Pramipexole in fibromyalgia “offers hope to patients”

A drug for Parkinson’s disease, the dopamine agonist pramipexole, “offers hope to patients with fibromyalgia,” say researchers reporting the first trial of the drug in this condition. Compared with placebo, pramipexole reduced pain and fatigue and improved function and global status, Dr Andrew Holman and Robin Myers (Pacific Rheumatology Associates, Renton, WA) report in the August 2005 issue of Arthritis & Rheumatism. This single-center study involving 60 patients was presented at the American College of Rheumatology meeting in October 2004 and was reported in detail by rheumawire at that time.

Holman tells rheumawire that he has been using pramipexole in the treatment of fibromyalgia for more than five years and conducted this study to “either confirm or refute our observation that it was very helpful.” He says the results show that pramipexole, dosed at 4.5 mg at bedtime, “demonstrated the greatest benefit, in terms of pain, of any fibromyalgia placebo-controlled study yet completed” and the drug also significantly improved fatigue, function, and global assessment. This study was unusual, Holman says, in that it included patients who were already taking other medications (nearly half were taking narcotic analgesics, and 30% of the patients were disabled). “Most other studies exclude these patients as ‘untreatable,’ ” he adds. “Therefore, these results are that much more meaningful and give hope to even our most severely affected patients.”Pramipexole is approved for use in Parkinson’s disease (at a daily dose of 1.5 mg to 4.5 mg) and has also shown benefit in clinical trials of restless-leg syndrome (although it’s not approved for this condition). Its use in fibromyalgia is also off label, but there are no drugs currently approved for this condition, Holman points out; as it showed significant benefit with few side effects, he says that trying pramipexole in fibromyalgia is a “reasonable consideration.” Why use a dopamine agonist? Pramipexole is a dopamine agonist with preferential affinity for the D3 receptor. Holman explains that these receptors are found in the mesolimbic area and are involved in inhibiting autonomic arousal (the fight-or-flight signals) coming from the brain stem. When this arousal is excessive and chronic, it disrupts deep-sleep stages “similar to when we worry at night, but more intense, persistent, and uncontrollable,” he comments. It has been suggested that the abnormality in central pain processing in the brain, also called central sensitization, that is seen in fibromyalgia patients may be a direct consequence of losing deep stage IV sleep (first proposed by Dr Harvey Moldofsky in 1975-1976). “Essentially, these are symptoms also noted by victims of sleep-deprivation torture,” Holman comments. Thus the rationale for trying out pramipexole in fibromyalgia rests on the idea that the drug may restore central brain control of this excessive arousal and so stop it from fragmenting normal sleep. “We do not induce sleep to treat fibromyalgia,” Holman emphasizes. “We allow sleep, by decreasing the brain activity that inhibits normal restorative sleep.” Patients already taking a variety of other drugs The study participants were nearly all women (57/60 patients), with a mean age of 49 years and a self-reported duration of fibromyalgia symptoms of 8.6 years. They were randomized in a 2:1 ratio to receive either pramipexole or placebo, and the study lasted 14 weeks. Pramipexole was taken daily at bedtime, and the dose was increased gradually, starting at 0.25 mg at week 1, 0.5 mg at week 2, etc, until it increased to 4.5 mg for weeks 12, 13, and 14. Patients were allowed to continue taking prior medication, to mimic a “real-world setting,” the researchers explain. They had to be taking stable doses for at least six weeks before enrolling and had to maintain these stable doses throughout the study. A variety of drugs were being used, including antiepileptics, anti-inflammatories, hypnotics, and analgesics (including narcotics, which were used by 31/60 patients). The primary end point was improvement in pain score on a visual analog scale (VAS); by week 14, the VAS pain score had decreased 36% in the pramipexole arm compared with 9% in the placebo arm (treatment difference of -1.77 cm). A 50% or greater reduction in pain was reported by 42% patients on pramipexole compared with 14% on placebo.Holman tells rheumawire that this is better than has been seen with other drugs that have been tried in fibromyalgia; in previous studies, pregabalin (Lyrica, Pfizer) achieved a reduction in pain by 50% or more in 29% patients (compared with 11% in the placebo arm), while with milnacipran (Cypress Bioscience Inc), it was 36% (and 14% on placebo). The drug also had a significant effect on several of the secondary end points, including the total score on the Fibromyalgia Impact Questionnaire (FIQ), the Multidimensional Health Assessment Questionnaire (MHAQ) global score (38% pramipexole vs 3% placebo), and two parts of the MHAQ, function (22% vs 0%) and fatigue (29% vs 7%). Other secondary outcomes also favored pramipexole over placebo, but the differences were not significant; these included the tender-point score and the psychiatric score. None of the end points showed a better trend for the placebo arm, the researchers note. The most common adverse effects associated with pramipexole were transient anxiety (reported by 18% of treated patients vs none in the placebo group, p=0.04) and weight loss (reported by 40% on pramipexole vs 10% on placebo, p=0.01; the mean loss was 3.3 lbs). The most significant adverse effect in the placebo group was weight gain (57% vs 27% on pramipexole, p=0.01; the mean gain was 4.7 lbs). Nausea was very common in both groups (71%-79% of patients), the researchers report, and they comment that they offered a proton pump inhibitor to control this symptom, with similar results in both groups. They note that two side effects that have been reported in Parkinson’s disease patients taking pramipexole, hallucinations and sleep attacks, were “noticeably absent in our study patients.”Pramipexole should be investigated further in fibromyalgia, Holman says, and future studies should include measurement of sleep stages as well as clinical benefits. He notes that another dopamine agonist used in Parkinson’s disease, ropinirole (Requip, Glaxo Wellcome), is also being investigated in fibromyalgia in a study being conducted in Europe by the manufacturer. Holman holds patents for the use of dopamine D3 and D2 agonists in the treatment of fibromyalgia. (Source: Holman AJ and Myers RR. A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum 2005; 52: 2492-2505: Joint and Bone: August 2005.)