BOSTON Restless Legs Syndrome (RLS) is both underdiagnosed and underreported, according to Richard P. Allen, Ph.D. Patients visit an average of four to five physicians before the diagnosis is made, and may spend as long as 15 years in search of help. Dr. Allen is affiliated with the Sleep Disorders Center at The Johns Hopkins University School of Medicine, Baltimore.

For initial therapy, benzodiazepines such as clonazepam are often used, especially in mild cases of RLS. When symptoms are moderate to severe however, more effective treatments may be needed. Dopaminergic agents and opioids were among the options discussed at a symposium chaired by Dr. Allen at the Eighth Annual Meeting of the Associated Professional Sleep Societies. Highlights of the symposium follow:

In a recent two-year, prospective study of 52 patients with RLS, 32% reported successful current therapy with standard carbidopa/levodopa, 9% with controlled-release carbidopa/levodopa, 28% with pergolide, 5% to 6% with opioids (hydrocodone or propoxyphene), and none with bromocriptine. Side effects had prompted the remaining 25% of patients to stop all medication, relying instead on individualized alternatives such as bicycling before bedtime. The study was conducted by Christopher Earley, MD, Ph.D., and colleagues from the Sleep Disorders Center at The Johns Hopkins University School of Medicine.

Dr. Earley's team used a standard pharmacologic protocol for RLS patience, including the following regimens: initial therapy with carbidopa/levodopa 25/100, up to four tablets before bedtime, followed by controlled-release carbidopa/levodopa 50/200, up to two tablets before bedtime; pergolide, up to 0.5 mg two hours before bedtime; propoxyphene, up to 400 mg before bedtime; or hydrocodone, up to 15 mg before bedtime Bromocriptine was initially among the options used, but it failed to demonstrate significant benefit; thereafter, pergolide was used as the primary dopamine agonist after carbidopa/levodopa therapy.

All patients were followed for at least three months. Patients on hemodialysis or with narcolepsy-related periodic leg movements were not included in the study. The results were based on objective data from ambulatory monitoring of periodic leg movements, as well as on patients' subjective responses to questions such as: "Do you think the medication is helping you sleep ar night?"

According to Dr. Earley, the medications were generally associated with "only a small number of side effects," primarily constipation, gastrointestinal upset, dry eyes, and dry mouth. "Constipation seemed to be worse in the propoxyphene group in general," he added. "Overall, most patients tolerated the medications fairly well in terms of general side effects."

The major side effect associated with both the standard and the controlled-release form of carbidopa/levodopa was RLS augmentation, with an incidence of about 78%. As dosages were increased above one tables per day, the intensity and duration of this side effect also increased.

As Dr. Earley explained, "Nighttime worsening of symptoms [ie, restlessness, paresthesias] has been the number one cause of our abandoning treatment with [carbidopa/ levodopa] in three-quarters of our patients. Patients present with minimal symptoms during the evening, with the dominant symptoms late at night or at bedtime. Within a week or two of the start of [carbidopa/levodopa] treatment, they complain that their symptoms are worse." At this point, many patients have symptoms in the evening or afternoon, which progressively worsen until the time of the nightly medication dose. Carbidopa/levodopa, he continued, "works very well, but this specific side effect [RLS augmentation] has become a major problem."

Dr. Earley concluded that "RLS and periodic leg movements are highly sensitive to the use of dopaminergic drugs." However, RLS augmentation is often problematic. In many patients, he suggested, pergolide may be an effective alternative with a lower risk of RLS augmentation.

Opioids typically reserved for severe, refractory symptoms have been found safe and effective in selected groups of patients. In a double-blind study, both subjective and objective features of RLS improved significantly with opioid therapy. Acetaminophen with oxycodone (5 mg) and acetaminophen with codeine (30 mg), in daily divided doses of one to three tablets were the most effective regimens reported Arthur S. Walters, MD, of Robert Wood Johnson Medical School and Lyons VA Medical Center, New Brunswick, NJ. Leg sensations, motor restlessness, next-day drowsiness, periodic limb movements in sleep, and arousals per hour were significantly diminished with treatment, and sleep efficiency improved.

In patients with the most severe symptoms. "surprisingly small" doses of methadone 5 to 20 mg, once daily were found to be effective. "Some of our more severe cases respond only to methadone; they don't respond to multiple doses of the less potent opioids or to levodopa." Dr. Walters noted. However, he added that "methadone should be used only after other opioids. dopaminergic agents, and benzodiazepines have been tried."

Problems with addiction or tolerance to opioids have been rare during Dr. Walters' 12 years of experience treating patients with RLS. In the few cases where problems developed, "quickly adjusting the dose or switching to another agent" was found to be an effective remedy, he concluded.

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