A pilot double-blind placebo-controlled trial of low-dose pramipexole in sleep-related eating disorder

A pilot double-blind placebo-controlled trial of low-dose pramipexole in sleep-related eating disorder
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  A pilot double-blind placebo-controlled trial of low-dose pramipexolein sleep-related eating disorder F. Provini, F. Albani, R. Vetrugno, L. Vignatelli, C. Lombardi, G. Plazzi and P. Montagna Department of Neurological Sciences, University of Bologna, Bologna, Italy Keywords: actigraphy, pramipexole,sleep, sleep-related eatingdisorder Received 14 April 2004Accepted 2 August 2004 Sleep-related eating disorder (SRED) is characterized by recurrent arousals from sleepassociated with compulsive ingestion of food. No controlled therapeutic trials areavailable for SRED. We assessed the safety, tolerability and efficacy of pramipexole, adopamine D3-receptor agonist, in the treatment of SRED. Eleven consecutive patientswith SRED in the absence of concurrent daytime eating disorders underwent acti-graphic recording and subjective sleep diary evaluation for a week before and everyweek for 2 weeks of treatment with pramipexole 0.18–0.36 mg or placebo, adminis-tered in a double-blind crossover randomized sequence. The primary outcomes of thetrial were actigraphic measures of night sleep parameters (sleep efficiency, motoractivity mean and median, number and duration of wake episodes), secondary out-comes were the number of good sleep nights/weekly, number and duration of noc-turnal awakenings/night, and visual analogue preference score. Pramipexole was welltolerated without any patient withdrawing from the study. Pramipexole reduced night-time activity median ( P  ¼  0.02) and increased the number of nights of good sleep/week ( P  ¼  0.02). All other measurements remained unaffected. Pramipexole at lowdoses was well tolerated, improving some measures of sleep quality and reducingmedian night activity in SRED. Further studies with higher dosages and for longertime-periods are warranted. Introduction Sleep-related eating disorder (SRED) consists of recurrent partial arousals or awakenings from sleepassociated with compulsive ingestion of food (Schenck et al. , 1991). SRED affects adults and may be associ-ated with other sleep disorders such as narcolepsy,somnambulism, restless legs syndrome (RLS) andperiodic limb movements of sleep (PLMS) (Schenck et al. , 1991). It is unclear whether SRED should becategorized as a sleep disorder or an eating disorder orboth. SRED affects 10% of obese patients (Ceru´-Bjo ¨rk et al. , 2001), 6% of insomniacs presenting to a generalhospital sleep disorders clinic (Manni  et al. , 1997) andup to 4% of college students (Winkelman  et al. , 1999).SRED, which has no entry in the International Classi-fication of Sleep Disorders (American Academy of Sleep Medicine, 2001) is distinct from the so-called  nocturnal eating (drinking) syndrome   that is primarilya problem of infancy and early childhood, affectingchildren who intake large volumes by nursing or bottlefeeding at times of waking and is thought to representan extrinsic sleep disorder (American Academy of SleepMedicine, 2001). The night eating syndrome (NES)represents yet another sleep disorder characterized bymorning anorexia, evening hyperphagia and insomnia(Stunkard  et al. , 1955). The relationship of NES toSRED remains unclear and controversial (Ceru´-Bjo ¨rk et al. , 2001). A number of potential treatments fornocturnal eating disorders and SRED have been des-cribed but nearly all reports have been retrospective,unblinded and not placebo-controlled (Schenck  et al. ,1993; Mancini and Aloe, 1994; Spaggiari  et al. , 1994;Schenck and Mahowald, 2002; Winkelman, 2003;O’Reardon  et al. , 2004). Amongst the drugs used,dopaminergic agents, such as levodopa/carbidopa atlow dosages of 100/10 mg at bedtime, sometimes com-bined with codeine and/or clonazepam, and bromo-criptine 2.5–15 mg at bedtime, have been reported asbeneficial in SRED, especially in those patients withassociated RLS (Schenck  et al. , 1993; Schenck andMahowald, 2002).The rationales for the use of dopaminergic agents areseveral: first, they display appetite-suppressing andweight-reducing effects in experimental animals (Mar-tin-Iverson and Dourish, 1988). Moreover, pramipexoleis a dopaminergic agent usually well tolerated andeffective in RLS at doses of 0.375–0.75 mg/day(Montplaisir  et al. , 1999). Given the association of SRED with RLS and PLMS (Schenck  et al. , 1991),pramipexole could thus be expected to affect the sleep-related eating behaviour too. We have had good clinical Correspondence: Prof. Pasquale Montagna, Dipartimento di ScienzeNeurologiche dell’Universita ` di Bologna, Via Ugo Foscolo 7, 40123Bologna, Italy (tel.: +39 051 6442179; fax: +39 051 6442165;e-mail: 432    2005 EFNS European Journal of Neurology   2005,  12:  432–436  results with pramipexole at low doses of 0.18–0.36 mg/bedtime in occasional patients with SRED, with areduction of the number of nocturnal awakeningsrelated to eating and an improvement in the quality of sleep. Therefore we performed a pilot double-blind,placebo controlled, randomized clinical and actigraphictrial of low-dose pramipexole in patients with SREDwith the aim of ascertaining its efficacy on nocturnalawakenings, sleep efficiency and quality, and patients  acceptance. The study was not funded by any phar-maceutical industry, and was conceived, funded andperformed entirely within our Clinical Department. Patients and methods We enrolled 11 consecutive patients (four men and se-ven women) presenting between May 2000 andNovember 2002 to the Sleep Disorders Center of theDepartment of Neurological Sciences of the Universityof Bologna for compulsive nocturnal eating episodesarising during arousals from sleep (SRED). Clin-ical characteristics of the 11 patients are presented inTable 1. No patients had any daytime or evening eatingproblem. All, except for the three patients with RLS,fell asleep normally at bedtime, but suffered recurrentarousals from sleep throughout the night during whichthey felt a compulsive desire to eat. In eight patients,eating behaviour was careless, sloppy and indiscrimin-ate. One patient preferred cakes, another salty foodsand yet another only cereals and milk. After the eatingepisode, all subjects went back to sleep. No patientreported accidents linked to the nocturnal eatingbehaviour. After awakening in the morning, patientshad only vague recollections of their nocturnal beha-viour and realized only by observing food remains inthe bed or in the kitchen. All patients complained of weight gain which they attributed to the nocturnaleating. All patients were administered a semistructuredclinical interview for medical and sleep disorders toelicit information regarding characteristics of SREDand possible other associated diseases and underwent adiagnostic video-polysomnography. Exclusion criteriawere serious psychiatric or physical illness, includingdiabetes mellitus and other metabolic and endocrinedisorders, use of psychotropic or dopaminergic medi-cations, steroids, diuretics or hypnotics, excessive con-sumption of alcohol and a concurrent daytime eatingdisorder. SRED was the primary reason for referral inall patients. Five patients also had sleepwalking, RLSand PLMS, five patients had a history of mild psychi-atric disorders, in particular mood depression and fivepatients had at least one first-degree relative with sleepand/or psychiatric disorders and/or SRED (Table 1).All subjects gave informed consent to participate in thisstudy and the protocol was approved by the localEthical Committee.Each patient underwent a basal evaluation with act-igraphic recording (utilizing a portable device MiniMotionlogger Actigraph Advanced; AmbulatoryMonitoring Inc., New York, NY, USA, worn on thenon-dominant wrist, recording movements for a wholeweek), and a subjective sleep diary for a week. There-after, each patient was randomized to receive a se-quence of treatments (pramipexole  fi  placebo orplacebo  fi  pramipexole) according to a computer-generated randomization list drawn up by our phar-macy department. At the baseline visit, each patientreceived the lowest number available and the associatedsequence of treatments. All study personnel and par-ticipants were blinded to the sequences of treatmentsthroughout the study and during analysis of the results.Each patient took an identical capsule of placebo orpramipexole 0.18 mg once a day 1–3 h before bedtimefor a week. Placebo capsules contained lactose. If thetherapy was effective in the patient’s judgement, treat-ment was continued at the same dosage for a secondweek during which the patient kept the sleep diary and Table 1  Demographic and clinical characteristics of patientsGender M: 4, F: 7Age (mean ± SD)years49 ± 16Body massindex (mean ± SD)27 ± 5Age of onset of SRED(mean ± SD) years39 ± 18SRED episodesper nightIn one patient oneepisode/night; in sevenpatients two to fourepisodes/night; in three patientsmore than five episodes/nightMonthly frequencyof SREDEvery or almost nightlyPositive family historyfor psychiatric disordersIn 1Positive family historyfor SREDIn 1Positive family historyfor insomniaIn 1Positive family historyfor psychiatric disordersand SREDIn 2Co-morbid disordersSleepwalking In 1RLS In 3PLMS In 1Sleep talking In 2Mood depression In 5Chronic B hepatitis In 1Gastritis In 1Hypertension In 1 Pramipexole in SRED  433   2005 EFNS  European Journal of Neurology   12 , 432–436  underwent actigraphic evaluation. If therapy was inef-fective, during the second week of treatment the patientincreased the dose to two capsules at night and duringthe third week the patient kept the sleep diary andunderwent actigraphic evaluation. At the end of thesecond or third week, patients began a 2-week washoutperiod after which the second treatment was initiatedand conducted with the same modalities as the first. Atbaseline and during the first and second periods of treatment, patients received a full physical and neuro-logical examination, compliance was checked, vital datawere recorded and routine blood and urine assays andECG were performed. Moreover, every patient com-pleted a visual analogue scale evaluating absolutedisease severity.The objective outcomes of the trial were the acti-graphic measurements of sleep–wake patterns esti-mated from periods of activity and inactivity basedon the movements. These included: sleep efficiency(total sleep time/total recording time), activity mean(mean activity score in counts/min), activity median(median activity score in counts/min), number of wake episodes (number of periods of contiguouswakefulness epochs) and mean duration of wakeepisodes (minutes). The subjective outcomes recordedin the sleep diary were the number of good sleepnights/weekly, judged on the basis of sleep as a wholeand not only of the sleep-related eating episodes, andthe number and duration of nocturnal awakenings/night related to eating.Comparison of results between pramipexole andplacebo arms was carried out with Student’s  t -test forpaired data in case of continuous data and with the signtest for two paired samples for categorial data. Statis-tical significance was defined at  P  < 0.05. No correc-tions for multiple analyses were made. The actigraphicdata were considered the primary outcome of the study. Results All patients completed the study protocol and wereincluded in the analysis. Pramipexole was well toleratedand routine blood and urine assays and ECG werenormal throughout the study. One patient on placeboand one on pramipexole stopped treatment at onecapsule/night, the remaining nine increasing bothtreatments to two capsules at night.No significant changes in body weight were observedfor either treatment option. Actigraphic data Actigraphic parameters are reported in Table 2. Onlythe median activity was significantly reduced by pram-ipexole ( P  < 0.02) (median values were reported in-stead of mean ones as basal motor activity during sleepvaried widely between subjects). Subgroup analysis(patients with SRED only versus patients withSRED + sleepwalking/RLS/PLMS) gave no furthersignificant data. Subjective outcomes and sleep diary During pramipexole treatment, nights of good sleep perweek were significantly increased ( P  ¼  0.02). However,number and duration of wake episodes in the sleepdiary were not significantly different. On the visualanalogue scale of absolute disease severity, there was no Table 2  Actigraphic and subjective sleep dataPramipexole Placebo StatisticsMean Range Mean Range Mean difference (95% CI)  P -valueActigraphic parametersSleep efficiency (%) 82.9 54.0–95.0 78.6 43.0–93.0 +4.3 ( ) 3.8; +12.3) 0.26Activity median (counts/min) 1 a 0–20 6 a 0–109  b 0.02Recording duration per night (min) 481 388–608 466 380–589 +15 ( ) 8; +38) 0.18Wake episodes (number of contiguous epochs of wakefulness)11.5 3.0–21.0 10.0 4.0–15.0 +1.5 ( ) 1.3; +4.4) 0.25Mean wake episodes duration (min) 8 4–17 15 5–53  ) 7 ( ) 15; +2) 0.12Subjective parametersNights of good sleep/week (number) 3.5 0–7.0 2.0 0–4.0 1.5 (+0.2; +2.7) 0.02Wake episodes per night/week (number) 1.7 1.0–2.7 2.2 1.0–5.2  ) 0.5 ( ) 1.6; +0.6) 0.35Mean wake episodes duration/week (min) 43 16–96 63 18–180  ) 20 ( ) 66; +25) 0.33VAS (absolute severity of SRED) 3 a 2–7 5 a 1–9  b 0.73VAS, Visual analogue scale; SRED, sleep-related eating disorder. a Median. b Sign’s test for paired samples. 434  F. Provini  et al.   2005 EFNS  European Journal of Neurology   12 , 432–436  significant difference between pramipexole and placebo(Table 2). Discussion Pramipexole, a full D3-receptor agonist, non-ergolinederivative, is a potent therapeutic agent in patients withRLS and PLMS (Montplaisir  et al. , 1999). Reduction orelimination of RLS symptoms is observed at the relat-ivelylowdosesof0.375–0.75 mg/day(Montplaisir et al. ,1999) with few side effects. The pathogenesis of SRED isstill unclear, but it has been proposed that internallygenerated stimuli, such as PLMS or sleep apnoea, couldtrigger partial awakenings in SRED patients and that, if such stimuli occur during non-rapid eye movementperiods in predisposed individuals, phenomena likesleep-relatedeatingmayensue(Winkelman,1998).Thus,monotherapy or combined therapy with dopaminergicagents directed towards decreasing the numbers of movementsduringsleeportheirassociatedarousalshavebeen proposed as successful treatments for SRED, inparticular for cases associated with sleepwalking, RLSand PLMS (Schenck  et al. , 1991, 1993). Moreover,dopaminergicagentsgenerallyhaveappetite-suppressingeffects (Martin-Iverson and Dourish, 1988). Based onthese rationales, the uncontrolled evidence in the litera-ture of the efficacy of low doses of levodopa andbromocriptine (Schenck  et al. , 1993) and our own anec-dotalexperienceoflowdosepramipexoleefficacyinsomepatients, we undertook a pilot randomized placebo-controlled double-blind trial of pramipexole in thetreatment of SRED. We assessed safety and tolerabilityof low doses of the drug (0.18–0.36 mg at bedtime) in ashort trial, and utilized actigraphy, a procedure oftenemployed in clinical trials to assess severity of sleep-related motor disorders (Littner  et al. , 2003), togetherwithsubjectiveoutcomesoftreatment.Theresultsofthiscontrolled therapeutic trial in SRED documented thatpramipexole at the doses and for the period of time usedin the study, is well tolerated and safe in patients withSRED: no patient dropped out of the study because of sideeffectsandtherapeuticcompliancewasexcellent.Ontwo measures of outcome, one objective (actigraphicmotor activity median) and the other subjective (numberof good nights of sleep per week), pramipexole was sig-nificantly more successful than placebo. Althoughpramipexole demonstrated a positive trend for manyactigraphic outcomes it did not, however, produce asignificant improvement in sleep efficiency or signifi-cantly reduce the number and duration of wake episodesrelated to eating behaviour. In good agreement with theactigraphic findings, number and duration of wake epi-sodesassubjectivelyassessedfromthesleepdiarydidnotsignificantly change with pramipexole.Finally, patients did not lose weight during the trial.These findings therefore imply that the therapeuticeffect of pramipexole is linked more to the improve-ment in the quality of sleep and/or to the reduction inmotor activity rather than to an effect on the eatingbehaviour  per se , and probably make any appetite-suppressing effects irrelevant. Besides its documentedeffect on pathological motor activity arising duringsleep, such as PLMS (Montplaisir  et al. , 1999),pramipexole may also have an antidepressant activitypossibly mediated through REM sleep inhibition(Montplaisir  et al. , 1999). Therefore, it may be difficultto differentiate between a possible sleep enhancingeffect of pramipexole and its effects on abnormalmotor activity during sleep. Judging however thatpramipexole did not significantly improve sleep effi-ciency or reduce the wake episodes, we prefer toattribute its therapeutic results to its reducing effectson pathological sleep-related motor activity. Our trialincluded only 11 patients and was meant as a pilotstudy. It is therefore too premature to draw any finalconclusions. Considering, however, the partially pos-itive results of this trial and the fact that all patientsexcept one went on to the maximum dose allowed(0.36 mg), further controlled studies with higher dos-ages of pramipexole and for more extended periods of time are warranted to assess the efficacy of prami-pexole on SRED. Acknowledgements We acknowledge the contribution of Ms A. Laffi fortyping the manuscript, Ms A. Collins for reviewing theEnglish text and Ms L. Solieri and our excellent tech-nical staff of the Sleep Laboratory for processing theactigraphic recordings. Supported by COFIN MIURex-40% 2000 prot. MM06244347_004 grant. References American Academy of Sleep Medicine (2001).  ICSD – International Classification of Sleep Disorders, Revised:Diagnostic and Coding Manual  . American Academy of Sleep Medicine, Rochester, MM.Ceru´-Bjo ¨rk C, Andersson I, Ro ¨ssner S (2001). 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