsy are twice as likely to have migraines as the general population.
Fibromyalgia
Systemic lupus erythematosus
Raynaud syndrome
Mitral valve prolapse
Narcolepsy

One study suggested that women with migraines tend to over-respond to stressful situations. In the study, they were more likely than other women to be diligent, conscientious, and overly sensitive to pressure from others. More likely, however, a person's family history of migraine, rather than any personality trait, is the important risk factor.

Diagnosis

Anyone, including children, who has recurring or persistent headaches should consult a doctor. There are no blood tests or imaging techniques that can be used to diagnose migraine headaches. A diagnosis will be made on the basis of history and physical exam, and, if necessary, tests may be necessary to rule out other diseases or conditions that may be causing the headaches. It is important to choose a doctor who is sensitive to the needs of headache sufferers and aware of the latest advances in treatment.

For an accurate diagnosis, the patient should describe:

Duration and frequency of headaches
Recent changes in their character
Location of pain
Type of pain (throbbing or steady pressure)
Intensity of the headache
Associated symptoms, such as visual disturbances or nausea and vomiting
Behaviors during a headache. This may help distinguish between migraine and tension headaches. The predominant behavior with tension headaches is massaging the scalp, temples, or the nape of the neck. A person with migraines is more apt to use compression (such as tying a scarf around the forehead and temples) or to apply cold. They also tend to isolate themselves, lie down, induce vomiting, and use more pillows than usual. (None of these maneuvers do much good in relieving either headache, unfortunately.)

The presence of auras or other visual disturbances do not always identify migraine:

Patients with severe sinus infections may experience double vision or visual loss. (This is an emergency condition, since it indicates the infection has spread to areas around the eyes.)
Many migraine sufferers have no auras.
Many elderly people with late-onset migraine have auras but no pain.

The patient should try to recall what seems to bring on the headache and anything that relieves it. Keeping a headache diary is a useful way to identify triggers that bring on headaches. Some tips include:

Note all conditions, including any foods eaten, preceding an attack. Often two or more triggers interact to produce a headache. For example, a combination of weather changes and fatigue can make headaches more likely than the presence of just one of these events.
Keep a migraine record for at least three menstrual cycles. For women, this can help to confirm or refute a diagnosis of menstrual migraine.
Track medications. This is important for identifying possible rebound headache or transformed migraine.
Attempt to define the intensity of the headache using a number system, such as:

1 = Mild, barely noticeable

2 = Noticeable, but does not interfere with work/activities

3 = Distracts from work/activities

4 = Makes work/activities very difficult

5 = Incapacitating

The patient should report any other conditions that might be associated with headache, including but not limited to:

Any chronic or recent illness and their treatments
Any injuries, particularly head or back injuries
Any uncharacteristic dietary changes
Any current medications or recent withdrawals from any drugs, including over-the-counter or natural remedies.
Any history of caffeine, alcohol, or drug abuse.
Any serious stress, depression, and anxiety.

The doctor will also need a general medical and family history of headaches or diseases, such as epilepsy, that may increase their risk. Migraine tends to run in families.

In order to diagnose a chronic headache, the doctor will examine the head and neck and will usually perform a neurologic examination, which includes a series of simple exercises to test strength, reflexes, coordination, and sensation. The doctor may ask questions to test short-term memory and related aspects of mental function.

Diagnosing the cause of persistent daily headache is difficult, even for expert doctors. Studies report that people who visit the emergency room with disabling headache are often misdiagnosed as tension-type headaches instead of migraines. It is important to choose a doctor who is sensitive to the needs of headache sufferers and aware of the latest advances in treatment.

Extensive testing may be advised for anyone with a chronic, daily headache. Tracking times of medications, withdrawal, and headache, using the headache diary, is usually very helpful in diagnosis.

Differentiating Rebound Headaches from Transformed Migraines. Migraines that evolve to chronic headaches must be first differentiated between natural transformed migraines and rebound headaches (the most common cause of persistent migraines):

A transformed migraine is usually more consistent in its severity and its location than a rebound headache.
Transformed migraines are less sensitive to triggers than rebound headaches.

Differentiating Transformed from Tension Headaches. Once rebound headache is ruled out, the doctor must then differentiate natural transformed migraines from tension headaches:

In most cases of transformed migraine (but not tension headache), gastrointestinal or neurologic symptoms are present.
Transformed migraine is also frequently associated with menstrual fluctuations in women.

Imaging tests of the brain may be recommended under the following circumstances:

If the results of the history and physical examination suggest neurologic problems.
For patients with headaches that wake them at night.
For new headaches in the elderly. In this age group, it is particularly important to first rule out age-related disorders, including stroke, hypoglycemia, hydrocephalus, and head injuries (usually from falls).
For patients with worsening headaches.

They are not recommended for patients with migraine and with no other abnormal indications.

The following tests may be used:

A CT (computed tomography) scan may be ordered to rule out brain disorders or headaches caused by chronic sinusitis.
X-rays and other tests may also be used if sinusitis is strongly suspected.
A neck x-ray can reveal arthritis or spinal problems.
Other imaging tests include an MRI (magnetic resonance imaging), EEG (electroencephalogram), lumbar puncture, ultrasound testing, and cerebral angiography, positron emission tomography (PET), and single-photon emission computed tomography (SPECT). These tests are only performed if there is reason to suspect an underlying disease or as part of clinical studies.

A CT (computed tomography) scan is a much more sensitive imaging technique than x-ray, allowing high definition of not only the bony structures but also the soft tissues. Clear images of organs and structures, such as the brain, muscles, joints, veins and arteries, as well as of tumors and hemorrhages, may be obtained with or without the injection of contrasting dye.

Headaches indicating a serious underlying problem, such as cerebrovascular disorder or malignant hypertension, are uncommon. (It should again be emphasized that a headache is not a common symptom of a brain tumor.) People with existing chronic headaches, however, might miss a more serious condition by believing it to be one of their usual headaches. Such patients should call a doctor promptly if the quality of a headache or accompanying symptoms has changed. Everyone should call a doctor for any of the following symptoms:

Sudden, severe headache that persists or increases in intensity over the following hours, sometimes accompanied by nausea, vomiting, or altered mental states (possible hemorrhagic stroke).
Sudden, very severe headache, worse than any headache ever experienced (possible indication of hemorrhage or a ruptured aneurysm).
Chronic or severe headaches that begin after age 50.
Headaches in the back of the head accompanied by other symptoms, such as memory loss, confusion, loss of balance, changes in speech or vision, or loss of strength in or numbness or tingling in arms or legs (possibility of small stroke in the base of the skull).
Headaches after head injury, especially if drowsiness or nausea are present (possibility of hemorrhage).
Headaches accompanied by fever, stiff neck, nausea and vomiting (possibility of spinal meningitis).
Headaches that increase with coughing or straining (possibility of brain swelling).
A throbbing pain around or behind the eyes or in the forehead accompanied by redness in the eye and perceptions of halos or rings around lights (possibility of acute glaucoma).
A one-sided headache in the temple in elderly people; the artery in the temple is firm and knotty and has no pulse; scalp is tender (possibility of temporal arteritis, which can cause blindness or even stroke if not treated).
Sudden onset and then persistent, throbbing pain around the eye possibly spreading to the ear or neck unrelieved by pain medication (possibility of blood clot in one of the sinus veins of the brain).

Treatment Approaches

Many effective headache remedies are available for treating a migraine attack. Still, a study that analyzed over 800,000 cases of migraine reported that most migraines are not treated according to any recommended guidelines. In the study, 30% of patients were treated with potentially addictive opioids -- most often merepidine (Demerol). Furthermore, 70% of these patients were not offered effective and available anti-migraine drugs. Anti-nausea drugs that have no effect on headaches were used six times more often than drugs that reduce headaches.

A 2007 survey of migraine sufferers, commissioned by the U.S. National Headache Foundation, reported that 20% of patients are prescribed non-approved medications containing opioids or barbiturates. The survey also indicated that patients who take non-approved drugs are more likely to experience drug-related side effects. For mild migraines, non-prescription treatments (Excedrin Migraine, Advil Migraine, Motrin Migraine Pain) are the best first choice. For severe migraines, doctors recommend starting with a triptan drug.

Preventive treatment, used to stop migraine attacks before they happen, may help many patients. According to another 2007 survey, more than 1 in 4 patients with migraine are candidates for preventive therapy but most do not receive it.

As many as 30% of patients with migraine also have accompanying headaches resulting from tension, drugs, infections, or other causes. It is important to distinguish between headache types in order to determine appropriate treatment.

General Guidelines. The general goals of treatment are:

Choose drugs with as few side effects as possible. Patients should talk to their doctors about various methods for administering the medication (pills, injections, nasal spray, or rectal suppositories) and begin with the one they believe will be the least distressing.
Treat the attack rapidly, within an hour of symptom onset if possible. Start with low doses, and build up dosage slowly.
Try to minimize the use of back-up or "rescue medications." (A rescue medication is typically a narcotic opiate drug, which is used for pain relief when other medications fail.)
Try to guard against rebound effect. Nearly all drugs used for migraine can cause rebound headache, and patients should not take any the drugs for longer than 2 days per week.
It may take 2 - 4 months for any drug to be effective.

Stepped-Up Treatment Approach. Some doctors recommend a stepped-up treatment course for an acute migraine attack. This involves starting with the least potent treatments and taking increasingly more powerful drugs until the pain stops. In this approach, patients may need up to five different medications to achieve pain relief. A typical stepped-up approach is the following:

The patient should first use nonprescription pain relievers (NSAIDs, Excedrin Migraine) and stress-reduction techniques.
If these are not effective within 2 hours, the patient should take migraine-specific drugs. Triptans are the first choice, then ergot derivatives.
Patients with migraines associated with severe nausea or vomiting may use injected or rectally administered drugs. Nausea itself should be treated with specific anti-nausea drugs, such as metoclopramide (Reglan).
If migraine medications fail to relieve symptoms within 4 hours, rescue drugs (opioids, corticosteroids) may be used.

Stratified Approach. Many doctors and patients now prefer the stratified approach. The doctor first estimates the severity of the patient's condition based on his or her history. Then, depending on the severity of a typical attack, the doctor decides whether the patient should start with more or less powerful drugs at the first signs of the migraine:

Patients with less disabling migraines start with general pain relievers.
Patients with a history of moderate-to-severe migraines start with migraine-specific prescription medicine, such as a triptan, at the onset of mild pain.

Some studies report dramatic relief with the stratified approach. In one study, zolmitriptan, a newer triptan, reduced the intensity of headaches within 2 hours in 70% of patients with moderate pain but only in 44% of those with severe headaches.

Side effects can be severe with many migraine drugs, although newer drugs, such as the recent generation triptans, may provide effective early relief without significant side effects.

Studies estimate that between 5 - 10% of children have migraines but that the disorder is underdiagnosed in children. An interesting study reported that when children drew pictures in response to their doctors' questions about their migraines, the doctors were able to tell the difference between migraine and non-migraine headaches in the majority of cases.

Symptoms in Children. The standard diagnostic criteria for migraine in adults may apply to only about two-thirds of migraines in children and adolescents. For example, doctors have seen the following differences:

Headaches tend to last for a shorter time (as little as an hour) in children.
Migraine pain tends to occur in the face and on both sides of the head in two-thirds of child patients.
Children often have a form of migraine known as a migraine equivalent or abdominal migraine, which does not cause a headache at all. Instead, children experience periodic bouts of nausea and vomiting (called cyclic vomiting syndrome) or other secondary symptoms found in adult migraine, such as a reaction against light or sound. Cyclic vomiting may occur in nearly 2% of school-aged children with or without a migraine association.
Migraine triggers in children are similar to those in adults, but common ones in children are anxiety and fear, and eating ice cream.

Outlook in Children. Migraine in children is disabling, as it is in adults, and they tend to lose more school days than other children. Children with frequent headaches may also be at higher risk for headaches in adulthood and also for other physical and psychiatric problems. However, some children who have migraine eventually stop having attacks when they reach adulthood, or have less severe types of headaches.

Treatments in Children. Most children with migraines may need only mild pain relievers and home remedies (such as ginger tea) to treat their headaches. The American Academy of Neurology’s 2004 practice guidelines for children and adolescents recommend the following drug treatments:

For children age 6 years and older, ibuprofen (Advil) is recommended. Acetaminophen (Tylenol) may also be effective. Acetaminophen works faster than ibuprofen, but the effects of ibuprofen last longer.
For adolescents age 12 years and older, sumaptriptan (Imitrex) nasal spray is recommended.

Preventive Measures in Children. Non-medication methods, including biofeedback and muscle relaxation techniques may be helpful. In one study of children with migraines and poor sleep habits, who were taught how to sleep better instructions without using medications had significantly fewer migraine attacks.

If these methods fail, then preventive drugs may be used, although evidence is weak on the effectiveness of standard migraine preventive drugs in children.

If medication overuse causes rebound migraines develop, the patients cannot recover without stopping the drugs. (If caffeine is the culprit, a person may need only to reduce coffee or tea drinking to a reasonable level, not necessarily stop drinking it altogether.) The patient can usually stop abruptly or gradually. The patient should expect the following:

Most headache drugs can be stopped abruptly, but the patient should talk to their doctor first. Certain non-headache medications, such as anti-anxiety drugs or beta-blockers, require gradual withdrawal.
If the patient chooses to taper off standard headache medications, withdrawal should be completed within three days.
The patient may take other pain medicines during the first days. Examples of drugs that may be used include dihydroergotamine (with or without metoclopramide), NSAIDs (in mild cases), corticosteroids, or valproate.
The patient must expect their headache to get worse after they stop taking their medications, no matter which method they use. Most people feel better within 2 weeks, although headache symptoms can persist up to 16 weeks (and in rare cases even longer).
If the symptoms do not respond to treatment and cause severe nausea and vomiting, the patient may need to be hospitalized.

On the encouraging side, some patients experience dramatic long-term relief from all headaches afterward, and one study reported that 82% of patients significantly improved 4 months after medication withdrawal.

Medications Used for Treatment

Many different medications are used to treat migraines. However, the Food and Drug Administration (FDA) has specifically approved only the following types of drugs for migraine treatment:

Non-prescription drugs: Excedrin Migraine, Advil Migraine, Motrin Migraine Pain
Prescription drugs: Triptans and ergotamine

Other types of drugs, including opioids and barbiturates, are sometimes prescribed off-label for migraine treatment. Opioids and barbiturates have not been approved by the FDA for migraine relief, and they can be addictive.

All FDA-approved migraine treatments are approved only for adults. No migraine products have officially been approved for use in children.

Some patients with mild migraines respond well to over-the-counter (OTC) painkillers, particularly if they take the medicine at the very first sign of an attack.

The Food and Drug Administration has approved three OTC (nonprescription) products to treat migraine. Excedrin Migraine (a combination of aspirin, acetaminophen, and caffeine) was the first such medication approved for the temporary relieve of migraine and its symptoms. Studies have reported significant relief in nearly 70% of patients. It may also help menstrual migraines. Advil Migraine and Motrin Migraine Pain, both containing ibuprofen, are also approved to treat migraine headache.

Cooling Pads. Cooling pads may help during an attack. Some products (Migraine Ice, TheraPatch Headache Cool Gel) use a pad containing a gel that cools the skin for up to 4 hours and can be placed on the forehead, temple, or back of the neck.

Non-steroidal anti-inflammatory drugs (NSAIDs) include aspirin, ibuprofen, and naproxen. They were among the first types of drugs tried to treat mild-to-moderate migraines. Aspirin, ibuprofen (Advil, Motrin), and naproxen (Anaprox, Aleve) are all available without prescription. Naproxen may have specific benefits for migraine. A 2007 study indicated that a combination of naproxen and sumatriptan provides better migraine pain relief than either drug alone.

Other types of NSAIDs are available only by prescription. Some studies indicate that the NSAID combination diclofenac-potassium (Cataflam) may work faster than the migraine drug sumatriptan (Imitrex) and help reduce nausea. The combination is not appropriate for people allergic to aspirin or at risk for bleeding.

Injectable NSAIDs, particularly ketorolac (Toradol), may be very effective for severe and persistent migraines. A 2003 study found that intravenous ketorolac provided greater pain relief than nasal sumatriptan (Imitrex). A 2005 study presented at the annual meeting of the American Headache Society reported that intravenous ketorolac was more effective than opioid drugs for late-stage treatment of severe migraine attacks.

COX-2s are a class of prescription drugs that have the anti-inflammatory effects of NSAIDs, but do not upset most people's stomachs. However, most of these drugs have been withdrawn from the U.S. market due to increased risk for heart attack and stroke. Celecoxib (Celebrex) is the only available COX-2, and it has a strong warning label alerting users of the potential for heart attack, stroke, and serious gastrointestinal problems. (The warning is the same one the Food and Drug Administration recommended for the labels of prescription NSAIDs in 2005.)

NSAID Side Effects. High dosages and long-term use of NSAIDs can increase the risk for heart problems, kidney problems, and stomach bleeding. In April 2005, the FDA asked drug manufacturers of prescription NSAIDs to include with their products the same boxed warning used for the COX-2 inhibitor celecoxib (Celebrex). This boxed warning emphasizes an increased risk for cardiovascular events and gastrointestinal bleeding in people taking these drugs. The FDA also requested manufacturers of over-the-counter NSAIDs to revise their labels to include more specific language concerning potential cardiovascular and gastrointestinal risks. Due to its proven heart benefits, aspirin was excluded from these labeling revisions.

Triptans (also referred to as serotonin agonists) were the first drugs specifically developed for use against migraine. They are the most important migraine drugs currently available. They help maintain serotonin levels in the brain, and so specifically target one of the major components in the migraine process.

Triptans are recommended as first-line drugs for adult patients with moderate-to-severe migraines when NSAIDs are not effective. Triptans have the following benefits:

They are effective for most patients with migraine, as well as patients with combination tension and migraine headaches.
They do not have the sedative effect of other migraine drugs.
Withdrawal after overuse appears to be shorter and less severe than with other migraine medications

Sumatriptan. Sumatriptan (Imitrex) has the longest track record and is the most studied of all triptans. It is available as a fast-dissolving pill, nasal spray, or injection. Injected sumatriptan works the fastest of all the triptans and is the most effective, but it can cause pain at the injection site. The nasal spray form bypasses the stomach and is absorbed more quickly than the oral form. Some patients report relief as soon as 15 minutes after administration. The spray tends to work less well when a person has nasal congestion from cold or allergy. It may also leave a bad taste. Sumatriptan is effective for many patients, but headache recurs in 20 - 40% of people within 24 hours after taking the drug.

A 2007 study in the Journal of the American Medical Association suggested that a combination of sumatriptan and naproxen works better than either drug alone.

Other Triptans. Newer triptans include almotriptan (Axert), zolmitriptan (Zomig), naratriptan (Amerge), rizatriptan (Maxalt), frovatriptan (Frova), and eletriptan (Relpax). Comparison studies with sumatriptan suggest that some of the newer drugs have fewer side effects and are superior to sumatriptan for providing immediate, sustained, and consistent pain relief. Recurrence rates are also lower. They are also being investigated for prevention under certain circumstances, such as menstrual migraines, but benefits appear limited.

Studies on newer triptans indicate:

Almotriptan is as effective as oral sumatriptan and may have fewer side effects, particularly chest pain, than most other triptans.
Rizatriptan may have the most rapid effects of all oral triptans. Zolmitriptan also has a more rapid effect than sumatriptan (although there appears to be no significant difference in adverse effects). Both rizatriptan and zolmitriptan are also available as rapidly dissolving wafers.
Eleptriptan is also very rapidly effective at high doses, but at those levels may have significant adverse effects. (To date, it does not seem to have any advantages over other triptans in head-to-head comparisons.)
Naratriptan and frovatriptan have a delayed response but long duration, few side effects, and lower risk for recurrence than with sumatriptan. Some evidence suggests that they may have specific benefits for stopping prolonged migraines and may even play a role in prevention.
Frovatriptan: A large study of more than 500 women with an average 12-year history of menstrual migraines examined the use of frovatriptan for the short-term prevention of such headaches. Researchers found that the migraines disappeared in over half of the women on the higher dose (5 mg) of frovatriptan.
Zolmitriptan (Zomig): Several studies indicate that zomitriptan nasal spray may be safe and effective for adolescents. In one study, zolmitriptan relieved pain within 2 hours for nearly half of the children (aged 12 - 17 years) enrolled in the trial. Zolmitriptan nasal spray is approved only for adults.

Side Effects. Many of the newer triptans may have fewer severe side effects than sumatriptan. Side effects of most triptans, however, can include:

Tingling and numbness in the toes
Sensations of warmth
Discomfort in the ear, nose, and throat
Nausea
Drowsiness
Dizziness
Muscle weakness
Heaviness, pain, or both in the chest. (About 40% of patients taking sumatriptan experience these symptoms, and they are major factors in discontinuing the drug. Newer drugs, such as almotriptan, produce fewer chest symptoms.)
Rapid heart rate

Complications of Triptans. The following are potentially serious problems.

Complications of heart and circulation. Triptans narrow (constrict) blood vessels. Because of this effect, spasms in the blood vessels may occur and cause serious side effects, including stroke and heart attack. Such events are rare, but patients with an existing history or risk factors for these conditions should generally avoid triptans.
Serotonin syndrome. Serotonin syndrome is a life-threatening condition that occurs from an excess of the brain chemical serotonin. Triptan drugs used to treat migraine, as well as certain types of antidepressant medications, can increase serotonin levels. These antidepressant drugs include serotonin reuptake inhibitors (SSRIs) -- such as fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft) -- and selective serotonin/norepinephrine reuptake inhibitors (SNRIs), such as duloxetine (Cymbalta) and venlafaxine (Effexor). It is very important that patients not combine a triptan drug with a SSRI or SNRI drug. Serotonin syndrome is most likely to occur when starting or increasing the dose of a triptan or antidepressant drug. Symptoms include restlessness, hallucinations, rapid heartbeat, tremors, increased body temperature, diarrhea, nausea, and vomiting. You should seek immediate medical care if you have these symptoms.

The following people should avoid triptans or take them with caution and only with the advisement of a doctor:

Anyone with a history or any risk factors for stroke, uncontrolled diabetes, high blood pressure, or heart disease.
People taking antidepressants that increase serotonin levels.
Children and adolescents. They may be safe, but controlled studies are needed to confirm this. (Triptans should not, in any case, be the first-line treatment for children.)
People with basilar or hemiplegic migraines. (Triptans are not indicated for these migraineurs.)
There is no evidence to date of any higher risk for birth defects in pregnant women who take triptans. Still, women should be cautious about taking any medications during pregnancy and discuss any possible adverse effects with their doctors.

Drugs containing ergotamine (commonly called ergots) constrict smooth muscles, including those in blood vessels, and are useful for migraine. They were the first anti-migraine drugs available. Ergotamine is available by prescription in the following preparations:

Dihydroergotamine (DHE) is an ergot derivative. It is administered as a nasal spray form (Migranal) or by injection, which can be performed at home.
Ergotamine is available tablets taken by mouth, tablets taken under the tongue (sublingual), and rectal suppositories. Some of the tablet forms of ergotamine contain caffeine.

Ergotamine’s role since the introduction of triptans is now less certain. Only the rectal forms of ergotamine are superior to rectal triptans. Injected, oral, and nasal-spray forms are all inferior to the triptans. Ergotamine may still be helpful for patients with status migrainous or those with frequent recurring headaches.

Side Effects. Side effects of ergotamine include:

Nausea
Dizziness
Tingling sensations
Muscle cramps
Chest or abdominal pain

The following are potentially serious problems:

Toxicity. Ergotamine is toxic at high levels.
Adverse effects on blood vessels. Ergot can cause persistent blood vessel contractions, which may pose a danger for people with heart disease or risk factors for heart attack or stroke.

Internal scarring (fibrosis). Scarring can occur in the areas around the lungs, heart, or kidneys. It is often reversible if the drug is stopped.

The following patients should avoid ergots:

Pregnant women. Ergots can cause miscarriage.
People over age 60.
Patients with serious, chronic health problems, particularly those of the heart and circulation.

Ergotamine can interact with other medications, such as antifungal drugs and some antibiotics. All ergotamine products approved by the Food and Drug Administration (FDA) contain a "black box" warning in the prescription label explaining these drug interactions. In 2007, the FDA pulled 15 unapproved older ergotamine products off the market, in part because they lacked this warning label. The five FDA-approved ergotamine products that remain on the market are:

Migergot suppository (marketed by G and W Labs)
Ergotamine Tartrate and Caffeine tablets (marketed by Mikart and West Ward)
Cafergot tablets (marketed by Sandoz)
Ergomar sublingual tablets (marketed by Rosedale Therapeutics)

Nasal drops containing lidocaine, a local anesthetic, can provide effective and quick pain relief within 15 minutes for many migraine sufferers. However, lidocaine has certain downsides:

It is rather difficult to administer. Patients must be lying down with their head dangling.
The headache often relapses in an hour, and other drugs must then be used.
Side effects include unpleasant taste, burning sensation, and facial numbness.

However, the drug does not cause drowsiness or heart rhythm disturbances as some other migraine treatments do. It should not be used for any other form of headache.

If the pain is very severe and does respond to other drugs, doctors may try painkillers containing opioids. Opioid drugs include morphine, codeine, meperidine (Demerol), and oxycodone (Oxycontin)]. Butorphanol is an opioid in nasal spray form that may be useful as a rescue treatment when others fail.

Opioids are not approved for migraine treatment and should not be used as first-line therapy. Nevertheless, many opioid products are prescribed to patients with migraine, sometimes with dangerous results. In 2007, following reports of several drug-related deaths, the Food and Drug Administration warned that the cancer pain pill fentanyl (Fentora) should not be used to treat patients with migraine or others conditions for which the drug is not specifically approved.

Side Effects. Side effects for all opioids include drowsiness, impaired judgment, nausea, and constipation. There is a risk for addiction, and these drugs can become ineffective with long-term use for chronic migraines. Doctors should not prescribe opioids to patients at risk for drug abuse, including those with personality or psychiatric disorders.

Metoclopramide (Reglan) is used in combinations with other drugs to treat the nausea and vomiting that occurs with other drugs and with migraine itself. Metoclopramide and other anti-nausea drugs, such as domperidone (Motilium), may help the intestine better absorb migraine medications.

New drugs in clinical trials include tonabersat (a gap junction blocker), trexima (a combination triptan and non-steroidal anti-inflammatory drug), GW274150 (a nitric oxide synthase inhibitor), and MK-0974 (a calcitonin gene-related peptide antagonist). Researchers are also investigating a nasal spray containing capsaicin, the chemical found in cayenne peppers.

Prevention

There are several ways to prevent migraine attacks. You should try a healthy diet, the right amount of sleep, and non-drug approaches, such as biofeedback, first for prevention.

Behavioral techniques that reduce stress and empower the patient may help some people with migraines. Studies report between 35 - 50% reduction in migraine and tension-type headaches with these approaches. They generally include:

Biofeedback therapy
Cognitive-behavioral therapy
Relaxation techniques

Behavioral methods may help counteract the tendency for muscle contraction and uneven blood flow associated with some headaches. They may be particularly beneficial for children, adolescents, and pregnant and nursing women, and anyone who cannot take most migraine medications.

Biofeedback. Studies have demonstrated some effectiveness from biofeedback for migraine headaches. Biofeedback training teaches the patient to monitor and modify physical responses, such as muscle tension, using special instruments for feedback.

Cognitive Behavioral Therapy. Behavioral therapy may be useful alone but is particularly beneficial for patients who are on preventive drug treatments. It typically uses the headache diary to track activities and headaches. The patient then works with the therapist to change or add behaviors or medications that will reduce the frequency and severity of attacks.

Alternative non-drug therapies used for headache management and prevention include hypnosis, meditation, visualization and guided imagery, acupuncture, acupressure, yoga, and other relaxation exercises. There is no clear evidence that any of these techniques have specific value for migraines.

Some studies report the following:

Acupuncture. Acupuncture is a Chinese medicine technique that uses thin needles to stimulate specific points aligned with energy pathways in the body. Studies have showed mixed results on the benefits of acupuncture for migraine. A 2005 study published in the Journal of the American Medical Association reported that acupuncture was no more effective than sham acupuncture (needles placed at non-acupuncture points) in preventing migraines. More than 300 people were enrolled in this randomized trial. A 2006 study of 960 people, published in Lancet Neurology, found that real acupuncture, sham acupuncture, and standard drug treatment were all equally effective in preventing migraine attacks.
Relaxation Techniques. Muscle relaxation techniques may be helpful. One study reported that relaxation treatments appeared to help adolescents with migraine but not tension headaches.

Hormonal drugs, such as oral contraceptives or hormone replacement therapy, have a mixed effect on women with migraines. Oral contraceptives have been associated with worse headaches in 18 - 50% of women and have also been linked to a higher risk for stroke in women with classic migraines (with auras). Young women should avoid or stop oral contraception if they have classic migraines, migraines that worsen or change character after oral contraceptives , if they have close relatives with stroke or heart disease, or if they smoke.

Some evidence suggests, however, that oral contraceptives may help prevent true menstrual migraines (which do not have auras). In such cases, their benefits may outweigh the low risk of a serious adverse event. Keeping a migraine record for at least three menstrual cycles can help confirm whether a woman actually has a true menstrual migraine.

Making a few minor changes in your lifestyle can make your migraines more bearable. Improving sleep habits is important for everyone, and especially those with headaches. What you eat also has a huge impact on migraines, so dietary changes can be extremely beneficial, too.

Avoiding Food Triggers. Avoiding foods that trigger migraine is an important preventive measure. Common food triggers include monosodium glutamate (MSG), processed lunch meats that contain nitrates, dried fruits that contain sulfites, aged cheese, alcohol and red wine, chocolate, and caffeine. However, people’s responses to triggers differ. Keeping a headache diary that tracks diet and headache onset can help identify individual food triggers.

Healthy Diet. One study indicated that a diet low in fat and high in complex carbohydrates may significantly reduce the frequency, severity, and duration of migraine headaches. Such a diet is healthy in general, in any case.

Eating Regularly. Eating regularly is important to prevent low blood sugar. People with migraines who fast periodically for religious reasons might consider taking preventive medications.

Fish Oil. Some studies suggest that omega-3 fatty acids, which are found in fish oil, have anti-inflammatory and nerve protecting actions. These fatty acids can be found in oily fish, such as salmon, mackerel, or sardines. They can also be obtained in supplements of specific omega-3 compounds (DHA-EPA).

Exercise is certainly helpful for relieving stress. An analysis of several studies reported that aerobic exercise in particular might help prevent migraines. It is important, however, to warm up gradually before beginning a session, since sudden, vigorous exercise might actually precipitate or aggravate a migraine attack.

Manufacturers of herbal remedies and dietary supplements do not need Food and Drug Administration approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been several reported cases of serious and even lethal side effects from herbal products. Patients should always check with their doctors before using any herbal remedies or dietary supplements.

Riboflavin (Vitamin B2). There is reasonable evidence on the benefits of vitamin B2 for migraine sufferers. In one study, patients who took 400 mg of vitamin B2 (riboflavin) reduced their migraine attacks by half, although the vitamin had no effect on the severity or duration of migraines that did occur. In another study, it helped increase the effectiveness of beta-blockers, drugs used to prevent migraines in some people. Vitamin B2 is generally safe, although some people taking high doses develop diarrhea.

Magnesium Supplements. Studies have reported a higher rate of magnesium deficiencies in some patients with migraine, such as those with menstrual migraines. Magnesium helps relax blood vessels. Some patients report relief from supplements.

Feverfew. Feverfew is the most studied herbal remedy for headaches and is effective in some cases. However, like all effective headache remedies, overuse can cause a rebound effect.

Ginger. In general, herbal medicines should never be used by children or pregnant or nursing women without medical counsel. One exception may be ginger, which has no side effects and can be eaten in powder or fresh form, as long as quantities are not excessive. Some people have reported less pain and frequency of migraines while taking ginger, and children can take it without danger.

Medications Used for Prevention

The Food and Drug Administration has approved four drugs for prevention of migraine:

Propanolol (Inderal)
Timolol (Blacadrene)
Divalproex sodium (Depakote)
Topiramate (Topamax)

Propanolol and timolol are beta-blocker drugs. Divalproex and topiramate are anti-seizure drugs. Many other drugs are also being used or investigated for preventing migraines.

Beta-blockers are usually prescribed to reduce high blood pressure. Some beta-blockers, however, are also useful in reducing the frequency of migraine attacks and their severity when they occur. Propranolol (Inderal) and timolol (Blocadren) have been approved specifically for prevention of migraine. Metoprolol (Toprol), atenolol (Tenormin), and nadolol (Corgard) are also being studied for migraine prevention.

Side Effects. Side effects may include:

Fatigue and lethargy are common.
Some people experience vivid dreams and nightmares, depression, and memory loss.
Dizziness and lightheadedness may occur upon standing.
Exercise capacity may be reduced.
Other side effects may include cold extremities, asthma, decreased heart function, gastrointestinal problems, and sexual dysfunction.

If side effects occur, the patient should call a doctor, but it is extremely important not to stop the drug abruptly. Some evidence suggests that people with migraines who have had a stroke should avoid beta-blockers.

Anti-seizure drugs, also called anti-epileptic drugs or anticonvulsants, affect the neurotransmitter gamma aminobutyric acid (GABA), which helps prevent nerve cells from over-firing. GABA may also have a role in migraines. These drugs are commonly used for epilepsy and bipolar disease. Anti-seizure drugs are more expensive than other drugs. They also have significant side effects. Divalproex sodium (Depakote) and topiramate (Topamax) are the only anti-seizure drugs that are approved for migraine prevention. However, if patients do not respond to either of these drugs, doctors may try other types of anti-seizure medications.

Divalproex Sodium (Depakote). Divalproex sodium (Depakote) was first approved in 1996 for migraine prevention. A once-a-day formulation of divalproex (Depakote ER) was approved in 2000. Doctors sometimes prescribe a similar drug, valproate (Depakene). Pregnant patients should not use these drugs, as they may cause birth defects.

Topiramate (Topamax). In 2004, the Food and Drug Administration approved topiramate for prevention of migraines in adults. Studies from 2006 indicated that the drug works well when used on a long-term basis. Patients in these studies experienced significantly fewer migraines for up to 14 months. Topiramate’s most common side effect is a tingling sensation in the arms and legs. Weight loss is also a side effect. In clinical trials, patients lost an average of 3.8% of their body weight.

Other Anti-Seizure Drugs Under Investigation. Researchers are studying other types of anti-seizure drugs for migraine prevention. These include levetiracetam (Keppra), gabapentin (Neurontin), pregabalin (Lyrica), zonisamide (Zonegran), tiagabine (Gabitril), and the investigational drug lacosamide (LCM).

Side Effects. Anti-seizure medication's side effects vary by drug but may include:

Nausea and vomiting
Diarrhea
Cramps
Hair loss
Dizziness
Sleepiness
Blurred vision
Weight gain
Valproate and divalproex can cause serious side effects of inflammation of the pancreas (pancreatitis) and damage to the liver

Amitriptyline (Elavil, Endep), a tricyclic antidepressant drug, has been used for many years as a first-line treatment for migraine prevention. It may work best for patients who also have depression or insomnia. Tricyclics can have significant side effects, including disturbances in heart rhythms, and can be fatal in overdose. Although other tricyclic antidepressants may have fewer side effects than amitritpyline, they do not appear to be particularly effective for migraine prevention.

Researchers have investigated newer types of antidepressants, including serotonin-reuptake inhibitors(SSRIs), such as fluoxetine (Prozac). However, studies to date do not indicate that SSRIs are helpful for migraine prevention.

Muscle Relaxants. Botulinum toxin A (Botox) injection, a common wrinkle treatment, causes small muscles to relax. This approach is now being used with some success for treating disorders that involve over-excited muscle activity, including myofascial pain syndrome and migraine. One study reported complete migraine relief in more than half of patients being tested and improvement of more than 50% in another 35% of patients. Relief lasted 3 - 4 months with no adverse effects. A study presented at the 2005 meeting of the American Headache Society reported that patients who regularly received Botox injections every 3 months reduced both the frequency of migraine attacks and their reliance on pain medications

Angiotensin Converting Enzyme Inhibitors. Commonly used for treating high blood pressure, angiotensin converting enzyme (ACE) inhibitors block the production of the protein angiotensin, which constricts blood vessels and may be involved in migraine. Studies using the ACE inhibitor lisinopril (Prinivil, Zestril) are reporting significant reduction in migraine attacks.

Angiotensin-Receptor Blockers. Angiotensin-receptor blockers (ARBs) have actions similar to ACE inhibitors, but may have fewer side effects. In one study, patients who took the ARB candesartan (Atacand) had significantly fewer headaches compared to patients who received placebo.

Neurostimulation Devices. Researchers are investigating a transcranial magnetic stimulation (TMS) device to help stop migraines before they occur. The hair dryer-size device is held to the back of the head and delivers quick magnetic pulses. The device is used when a patient experiences the first signs of a migraine. Other types of nerve stimulation devices are also under investigation.

Inhalation Devices. These devices use heat to vaporize a drug so that it can be inhaled into the lungs. Clinical trials are currently testing this device with procholorperazine (Compazine), a tranquilizer drug that is used to treat nausea and vomiting.

Nasal Devices. New types of nasal sprays and powders are being researched. Some of them use capsaicin, the chemical found in cayenne peppers, to help relieve pain.

Skin Patches. The Actyve transdermal patch uses a small battery-powered system to deliver a triptan drug through the skin.

Drugs. New drugs in development include tonabersat (gap junction blocker), trexima (combination triptan and non-steroidal anti-inflammatory drug), and GW274150 (nitric oxide synthase inhibitor).

Resources

www.headaches.org -- National Headache Foundation
www.americanheadachesociety.org -- American Headache Society
www.aan.com -- American Academy of Neurology
www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
www.clinicaltrials.gov -- Find clinical trials
www.migraineinfo.org -- National Migraine Association

References

Brandes JL, Kudrow D, Stark SR, O'Carroll CP, Adelman JU, O'Donnell FJ, et al. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA. 2007 Apr 4;297(13):1443-54.

Lewis DW, Winner P, Hershey AD, Wasiewski WW; Adolescent Migraine Steering Committee. Efficacy of zolmitriptan nasal spray in adolescent migraine. Pediatrics. 2007 Aug;120(2):390-6.

Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007 Jan 30;68(5):343-9.

Monastero R, Camarda C, Pipia C, Camarda R. Prognosis of migraine headaches in adolescents: a 10-year follow-up study. Neurology. 2006 Oct 24;67(:1353-6.

Rose KM, Wong TY, Carson AP, Couper DJ, Klein R, Sharrett AR. Migraine and retinal microvascular abnormalities: the Atherosclerosis Risk in Communities Study. Neurology. 2007 May 15;68(20):1694-700.

Review Date:
11/1/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows rigorous standards of quality and accountability. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial policy, editorial process and privacy policy. A.D.A.M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

A.D.A.M. Copyright

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-2009 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

adam.com

Insomnia

FitSugar — Wed, 08 Oct 2008 17:35:00 -0700

In This Report

Highlights
Introduction
Causes of Short-Term or Tra...
Causes of Chronic Insomnia...
Risk Factors
Prognosis
Diagnosis
Treatment
Medications
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Sedative Hypnotic Drug Warnings

In March 2007, the FDA ordered stronger warning labels on sedative hypnotic drugs. These medications include benzodiazepine and non-benzodiazepine drugs, such as zolpidem (Ambien), eszopiclone (Lunesta), ramelteon (Rozerem), and triazolam (Halcion). The FDA warned that these drugs may be associated with:

Severe allergic reactions (anaphylaxis) and severe facial swelling (angioedema), which can occur even the first time a drug is taken
Complex sleep-related behaviors, such as sleep driving, making phone calls, and preparing and eating food while asleep

Patients who take sleeping pills should be sure to follow the directions. These include not combining sleeping pills with alcohol or other drugs and not taking more than the prescribed dose. All patients prescribed sedative hypnotic drugs should receive a patient medication guide that describes the potential risks, and precautions to reduce these risks.

Behavioral and Psychological Therapies

Behavioral and psychological treatments, such as cognitive behavioral therapy and relaxation techniques, are effective approaches for insomnia and can produce long-lasting benefits, according to a 2006 study in Sleep.
Behavioral interventions help over 80% of children who try them, indicates another 2006 Sleep study.

Complementary and Alternative Medicine

More than 1.6 million adults use complementary and alternative medicine to treat their insomnia, according to results of a national survey published in the Archives of Internal Medicine. About half of patients who tried herbal medicine or relaxation techniques found that these approaches helped improve their sleep.
In 2006, the American Academy of Sleep Medicine issued a position statement advising that there is only limited scientific evidence that herbal remedies are effective sleep aids.

Insomnia and Mood Disorders

Chronic insomnia can increase the risk of developing depression and anxiety, according to a 2007 study in Sleep. Research also indicates that insomnia and daytime sleepiness can cause and worsen depression and anxiety in children as well as adults.

Introduction

Insomnia comes from the Latin words for “no sleep.” Insomnia is characterized by:

Difficulty falling asleep
Difficulty staying asleep
Waking up too early in the morning

Some experts believe that poor quality (“non-restorative”) sleep is also related to insomnia. Insomnia can cause daytime fatigue, irritability, and impaired performance. About 60 million Americans each year suffer from insomnia.

Insomnia may be primary or secondary:

Primary insomnia means that the inability to sleep is not caused by other health problems.
Secondary insomnia is due to other health conditions that interfere with sleep. Some experts prefer the term “co-morbid insomnia.”

Insomnia, usually temporary, is often categorized by how long it lasts:

Transient insomnia lasts for a few days.
Short-term insomnia lasts for no more than 3 weeks.
Chronic insomnia occurs at least 3 nights per week for 1 month or longer.

Insomnia may also be defined in terms of inability to sleep at conventional times. The following examples are referred to as circadian rhythm disorders:

Delayed Sleep-Phase Syndrome. Delayed sleep-phase syndrome is the term for a circadian clock that runs late but reliably. People who have this condition (usually adolescents) fall asleep very late at night or in early morning hours, but then sleep normally.
Advanced Sleep-Phase Syndrome. This syndrome tends to develop in older people. It produces excessive sleepiness in the morning and undesired awakening early (3 - 5 a.m.) in the morning.

In sleep studies, subjects spend about one-third of their time asleep, suggesting that most people need about 8 hours of sleep each day. Individual adults differ in the amount of sleep they need to feel well rested, however. (Infants may sleep as many as 16 hours a day.)

The daily cycle of life, which includes sleeping and waking, is called a circadian (meaning "about a day") rhythm, commonly referred to as the biologic clock. Hundreds of bodily functions follow biologic clocks, but sleeping and waking comprise the most prominent circadian rhythm. The sleeping and waking cycle is approximately 24 hours. (If confined to windowless apartments, with no clocks or other time cues, sleeping and waking as their bodies dictate, humans typically live on slightly longer than 24-hour cycles.) It usually takes the following daily patterns:

Humans are designed for daytime activity and nighttime rest.
Additionally, there is a natural peak in sleepiness at mid-day, the traditional siesta time.

In addition, daily rhythms intermesh with other factors that may interfere or change individual patterns:

The fraction-of-a-second-firing of nerve cells in the brain may be faster or slower in different individuals.
The monthly menstrual cycle in women can shift the pattern.
Light signals coming through the eyes reset the circadian cycles each day, so changes in season or various exposures to light and dark can unsettle the pattern. The importance of sunlight as a cue for circadian rhythms is dramatized by the problems experienced by people who are totally blind. They commonly suffer trouble sleeping and other rhythm disruptions.

The response to light signals in the brain is an important key factor in sleep:

Light signals travel to a tiny cluster of nerves in the hypothalamus in the center of the brain, the body's master clock, which is called the supra chiasmatic nucleus (SCN).
This nerve cluster takes its name from its location, which is just above (supra) the optic chiasm, which is a major junction for nerves transmitting information about light from the eyes.
The approach of dusk each day prompts the SCN to signal the nearby pineal gland (named so because it resembles a pine-cone) to produce the hormone melatonin.
Melatonin is thought to act as the body's time-setting hormone. The longer a person is in darkness the longer the duration of melatonin secretion. Secretion can be diminished by staying in bright light. Melatonin also appears to trigger the need to sleep.

Sleep consists of two distinct states that alternate in cycles and reflect differing levels of brain nerve cell activity:

Non-Rapid Eye Movement Sleep (NonREM). NonREM sleep is also termed quiet sleep. NonREM is further subdivided into three stages of progression:

Stage 1 (light sleep)
Stage 2 (so-called true sleep)
Stage 3 to 4 (deep "slow-wave" or delta sleep)

With each descending stage, awakening becomes more difficult. It is not known what governs NonREM sleep in the brain. A balance between certain hormones, particularly growth and stress hormones, may be important for deep sleep.

Rapid Eye-Movement Sleep (REM). REM sleep is termed active sleep. Most vivid dreams occur in REM sleep. REM-sleep brain activity is comparable to that in waking, but the muscles are virtually paralyzed, possibly preventing people from acting out their dreams. In fact, except for vital organs like lungs and heart, the only muscles not paralyzed during REM are the eye muscles. REM sleep may be critical for learning and for day-to-day mood regulation. When people are sleep-deprived, their brains must work harder than when they are well rested.

The REM/NREM Cycle. The cycle between quiet (nonREM) and active (REM) sleep generally follows this pattern:

After about 90 minutes of nonREM sleep, eyes move rapidly behind closed lids, giving rise to REM sleep.
As sleep progresses the nonREM/REM cycle repeats.
With each cycle, nonREM sleep becomes progressively lighter, and REM sleep becomes progressively longer, lasting from a few minutes early in sleep to perhaps an hour at the end of the sleep episode.

Causes of Short-Term or Transient Insomnia

A reaction to change or stress is one of the most common causes of short-term and transient insomnia. This condition is sometimes referred to as adjustment sleep disorder.

The trigger could be a major or traumatic event such as:

An acute illness
Injury or surgery
The loss of a loved one
Job loss

Temporary insomnia could also develop after a relatively minor event, including:

Extremes in weather
An exam
Traveling
Trouble at work

In most cases, normal sleep almost always returns when the condition resolves, the individual recovers from the event, or the person becomes used to the new situation. Treatment is needed if sleepiness interferes with functioning or if it continues for more than a few weeks. Individual responses to stress vary and some people may not experience insomnia at all, even during very stressful situations while others may suffer from insomnia in response to very mild stressors.

Fluctuations in female hormones play a major role in insomnia in women over their lifetimes. This insomnia is usually temporary.

During Menstruation. Progesterone promotes sleep, and levels of this hormone plunge during menstruation, causing insomnia. (When they rise during ovulation, women may become sleepier than usual.)
During Pregnancy. The effects of changes in progesterone levels in the first and last trimester can disrupt normal sleep patterns.
Menopause. Insomnia can be a major problem in the first phases of menopause, when hormones are fluctuating intensely. Insomnia during this period may be due to different factors that occur. In some women, hot flashes, sweating, and a sense of anxiety can awaken women suddenly and frequently at night. Insomnia may also be caused by psychologic distress provoked by this life passage. In many cases, insomnia is temporary. However, a 2006 study found that hot flashes in perimenopausal and postmenopausal women are strongly associated with chronic insomnia (sleep problems lasting more than 1 month). Treating hot flashes may help resolve chronic insomnia.

Air travel across time zones often causes insomnia. After long plane trips, 1 day of adjustment is usually needed for each time zone crossed. Traveling west to earlier times seems to be less traumatic than going east to a later time because it is easier to lengthen a circadian phase than to shorten it.

In one study, 20% of adults reported that light, noise, and uncomfortable temperatures caused their sleeplessness. Depending on the time of day, too much or too little light can disrupt sleep.

Excessive Light at Night. A person's biologic circadian clock is triggered by sunlight, and very bright artificial light maintains wakefulness. One study indicated that even dim artificial light might disrupt sleep.
Insufficient Light During the Day. Insufficient exposure to light during the day, as occurs in some disabled elderly patients who rarely venture outside, may also be linked with sleep disturbances. One study suggested that when a person is exposed to bright daylight, melatonin levels increase in response to darkness at night, which aids sleep.

Caffeine. Caffeine is a stimulant, which can interfere with falling asleep.

Nicotine. Nicotine is also a stimulant, but quitting smoking itself can lead to transient insomnia. In fact, it has been suggested that if sleeping could be improved during withdrawal from smoking, perhaps it would be easier to quit smoking.

Partner's Sleep Habits. In one survey, 17% of women and 5% of men reported that their partner's sleep habits impaired their own sleep. Snoring can certainly be a factor in a partner's insomnia.

Medications. Insomnia is a side effect of many common medications, including over-the-counter preparations that contain caffeine. People who suspect their medications are causing them to lose sleep should check with their doctors or pharmacists.

Causes of Chronic Insomnia

Sleep problems seem to run in families. About 35% of people with insomnia have a family history of insomnia, with the mother being the most commonly affected family member. Still, because so many factors are involved in insomnia, a genetic component is difficult to define.

Abnormal levels of certain brain chemicals have been observed in some people with chronic insomnia.

Melatonin. Low levels of melatonin, the hormone secreted by the pineal gland, have sometimes been observed in chronic insomnia.
Stress Hormones. Some studies have reported persistently high levels of stress hormones, particularly cortisol, in people with chronic insomnia, particularly insomnia related to aging and psychiatric disorders. High levels of cortisol reduce REM sleep. However, a 2003 study of people with chronic insomnia reported that cortisol levels were high only when their sleep was of poor quality. When they slept well, levels were lower. This study and other research suggests that high levels of stress hormones are caused by poor sleep, rather than being the cause.
Growth Hormone. Normal aging is associated with a blunting of regular, cyclical surges of growth hormone, which may affect sleep as one gets older. This hormone, which is normally secreted in the late night, is associated not only with growth but with deep, slow-wave sleep. (Older people generally have less slow-wave sleep.)

Chronic insomnia occurs in people who have persistently high levels of stress hormones and a shift in the levels of certain immune factors. Studies indicate that people with chronic insomnia have higher levels of interleukin-6 and tumor necrosis factor during the day, but lower levels at night. These immune factors, called cytokines, cause symptoms of fatigue. Levels are usually higher at night in people with healthy sleep. The implications of these immune changes in people with insomnia are not known.

Many cases of chronic insomnia cases have a psychologic or psychiatric basis. The disorders that most often cause insomnia are:

Anxiety.
Depression. Sleep abnormalities are an integral part of depressive disorders, with more than 90% of depressed patients experiencing insomnia.
Bipolar disorder.

Insomnia may also cause emotional problems. It is often unclear which condition has triggered the other, or if the two conditions, in fact, have a common source.

In many cases, it is unclear if chronic insomnia is a symptom of some physical or psychological condition or if it is a primary disorder of its own. In most instances, a mix of psychological and physical conditions causes the insomnia.

Psychophysiologic insomnia occurs when:

An episode of transient insomnia disrupts the person's circadian rhythm.
The patient begins to associate the bed not with rest and relaxation but with a struggle to sleep. A pattern of sleep failure emerges.
Over time, this event repeats, and bedtime becomes a source of anxiety. Once in bed, the patient broods over the inability to sleep, the consequences of sleep loss, and the lack of mental control. All attempts to sleep fail.
Eventually excessive worry about sleep loss becomes persistent and provides an automatic nightly trigger for anxiety and arousal. Unsuccessful attempts to control thoughts, images, and emotions only worsen the situation. After such a cycle is established, insomnia becomes a self-fulfilling prophecy that can persist indefinitely.

Sometimes anxiety and the inability to sleep dates back to childhood when parents used various threats to force their children into sleep for which they may not have been ready.

In one survey, 22% of adults reported that health conditions, pain, or discomfort impaired their sleep. These conditions can include:

Nightly Leg Problems. Leg disorders that occur at night, such as restless legs syndrome or leg cramps, are of special note. They are very common and an important cause of insomnia, particularly in older people.

Medical Problems. Among the many medical problems that can cause chronic insomnia are allergies, arthritis, cancer, fibromyalgia, heart disease, gastroesophageal reflux disease (GERD), hypertension, asthma, emphysema, rheumatologic conditions, Alzheimer's disease, Parkinson's disease, hyperthyroidism, and attention deficit hyperactivity disorder.

Medications. Among the many medications that can cause insomnia are antidepressants (fluoxetine, bupropion), theophylline, lamotrigine, felbamate, beta-blockers, and beta-agonists.

An estimated 10 -15% of chronic insomnia cases result from substance abuse, especially alcohol, cocaine, and sedatives. One or two alcoholic drinks at dinner, for most people, pose little danger of alcoholism and may help reduce stress and initiate sleep. Excess alcohol or alcohol used to promote sleep, however, tends to fragment sleep and cause wakefulness a few hours later. It also increases the risk for other sleep disorders, including sleep apnea and restless legs. Alcoholics often suffer insomnia during withdrawal and, in some cases, for several years during recovery.

Shift work throws off the body's circadian rhythm and may lead to chronic insomnia.

Risk Factors

Studies estimate that between 25 - 33% of adults experience some insomnia each year. In spite of this widespread problem, however, studies suggest that only about 30% of American adults who visit their doctor ever discuss sleep problems. And, doctors seem rarely to ask patients about their sleep habits or problems.

A 2003 study suggested that there were seven significant factors that predicted high risk for insomnia:

Being older
Having conflicts with relatives
Being overworked on the job
Being overworked at home
Having a sick relative
Having low social status
Having a psychiatric or psychologic problem

Stressful events do not cause insomnia in everyone. However, negative thoughts and attitudes toward events can be significant factors in insomnia. In one study, for example, the number of stressful events did not differ between good and poor sleepers. Those with insomnia, however, tended to experience these stressful events more intensively than the healthy sleepers.

In another study, patients with insomnia and good sleepers were asked to record their pre-sleep images using a handheld counter. People with insomnia not only reported fewer images, but their images also tended to be more unpleasant than those of good sleepers. More of the images in people with insomnia were related to intimate relationships and to sleep itself. The images of sleepers were more likely to be random and disconnected.

Studies report that the strongest risk factors for insomnia are psychiatric problems (particularly depression) and physical complaints (such as headaches and chronic pain) that have no identifiable cause (called somatic symptoms). About 90% of people with depression have insomnia. A study presented at the 2005 Associated Professional Sleep Societies meeting indicated that insomnia may contribute to, and prolong, depression. Researchers analyzed data from over 1,800 adults age 65 years and older. Compared with depressed patients who did not have sleep problems, depressed patients with insomnia were 11 times more likely to remain depressed after 6 months and 17 times more likely to still be depressed after a year. The researchers suggested that treating insomnia may help patients recover from depression more quickly.

Overall, insomnia is more common in women than men, although men are not immune from insomnia. Sleep efficiency deteriorates equally in men and women as they get older.

Men. One major study suggested that as men age from 16 - 50, they lose about 80% of their deep sleep. During that period, light sleep increases and REM sleep remains unchanged. (The study did not use women as subjects, and there is some evidence to suggest they are not as affected.) After age 44, REM and total sleep diminish and awakenings increase.

Women. It is not clear why women suffer more from insomnia than men. Some theories include:

In women, a number of hormonal events can disturb sleep, including premenstrual syndrome, menstruation, pregnancy, and menopause. All these conditions are short-term, however, and in most cases the wakefulness associated with them is temporary and can be eliminated with sleep hygiene and time.
After childbirth, most women develop a high sensitivity to the sounds of their children, which causes them to wake easily. Women who have had children sleep less efficiently than women who have not had children. It is possible that many women never unlearn this sensitivity and continue to wake easily long after the children have grown.
Women are at higher risk than men are for depression and anxiety, which are known risk factors for insomnia. In fact, some researchers believe that this is a main reason for the gender differences in insomnia.

After menopause, women are susceptible to the same environmental and biologic causes of insomnia as men. In fact, older women who are not bothered by sleeplessness tend to have longer and better sleep than noninsomniac men their own age.

As people grow older, sleep patterns change. In a major 2003 survey, a third of older adults reported that they woke up frequently during the night. About a quarter of participants reported waking up too early and being unable to go back to sleep. In the same study, 33% of adults age 55 - 64 reported waking up feeling unrefreshed.

Although age itself does not appear to be a risk factor for insomnia, a number of factors may interfere with sleep as one gets older:

Elderly people are more likely to be sedentary than younger adults.
Medical conditions that cause pain or nighttime distress are common in the elderly and pose a high risk for insomnia. They include arthritis, gastrointestinal distress, frequent urination, lung disease, and heart conditions.
Neurologic diseases in the elderly, such as restless legs syndrome, Parkinson's, Alzheimer's, and other forms of dementia can cause nighttime disorientation, confused wandering, and delirium.
Older people often take a number of prescription drugs whose side effects include insomnia.
The elderly are prone to grief, depression, and anxiety, emotional factors that can cause sleeplessness. One study of healthy older adults found that psychologic factors, such as anxiety and depression, were more likely to cause insomnia than illness, medications, or living conditions.
Melatonin levels are generally lower in older people. Some research suggests, however, that elderly people have lower levels simply because they stay mostly indoors and do not receive adequate sunlight.

Lack of sleep at night can lead to excessive sleepiness during the day. A 2006 study reported the following risk factors for excessive daytime sleepiness among the elderly:

Male gender
Sleep apnea or other sleep breathing disorders
Nighttime chest wheezing
Poor sleep quality
Longer time spent in REM sleep
More than 3 episodes of nighttime pain within a week
Medications that cause sleepiness

Sleep loss among the elderly is not inevitable. While older people are more susceptible to many conditions that can cause insomnia, treatments and a healthy lifestyle, particularly regular exercises, are as useful in providing relief to the elderly as to the young. And, a number of studies have found no significant increase in insomnia in older healthy adults.

Shift workers are at considerable risk for insomnia. In a major survey, 65% of shift workers reported one or more symptoms of insomnia at least a few nights a week. Workers over age 50 and those whose shifts are always changing are particularly susceptible to insomnia, although night-shift workers also have a high rate of sleeplessness. One study found that 53% of night-shift workers fall asleep on the job at least once a week, implying that their internal clocks do not adjust to unusual work times. (They are also at much higher risk than other workers for automobile accidents due to their drowsiness and may also have a higher risk for health problems in general.) A Japanese study reporting on different aspects of insomnia found that excessive computer work was associated with all forms of insomnia. People who were over-involved with their work tended to have trouble falling asleep, and they tended to awaken earlier than average.

Among the many conditions that pose a high risk for insomnia are:

Frequent travel, particularly crossing time lines
Post-traumatic stress syndrome
Brain injuries
Many chronic medical conditions ranging from seemingly minor ones, such as tinnitus (ringing in the ears) to major conditions, such as respiratory problems, heart disease, or being on dialysis

Prognosis

A 2002 study of sleeping habits in over 1 million people reported that people who slept 7 hours a night lived the longest. People who slept more than 8 hours or less than 6 hours, or who took sleeping pills, had lower survival rates.

Insomnia is not life-threatening, except in very rare cases, such as in those who have the genetic disorder called fatal familial insomnia. This rare degenerative brain disease develops in late adulthood.

Sleepiness causes as many as 200,000 automobile accidents in the U.S. and 1,500 deaths from such accidents. Studies indicate that drowsy driving is as risky as drunk driving. In a major 2003 survey, 60% of young adults reported driving while drowsy, and 20% dosed off while driving. In the study, 1% of adults who dozed off reported having an accident because of it. (One study strongly suggested that it is habitual sleepiness, however, and not just being sleepy at the time of an accident that places people at higher risk.)

Surveys show that people with severe insomnia have a quality of life that is almost as poor as those who have chronic conditions, such as heart failure. In addition to more daytime sleepiness, people with insomnia complain of more attention and memory problems compared to good sleepers.

Insomnia can also lead to irritability, mistakes at work, and poorer relationships.

Effect on Thinking and Performance. Studies suggest that insomnia makes it harder to concentrate and perform tasks.

Reduced concentration. Deep sleep deprivation impairs the brain's ability to process information.
Impaired task performance. One study reported that missing only 2 - 3 hours of sleep every night for a week significantly impaired performance and mood. An Australian study reported that 17 hours of sleep deprivation causes impaired performance levels comparable to those found in people who have blood alcohol levels indicating intoxication.
Memory problems. Whether insomnia significantly impairs learning is unclear. Some studies have reported problems in memorization, although others have found no differences in test scores between people with temporary sleep loss and those with full sleep.

Insomnia and Depression. Although stress and depression are major causes of insomnia, insomnia may also increase the activity of the hormones and pathways in the brain that can produce emotional problems. Research indicates that chronic insomnia can increase the risk of developing depression and anxiety. Some investigators are exploring the possibility of preventing psychiatric disorders by early recognition and treatment of insomnia.

Even modest alterations in waking and sleeping patterns can have significant effects on a person's mood. In both children and adults, the combination of insomnia and daytime sleepiness can produce more severe depression than either condition alone.

Effects on the Heart. Although there has been some concern that insomnia may increase the risk for heart problems, little evidence has supported any significant dangers. One study reported signs of heart and nervous system activity in people with chronic insomnia that might place such individuals at risk for coronary heart disease. If it exists, however, this increased danger is very modest compared with other risk factors for heart disease. Yet another report suggested that sleep complaints in elderly people without coronary artery disease predicted a first heart attack. Sleep disorders in such cases may have been a marker for depression, however, which is a risk factor for heart attacks in elderly people.

Effects on Weight. Lack of sleep can cause weight gain and obesity. In a 16-year study of over 68,000 women, those who slept no more than 5 hours a night were 32% more likely to gain at least 33 pounds, and those who slept 6 hours had a 12% increased risk of weight gain compared to women who slept at least 7 hours a night.

Effects on the Immune System. A 2003 study reported significant differences in immune factors among sleepers, with higher levels of certain infection-fighters observed in good sleepers than in people with chronic insomnia. The significance of these findings is still unknown, however.

Diagnosis

Diagnosing sleep disturbance and its cause is the most important step in restoring healthy sleep. However, there is little agreement, even among experts, on the best methods for effectively assessing a patient's insomnia.

A major difficulty in diagnosing this problem is its subjective nature. One study showed that there was no difference in sleep behaviors between people who said they were insomniacs and people who said they weren't. People who believe they have insomnia may have actually had frequent brief awakenings during sleep that they perceive as being continuously awake.

A number of questionnaires are available for determining whether a patient has insomnia or other sleep disorders. For example, the doctor may ask:

How would you describe your sleep problem?
How long have you had the sleep problem?
How long does it take to fall asleep?
How many times a week does it occur?
How restful is sleep?
Do you have trouble falling asleep or do you wake up too early?
What is the sleep environment like (Noisy? Not dark enough?)?
How does insomnia affect daytime functioning?
What medications do you take? (Include herbs, alcohol, and over-the-counter or prescription drugs.)
Are you taking or withdrawing from stimulants, such as coffee or tobacco?
How much alcohol is consumed per day?
What stresses or emotional factors may be present?
Have you experienced any significant life changes?
Do you snore or gasp during sleep (an indication of sleep apnea)?
Do you have leg problems (cramps, twitching, crawling feelings)?
If there is a bed partner? Is this person's behavior distressing or disturbing?
Are you a shift worker?

Sleep Diary. If the patient cannot answer these questions, keeping a sleep diary is a helpful diagnostic tool. Every day for 2 weeks, the patient should record all sleep-related information, including responses to questions listed above described on a daily basis. A bed partner can help by adding their observations of the patient's sleep behavior.

The Epworth Sleepiness Scale. The Epworth Sleepiness Scale (ESS) uses a simple questionnaire to measure excessive sleepiness during eight situations.


Situation	Chance of Dozing 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing
Sitting and reading.	(Indicate a score of 0 to 3)
Watching TV.	(Indicate a score of 0 to 3)
Sitting inactive in a public place (e.g., a theater or a meeting).	(Indicate a score of 0 to 3)
As a passenger in a car for an hour without a break.	(Indicate a score of 0 to 3)
Lying down to rest in the afternoon when circumstances permit.	(Indicate a score of 0 to 3)
Sitting and talking to someone.	(Indicate a score of 0 to 3)
Sitting quietly after a lunch without alcohol.	(Indicate a score of 0 to 3)
In a car, while stopped for a few minutes in traffic.	(Indicate a score of 0 to 3)
Score Results	1-6: Getting enough sleep 4-8: Tends to be sleepy but is average. 9-15: Very sleepy and should seek medical advice. Over 16: Dangerously sleepy

Multiple Sleep Latency Test. The multiple sleep latency test (MSLT) uses a machine to measure the time it takes to fall asleep while lying in a quiet room during the day:

The patient takes four or five scheduled naps 2 hours apart.
People with healthy sleep habits fall asleep in about 10 - 20 minutes.
The test can detect changes in sleepiness associated with sleep deprivation in patients with insomnia.

It has limitations, however, and does not take into consideration any situations that may affect the patients' mental state and the actual home situation. The test is used mainly after other sleep disorders have been ruled out and the doctor is uncertain whether or not insomnia is a correct diagnosis.

If unexplained insomnia persists after treatment or there is evidence of a primary sleep disorder, such as sleep apnea or narcolepsy, the doctor may recommend a sleep specialist or a sleep disorders center. Centers are accredited by the American Academy of Sleep Medicine. Patients should investigate centers carefully, to be sure that they offer full sleep studies.

Among the signs that may indicate a need for a sleep disorders center are:

Insomnia due to psychologic disorders
Sleeping problems due to substance abuse
Snoring and sudden awakening with gasping for breath (possible sleep apnea)
Severe restless legs syndrome
Persistent daytime sleepiness
Sudden episodes of falling asleep during the day (possible narcolepsy)

At most sleep disorders centers, patients undergo an in-depth analysis, usually supervised by a multidisciplinary team of consultants who can provide both physical and psychiatric evaluations.

Treatment

The American Academy of Sleep Medicine (AASM) recommends cognitive behavioral therapy (CBT) and prescription medications as the main treatments for insomnia. According to the AASM, these treatment options can improve both quality and quantity of sleep for people with insomnia.

Experts agree that behavioral therapies should be the first-line treatment for insomnia. For children in particular, medications should rarely be used as initial treatment. A 2006 study reported that behavioral interventions can provide sustained improvement in over 80% of children with insomnia.

Prevention of sleeplessness depends upon the patient's ability to learn how to relax and sleep well. A number of behavioral methods are aimed at achieving these goals. Behavioral techniques can actually cure chronic insomnia in many cases and studies report that they help nearly all patients with primary chronic insomnia. The benefits of psychological and behavioral therapy in managing insomnia are long-lasting.

Although medications are equally effective for helping people with insomnia to sleep, they cannot cure the condition. In addition, behavioral methods act faster. Behavioral methods work in all age groups, including children and elderly patients.

Behavioral methods include:

Stimulus control
Cognitive behavioral therapy
Progressive muscle relaxation
Paradoxical intention
Biofeedback
Sleep restriction
Imagery tasks

Studies have reported that between 70 - 80% of patients who are treated with non-drug methods experience improved sleep with an average treatment duration of only 5 hours over a 4-week period. Furthermore, studies report that 75% of those who have been taking drugs are able to stop or reduce their use.

Proper sleep hygiene is the first step and should accompany any behavioral method. A number of behavioral approaches are available, but all have the same basic goals:

To reduce the time it takes to go to sleep to below 30 minutes
Reduce wake-up periods during the night

Stimulus Control. Stimulus control is now considered the standard treatment for primary chronic insomnia and may be helpful for some patients with secondary insomnia as well. The primary goal of stimulus control is to regain the idea that the bed is for sleeping. It involves the following:

Go to bed only when ready to sleep or for sex.
If unable to sleep within 15 - 20 minutes, get up and go into another room. (People who find it physically difficult to get out of bed should sit up and do something relatively arousing, like reading a book.)
Maintain a regular wake-up time no matter how few hours you actually sleep.
Avoid naps.

Cognitive-Behavioral Therapy. Cognitive behavioral therapy (CBT) is a form of therapy that emphasizes observing and changing negative thoughts about sleep such as, "I'll never fall asleep." It uses actions intended to change behavior. A 2004 study of young and middle-aged adults suggested that CBT is more effective than medication in treating chronic insomnia, and should be considered as a first-line intervention. Adding medication to CBT did not provide additional benefit. In a 2006 study of older adults, CBT worked better than zopiclone (Imovane) in managing chronic insomnia. [Zopiclone is a European sleep medication that is similar to the American drug eszopiclone (Lunesta).] Compared to zopiclone or placebo, CBT helped patients spend less time awake at night. The benefits of 6 weeks of weekly CBT sessions lasted for 6 months.

Progressive Muscle Relaxation. Progressive muscle relaxation is another technique for inducing sleep that works well for many people. It takes about 10 minutes to perform:

Focus on one specific muscle group at a time. Most people start with the muscles in one foot. Inhale and tense the foot muscles for about 8 seconds. (Do this gently. It is not intended to cause severe pain or muscle contractions.)
Relax the foot, and let it become loose and limp. Stay relaxed for 15 seconds, then repeat with the other foot.
Move up to the next muscle group and repeat the sequence, doing one side of the body at a time. Move progressively from each foot and leg up through the abdomen and chest, to each hand and arm, then to the neck, shoulders, and face.

Paradoxical Intention. Paradoxical intention is a psychological approach that is based on doing the opposite of what one wants or fears and takes it to the extreme. The first step is to make a plan to take such a paradoxical approach to insomnia.

Instead of going through activities leading to sleep, the patient prepares for staying awake and doing something energetic.
In some cases, people may take specific psychological barriers to sleep to an extreme limit. For example, if worry is a factor in insomnia, the patient intensifies the worries.

Biofeedback. Biofeedback is also effective, but requires being monitored with an electroencephalogram (EEG), a device that measures brain waves. Patients are given feedback to recognize certain states of tension or sleep stages so that they can either avoid or repeat them voluntarily.

Sleep Restriction Therapy. Sleep restriction therapy may be effective, although evidence is inconclusive. In a 2001 study, patients practiced sleep hygiene and sleep restriction. Sleep hygiene was very helpful during the first 2 months while sleep restriction led to sustained benefits and deeper sleep. The approach is a systematic method for achieving sleep and restricting the time spent in bed.

The first step is to calculate a person's sleep efficiency number:

Keep a sleep diary for 14 days. Calculate the average hours of actual sleep and hours in bed. Then divide the average hours slept by the hours spent in bed. The result, given as a percentage, is the sleep efficiency number. (For example, if a patient sleeps an average of 5 hours out of 7 hours spent in bed then the result is .714, and the sleep efficiency percentage is 71%.)
The patient's goal is to achieve sleep efficiencies of between 85 - 90%, which means only 10 - 15% of the time is spent staying awake in bed. (Sleep efficiency in older people normally falls between 75 - 85%.)

To achieve this goal, the patient takes the following actions:

Begin by going to bed 15 minutes later than usual the first week.
If 85% sleep efficiency isn't reached by the end of the week, add another 15 minutes before going to bed. Refrain from going to bed even if tired, although bedtime should not be reduced below 5 hours.
Once efficiency reaches 90% or more, begin to go to bed 15 minutes earlier each week.

Other parts of the program include stopping any sleep medications and following good sleep hygiene. People using this treatment have reported lasting improvements after just 8 weeks, and studies suggest that it is significantly more successful than relaxation techniques.

Imagery Tasks. A 2002 study enrolled people whose chronic insomnia was associated with unwanted thoughts and worries. They were given specific positive mental tasks that gave them a sense of positive control (as opposed to their real life concerns, which felt out of their control). These images distracted them and allowed them to fall asleep faster. In support of this approach, another study evaluated patients with insomnia who were given a problem before sleep. One group was asked to think of the problem in images and the other in words. The group who used imagery fell asleep more quickly and woke up with less anxiety.

Sleep Hygiene. The term sleep hygiene is used to describe simple behaviors that may help everyone improve their sleep.

Establish a regular time for going to bed and getting up in the morning. Stick to this schedule even on weekends and during vacations.
Use the bed for sleep and sexual relations only, not for reading, watching television, or working. Excessive time in bed disrupts sleep.
Avoid naps, especially in the evening.
Exercise before dinner. A low point in energy occurs a few hours after exercise; sleep will then come more easily. Exercising close to bedtime, however, may increase alertness.
Take a hot bath about 1.5 - 2 hours before bedtime. This alters the body's core temperature rhythm and helps people fall asleep more easily and more continuously. (Taking a bath shortly before bed increases alertness.)
Do something relaxing in the 30 minutes before bedtime. Reading, meditation, and a leisurely walk are all appropriate activities.
Keep the bedroom relatively cool and well ventilated.
Do not look at the clock. Obsessing over time will just make it more difficult to sleep.
Eat light meals, and schedule dinner 4 - 5 hours before bedtime. A light snack before bedtime can help sleep, but a large meal may have the opposite effect.
Spend a half hour in the sun each day. The best time is early in the day. (Take precautions against overexposure to sunlight by wearing protective clothing and sunscreen.)
Avoid fluids just before bedtime so that sleep is not disturbed by the need to urinate.
Avoid caffeine in the hours before sleep.
If one is still awake after 15 - 20 minutes, go into another room, read or do a quiet activity using dim lighting until feeling very sleepy. (Don't watch television or use bright lights.)
If distracted by a sleeping bed partner, moving to the couch or a spare bed for a couple of nights might be helpful.
If a specific worry is keeping one awake, thinking of the problem in terms of images rather than in words may allow a person to fall asleep more quickly and to wake up with less anxiety.

Exercise may be one of the best ways to promote healthy sleep. One study found that exercise is as good for inducing sleep as the use of benzodiazepines, a prescription sleep aid. Some research has found that yoga practice may have specific benefits on sleep health. Yoga uses meditation, deep breathing techniques, and movements that emphasize stretching and balance.

The circadian rhythm is more a function of darkness and light rather than actual time of day. Bright light can discourage drowsiness, and darkness can cause sleepiness, day or night. The use of a special box that gives off very bright fluorescent light (over 4,000 lux) for about 30 minutes each day may be helpful.

The following people might benefit from light therapy:

Shift workers. Light therapy should be maximized during hours they are at work and minimized when they need to sleep.
Frequent travelers. Light therapy may be useful for adjusting to new time zones and reducing jet lag.
Nursing home patients.
People with delayed sleep-phase syndrome. These people have a natural tendency to fall asleep very late at night or in early morning hours, but then sleep normally.

Patients should check with their doctors before using light therapy. The following people should avoid light therapy or use it only under a doctor's direction:

Anyone with eyes or skin that are highly sensitive to light
Anyone taking medications that increase the risk for photosensitivity
People with bipolar disorder

Timing of the therapy depends on the type of insomnia or sleep schedule of the individual. For example, in people who cannot get to sleep at night, light therapy in the morning and restricting bright light at night may be helpful. People who wake up early in the morning may benefit from light therapy performed in the evening, although a 2002 study reported that it had no effect in this group. Some light boxes have dawn/dusk simulators that help determine the correct brightness.

Medications

According to a major 2003 survey, about 20% of American older adults use some form of sleep aid, including prescription or over-the-counter drugs or alcohol. Furthermore, 15% use such aids every night.

However, while behavioral or psychologic techniques can actually cure insomnia, prolonged use of sleeping pills can only result in dependency.

In general, the following precautions are important:

Start with non-prescription medication.
Drugs used specifically for improving sleeping are called sedative hypnotics. These drugs include benzodiazepines and non-benzodiazepines. Until recently benzodiazepines were most commonly prescribed, but newer non-benzodiazepines may be better tolerated and have less risk of dependency. These medicines, however, may be associated with potentially severe allergic reactions, such as anaphylaxis and facial swelling (angioedema). These medicines may also cause hazardous behaviors, such as driving, making phone calls, or eating while asleep. If you need to take one of these prescription drugs, start with as low a dose as possible.
For adults over age 60 years, studies suggest that the risks of sedative hypnotics may far outweigh their benefits.
As a general rule, do not take either prescription nor non-prescription sleeping pills on consecutive days or for more than 2 - 4 days a week.
If insomnia is still a problem after stopping the drug and continuing with good sleep hygiene, this pattern can be repeated again, but for only up to 4 weeks.
Medication should be withdrawn gradually, and the patient should be aware of the possibility of rebound insomnia after stopping medication.
Alcohol intensifies the side effects of all sleeping medication and should be avoided.
If chronic insomnia is a companion to depression or anxiety, treating these problems first may be the best approach.

Brands with Antihistamines. Many over-the-counter sleeping medications use antihistamines, which cause drowsiness. Diphenhydramine is the most common antihistamine used non-prescription sleep aids. Some drugs contain diphenhydramine alone (Nytol, Sleep-Eez, Sominex), while others contain combinations of diphenhydramine with pain relievers (Anacin P.M., Excedrin P.M., Tylenol P.M.). Doxylamine (Unison) is another antihistamine used in sleep medications. Certain antihistamines indicated only for allergies, such as chlorpheniramine (Chlor-Trimeton), diphenhydramine (Benadryl), or hydroxyzine (Atarax or Vistaril) may also be used as mild sleep-inducers.

Unfortunately, most of these drugs leave patients feeling drowsy the next day and may not be very effective in providing restful sleep. Side effects include:

Daytime sleepiness
Dizziness
Drunken movements
Blurred vision
Dry mouth and throat

In general, these drugs should be avoided by people with angina, heart arrhythmias, glaucoma, or problems urinating. They should not be used at the same time as medications that prevent nausea or motion sickness. Some non-prescription sleeping aids, such as those containing doxylamine, should also be avoided by patients with chronic lung disease.

Common Pain Relievers. When sleeplessness is caused by minor pain, simply taking acetaminophen (Tylenol) or a non-steroidal anti-inflammatory drug (NSAID) such as ibuprofen (Advil, Motrin), can be very helpful without causing any daytime sleepiness. The extra "P.M." antihistamine found in combination products is simply an extra, needless chemical in these situations.

Benzodiazepines, also referred to as benzodiazepine receptor agonists (BzRAs), were once the most commonly prescribed sedative hypnotics. Originally developed in the 1960s to treat anxiety, these drugs nonselectively target receptor sites in the brain that modulate the effects of the neurotransmitter gamma-aminobutyric acid (GABA).

Brands. Commonly prescribed benzodiazepines:

Long-acting benzodiazepines include flurazepam (Dalmane) and clonazepam (Klonopin), quazepam (Doral).
Medium- to short-acting benzodiazepines include triazolam (Halcion), lorazepam (Ativan), alprazolam (Xanax), temazepam (Restoril), oxazepam (Serax), prazepam (Centrax), estazolam (ProSom), and flunitrazepam (Rohypnol). Short-acting benzodiazepines may be useful for air travelers who want to reduce the effects of jet lag.

Side Effects. Elderly people are more susceptible to side effects and should usually start at half the dose prescribed for younger people. They should not take long-acting forms.

Side effects may differ depending on whether the benzodiazepine is long- or shorting acting. They include:

Severe allergic reactions, including facial swelling, can occur even with the first use of a benzodiazepine drug.
Respiratory problems may occur with overuse or in people with pre-existing respiratory illness
The drugs may increase depression, a common co-condition in many people with insomnia.
Respiratory depression may occur with overuse or with people with pre-existing respiratory illness.
Long-acting drugs have a very high rate of residual daytime drowsiness compared to other types of sleeping pills. They have been associated with a significantly increased risk for automobile accidents and falls in the elderly, particularly in the first week after taking them. Shorter-acting benzodiazepines do not appear to pose as high a risk.
Memory loss (so-called traveler's amnesia), sleepwalking, sleep driving, eating while asleep and other odd mood states may occur. These effects are enhanced by alcohol.
Incontinence. In one study, 33% of patients experienced incontinence at least twice a week. The risk is highest in the elderly and with older, long-acting drugs.
Because these drugs cross the placenta and enter breast milk, pregnant women or nursing mothers should not use them. Benzodiazepine use in the first trimester of pregnancy may be associated with the development of cleft lip in newborns.
In rare cases, overdoses have been fatal.

Interactions. Benzodiazepines are potentially dangerous when combined with alcohol. Some medications, like the ulcer medication cimetidine, can slow the metabolism of the benzodiazepine.

Withdrawal Symptoms. Withdrawal symptoms usually occur after prolonged use and indicate dependence. They can last 1 - 3 weeks after stopping the drug and may include:

Gastrointestinal distress
Sweating
Disturbed heart rhythm
In severe cases, patients might hallucinate or experience seizures, even a week or more after the drug has been stopped.

Rebound Insomnia. Rebound insomnia, which often occurs after withdrawal, typically includes 1 - 2 nights of sleep disturbance, daytime sleepiness, and anxiety. In some cases, patients may experience the return of the original severe insomnia. The chances for rebound are higher with the short-acting benzodiazepines than with the longer-acting ones.

Newer short-acting non-benzodiazepines can induce sleep with fewer side effects than the benzodiazepines. Both benzodiazepine and non-benzodiazepine sedative hypnotics act on GABA-A receptor sites in the brain, but non-benzodiazepines are more specific in the subunits they target. Developed in the late 1980s, these drugs are increasingly prescribed and are becoming the hypnotics of choice for many doctors.

Brands and Benefits. Non-benzodiazepine hypnotics currently approved in the United States are zolpidem (Ambien, Ambien CR), zaleplon (Sonata), eszopiclone (Lunesta), and ramelteon (Rozerem).

Zolpidem (Ambien, generic) is one of the most commonly prescribed drugs for insomnia. It lasts longer than zaleplon. Patients should not take it unless they plan on getting at least 7 - 8 hours of sleep. The recommended dose is 10 mg/day for adults, although elderly patients may be prescribed half that dose. A 2002 study suggested that the drug might be used on an as-needed basis, with up to 5 tablets taken a week. After 3 weeks, two-thirds of the patients taking zolpidem this way were able to reduce their tablet intake by more than 25% without losing improvements in sleep. Ambien CR, an extended-release form, received approval from the Food and Drug Administration (FDA) in late 2005. It is the first extended-release prescription medicine for insomnia. The medicine is delivered in two steps. The first layer dissolves quickly, allowing the patient to fall asleep. The second layer helps the patient stay asleep.
Zaleplon (Sonata) is the shortest-acting hypnotic available. Because it is rapidly eliminated from the body it may be best for people who have difficulty falling asleep, not those who wake up often throughout the night. The drug takes effect within 30 minutes and may be taken at bedtime or later as long as the patient can sleep for at least 4 hours. The recommended dose is 5 - 10 mg/day. The drug is usually taken for 7 - 10 days.
Eszopiclone (Lunesta) is a newer, non-benzodiazepine hypnotic approved by the FDA in 2004. It may help improve both sleep maintenance and daytime alertness. Eszopiclone is related to zopiclone (Imovane), which has been used for many years in Europe. Unlike other sleep medications, eszopiclone can be taken on a long-term basis. In clinical trials, patients used eszopiclone for up to 6 months. Recommended doses are 2 - 3 mg/day for adults and 2 mg/day for elderly patients. Patients whose main problem is falling asleep may need only 1 mg/day.
Ramelteon (Rozerem) was approved by the FDA in 2005. Ramelteon is a novel non-benzodiazepine hypnotic. Unlike most sleep drugs, which target the gamma-aminobutyric acid (GABA) receptors, ramelteon targets the MT1 and MT2 receptors. Ramelteon does not cause dependence and is the first sleep drug not designated as a controlled substance.

These drugs can be particularly helpful for preventing jet lag (but zolpidem should not be used on flights less than 7 - 8 hours). They also may be helpful for people who also have accompanying mood disorders, such as depression or post-traumatic stress disorder. Because they are short-acting, zaleplon and zolpidem may pose fewer risks for falls and memory loss in elderly patients. In general, these drugs are recommended for short-term use (7 - 10 days) and treatment should not exceed 4 weeks. No studies have yet confirmed safety for longer-term use.

Side Effects. All of these drugs have fewer morning side effects than the benzodiazepines, including morning sedation and memory loss (although they can occur to some degree). Zolpidem’s (Ambien) record of adverse effects is similar to that of triazolam (Halcion), the short-acting benzodiazepine. Zaleplon (Sonata) and Ramelteon (Rozerem) appear to have less severe morning side effects. When patients first start taking any of these drugs, they should use caution during morning activities until they are sure how the drug affects them.

General side effects are mild but may include:

Drowsiness
Dizziness
Fatigue
Headache
Unpleasant taste
Diarrhea

Rarer side effects may include sleepwalking and hallucinations. In 2006, reports emerged of zolpidem (Ambien) causing sleepwalking and, even more bizarrely, sleep-driving. Most of these cases likely were due to patients using zolpidem along with alcohol or other drugs or taking more than the recommended dose. However, in March 2007, the FDA ordered stronger warning labels for zolpidem and all other non-benzodiazepine drugs. The new labels warn that that these drugs can cause sleep-related behavior, including sleep-driving, making phone calls, and preparing and eating food while asleep. In addition, severe allergic reactions (anaphylaxis) and facial swelling (angioedema) can occur even the first time one of these drugs is taken.

Anyone who receives a prescription for these medicines will also get a patient medication guide explaining the risks of the drugs and the precautions to take. Talk to your doctor if you have any questions concerning these drugs or their potential side effects.

Patients should carefully read the information labels for all drugs and follow the directions. Some sleeping pills take 30 - 60 minutes to take effect, while others (such as zolpidem) are fast-acting. For zolpidem, patients should:

Take zolpidem immediately before going to sleep
Take zolpidem only when able to get a full night’s sleep (7 – 8 hours)
Not drink alcohol the same evening
Not take more than the prescribed dose
Use caution in the morning when getting out of bed, driving, or operating heavy machinery

Interactions. As with any hypnotics, alcohol increases the sedative effects of these drugs. These hypnotics also interact with other drugs, including rifampin, ketoconazole, erythromycin, and cimetidine. They may also interfere or be interfered by other drugs. Patients should report all medications to their doctors.

Dependency, Withdrawal Symptoms, and Rebound Insomnia. The risk for rebound insomnia, dependence, and tolerance is lower with non-benzodiazepine hypnotics than with benzodiazepine drugs. These drugs are still subject to abuse. In any case, no hypnotic should be taken for more than 7 - 10 days or at higher than the recommended dose without a doctor's approval.

Antidepressants are sometimes used to treat insomnia that may be caused by depression (secondary insomnia). In addition, some antidepressants with sedating properties are prescribed for the treatment of primary insomnia. For example, trazodone has been frequently prescribed in low doses as a hypnotic to help induce sleep. However, there are few studies that address its safety and efficacy as a drug for treating insomnia in non-depressed patients. Several studies have warned against trazodone's use in elderly patients, due to its risk for side effects (daytime sleepiness, dizziness, priapism) and drug interactions. In fact, all hypnotics can have serious side effects in the elderly, and all must be used with caution.

Chloral Hydrate. Chloral hydrate has been in use since 1832. It has significant adverse effects, however, and most experts believe it no longer has a role in the treatment of insomnia. In any case, it does not appear to be effective in the elderly. Chloral hydrate poses a risk for addiction, and it can be fatal in overdose. It also has cancer-causing properties. Side effects include irritation of the skin, mucous membranes, and stomach. People with stomach, heart, kidney, or liver disorders should not take this drug at all. If a child is given it (usually for minor surgery), that child should never be given chloral hydrate again in their lifetime.

Barbiturates. Barbiturates (Seconal, Nembutal) were the standard sleeping medications before the introduction of benzodiazepines. Overdose is dangerous and frequent; addiction and abuse are common. These drugs should rarely or never be prescribed for insomnia.

Indiplon. The FDA is reviewing indiplon, a new non-benzodiazepine hypnotic.

According to results from a national survey published in 2006 in the Archives of Internal Medicine, more than 1.6 million Americans use complementary and alternative therapies to treat insomnia. Many people choose herbal and dietary supplement remedies. Some, such as chamomile tea or lemon balm, are generally harmless for most people. Others have more serious side effects and interactions. [See Box.] According to a 2007 study, valerian and melatonin are among the most popular alternative remedies for insomnia.

Although about half of people who use herbal medicine report that these products help their sleep, experts are not sure whether these remedies really work or whether a placebo effect is the main reason for the improvement. The American Academy of Sleep Medicine (AASM) states that there is only limited scientific evidence to show that herbal and dietary supplements are effective sleep aids. The AASM recommends that these products should be taken only if approved by a doctor. Be sure to talk to your doctor if you are considering taking any herbal or dietary supplement. Some of these products can interact with prescription medications.

Melatonin is the most studied natural remedy for insomnia. A 2005 analysis of 17 melatonin studies found that melatonin significantly reduced the time to fall asleep (sleep onset) and the time spent asleep (sleep duration). However, there are no consistent standards on melatonin doses. Some research suggests that 0.3 mg may be the most effective dosage in many people with insomnia. However, higher doses may keep some people awake.

Although melatonin may not have many benefits for most people with chronic insomnia, studies suggest that it may help the following individuals:

Elderly people. It may help certain older people with insomnia, such as those with evidence of low melatonin levels and those dependent on prescription sleeping medications. It is not clear, however, how significant the benefits are.
People without sight. A 2000 study reported that melatonin can help people without sight retrain their circadian cycle so that they can sleep at regular hours. The best dosages and timing, however, need to be clarified.
Travelers suffering jet lag. Some studies have reported that melatonin may help prevent jet lag in some travelers.
Those in withdrawal from prescription sleep medication. Melatonin may help people who are dependent on sleeping medications withdraw from these drugs and maintain good quality sleep.
People with delayed sleep syndrome. It might be somewhat helpful for people who fall asleep very late at night or in early morning hours but then sleep normally.
Children. Melatonin may help some children with chronic insomnia. In one small study, or example, melatonin was specifically helpful for children with Asperger syndrome, who are at risk for sleep disturbances. More research is warranted, however. At this time, no one should give their child melatonin without a doctor's recommendation.

Melatonin is a powerful hormone that can have major effects on all parts of the body. Doses of melatonin over 0.3 mg can disrupt the circadian system in the brain. Long-term consequences are unknown. High doses have been associated with the following adverse events:

Mental impairment
Severe headaches
Nightmares

Interactions with other drugs are not completely known. Melatonin is classified as a dietary supplement and not as a drug, so its quality is not regulated in the U.S.

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Patients should always check with their doctors before using any herbal remedies or dietary supplements.

The following are special concerns for people taking natural remedies for insomnia:

Chamomile. Many people drink chamomile tea for its sedative properties. Although it is generally safe, it may cause allergic reactions in people who have plant or pollen allergies.

Valerian root. Valerian is an herb that has sedative qualities and has been helpful in people with insomnia. One study reported that it was also useful for helping patients withdraw from benzodiazepines -- the standard prescription sleeping pills. In another study, 83% of patients rated the effects of valerian on sleep as being very good. In the same study, valerian was as effective as oxazepam, a standard prescription sleeping medication. Valerian's side effects may include vivid dreams. High doses of valerian can cause blurred vision, excitability, and changes in heart rhythm. Valerian's effects can be dangerously increased if it is used with standard sedatives.

Chinese Herbal Remedies. Studies suggest that up to 30% of herbal patent remedies imported from China are laced with potent pharmaceuticals such as phenacetin and steroids. They may also contain toxic metals. The herbal remedy Sleeping Buddha was recalled in 1998 because it contained a benzodiazepine, the major ingredient in many prescription sleeping pills, and also appeared to increase the risk for birth defects in pregnant women. Reports of a few cases of acute hepatitis have occurred from Jin Bu Huan, a Chinese herbal remedy sold as treatment for pain and insomnia.

Kava. Kava has been used to relieve anxiety and improve sleep. It is not considered safe. There have been reports of liver failure and death from this herb, with highest risk in those with liver disease. Other side effects include itchy, scaly skin, muscle weakness, and problems with coordination. It also interacts dangerously with certain medications, including alprazolam, an anti-anxiety drug. Kava also increases the strength of certain other drugs, including other sleep medications, alcohol, and antidepressants.

Tryptophan and 5-L-5-hydroxytryptophan (HTP). Tryptophan is an amino acid used in the formation of the neurotransmitter serotonin, which is known to promote well-being and has been associated with healthy sleep. L-tryptophan was marked for insomnia and other disorders but was withdrawn from the market after contaminated batches caused a rare and even fatal disorder called eosinophilia myalgia syndrome. 5-HTP, a byproduct of tryptophan, is still available as a supplement. There have been reports that some brands contain a substance called Peak X, which may be harmful. There is little evidence that 5-HTP relieves insomnia.

Resources

www.aasmnet.org -- American Academy of Sleep Medicine
www.nhlbi.nih.gov/about/ncsdr -- National Center for Sleep Disorders Research
www.sleepfoundation.org -- National Sleep Foundation
www.sleepeducation.com -- Sleep Education from the American Academy of Sleep Medicine
www.wfsrs.org -- World Federation of Sleep Research Societies
www.clinicaltrials.gov -- Find clinical trials

References

Bliwise DL, Ansari FP. Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. Sleep. 2007 July 1;30(7):881-884.

Liu X, Buysse DJ, Gentzler AL, Kiss E, Mayer L, Kapornai K, et al. Insomnia and hypersomnia associated with depressive phenomenology and comorbidity in childhood depression. Sleep. 2007 Jan 1;30(1):83-90.

Mindell JA, Emslie G, Blumer J, Genel M, Glaze D, Ivanenko A, et al. Pharmacologic management of insomnia in children and adolescents: consensus statement. Pediatrics. 2006 Jun;117(6):e1223-32.

Mindell JA, Kuhn B, Lewin DS, Meltzer LJ, Sadeh A; American Academy of Sleep Medicine. Behavioral treatment of bedtime problems and night wakings in infants and young children. Sleep. 2006 Oct 1;29(10):1263-76.

Morin CM, Bootzin RR, Buysse DJ, Edinger JD, Espie CA, Lichstein KL. Psychological and behavioral treatment of insomnia: update of the recent evidence (1998-2004). Sleep. 2006 Nov 1;29(11):1398-414.

Neckelmann D, Mykletun A, Dahl AA. Chronic insomnia as a risk factor for developing anxiety and depression. Sleep. 2007 July 1;30(7):873-880.

Pearson NJ, Johnson LL, Nahin RL. Insomnia, trouble sleeping, and complementary and alternative medicine: Analysis of the 2002 National Health Interview Survey data. Arch Intern Med. 2006 Sep 18;166(16):1775-82.

Review Date:
7/18/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Diabetes - type 2

FitSugar — Wed, 08 Oct 2008 17:34:58 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Symptoms
Screening Tests
Treatment
Lifestyle Changes
Medications
Long-Term Complications
Emergency Complications
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approvals

Sitagliptin (Januvia), the first in a new class of diabetes drugs called DPP-4 inhibitors, was approved in 2006.
Janumet, a 2-in-1 pill that contains both sitagliptin and metformin, was approved in 2007.
These drugs are taken by mouth and may be more convenient for patients than exenatide (Byetta), a similar drug. DPP-4 inhibitors do not cause weight gain and may pose a lower risk for hypoglycemia than some other diabetes drugs.

Drug Safety Alert

Rosiglitazone (Avandia) may significantly increase the risk for heart attack, indicates a review published in the Journal of the American Medical Association. In 2007, a panel of experts from the Food and Drug Administration (FDA) agreed the drug increases the risk of heart attacks -- but concluded it should remain on the market. The panel did, however, recommend the FDA require rosiglitazone's maker to add warnings to the drug's label. Rosiglitazone and a similar drug, pioglitazone (Actos), are known to significantly increase the risks for heart failure. There is also evidence that these drugs increase the risk for bone fracture.

Anemia Drugs Warning

Patients with anemia associated with end-stage kidney disease, especially those on dialysis, should be aware of new warnings concerning dosing target levels of erythpoiesis-stimulating drugs. In 2007, the FDA warned that darbepoetin alfa (Aranesp) and epoetin alfa (Epogen and Procrit) can increase the risk for blood clots, stroke, and heart attacks when excessive doses are given. The FDA has defined target hemoglobin levels and recommends that patients who receive these drugs have frequent blood tests. Patients should also report to their doctors any unusual symptoms.

Genetics Research Breakthroughs

Scientists have now identified 10 genes that are associated with increased risk for type 2 diabetes. Six of these genes were discovered in 2006 and 2007.

Diabetes and Pre-Diabetes

About 20 million Americans have type 2 diabetes, and an additional 54 million have pre-diabetes. According to a 2007 study by the U.S. Centers for Disease Control, the prevalence of type 2 diabetes has been increasing by 5% each year since 1990. Rising rates of obesity may be one factor.
For people with pre-diabetes, lifestyle changes, such as losing weight, appear to work as well as drug treatment in delaying the progression to diabetes, according to a 2007 British Medical Journal study.

Introduction

The two major forms of diabetes are type 1 (previously called insulin-dependent diabetes mellitus, IDDM, or juvenile-onset diabetes) and type 2 (previously called noninsulin-dependent diabetes mellitus, NIDDM, or maturity-onset diabetes).

Both type 1 and type 2 diabetes share one central feature: elevated blood sugar (glucose) levels due to insufficiencies of insulin, a hormone produced by the pancreas. Insulin is a key regulator of the body's metabolism. It works in the following way:

During and immediately after a meal the process of digestion breaks down carbohydrates into sugar molecules (including glucose) and proteins into amino acids.
Right after the meal, glucose and amino acids are absorbed directly into the bloodstream, and blood glucose levels rise sharply.
The rise in blood glucose levels signals important cells in the pancreas, called beta cells, to secrete insulin, which pours into the bloodstream. Within 10 minutes after a meal, insulin rises to its peak level.
Insulin enables glucose and amino acids to enter cells in the body, particularly muscle and liver cells. Here, insulin and other hormones direct whether these nutrients will be burned for energy or stored for future use. (The brain and nervous system are not dependent on insulin; they regulate their glucose needs through other mechanisms.)
When insulin levels are high, the liver stops producing glucose and stores it in other forms until the body needs it again.
As blood glucose levels reach their peak, the pancreas reduces the production of insulin.
About 2 - 4 hours after a meal, both blood glucose and insulin are at low levels, with insulin being slightly higher. The blood glucose levels are then referred to as fasting blood glucose concentrations.

The pancreas is located behind the liver and is where the hormone insulin is produced. Insulin is used by the body to store and utilize glucose.

Type 2 diabetes is the most common form of diabetes, accounting for 90 - 95% of cases. The disease mechanisms in type 2 diabetes are not wholly known, but some experts suggest that it may involve the following three stages in most patients:

The first stage in type 2 diabetes is the condition called insulin resistance. Although insulin can attach normally to receptors on liver and muscle cells, certain mechanisms prevent insulin from moving glucose (blood sugar) into these cells where it can be used. Most patients with type 2 diabetes produce variable, even normal or high, amounts of insulin. In the beginning, this amount is usually sufficient to overcome such resistance.
Over time, the pancreas becomes unable to produce enough insulin to overcome resistance. In type 2 diabetes, the initial effect of this stage is usually an abnormal rise in blood sugar right after a meal (called postprandial hyperglycemia). This effect is now believed to be particularly damaging to the body.
Eventually, the cycle of elevated glucose further impairs and possibly destroys beta cells, thereby stopping insulin production completely and causing full-blown diabetes. This is made evident by fasting hyperglycemia, in which elevated glucose levels are present most of the time.

In type 1 diabetes, the disease process is more severe and onset is usually in childhood:

Beta cells in the pancreas that produce insulin are gradually destroyed. Eventually insulin deficiency is absolute.
Without insulin to move glucose into cells, blood glucose levels become excessively high, a condition known as hyperglycemia.
Because the body cannot utilize the sugar, it spills over into the urine and is lost.
Weakness, weight loss, and excessive hunger and thirst are among the consequences of this "starvation in the midst of plenty."
Patients become dependent on administered insulin for survival. [See In-Depth Report #9: Diabetes - type 1.]

Click the icon to see an image of the pancreas.

Conditions that damage or destroy the pancreas, such as pancreatitis, pancreatic surgery, or certain industrial chemicals can cause diabetes. Polycystic ovaries are highly associated with diabetes. Certain drugs can also cause temporary diabetes, including corticosteroids, beta-blockers, and phenytoin. Rare genetic disorders (Klinefelter's syndrome, Huntington's chorea, Wolfram's syndrome, leprechaunism, Rabson-Mendenhall syndrome, lipoatrophic diabetes) and hormonal disorders (acromegaly, Cushing syndrome, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma) are associated with or increase the risk for diabetes.

Causes

Type 2 diabetes is caused by a complicated interplay of genes, environment, insulin abnormalities, increased glucose production in the liver, increased fat breakdown, and possibly defective hormonal secretions in the intestine. The recent dramatic increase indicates that lifestyle factors (obesity and sedentary lifestyle) may be particularly important in triggering the genetic elements that cause this type of diabetes.

The characteristic features of most patients with type 2 diabetes are:

Insulin resistance in muscle cells
Normal or even excessive levels of insulin (to compensate for this resistance), eventually followed by a drop in insulin production

In addition, researchers are trying to determine the factors that might promote insulin resistance:

Both obesity and insulin resistance at different phases are marked by elevated levels of free fatty acids and the hormones resistin and leptin. It is not known yet if elevated levels are simply a product of obesity or play some causal role in diabetes.
Insulin resistance is associated with a chronic low inflammatory response, which involves a number of immune factors, such as TGH-beta 1 and C-reactive protein. Such factors can cause damage over time and may be responsible for the association between insulin resistance and heart disease.

Type 2 diabetes has a genetic component. In 2006 and 2007, major breakthroughs in genetic research identified six new genes associated with type 2 diabetes. Ten genes have now been positively confirmed as increasing the risk for type 2 diabetes: TCF7L2, SLC30A8, HHEX, PPARG, KCNJ11, IGF2B2, CDKAL1, CDKN2A, CDKN2B, and FTO.

Most of these genes play a role in regulating insulin action, including the processes that occur in the pancreas’ insulin-producing beta cells. The FTO gene increases the risk for obesity, which itself is a risk factor for type 2 diabetes. These genes appear to cluster around three genetic regions that include a number of chromosomes. Scientists hope that future research will help uncover how genes influence the progression from pre-diabetes to diabetes, and how lifestyle and medical intervention may help delay or prevent this process.

Risk Factors

Nearly 21 million Americans have diabetes; up to 95% of these cases are type 2. In addition, 26% of Americans age 20 and older (and 40% of Americans age 65 and older) have impaired fasting glucose, a pre-diabetes condition that increases the risk for diabetes. According to the American Diabetes Association, 54 million people have pre-diabetes, bringing a total of 75 million Americans who either have diabetes or are at risk of developing it.

Historically, type 2 diabetes usually developed after the age of 40, but it is now also increasing in children. The prevalence of diabetes in the U.S. has increased by 5% each year since 1990, and experts believe that obesity is the major factor behind this dramatic growth rate. Given the current epidemic of obesity, experts estimate that over a third of all people born in 2002 will eventually develop diabetes. Furthermore, the dramatic increase in diabetes is occurring worldwide as American lifestyles become global. Evidence strongly suggests that healthy lifestyles can prevent most cases of type 2 diabetes. People with pre-diabetes can substantially lower their risk by losing weight through diet and exercise.

Healthy adults age 45 and older should get tested for diabetes. Patients who are younger than age 45 and who are overweight or have other risk factors should also ask their doctors about testing. According to the National Institutes of Health, the following are major risk factors for diabetes and pre-diabetes:

Age 45 or older
Family history of diabetes
Overweight
Inactive lifestyle (exercise less than 3 times a week)
African-American, Hispanic/Latin American, American Indian and Alaska Native, Asian-American, or Pacific Islander ethnicity
High blood pressure (140/90 mm/Hg or higher)
HDL (“good”) cholesterol less than 35 mg/dL or triglyceride level 250 mg/dL or higher
Have had diabetes during pregnancy (gestational diabetes) or have given birth to a baby that weighed more than 9 pounds
Polycystic ovary syndrome (metabolic disorder that affects female reproductive system
Acanthosis nigricans (dark, thickened skin around neck or armpits)
History of disease of blood vessels to the heart, brain, or legs
Diabetes test history of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT)

Obesity is the number one risk factor for type 2 diabetes. It is estimated that 80 - 95% of the current dramatic increases in type 2 diabetes are due to obesity. Excess body fat appears to play a strong role in insulin resistance, but the way the fat is distributed is also significant. Weight concentrated around the abdomen and in the upper part of the body (apple-shaped) is associated with insulin resistance and diabetes, heart disease, high blood pressure, stroke, and unhealthy cholesterol levels. Waist circumferences greater than 35 inches in women and 40 inches in men have been specifically associated with a greater risk for heart disease and diabetes. (People with a "pear-shape" -- fat that settles around the hips and flank -- appear to have a lower risk for with these conditions.) However, obesity does not explain all cases of type 2 diabetes. It is also common among people in countries where weights tend to be low, such as Asia or India.

Metabolic Syndrome. A set of conditions referred to as metabolic syndrome (also called Syndrome X) is a pre-diabetic condition that is significantly associated with heart disease and higher mortality rates from all causes. The syndrome consists of obesity marked by abdominal fat, unhealthy cholesterol levels, high blood pressure, and insulin resistance. A 2002 study estimated that nearly a quarter of the U.S. population now has this condition. Even worse, according to a 2003 study, nearly a million American teenagers have this syndrome.

Between 25 - 33% of patients with type 2 diabetes have family members with diabetes. Having a first-degree relative with the disease poses a 40% risk of developing diabetes. One study reported that people with diabetic family histories have a higher risk for developing the disease at an earlier stage and with more severe features. Because families share many lifestyle features (eating and exercise habits) it is difficult to determine when genetics or environment play the major role. When clusters of type 1 and type 2 diabetes appear within families, genetic factors should be strongly suspected.

The risk for type 2 diabetes varies among population groups. Diabetes also seems to pose higher or lower risks for specific complications among ethnic groups. Genetic and socioeconomic factors, or both, seem to be involved in some ethnic differences, but in most cases the observed increase in ethnic groups in Americans is due to changes in traditional lifestyles.

African-Americans. African-American men have twice the risk of developing type 2 diabetes as Caucasian men. African-Americans with diabetes are also at higher risk for amputations than Caucasians. This is most likely due to a higher incidence of high blood pressure and smoking as well as poorer health care in African-Americans. Genetic factors may also play a role. For example, there is some evidence that African-Americans process insulin in the liver differently from Caucasians, which may make them more susceptible to diabetes when other risk factors are present.
Native Americans. The Pima tribe in Arizona has an incidence of type 2 diabetes that is 19 times higher than that of the white population. The risk for diabetic complications among young Pima adults is also very high. Other Native American tribes in North America are also at high risk for type 2 diabetes. The association between diet and diabetes among this population remains critical, however, in assessing the reason for their higher risk. For example, Pimas who live in Mexico exercise more and eat less fat (but consume more calories) than Pima tribes in Arizona. Mexican Pimas have a prevalence of diabetes of only 6%, while half of their Arizona Pima neighbors have diabetes.
Hispanic Americans. The rate of type 2 diabetes is also very high among Mexican-Americans, approximately double that for Caucasians. This group may also be at higher risk for heart problems than other ethnic groups with diabetes.
Asian-Americans. Overweight Asian-Americans and Pacific Islanders are at increased risk for developing type 2 diabetes. The risk for some Asian ethnic groups (such as Native Hawaiians and Filipinos) is twice that of Caucasians.

Smoking increases the risk for diabetes. According to a 2006 study, smokers are more than twice as likely to develop diabetes as people who have never smoked. Another 2006 study found that exposure to second-hand cigarette smoke also increases the risk for diabetes in non-smokers.

Low birth weight is now a recognized risk factor for type 2 diabetes and heart disease in adulthood. The reasons are unclear, although studies suggest it may represent a genetic factor. Studies have observed that babies of fathers with type 2 diabetes and of women who later developed type 2 diabetes tend to weigh less than babies of parents without diabetes. Such studies suggest that some parents may have some specific gene that affects insulin factors, putting both themselves and their children at risk for future diabetes. Theoretically, such a gene might also affect insulin factors in the developing fetus, causing low birth weight. (Of note, mothers of very high-weight babies are also at risk for diabetes -- although in these cases it is most often associated with gestational diabetes.)

Obesity-Related Type 2 Diabetes in Children. Until recent years, diabetes in children was almost always type 1 (an autoimmune disease). Between 1982 - 1994, however, the incidence of type 2 diabetes in children increased 10-fold. By 1996, a study reported that a third of all new diabetes cases in children were type 2. This increase parallels the rising epidemic in childhood obesity that has occurred both in the U.S. and worldwide, notably Europe and Japan. In some areas of Japan, type 2 diabetes has now become the dominant form of diabetes in children and adolescents. Obesity in children is also related to abnormalities in cholesterol, blood pressure, and insulin levels in adults. Administering glucose tolerance tests in overweight children may be helpful in identifying those at high risk for diabetes.

Maturity-Onset Diabetes in Caucasian Youth. Maturity-onset diabetes in youth (MODY) is a rare genetic form of type 2 diabetes that develops only in Caucasian teenagers. It accounts for 2 - 5% of type 2 cases. (This form of type 2 diabetes is not associated with obesity.)

An estimated 5% of pregnant women develop a form of type 2 diabetes, usually temporary, in their third trimester called gestational diabetes.

Gestational diabetes is diabetes that first appears during pregnancy. It usually develops during the third trimester of pregnancy. After delivery, blood sugar (glucose) levels generally return to normal, although 25% of these women develop type 2 diabetes within 15 years.

Who Gets Gestational Diabetes? Estimates for the prevalence of gestational diabetes are generally about 4%. Some studies, however, have suggested significantly higher rates. In one German study, 13% of pregnant women were diagnosed with this form of diabetes, including many who did not have any risk factors.

A pregnant woman's risk factors include:

Family history of diabetes
African-American, Hispanic, Asian, or Pacific Islander ethnicity
Overweight
Older than 25 years
Gestational diabetes with past pregnancy
Having given birth to a child weighing over 9 pounds
Diagnosis of pre-diabetes

Who Should Be Tested for Gestational Diabetes? A number of expert groups recommend that all pregnant women be tested for gestational diabetes between their 24th - 28th week. Pregnant women at high risk for diabetes should be tested earlier. The only women who do not need to be tested are those at very low risk. Generally they have the following characteristics:

Under 25 years old
Normal weight
No first-degree relatives with diabetes
Not belonging to high-risk ethnic groups

Effect of Diabetes on the Fetus. Because glucose crosses the placenta, a woman with diabetes can pass high levels of blood glucose to the fetus. In response, the fetus secretes high level of insulin. Studies indicate that such conditions may affect the developing fetus as soon as it is conceived, placing the unborn child at risk for:

Excessive fetal weight gain, which can lead to complications during delivery
Birth defects
Breathing problems and delayed lung development
Low blood sugar
Higher future risk for obesity and diabetes

Effect of Diabetes on the Pregnant Woman. In addition to endangering the fetus, diabetes also presents risks to the pregnant woman.

The most serious potential complications from gestational diabetes are high blood pressure during pregnancy, a condition called preeclampsia that is potentially dangerous. Because gestational diabetes increases the size of the fetus, it is also increases the likelihood that a woman will require a Cesarean delivery. Gestational diabetes also increases the risk that a woman will later develop type 2 diabetes.

How Is Gestational Diabetes Managed? Some suggestions for preventing complications include:

In most cases, increases in glucose levels can be managed with diet and exercise. Aerobic exercise before and during pregnancy may lower glucose levels and help protect women at risk or those who have gestational diabetes. (Any pregnant woman should check with her doctor before embarking on a vigorous exercise regimen.)
If a woman with gestational diabetes cannot control her glucose with lifestyle measures, she is usually given insulin.

The placenta provides the fetus with oxygen and nutrients and takes away waste, such as carbon dioxide, via the umbilical cord.

Polycystic Ovary Syndrome. Polycystic ovary syndrome (PCOS) is a condition that affects about 6% of women and results in the ovarian production of high amounts of androgens (male hormones), particularly testosterone. It appears to be an important cause of many menstrual disorders. Women with PCOS are at higher risk for insulin resistance, and about half of PCOS patients also have diabetes.

Click the icon to see an image of polycystic ovary syndrome.

Schizophrenia. While no definitive association has been established, research has suggested an increased background risk of diabetes among people with schizophrenia. In addition, many of the new generation of antipsychotic medications may elevate blood glucose levels. Patients taking antipsychotic medications (such as clozapine, olanzapine, risperidone, aripiprazole, quetiapine fumarate, ziprasidone) should receive a baseline blood glucose level test and be monitored for any increases during therapy.

Depression. According to a 2007 study, adults who have severe clinical depression may have a greater risk of developing type 2 diabetes than those who have never experienced depressive symptoms.

Hepatitis C. Patients with hepatitis C have a higher incidence of type 2 diabetes. The reasons for this are unclear.

Symptoms

Type 2 diabetes usually begins gradually and progresses slowly. Symptoms in adults include:

Excessive thirst
Increased urination
Fatigue
Blurred vision
Weight loss
In women, vaginal yeast infections or fungal infections under the breasts or in the groin
Severe gum problems
Itching
Erectile dysfunction in men
Unusual sensations, such as tingling or burning, in the extremities

Symptoms in children are often different:

Most children are obese or overweight
Increased urination is mild or even absent
Many children develop a skin problem called acanthosis, which is characterized by velvety, dark colored patches of skin

Screening Tests

There are no clear-cut guidelines for when to screen for diabetes. Some experts recommend that everyone over age 45 be tested regularly for diabetes, although others do not feel this necessary in people without symptoms or risk factors. In fact, early screening may identify some people with impaired glucose levels that would eventually normalize. Such people might be treated unnecessarily with medications that pose a risk for high blood sugar (hypoglycemia).

Still, given the risk for serious complications with diabetes and the potential value of early treatments, most experts recommend that all adults over 45 be screened and that younger adults be screened if they have one or more of the following conditions:

A weight that is 20% more than ideal body weight
Risk factors for heart disease (high blood pressure, unhealthy cholesterol levels -- especially for patients with low HDL cholesterol and high triglyceride levels
A close relative with diabetes
A high-risk ethnic group background
In women, having delivered a baby weighing over 9 pounds or having a history of gestational diabetes

Some experts recommend that children over age 10 should be tested for type 2 diabetes (even if they have no symptoms), if they are overweight and have at least two of the above mentioned risk factors.

Fasting Plasma Glucose. The fasting plasma glucose (FPG) test is the standard test for diabetes. It is a simple blood test taken after 8 hours of fasting. Results indicate:

FPG levels are considered normal up to 100 mg/dL (or 5.5 mmol/L).
Levels between 100 - 125 mg/dL (5.5 - 7.0 mmol/L) are referred to as impaired fasting glucose or pre-diabetes. These levels are considered to be risk factors for type 2 diabetes and its complications.
Diabetes is diagnosed when FPG levels are 126 mg/dL (7.0 mmol/L) or higher.

The FPG test is not always reliable, so a repeat test is recommended if the initial test suggests the presence of diabetes, or if the test is normal in people who have symptoms or risk factors for diabetes. For example, people who take the test in the afternoon and show normal results may actually have abnormal levels that would be revealed if they were tested in the morning.

A 2005 study suggested that even people with FPG levels in the high end of the normal range (high 90s) may be at increased risk for developing type 2 diabetes. Obesity further increases this risk. Patients with FPG levels in the upper 90s should strive to exercise and lose weight to help lower their FPG levels.

Glucose Tolerance Test. The oral glucose tolerance test (OGTT) is more complex than the FPG and may overdiagnose diabetes in people who do not have it. Some experts recommend it as a follow-up after FPG, if the latter test results are normal but the patient has symptoms or risk factors of diabetes. The test uses the following procedures:

It first uses an FPG test.
A blood test is then taken 2 hours later after drinking a special glucose solution.

The following results suggest different conditions:

OGTT levels are considered normal up to 140 mg/dL.
Levels between 140 - 199 mg/dL are referred to as impaired glucose tolerance or pre-diabetes.
Diabetes is diagnosed when OGTT levels are 200 mg/dL or higher.

Both the FPG and OGTT require that the patient not eat for at least 8 hours prior to the test.

Test for Glycated Hemoglobin. Tests for blood levels of glycated hemoglobin, also known as hemoglobin A1c (HbA1c), are not currently used for an initial diagnosis, but they are useful for determining the severity of diabetes. Some experts think this test can help predict complications in people who have FPG levels between 110 - 139, which are above normal but do not indicate full-blown diabetes.

The basis for its use as a diagnostic measurement in diabetes is as follows:

Hemoglobin is a protein molecule found in red blood cells. When glucose binds to it, the hemoglobin becomes modified, a process called glycosylation.
Glycosylation affects a number of proteins, and elevated levels of glycolated hemoglobin are strongly associated with complications of diabetes.
A glycated hemoglobin level of 1% above normal range identifies diabetes in 98% of patients. Normal HbA1c levels do not necessarily rule out diabetes, but if diabetes is present and levels are normal, the risk for complications is low.

The test is not affected by food intake so it can be taken at any time. A home test has been developed that might make it easier to measure HbA1c. In general, measurements suggest the following:

Normal HbA1c levels should be below 7%.
Levels of 11 - 12% glycolated hemoglobin indicate poor control of carbohydrates. High levels are also markers for kidney trouble.

Screening for Heart Disease. All patients with diabetes should be tested for hypertension and unhealthy cholesterol and lipid levels and given an electrocardiogram. For cholesterol, people with diabetes should aim for LDL levels below 100 mg/dL, HDL levels over 50 mg/dL, and triglyceride levels below 150 mg/dL. Blood pressure goals should be 130/80 mmHg or lower. Other tests may be needed in patients with signs of heart disease.

The electrocardiogram (ECG, EKG) is used extensively in the diagnosis of heart disease, from congenital heart disease in infants to myocardial infarction and myocarditis in adults. Several different types of electrocardiogram exist.

Screening for Kidney Damage. The earliest manifestation of kidney damage is microalbuminuria, in which tiny amounts (30 - 300 mg per day) of protein called albumin are found in the urine. About 20% of type 2 patients show evidence of microalbuminuria upon diagnosis of diabetes. (However, not all people with type 2 diabetes eventually develop kidney disease.) Microalbuminuria typically shows up in patients with type 2 diabetes who have high blood pressure.

The American Diabetes Association recommends that people with diabetes receive an annual microalbuminuria urine test. Patients should also have their blood creatinine tested at least once a year. Creatinine is a waste product that is removed from the blood by the kidneys. High levels of creatinine may indicate kidney damage. A doctor uses the results from a creatinine blood test to calculate the glomerular filtration rate (GFR). The GFR is an indicator of kidney function; it estimates how well the kidneys are cleansing the blood.

Screening for Retinopathy. The American Diabetes Association recommends that patients with type 2 diabetes get an initial comprehensive eye exam by an ophthalmologist or optometrist shortly after they are diagnosed with diabetes, and once a year thereafter. (People at low risk may need follow-up exams only every 2 - 3 years.) The eye exam should include dilation to check for signs of retinal disease (retinopathy).

Screening for Neuropathy. All patients should be screened for nerve damage (neuropathy), including a comprehensive foot exam. Patients who have loss of sensation in their feet should be sure to have a foot exam every 3 - 6 months to check for ulcers or infections.

Screening for Thyroid Abnormalities. Thyroid function tests should be administered.

Treatment

Pre-diabetes precedes the onset of type 2 diabetes. People who have pre-diabetes have fasting blood glucose levels that are 100 - 125 mg/dL -- higher than normal, but not yet high enough to be classified as diabetes. (Pre-diabetes used to be referred to as “impaired glucose tolerance.”) Pre-diabetes greatly increases the risk for diabetes.

Treatment of pre-diabetes is very important. Research shows that lifestyle and medical interventions can help prevent, or at least delay, the progression to diabetes. While insulin-regulating drugs such as metformin (Glucophage) and acarbose (Precose) are sometimes prescribed, evidence indicates that lifestyle changes can be at least as effective as drug therapy. The most important lifestyle treatment for people with pre-diabetes is to lose weight through diet and regular exercise. Even a modest weight loss of 10 - 15 pounds can significantly reduce the risk of progressing to diabetes.

Because people with pre-diabetes have a higher risk for heart disease and stroke, diet and exercise are also very important for heart health, as is quitting smoking. It is also important to have your doctor check your cholesterol and blood pressure levels on a regular basis. Your doctor should also check your fasting blood glucose levels every 1 - 2 years.

The major treatment goals for people with type 2 diabetes are:

Treat all conditions that place the patients at risk for heart disease and stroke, which are the major killers of people with type 2 diabetes.
Control blood glucose levels. The goal is to achieve fasting blood glucose levels of less than 110 mg/dL and glycolated hemoglobin (HbA1c) levels of less than 7%. The objective is to reduce complications in small blood vessels and the nerve damage associated with diabetes.

An intensive multi-pronged approach is critical for reducing complications and improving survival rates in patients with diabetes. Intensive therapy includes:

Healthy lifestyle changes: Regular exercise; heart-healthy diet; quitting smoking.
Controlling blood sugar levels. Monitor blood sugar and hemoglobin HbA1C levels. Oral anti-hyperglycemic drugs such as metformin are first-line drug treatments. Insulin may eventually be needed.
Heart-protective drugs. These medications include various drugs to control high blood pressure (ACE inhibitors, diuretics, others) and cholesterol (statins, fibrates). Controlling high blood pressure is a proven factor in reducing mortality rates. Aspirin may help prevent blood clots and heart attack.

Different goals may be required for specific individuals, including pregnant women, very old and very young people, and those with accompanying serious medical conditions. Treating children with type 2 diabetes depends on the severity of the condition at diagnosis. Metformin is approved for children. Formerly, only insulin was approved for treating children with diabetes.

Lifestyle Changes

A simple heart-healthy diet with weight control and exercise is important for people with pre-diabetes and may be sufficient for some people with type 2 diabetes. Some patients may be able to control their blood sugar with lifestyle measures and not need medication. Even for patients who do need to take drugs, lifestyle plays an essential role in controlling diabetes. Lifestyle changes can be difficult to initiate and sustain, however. Patients should surround themselves with a solid network of doctors, dietitians, family, and friends who understand both their condition and their needs.

Although there are many major dietary approaches for protecting health, experts generally agree on the following recommendations for heart protection:

Choose fiber-rich food (whole grains, legumes, nuts) as the main source of carbohydrates, along with a high intake of fresh fruits and vegetables. High fiber foods help improve blood glucose levels. Whole grain cereals, which are rich in both fiber and magnesium, may also help reduce the risk for diabetes.
Limit saturated fats (found mostly in animal products) to less than 7% of total daily calories and avoid trans fatty acids (found in hydrogenated fats and many commercial products and fast foods). Choose unsaturated fats (particularly omega-3 fatty acids found in vegetable and fish oils).
In selecting proteins, choose soy protein, poultry, and fish over meat. A 2006 study found that soy does not help improve cholesterol. However, experts still recommend it as a heart-healthy food choice.
Weight control, quitting smoking, and exercise are essential components of any diet program.

[See In-Depth Report #43: Heart-healthy diet.]

There is no such thing as a single diabetes diet. Patients should meet with a professional dietitian to plan an individualized diet within the general guidelines that takes into consideration their own health needs.

Healthy eating habits along with good control of blood glucose are the basic goals, and several good dietary methods are available to meet them. General dietary guidelines for diabetes recommend:

Carbohydrates should provide 45 - 65% of total daily calories. The type and amount of carbohydrate are both important. Best choices are vegetables, fruits, beans, and whole grains. These foods are also high in fiber. Patients with diabetes should monitor their carbohydrate intake either through carbohydrate counting or meal planning exchange lists.
Fats should provide 25 - 35% of daily calories. Monounsaturated (olive, peanut, canola oils; avocados; nuts) and omega-3 polyunsaturated (fish, flaxseed oil, walnuts) fats are the best types. Limit saturated fat (red meat, butter) to less than 7% of daily calories. Choose nonfat or low-fat dairy instead of whole milk products. Limit trans-fats (hydrogenated fat found in snack foods, fried foods, commercially baked goods) to less than 1% of total calories.
Protein should provide 12 - 20% of daily calories, although this may vary depending on a patient’s individual health requirements. Patients with kidney disease should limit protein intake to less than 10% of calories. Fish, soy, and poultry are better protein choices than red meat.

[For detailed information, including diabetic exchange lists and carbohydrate counting, see In-Depth Report #42: Diabetes diet.]

Being overweight is the number one risk factor for type 2 diabetes. Even modest weight loss can help prevent type 2 diabetes from developing. It can also help control or even stop progression of type 2 diabetes in people with the condition and reduce risk factors for heart disease. Patients should aim to lose weight if their body mass index (BMI) is 25 - 29 (overweight) or higher (obese).

The American Diabetes Association recommends that patients aim for a small but consistent weight loss of ½ - 1 pound per week. Most patients should follow a diet that supplies at least 1,000 - 1,200 kcal/day for women and 1,200 - 1,600 kcal/day for men.

Unfortunately, not only is weight loss difficult to sustain, but many of the oral medications used in type 2 diabetes cause weight gain as a side effect. For obese patients who cannot control weight using dietary measures alone, weight-loss drugs, such as orlistat (Xenical) or sibutramine (Meridia), may be helpful. Orlistat may have specific benefits for people with diabetes. It may not only help achieve weight but also improve glucose, cholesterol, and lipid levels. In 2007, the FDA approved a non-prescription form of orlistat (alli). [See In-Depth Report #53: Obesity.]

Sedentary habits, especially TV watching, are associated with significantly higher risks for obesity and type 2 diabetes. Regular exercise, even of moderate intensity (such as brisk walking), improves insulin sensitivity and may play a significant role in preventing type 2 diabetes -- regardless of weight loss. An important study reported a 58% lower risk for type 2 diabetes in adults who performed moderate exercise for as little as 2.5 hours a week.

Aerobic Exercise. Aerobic exercise has significant and particular benefits for people with diabetes. Regular aerobic exercise, even of moderate intensity, improves insulin sensitivity. People with diabetes are at particular risk for heart disease, so the heart-protective effects of aerobic exercise are especially important. Moderate exercise protects the heart in people with type 2 diabetes, even if they have no risk factors for heart disease other than diabetes itself.

For improving glycemic control, the American Diabetes Association recommends at least 150 minutes per week of moderate-intensity physical activity (50 - 70% of maximum heart rate) or at least 90 minutes per week of vigorous aerobic exercise (more than 70% of maximum heart rate). Exercise at least 3 days a week, and do not go more than 2 consecutive days without physical activity.

Strength Training. Strength training, which increases muscle and reduces fat, is also helpful for people with diabetes who are able to do this type of exercise. The American Diabetes Association recommends performing resistance exercise three times a week. Build up to three sets of 8 - 10 repetitions using weight that you cannot lift more than 8 - 10 times without developing fatigue. Be sure that your strength training targets all of the major muscle groups.

Exercise Precautions. The following are precautions for all people with diabetes, both type 1 and type 2:

Because people with diabetes are at higher than average risk for heart disease, they should always check with their doctors before undertaking vigorous exercise. For fastest results, frequent high-intensity (not high-impact) exercises are best for people who are cleared by their doctors. For people who have been sedentary or have other medical problems, lower-intensity exercises are recommended.
Strenuous strength training or high-impact exercise is not recommended for people with uncontrolled diabetes. Such exercises can strain weakened blood vessels in the eyes of patients with retinopathy. High-impact exercise may also injure blood vessels in the feet.

Patients who are taking medications that lower blood glucose, particularly insulin, should take special precautions before embarking on a workout program:

Monitor glucose levels before, during, and after workouts (glucose levels swing dramatically during exercise).
Avoid exercise if glucose levels are above 300 mg/dL or under 100 mg/dL.
Inject insulin in sites away from the muscles used during exercise; this can help avoid hypoglycemia.
Drink plenty of fluids before and during exercise; avoid alcohol, which increases the risk of hypoglycemia.
Insulin-dependent athletes may need to decrease insulin doses or take in more carbohydrates prior to exercise, but may need to take an extra dose of insulin after exercise (stress hormones released during exercise may increase blood glucose levels).
Wear good, protective footwear to help avoid injuries and wounds to the feet.
Some blood pressure drugs can interfere with exercise capacity. Patients who use blood pressure medication should consult their doctors on how to balance medications and exercise. Patients with high blood pressure should also aim to breathe as normally as possible during exercise. Holding the breath can increase blood pressure.

[See In-Depth Report #29: Exercise.]

According to the American Diabetes Association, people with diabetes should aim for preprandial (before eating) plasma glucose levels of 90 - 130 mg/dL and postprandial (after eating) plasma glucose levels less than 180 mg/dL. Hemoglobin A1C levels should be less than 7%.

Measuring Blood Glucose. In patients being treated with insulin or insulin-producing or sensitizing drugs, it is important to monitor blood glucose levels carefully to avoid hypoglycemia. Different goals may be required for specific individuals, including pregnant women, very old and very young people, and those with accompanying serious medical conditions.

Blood glucose levels are generally more stable in type 2 diabetes than in type 1, so experts usually recommend measuring blood levels only once or twice a day. For patients who have become insulin-dependent, more intensive monitoring is necessary. Usually, a drop of blood obtained by pricking the finger is applied to a chemically treated strip. The glucose level is read on a standard meter or a small, portable digital display device. For patients who have trouble controlling hypoglycemia (low blood sugar) or fluctuating blood sugar levels, continuous glucose sensor monitors are also available. In 2007, the FDA approved the STS-7 System, which continuously measures glucose levels for up to 7 days through a sensor inserted beneath the skin of the abdomen. Continuous glucose sensor monitors do not replace fingerstick glucose meters and test strips, but are used in combination with them. [See In-Depth Report #9: Diabetes - type 1.]

Measuring Hemoglobin A1C. Hemoglobin A1c (also called HbA1c , HA1c, or A1C) is measured periodically every 2 - 3 months to determine the average blood-sugar level over the lifespan of the red blood cell. Normal A1C levels should be below 7%. Home tests are also available for measuring A1C.

To monitor the amount of glucose within the blood a person with diabetes should test their blood regularly. The procedure is quite simple and can often be done at home.

Some research suggests that not getting enough sleep may impair insulin use and increase the risk for obesity. More research is needed, but it is always wise to improve sleep habits.

Medications

The American Heart Association now recommends that patients should aim for the following test results for intensive control of glucose levels:

Fasting plasma glucose concentrations below 110 mg/dL.
Glycolated hemoglobin (HbA1c) levels of less than 7%. Controlling HbA1c is the most important factor for reducing the risk of complications in patients with diabetes. According to one 2000 study, a 1% reduction in people with elevated glycolated hemoglobin levels lowers the risk for complications by 21%.

Evidence clearly supports strict glycemic control for reducing complications in the nervous system and blood vessels that occur in both type 1 and type 2 diabetes. Research shows that tight glucose control can help prevent heart disease and complications.

Managing risk factors for heart disease and stroke, particularly strict control of blood pressure, may be more important for improving survival than strict control of blood glucose levels for some patients. Such goals also seem to be more attainable for many patients with type 2 diabetes.

Oral Anti-Hyperglycemic Drugs. Many oral anti-hyperglycemic drugs are available to help patients with type 2 diabetes control their blood sugar levels. Most of these drugs are aimed at using or increasing sensitivity to the patient's own natural stores of insulin. Metformin is the only drug to date that achieves lower mortality rates. Oral type 2 diabetes drugs include:

Biguanides (metformin). Metformin increases tissue sensitivity to available insulin. Metformin also has beneficial effects on cholesterol, blood pressure, and clotting factors. It does not cause weight gain or hypoglycemia. Diarrhea and digestive problems are the most common side effects. Metformin produces lower mortality rates than other drugs, including insulin, and should be considered as first-line therapy for most patients with type 2 diabetes.
Sulfonylureas (glyburide, glipizide, glimepiride, repaglinide). Stimulate insulin secretion but can cause hypoglycemia more than other drugs.
DPP-4 inhibitors (sitagliptin). Also called gliptins, DPP-4 inhibitors were first approved in 2006 and are the newest class of oral diabetes drugs. Like metformin, they do not cause weight gain and have low risks for hypoglycemia.
Meglitinides (repaglinide, nateglinide). Stimulate insulin secretion. These newer drugs are better than sulfonylureas in controlling glucose spikes after meals.
Thiazolidinediones (pioglitazone and rosiglitazone). Reduce insulin resistance. These drugs improve cholesterol levels and may reduce the risk for blood clots. However, they can cause swelling from fluid build-up, which can worsen heart failure or even precipitate it. They may also injure the liver.
Alpha-glucosidase inhibitors (acarbose and miglitol). Slow intestinal absorption of carbohydrates. Have only modest effects on diabetes and have gastrointestinal side effects. Can slightly raise HDL (“good”) cholesterol levels.
Combinations of these drugs, particularly with metformin, are often used to increase effectiveness.

A 2007 review in the Annals of Internal Medicine compared these various classes of medications. The review found that older drugs -- such as metformin and sulfonylureas -- are less expensive than and work as well as newer diabetes drugs. In particular, the review cited metformin as a safe and effective drug because it does not cause weight gain or too-low blood sugar. Metformin can also help lower LDL (“bad”) cholesterol.

Injectable Anti-Hyperglycemic Drugs. In 2005, the FDA approved two new injectable drugs to help patients improve blood sugar control:

Exenatide (Byetta). Exenatide is the first drug in a new class of drugs called incretin mimetics. It lowers blood glucose levels by increasing insulin secretion. Exenatide is used in combination with oral antihyperglycemics, such as metformin or a sulfonylurea drug.
Pramlintide (Symlin). Pramlintide is a first-in-class drug that is a synthetic form of the hormone amylin. The drug is meant for patients who take insulin but still have difficulty controlling their glucose levels.

Insulin Replacement. Insulin replacement may be required when natural insulin reserves are depleted. It is typically started in combination with an oral drug. Eventually, some patients may need to go on full insulin replacement. In addition to injectable forms of insulin, an inhaled insulin product (Exubera) is now available.

Metformin (Glucophage) is a biguanide, which works by reducing glucose production in the liver and by making tissues more sensitive to insulin. Many experts recommend it as a first choice for most patients with type 2 diabetes who are insulin resistant, particularly if they are overweight. Metformin achieves lower mortality rates from diabetes and all causes than other drugs. In one comparison study, it achieved the lowest mortality rates (8%) compared to insulin (28%), a sulfonylurea (16%), and a thiazolidinedione (14%). Combinations with insulin-secreting drugs, other insulin-sensitizing drugs, or insulin itself are particularly effective.

Metformin does not cause hypoglycemia or add weight, so it is particularly well-suited for obese patients with type 2 diabetes. (In some studies, in fact, patients lost weight.) Metformin also appears to have beneficial effects on cholesterol and lipid levels and may help protect the heart. Some research has suggested that it significantly reduces the risk for heart attack. It is also the first choice for children who need oral drugs and is proving to be very effective for women with polycystic ovary syndrome and insulin resistance.

Side Effects. Side effects include:

A metallic taste
Gastrointestinal problems, including nausea, and diarrhea
Interference with absorption of vitamin B12 and folic acid, (which are important for protection against heart disease)
Rare reports of lactic acidosis, a potentially life-threatening condition, particularly in people with risk factors for it. Major studies, however, found no greater risk with metformin than with any of the other drugs used for type 2 diabetes.

Certain people should not use this drug, including anyone with heart failure or kidney or liver disease. It is rarely suitable for adults over age 80.

Sulfonylureas are oral drugs that stimulate the pancreas to release insulin. They are also first-line oral drugs. For adequate control of blood glucose levels, the drugs should be taken only 20 - 30 minutes before a meal. A number of brands are available, including chlorpropamide (Diabinese), tolazamide (Tolinase), acetohexamide (Dymelor), glipizide (Glucotrol), tolbutamide (Orinase), glyburide (Micronase), glimepiride (Amaryl), and repaglinide (Prandin).

Most patients can take sulfonylureas for 7 - 10 years before they lose effectiveness. Combinations with small amounts of insulin or with other oral anti-hyperglycemic drugs (such as metformin or a thiazolidinedione) may extend their benefits. A combination of glyburide and metformin in one pill (Glucovance) is available. Glucovance may be particularly beneficial for patients with unhealthy cholesterol levels and poor control of their blood sugar levels. Some doctors recommend the combination as first-line treatment.

An encouraging 2000 study of patients with severe type 2 diabetes reporting that combinations of insulin with either chlorpropamide or glipizide achieved better glucose control over the long term than insulin alone.

Side Effects and Complications. In general, sulfonylureas should not be used by women who are pregnant or nursing or by individuals who are allergic to sulfa drugs. Side effects may include:

Weight gain (some sulfonylureas, such as glimepiride, may produce less weight gain than others)
Water retention
Although sulfonylureas pose a lower risk for hypoglycemia than insulin does, the hypoglycemia produced by sulfonylureas may be especially prolonged and dangerous. The newer sulfonylureas, such as glimipiride, have much less risk of hypoglycemia than older sulfonylureas.
Some sulfonylureas may pose a slight risk for cardiac events.

Sulfonylureas interact with many other drugs, and patients should be sure to inform their doctor of any medications they are taking, including alternative or over-the-counter drugs.

Meglitinides stimulate beta cells to produce insulin. They include repaglinide (Prandin), nateglinide (Starlix), and mitiglinide. These drugs are rapidly metabolized and short-acting. If taken before every meal, they actually mimic the normal effects of insulin after eating. Patients, then, can vary their meal times with this drug. (Nateglinide appears to work more quickly and is shorter-acting than repaglinide). These drugs may be particularly helpful in combination with metformin or other drugs. They may also be a good choice for people with potential kidney problems.

Side Effects. Side effects include diarrhea and headache. As with the sulfonylureas, repaglinide poses a slightly increased risk for cardiac events. (Newer drugs, such as nateglinide, may pose less of a risk.) People with heart failure or liver disease should use them with caution and be monitored.

Thiazolidinediones, also known as peroxisome proliferator-activated receptor (PPAR) agonists, include rosiglitazone (Avandia) and pioglitazone (Actos). They improve insulin sensitivity by activating certain genes involved in fat synthesis and carbohydrate metabolism. These drugs are usually taken once or twice per day; however, it may take several days before the patient notices any results from them and several weeks before they take full effect. Thiazolidinediones are usually taken in combination with other oral drugs or insulin.

Side Effects. Thiazolidinediones can have serious side effects. They tend to increase fluid-build up, which can cause or worsen heart failure in some patients. Combinations with insulin increase the risk. They should not be used by patients with existing heart failure and should be used cautiously in those with risk factors for heart failure.

In 2007, a study published in the New England Journal of Medicine (NEJM) raised serious concerns that rosiglitazone may increase the risk of heart attack. The study reviewed 42 clinical trials of rosiglitazone. Results suggested that patients who took rosiglitazone were 43% more likely to have a heart attack, and 64% more likely to die from overall heart causes, than patients with diabetes who did not take the drug. A subsequent interim analysis in the NEJM found that while rosiglitazone was definitely associated with increased risk of heart failure, the data were insufficient to determine if the drug increases heart attack risk. The FDA has concluded that rosiglitazone may increase the risk of heart attack and will likely restrict its use. In 2007, a panel of experts from the Food and Drug Administration (FDA) agreed the drug increases the risk of heart attacks -- but concluded it should remain on the market. The panel did, however, recommend the FDA require rosiglitazone's maker to add warnings to the drug's label. Patients who take rosiglitazone, especially those who have heart disease or who are at high risk for heart attack, should discuss their treatment options with their doctors.

Thiazolidinediones may cause more weight gain than other diabetes medications or insulin. Any patient who experiences sudden weight gain, water retention, or shortness of breath should immediately call their doctor. These drugs have also been linked to increased risks for bone fracture.

There have been rare reports of rosiglitazone causing or worsening diabetic macular edema. This is an eye condition associated with diabetic retinopathy that causes swelling in the macular area of the retina. Symptoms include blurred vision and decreased color sensitivity. Most patients who had this side effect also had swelling in the feet and legs (peripheral edema). The condition resolved or improved when patients stopped taking the drug.

Thiazolidinediones can also cause liver damage. Patients who take these drugs should have their liver enzymes checked regularly.

Alpha-glucosidase inhibitors, including acarbose (Precose, Glucobay) and miglitol (Glyset), reduce glucose levels by interfering with the absorption of starch in the small intestine. Acarbose tends to lower insulin levels after meals, a particular advantage, since higher levels of insulin after meals are associated with an increased risk for heart disease. Some evidence suggests that early use of these drugs may reduce heart risk factors, including high blood pressure. A 2002 study of acarbose suggested that these drugs may possibly delay the development of type 2 diabetes in high-risk individuals. Alpha-glucosidase inhibitors are not as effective alone as other single oral drugs, but combinations, such as with metformin, insulin, or a sulfonylurea, increase their effectiveness.

Side Effects. These medications need to be taken with meals. Unfortunately, about a third of patients stop taking the drug because of flatulence and diarrhea, particularly after high-carbohydrate meals. The drug may also interfere with iron absorption.

Alpha-glucosidase inhibitors do not cause hypoglycemia when used alone, but combinations with other drugs do. In such cases, it is important that the patient receive a solution that contains glucose or lactose, not table sugar. This is because acarbose inhibits the breakdown of complex sugar and starches, which includes table sugar.

Incretin mimetics belong to a new class of drugs that help improve blood sugar control. Incretins include glucagon-like peptide-1 (GLP-1) inhibitors and DDP-4 inhibitors.

In 2005, the FDA approved exenatide (Byetta), the first GLP-1 inhibitor drug. Exenatide is an injectable drug that is a synthetic version of the hormone found in the saliva of the Gila monster, a venomous desert lizard. Exenatide is injected twice a day, 1 hour before morning and evening meals. It is prescribed for patients with type 2 diabetes who have not been able to control their glucose with metformin or a sulfonylurea drug. It can be taken in combination with these drugs or alone.

Side Effects. Exenatide stimulates insulin secretion only when blood sugar levels are high and so has less risk for causing low blood sugar (hypoglycemia) when it is taken alone. However, the risk for hypoglycemia increases when exenatide is taken along with a sulfonylurea drug. There does not appear to be a risk for hypoglycemia when exenatide is used along with metformin. Other side effects may include nausea, vomiting, and diarrhea.

A 2005 study compared exenatide to insulin for improving glucose control in patients taking metformin and a sulfonylurea. Both insulin and exenatide worked well for glucose control. Patients lost weight with exenatide and gained weight with insulin. However, patients who received exenatide had significantly more problems with nausea, vomiting, and diarrhea than those who received insulin.

Dipeptidyl peptidase-4 (DPP-4) inhibitors, also called gliptins, are the second class of incretin drugs. In October 2006, the FDA approved the first DPP-4 inhibitor -- sitagliptin (Januvia). It can be used alone or in combination with metformin or a thiazolidinedione drug. In April 2007, the FDA approved Janumet, which combines sitagliptin with metformin in one pill. Other DPP-4 drugs being studied include vildagliptin (Galvus) and saxagliptin.

DPP-4 inhibitors work in a similar way to GLP-1 inhibitors. However, unlike exenatide, which is given by injection, DPP-4 inhibitor drugs are taken as pills by mouth.

Like exenatide, DPP-4 inhibitors do not cause weight gain, have low risks for hypoglycemia, and have few severe side effects. The most common side effects include upper respiratory tract infection, sore throat, and diarrhea.

Insulin replacement is the best treatment for strict control of blood glucose and is required once natural insulin reserves are depleted. Because type 2 diabetes is progressive, most patients eventually require insulin, typically starting it in combination with an oral anti-hyperglycemic drug. However, when a single oral drug fails to control blood sugar it is not clear whether it is better to add insulin replacement or to add a second or third oral drug.

Some experts advocate using insulin as early as possible for optimal control. However, in patients who still have insulin reserves, there is concern that extra natural insulin will have adverse effects. Low blood sugar (hypoglycemia) and weight gain are the main side effects of insulin therapy. Some research suggests that insulin may also cause heart complications. A 2006 study reported that insulin therapy increases the risk of developing high blood pressure (hypertension). It is still not clear if insulin replacement improves survival rates compared to oral drugs, notably metformin.

One approach is to combine insulin with metformin, which achieves blood glucose control without added weight gain. Newer forms of insulin analogues, such as glargine, may be especially helpful for people with type 2 diabetes and reduce the risk for hypoglycemia.

Fortunately, studies to date have not reported any adverse cardiac effects in patients with type 2 diabetes who take insulin. In fact, insulin has been associated, in some cases, with improvement in heart risk factors. More research is needed to clarify these important issues.

Forms of Insulin. Experts are working toward administering insulin so that it closely mimics the daily pattern of insulin, which responds to blood sugar levels by surging after meals and then falling to a steady base level afterward. To achieve this, doctors may use two insulin types:

Fast-Acting Insulins for Surges. Insulin lispro and aspart are fast-acting insulins. They mimic insulin's response to food intake. They are taken before meals, and their short action reduces the risk for hypoglycemia afterward.
Slower Insulins for Base Levels. Intermediate forms (including NPH and lente) and long-acting forms (glargine, ultralente) were developed to provide a steady level of insulin throughout the day. To date, glargine (Lantus) seems to be the most successful in achieving this goal in type 2 diabetes.

In 2006, the FDA approved the first non-injected form of insulin. Exubera is an inhaled form of insulin. It is approved for adults but should not be used by patients who smoke or have quit smoking within the past 6 months. Patients with asthma, bronchitis, or emphysema should also not use inhaled insulin. Clinical trials indicate that Exubera can provide sustained blood sugar control over a 2-year period. Patients in the trials who took Exubera experienced half as much weight gain as those who took injected insulin. Scientists are also developing other types of non-injected insulin, including spray formulas.

In a 2005 trial, Exubera improved blood sugar control when it was added to or substituted for combination oral drug therapy (sulphonylurea and thiazolidenedione). However, as with other forms of insulin, Exubera caused more hypoglycemia and weight gain than the oral anti-hyperglycemic drugs.

Pramlintide (Symlin) is a new type of injectable drug that may help patients who take insulin but still need better blood sugar control. The FDA approved this drug in 2005. Pramlintide is a synthetic form of amylin, a hormone that is related to insulin. Pramlintide is used in combination with insulin to lower blood sugar levels in the 3 hours after meals.

[See In-Depth Report #9: Diabetes - type 1.]

Sodium Glucose Uptake Transporter 2 (SGLT-2) Inhibitors. SGLT-2 inhibitors are a new class of drug being investigated for treatment of type 2 diabetes. Preliminary trials for two of these drugs, dapagliflozin and serglifozin, have shown promising results in helping improve blood glucose control. The drugs are being tested in combination with metformin.

Various fraudulent products are often sold on the Internet as “cures” or treatments for diabetes. These dietary supplements have not been studied or approved. In 2006, the FDA and Federal Trade Commission (FTC) launched a crackdown on these scams. The FDA and FTC warn patients with diabetes not to be duped by bogus and unproven remedies.

Long-Term Complications

Patients with diabetes have higher mortality rates than people who do not have diabetes regardless of sex, age, or other factors. Heart disease and stroke are the leading causes of death in these patients. All lifestyle and medical efforts should be made to reduce the risk for these conditions.

People with type 2 diabetes are also at risk for nerve damage (neuropathy) and abnormalities in both small and large blood vessels (vascular injuries) that occur as part of the diabetic disease process. Such abnormalities produce complications over time in many organs and structures in the body. Although these complications tend to be more serious in type 1 diabetes, they still are of concern in type 2 diabetes. All people with diabetes should aim for fasting blood glucose levels of less than 110 mg/dL and hemoglobin HbA1C of less than 7%.

There are two important approaches to preventing complications from diabetes:

Intensive control of blood glucose and keeping glycosylated hemoglobin (HbA1c) levels below 7%. Tight blood glucose and HbA1c control can prevent complications due to vascular (blood vessel) abnormalities and nerve damage (neuropathy) that can cause major damage to organs, including the eyes, kidneys, and heart.
Managing risk factors for heart disease. Control of blood glucose also helps the heart, but its benefits occur over time. It is very important that people with diabetes control blood pressure, cholesterol levels, and other factors associated with heart disease.

Heart attacks account for 60% and strokes for 25% of deaths in patients with diabetes. Diabetes affects the heart in many ways:

Both type 1 and 2 diabetes speed the progression of atherosclerosis (hardening of the arteries). Diabetes can adversely affect blood lipid levels by lowering HDL ("good cholesterol") and increasing triglycerides. This can lead to coronary artery disease, heart attack, or stroke. According to a 2007 study, the risk of stroke doubles within 5 years of type 2 diabetes diagnosis.
Impaired nerve function (neuropathy) associated with diabetes also causes heart abnormalities. Some experts estimate that the mortality rates from neuropathy-related heart conditions range between 15 - 53%.
Women with diabetes are at particularly high risk for heart problems. A 2007 study indicated that while progress has been made in reducing mortality rates among men with diabetes, women with diabetes continue to face a high risk of death from heart disease and overall causes.

Tight blood sugar control may help protect blood vessels and reduce the risk for blood clotting. It is still not known whether intensive control will have a major protective effect on the heart, however. People with diabetes must be sure to use other measures as well to protect the heart.

Aspirin for Reducing the Risk for Blood Clots. Taking a daily aspirin (75 - 162 mg/day) reduces the risk for blood clotting and may help protect against heart attacks and heart disease. In a 2000 study, low-dose aspirin was associated with a 30% lower risk for death from heart disease in adults with type 2 diabetes.

Controlling Blood Pressure. Strict control of blood pressure is critical for preventing complications of diabetes and has proven to improve survival rates. Patients should strive for blood pressure levels of less than 130/80 mm Hg (systolic/diastolic). (Controlling systolic pressure may be especially important for reducing the risk for kidney complications.)

Dozens of anti-hypertensive drugs are available. Most fall into the following categories:

Diuretics rid the body of extra sodium (salt) and water. There are three main types of diuretics: Potassium-sparing, thiazide, and loop.
Angiotensin-converting enzyme (ACE) inhibitors reduce the production of angiotensin, a chemical that causes arteries to narrow.
Angiotensin-receptor blockers (ARBs) block angiotensin.
Beta-blockers block the effects of adrenaline and ease the heart’s pumping action.
Calcium-channel blockers (CCBs) decrease the contractions of the heart and widen blood vessels.

The American Diabetes Association (ADA) recommends any of these classes of drugs as first-line treatment for hypertension. New research suggests, however, that beta-blockers are less effective at preventing strokes and heart attacks than other types of blood pressure medications. Many patients require more than one type of drug to control blood pressure. For patients with diabetes who have microalbuminuria, the ADA strongly recommends ACE inhibitors or ARBs. Microalbuminuria is an accumulation of protein in the blood, which can signal the onset of kidney disease (nephropathy).

Anti-hypertensive drugs that block or reduce angiotensin are the first option for many people with diabetes. Angiotensin is a natural chemical that influences all aspects of blood pressure control and also interferes with insulin's normal metabolic signaling. In fact, angiotensin may be the common factor linking diabetes and high blood pressure.

The 2005 landmark Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) indicated that a thiazide-type diuretic works as well as an ACE inhibitor or CCB for patients with diabetes and high blood pressure. Compared with ACE inhibitors or CCBs, diuretics appeared to be better at lowering systolic blood pressure and preventing heart failure. In addition, the trial suggested that diuretics are especially helpful for African-Americans, by offering greater protection than ACE inhibitors or CCBS in preventing strokes.

Several 2006 studies suggested that anti-hypertensive drugs may increase the risk of developing diabetes. One study found more risk for thiazide diuretics and beta-blockers than ACE inhibitors and CCBs. Another study indicated that the ACE inhibitor ramipril had a lower risk of causing diabetes in African-Americans than a CCB or beta-blocker. A 2007 review in the Lancet also found a higher risk for new-onset diabetes with beta-blockers and diuretics, a medium risk with CCBs, and the lowest risk with ARBs and ACE inhibitors.

Research in this subject is important for patients with pre-diabetes who have high blood pressure. Results of future research may help doctors decide which treatment is most appropriate for patients with high blood pressure who are at high risk for diabetes. [See In-Depth Report #14: High blood pressure.]

Improving Cholesterol and Lipid Levels. Abnormal cholesterol and lipid levels are common in diabetes. High LDL (“bad”) cholesterol should always be lowered, but people with diabetes also often have additional harmful imbalances including low HDL (“good”) cholesterol and high triglycerides. Patients should aim for LDL levels below 100 mg/dL, HDL levels over 50 mg/dL and triglyceride levels below 150 mg/dL. Patients with diabetes and existing heart disease should strive for even lower LDL levels; the American Diabetes Association recommends LDL levels below 70 mg/dL for these patients.

Statins are the best cholesterol-lowering drugs. They include atorvastatin (Lipitor), lovastatin (Mevacor, generics), pravastatin (Pravachol), simvastatin (Zocor, generics), fluvastatin (Lescol), and rosuvastatin (Crestor). These drugs are very effective for lowering LDL cholesterol levels. Recent studies indicate that aggressive high-dose statin therapy may be an important treatment approach for high-risk patients who need to substantially lower their LDL levels. A 2006 study found that patients with diabetes and heart disease who were treated with 80 mg daily of atorvastatin had a 25% lower risk of heart attack and stroke than patients who received the standard 10 mg daily dose.

The primary safety concern with statins has involved myopathy, an uncommon condition that can cause muscle damage and, in some cases, muscle and joint pain. A specific myopathy called rhabdomyolysis can lead to kidney failure. People with diabetes and risk factors for myopathy should be monitored for muscle symptoms

Although lowering LDL is beneficial, statins are not as effective as other medications -- such as fibrates, niacin, ezetimbe, or bile acid sequesters -- in addressing HDL and triglyceride imbalances. This is a common problem in type 2 diabetes. Combinations of statins with one of these drugs may be helpful for people with diabetes who have heart disease, low HDL, and near-normal LDL levels. Although combinations of statins and fibrates or niacin increase the risk of myopathy, both combinations are considered safe if used with extra care. Research presented at the 2007 annual meeting of the American Diabetes Association suggested that statins and fibrates may also help reduce the risk of developing peripheral neuropathy, the diabetes-associated nerve damage that can lead to loss of sensation in the feet.

Gemfibrozil (Lopid) and fenofibrate (Tricor) are usually the first choice for fibrate drugs. Niacin has the most favorable effect on raising HDL and lowering triglycerides of all the cholesterol drugs. However, about 30% of patients who take high-dose niacin experience increased blood glucose levels. Moderate doses of niacin can achieve lipid control without causing serious blood glucose problems. [See In-Depth Report #23: Cholesterol.]

Kidney disease (nephropathy) is a very serious complication of diabetes. With this condition, the tiny filters in the kidney (called glomeruli) become damaged and leak protein into the urine. Over time this can lead to kidney failure. Urine tests showing microalbuminuria (small amounts of protein in the urine) are important markers for kidney damage.

Prevention and Treatment of Nephropathy. Tight control of blood sugar and blood pressure is essential for preventing the onset of kidney disease. Long-term studies report that strict control of these two conditions produces a 60% reduction in new cases of nephropathy and a delay in progression of the disease. ACE inhibitors and ARBs, two classes of blood pressure medications, are very helpful for preventing or slowing the progression of diabetic kidney disease.

A doctor may recommend a low-protein diet for patients whose kidney disease is progressing despite tight blood sugar and blood pressure control. Protein-restricted diets can help slow disease progression and delay the onset of end-stage renal disease (kidney failure). However, patients with end-stage renal disease who are on dialysis generally require higher amounts of protein. [See In-Depth Report #42: Diabetes diet.]

Diabetic nephropathy occurs in about 20 - 40% of patients with diabetes and is the leading cause of end-stage renal disease. If the kidneys fail, dialysis is required. Symptoms of kidney failure may include swelling in the feet and ankles, itching, fatigue, and pale skin color.

Anemia is a common complication of end-stage kidney disease. Patients on dialysis usually require injections of erythropoiesis-stimulating drugs to increase red blood cell counts and control anemia. Dosing target levels of erythropoiesis-stimulating drugs are controversial, especially for patients with chronic kidney disease. In 2006, two important New England Journal of Medicine studies indicated that aggressive dosing to completely normalize hemoglobin levels does not work better than standard dosing that only partially corrects anemia.

In 2007, the FDA issued new warnings on darbepoetin alfa (Aranesp) and epoetin alfa (Epogen and Procrit). The warnings describe an increased risk with blood clots, strokes, and heart attacks in patients with end-stage kidney disease when these drugs were given at higher than recommended doses. The FDA has set new dosing and hemoglobin target levels for these drugs.

Another controversy surrounding erythropoiesis-stimulating drugs concerns their overuse at dialysis centers. A 2007 study in the Journal of the American Medical Association suggested that large, for-profit dialysis centers tend to administer higher-than-appropriate doses of these drugs compared to nonprofit facilities. The study suggested that for-profit centers are giving higher doses for financial, not medical, reasons.

The FDA recommends that patients with end-stage kidney disease who receive erythropoiesis-stimulating drugs should:

Maintain hemoglobin levels that do not exceed 12 g/dL
Receive frequent blood tests to monitor hemoglobin levels
Contact their doctors if they experience such symptoms as shortness of breath, pain, swelling in the legs, or increases in blood pressure

[See In-Depth Report #57: Anemia.]

Click the icon to see an image of the pancreas and kidneys.

Diabetes reduces or distorts nerve function, causing a condition called neuropathy. Neuropathy refers to a group of disorders that affect nerves. The two main types of neuropathy are:

Peripheral (affects nerves in the toes, feet, legs, hand, and arms)
Autonomic (affects nerves that help regulate digestive, bowel, bladder, heart, and sexual function)

Peripheral neuropathy particularly affects sensation. It is a common complication that affects nearly half of people with type 1 or type 2 diabetes after 25 years. The most serious consequences of neuropathy occur in the legs and feet and pose a risk for ulcers and, in very severe cases, amputation. Peripheral neuropathy usually starts in the fingers and toes and moves up to the arms and legs (called a stocking-glove distribution). Symptoms include:

Tingling
Weakness
Burning sensations
Loss of the sense of warm or cold
Numbness (if the nerves are severely damaged, the patient may be unaware that a blister or minor wound has become infected)
Deep pain

Autonomic neuropathy can cause digestive problems (constipation, diarrhea, nausea, vomiting), bladder infections, and erectile dysfunction. In some cases, neuropathy may mask angina, the chest pain warning for heart disease and heart attack. Patients with diabetes should be aware of other warning signs of a heart attack, including sudden fatigue, sweating, shortness of breath, nausea, and vomiting.

Blood sugar control is the only treatment for neuropathy. Studies show that tight control of blood glucose levels delays the onset and slows progression of neuropathy. A 2005 study also suggested that heart disease risk factors can increase the likelihood of developing neuropathy. Lowering triglycerides, losing weight, reducing blood pressure, and quitting smoking may help prevent the onset of neuropathy.

Prevention of Neuropathy. Patients with type 2 diabetes should receive regular screenings for loss of sensation in feet and other signs of neuropathy. A 2007 study suggested that statin and fibrate drugs, which are used to control cholesterol, may help protect against diabetic peripheral neuropathy.

Pain Relief for Peripheral Neuropathy. A number of different drugs are used for peripheral neuropathy pain relief. They include:

Nonprescription analgesics such as aspirin, acetaminophen, and non-steroidal anti-inflammatory drugs (NSAIDs). (Patients with stomach or kidney problems should check with their doctors before using these drugs.)
Prescription painkillers, such as tramadol (Ultram). Tramadol is a drug that is similar to opioids. It can help relieve pain but has significant side effects, including nausea, constipation, and headache.
Topical medications, particularly capsaicin (the active ingredient in hot peppers), are applied to the skin to relieve minor local pain. A 5% lidocaine patch has also shown good results in clinical trials.
Tricyclic antidepressants, such as amitriptyline (Elavil) or doxepin (Sinequan), are effective in reducing pain from neuropathy in up to 75% of patients. A combination of doxepin and capsaicin (applied to the skin) may be particularly beneficial. Unfortunately, tricyclics may cause heart rhythm problems.
Duloxetine (Cymbalta) is a serotonin and norepinephrine reuptake inhibitor, a newer type of antidepressant, which was approved in 2004 for treatment of pain associated with diabetic peripheral neuropathy.
The anti-convulsant drug pregabalin (Lyrica) was approved in 2004 for neuropathic pain management. It is classified as a controlled substance (like narcotics), which indicates a potential risk for abuse. Other anti-seizure drugs used for peripheral neuropathy pain relief include gabapentin (Neurontin) and valproate (Depakote).

Treatments under investigation include acetyl-l-carnitine and intravenous alpha-lipoic acid. Patients may also benefit from transcutaneous electrostimulation (TENS), a treatment that involves administering mild electrical pulses to painful areas. Alternative treatments such as hypnosis, biofeedback, relaxation techniques, and acupuncture have helped some patients manage pain. Doctors also recommend lifestyle measures such as walking and wearing elastic stockings.

Treatments for Other Complications of Neuropathy. Neuropathy also impacts other functions, and treatments are needed to reduce their effects. If diabetes affects the nerves in the autonomic nervous system, then abnormalities of blood pressure control and bowel and bladder function may occur. Erythromycin, domperidone (Motilium), or metoclopramide (Reglan) may be used to relieve delayed stomach emptying caused by neuropathy.

Erectile dysfunction is also associated with neuropathy. Evidence shows that phosphodiesterase type 5 (PDE-5) drugs, such as sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis), are safe and effective, at least in the short term, for patients with diabetes. Typical side effects are minimal but may include headache, flushing, and upper respiratory tract and flu-like symptoms.

Perhaps the most serious consequences of diabetic neuropathy occur in the lower limbs. An estimated 15% of patients with diabetes experience serious foot problems. They are the leading cause of hospitalizations for these patients.

Diabetes is responsible for more than half of all lower limb amputations performed in the U.S. Each year there are about 88,000 non-injury amputations, 50 - 75% of them due to diabetes. The number is increasing as the prevalence in diabetes type 2 rises. According to a 2005 study in the Lancet, every 30 seconds someone in the world receives a lower limb amputation due to diabetes. About 85% of amputations start with foot ulcers, which develop in about 12% of people with diabetes.

In general, foot ulcers develop from infections, such as those resulting from blood vessel injury. A 2006 study reported that people with diabetes who develop foot infections are 155 times more likely to have an amputation than people who did not develop infections. Foot infections often develop from injuries. Even minor infections can develop into severe complications. Numbness from nerve damage, which is common in diabetes, compounds the danger since the patient may not be aware of injuries. About one-third of foot ulcers occur on the big toe.

A 2003 government survey found that those at higher risk for foot ulcers tend to be people with diabetes who are overweight, smokers, and those with a long history of diabetes. People who have the disease for more than 20 years and are insulin-dependent are at the highest risk. Related conditions that put people at risk include peripheral neuropathy, peripheral artery disease, foot deformities, and a history of ulcers. [See In-Depth Report #102: Peripheral artery disease and intermittent claudication.]

Charcot Foot. Charcot foot or Charcot joint (medically referred to as neuropathic arthropathy) occurs in about 2.5% of people with diabetes. Early changes appear like an infection, with the foot becoming swollen, red, and warm. A seriously affected foot can become deformed. The bones may crack, splinter, and erode, and the joints may shift, change shape, and become unstable. It typically develops in people who have neuropathy to the extent that they cannot feel sensation in the foot and are not aware of an existing injury. Instead of resting an injured foot or seeking medical help, the patient often continues normal activity, causing further damage.

Charcot foot is initially treated with strict immobilization of the foot and ankle; some centers use a cast that allows the patient to move and still protects the foot. A 2001 study in the U.K. concluded that a single dose of pamidronate, a bisphosphonate, reduces bone turnover, symptoms, and disease activity. When the acute phase has passed, patients usually need lifelong protection of the foot using a brace initially and custom footwear.

Measures to Prevent Foot Ulcers. Preventive foot care can significantly reduce the risk of ulcers and amputation. Some tips for preventing problems include:

Patients should inspect their feet daily and watch for changes in color or texture, odor, and firm or hardened areas, which may indicate infection and potential ulcers.
When washing the feet, the water should be warm (not hot), and the feet and areas between the toes should be thoroughly dried afterward. Check water temperature with the hand or a thermometer before stepping in.
Moisturizers should be applied, but not between the toes.
Corns and calluses should be gently pumiced and toenails trimmed short and the edges filed to avoid cutting adjacent toes.
Patients should not use medicated pads or try to shave the corns or calluses themselves.
Well-fitting footwear is very important. People should be sure the shoe is wide enough; according to a 2001 study, 30% of patients with diabetes wear shoes that are too narrow. Patients should also avoid high heels, sandals, thongs, and going barefoot. Shoes with a rocker sole reduce pressure under the heel and front of the foot by 35 - 65% and may be particularly helpful. Custom-molded boots increase the surface area over which foot pressure is distributed. This reduces stress on the ulcers and allows them to heal.
Shoes should be changed often during the day.
Wear socks, particularly with extra padding (which can be specially purchased).
Patients should avoid tight stockings or any clothing that constricts the legs and feet.
Foot pain, numbness, or tingling is worse at night; diphenhydramine (Benadryl) may help.
A specialist in foot care should be consulted for any problems.

People with diabetes are prone to foot problems because the disease can cause damage to the blood vessels and nerves, which may result in decreased ability to sense trauma to the foot. The immune system is also altered, so that the patient cannot efficiently fight infection.

Treating Foot Ulcers in Diabetes. About one-third of foot ulcers will heal within 20 weeks with good wound care treatments. Treatments include:

Antibiotics are generally given. In some cases, hospitalization and intravenous antibiotics for up to 28 days may be needed for severe foot ulcers.
In virtually all cases, wound care requires debridement, which is the removal of injured tissue until only healthy tissue remains. Debridement may be accomplished using chemical (enzymes), surgical, or mechanical (irrigation) means.
Hydrogels (Nu-Gel, Intrasite Gel, Scherisorb, Clearsite, Duoderm, Geliperm) are helpful in healing ulcers and are noninvasive and soothing.
Felted foam may be helpful in healing ulcers on the sole of the foot. Felted foam uses a multi-layered foam pad over the bottom of the foot with an opening over the ulcer.

Other Treatments for Foot Ulcers. Doctors are also using or investigating other treatments to heal ulcers. These include:

Administering hyperbaric oxygen (oxygen given at high pressure) is showing promise in promoting healing. In one study, patients who had had ulcers that had not responded to treatment for over 3 months received daily treatments that lasted 90 minutes for 2 weeks. About 15 days after completion, patients who received oxygen had significant reduction in ulcers, sometimes with complete healing. Other studies are also demonstrating good results.
Monochromatic near-infrared photo energy (MIRE) uses light therapy to improve sensation in the feet of patients with peripheral neuropathy.
Total-contact casting (TCC) uses a cast that is designed to match the exact contour of the foot and to distribute weight along the entire length of the foot. It is usually changed weekly. It may be helpful for ulcer healing and for Charcot foot. Although it is very effective in healing ulcers, recurrence is common.

Diabetes accounts for 12,000 - 24,000 of new cases of blindness annually and is the leading cause of new cases of blindness in adults age 20 - 74. The most common eye disorder in diabetes is retinopathy. People with diabetes are also at higher risk for developing cataracts and certain types of glaucoma, such as primary-open angle glaucoma (POAG). The risk for POAG is especially high for women with type 2 diabetes. [See In-Depth Report #26: Cataracts and In-Depth Report #25: Glaucoma.]

Description of Retinopathy. Retinopathy is a condition in which the retina in the eye becomes damaged. The two primary abnormalities that occur are a weakening of the blood vessels in the retina and the obstruction in the capillaries -- probably from very tiny blood clots. Retinopathy generally occurs in one or two phases:

Click the icon to see an image of diabetic retinopathy.

The early and more common type of this disorder is called nonproliferative or background retinopathy. The blood vessels in the retina are abnormally weakened. They rupture and leak, and waxy areas may form. If these processes affect the central portion of the retina, swelling may occur, causing reduced or blurred vision.
If the capillaries become blocked and blood flow is cut off, soft, "woolly" areas may develop in the retina's nerve layer. These woolly areas may signal the development of proliferative retinopathy. Often there are no symptoms of progressing retinopathy. In this more severe condition, new abnormal blood vessels form and grow on the surface of the retina. They may spread into the cavity of the eye or bleed into the back of the eye. Major hemorrhage or retinal detachment can result, causing severe visual loss or blindness. The sensation of seeing flashing lights may indicate retinal detachment.

Click the icon to see an animation on diabetic retinopathy.

According to a 2003 study, about 40% of young adults with type 1 diabetes had developed retinopathy within 10 years of diagnosis. (Although this rate is high, it is significantly lower than in previous years when blood glucose control was not as strict.) The risk is lower in patients with type 2 diabetes, although in one study over 20% had signs of retinopathy 6 years after diagnosis. Patients who are newly diagnosed with type 2 diabetes should get a comprehensive eye examination, including dilation. In general, all patients with diabetes should have a yearly eye examination. Patients with no signs of retinal damage or low risk factors for retinopathy may only require screening every 2 - 3 years.

Prevention of Retinopathy. Fortunately, severe and even moderate vision loss is largely preventable with tight control of blood glucose levels. (Intense glucose control can cause early worsening of retinopathy, although this is nearly always counterbalanced by long-term benefits.) Tight control of blood pressure can also help protect against retinopathy. Aspirin therapy does not help prevent retinopathy.

Treatment of Retinopathy. Patients with severe diabetic retinopathy or macular edema (swelling of the retina) should be sure to see an eye specialist who is experienced in the management and treatment of diabetic retinopathy. Once damage to the eye develops, laser eye surgery may be needed. Laser surgery can help reduce vision loss in high-risk patients.

Studies indicate that patients with type 2 diabetes face a higher than average risk of developing dementia caused either by Alzheimer's disease or problems in blood vessels in the brain. Problems in attention and memory can occur even in people under age 55 who have had diabetes for a number of years. In one study of people with type 1 diabetes, high glucose levels (hyperglycemia) were associated with slower brain function, including less verbal fluency and slower ability to do mental arithmetic.

Respiratory Infections. People with diabetes face a higher risk for influenza and its complications, including pneumonia, possibly because the disorder neutralizes the effects of protective proteins on the surface of the lungs. In fact, deaths among people with diabetes increase by 5 - 15% during flu epidemics, and they are six times more likely to be hospitalized with complications from flu than nondiabetic patients who have flu. Everyone with diabetes should have annual influenza vaccinations and a vaccination against pneumococcal pneumonia.

Urinary Tract Infections. Women with diabetes face a significantly higher risk for urinary tract infections, which are likely to be more complicated and difficult to treat than in the general population.

Diabetes doubles the risk for depression. Furthermore, according to one study, depression, in turn, increases the risk for hyperglycemia and complications of diabetes. Restoring mental health, both through medication and psychotherapy, not only improves quality of life but may help patients control their blood sugar levels.

Diabetes changes bone quality and density, but the effects differ, depending on type:

Type 1 diabetes is associated with a slightly reduced bone density, putting patients at risk for osteoporosis and possibly fractures. The best medications for bone loss in patients with diabetes are bisphosphonates, such as alendronate (Fosamax) and risedronate (Actonel). They not only help prevent bone loss but may even reduce daily insulin requirements in patients taking insulin. [See In-Depth Report #18: Osteoporosis.]
Type 2 diabetes, on the other hand, is associated with an increased bone density but is also associated with fractures. In such cases, the bone quality itself may be impaired.

Older patients with either type of diabetes are at risk for falling, which compounds the risk for fracture.

Diabetes increases the risk for other conditions, including:

Hearing loss
Periodontal disease
Carpal tunnel syndrome
Nonalcoholic fatty liver disease, also called nonalcoholic steatohepatitis (NASH), a particular danger for people who are obese
Colorectal cancer
Uterine cancer

Emergency Complications

People with diabetes who need to intensively control glucose levels are at risk for low blood sugar (hypoglycemia). Hypoglycemia, also called insulin shock, develops if blood sugar levels fall below normal. It may also be caused by insufficient intake of food, excess exercise, or alcohol intake. The condition is usually manageable, but occasionally it can be severe or even life threatening, particularly if the patient fails to recognize the symptoms. Mild hypoglycemia is common among people with type 2 diabetes, but severe episodes are rare, even among those who are taking insulin. Still, all patients who intensively control blood sugar (glucose) levels should be aware of warning symptoms.

Risk Factors for Severe Hypoglycemia. People at highest risk for severe hypoglycemia are those who intensively control blood glucose and also have one or more of the following conditions:

Long-term diabetes
Less education on their condition
A previous history of severe hypoglycemia
Hypoglycemia unawareness

Hypoglycemia unawareness is a condition in which people become insensitive to hypoglycemic symptoms. It affects about 25% of patients who use insulin, nearly always people with type 1 diabetes. In such cases, hypoglycemia appears suddenly, without warning, and can escalate to a severe level. Even a single recent episode of hypoglycemia may make it more difficult to detect the next episode. With vigilant monitoring and by rigorously avoiding low blood glucose levels, patients can often regain the ability to sense the symptoms. However, even very careful testing may fail to detect a problem, particularly one that occurs during sleep.

Symptoms. Mild hypoglycemia symptoms usually occur at moderately low and easily correctable levels of blood glucose. They include:

Sweating
Trembling
Hunger
Rapid heartbeat

Severely low blood glucose levels can cause neurologic symptoms, such as:

Confusion
Weakness
Disorientation
Combativeness
In rare and worst cases, coma, seizure, and death

Preventive Measures. The following tips may help avoid hypoglycemia or prepare for attacks:

Patients are at highest risk for hypoglycemia at night. Bedtime snacks may be helpful.
Patients who intensively control their blood sugar should monitor blood levels as often as possible, four times or more per day. This is particularly important for patients with hypoglycemia unawareness.
In adults, it is also particularly critical to monitor blood glucose levels before driving, when hypoglycemia can be very hazardous.
Patients who use medications that put them at risk for hypoglycemia should always carry hard candy, juice, sugar packets, or commercially available glucose substitutes designed for individuals with diabetes.

Family and friends should be aware of the symptoms and be prepared:

If the patient is helpless (but not unconscious), family or friends should administer three to five pieces of hard candy, two to three packets of sugar, half a cup (four ounces) of fruit juice, or a commercially available glucose solution.
If there is inadequate response within 15 minutes, additional oral sugar should be provided or the patient should receive emergency medical treatment, including intravenous administration of glucose.
Family members and friends can learn to inject glucagon, a hormone, which, in contrast to insulin, raises blood glucose.

Click the icon to see a glucagon kit.

Diabetic ketoacidosis (DKA) is a life-threatening complication caused by insulin depletion. Until recently, it was a complication almost exclusively of type 1 diabetes. In such cases, it is nearly always due to noncompliance with insulin treatments. However, DKA is being reported increasingly in type 2 diabetes, especially among Hispanic- and African-Americans. It is not clear what causes total insulin depletion in these patients. Researchers are trying to learn which individuals are at particular risk.

Diabetic ketoacidosis often develop as follows:

The process is usually triggered in insulin-deficient patients by a stressful event, most often pneumonia or urinary tract infections. Other triggers include alcohol abuse, physical injury, pulmonary embolism, heart attacks, or other illnesses.
Severely low insulin levels cause excessive amounts of glucose in the bloodstream (hyperglycemia).
Fat breakdown then accelerates and increases the production of fatty acids.
These fatty acids are converted into chemicals called ketone bodies, which are toxic at high levels.

Symptoms and complications may include:

Nausea and vomiting
Abnormally deep and rapid breathing with frequent sighing
Rapid heartbeat
If the condition persists, coma and, eventually, death, may occur; however, over the past 20 years, death from DKA has decreased to about 2% of all cases.
Other serious complications from DKA include aspiration pneumonia and adult respiratory distress syndrome.

Life-saving treatment uses rapid rehydration with a saline solution followed by low-dose insulin and potassium replacement.

Resources

www.diabetes.org -- American Diabetes Association
www.niddk.nih.gov -- National Institute of Diabetes and Digestive and Kidney Diseases
www.americanheart.org -- American Heart Association
www.kidney.org -- National Kidney Foundation
www.nei.nih.gov -- National Eye Institute
www.medicalert.org -- Medic Alert
www.eatright.org -- American Dietetic Association
http://limaye.ecri.org -- Limaye Center

References

American Diabetes Association (ADA). Standards of medical care in diabetes. IV. Prevention/delay of type 2 diabetes. Diabetes Care. 2007 Jan;30(Suppl 1):S7-8.

American Diabetes Association (ADA). Standards of medical care in diabetes. V. Diabetes care. Diabetes Care. 2007 Jan;30(Suppl 1):S8-15.

American Diabetes Association (ADA). Standards of medical care in diabetes. VI. Prevention and management of diabetes complications. Diabetes Care. 2007 Jan;30(Suppl 1):S15-24.

Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007 July 11;298:194-206.

Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006 Dec;29(12):2632-7.

Bolen S, Feldman L, Vassy J, Wilson L, Yeh H-C, Marinopoulos S, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007 Jul 17; 147(6). [Epub ahead of print]

Carnethon MR, Biggs ML, Barzilay JI, Smith NL, Vaccarino V, Bertoni AG, et al. Longitudinal association between depressive symptoms and incident type 2 diabetes mellitus in older adults: the cardiovascular health study. Arch Intern Med. 2007 Apr 23;167(:802-7.

Charbonnel B, Karasik A, Liu J, Wu M, Meininger G; Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 Dec;29(12):2638-43.

Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006 Nov 16;355(20):2071-84.

Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007 Jan 20;369(9557):201-7.

Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PI, Shuldiner AR, et al. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med. 2006 Jul 20;355(3):241-50.

Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007 May 11;316(5826):889-94. Epub 2007 Apr 12.

Gillies CL, Abrams KR, Lambert PC, Cooper NJ, Sutton AJ, Hsu RT, et al. Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ. 2007 Feb 10;334(7588):299. Epub 2007 Jan 19.

Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006 Mar;38(3):320-3. Epub 2006 Jan 15.

Gregg EW, Gu Q, Cheng YJ, Narayan KM, Cowie CC. Mortality trends in men and women with diabetes, 1971-2000. Ann Intern Med. 2007 Jun 18; [Epub ahead of print]

Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones NP, et al. Rosiglitazone evaluated for cardiovascular outcomes--an interim analysis. N Engl J Med. 2007 Jul 5;357(1):28-38. Epub 2007 Jun 5.

Jeerakathil T, Johnson JA, Simpson SH, Majumdar SR. Short-term risk for stroke is doubled in persons with newly treated type 2 diabetes compared with persons without diabetes: a population-based cohort study. Stroke. 2007 Jun;38(6):1739-43. Epub 2007 May 3.

Lee AJ, Hiscock RJ, Wein P, Walker SP, Permezel M. Gestational diabetes mellitus: clinical predictors and long-term risk of developing type 2 diabetes: a retrospective cohort study using survival analysis. Diabetes Care. 2007 Apr;30(4):878-83.

Pasquale LR, Kang JH, Manson JE, Willett WC, Rosner BA, Hankinson SE. Prospective study of type 2 diabetes mellitus and risk of primary open-angle glaucoma in women. Ophthalmology. 2006 Jul;113(7):1081-6. Epub 2006 Jun 6.

Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007 Jun 14;356(24):2457-71. Epub 2007 May 21.

Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med. 2007 Jun 14;356(24):2522-4. Epub 2007 May 21.

Schulze MB, Schulz M, Heidemann C, Schienkiewitz A, Hoffmann K, Boeing H. Fiber and magnesium intake and incidence of type 2 diabetes: a prospective study and meta-analysis. Arch Intern Med. 2007 May 14;167(9):956-65.

Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007 Jun 1;316(5829):1341-5. Epub 2007 Apr 26.

Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006 Nov 16;355(20):2085-98.

Thamer M, Zhang Y, Kaufman J, Cotter D, Dong F, Hernen MA. Dialysis facility ownership and epoetin dosing in patients receiving hemodialysis. JAMA. 2007 Apr 18;297(15):1667-74.

Vardi M, Nini A. Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus. Cochrane Database Syst Rev. 2007 Jan 24(1):CD002187.

Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007 Jun 1;316(5829):1336-41. Epub 2007 Apr 26.

Review Date:
7/31/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Peptic ulcers

FitSugar — Wed, 08 Oct 2008 17:35:38 -0700

In This Report

Highlights
Introduction
Causes
Symptoms
Complications
Risk Factors
Diagnosis
Treatment
Treatment for NSAID-Induced...
Medications
Treatment for Bleeding Ulce...
Lifestyle Changes
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Risk with cardiovascular medications

While nonsteroidal anti-inflammatory drugs are the major medications responsible for causing peptic ulcers, drugs taken for cardiovascular disease and its risk factors may also cause ulcers. Recent studies have found an association between increased risk of ulcer and the following drugs:

Spironolactone, a common diuretic used in heart failure
Niacin, a drug used to lower "bad" cholesterol and raise "good" cholesterol
Vitamin K antagonists, commonly prescribed anticoagulants
Dipyridamole, a drug for secondary stroke prevention
Low-dose aspirin, prescribed for both heart attack and stroke prevention

Risk of peptic ulcer increases dramatically when these drugs are used in combination. Considering the millions of people who take these medications to prevent a life-threatening cardiovascular event, their impact on peptic ulcer development could be monumental.

Atypical symptoms of GERD

The burning pain of gastroesophageal reflux disease (GERD) can be confused with that of an ulcer. However, GERD pain typically develops after meals and is relieved by antacids. Elderly patients may have different symptoms that can include loss of appetite, weight loss, anemia, vomiting, or difficulty swallowing. A careful examination may be necessary to diagnose the underlying cause, since GERD and peptic ulcer may coexist.

Adjustments in triple therapy

Peptic ulcers are commonly treated with the triple combination of two antibiotics (amoxicillin and clarithromycin) and a proton-pump inhibitor. Therapy usually lasts for 2 weeks. Recent studies indicate that 1 week may be just as effective. In addition, taking the antibiotics in sequence, rather than at the same time, may work better to eliminate H. pylori, the bacteria responsible for most ulcers.

Healing foods

Milk may not be the ideal food for people with peptic ulcers because it encourages the production of stomach acid. However, certain qualities found in fermented milks and yogurts may actually offer protection against gastric ulcers. Likewise, the phenolic compounds found in virgin olive oil appear to kill many strains of H. pylori, including some that have become resistant to antibiotics. Vegetables contain dietary nitrate, which increases nitric oxide in the gut, causing the mucus layer to thicken. This increases protection against H. pylori invasion.

Protection when taking NSAIDs

People who take NSAIDs for pain control have an immediate increased risk of ulcers. Chronic use increases risk dramatically. Taking a proton-pump inhibitor (PPI) or H2 blocker is necessary to reduce this risk. A review of clinical trials found three PPIs [omeprazole (Prilosec), esomeprazole (Nexium), and lansoprazole (Prevacid)] to be more effective than the H2 blocker ranitidine (Zantac). When NSAIDs were discontinued, however, healing rates with ranitidine reached nearly 100%.

Introduction

A peptic ulcer is an open sore or raw area that tends to develop in one of two places:

The lining of the stomach ( gastric ulcer), or
The upper part of the small intestine -- the duodenum ( duodenal ulcers). In the U.S., duodenal ulcers are 3 times more common than gastric ulcers.

A peptic ulcer is an open sore or raw area in the lining of the stomach (gastric) or the upper part of the small intestine (duodenal).

Ulcers average between one-quarter and one-half inch in diameter. They develop when digestive juices produced in the stomach, intestines, and digestive glands damage the lining of the stomach or duodenum.

The two important digestive juices are hydrochloric acid and the enzyme pepsin. Both substances are critical in the breakdown and digestion of starches, fats, and proteins in food. They play different roles in ulcers:

Click the icon to see an image of the stomach.

Hydrochloric acid. A common misbelief is that excess hydrochloric acid, which is secreted in the stomach, is solely responsible for producing ulcers. Patients with duodenal ulcers do tend to have higher-than-normal levels of hydrochloric acid, but most patients with gastric ulcers have normal or lower-than-normal acid levels. Some stomach acid is important for protecting against H. pylori, the bacteria that causes most peptic ulcers. [Note: An exception is ulcers that occur in Zollinger-Ellison syndrome. This is a rare genetic condition in which very high levels of gastrin, a potent acid, are secreted by tumors in the pancreas or duodenum.]
Pepsin. Pepsin is an enzyme that breaks down proteins in food. Since the stomach and duodenum are also composed of protein, they are also susceptible to the actions of pepsin. Pepsin is, then, also important in the formation of ulcers.

Fortunately, the body has a defense system to protect the stomach and intestine against these powerful substances:

The mucous layer, which coats the stomach and duodenum, forms the first line of defense.
Bicarbonate, which the mucous layer secretes, neutralizes the digestive acids.
Hormone-like substances called prostaglandins help dilate the blood vessels in the stomach to ensure good blood flow and protect against injury. Prostaglandins are also believed to stimulate bicarbonate and mucus production.

Disrupting any of these defense mechanisms makes the stomach and intestine lining susceptible to the actions of acid and pepsin, increasing the risk for ulcers.

Causes

Before the discovery of the bacterium Helicobacter (H.) pylori, the stomach was believed to be a sterile environment. However, in 1982 two Australian scientists identified H. pylori as the main cause of stomach ulcers. They showed that inflammation of the stomach and stomach ulcers result from an infection of the stomach caused by the H. pylori bacteria. This discovery was so important that the researchers were awarded the Nobel Price in Medicine in 2005. The bacteria appear to trigger ulcers in the following way:

H. pylori's corkscrew shape enables it to penetrate the mucous layer of the stomach or duodenum so it can attach itself to the lining.
It survives in the highly acidic environment by producing urease, an enzyme that generates ammonia to neutralize the acid.
H. pylori then produces a number of toxins and factors that can cause inflammation and damage to the lining, leading to ulcers in certain individuals.
It also alters certain immune factors that allow it to evade detection and cause persistent inflammation for a life -- even without invading the mucous membrane.

Even if ulcers do not develop, the bacterium is now considered to be a major cause of active chronic inflammation in the stomach (gastritis) and in the upper part of the small intestine (duodenitis).

It is also strongly linked to stomach (gastric) cancer and possibly other non-intestinal problems.

Factors that Trigger Ulcers in H. pylori Carriers.H. pylori is found in about 25% of people who do not have peptic ulcers. The magnitude of H. pylori infection, particularly in older people, may not always predict the presence or absence of peptic ulcers. Other variables must to be present to actually trigger ulcers. These may include:

Genetic Factors. Some people harbor genetic strains of H. pylori that may make the bacteria more dangerous and increase the risk for ulcers. The most intensively investigated genetic factor is cytotoxin-associated gene A (CagA), which has been associated with both gastric and duodenal ulcers, as well as with stomach cancer. Other genetic types that may also increase bacterial severity are called vacuolating cytotoxin (vacA) and antigen-binding adhesin (BabA) genotypes. Some of these genetic factors may be more or less important for development of ulcers, depending on ethnicity.
Immune Abnormalities. Some experts suggest that certain individuals have abnormalities in the immune response of the intestine, which allow the bacteria to injure the lining.
Lifestyle Factors. Although lifestyle factors such as chronic stress, drinking coffee, and smoking were long believed to be primary causes of ulcers, it is now thought they only increase susceptibility to ulcers in some H. pylori carriers.
Shift Work and Other Causes of Interrupted Sleep. People who work the night shift have a significantly higher incidence of ulcers than day workers. Researchers suspect that frequent interruptions of sleep may weaken the ability of the immune system to protect against endotoxins.

When H. pylori was first identified as the major cause of peptic ulcers, it was found in 90% of people with duodenal ulcers and in about 80% of people with gastric ulcers. As more people are being tested and treated for the bacteria, however, the rate of H. pylori- associated ulcers has declined. For example, a 2001 study suggested that about half of ulcers are not caused by H. pylori. Instead, they tend to be caused by regular use of nonsteroidal anti-inflammatory drugs (NSAIDs), which include aspirin and other common pain relievers. Genetic factors or, rarely, Crohn's disease or Zollinger-Ellison syndrome, also cause ulcers.

Some researchers now believe that duodenal ulcers are not caused by H. pylori, but that the presence of the bacteria simply delays healing. This fact, they say, may explain why up to half of cases of acute duodenal perforation show no evidence of H. pylori, and why duodenal ulcers can recur even after H. pylori has been eradicated.

A 2006 study published in the Journal of Biological Chemistry indicates that a protein called decay-accelerating factor (DAF) acts as receptor for H. pylori. Animal studies show that blocking this interaction renders H. pylori harmless to the stomach. Researchers hope the discovery leads to new drugs that can reduce the risk of peptic ulcer.

Long-term use of NSAIDs is the second most common cause of ulcers, and the rate of NSAID-caused ulcers is increasing. About 20 million people take prescription NSAIDs regularly, and more than 25 billion tablets of over-the-counter brands are sold each year in the U.S. alone. The most common NSAIDs are aspirin, ibuprofen (Advil), and naproxen (Aleve, Naprosyn), although many others are available. Patients with NSAID-caused ulcers should stop taking these drugs.

There is no doubt NSAIDs increase the risk of ulcers and gastrointestinal (GI) bleeding. The risk of bleeding is continuous for as long as a patient takes these drugs and may persist for about one year after stopping. Short courses of NSAIDs for temporary pain relief should not cause major problems, because the stomach has time to recover and repair any damage that has occurred.

Specific NSAIDs pose greater or lesser risks for ulcers and bleeding. No NSAIDs, however, even over-the-counter brands, should be used long-term except under a doctor's direction.

Lowest Risk

Medium Risk

Highest Risk

Nabumetone (Relafen)

Etodolac (Lodine)

Salsalate

Sulindac (Clinoril)

Aspirin. Even low-dose ("baby") aspirin (81 mg) may pose some risk

Ibuprofen (Motrin, Advil, Nuprin, Rufen)

Naproxen (Aleve, Naprosyn, Naprelan, Anaprox)

Diclofenac (Voltaren), Tolmetin (Tolectin)

NOTE: Drugs in the medium risk group vary in risk. For example, studies show that naproxen is twice as likely as ibuprofen to be associated with hospitalization from GI bleeding.

Flurbiprofen (Ansaid), Piroxicam (Feldene), Fenoprofen Indomethacin (Indocin), Meclofenamate (Meclomen)

Ketoprofen (Actron, Orudis KT). Note: Ketoprofen is often considered a medium-risk drug, but one study reported that taking the drug in low doses for as little as 1 week causes significant GI injury.

Certain drugs other than NSAIDs may cause or aggravate ulcers, particularly those taken for cardiovascular disease and its risk factors. A review of more than 306,000 primary care patients found that spironolactone, a common diuretic prescribed in heart failure, was associated with a 2.7% increased risk of ulcer or upper GI bleeding. Exacerbation of peptic ulcers is a rare but noted side effect of niacin, a drug that can reduce LDL cholesterol and raise HDL cholesterol. Low-dose aspirin, dipyridamole, and vitamin K antagonists such as Coumadin nearly double the risk of upper GI bleeding. When these drugs are used in combination, the risk soars.

Risk of GI perforation was seen in phase 3 clinical trials of bevacizumab, the first vascular endothelial growth factor agent (VEGF) approved by the FDA. This drug has been shown to increase survival and stop the progression of metastatic colorectal cancer when used in combination with chemotherapy. While the benefits of bevacizumab outweigh the risks, GI perforation is very serious. If it occurs, the drug must be discontinued.

The least common major cause of peptic ulcer disease is Zollinger-Ellison syndrome (ZES).

Rarely, certain conditions may cause ulceration in the stomach or intestine, including:

Radiation treatments
Bacterial or viral infections
Alcohol abuse
Physical injury
Burns

What is ZES? Zollinger-Ellison syndrome (ZES) is the least common major cause of peptic ulcer disease. In this condition, tumors in the pancreas and duodenum (gastrinomas) produce excessive amounts of gastrin, a hormone that stimulates gastric acid formation. These tumors are usually malignant, so proper and prompt management of the disease is essential.

Another cause of peptic ulcer, although far less common than H. pylori or NSAIDs, is Zollinger-Ellison syndrome. A large amount of excess acid is produced in response to the overproduction of the hormone gastrin, which in turn is caused by tumors on the pancreas or duodenum. These tumors are usually malignant, must be removed and acid production suppressed to relieve the recurrence of the ulcers.

Who Gets ZES? The incidence of ZES in the United States is estimated at 1 case per million people per year, and at 0.1 - 1% among patients with peptic ulcers. The mean age at onset is 45 - 50, and men are affected more often than women.

How Is ZES Diagnosed? ZES should be suspected in patients with ulcers who are not infected with H. pylori and have no history of NSAID use. Diarrhea may precede ulcer symptoms. Ulcers occurring in the second, third, or fourth portions of the duodenum or the jejunum (the middle section of the small intestine) are signs of ZES. GERD is more prevalent and often more severe in patients with ZES, and can be complicated by ulcerations and strictures of the esophagus.

How Is ZES Treated? Peptic ulcers associated with ZES are typically persistent and difficult to treat. Treatment consists of removing the tumors and suppressing acid with an intravenous proton-pump inhibitor (Protonix). Previously, removing the stomach was the only option.

Symptoms

Dyspepsia. The most common symptoms of peptic ulcer are known collectively as dyspepsia. Peptic ulcers can occur without dyspepsia or any other gastrointestinal symptom, especially when caused by NSAIDs. Dyspepsia may be persistent or recurrent and can encompass a variety of symptoms in the upper abdomen, including:

Pain or discomfort
Bloating
A feeling of fullness. People with severe dyspepsia are unable to drink as much fluid as people with mild or no dyspepsia.
Hunger and an empty feeling in the stomach, often 1 - 3 hours after a meal
Mild nausea (Vomiting, in fact, may relieve symptoms.)
Regurgitation (sensation of acid backing up into the throat.)
Belching

Ulcer Pain. The pain of ulcers can be either localized in one place or diffuse. The pain is described as a burning, gnawing, or aching in the upper abdomen, or as a stabbing pain penetrating through the gut. The symptoms may vary depending on the location of the ulcer:

Duodenal ulcers often cause a gnawing pain in the upper stomach area several hours after a meal, and the pain is often relieved by eating a meal.
Gastric ulcers may cause a dull, aching pain, often right after a meal; eating does not relieve the pain and may even worsen it. Pain may also occur at night.

Ulcer pain may be particularly confusing or disconcerting when it radiates to the back or to the chest behind the breastbone. In such cases it can be confused with other conditions such as heart attack.

Because ulcers can cause hidden bleeding, patients may experience the symptoms of anemia, including fatigue and shortness of breath.

A sudden onset of severe symptoms may indicate intestinal obstruction, perforation, or hemorrhage, all of which are emergencies. Symptoms may include:

Tarry, black, or bloody stools
Severe vomiting, which may include blood or a substance with the appearance of coffee grounds (a sign of a serious hemorrhage) or entire stomach contents (sign of intestinal obstruction)
Severe abdominal pain with or without vomiting or evidence of blood

Anyone who experiences any of these symptoms should go to the emergency room immediately.

Peptic ulcers may lead to emergency situations. Severe abdominal pain with or without evidence of bleeding may indicate a perforation of the ulcer through the stomach or duodenum. Vomiting of a substance that resembles coffee grounds or the presence of black tarry stools may indicate serious bleeding.

Complications

Most people with severe ulcers experience significant pain and sleeplessness, which can have a dramatic and adverse impact on their quality of life.

Peptic ulcers caused by H. pylori or NSAIDs can be very serious if they hemorrhage or perforate the stomach or duodenum. Up to 15% of people with ulcers experience some degree of bleeding, which can be life-threatening. Ulcers that form where the small intestine joins the stomach can swell and scar, resulting in a narrowing or closing of the intestinal opening. In such cases, the patient will vomit the entire contents of the stomach, and emergency treatment is necessary.

Complications of peptic ulcers cause an estimated 6,500 deaths each year. These figures, however, do not reflect the high number of deaths associated with NSAID use. Ulcers caused by NSAIDs are more likely to bleed than those caused by H. pylori. NSAID-related bleeding and stomach problems may be responsible for as many as 107,000 hospital admissions and 16,500 deaths each year.

Because there are usually no GI symptoms from NSAID ulcers until bleeding begins, doctors cannot predict which patients taking these drugs will develop bleeding. The risk for a poor outcome is highest in people who have had long-term bleeding from NSAIDs, blood clotting disorders, low systolic blood pressure, mental instability, or the presence of another serious, unstable medical condition. Populations at greatest risk are the elderly and those with other serious conditions, such as heart problems.

H. pylori is strongly associated with certain cancers. Some studies have also linked it to a number of non-gastrointestinal illnesses as well, although the evidence is inconsistent.

Stomach Cancers. Stomach cancer, also called gastric cancer, is the second most common cause of cancer worldwide. In developing countries where the rate of H. pylori is very high, the risk of stomach cancer is 6 times higher than in the U.S. An important 2001 study strongly supported previous work that found a causal link between H. pylori infection and stomach cancer. In this study, uninfected people did not develop stomach cancer. However, the stomach cancer rates for H. pylori-associated conditions were 4.7% for nonulcer dyspepsia, 3.4% for gastric ulcers, and 2.2% of stomach polyps. Experts now suggest that H. pylori may be as carcinogenic to the stomach as cigarette smoke is to the lungs.

Eradication of H. pylori may reduce the risk of stomach cancer, but not eliminate it. A Japanese study found that continued risk is associated with degree of mucosal atrophy before H. pylori eradication therapy is started. This is something than can be measured during an endoscopy.

The process most likely starts in childhood. Infection with H. pylori promotes a precancerous condition called atrophic gastritis. This may lead to cancer through the following steps:

The stomach becomes chronically inflamed and loses patches of glands that secrete protein and acid.
Acid protects against carcinogens, substances that cause cancerous changes in cells.
New cells replace destroyed cells, but the new cells do not produce enough acid to protect against carcinogens.
Over time, cancer cells may develop and proliferate in the stomach.

Onset of H. pylori infection in adulthood poses a lower risk, since the development of atrophic gastritis takes years, and an adult is likely to die of other causes first. Other factors, such as specific genetic strains and diets, might also influence a higher risk for stomach cancer. For example, a diet high in salt and low in fresh fruits and vegetables has been associated with a greater risk. Some evidence suggests that the virulent H. pylori strain called cytotoxin-associated gene A (CagA) may also be a particular risk factor for precancerous changes.

Interestingly, people with duodenal ulcers caused by H. pylori appear to have a lower risk of stomach cancer, although scientists do not know why. It may be that different H. pylori strains affect the duodenum and the stomach. Or, the high levels of acid found in the duodenum may help prevent the spread of the bacteria to critical areas of the stomach.

Pancreatic Cancer. H. pylori has recently been linked to pancreatic cancer. The excess risk is high in patients with unoperated gastric ulcers -- 20% after 15 years and 50% after the first hospitalization. Surgery decreased the risk dramatically. Unoperated duodenal ulcers, on the other hand, were not associated with increased risk of pancreatic cancer.

Heart Disease. Some research has reported a very high rate of H. pylori infection in men with coronary artery disease, but more recent work has found no relationship between the bacteria and heart disease. A 2001 study suggested that the only relationship between H. pylori and heart disease may be that people with both tend to be in lower socioeconomic groups. Further studies are needed.

Other Diseases. H. pylori has also been weakly associated with other nonintestinal disorders, including migraine, Raynaud's disease (marked by cold extremities), and some skin disorders, such as chronic hives.

Risk Factors

About 25 million people in the U.S. are expected to develop peptic ulcers at some point in their lives. Peptic ulcer disease affects all age groups, but is rare in children. Men have twice the risk of ulcers as women. The risk of duodenal ulcers tends to rise beginning around age 25 and continues until age 75; gastric ulcers peak at age 55 - 65.

Peptic ulcers are less common than they once were. Research suggests that ulcer rates have even declined in areas with widespread H. pylori infection. The increased use of proton-pump inhibitor drugs may be responsible for this trend.

H. pylori grows and colonizes only in the intestinal tracts of primates. The bacteria are most likely transmitted directly from person to person. Still, little is yet known about its transmission.

Who Is Infected with H. pylori? About half the world's adults are infected with H. pylori. The bacteria are nearly always acquired during childhood and persist throughout life, if not treated. The prevalence in children ranges from less than 10% to more than 80%, with the highest infection rates (3 - 10%) in developing countries and the lowest (0.5%) in industrialized nations, where rates continue to decline. Even in industrialized countries, however, infection rates in regions with crowded, unsanitary conditions are equal to those in developing countries.

How Does the Bacteria Pass from Person to Person? It is not entirely clear how the bacteria are transmitted. One study did not find that infected students posed any risk for their classmates. Transmission within families may be the most important route for H. pylori. A 2002 study reported that spouses of people with peptic ulcers are at significantly higher risk for ulcers, suggesting that the bacteria may be transmitted during intimate contact. Some evidence suggests that bacteria may spread during GI tract illness, particularly when vomiting occurs. The bacteria also may be passed in stools. Since H. pylori can live in water, but not apparently in food, the bacteria may also be transmitting through sewage-contaminated water.

Who Is at Risk for Ulcers from H. pylori? Although H. pylori infection is common, ulcers in children are very rare, and only a minority of infected adults develops ulcers. Some known risk factors include smoking, alcohol use, having a relative with peptic ulcers, being male, and the presence of the cytotoxin-associated gene A (CagA). Experts are unable to determine, however, any single factor or group of factors that can determine which infected patients are most likely to develop ulcers.

Between 15 - 25% of patients who have taken NSAIDs regularly will have evidence of one or more ulcers, but in most cases these ulcers are very small. Given the widespread use of NSAIDs, however, the potential total number of people who can develop serious problems may be very large. Long-term NSAID use can damage the stomach and, possibly, the small intestine.

In April 2005, the FDA asked manufacturers of prescription NSAIDs to include with their products the same boxed warning used for the COX-2 inhibitor celecoxib (Celebrex). This boxed warning emphasizes the increased risk for cardiovascular events and GI bleeding in people taking these drugs. (Pharmaceutical companies are trying to develop new COX-2 inhibitors without these dangerous side effects. Early safety studies of the novel COX-2 inhibitor known as CS-706 showed its effect on gastric mucosa to be the same as placebo.)

The FDA also requested manufacturers of over-the-counter NSAIDs to revise their labels to include more specific language concerning potential cardiovascular and GI risks. Due to its proven heart benefits, aspirin was excluded from these labeling revisions.

Frequent Users of NSAIDs. Anyone who uses NSAIDs regularly is at risk for gastrointestinal problems. Even low-dose aspirin (81 mg) may pose some risk, although the risk is lower than with standard doses. In one 4-year study, 4.5% of regular NSAID users were hospitalized for GI bleeding. The highest risk, however, was found in people who require long-term use of very high-dose NSAIDs, notably patients with rheumatoid arthritis. Other people who take high doses of NSAIDs include those with chronic low back pain, fibromyalgia, and chronic stress.

Contributing Factors. Certain factors add to the risk for ulcers in NSAID-users:

Age 65 and older
History of peptic ulcers or upper gastrointestinal bleeding
Other serious ailments, such as congestive heart failure
Use of other medications, such as the anticoagulant warfarin (Coumadin), corticosteroids, or the osteoporosis drug alendronate (Fosamax)
Alcohol abuse
Those infected with H. pylori. A 2002 study reported that the combination of NSAID use and H. pylori posed a 3.5-fold greater risk of ulcers than either factor alone. However, not all studies have reported the higher risk in infected patients.

Stress and Psychological Factors. Although stress is no longer considered a cause of ulcers, studies still suggest that stress may predispose a person to ulcers or prevent existing ulcers from healing. Some experts estimate that social and psychological factors play a contributory role in 30 - 60% of peptic ulcer cases, whether they are caused by H. pylori or NSAIDs. Some experts even believe that the anecdotal relationship between stress and ulcers is so strong that treatment of psychological factors is warranted.

Smoking. Smoking increases acid secretion, reduces prostaglandin and bicarbonate production, and decreases mucosal blood flow. Results of studies on the actual effect of smoking on ulcers, however, are mixed. Some evidence suggests that smoking delays the healing of gastric and duodenal ulcers. One study reported that after ulcers healed, about half of nonsmokers experienced a relapse of their ulcer disease after 1 year, but that all heavy smokers relapsed after 3 months. Other studies have found no increased risk for ulcers in smokers. In any case, any impact of smoking on ulcers does not seem to be affected by the presence of H. pylori.

Tobacco use and exposure may cause an acceleration of coronary artery disease and peptic ulcer disease. It is also linked to reproductive disturbances, esophageal reflux, hypertension, fetal illness and death, and delayed wound healing.

Diagnosis

Peptic ulcers are always suspected in patients with persistent dyspepsia (bloating, belching, and abdominal pain). Dyspepsia, however, occurs in 20 - 40% of people who live in industrialized nations, and only about 15 - 25% of these people actually have ulcers. A number of steps are needed to make an accurate diagnosis of ulcers.

The doctor will ask for a thorough report of a patient's dyspepsia and other important symptoms, such as weight loss or fatigue, present and past medication use (especially chronic use of NSAIDs), family members with ulcers, and drinking and smoking habits.

In addition to peptic ulcers, a number of conditions, notably gastroesophageal reflux disease (GERD) and irritable bowel syndrome, cause dyspepsia. Often, however, no cause can be determined. In such cases, the symptoms are referred to collectively as functional dyspepsia.

Peptic ulcer symptoms, particularly abdominal pain and chest pain, may resemble those of other conditions, such as gallstones or heart attack. Certain features may help to distinguish these different conditions. However, symptoms often overlap, and it is impossible to make a diagnosis based on symptoms alone. A number of tests are needed.

The following disorders may be confused with peptic ulcers:

GERD. About half of patients with GERD also have dyspepsia. With GERD or other problems in the esophagus, the main symptom is usually heartburn, a burning pain that radiates up to the throat. It typically develops after meals and is relieved by antacids. The patient may have difficulty swallowing and may experience regurgitation or acid reflux. Elderly patients with GERD are less likely to have these symptoms, but instead may experience loss of appetite, weight loss, anemia, vomiting, or dysphagia (difficulty or painful swallowing). [See In-Depth Report #85: Gastroesophageal Reflux Disease.]
Heart Events. Cardiac pain, such as angina or a heart attack, is more likely to occur with exercise and may radiate to the neck, jaw, or arms. In addition, patients typically have distinct risk factors for heart disease, such as a family history, smoking, high blood pressure, obesity, or high cholesterol. [See In-Depth Report #12: Heart Attack.]
Gallstones. The primary symptom in gallstones is typically a steady gripping or gnawing pain on the right side under the rib cage, which can be quite severe and can radiate to the upper back. Some patients experience pain behind the breastbone. The pain is often precipitated by a fatty or heavy meal, but gallstones almost never cause dyspepsia. [See In-Depth Report #10: Gallstones and Gallbladder Disease.]
Irritable Bowel Syndrome. Irritable bowel syndrome can cause dyspepsia, nausea and vomiting, bloating, and abdominal pain. It occurs more often in women than in men.

Dyspepsia may also occur with gastritis, stomach cancer, or as a side effect of certain drugs, including NSAIDs, antibiotics, iron, corticosteroids, theophylline, and calcium blockers.

When ulcers are suspected, the doctor will prescribe tests to detect bleeding. These may include a rectal exam, a complete blood count, and a fecal occult blood test (FOBT). The FOBT tests for hidden (occult) blood in stools. Typically, the patient is asked to supply up to 6 stool specimens in a specially prepared package. A small quantity of feces is smeared on treated paper, which reacts to hydrogen peroxide. If blood is present, the paper turns blue.

Traditional radiology tests have not yet proven valuable for diagnosing ulcers. However, radiologists in France who performed multidetector computed tomography (MDCT) scans on preoperative patients with proven GI perforations found the technology to be highly accurate in pinpointing the location of the perforations.

Simple blood, breath, and stool tests can now detect H. pylori with a fairly high degree of accuracy. It is not entirely clear, however, which individuals should be screened for H. pylori.

Candidates for Screening. Some doctors currently test for H. pylori only in individuals with dyspepsia who also have high-risk conditions, such as:

Strong indication for ulcers, such as weight loss, anemia, or indications of bleeding
History of active ulcers
Risk factors for stomach cancer or other complications from ulcers

Smokers and those who experience regular and persistent pain on an empty stomach may also be good candidates for screening tests. Some doctors argue that testing for H. pylori may be beneficial for patients with dyspepsia who are regular NSAID users. In fact, given the possible risk for stomach cancer in H. pylori- infected people with dyspepsia, some experts now recommend that any patient with dyspepsia lasting longer than 4 weeks should have a blood test for H. pylori. This is a subject of considerable debate, however.

Specific Screening Tests for H. pylori. The following screening tests used or under investigation for H. pylori:

Breath Test. A simple test called the carbon isotope-urea breath test (UBT) can identify up to 99% of people who harbor H. pylori. Up to 2 weeks before the test, the patient must discontinue taking any antibiotics, bismuth-containing agents such as Pepto-Bismol, and proton-pump inhibitors (PPIs). As part of the test, the patient swallows a special substance containing urea (a compound in mammals metabolized from nitrogen) that has been treated with carbon atoms. If H. pylori is present, the bacteria convert the urea into carbon dioxide, which is detected and recorded in the patient's exhaled breath after 10 minutes.
Blood Tests. Blood tests are used to measure antibodies to H. pylori, with results available in minutes. Diagnostic accuracy is reported at 80 - 90%. One such important test is called enzyme-linked immunosorbent assay (ELISA). An ELISA test of the urine is also showing promise in children.
Stool Test. A test to detect genetic fingerprints of H. pylori in the feces appears to be as accurate as the breath test for initial detection of the bacteria and for detecting recurrences after antibiotic therapy.

It should be noted that such tests are not as accurate as endoscopy, an invasive procedure, which is needed to confirm a diagnosis of H. pylori. The breath and stool tests, however, can be particularly useful after treatment to determine if a patient has been cured.

Test and Treat. Depending on the results of the screening tests, some doctors take the following steps:

Approach for Noninfected Individuals. People who do not have evidence of H. pylori on a blood or breath test are typically given a 4-week course of acid-suppressing medication, usually a PPI such as omeprazole (Prilosec).
Approach for H. pylori-Infected Individuals. Patients with evidence of bacterial infection are given antibiotics. If this does not relieve symptoms, they are given a 6-week course of the PPI omeprazole (Prilosec). (Whether to give antibiotics to infected patients with non-ulcer dyspepsia is controversial and is discussed in the section, What Are the Guidelines for Treating Peptic Ulcers Caused by H. pylori?)

If symptoms persist, endoscopy is usually performed. Endoscopy is an invasive procedure, but is the only procedure in which a biopsy of stomach tissue can be taken, making it the most accurate test.

Experts debate whether endoscopy should be performed on all patients who do not respond to initial medication, since it does not appear to add any useful information on treatment choices, unless there is evidence or suspicion of bleeding or serious complications.

While endoscopy is the gold standard for diagnosing upper GI disorders, because it allows doctors to biopsy the stomach, 3-dimensional CT imaging may also be valuable. Researchers in China compared the results of endoscopy to the results of noninvasive CT imaging performed to diagnose GI disease. They found that the CT imaging correctly diagnosed 50 of 52 cases, including 5 cases of peptic ulcer disease. Three-dimensional CT imaging clearly showed the GI tract lesions. It is currently considered a valuable complement to endoscopy.

Endoscopy is a procedure used to evaluate the esophagus, stomach, and duodenum using a long, thin tube tipped with a tiny video camera (endoscope). When combined with biopsy, endoscopy is the most accurate procedure for detecting the presence of peptic ulcers, bleeding, and stomach cancer, or for confirming the presence of H. pylori.

Appropriate Candidates for Endoscopy. Because endoscopy is invasive and expensive, it is unsuitable for screening everyone with dyspepsia. Most individuals with these symptoms are managed effectively without endoscopy. Endoscopy is usually reserved for patients with dyspepsia who also have risk factors for ulcers, stomach cancer, or both. Such factors include the following:

Having so-called "alarm" symptoms (unexplained weight loss, gastrointestinal bleeding, vomiting, difficulty swallowing, or anemia).
Being over 45 (when the risk for stomach cancer increases).

There is some debate whether patients under 45 with persistent dyspepsia and no alarm symptoms should have endoscopy.

The Procedure. Endoscopy may be performed in a hospital, doctor's office, or outpatient surgery center, and typically involves the following:

The doctor administers a local anesthetic using an oral spray and an intravenous sedative to suppress the gag reflex and relax the patient.
The doctor then places the thin, flexible plastic tube into the patient's mouth and down the esophagus into the stomach.
A tiny camera in the endoscope allows the doctor to see the surface of the esophagus, stomach, and duodenum, and to search for abnormalities.
The doctor will remove about 10 small tissue samples (biopsies), which will be tested for H. pylori.

In endoscopy, the doctor places a long, thin, flexible tube (called an endoscope) down the patient's throat and into the stomach and duodenum. A camera and light on the tip of the endoscope enables the doctor to check for abnormalities. Tiny samples may be taken to check for H. pylori bacteria, a cause of many peptic ulcers. If a bleeding ulcer is found, it may be sealed with a burning tool (cauterized) during the procedure.

Note: Some evidence suggests that patients who take PPIs should stop taking the medication 2 weeks before an endoscopy, since it may mask ulcers.

Capsule Endoscopy.Capsule endoscopy involves swallowing a capsule the size of a large vitamin, which contains tiny camera, light source, and radio transmitter. The device takes pictures as it passes through the intestinal tract. At this point, its benefits are limited to the small intestine, so it is unlikely to play a role in the diagnosis of peptic or gastric ulcers. However, capsule endoscopy has the potential to be an important tool for the diagnosis of obscure upper GI bleeding. Patients who have used it have usually found it painless and preferable to conventional endoscopy.

An upper GI (gastrointestinal) series was the standard diagnostic method for peptic ulcers until the introduction of adequate tests for detecting H. pylori. In an upper GI series, the patient drinks a solution containing barium. X-rays are then taken, which may reveal inflammation, active ulcer craters, or deformities and scarring due to previous ulcers. Endoscopy is more accurate, although it is more invasive and expensive.

Click the icon to see an illustrated series detailing treatment of GI bleeding.

Stool tests may show traces of blood that are not visible to the naked eye, and blood tests may reveal anemia in those who have bleeding ulcers. If Zollinger-Ellison syndrome is suspected, blood levels of gastrin should be measured.

Treatment

Antibiotic regimens that eradicate H. pylori can cure peptic ulcers and are now the standard medications used for ulcers in infected individuals who are not taking NSAIDs. Eliminating H. pylori can also cure the rare MALT lymphomas caused by this bacterium. Other drugs, such as proton-pump inhibitors or H2 blockers, are useful for relieving ulcer symptoms.

Patients with Clear Evidence of Ulcers. Antibiotics are clearly indicated for patients who have both ulcers and H. pylori infection. Despite such clear indications, however, European and American studies continue to suggest that many doctors only treat symptoms and not the ulcers themselves. Studies also suggest that most doctors do not counsel patients on the potential dangers of NSAIDs and other drugs that can cause ulcers.

There is considerable debate about whether to test for H. pylori and treat infected patients who have dyspepsia, but no evidence of ulcers.

The best approach for treating dyspepsia is highly controversial. Options include the following:

Test and Treat. This approach involves testing for H. pylori and eradicating the bacteria in infected patients.
Prescribing potent acid-suppressing agents. This approach generally employs a trial of potent acid-suppressing drugs called proton-pump inhibitors (PPIs), such as omeprazole (Prilosec) or esomeprazole (Nexium).

In either case, endoscopy is usually performed if symptoms persist after 4 weeks. Some evidence suggests that PPIs may mask ulcers, so patients taking these drugs may need to discontinue them for 2 weeks before endoscopy.

Arguments for Testing and Treating Patients with Dyspepsia. The argument supporting testing and treating patients with nonulcer dyspepsia is as follows:

Protection against ulcers. Some evidence suggests that antibiotic treatments for infected patients with dyspepsia may prevent ulcers from developing. A 2002 study found that antibiotic regimens to eradicate H. pylori greatly decreased the likelihood of ulcers in infected patients with nonulcer dyspepsia who were chronic NSAID users.
Protection against gastric cancer. Some evidence suggests that eradicating H. pylori may prevent or delay the onset of stomach cancer in people with long-term dyspepsia who are infected with the bacteria. A large 2001 study conducted in Japan, where gastric cancer is especially common, found that such cancers developed in about 3% of infected patients with nonulcer dyspepsia. However, none occurred in dyspeptic patients who were treated with antibiotics for H. pylori.

Arguments against Testing and Treating Patients with Dyspepsia. The arguments against testing and treating are as follows:

Lack of significant effect on symptoms. Studies are mixed on whether antibiotics have much effect on dyspepsia symptoms. In a 2003 study, overall symptom scores after 1 year were not significantly different between dyspeptic patients who were treated for H. pylori and patients who were maintained on PPIs.
Lower rates of H. pylori in the U.S. The number of people with H. pylori infection is declining in the U.S., possibly making the test-and-treat approach too expensive for the number of people it helps.
Increased risk for gastroesophageal reflux disease (GERD). A number of studies suggest that H. pylori in the intestinal tract protects against GERD, which in severe cases can be a risk factor for cancer of the esophagus. Eliminating H. pylori may also have other adverse effects.
Overuse of antibiotics. Concern that such treatments without clear evidence of ulcers will lead to unnecessary antibiotic prescriptions, increasing the risk for side effects. Overuse may also contribute to a growing public health problem -- the emergence of bacteria that are resistant to antibiotics.

The standard treatment regimen for H. pylori uses 2 antibiotics and a PPI. Cure rates after antibiotic treatment range from 70 - 90%. A typical regimen contains three drugs:

A PPI. These drugs include omeprazole (Prilosec), lansoprazole (Prevacid), esomeprazole (Nexium), and rabeprazole (Aciphex). PPIs are important for all types of peptic ulcers, and are a critical partner in antibiotic regimens. They reduce acidity in the intestinal tract, and increase the ability of antibiotics to destroy H. pylori.
Two antibiotics. The standard antibiotics are clarithromycin (Biaxin) and amoxicillin. Some doctors substitute the antibiotic metronidazole (Flagyl) for either clarithromycin or amoxicillin.

This combination treatment is typically taken for at least 14 days. Many studies, however, suggest that a 7-day treatment may work just as well. A report published in 2006 evaluated a shorter course of treatment using the PPI rabeprazole and 2 antibiotics. They found that a 4-day treatment eliminated H. pylori and was associated with fewer side effects. A study published in 2007 comparing 1- and 2-week treatments with amoxicillin, clarithromycin, and omeprazole for H. pylori eradication found both regimens to be similar in efficacy, safety, and compliance.

Interestingly, an Italian study indicated that giving antibiotics sequentially instead of at the same time may be even more effective. The researchers found that patients who took amoxicillin for 5 days, followed by clarithromycin for 5 days, had higher H. pylori eradication rates (89%) than those who took both antibiotics for 10 days (77%).

A 2007 study showed that eradication rates with this 3-drug regimen could be improved, and side effects reduced, by adding probiotics ("good" bacteria) and the milk protein bovine lactoferrin. These products are often found in yogurts and other forms of fermented milk.

Follow-Up. Follow-up testing for the bacteria should be done no sooner than 4 weeks after therapy is completed. Test results before that time may not be accurate.

In most cases, drug treatment relieves ulcer symptoms. However, symptom relief does not always indicate success, nor does persistence of dyspepsia necessarily mean that treatment has failed. Heartburn and other symptoms from GERD, for example, can worsen and require acid-suppressing medication.

Failure. Treatment fails in about 15% of patients, mostly when they fail to adhere to the regimen. Compliance with standard antibiotic regimens may be poor for the following reasons:

The triple-drug regimens are complicated and require many pills. Helicide or two-drug combinations may help offset this problem.
About 30% of patients suffer side effects from the H. pylori regimen. Gastrointestinal problems are very common, and severe diarrhea can occur.

Treatment may also fail if the patients harbor strains of H. pylori that are resistant to the antibiotics. When this happens, different drugs are tried.

Reinfection after Successful Treatment. Studies in developed countries indicate that once the bacteria are eliminated, recurrence rates are below 1% per year. Reinfection with the bacteria is possible, however, in areas where the incidence of H. pylori is very high and sanitary conditions are poor. In such regions, reinfection rates are 6 - 15%.

Weight Gain. Some patients may gain weight.

Gastroesophageal Reflux Disease. Of ongoing interest are reports of a lower incidence of H. pylori in patients with GERD. There are some important unanswered questions associated with this issue:

Is the lower incidence of H. pylori in GERD patients significant, and does the bacteria actually protect against GERD? Studies have not conclusively found any significant risk for GERD in people who are not infected with H. pylori, except possibly in certain regions. In a 2003 study, the absence of H. pylori infection in people with GERD was more pronounced in Asian patients than in those from Europe and North America. That being said, guidelines for eradication of H. pylori infection published in 2007 by the European Helicobacter Study Group state that "Eradication of H. pylori infection does not cause gastroesophageal reflux disease (GERD) or exacerbate GERD, and may prevent peptic ulcer in patients who are naive users of NSAIDs."
Does eliminating the bacteria with antibiotic therapy actually produce GERD in some people? One study observed that patients cured of H. pylori infection were twice as likely to develop GERD as those who remained infected. However, a 2003 analysis of 8 studies reported no higher risk for GERD after antibiotic treatments. In addition, GERD patients did not experience worsening of symptoms. Longer follow-up studies are needed however to determine the long-term consequences, if any.
What is the proper management of people who have GERD and H. pylori infection? Patients with severe GERD usually require on-going therapy with PPIs, which are powerful acid-suppressors. Some evidence suggests that in such patients, the combination of H. pylori and chronic acid suppression may lead to atrophic gastritis, a precancerous condition in the stomach. Guidelines then advocate eliminating the bacteria with antibiotics. There is some concern that once the bacteria are eliminated, however, GERD may worsen, which can pose a risk for Barrett's esophagus, which is also a precancerous condition. On the encouraging side, however, evidence to date does not suggest any higher risk for more serious GERD complications after H. pylori is eliminated.

Effects on Other Gastrointestinal Infections. In children, there is some evidence that H. pylori protects against E. coli and other GI infections, particularly those that cause diarrhea. If this is true, treating infected children for H. pylori should be done only if the bacteria are causing harm.

Click the icon to see an animation on ulcer treatment.

Treatment for NSAID-Induced Ulcers

Preventing Ulcers or Rebleeding Caused by NSAIDs. If NSAID-caused ulcers or bleeding are identified, patients should:

Get tested for H. pylori and, if they are infected, take antibiotics.
Possibly use a PPI. Studies suggest these medications lower the risk for NSAID-caused ulcers, although they do not completely prevent them.

People who still need to take NSAIDs should:

Use the lowest NSAID dose possible.
Try the prescription drugs misoprostol (Cytotec) or Arthrotec. Misoprostol works as well as a PPI, however, it has many side effects. Arthrotec is a combination of misoprostol and the NSAID diclofenac.

A warning to women: misoprostol can induce labor at any stage of pregnancy. Pregnant women should not use the drug.

Healing Existing Ulcers. A number of drugs are used to treat NSAID-caused ulcers. PPIs -- omeprazole (Prilosec), lansoprazole (Prevacid), or esomeprazole (Nexium) -- are used most often. Other drugs that may be useful include H2 blockers, such as famotidine (Pepcid AC), cimetidine (Tagamet), and ranitidine (Zantac). Sucralfate is another drug used to heal ulcers and reduce the stomach upset caused by NSAIDs.

COX-2 Inhibitors (Coxibs). Coxibs block an inflammation-promoting enzyme called COX-2. This drug class was initially thought to work as well as NSAIDs, while causing less gastrointestinal distress. However, following numerous reports of cardiovascular events, the FDA banned rofecoxib (Vioxx) and valdecoxib (Bextra) from use in the U.S. Celecoxib (Celebrex) is still available, but patients should discuss with their doctor whether this drug is appropriate and safe for them.

Arthrotec. Arthrotec is a combination of misoprostol and the NSAID diclofenac. It may reduce the risk for gastrointestinal bleeding. One study found that patients taking Arthrotec had 65 - 80% fewer ulcers than those who took NSAIDs alone.

Acetaminophen. Acetaminophen (Tylenol, Anacin-3) is the most common alternative to NSAIDs. Acetaminophen is inexpensive and generally safe. It poses far less of a risk of gastrointestinal problems than NSAIDs. It does have some adverse effects, however, and the daily dose should not exceed 4 grams (4,000 mg); some studies suggest that ulcer risk is increased even in doses exceeding 2 grams (2,000 mg) a day, if the drug is used on a long-term basis. Patients who take high doses of acetaminophen for long periods are also at risk for liver damage, particularly if they drink alcohol. It may pose a small risk for serious kidney complications in people with preexisting kidney disease, although acetaminophen remains the drug of choice for patients with impaired kidney function.

Tramadol. Tramadol (Ultram) is a pain reliever that has been used as an alternative to opioids. It has opioid-like properties, but is not as addictive. However, dependence and abuse have been reported. It can cause nausea, but does not cause severe gastrointestinal problems, as NSAIDs can. Some patients experience severe itching. A combination of tramadol and acetaminophen (Ultracet) provides more rapid pain relief than tramadol alone and more durable relief than acetaminophen alone. Side effects are the same as for each of these agents.

Medications

The following drugs are sometimes used in the treatments of peptic ulcers caused by either NSAIDs or H. pylori. They are described in alphabetical order.

Many antacids are available without prescription and are the first drugs recommended to relieve heartburn and mild dyspepsia. They play no major role in either the prevention or healing of ulcers, but help in the following ways:

All rely on various combinations of three basic compounds -- magnesium, calcium, or aluminum -- to neutralize stomach acid.
They may defend the stomach by increasing acid-buffering bicarbonate and mucus secretion.

It is generally believed that liquid antacids work faster and are more potent than tablets, although some evidence suggests that both forms work equally well.

Basic Salts Used in Antacids. There are three basic salts used in antacids:

Magnesium. Magnesium compounds are available in the form of magnesium carbonate, magnesium trisilicate, and, most commonly, magnesium hydroxide (Milk of Magnesia). The major side effect of these magnesium compounds is diarrhea.
Calcium. Calcium carbonate (Tums, Titralac, and Alka-2) is a potent and rapid-acting antacid, but it can cause constipation. There have been rare cases of hypercalcemia (elevated levels of calcium in the blood) in people taking calcium carbonate for long periods of time. Hypercalcemia can lead to kidney failure.
Aluminum. The most common side effect of antacids containing aluminum compounds (Amphogel, Alternagel) is constipation. Maalox and Mylanta are combinations of aluminum and magnesium, which balance the side effects of diarrhea and constipation. People who take large amounts of antacids containing aluminum may be at risk for calcium loss and osteoporosis. Long-term use also increases the risk of kidney stones. People who have recently experienced GI bleeding should not use aluminum compounds.

Interactions with Other Drugs. Antacids can reduce the absorption of a number of drugs. Conversely, some antacids increase the potency of certain drugs. The interactions can be avoided by taking these other drugs 1 hour before or 3 hours after taking the antacid.

Drugs that are absorbed less well if taken with antacids

Drugs that are made more potent by antacids

Tetracycline

Ciprofloxacin (Cipro)

Propranolol (Inderal)

Captopril (Capoten)

Ranitidine (Zantac)

Famotidine (Pepcid AC)

Valproic acid

Sulfonylureas

Quinidine

Levodopa

H. pylori is usually highly sensitive to certain antibiotics, particularly amoxicillin, and to antibiotics in the macrolide class, such as clarithromycin. Either type of agent serves effectively as a second antibiotic in a three-drug regimen. Other antibiotics that are sometimes used include tetracycline, metronidazole, and ciprofloxacin.

Amoxicillin is the most common form of penicillin. It is inexpensive, but many people are allergic to it.
Clarithromycin (Biaxin) is a macrolide and is the most expensive antibiotic used against H. pylori. It is very effective, but there is growing bacterial resistance to this drug. Resistance rates tend to be higher in women and increase with age. Researchers fear that resistance will increase as more people use the drug.
Tetracycline is effective, but this medicine has unique side effects, including skin reactions to sunlight, possible burning in the throat, and tooth discoloration. Pregnant women cannot take tetracycline.
Ciprofloxacin (Cipro), a fluoroquinolone, is also sometimes used in ulcer regimens.
Metronidazole (Flagyl) was the mainstay in initial combination regimens for H. pylori. As with clarithromycin, however, there continues to be growing bacterial resistance to the drug. Today, about 25 - 35% of H. pylori bacteria are metronidazole-resistant.

Side Effects of Antibiotics.

The most common side effects of nearly all antibiotics are gastrointestinal problems such as cramps, nausea, vomiting, and diarrhea.
Allergic reactions can also occur with all antibiotics, but are most common with medications derived from penicillin or sulfa. These reactions can range from mild skin rashes to rare, but severe -- even life-threatening -- anaphylactic shock.
Some drugs, including certain over-the-counter medications, interact with antibiotics; patients should report to all medications they are taking to their doctor.
Antibiotics double the risk of vaginal infections in women.

Compounds that contain bismuth are often used in the three-drug antibiotic regimens. They destroy the cell walls of H. pylori bacteria. The only bismuth compound available in the U.S. has been bismuth subsalicylate (Pepto-Bismol), although a drug combination of the H2 blocker ranitidine and bismuth citrate (Tritec) has been released. High doses can cause vomiting and depression of the central nervous system, but the doses given for ulcer patients rarely cause side effects.

H2 blockers interfere with acid production by blocking histamine, a substance produced by the body that encourages acid secretion in the stomach. H2 blockers were the standard treatment for peptic ulcers until antibiotic regimens against H. pylori were developed. These drugs cannot cure ulcers, but they are useful in certain cases. They are effective only for duodenal ulcers, however.

Four H2 blockers are currently available over-the-counter in the U.S.: famotidine (Pepcid AC), cimetidine (Tagamet), ranitidine (Zantac), and nizatidine (Axid). All have good safety profiles and few side effects. There are some differences between these drugs:

Famotidine (Pepcid AC). Famotidine is the most potent H2 blocker. The most common side effect is headache, which occurs in 4. 7% of people who take it. Famotidine is virtually free of drug interactions, but it may have significant adverse effects in patients with kidney problems.
Cimetidine (Tagamet). Cimetidine has few side effects; about 1% of people taking cimetidine experience mild temporary diarrhea, dizziness, rash, or headache. Cimetidine interacts with a number of commonly used medications, including phenytoin, theophylline, and warfarin. Long-term use of excessive doses (more than 3 grams a day) may cause impotence or breast enlargement in men. These problems resolve after the drug is discontinued.
Ranitidine (Zantac). Ranitidine interacts with very few drugs. In one study, ranitidine provided more pain relief and healed ulcers more quickly than cimetidine in people younger than age 60, but there was no difference in older patients. A common side effect of ranitidine is headache, which occurs in about 3% of people who take it.

That being said, a literature review of clinical trials showed that the PPIs are more effective than the H2 blockers in healing ulcers in people who take NSAIDs. After 8 weeks of treatment, healing rates of both gastric and duodenal ulcers were:

92% and 88% with esomeprazole 40 mg and 20 mg (vs 74% with ranitidine).
87% and 84% with omeprazole 40 mg and 20 mg (vs 64% with ranitidine).
And 73 - 74% and 66 - 69% with lansoprazole 30 mg and 15 mg (vs 50 - 53% with ranitidine).
However, healing rates with ranitidine reached nearly 100% when NSAIDs were discontinued.

Nizatidine (Axid). Nizatidine is nearly free of side effects and drug interactions.

Long-Term Concerns. In most cases, these H2 blockers have good safety profiles and few side effects. Because H2 blockers can interact with other drugs, be sure to tell your doctor about any other drugs you are taking. There are also some concerns about possible long-term effects -- for example, that long-term acid suppression with these drugs may cause cancerous changes in the stomach in patients who also have untreated H. pylori infection. More research is needed. However, the following concerns are real:

Liver damage. This is more likely with ranitidine than other H2 blockers, but is rare in any event.
Kidney-related complications. With famotidine, adverse effects on the central nervous system in patients with even moderate kidney insufficiency have been reported, resulting in anxiety, depression, and mental disturbances.
Increased risk for pneumonia in hospitalized patients.
Ulcer perforation and bleeding. Some experts are concerned that the use of acid-blocking drugs may actually increase the risk for serious complications by masking the ulcer's symptoms.

Misoprostol (Cytotec) increases prostaglandin levels in the stomach lining, which protects against the major intestinal toxicity of NSAIDs.

Actions against Ulcers. Misoprostol can reduce formation of ulcers in the upper small intestine by two-thirds and in the stomach by three-fourths. It does not neutralize or reduce acid, so although the drug is helpful for preventing NSAID-induced ulcers, it is not useful in healing existing ulcers.

Side Effects.

Diarrhea and other gastrointestinal problems are severe enough to cause 20% of patients to stop taking the drug. Taking misoprostol after meals should minimize these effects. One study indicated that taking the drug 2 - 3 times a day, instead of the standard regimen of 4 times, may prove to be just as effective and cause fewer side effects.
Misoprostol can induce abortion or cause birth defects and should not be taken by pregnant women. If pregnancy occurs during treatment, the drug should be discontinued at once and the doctor contacted immediately.

Actions against Ulcers. PPIs are the drugs of choice for managing patients with peptic ulcers from any cause. They suppress the production of stomach acid by blocking the gastric acid pump -- the molecule in the stomach glands that is responsible for acid secretion.

PPIs can be used either as part of a multidrug regimen for H. pylori or alone for preventing and healing NSAID-caused ulcers. One retrospective study found that adding a PPI to diclofenac therapy reduced hospitalization for ulcers by 60%. They are also useful in treating ulcers caused by Zollinger-Ellison syndrome. Some people carry a gene that reduces the effectiveness of PPIs. This gene is present in 18 - 20% of people of Asian descent.

Standard Brands. Most PPIs are available by prescription as oral drugs. There is no evidence that one brand of PPI works better than another. Brands approved for ulcer prevention and treatment include:

Omeprazole (generic, Prilosec OTC)
Esomeprazole (Nexium)
Lansoprazole (Prevacid)
Rabeprazole (Aciphex)

Possible Adverse Effects.

Side effects are uncommon, but may include headache, diarrhea, constipation, nausea, and itching.
Pregnant women and nursing mothers should avoid taking PPIs, although recent studies suggest that these drugs do not increase the risk of birth defects.
PPIs may interact with certain drugs, such as antiseizure agents (such as phenytoin), antianxiety drugs (such as diazepam), and blood thinners (such as warfarin).
Long-term use of high-dose PPIs may produce vitamin B12 deficiency, but studies are needed to confirm this risk.
In theory, long-term use of PPIs by people with H. pylori may reduce acid secretion enough to cause atrophic gastritis (chronic inflammation of the stomach), a risk factor for stomach cancer. Long-term use of PPIs may also mask symptoms of stomach cancer and delay diagnosis. At this time, however, there have been no reports of an increase in stomach cancer with long-term use of these drugs.

Sucralfate (Carafate) seems to work by adhering to the ulcer crater and protecting it from further damage by stomach acid and pepsin. It also promotes the defensive processes of the stomach. Sucralfate has an ulcer-healing rate similar to that of H2 blockers. Other than constipation, which occurs in 2.2% of patients, the drug has few side effects. Sucralfate does interact with a wide variety of drugs, however, including warfarin, phenytoin, and tetracycline.

Treatment for Bleeding Ulcers

When a patient comes to the hospital with bleeding ulcers, endoscopy is usually performed. This procedure is critical for the diagnosis, determination of treatment options, and treatment of bleeding ulcers.

In high-risk patients or those with evidence of bleeding, options include watchful waiting with medical treatments or surgery. The first critical steps for massive bleeding are to stabilize the patient and support vital functions with fluid replacement and possibly blood transfusions. People on NSAIDs should discontinue them, if possible.

Depending on the intensity of the bleeding, patients can be released from the hospital within a day or kept up to 3 days after endoscopy. Bleeding stops spontaneously in about 70 - 80% of patients, but about 30% of patients who come to the hospital for bleeding ulcers need surgery. Endoscopy is the surgical procedure most often used for treating bleeding ulcers and patients at high-risk for rebleeding. It is usually combined with medications, such as epinephrine and intravenous proton-pump inhibitors.

Between 10 - 20% of patients require more invasive procedures for bleeding, usually major abdominal surgery.

Endoscopy is important for both diagnosing and treating bleeding ulcers. The doctor first places a thin, flexible plastic tube called an endoscope into the patient's mouth and down the esophagus into the stomach.

Endoscopy for Diagnosing Bleeding Ulcers and Determining Risk of Rebleeding. With endoscopy, doctors are able to detect the signs of bleeding, such as active spurting or oozing of blood from arteries. Endoscopy can also detect specific features in the ulcers referred to as stigmata, which indicate a higher or lower risk of rebleeding.

Such features include the following:

Low risk (5 -15%) for bleeding: flat dot; a clean or white base.
High risk (30 - 50%) for bleeding: swollen but nonbleeding blood vessels; blood clots that adhere to ulcers.
According to one study, if patients with these high-risk features are untreated, their risk for rebleeding after endoscopy ranges from about 10% on the first day after endoscopy to about 3% by the third day. Identifying and treating patients with stigmata can reduce these risks. Other factors that increase the risk for rebleeding include bleeding disorders, very low blood pressure, other serious medical conditions, and bleeding that started after hospitalization.
After endoscopy, high-dose PPI therapy has been shown to significantly reduce the rate of rebleeding, need for surgery, and death from hemorrhage. The medication may be given intravenously, but studies show that oral PPI therapy is probably just as effective.

Endoscopy as Treatment. Endoscopy is usually used to treat bleeding from visible vessels that are less than 2 mm in diameter. This approach also appears to be very effective in preventing rebleeding in patients whose ulcers are not bleeding, but who have high-risk features (swollen blood vessels or clots adhering to ulcers).

The following is a typical endoscopy procedure:

The surgeon passes a probe through an endoscopic tube and applies electricity, heat, or small clips to coagulate the blood and stop the bleeding. This procedure also causes fluid buildup, which helps to compress the blood vessels.
In high-risk cases, the doctor may inject epinephrine (commonly known as adrenaline) directly into the ulcer to enhance the effects of the heating process. Epinephrine activates the process leading to blood coagulation, narrows the arteries, and enhances blood clotting.
Intravenous (IV) administration of a PPI (usually omeprazole or pantoprazole) significantly prevents rebleeding and appears to be cost-effective. In one study, the use of IV PPIs reduced the risk of bleeding from 23% to 7%. (Oral PPIs are also effective, but studies are needed to compare their effectiveness versus IV PPIs.) A PPI may also be useful for initial bleeding episodes when endoscopy is unsuccessful, inappropriate, or unavailable.

Intravenous H2 blockers are often used, but a major analysis reported no benefit in bleeding duodenal ulcers, although they may be effective in gastric ulcers.

Endoscopy is effective in controlling bleeding in more than 85% of appropriate candidates. If rebleeding occurs, a repeat endoscopy is effective in about 75% of patients. Those who fail to respond require major abdominal surgery. The most serious complication from endoscopy is perforation of the stomach or intestinal wall, which occurred in about 1.4% of patients in a large 2002 study.

While endoscopy and clipping are routine treatment for bleeding ulcers in the U.S., a Korean study found little difference in outcomes between clipping (plus H2 therapy) and oral PPI therapy alone. In a randomized test of 129 patients, hemostasis (end of bleeding) was achieved in 93.5% of patients after clipping and 92.5% of patients on oral PPIs at 24 hours. The rate of rebleeding was 6.9% with clipping and 7.5% with PPIs.

Other Medical Considerations. Certain agents may be warranted after endoscopy:

Patients who harbor the H. pylori bacteria, even when the bleeding has been caused by NSAID use, should be treated with antibiotic therapy to eliminate the bacteria. Triple therapy, including antibiotics, to eliminate H. pylori immediately after endoscopy is warranted in most patients infected with the bacteria.
Somatostatin (a hormone used to prevent bleeding in cirrhosis) is also useful for reducing persistent peptic ulcer bleeding or the risk of recurrence. Researchers are investigating adding other therapies, such as fibrin glue, a blood clotting factor. To date, no therapy has proven to be more effective than current treatments.

Major abdominal surgery for bleeding ulcers is now generally performed only when endoscopy fails or is not appropriate. Certain emergencies may require surgical repair, such as when an ulcer perforates the wall of the stomach or intestine, causing sudden intense pain and life-threatening infection.

Surgical Approaches. The standard major surgical approach uses a wide abdominal incision and standard surgical instruments (called open surgery). Laparoscopic techniques employ small abdominal incisions and the insertion of tubes that contain miniature cameras and instruments. Laparoscopic techniques are increasingly being used for perforated ulcers. Surgery is not effective for upper GI ulceration caused by chronic NSAID use.

Major Surgical Procedures. There are a number of surgical procedures aimed at long-term relief of ulcer complications. These include:

Click the icon to see an illustrated series detailing a gastrectomy procedure.

Vagotomy, in which the vagus nerve is cut to interrupt messages from the brain that stimulate acid secretion in the stomach. This surgery may impair stomach emptying. A recent variation that cuts only parts of the nerve may reduce this complication.
Antrectomy, in which the lower part of the stomach is removed. This part manufactures the hormone responsible for stimulation of digestive juices.
Pyloroplasty, which enlarges the opening into the small intestine so that stomach contents can pass into it more easily.

Antrectomy and pyloroplasty are usually performed with vagotomy.

Lifestyle Changes

In the past, it was common practice to tell people suffering from peptic ulcers to consume small, frequent amounts of bland foods. Exhaustive research conducted since that time has shown that a bland diet is not effective in reducing the incidence or recurrence of ulcers, and that eating numerous small meals throughout the day is no more effective than eating three meals a day. Large amounts of food should still be avoided, because stretching the stomach can result in painful symptoms.

Fruits and Vegetables. The good news is that a diet rich in fiber may cut the risk of developing ulcers in half and speed healing of existing ulcers. Fiber found in fruits and vegetables is particularly protective; vitamin A contained in many of these foods may increase the benefit. Some studies on associations between specific food chemicals and ulcers are as follows:

In one study, apples and yams appeared to be especially helpful.
Apples, celery, cranberries, onions, red wine, and green and black tea are also high in natural chemicals known as flavonoids, which appear to inhibit H. pylori growth and have many other health benefits. Cranberry juice specifically may have properties that help prevent H. pylori from infecting the intestinal lining.
Grapefruit has antioxidant properties that may help heal ulcers.
Studies on rats have found that dietary nitrate increases nitric oxide in the gut and causes the mucus layer to thicken. Pretreatment with nitrate provided dramatic protection against diclofenac-induced ulcers. High levels of dietary nitrate are found in many vegetables.
Laboratory experiments suggest that sulforaphone, a compound found in broccoli and broccoli sprouts, may be lethal to even drug-resistant strains of H. pylori.
Tea has chemicals that may help protect against cancers in the stomach and esophagus.

Milk. Milk actually encourages the production of acid in the stomach, although moderate amounts (2 - 3 cups a day) appear to do no harm. Animal studies show that a milk protein called bovine alpha-lactalbumin protects against gastric ulcers caused by stress. Certain probiotics, which are "good" bacteria added to yogurt and other fermented milk drinks, may also have gastric protective qualities.

Coffee and Carbonated Beverages. Coffee (both caffeinated and decaffeinated), soft drinks, and fruit juices with citric acid increase stomach acid production. Although no studies have proven that any of these drinks contribute to ulcers, consuming more than 3 cups of coffee per day may increase susceptibility to H. pylori infection.

Spices and Peppers. Studies conducted on spices and peppers have yielded conflicting results. The rule of thumb is to use these substances moderately, and to avoid them if they irritate the stomach.

Garlic. Some studies suggest that high amounts of garlic may have some protective properties against stomach cancer, although a recent study concluded that it offered no benefits against H. pylori and, in high amounts, can cause considerable GI distress.

Olive Oil. Studies from Spain have shown that phenolic compounds in virgin olive oil may have strong bactericidal activity against 8 strains of H. pylori, 3 of which are resistant to antibiotics.

Vitamins. Although no vitamins have been shown to protect against ulcers, H. pylori appears to impair absorption of vitamin C, which may play a role in the higher risk of stomach cancer.

Some evidence exists that exercise may help reduce the risk for ulcers in some people. In one study, exercise was associated with a lower risk for duodenal, but not gastric, ulcers in men. In this study, exercise appeared to have no effect on ulcer development in women.

Stress relief programs have not been shown to promote ulcer healing, but they may have other health benefits.

Melatonin is a hormone found in the brain that is normally associated with sleep. Researchers have observed that the GI tract is rich in melatonin, and that the hormone may have properties that help prevent ulcers, reduce acid secretion, and improve blood flow. It is not known whether this would benefit people with peptic ulcers, but it appears to warrant some research. In the U.S., melatonin is classified as a dietary supplement and not a drug, so its quality and effectiveness are uncontrolled. The U.S. is the only developed nation that does not regulate this agent.

Resources

http://digestive.niddk.nih.gov -- National Digestive Diseases Information Clearinghouse
www.gastro.org -- American Gastroenterological Association
www.acg.gi.org -- American College of Gastroenterology

References

deBortoli M, Leonardi G, Ciancia E, et al. Helicobacter pylori eradication: a randomized prospective study of triple therapy versus triple therapy plus lactoferrin and probiotics. Am J. Gastroenterol. 2007;102(5):951-956.

Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol. 2007;99(6A):22C-31C.

Hainaux B, Agneessens E, Bertinotti R, et al. Accuracy of MDCT in predicting site of gastrointestinal tract perforation. Am J Roentgenol. 2006;187(5):1179-1183.

Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMS. 2006;333(7571):726. Epub 2006 Sept 19.

Hobsley M, Tovey F, Horton J. Precise role of H. pylori in duodenal ulceration. World J Gastroenterol. 2006;12(40):6413-6419.

Goer A, Gothe H, Schiffhorst G, Sterzel A, Grass U, Haussler B. Comparison of the effects of diclofenac or other non-steroidal anti-inflammatory drugs (NSAIDs) and dicolfenac or other NSAIDs in combination with proton pump inhibitors (PPI) on hospitalization due to peptic ulcer disease. Pharmacoepidemiol Drug Saf. 2007 Feb 26 [Epub ahead of print].

Jansson EA, Petersson J, Reinders C, et al. Protection from nonsteroidal anti-inflammatory (NSAID)-induced gastric ulcers by dietary nitrate. Free Radic Biol Med. 2007;41(4):510-518.

Keefer L, Stepanski EJ, Ranjbaran Z, Benson LM, Keshavarzian A. An initial report of sleep disturbance in inactive inflammatory bowel disease. J Clin Sleep Med. 2006;2(4):409-416.

Kim JI, Cheung DY, Cho SH, et al. Oral proton pump inhibitors are as effective as endoscopic treatment for bleeding peptic ulcer: a prospective, randomized, controlled trial. Dig Dis Sci. 2007 May 19 [Epub ahead of print].

Luo J, Nordenvall C, Nyren O, Adami HO, Permert J, Ye W. The risk of pancreatic cancer in patients with gastric or duodenal ulcer disease. Int J Cancer. 2007;120(2):368-372.

Malfertheiner P, Megraud F, O'Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastrict III Consensus Report. Gut. 2007;56(6):772-781.

Miki K, Urita Y, Ishikawa F, et al. Effect of Bifidobacterium bifidum fermented milk on Helicobacter pylori and serum pepsinogen levels in humans. J Dairy Sci. 2007;90(6):2630-2640.

Moberly JB, Harris SI, Diff DS, et al. A randomized, double-blind, one-week study comparing the effects of a novel COX-2 inhibitor and naproxen on the gastric mucosa. Dig Dis Sci. 2007;52(2):442-450.

Moore ML. Misoprostol-is more research needed? J Perinat Educ. 2002;11(3):43-47.

Murthy S, Keyvani L, Leeson S, Targownik LE. Intravenous versus high-dose oral proton pump inhibitor therapy after endoscopic hemostasis of high-risk lesions in patients with acute nonvariceal upper gastrointestinal bleeding. Dig Dis Sci. 2007;63(11):773-775.

Pietroiusti A, Forlini A, Magrini A, et al. Shift work increases the frequency of duodenal ulcer in H. pylori infected workers. Occup Environ Med. 2006;63(11):773-775.

Pilotto A, Franceschi M, Leandro G, et al. Clinical features of reflux esophagitis in older people: a study of 840 consecutive patients. J Am Geriatr Soc. 2006;54(10):1537-1542.

Romero C, Medina E, Vargas J, Brenes M, De Castro A. In vitro activity of olive oil polyphenols against Helicobacter pylori. J Agric Food Chem. 2007;55(3):680-688.

Saif MW, Elfiky A, Salem RR. Gastrointestinal perforation due to bevacizumab in colorectal cancer. Ann Surg Oncol. 2007;14(6):1860-1869.

Simon-Rudler M, Massard J, Bernard-Chabert B, et al. Continuous infusion of high-dose omeprazole is more effective than standard-dose omeprazole in patients with high-risk peptic ulcer bleeding: a retrospective study. Aliment Pharmacol Ther. 2007;25(:949-954.

Take S, Mizuno M, Ishiki K, et al. Baseline gastric mucosal atrophy is a risk factor associated with the development of gastric cancer after Helicobacter pylori eradication therapy in patients with peptic ulcer disease. J Gastroenterol. 2007;42(suppl 17):21-27.

Ushida Y, Shimokawa Y, Toida T, Matsui H, Takase M. Bovine alpha-lacalbumin stimulates mucus metabolism in gastric mucosa. J Dairy Sci. 2007;90(2):541-546.

Vaira D, Zullo A, Vakil N, et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial. Ann Intern Med. 2007;146(:556-563.

Verhamme K, Mosis G, Dieleman J, Stricker B, Sturkenboom M. Spironolactone and risk of upper gastrointestinal events: population-based case-control study. BMJ. 2006;333(7563):330. Epub 2006 Jul 13.

Yeomans ND, Svedberg LD, Naesdal J. Is ranitidine therapy sufficient for healing peptic ulcers associated with non-steroidal anti-inflammatory drug use? Int J Clin Pract. 2006;60(11):1401-407.

Zagari RM, Bianchi-Porro G, Fiocca R, Gasbarrini G, Roda E, Bazzoli F. Comparison of 1 and 2 weeks of omeprazole, amoxicillin and clarithromycin treatment for Helicobacter pylori eradication: the HYPER study. Gut. 2007;56(4):475-479.

Review Date:
6/22/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com