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Amitriptyline: Older fibromyalgia drug still holds its own

Last updated: April 2011

People who have fibromyalgia hurt all over. And to make matters worse, many of them have been told, "It's all in your head." Marked by chronic, body-wide pain, the disorder may bring with it fatigue, poor sleep, stiffness, thinking and memory problems, as well as depression and anxiety. Yet people with fibromyalgia often look well, and results from conventional tests typically come back normal, making the condition difficult to diagnose and treat.

Research suggests that the problem may actually stem from abnormal pain processing in the brain and spinal cord. That can result in a lowered threshold for pain and a heightened response to sensations that wouldn't be painful for healthy people. But despite improved understanding of fibromyalgia, finding the right treatment for it is challenging and there's no cure.

The Food and Drug Administration has approved three drugs to treat fibromyalgia: the antidepressants duloxetine (Cymbalta) and milnacipran (Savella), and the anticonvulsant pregabalin (Lyrica). Yet an older and much cheaper drug that is not FDA approved to treat fibromyalgia—amitriptyline—has long been the first-line treatment.

Used "off-label," meaning that it's prescribed for a condition other than the one approved by the FDA, studies find amitriptyline is still a good, first-choice treatment for short-term use—about 12 weeks—along with other drug and nondrug strategies to relieve pain, according to a recent analysis of the evidence by the American Society of Health-System Pharmacists (ASHP). Doctors can legally prescribe any medication they deem appropriate to treat a patient's condition.

Amitriptyline is an older drug in a class of medications called tricyclic antidepressants. The medication increases the amount of two mood-regulating chemicals in the brain. Because those chemicals—serotonin and noradrenalin—also play an important role in pain perception, the drug is prescribed to relieve the symptoms of fibromyalgia. In addition, it has a sedative effect that can improve sleep, which might in turn ease pain.

"There is strong evidence for the efficacy of amitriptyline," says Don L. Goldenberg, M.D., chief of rheumatology and director of the Arthritis-Fibromyalgia Center at Newton-Wellesley Hospital in Massachusetts. "But none of the drugs used for fibromyalgia are highly effective. People do better with a combination of nonmedication management and medication management integrated together, rather than just relying on drugs."

What is the evidence?

Three large meta-analyses, in which researchers combined the results of prior trials, provide strong evidence that amitriptyline can be effective. One found that tricyclic antidepressants, including amitriptyline, were especially helpful in improving sleep quality. Another analysis—which looked at 13 trials overall, including eight in which people took amitriptyline—concluded that fibromyalgia patients treated with various antidepressants reported moderate reductions in pain. And they were more than four times as likely to report overall improvement of all symptoms, not just pain, compared with people taking a placebo. The largest and most recent analysis, which looked at 18 trials, concluded that amitriptyline reduced pain, fatigue, and sleep disturbances.

But most of those studies lasted just six to 12 weeks. And the longest, which lasted 26 weeks, found that for many people, the benefits waned or even disappeared with time.

The American Pain Society says there's good evidence that low doses of amitriptyline at bedtime can improve sleep and reduce pain and fatigue. It recommends amitriptyline as an initial treatment at bedtime to improve sleep, along with other nondrug treatments including a combination of aerobic exercise, patient education, and a type of psychological counseling known as cognitive behavioral therapy (CBT). European guidelines make similar medication recommendations.

What are the risks and warnings?

Most of the known risks associated with amitriptyline are linked to its use in treating depression. Doses to treat fibromyalgia are usually much lower, which in theory should reduce the severity and risk of side effects. Still, anyone taking the drug should be aware of these potential risks:

Suicidal thinking and behavior. Antidepressants including amitriptyline may increase this risk in children, adolescents, and young adults who have major depression or another mental illnesses. The drug actually has a "black box" warning from the Food and Drug Administration—the strongest warning of its kind—about this risk. Call a doctor if you notice new or worsening depression, extreme worry, agitation, panic attacks, irritability, or thoughts of self-harm.

Cardiovascular problems. These include irregular heartbeats (arrhythmias), heart attacks, and strokes. Use the drug with extreme caution if you have a history of heart disease, and don't take it at all if you've had a recent heart attack.

Dizziness and drowsiness. The drug has a sedating effect, so don't drive until you know how it affects you. Certain antihistamines, sleeping pills, and muscle relaxants can increase that sedating effect. Alcohol should not be consumed while taking this medication, since it might also increase sedation as well as the possibility of a suicide attempt or overdose.

Dangerously low blood pressure. That can cause dizziness, lightheadedness, or fainting when you get up quickly from a lying position. So get out of bed slowly, resting your feet on the floor for a few minutes before standing.

Withdrawal symptoms. If you want to stop taking amitriptyline, talk with your doctor, who can reduce your dose gradually over several weeks to reduce this risk.

Toxicity. A toxic dose of amitriptyline varies considerably among individuals and can cause life-threatening reactions, so dosages should start low and be increased slowly. But because lower doses are generally used to treat fibromyalgia anyway, there is less risk a person would experience these side effects. Nevertheless, patients—especially children, older people, and those with heart disease—should be monitored for abnormal heart rhythms (arrhythmias), high fever, agitation, confusion, excessively low blood pressure (hypotension), hallucinations, irritability, muscle rigidity, and seizures.

Other side effects. Fibromyalgia patients treated with amitriptyline in clinical trials have reported dry mouth, constipation, headaches, nausea, rashes, sleepiness, sweating, urinary retention, vomiting, and weight gain.

Drug interactions. Don't use amitriptyline if you are taking or have recently taken a monoamine oxidase (MAO) inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate). Because amitriptyline interacts with many drugs, tell your doctor about all prescription and nonprescription medications you are taking.

Disease interactions. Amitriptyline can worsen certain conditions, including bipolar disorder, enlarged prostate, glaucoma, liver disease, overactive thyroid, schizophrenia, seizures, and urinary difficulties. The drug also might cause problems in a fetus or infant, so it shouldn't be taken by pregnant women or those who are breast-feeding except in extreme cases.

What other steps can you try?

Relax. Deep-breathing exercises and meditation help reduce stress that can worsen fibromyalgia symptoms.

Improve your sleep. Set a bedtime and wakeup time, avoid napping, and limit alcohol, caffeine, nicotine, and late meals, which can disrupt sleep.

Exercise regularly. It reduces pain symptoms and fatigue. Start slowly, building up to 20 minutes of low-impact activity three times a week, such as walking, swimming, using a stationary bike, or doing water aerobics.

Get support. Cognitive-behavioral therapy can improve coping skills, and fibromyalgia support groups, found in most communities, can provide important information.

Consider tai chi. Fibromyalgia patients who practiced this mind-body exercise—a combination of meditation, slow, gentle movements, and deep breathing—had relief from pain, fatigue, stiffness, and improved well-being after 12 weeks in a 2010 randomized, controlled trial by the Tufts Medical Center in Massachusetts.

Bottom line. Strong evidence supports the use of amitriptyline as an initial short-term treatment for fibromyalgia in appropriate patients, although evidence for its long-term effectiveness is lacking. It also appears to be more effective with other drug and nondrug measures. Our advice: Consider taking amitriptyline only after your doctor has explained the risks and benefits to you.

This off-label drug use report is made possible through a collaboration between Consumer Reports Best Buy Drugs and the American Society of Health-System Pharmacists. This is the 22nd in a series based on professional reports prepared by ASHP.

These materials were made possible by a grant from the state Attorney General Consumer and Prescriber Education Grant Program, which is funded by a multistate settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin (gabapentin).
   

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