Efficacy and safety of pramipexole in restless legs syndrome

We read the article by Winkelman et al with interest. [1] We noted that every author in this review works for, or receives money from, Boehringer Ingelheim Pharmaceuticals, Inc. In their abstract, the authors make the following conclusion: "As rated by patients and by clinicians, pramipexole was efficacious and safe in reducing the symptoms of Restless Legs Syndrome." While we do not dispute that the data infers that pramipexole may have a role in the treatment of Restless Legs Syndrome (RLS), we have several concerns.

The authors listed adverse events in Table 2. The 'safety' that the authors describe is not affirmed when 50.8% of those receiving pramipexole (all doses; compared to 31.4% for placebo) suffered adverse events, including about 37% more of those rated to be severe in intensity.

Less frequently occurring adverse events are not reported. We would be interested to learn of neuropsychiatric adverse events (e.g., dyskinesia, hallucinations, mood alterations, psychotic reactions), similar to those reported in the USFDA-approved product label for pramipexole (as Mirapex.)

Secondly, a concern to both the authors and to us was the exceptionally high placebo rate. In the results section of their abstract, the authors reported the placebo rate of 51.2%, but failed to mention this in their conclusion. Moreover, in the authors' discussion about the significant placebo response, they offer a salutary statement that the placebo response might become less prominent when more objective outcomes are used to measure RLS. Of course, the opposite is equally valid: More objective determinants of RLS may reveal that the treatment had less effect.

In percentage terms, the difference between a 51.2% placebo response and a 72% treatment response represents 20.8% of individuals who reported a somewhat better response to pramipexole than with placebo. However, when the percentages of adverse events are examined, 19.4% more individuals who received treatment were subjected to adverse events, including many of them described as 'severe'.

We do not believe that the robustly positive safety and efficacy conclusions of the authors, all of whom were subsidized by Boehringer Ingelheim, are justified by those results. One could easily make the case that placebo treatment, conferring a significantly lower risk of adverse events, was more likely to produce "safe and efficacious" treatment results than the 'treatment' itself.

References

1. Winkelman JW, Sethi KD, Kushida CA, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology 2006;67:1034-1039.

Disclosure: The authors report no conflicts of interest.

We welcome the comments of Drs. Kruszewski and Shane as an opportunity to clarify the suffering caused by restless legs syndrome (RLS), and the safety and efficacy results of pramipexole. [1]

Until recently, there were no FDA-approved treatments for RLS, which is present to a clinically significant degree in 2.7% of adults in the general population. [2] Although all agree that double-blind safety and efficacy trials for RLS are essential, no agencies (NIH, foundations) have supported assessment of medications for this disorder. All authors of this paper were study investigators, and therefore appropriately received research support for their work. The four lead authors are no more "subsidized" by Boehringer-Ingelheim than are Drs. Kruszewski and Shane subsidized by insurance companies for their clinical work.

Our report of adverse events is accurate and as complete as space allows. In this forced-titration trial, most adverse events (AEs) were of minor severity and overall rates were similar between arms (placebo, 80.2%; pramipexole, 81.0%; see Table 2). Indeed, with the exception of nausea and dizziness, AEs were similar between groups. None of the questioned adverse neuropsychiatric side-effects were observed with the doses used in this trial, which are roughly 10% of those used in Parkinson's disease. The doctors should also note that the true rates of severe AEs in this trial were 17.4% with pramipexole and 12.8% for placebo, a 4.6% difference (not 37%). No serious AEs were considered related to the study drug by investigators.

Diagnosis and accepted trial outcome measures in RLS are based on subjective criteria. The placebo effect is a potentially important confounder in all studies with subjective endpoints [3], and our study had similar rates to other RLS trials [4]. In fact, pramipexole demonstrated significant (and clinically meaningful) improvements in both primary endpoints, as well as a range of secondary endpoints compared with placebo, despite the placebo effect. Contrary to the doctors' prediction, a recent study demonstrated that rates of periodic leg movements of sleep (PLMS), an objective polysomnographic finding in RLS, were substantially (74-84%) reduced with pramipexole (0.125-0.75 mg), compared to placebo (6%). [5]

Dr. Kruszewski's argument that placebo would produce superior treatment for RLS belittles the suffering of individuals with RLS. If a placebo response obviates the value of an active comparator with demonstrated superiority in clinical trials, then treatments for depression, anxiety disorders, substance abuse, chronic pain, insomnia, and Parkinson's disease should also be discarded. We believe that the data as published demonstrates that pramipexole is efficacious and safe for treatment of RLS.

References

1. Winkelman JW, Sethi KD, Kushida CA, Becker PM, Koester J, Cappola JJ, and Reess J. Efficacy and safety of pramipexole in restless legs syndrome. Neurology. 2006; 67: 1034-1039.

2. Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, Ferini-Strambi L. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med. 2005;165:1286-1292.

3. Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression: variable, substantial, and growing. JAMA. 2002;287:1840-1847

4. Trenkwalder C, Garcia-Borreguero D, Montagna P, et al. Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry. 2004;75:92-97.

5. Partinen M, Hirvonen K, Jama L, et al. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose- finding study: the PRELUDE study. Sleep Med. 2006;7:407-417.

Disclosures: Disclosures related to article to which this Correspondence refers: P.M. Becker has received grants from Boehringer Ingelheim Pharmaceuticals, Inc., not in excess of US$10,000 per year, for other research or activities not reported in this article. C.A. Kushida has received grants from Boehringer Ingelheim Pharmaceuticals, Inc., not in excess of US$10,000 per year, for other research or activities not reported in this article. K.D. Sethi has received grants for other research or activities not reported in this article and has received honoraria during the course of this study from Boehringer Ingelheim Pharmaceuticals, Inc. in excess of US$10,000 per year. J.W. Winkelman has received grants for other research or activities not reported in this article and has received honoraria during the course of this study from Boehringer Ingelheim Pharmaceuticals, Inc. in excess of US$10,000 per year. All other authors listed report no conflicts of interest.