Clinical Inquiries

What drugs are effective for periodic limb movement disorder?

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CLONAZEPAM improves subjective sleep quality and polysomnogram (PSG) measures of leg movements more than placebo (strength of recommendation [SOR]: B, a small randomized controlled trial [RCT]); temazepam produces similar results (SOR: C, extrapolated from a small comparison trial).

Melatonin and L-dopa consistently improve certain PSG measures, but their effect on subjective sleep quality varies; valproate improves only subjective measures; apomorphine injections reduce limb movements but not awakenings (SOR: C, very small crossover and cohort trials).

Estrogen replacement therapy is ineffective for periodic limb movement disorder (PLMD) associated with menopause (SOR: B, RCT).

Evidence summary

Although PLMD often occurs in association with restless legs syndrome, sleep apnea, narcolepsy, and other sleep disorders, it is itself an intrinsic sleep disorder characterized by stereotyped limb movements and sleep disruption.1 Most treatment studies of PLMD report both subjective and objective measures of sleep quality. Two commonly used objective measures, obtained by PSG, are the periodic leg movement (PLM) index and the PLM arousal index. The TABLE summarizes the evidence of medication trials.

Clonazepam improves subjective sleep measures, leg movements
Three comparative trials evaluated clonazepam against placebo, temazepam, and cognitive behavioral therapy (CBT).1-3 In the placebo-controlled and temazepam trials, clonazepam significantly improved subjective sleep parameters and leg movements.1,2 However, the studies produced conflicting results as to whether clonazepam reduced awakening from limb movements. Both temazepam and clonazepam appeared to be comparably effective; the trial was underpowered to detect a difference between them.

The CBT trial didn’t describe the frequency or duration of CBT clearly.3 It isn’t included in the TABLE.

L-Dopa decreases leg motions, effects on subjective sleep symptoms vary
Two comparison trials evaluated L-dopa (combined with carbidopa). One trial compared L-dopa with propoxyphene and placebo, and the other compared it with pergolide, a bromocriptine agonist available in Canada and Europe.4,5

In both trials, L-dopa consistently reduced leg motions at night but produced a variable response in subjective sleep symptoms and nocturnal waking. Propoxyphene yielded modest improvements in subjective sleep symptoms and nocturnal waking over placebo. The L-dopa–propoxyphene comparison trial was underpowered to allow a statistical comparison between the 2 medications.

Melatonin and valproate produce opposite effects in small studies
Three very small trials recorded symptoms and PSG findings in patients taking melatonin, apomorphine, or valproate, and compared them with the values observed at baseline.6-8 Melatonin significantly improved objective measures, but most patients didn’t feel less sleepy. Valproate produced the opposite effect—no clear PSG improvements, but all study patients felt better. Injected apomorphine reduced limb movements but not awakenings.

Estrogen replacement therapy doesn’t help
An RCT of estrogen replacement therapy for PLMD enrolled postmenopausal women, about half of whom were found to have PLMD.9 The study found estrogen replacement therapy to be ineffective for treating menopause-associated PLMD.


Practice parameters developed by the American Academy of Sleep Medicine state that clonazepam, pergolide, L-dopa (with a decarboxylase inhibitor), oxycodone, and propoxyphene are all reasonable choices for medical treatment of PLMD.10 The practice parameters don’t specify a preference for any of these medications.

Evidence-based answers from the Family Physicians Inquiries Network

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