Placebo and nocebo responses in restless legs syndrome

Silva, Maria A.; Duarte, Gonçalo S; Câmara, Raquel; Rodrigues, Filipe B; Fernandes, Ricardo M; Abreu, Daisy; Mestre, Tiago; Costa, João; Trenkwalder, Claudia; Ferreira, Joaquim J.

doi:10.1212/wnl.0000000000004004

Cited by 50 publications

(41 citation statements)

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“…The pooled effect size for a placebo response was –1.41 (95% CI: –1.56, –1.25), considering various validated RLS severity assessments. Considering only the IRLS, the meta‐analyses found an average mean reduction in the IRLS score of 6.58 points (95% CI: 4.86–8.29) in the placebo group . Interestingly, the reported magnitude of a placebo response exceeded the proposed threshold for a minimal clinically important difference (MCID) in the IRLS (i.e., 5.6 points) .…”

Section: Resultsmentioning

confidence: 95%

“…The known efficacy of levodopa, dopamine agonists, and opioidergic agents places RLS as a unique human model for the study of the placebo effect in movement disorders, given that both the dopaminergic and opioid‐based endorphin systems have been implicated in the placebo response in other fields such as analgesia . We identified two systematic reviews with meta‐analyses in RLS that concluded the presence of a robust placebo response …”

Section: Resultsmentioning

confidence: 99%

“…Subgroup analyses showed that placebo and nocebo responses were higher in studies with 12 or more weeks, for pharmacological interventions, in industry‐funded trials or unpublished trials, and for participants with idiopathic RLS …”

Section: Resultsmentioning

confidence: 99%

“…14,15 We identified two systematic reviews with meta-analyses in RLS that concluded the presence of a robust placebo response. 16,17 The first systematic review covered the period from 1966 to March 2007 and included 36 trials. 16 Twentyfour of these studies (placebo arm, n = 1,527 participants; treatment arm, n = 1,665 participants) reported response rates for efficacy outcomes during a placebo treatment based on responder analyses.…”

Section: Rlsmentioning

confidence: 99%

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Placebo and nocebo responses in other movement disorders besides Parkinson's disease: How much do we know?

2018

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Among movement disorders and medicine in general, PD is one of the conditions for which there is a greater knowledge of the placebo and nocebo responses. In other movement disorders, the knowledge of placebo and nocebo responses is less. An advance in this field is expected to contribute to a better understanding of the nature of a therapeutic benefit in clinical research and clinical practice, and mechanisms of placebo and nocebo. We conducted a review on placebo and nocebo responses in other movement disorders besides PD by primarily examining meta-analyses of clinical trials assessing specifically the placebo and/or nocebo responses. Second, we examined both efficacy and safety results of a placebo arm in pivotal placebo-controlled trials for the different movement disorders. RLS is the movement disorder for which the most data exist, followed by tic disorders and Huntington's disease. Data available in other conditions document a placebo response in a varied phenomenology. We found different placebo responses according to clinical domains assessed, type of outcomes used for the same clinical domain, and modes of treatment administration, including rehabilitation and surgical interventions. Data on the nocebo response were very scarce. Although the data available are limited, RLS has the better documentation of placebo and nocebo responses. In contrast, atypical parkinsonisms are the group of movement disorders with the least knowledge. The clinical entities with a more robust placebo response are those that have the most beneficial available symptomatic treatments. © 2018 International Parkinson and Movement Disorder Society.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Rlsmentioning

confidence: 99%

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Placebo and nocebo responses in other movement disorders besides Parkinson's disease: How much do we know?

2018

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“…Although this is a single case and SCS‐induced paresthesia renders blinding difficult, symptom recurrence/improvement upon IPG depletion/replacement, respectively, is encouraging. However, a placebo response, common in RLS, cannot be excluded. Further study is warranted to define the role of SCS in medication‐refractory RLS.…”

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confidence: 99%

Successful spinal cord stimulation for severe medication‐refractory restless legs syndrome

et al. 2019

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Proper or Improper Use of the Crossover Design in Clinical Trials in Chronic Sciatica?

2019

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To the Editor Robertson et al 1 conducted a crossover randomized clinical trial of gabapentin (GBP) vs pregabalin (PBG) in chronic sciatica (CS). We congratulate the authors for their effort toward improving CS management. However, some methodological issues hinder the conclusions in this trial.First, we believe that a crossover design may be inappropriate to answer the question of interest. Crossover trials assume that the disease is stable and the effects of an intervention do not carry over from one period to the next. Chronic sciatica intensity fluctuates over time and the 1-week washout period may be insufficient, meaning that the observed effects may be attributable to a longer clinical effect or the disease course and not exclusively to the differences between GBP and PBG. More important than surpassing a given number of half-lives, a preliminary test for differential carryover effects between the drugs should be made and the sequence and period effects should be accounted for to ensure washout period adequacy. Otherwise, the carryover effect is not excluded and only the first parallel phase of the study can be interpreted.Second, the choice of comparator is also important. Although there are some data supporting the efficacy of GBP and PBG in CS, we believe a placebo comparator is still mandatory given the current low level of evidence for these 2 drugs and the high placebo response in pain trials. 2,3 Additionally, safety analyses of randomized clinical trials may be also confounded by the nocebo effect, 4 which is nonnegligible in neuropathic pain trials. 5 In this trial, 12 participants (67%) reported 38 adverse events, with significantly more adverse events reported with PBG vs GBP (31 vs 7; P = .002). This can be partly a consequence of the 20% difference in group size. Hence, a common placebo comparison would also benefit the safety assessment of the drugs.Finally, the small number of participants ( 18) from a single center limits the generalizability of any findings. Despite the significant visual analog pain intensity scale reduction, a simple post hoc sample size calculation (SD, 1.35) shows that 48 participants would be required to demonstrate the same effect size. We believe that placebo-controlled, parallel-group multicentered trials are still needed for firmer conclusions on the benefit of new therapeutic interventions in CS.

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Placebo and nocebo responses in restless legs syndrome

Abstract: The magnitude of the placebo response in RLS is above the threshold of minimal clinical important difference, and the frequency of adverse events is also considerable. These results are relevant to inform the design and interpretation of future clinical trials.

Cited by 50 publications

References 23 publications

Placebo and nocebo responses in other movement disorders besides Parkinson's disease: How much do we know?

Placebo and nocebo responses in other movement disorders besides Parkinson's disease: How much do we know?

Successful spinal cord stimulation for severe medication‐refractory restless legs syndrome

Proper or Improper Use of the Crossover Design in Clinical Trials in Chronic Sciatica?

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