Dopamine agonist pramipexole "most promising" in fibromyalgia

Zosia Chustecka

November 09, 2004

Nov 9, 2004

San Antonio, TX - Pramipexole (Mirapex, Boehringer Ingelheim), a dopamine-3 agonist already used in the treatment of Parkinson's disease and restless-leg syndrome, has shown efficacy in fibromyalgia in a single-center trial reported during a late-breaking session at the recent American College of Rheumatology (ACR) meeting [ 1 ]. The responses seen with the drug look better than those reported recently in fibromyalgia with other agents, and lead investigator Dr Andrew Holman (Pacific Rheumatology Associates, Renton WA) tells rheumawire says this is "the most promising treatment option I've seen in 12 years for fibromyalgia."

"The rationale behind using a dopamine agonist in fibromyalgia is not well worked out, but the leading theory—at least in my mind—is that these drugs act to decrease the autonomic arousal that fragments deep sleep," Holman explains. Dopamine in the brain affects a variety of functions, including pain, and the D3 dopamine receptors are found in the mesolimbic area, which is the part of the brain that inhibits arousal coming from the brain stem. The theory is that the D3 agonist at higher doses increases postsynaptic neurotransmission, possibly in the hippocampus, and this increases inhibition of the arousal, but he points out that the theory is still controversial—"it's highly speculative but intriguing," he comments.

Long-standing, severe fibromyalgia

The trial was conducted in 60 patients with long-standing, severe fibromyalgia (mean duration 8 years, range 1-50), who continued taking their usual medications. Just over half (52%) were taking narcotic analgesics, and 28% of patients were disabled. "One important point is that 2 groups of patients were excluded from this study—those with untreated sleep apnea and cervical-cord compression. Both of these potently intensify autonomic arousal, which we are trying to inhibit with this medication. But once the sleep apnea is treated, these patients have some of the best responses," Holman comments.

Patients were randomized to a 2:1 ratio of pramipexole vs placebo, and the dose of the drug was increased gradually to reach 4.5 mg daily. After 14 weeks, a statistically significant difference was seen in the primary outcome measure, pain assessed on a visual analog score (VAS), which was reduced from 7.01 to 4.48 (36%) on pramipexole vs 7.54 to 6.82 (9%) on placebo (p=0.008). Many of the secondary end points also showed statistically significant better results for the drug, eg, the patient global impression of change (PGIC), with a moderate or greater improvement reported by 63% pramipexole vs 38% placebo patients (p=0.01), and the fibromyalgia index questionnaire (FIQ), for which patients on pramipexole scored 25% vs 7% for those on placebo (p=0.03). Some of the secondary end points trended better for pramipexole but did not achieve statistical significance, eg, tender point score and the psychiatric score portion of the Multidimensional Health Assessment Questionnaire (MDHAQ). But no end point trended better for the placebo arm, Holman told the meeting.

Pramipexole was well tolerated, he commented. The most common adverse events in the drug-treated group were a >5-lb weight loss (p=0.01) and anxiety (0.04), which was temporary and seen when the drug was first started, Holman explained. In the placebo group, the most common event was a >5-lb weight gain (0.01). Both groups showed an equal distribution of nausea, and a similar number of patients in each group took proton pump inhibitors for relief of this, he said. Of particular note was the fact that sleep attacks and hallucinations as well as the drug interactions that have been reported in patients with Parkinson's disease taking this drug were not seen in this study, he added.

"Very encouraging response"

In an interview, Holman said that pramipexole showed a "very encouraging response" in measures of pain, fatigue, function, and global assessment and that the results were "very statistically significant." Asked how the results compare with other drugs that have been tried in fibromyalgia patients, he noted that 1 measure of effectiveness commonly used is the proportion of patients who achieve a greater than 50% decrease in pain. In the pramipexole study, 42% of patients achieved this, compared with 14% on placebo. In previously reported studies, the antiepileptic drug pregabalin achieved this result in 29% of treated patients vs 11% of those on placebo, and the antidepressant milnacipran in 36% patients vs 16% on placebo. "So pramipexole appears to be the best so far for pain," Holman commented.

However, he noted that the 3 studies are very different. "The other 2 studies didn't include patients who had the most severe cases of fibromyalgia, they included only those patients who were willing to stop taking most of their medications to participate—that's a unique difference, as in our study 52% of patients were on chronic narcotic analgesics and nearly 30% of patients were disabled, so this is a very challenging group."

Holman would like to continue studying pramipexole in fibromyalgia and is hoping that the manufacturer will now take an interest (the company hasn't been involved so far). "They have a tremendous opportunity here to begin to explore pain and dopamine and autonomic function in fibromyalgia patients," he says. There is a need for a separate independent study for validation, he says. But "as a clinical rheumatologist, I use this drug already in my practice because it's available," he tells rheumawire . "I've been using dopamine agonists for 5 years in my practice, and they are the most promising treatment option I've seen in 12 years for fibromyalgia."

Pramipexole has not been FDA-approved for use in fibromyalgia, so this use is off label. "But we have no FDA-approved treatments for fibromyalgia," he points out. "In that setting, we need to find something to help these patients—here we have a medicine that shows a very significant response rate, with a primary adverse event of weight loss, so it appears to be a reasonable consideration."

"Overall, the safety profile is remarkably encouraging," he adds. "Patients with fibromyalgia are very sensitive to medications, and the nature of the condition leads to side effects with everything, even Tylenol."

For fibromyalgia patients who have tried other options without success, pramipexole is worth a try, says Holman. "We need to remember that not all medications will work for everyone, but this may help some patients."

Trials ongoing with another dopamine agonist

Another dopamine agonist for Parkinson's disease, ropinirole (Requip, Glaxo Wellcome), is also being tested in fibromyalgia. At the ACR meeting, Holman reported a pilot study in 30 patients [ 2 ] that showed no significant difference between the drug and placebo but noted that ropinirole was being used at a dose of 8 mg daily, which is equivalent to about 1.5-mg pramipexole (one third of the dose used in the successful trial described above). The safety data were reassuring, and again there were no reports of hallucinations and sleep attacks that "are such an issue" in Parkinson's disease patients, leading him to speculate that the safety profile may be different in patients with fibromyalgia. Although the responses were not statistically significant, they were sufficiently encouraging to consider a larger randomized trial, he commented, and noted that this is now ongoing in Europe using higher doses of the drug, up to 24-mg ropinirole daily.

Asked to comment on this study by rheumawire , Dr Leslie Crofford (University of Kentucky, Lexington), who led the study of pregabalin in fibromyalgia, said: "Further study of dopamine agonists appears warranted in [fibromyalgia] and other chronic pain conditions. . . . It should be noted that the doses of pramipexole used in this study were far higher than those used in conditions such as restless-leg syndrome. It was quite surprising that patients seemed not to complain of adverse events. The role of other psychoactive drugs, some of which could affect dopaminergic systems, in modulating the requirement for very high doses and adverse events, is unclear."



  1. Holman AJ, Myers RR. Treatment of fibromyalgia syndrome with the dopamine3 receptor agonist pramipexole: a double-blinded, randomized placebo-controlled trial. American College of Rheumatology meeting; San Antonio, TX; Oct 16-21, 2004; Abstract L19.

  2. Holman AJ. Treatment of fibromyalgia with the dopamine agonist ropinirole: a 14-week double-blind pilot randomized controlled trial with 14-week blinded extension. American College of Rheumatology meeting; San Antonio, TX; Oct 16-21, 2004; Abstract 1870.



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