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Pharmacologically Induced/Exacerbated Restless Legs Syndrome, Periodic Limb Movements of Sleep, and REM Behavior Disorder/REM Sleep Without Atonia: Literature Review, Qualitative Scoring, and Comparative Analysis

2010; American Academy of Sleep Medicine; Volume: 06; Issue: 01 Linguagem: Inglês

10.5664/jcsm.27716

1550-9397

Romy Hoque, Andrew L. Chesson,

Parkinson's Disease Mechanisms and Treatments

Free AccessAntidepressantsPharmacologically Induced/Exacerbated Restless Legs Syndrome, Periodic Limb Movements of Sleep, and REM Behavior Disorder/REM Sleep Without Atonia: Literature Review, Qualitative Scoring, and Comparative Analysis Romy Hoque, M.D., Andrew L. Chesson, M.D. Romy Hoque, M.D. Address correspondence to: Romy Hoque, M.D., Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA E-mail Address: [email protected] Sleep Medicine Program, Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA , Andrew L. Chesson, M.D. Sleep Medicine Program, Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA Published Online:February 15, 2010https://doi.org/10.5664/jcsm.27716Cited by:179SectionsAbstractPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutABSTRACTBackground:Pharmacologically induced/exacerbated restless legs syndrome (RLS), periodic limb movements in sleep (PLMS), and REM behavior disorder/REM sleep without atonia (RSWA) are increasingly recognized in clinical sleep medicine. A scoring system to evaluate the literature was created and implemented. The aim was to identify the evidence with the least amount of confound, allowing for more reliable determinations of iatrogenic etiology.Methods:Points were provided for the following criteria: manuscript type (abstract, peer-reviewed paper); population size studied (large retrospective study, small case series, case report); explicitly stated dosage timing; identification of peak symptoms related to time of medication administration (i.e., medication was ingested in the evening or at bedtime); initiation of a treatment plan; symptoms subsided or ceased with decreased dosage or drug discontinuation (for RLS articles only); negative personal history for RLS prior to use of the medication; exclusion of tobacco/alcohol/excessive caffeine use; exclusion of sleep disordered breathing by polysomnography (PSG); and PSG documentation of presence or absence of PLMS. For RLS and PLMS articles were also given points for the following criteria: each 2003 National Institutes of Health (NIH) RLS criteria met; exclusion of low serum ferritin; and exclusion of peripheral neuropathy by neurological examination.Results:Thirty-two articles on drug-induced RLS, 6 articles on drug-induced PLMS, and 15 articles on drug-induced RBD/RSWA were analyzed.Conclusion:Based on scores ≥ 10 and trials of medication reduction/cessation, the strongest evidence available for drug induced RLS are for the following drugs: escitalopram; fluoxetine; L-dopa/carbidopa and pergolide; L-thyroxine; mianserin; mirtazapine; olanzapine; and tramadol. Since none of the PLMS articles assessed PLMI in trials of medication reduction/cessation, the strongest evidence based on scores ≥ 10 are for the following drugs: bupropion, citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine. Based on scores ≥ 10 and/or trials of medication cessation, the strongest evidence for drug induced RBD/RSWA is for the following drugs: clomipramine, selegiline, and phenelzine.Citation:Hoque R; Chesson Jr AL. Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and rem behavior disorder/rem sleep without atonia: literature review, qualitative scoring, and comparative analysis. J Clin Sleep Med 2010;6(1):79-83.INTRODUCTIONRestless legs syndrome (RLS) is a sensorimotor disorder characterized by complaints of a strong urge to move the legs during periods of rest or inactivity (usually in the evening or night) that is relieved by movement.1 RLS is rapidly becoming a widely recognized phenomenon with a range of pharmacological treatment options. With increased recognition of RLS more physicians are becoming aware that certain medications may induce RLS in their patients. Similar realizations are being made for patients with period limb movements in sleep (PLMS) and REM behavior disorder (RBD)/REM sleep without atonia (RSWA). There are many reports in the literature asserting pharmacologically induced RLS, PLMS, and RBD/RSWA; but the quality of the available evidence varies. These phenomena were likely not assessed in post-marketing surveillance studies of the medications mentioned in these reports. To establish true causation for drug-induced RLS the following features are useful: no prior history of the disease prior to drug initiation, ruling out other secondary causes (serum ferritin < 50 mcg/L,2–4 renal failure,5–7 peripheral neuropathy,8–10 pregnancy,7,11 excessive alcohol or caffeine use,12,13 tobacco use12); dosage timing close to bedtime to help explain nocturnal symptoms; endorsement of all four 2003 National Institute of Health (NIH) criteria for definitive diagnosis of RLS14; and a polysomnogram (PSG) to rule out sleep disordered breathing as a cause of nocturnal disturbance that may be associated with RLS.15 Secondary causes for PLMS and RBD/RSWA include excessive alcohol use for PLMS; and excessive alcohol and caffeine use for RBD/RSWA.16–19 Most important for etiologic determination are trials on and off the offending medication with clinical re-assessment for changes in RLS, PLMS, or RBD/RSWA. In cases of PLMS and RBD/RSWA, multiple polysomnograms are necessary to assess changes in PLMS and RBD/RSWA on and off medication. We report a literature survey in which the evidence for drug-induced RLS, PLMS, and RBD/RSWA are scored according to qualitative criteria. We also identify reports where trials of reduction in medication dosage or cessation of medication were performed. These results are used in combination with our scoring system to help identify the medications with the strongest evidence for inducing RLS, PLMS, or RBD/RSWA.METHODSWe performed a PubMed search for all articles prior to January 2009 using the following terms alone and/or in combination: restless legs syndrome, RLS, periodic limb movements of sleep, PLMS, rapid eye movement behavior disorder, RBD, REM sleep without atonia, drug induced, and pharmacologically induced. We analyzed all papers that dealt with drug induced RLS, PLMS, and RBD/RSWA. The citation lists of these papers were also analyzed to find additional relevant articles.A scoring system was created and implemented to evaluate the evidence. Two points were given to peer-reviewed papers; 1 point for published abstracts. Three points were given for large population studies, 2 for small series, and 1 for case reports. Additional points were then given for details that removed confounding factors in the determination of causation for drug induced movements. One point was given for each of the following criteria in the drug-induced RLS articles: explicitly stated dosage timing; medication ingested in the evening or at bedtime; initiation of a treatment plan for the RLS; RLS subsided or ceased with decreased dosage or drug discontinuation; negative personal history for RLS prior to use of the medication; exclusion of tobacco/alcohol/excessive caffeine use; each 2003 National Institutes of Health (NIH) RLS criteria endorsed14; exclusion of low serum ferritin; peripheral neuropathy excluded by neurological examination; sleep disordered breathing ruled out by PSG; and PSG documentation of presence or absence of PLMS. Maximum possible scores are listed in online Table 7 (all tables for this article are available online only at www.aasmnet.org/jcsm). The 2003 NIH RLS criteria are: (1) an urge to move the limbs with or without sensation; (2) worsening at rest; (3) improvement with activity; and (4) worsening in the evening or night.Similar scoring was applied to drug-induced PLMS and RBD/RSWA articles. Given the potential interrelation between RLS and PLMS, secondary causes of RLS were assessed in the PLMS literature. Individual articles analyzed in this review from here forward will be identified by the last name of the first author followed by the year of publication.RESULTSThe PubMed search yielded 32 articles on drug-induced RLS—(31 peer-reviewed papers, 1 abstract), 6 articles on drug-induced PLMS (5 peer-reviewed papers and 1 abstract), and 15 articles on drug-induced RBD/RSWA (13 peer-reviewed papers and 2 abstracts). The headings for the data extraction table for RLS, PLMS, and RBD/RSWA articles are shown online Tables 1–3). Table 4 online summarizes the extracted data. Thirty-one of 32 RLS articles were peer-reviewed papers. Dedrick et al. 2001 was the sole abstract evaluated for RLS; it did not mention specific medications. There were fewer articles on drug-induced PLMS or RBD/RSWA. There were few large retrospective studies in the RLS literature (4/31),20–23 the PLMS literature (3/6),24–26 and the RBD/RSWA literature (3/15).27–29 The vast majority of the RLS literature is in the form of case reports (23/31).3033–51Table 1 Literature on pharmacologically induced/exacerbated restless legs syndrome (RLS) ordered by publication date.Area shaded gray is the key for Table 1Reference—Drug, Dosage Used• Drug mechanism of action• Other medicationsNumber of patients evaluated, age, sex (for women of child bearing age, is a negative β-hCG documented)2003 NIH RLS diagnostic criteria met***Normal serum BUN and creatininePSG documenting PLMSTobacco use evaluatedDid patient have RLS features prior to using the drug?• T1/2, Tmax• Treatment for RLS → Response to treatmentCaffeine use evaluated2003 NIH RLS criteria not clearly metNormal serum FerritinPSG excluding OSA• Timing of medication dosageAlcohol use evaluatedPeripheral neuropathy explicitly excludedHeiman et al. 198630—Lithium, 1800 mg/dayIncreased intraneuronal catecholamine metabolismAltered sodium channel permeability• Unknown1, 48, female (No)(1), (4)UnknownNoNoYes• 20-24 h, 2-4 hLithium was withdrawn → RLS subsidedLithium restarted with clonazepam 2 mg at bedtime → failedNo(2), (3)UnknownNo• UnknownNoNoMyers et al. 198631—Clomipramine, 200 mg/dayTricyclic antidepressantInhibits re-uptake of serotoninUnknown1, 49, female (No)(3)UnknownNo. A "sleep EEG" revealed myoclonus.NoNo• 19-37 h; 2-6 h• Clonazepam 0.5 mg/night → RLS ceasedNo(1),(2),(4). Patient experienced nocturnal myoclonus, and nightmares on clomipramine.UnknownNo.• UnknownNoNoDrake et al. 198863—Patient 1: Methsuximide, dose unknown; Patient 2: Phenytoin, dose unknown, phenytoin level: 19 mg/LMethsuximide: anticonvulsant succinimidePhenytoin: anticonvulsant that mediates voltage dependent sodium and calcium channelsPatient 1: Phenytoin, carbamazepinePatient 2: Unknown2, Patient 1: 30, female (No, patient having menstrual cycles); Patient 2: 56, malePatient 1: (1) Patient 2: (1), (4)Patient 1: Yes Patient 2: YesNoNoNoMethsuximide: 2-3 h, unknownPhenytoin: 7-42 hours, 4-12 hPatient 1: Switched from methsuximide to valproate → RLS ceasedPatient 2: Switched from phenytoin to carbamazepine → RLS subsidedNoPatient 1: (2), (3), (4) Patient 2: (2), (3)Patient 1: Ferritin unknown, no anemia Patient 2: Ferritin unknown, no anemiaNo• UnknownNoPatient 1: Yes Patient 2: YesPaik et al. 198960—Mianserin, Patient 1: 90 mg/day; Patient 2: 60 mg/day; Patient 3: 90 mg/dayAdrenergic alpha antagonistHistamine H1 antagonistSerotonin antagonist• Unknown3; 44, 45, 49; all male1: (1), (2), (3), (4) 2: (1), (4) 3: (3), (4)1: Unknown 2: Normal comprehensive labs 3: UnknownNoNoNo• 1 h, 3 hPatients 1-3 1: Added diazepam 10 mg/day and hot pad → failed; Switch from mianserin to amitriptyline 100mg/day → RLS ceased2: Switch from mianserin to amitriptyline 10 mg/day → RLS ceased3: ↓dose of mianserin dose from 90 to 30 mg/day → RLS subsidedNo1: None 2: (2), (3) 3: (1), (2)1: Ferritin unknown, normal iron 2: Ferritin unknown, no anemia 3: Ferritin unknown, no anemiaNo• UnknownNoAll three had normal neurological examinationsTerao et al. 199132—Lithium, 800 mg/dayIncreased intraneuronal catecholamine metabolismAltered sodium channel permeability• Levomepromazine 5-25 mg/day. Discontinued to help rule it out as a cause of RLS. RLS persisted after discontinuation.1, 18, male(1)UnknownNoNoUnknown20-24 h, 2-4 hL-tryptophan dose unknown taken intermittently → partial relief of crawling sensation.Decrease of lithium to 400 mg/day → RLS ceasedNo(2), (3), (4)Unknown (Normal serum iron)No• UnknownNoNoO'Sullivan et al. 199333—Cimetidine, 1200 mg/day• Histamine H2 receptor antagonist• Prednisone taper1, 65, female(1), (2), (3), (4)NormalNoNoUnknown• 2 h, 45–90 minClonazepam 6 mg/day → RLS subsidedPropranolol 20 mg/day → RLS subsidedAcetaminophen with codeine 600 mg/60 mg per day → RLS ceasedNoNoneUnknown (marginally low serum iron: 188 pg/mL)NoUnknownNoNo. Patient had poliomyelitis.Bakshi et al. 199634—Fluoxetine, 60 mg/day• SSRI• Oral contraceptives1, 22, female (No)(1), (2), (3), (4)NormalNoNoUnknown• 1-3 days, 6-8 h• Fluoxetine discontinued → RLS ceased 6 weeks laterNoNoneNormalNo• UnknownNo. No history of "substance abuse."NoSanz-Fuentenebro et al. 199635—Paroxetine, 20 mg/day• SSRI• Unknown1, 33, male(1), (3), (4)Normal routine blood and urine testsNoNoNo• 21 h; 5 h• Lormetazepam 1mg before bed → RLS subsidedNo(2)Not availableNo• morning Infrequently consumes small amounts of alcoholNoMarkkula et al. 199762—Mianserin, 30-90 mg/dayAdrenergic αa antagonistHistamine H1 antagonistSerotonin antagonistPatients 1-6: UnknownUnknownAlprazolam 3 mg/dayUnknownUnknownDoxepin 100 mg/day6; 54, 71, 29, 59, 78, 53; 2 men and 4 women (No)Patients 1, 3, 5: had motor restlessness before mianserin was started. Only patient 5 had mianserin explicitly exacerbate previous symptomsPatient 2, 4, 6: RLS was proceeded by mianserin use(1)No *NoNo1: Familial RLS 2: Unknown 3: Motor restlessness 4: Unknown 5: Familial RLS 6: Unknown• 1 h, 3 hPatient 1Clonazepam → failedCarbamazepine → failedLevodopa-benserazide → RLS subsided and returnedTemazepam → failedOpioid analgesics → failedSwitch from mianserin to trazodone → RLS ceased Patient 2Switch from mianserin to doxepin and flupenthixol → RLS ceased Patient 3Switch from mianserin to fluvoxamine → RLS ceased Patient 4Switch from mianserin to clonazepam → RLS ceased Patient 5Levodopa-carbidopa → RLS subsided but returned with time;The following used without mianserin: diazepam, oxazepam, clonazepam, chlordiazepoxide, amitriptyline, citalopram → all failed Patient 6Doxepin discontinued → failedmianserin dose reduced from 60 mg/day to 30 mg/day → RSL ceasedNo(2), (3), (4)No * (*: patients were evaluated to exclude "general medical conditions behind" the RLS)No• UnknownNoNoHargrave et al. 199836—Sertraline, 25 mg/day• SSRI• Lorazepam 1 mg/day1, 75, maleUnknownNoNoNoYes• 62-100 h; 4-8 h• NoneNoUnknownNoNo• morningNoNoHoriguchi et al. 199937—Haloperidol 3mg/dayNeurolepticDopamine antagonistMinor antihistaminergic and anticholinergic properties• Biperiden 3 mg/day1, 51, male(1)UnknownYes. Total # of PLMs: 65 Mean intermovement interval: 33 sec Unknown whether criteria met for PLMSYes. No tobacco use.Unknown3 weeks; 6 days• Switched from biperiden to trihexyphenidyl 6 mg/day and flunitrazepam 2 mg/day. (Haldol continued unchanged) → failedNo(2), (3), (4)NormalNot explicity stated• UnknownYes. Denied alcohol abuse.NoKraus et al. 199938—Olanzapine, 20 mg/day• Atypical antipsychotic• Unknown1, 41, male(2), (3), (4)Normal routine labsYes 1st PSG on olanzapine 20 mg/day: PLMI=39 2nd PSG off olanzapine for one day: PLMI=12 3rd PSG off olanzapine for 1 month: PLMI=20NoNo• 21 to 54 h, 6 hDecrease of olanzapine from 20 mg/day to 10 mg/day → RLS subsidedDiscontinuation of olanzapine → RLS ceasedNo(1)Normal. Normal iron as well.Yes. No evidence OSA on all three studies. • UnknownNoNoBonin et al. 200039—Mirtazapine, 15 mg/daypost-synaptic 5-HT2 and 5-HT3 antagonistPost-synaptic 5-HT1 agonistPre-synaptic α2 agonist• Zopiclone 7.5 mg/day; Valpromide 300 mg/day1, 33, male(2), (4)UnknownNoNoUnknown• 20-40 h; 2 h• Switch from mirtazapine to fluvoxamine 100 mg/day → RLS ceasedNo(1), (3)UnknownNo• UnknownNoNoDimmitt et al. 200020—Sertraline, 29 patients; Paroxetine, 34 patients; Fluoxetine, 3 patients, Doses varied• SSRI• Unknown66; age range: 19 to 86, mean age unknown; 65% female(1), (4) UnknownNoNo(2), (3)• Various medicationsPatients with RLS prior to use of SSRI: 43 (65%)SSRI → RLS subsided (25 patients) SSRI → RLS ceased (5 patients) SSRI → no change in RLS (13 patients)Patient without RLS prior to use of SSRI: 23 patients (34%) SSRI → developed RLS (2 patients)NoUnknownNoUnknownNo1 patient with diabetic peripheral neuropathy. Pre-existing RLS subsided with SSRI use. Dedrick et al. 2001*21—Specific medications not specifiedTCA: 13 patientsSSRI: 17 patients"Other': 18 patientsUnknown. Patients in the "other" category may have used more than one type of antidepressant.49 patients with RLS. 26 on antidepressants, 23 were not.100 consecutive patient chart review; mean age: 53.9 ±14.8; 62 male, 38 femaleUnknownUnknownNoUnknown• Unknown• NoUnknownUnknownUnknownNo• UnknownUnknownNoAgargun et al. 200240—Mirtazapine, 30 mg/daypost-synaptic 5-HT2 and 5-HT3 antagonistPost-synaptic 5-HT1 agonistPre-synaptic α2 agonist• Unknown1, 45, male(2), (4)UnknownYes. 1st and 2nd PSG performed over two consecutive nights before mirtazapine treatment: no PLMS documented 3rd PSG performed after a week of mirtazapine: PLMI=41NoUnknown• 20-40 h; 2 h• Clonazepam 1 mg/day added → RLS subsidedNo(1), (3)Unknown• eveningNoNoBahk et al. 200241—Mirtazapine, 15 mg/daypost-synaptic 5-HT2 and 5-HT3 antagonistPost-synaptic 5-HT1 agonistPre-synaptic α2 agonist• Alprazolam 0.5 mg/day1, 56, female(3)Normal blood chemistryNoNoNo• 20-40 h; 2 hClonazepam 0.5 mg/day added for 7 days → failedSwitching mirtazapine to paroxetine → RLS ceasedNo(1), (2), (4)UnknownNoEveningNoNoWetter et al. 200242—Risperidone, 6 mg/dayAtypical antipsychoticD2 receptor antagonist5-HT2 receptor antagonist• Valproic acid 900 mg/day1, 31, female (No)(1), (2), (3), (4)Normal routine labsYes. 1st PSG done on risperidone 4 mg/day: PLMI=12.6 2nd PSG done on quetiapine 400 mg/day: PLMI=1.5NoUnknown• 3-20 h, 1 hDose of risperidone decreased to 4 mg/day → failedSwitch from risperidone to haloperidol 10 mg/day → failedSwitch from haloperidol to quetiapine 400 mg/day → RLS ceasedNoNoneNormal ferritin and ironNot explicitly stated• UnknownNoNoLeutgeb et al. 200222—TCAs: Amitriptyline, Trimipramine, Clomipramine, Doxepin, Dibenzepin, Imipramine, Maprotiline, Opipramol, Nortriptyline. SSRIs: Paroxetine, Fluoxetine, Sertraline, Citalopram. Number of patients on each medication unknown. Dosages varied.TCASSRINeuroleptics: Fluspirilene, Sulpiride, Flupentixol, Zotepine, Perphenazine, Levomepromazine, Thioridazine, Promethazine, Perazine, Melperone, Bromperidol, Triflupromazine, Prothipendyl, Haloperidol, RisperidoneMetoclopramideNon-opioid analgesics243 patients interviewed before and 6 months after initiating antidepressant treatment; Mean age: 44.7 ± 11.3; 64 % female(1), (2), (3), (4)No patients with a history of renal failure. NoNoUnknownVarious medications• NoYes. 11 RLS patients drank 5+ cups of coffee per day (all of these patients were also on non-opioid analgesics). 6 non-RLS patients drank 5+ cups of coffee per day. NoneUnknown. No patients with a history of anemia. NoUnknownNoNoSantamaria et al. 2003 **43—Two medications used to treat PLMS. Sinemet CR: Levodopa, 300 mg at bedtime (carbidopa dose unknown) and levodopa, 100 mg at 4am (carbidopa dose unknown). Pergolide, 0.60 mg/day at bedtime,L-dopa: DopaminePergolide: ergot derived dopamine receptor agonist• Unknown1, 50, male(1), (4)Normal "blood tests"Yes 1st PSG before L-dopa therapy: PLMI=102 2nd PSG after 7 months of L-dopa therapy: PLMI=13NoUnknownL-dopa: 1.5 h, 2 hPergolide: 27 h, 2-3 hDiscontinuation of L-dopa → RLS ceased, effect on PLMS not statedPergolide started → RLS returned, PLMS movements decreasedDiscontinuation of pergolide → RLS ceased and PLMS returnedNo(2), (3)Low normal ferritin: 31 mcg/L, 60 mcg/LNot explicitly statedL-dopa: Bedtime and 4amPergolide: BedtimeNoNormal neurological examination. Normal EMG examination (muscles tested not described).Chen et al. 200344—Zonisamide, 200 mg twice a day• Voltage gate calcium channels and sodium channel blockade• None1, 27, female (No)(1), (2), (3), (4)NormalNoNoNo60 h, 2-6 hDecrease dosage of zonisamide from 400 mg every day to 400 mg/day alternating with 300 mg/day → RLS subsidedFerrous sulfate 325 three times a day for 2 months → failedNoNoneLow ferritin: 42 ng/mLNoTwice a dayNoNoTan et al. 200445—L-thyroxine, 1000 →g/day• Thyroid hormone• Unknown1, middle aged, male(1), (2), (3), (4)UnknownYes. 1st PSG done during L-thyroxine therapy: PLMI=20 2nd PSG done one month after L-thyroxine withdrawal: PLMI=10NoNo• 7 days, • Discontinuation of L-thyroxine → RLS subsided (→ RLS score from 24 to 6), and PLMS subsided (→ PLMI from 20 to 10)NoNoneLow ferritin: 10 ng/mLNot explicitly statedUnknownNoNoPae et al. 200461—Patient 1: Mirtazapine, dose unknown; Patient 2: Mirtazapine, 30 mgpost-synaptic 5-HT2 and 5-HT3 antagonistPost-synaptic 5-HT1 agonistPre-synaptic α2 agonistPatient 1: unknown Patient 2: unknown2. Both female. Patient 1: 56; Patient 2: 58Patient 1: none Patient 2: (2)Patient 1: no laboratory abnormalities Patient 2: no laboratory abnormalitiesNoNoNo• 2 h, 20-40 hPatient 1: NonePatient 2: NoneNoPatient 1: (1) – (4) Patient 2: (1), (3), (4)UnknownNo• UnknownNoNoBrown et al. 200523 TCAs: 21 patients - Amitriptyline (16), Imipramine (2), Nortriptyline (3), Clomipramine (1). SSRIs: 36 patients - Fluoxetine (17), Paroxetine (8), Sertraline (9) Other: Bupropion (7), Buspirone (3), Lithium (1), Mirtazapine (2), Venlafaxine (4), Nefazodone (5), Trazodone (18).• Various medications• Unknown200 consecutive charts reviewedUnknown. 45% of patients met "clinical criteria" for RLS. UnknownNoNo• Various medications• No significant correlation found between antidepressant use and RLSNoUnknownUnknownNo• UnknownNoNoEarley et al. 2006 **68—Tramadol, 100-300 mg/day• Synthetic opioid analgesic• Unknown9 patients on tramadol from a clinical database of unknown number of patientsUnknown. 4 patients experienced augmentation of previous RLS. 7 of 9 patients were given tramadol to treat RLS.UnknownNoNo• 2 h, 6 h• 2 patients discontinued tramadol → return to pre-treatment RLS severityNoUnknownUnknownNoUnknownNo2 patients had evidence of small fiber neuropathyOzturk et al. 200646—Paroxetine, 60 mg/day• SSRI• None1, 36, male(3), (4)UnknownNoNoNo21 h; 5 hDecreased dose of paroxetine to 50 mg/day → RLS subsided (↓RSL score from 32 to 19)Paroxetine 60 mg/day and oxcarbazepine 300 mg/day → RLS subsided (RLS score of 8)No(1), (2)UnknownNo• UnknownNoNoChang et al. 200647—Mirtazapine, 60 mg/daypost-synaptic 5-HT2 and 5-HT3 antagonistPost-synaptic 5-HT1 agonistPre-synaptic α2 agonist• Domperidone, dose unknown1, 32, Male(1),(2),(4)UnknownNoNo "substance abuse."No• 20-40 hours; 2 hoursClonazepam 2mg/day → FailedSwitching of mirtazapine to cirzodone → RLS ceasedNo(3)Normal ferritin levelNoUnknownYes. No alcohol abuse. Normal EMG and NCV studies. Muscles tested unknown. Prospero-Garcia et al. 200652—Fluoxetine, 20 mg/day; Mirtazapine, 15 mg/dayFluoxetine: SSRIMirtazapine: post-synaptic 5-HT2 and 5-HT3 antagonistPost-synaptic 5-HT1 agonistPre-synaptic α2 agonist• Unknown3 Age: Females: 63, 50; Male: 41 Sex: 2 females; 1 male(3),(4)Unknown1st PSG: after 2 weeks of fluoxetine use. 2nd PSG: after 2 weeks of fluoxetine and mirtazapine. Women Δ in PLMD index: 30 →32; 41 → 56 Man Δ in PLMD index: 67 → 61NoNoT1/2: Fluoxetine: 1-3 days. Mirtazapine: 20-40 hTmax: Fluoxetine: 6-8 h. Mirtazapine: 2 h• NoNo(1), (2)UnknownNoNightlyNoNoPerroud et al. 200748—Paroxetine, 20 mg/day• SSRI• Unknown1, 48, female(1), (2), (3), (4)Normal routine blood screeningNoNoNo• 21 h, 5 h• Switch from paroxetine to citalopram 60 mg/day → RLS worsenedNoNoneNormal ferritin levelNo• UnknownNoNormal neurological examinationAbril et al. 200749—Sodium oxybate (γ-hydroxybutyrate), 9 g/day• Binds to GABA-B and GHB receptors• Unknown1, 52, male(1), (2), (3), (4)UnknownYes PSG performed prior to use of GHB: PLMI=17NoNo• 0.5-1.25 h, 0.5-1 h• Discontinuation of sodium oxybate → RLS ceased (→RLS score from 30 to 0)NoNoneNormal ferritin and iron. Yes. Apnea-hypopnea index=5. Patient has mild OSA. • UnknownNoNoVetrugno et al. 2007 **50—Tramadol, 100 every 2-3 h• Synthetic opioid analgesic• Unknown1, 86, female(1), (2), (3), (4)NormalYes. 1st PSG done on tramadol: PLMI=142 2nd PSG done 2 months after switch from tramadol to niaprazine: PLMI=138NoYes• 2 h, 6 h• Switched from tramadol to niaprazine 30 mg/every night → RLS subsided (↓ RLS score from 30 to 9), PLMS subsided (↓ PLMI from 142 to 138)NoNoneNormalYes. No chest and abdominal leads were used in the PSG. OSA was ruled out by finger pulse oximetry and larynx microphone• 10am, 1pm, 4pm, 6pm, 8pm, 1pmNoNoPage et al. 200851—Escitalopram, 20 mg/day• SSRI• Unknown1, 34, female (No)(1), (2), (3), (4)Increased BUN: 36 mg/dL (normal: 6-23 mg/dL) Increased creatinine: 1.6 mg/dl. Baseline 1.3 mg/dL; normal range: 0.4-1.2 mg/dL)NoDenied tobacco useNo• 27-32 h, 5 hCyclobenzaprine 5 mg every 4 h as needed → failedDiscontinuation of escitalopram and switching of cyclobenzaprine to lorazepam 0.5 mg every 4 h → RLS subsided (↓ RLS score from 32 to 2)NoNoneNormal ferritin: 100 ng/mLNo• BedtimeDenied alcohol useNoBrown 2005 showed no significant correlation between antidepressant use and RLS symptoms. Dimmit 2000 showed that SSRI may actually improve RLS symptoms in some patients. All other reports show worsening of RLS with medications used.*Reference is a published abstract (Dedrick 2001).**Sinemet, pergolide, tramadol are commonly used to treat RLS. Sinemet and pergolide induced RLS. Tramadol augmented previously present RLS.***2003 NIH diagnostic criteria include the following: (1) an urge to move the limbs with or without sensations, (2) worsening at rest, (3) improvement with activity, and (4) worsening in the evening or night.14 Frequency of RLS symptoms with medication use was difficult to assess from the reports listed.β-hCG, β-human chorionic gonadotropin; BUN, blood urea nitrogen; EEG, electroencephalogram; GABA, gamma-amino-butyric-acid; GHB, gamma-hydroxy-butyrate; PLMI, periodic limb movement index; EMG, electromyogram; OSA, Obstructive sleep apnea; NIA, neuroleptic induced akathisia; NCS, nerve conduction study; PLMS, periodic leg movements of sleep; PLMI, periodic limb movement index; PSG, polysomnogram; SSRI, selective serotonin reuptake inhibitor; Tmax, time to maximum serum concentration; T1/2, serum half-life; NIH, National institutes of health; TCA, tricyclic antidepressants; Δ, change.Table 2 Literature on pharmacologically induced periodic limb movements of sleep (PLMS) ordered by publication date.Area shaded gray is the key for Table 2ReferenceDrugs evaluated, Time of medication dosageNumber of patients, mean age ± standard deviationNumber of patients who developed RLS with medicationNormal serum BUN and creatininePSG documenting PLMSTobacco use evaluatedNormal serum FerritinOther medicationsCaffeine use evaluated2003 NIH RLS criteria metPeripheral neuropathy excludedPSG excluding OSAAlcohol use evaluatedTreatment of RLS → Response to treatmentWare et al. 1984*66Trimipramine Imipramine Dosage for each was titrated from 75 mg/day to 200 mg/day over 20 days Timing of medications unknownTrimipramine: 13 patients, age unknown Imipramine: 14 patients, age unknownNot evaluatedUnknownYes. PSGs were performed before titration and during the titration. Antidepressant use increased nocturnal myoclonus index in patients who had movements in the baseline PSG. Specific PLMIs not provided. NoUnknownUnknownNoNot evaluatedNoNot explicitly stated.NoNot evaluatedGarvey et al. 198724Imipramine 45 patients Desipramine 25 patients Amitriptyline 16 patients Doxepin 5 patients Trazodone 4 patients Nortriptyline 2 patients Maprotiline 2 patients Doses unknown, timing of medication unknown98, 40 ± 14Not explicitly stated. 2 patients developed "nocturnal myoclonus" involving upper and lower extremities, starting shortly after sleep onset, and lasting most of the night. The drugs used in these cases are unknown. UnknownNoNoUnknownUnknownNoUnknownNoNoDorsey et al. 199676Fluoxetine 10 mg/day (1 patient) 20 mg/day (2 patients) 40 mg/day (3 patients) 80 mg/day (2 patients) Timing of medications unknown9; 25 ± 6; 77% femaleNot evaluatedUnknownYes. PLM arousal was elevated in 4 patients Patient on fluoxetine 10 mg/day: 8 Patient on fluoxetine 20mg/day: 15 Patient on fluoxetine 40 mg/day: 8 Patient on fluoxetine 80 mg/day: 9NoUnknownUnknownNoNot evaluatedNoNot explicitly stated.NoNot evaluatedNoNoneHussain et al. 1997*25Fluoxetine Sertraline Amitriptyline Paroxetine Dosages unknown, timing of medications unknownFluoxetine: 56 patients, 39.7 ± 11.6 Sertraline: 21 patients, 41.6 ± 16.8 Amitriptyline: 16 patients, 50.4 ± 10.3 Paroxetine: 12 patients, 43.2 ± 16.8Not evaluatedUnknownYes. PLMI for all patients: median = 4, (range: 0-52). 43% had PLMI > 5. No significant differences between the different medications.NoUnknownUnknownNoNot evaluatedNoNot explicitly stated.NoNot evaluatedSalin-Pascual et al. 199753Venlafaxine First 2 nights: 75 mg/day Next 2 nights: 150 mg/day Medication were taken at 2100 h, 1 h after start of PSG8; 29 ± 9; 37% female2/8 patients developed RLS.UnknownYes. 6/8 patients had PLMS observed on PSG. PLMI was 25 for these 6 patients. NoUnknownNoneNoUnknownNoNot explicitly statedNoNoneYang et al. 200526Bupropion 238 mg ±87 mg Venlafaxine 157 ± 101 mg SSRI: Citalopram 30 ± 13 mg, fluoxetine, 37 ± 20, paroxetine 27 ± 12, sertraline 124 ± 63 Timing of medication unknownBupropion: 34 patients, 34 y ± 1 Venlafaxine: 49 patients, 39 y ± 1 SSRI: 191 patients,38 ± 0.6Not evaluatedYesYes. PLMIs: Bupropion 43 ± 1.1 Venlafaxine 13.6 ± 2.1 Citalopram 14.0 ± 2.0 Fluoxetine 13.6 ± 2.3 Par