What Drugs Are Effective for Periodic Limb Movement Disorder?

Evidence-based answers from the clinical inquiries Family Physicians Inquiries Network

Yuri A. Lee, MD; Philip Huynh, PharmD; Jon O. Neher, MD What drugs are effective Valley Family Medicine, Renton, Wash for periodic limb Sarah Safranek, MLIS University of Washington Health Sciences movement disorder? Library, Seattle Evidence-based answer ASSISTANT EDITOR Gary Kelsberg, MD Valley Family Medicine, clonazepam improves subjective effect on subjective sleep quality varies; Renton, Wash A sleep quality and polysomnogram valproate improves only subjective mea- (PSG) measures of leg movements more sures; apomorphine injections reduce limb than placebo (strength of recommendation movements but not awakenings (SOR: C, [SOR]: B, a small randomized controlled very small crossover and cohort trials). trial [RCT]); temazepam produces similar Estrogen replacement therapy is inef- results (SOR: C, extrapolated from a small fective for periodic limb movement disor- comparison trial). der (PLMD) associated with menopause Melatonin and L-dopa consistently (SOR: B, RCT). improve certain PSG measures, but their

Evidence summary mazepam and clonazepam appeared to be Although PLMD often occurs in association comparably effective; the trial was under- with restless legs syndrome, sleep apnea, nar- powered to detect a difference between them. colepsy, and other sleep disorders, it is itself The CBT trial didn’t describe the fre- an intrinsic sleep disorder characterized by quency or duration of CBT clearly.3 It isn’t in- stereotyped limb movements and sleep dis- cluded in the TABLE. ruption.1 Most treatment studies of PLMD report both subjective and objective measures L-Dopa decreases leg motions, of sleep quality. Two commonly used objec- effects on subjective sleep symptoms vary tive measures, obtained by PSG, are the peri- Two comparison trials evaluated L-dopa odic leg movement (PLM) index and the PLM (combined with carbidopa). One trial com- arousal index. TheTABLE summarizes the evi- pared L-dopa with propoxyphene and place- dence of medication trials. bo, and the other compared it with pergolide, a bromocriptine agonist available in Canada Clonazepam improves subjective and Europe.4,5 sleep measures, leg movements In both trials, L-dopa consistently re- Three comparative trials evaluated clon- duced leg motions at night but produced a azepam against placebo, temazepam, and variable response in subjective sleep symp- cognitive behavioral therapy (CBT).1-3 In the toms and nocturnal waking. Propoxyphene placebo-controlled and temazepam trials, yielded modest improvements in subjec- clonazepam significantly improved subjective sleep symptoms and nocturnal waking tive sleep parameters and leg movements.1,2 over placebo. The L-dopa–propoxyphene However, the studies produced conflicting comparison trial was underpowered to al- results as to whether clonazepam reduced low a statistical comparison between the awakening from limb movements. Both te- 2 medications. continued

296 The Journal of Family Practice | may 2012 | Vol 61, No 5 TABLE How well do these medications work for periodic limb movement disorder?

Improvement in Improvement in leg Improvement in waking subjective sleep movements: from leg movements: quality vs baseline, PLM index* vs baseline, PLM-arousal index† vs except where indicated Study design, Medication except where indicated baseline, except where duration (N) (daily dose) (P value) (P value) indicated (P value) Crossover, Clonazepam Subject sleep score 26% vs placebo (<.05) 28% vs placebo (NS) placebo-controlled, (1 mg PO) (Self-Assessment of 3 days Sleep and Awakening (26)1 Quality Scale), 25% vs placebo (<.05) Double-blind Clonazepam Sleep maintenance: 34% (.025) 44% (.005) crossover, placebo- (1 mg PO) 37% (.025) controlled, 30 days (10)2 Temazepam Sleep maintenance: 26% (.05) 42% (.013) (30 mg PO) 67% (.005) Double-blind, L-Dopa Improved sleep 87% vs placebo 89% vs placebo (<.01) crossover, placebo- (100-200 mg PO) vs placebo: 6/6 patients (<.01) controlled, 42 days (6)4 Propoxyphene Improved sleep 35% vs placebo 57% vs placebo (<.05) (100-200 mg PO) vs placebo: (NS) 3/6 patients Double-blind, L-Dopa Complete relief 45% (decrease in 56% (decrease in total crossover, (250 mg PO) of restlessness: nocturnal myoclonus nocturnal awakenings) 36 days 1/11 patients syndrome disturbed (NS) (11)5 cluster time) (<.025)

Pergolide‡ Complete relief 79% (decrease in 56% (decrease in total (0.125 mg PO) of restlessness: nocturnal myoclonus nocturnal awakenings) 9/11 patients syndrome disturbed (NS) cluster time) (<.001) Cohort, Melatonin Resolved daytime 60% (.004) 59% (.031) 42 days (3 mg PO) sleepiness: (9)6 4/9 patients Cohort, Apomorphine Not reported 38% (<.05) 30% (NS) 3 days (0.5 mg (9)7 subcutaneous) Cohort, Valproate Improved daytime 61% (NS) 62% (NS) 180 days (125-600 mg PO) alertness: (6)8 6/6 patients Double-blind, Estrogen Not reported 0% vs placebo 23% vs placebo crossover, replacement (NS) (NS) placebo-controlled, therapy 210 days (71)9 (2.5 g estradiol gel or 50 µg estradiol patch)

NS, not significant; PLM, periodic limb movement. *PLM Index=number of abnormal leg motions per hour. †PLM-arousal Index=number of awakenings from abnormal leg movements per hour of sleep. ‡Pergolide is available in Canada and Europe, but not in the United States. continued

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Melatonin and valproate produce for PLMD enrolled postmenopausal wom- opposite effects in small studies en, about half of whom were found to have Three very small trials recorded symptoms and PLMD.9 The study found estrogen replace- PSG findings in patients taking melatonin, apo- ment therapy to be ineffective for treating morphine, or valproate, and compared them menopause-associated PLMD. with the values observed at baseline.6-8 Melato- nin significantly improved objective measures, but most patients didn’t feel less sleepy. Val- Recommendations proate produced the opposite effect—no clear Practice parameters developed by the Ameri- PSG improvements, but all study patients felt can Academy of Sleep Medicine state that better. Injected apomorphine reduced limb clonazepam, pergolide, L-dopa (with a de- movements but not awakenings. carboxylase inhibitor), oxycodone, and propoxyphene are all reasonable choices for Estrogen replacement therapy medical treatment of PLMD.10 The practice doesn’t help parameters don’t specify a preference for any An RCT of estrogen replacement therapy of these medications. JFP

References 1. Saletu M, Anderer P, Saletu-Zyhlarz G, et al. Restless legs syn- Sleep. 1993;16:717-723. drome (RLS) and periodic limb movement disorder (PLMD): 6. Kunz D, Bes F. Exogenous melatonin in periodic limb move- acute placebo-controlled sleep laboratory studies with clonaz- ment disorder: an open clinical trial and a hypothesis. Sleep. epam. Eur Neuropsychopharmacol. 2001;11:153-161. 2001;24:183-187. 2. Mitler MM, Browman CP, Menn SJ, et al. Nocturnal myoclo- 7. Haba-Rubio J, Staner L, Cornette F, et al. Acute low single dose nus: treatment efficacy of clonazepam and temazepam. Sleep. of apomorphine reduces periodic limb movements but has 1986;9:385-392. no significant effect on sleep arousals: a preliminary report. 3. Edinger JD, Fins AI, Sullivan RJ, et al. Comparison of cognitive- Neurophysiol Clin. 2003;33:180-184. behavioral therapy and clonazepam for treating periodic limb 8. Ehrenberg BL, Eisensehr I, Corbett KE, et al. Valproate for movement disorder. Sleep. 1996;19:442-444. sleep consolidation in periodic limb movement disorder. J Clin 4. Staedt J, Wassmuth F, Ziemann U, et al. Pergolide: treatment Psychopharmacol. 2000;20:574-578. of choice in restless legs syndrome (RLS) and nocturnal 9. Polo-Kantola P, Rauhala E, Erkkola R, et al. Estrogen replace- myoclonus syndrome (NMS). A double-blind randomized ment therapy and nocturnal periodic limb movements: a ran- crossover trial of pergolide versus L-Dopa. J Neural Transm. domized controlled trial. Obstet Gynecol. 2001;97:548-554. 1997;104:461-468. 10. Chesson AL Jr, Wise M, Davila D, et al. Practice parameters 5. Kaplan PW, Allen RP, Buchholz DW, et al. A double-blind, pla- for the treatment of restless legs syndrome and periodic limb cebo-controlled study of the treatment of periodic limb move- movement disorder. An American Academy of Sleep Medicine ments in sleep using carbidopa/levodopa and propoxyphene. Report. Sleep. 1999;22:961-968. SUPPLEMENT Health care models for treatment and management of diabetes

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This supplement was sponsored by the Primary Care Metabolic Group and the Primary Care 298 The Journal of Family Practice | may 2012 | Vol 61, No 5 Education Consortium and was supported by funding from Novo Nordisk, Inc.