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J Clin Sleep Med. Feb 15, 2010; 6(1): 79–83.
PMCID: PMC2823282

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

Abstract

Background:

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.

Keywords: Pharmacologically induced, periodic limb movements of sleep, rapid eye movement behavior disorder, REM sleep without atonia, restless legs syndrome

Restless 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,24 renal failure,57 peripheral neuropathy,810 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.1619 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.

METHODS

We 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.

Table 7
Maximum scores based on article type

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.

RESULTS

The 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 13). 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),2023 the PLMS literature (3/6),2426 and the RBD/RSWA literature (3/15).2729 The vast majority of the RLS literature is in the form of case reports (23/31).30,3351

Table 1
Literature on pharmacologically induced/exacerbated restless legs syndrome (RLS) ordered by publication date.
Table 3
Literature on drug-induced REM behavior disorder (RBD) ordered by publication date.
Table 4
Data extraction of important criteria performed in the literature analysis.
Table 2
Literature on pharmacologically induced periodic limb movements of sleep (PLMS) ordered by publication date.

Few articles described whether patients were taking the offending medication resulting in RLS, PLMS or RBD/RSWA at or close to bedtime (RLS: 5/31,40,41,43,51,52 PLMS: 1/6,53 RBD/RSWA: 2/1554,55). Approximately one-third of the RLS articles (11/31)22,3234,36,37,39,41,42,44,47 clearly documented other medications the patient was taking; this was done in none of the PLMS articles and 5/15 of the RBD/RSWA articles.27,5659 Few articles ruled out secondary causes of RLS, PLMS, or RBD/RSWA. Excessive caffeine use was not ruled out in any of the articles assessed in this review. Tobacco use was ruled out in 2/31,37,51 and excessive alcohol use was ruled out in 4/3135,37,47,51 RLS articles. None of the PLMS or RBD/RSWA articles ruled out tobacco or alcohol use. Fourteen of 32 RLS articles ruled out renal failure,22,3335,38,4144,48,50,60,61 9/31 ruled out low serum ferritin or anemia,34,37,38,42,43,4750 and 3/31 ruled out peripheral neuropathy.43,48,60 The article by Yang was the only PLMS article to rule out renal failure, low serum ferritin, and sleep disordered breathing; however, peripheral neuropathy was not ruled out.26 Three of 31 RLS articles38,49,50 and 1/15 RBD/RSWA29 articles excluded sleep disordered breathing, a common mimic of RLS, PLMS, and RBD/RSWA. Ten RLS articles described women of childbearing age, and none of them explicitly used a negative β-human chorionic gonadotropin assay to rule out pregnancy.2022,30,31,34,42,44,51,62 Drake noted that a 30-year-old woman on methsuximide for epilepsy had regular menstrual cycles.63

Table 5 online shows the compiled scores for each article categorized by drug. Table 6 online shows the articles in which RLS or RBD/RSWA subsided or ceased with reduction or withdrawal of medication. Based on scores ≥ 10 and the presence of trials of medication reduction/cessation, the strongest evidence available for drug induced/exacerbated RLS are for the following drugs: escitalopram,51 fluoxetine,34 L-dopa/carbidopa and pergolide,43 L-thyroxine,45 mianserin,60 mirtazapine,41,47 olanzapine,38 and tramadol.50 Vetrugno described a case of previously identified RLS exacerbated by tramadol use. Neither Bakshi (reporting a case of fluoxetine use) nor Santamaria (reporting a case of L-dopa/carbidopa and pergolide use) state if their patients had RLS prior to medication use. The remaining articles exclude RLS prior to medication use.

Table 5
Drug-induced restless legs syndrome (RLS), periodic limb movements of sleep (PLMS), and rapid eye movement behavior disorder/rem sleep without atonia (RBD/RSWA)
Table 6
Medications with best evidence for inducing nocturnal events based on trials of medication reduction in dosage and withdrawal of medication and evidence scores (see methodology section for scoring guidelines)

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 evaluated by Yang in 2005: bupropion, citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.26 Based on an arbitrary score ≥ 10 (50% of the maximum possible score) and trials of medication reduction/cessation, the strongest evidence for drug induced RBD/RSWA is for the following drugs: clomipramine27 and selegiline.57 The article by Akindele is also considered strong evidence for drug induced RBD/RSWWA with a score of 8, because it was the only RBD/RSWA article with a repeat PSG off medication (phenelzine) to demonstrate discontinuation of RSWA.56

DISCUSSION

All the articles in this analysis were Level 4 evidence or higher according to the American Academy of Sleep Medicine Standards of Practice Committee rating of evidence for movements in sleep.64,65 None of the articles analyzed in this study were Level 1, 2, or 3. All the studies analyzed in this review were either observational outcome studies or case series. Our scoring system was useful in assessing the current literature given the lack of controlled or uncontrolled randomized trials.

Medication timing was an issue in many of the articles analyzed. Potentially drug induced movements have to be correlated with dose timing and drug pharmacokinetics (i.e., time to peak plasma concentration and serum half-life). Drug induced movements would presumably occur most dramatically at the time of peak plasma concentration and during a window where there is remaining in the bloodstream depending on serum half-life. When medications that may induce nocturnal movement are not taken close to bedtime an accurate determination of causation is difficult, since peak plasma concentrations may be reached well before bedtime if the medications is taken at earlier times in the day. Also, if the medication serum half-life is short and the dosage timing is early in the day, serum levels of medication may be low or non-existent during time in bed in circadian related disorders such as RLS or sleep stage related disorders (PLMS, RBD/RSWA).

Determination of causation is complicated in patients with a clouded pharmacological milieu. Drug-drug interactions could lead to altered elimination times and for possible augmentation of drug-induced movements. Polypharmacy is more the rule than the exception for many patients. However, polypharmacy could be experimentally accounted for by repeated trials on-and-off the medication with the effects on nocturnal symptoms noted. Unfortunately this type of repeated trial was not performed in any of the RLS, PLMS, or RBD/RSWA articles analyzed. Assessing changes in PLMS or RBD/RSWA in repeated trials off medication is a financial challenge, since both are PSG-dependent diagnoses. One PLMS article (Ware) showed an increase in “nocturnal myoclonus index” above baseline with use of 200 mg per day of trimipramine or imipramine in patients who had movements in the baseline PSG on 75 mg per day of trimipramine or imipramine, respectively.66 None of the remaining PLMS articles and none of the RBD/RSWA articles assessed PSG changes in movements in even a single trial on and off medications. The known nightly variation of PLMS makes this a challenge also.

Recent genetic studies have shown that the risk for RLS is strongly associated with PLMS.67 Full understanding of the epidemiology and etiology of RLS necessitates PLMS assessment. Nine RLS articles assessed presence or absence of PLMS on PSG.37,38,40,42,43,45,49,50,52 Five RLS articles assessed changes in concomitant PLMS with PSG on and off medication.38,40,45,50,52 Kraus showed decreased PLMI (periodic limb movement index, per hour of sleep) from a PSG on olanzapine (PLMI: 39) to PSGs performed after one day off olanzapine (PLMI: 12) and one month off olanzapine (PLMI: 20).38 Agargun performed 2 PSGs over consecutive nights before the initiation of mirtazapine that confirmed no PLMS prior to drug initiation.40 A third PSG performed after one week of mirtazapine showed a PLMI of 41. Tan performed a PSG on L-thyroxine with a PLMI of 20, and a second PSG one month after L-thyroxine withdrawal with a PLMI of 10.45 Prospero-Garcia showed an increased PLMI in 2 women from baseline PSGs performed after 2 weeks of fluoxetine use to repeat PSGs performed after 2 weeks on fluoxetine and mirtazapine.52 The women (ages 63 and 50) had increases in PLMI of 30 to 32, and 41 to 56 respectively. A 41-year-old man from this study also had 2 similar PSGs performed and showed a decrease in PLMI on the combination of fluoxetine and mirtazapine from 67 to 61. Vertrugno showed a decrease in international RLS score from 30 to 9 and a slight decrease in PLMI from 142 to 138 after the discontinuation of tramadol and initiation of niaprazine, a sedating antihistamine.50

PLMS is highly variable from night to night. Except for Ware 1984, none of the articles on drug-induced PLMS assessed patients PLMI on medication across multiple nights. In an abstract publication, Ware showed that for patients with nocturnal myoclonus on 70 mg per day of trimipramine, nocturnal myoclonus increased with a titration of the dose to 200 mg per day.66 Exact quantification of PLMIs was not provided in the abstract. In the articles on drug-induced RLS that evaluated PLMS, none of the articles assessed PLMI on multiple nights of drug use. Conflicting results like those presented by Prospero-Garcia, and small increases in PLMI in one PSG on medication like those presented by Kraus, Tan, and Vertrugno are difficult to interpret without the use of multiple PSGs or multi-night actigraphy during medication use.38,45,50,52

Endorsement of the 2003 NIH RLS criteria is another area of variability from report to report. Only 11 drug induced RLS articles met all 4 RLS criteria by presenting all 4 criteria in the case history or explicitly stating that all 4 RLS criteria were met.22,33,34,42,44,45,4851,60 Four of 32 RLS articles endorsed none of the RLS criteria.21,23,36,68 Of the articles about drug-induced PLMS, only Salin-Pascual made reference to the development of RLS symptoms in 2 patients of a cohort of 8.53 None of the PLMS articles evaluated patients according to NIH consensus criteria. This is problematic not only for the RLS articles, since drug-induced RLS can probably only be assessed in patients who endorse all 4 criteria, but also for the PLMS articles, given the close interrelation of these phenomenon revealed by recent genetic data.67 Stefansson et al. has shown that self-administered 4/4 consensus criteria endorsement agrees with expert clinical diagnosis approximately 74% of the time.67 Even when patients endorse all 4 consensus criteria, they may still have conditions that mimic RLS, such as sleep disordered breathing and diabetic neuropathy. Assessment of family history of RLS may be useful in that a negative family history may help rule out idiopathic RLS. Actigraphy would also be helpful in evaluating for RLS or PLMS across multiple nights. Actigraphy was not used in any of the articles analyzed.

Ruling out alcohol, tobacco, or excessive caffeine use are done by taking a relevant clinical history. Ruling out pregnancy in women of child bearing age; elevated blood urea nitrogen; elevated serum creatinine; or a low serum ferritin require appropriate laboratory testing. Serum testing for hyperthyroidism may also be useful given Tan's report of L-thyroxine induced RLS.45 Other factors that may also be useful to assess in patients with RLS, PLMS, or RBD/RSWA include behaviorally induced insufficient sleep syndrome and lack of exercise. The Michigan Neuropathy Screening Instrument is a validated questionnaire that sleep physicians can use that allows for quick screening for peripheral neuropathy with 15 simple “Yes” or “No” questions.69,70

Assessment of patients with drug induced RLS, PLMS, or RBD/RSWA may provide insights into the underlying pathophysiology of these disorders. For example, Santamaria described a patient in whom the discontinuation of a trial of L-dopa and the discontinuation of a trial of pergolide both led to the cessation of RLS symptoms.43 Though multiple trials on and off L-dopa/carbidopa or pergolide were not performed, RLS symptoms with dopamine or dopamine agonists are similar to the augmentation of RLS with dopamine and dopamine agonists and may share a common mechanism.43

RBD/RSWA overlaps were not addressed using the 2007 AASM Scoring Manual criteria of subdividing REM epochs into 10 three-second mini-epochs was not clearly used by any of the RBD/RSWA articles reviewed.71 Without a standard method to assess RBD/RSWA, conclusions are difficult to draw from the available literature. Also, RBD/RSWA may be secondary to a range of comorbid neurological conditions including Parkinson disease and narcolepsy. Two of 1557,59 and 4/1527,55,72,73 RBD/RSWA articles analyzed patients with comorbid Parkinson disease and narcolepsy, respectively. Assessment of drug-inducement of RBD/RSWA in patients with these comorbidities requires repeated trials on-and-off medication with standardized assessment of the REM epochs using AASM scoring criteria for RBD/RSWA. This was done in none of the articles analyzed. Five of 15 RBD/RSWA had patients who did not exhibit clinical manifestations of RBD.27,29,54,74,75 Patients with RSWA may progress into clinically significant RBD, but the rate is unknown. As a result, the risk of developing clinically significant RBD from drug-induced RSWA is also unknown.

Future studies of RLS, PLMS and RBD/RSWA must take into account drug use given the widespread use of many of the medications described in this review, especially SSRI antidepressant medications. For the treating clinician, awareness of the medications that can potentially lead to RLS, PLMS, or RBD/RSWA is crucial because it changes treatment strategy. Instead of starting another medication such as a dopamine agonist to treat iatrogenic RLS or PLMS, or clonazepam to treat iatrogenic RBD/RSWA, it may be more prudent to withdraw the potentially offending medication as a first line intervention. For the researcher, awareness of these observations may facilitate development of more effective future studies and foster translational applications to the care of our patients. reuptake inhibitors. Subclinical RBD in Schenck 1992 is defined as increased electromyogram tone in REM with no specific clinical correlates. PLMI: periodic limb movement index. AHI: apnea hypopnea index. QID: four times a day. PLMS: Periodic limb movements of sleep. OSA: obstructive sleep apnea. TCA: tricyclic antidepressants. RSWA: REM sleep without atonia. Tmax: time to maximum serum concentration. T1/2: serum half-life.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest.

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