In response to encouraging results from the use of dopamine agonists for the treatment of restless legs syndrome (RLS), which occurs disproportionately among fibromyalgia (FM) patients, researchers have speculated that this class of agents may play a role in the treatment of fibromyalgia syndrome (FMS).

Now a new study shows that FM patients taking pramipexole, the dopamine₃-receptor agonist developed for the treatment of Parkinson's disease, reported decreased pain and fatigue and improved function and global status compared with study participants taking placebo.¹ The new study appears in the August issue of Arthritis and Rheumatism.

"I am remarkably hopeful for patients with FMS based on treating FMS with dopamine agonists for 5 years and from the results of this study," lead researcher Andrew J. Holman, MD, a rheumatologist at Pacific Rheumatology Associates in Renton, Washington, tells CIAOMed. Dr. Holman has patents for the use of dopamine₂ /dopamine₃-receptor agonists for the treatment of FM.

Rationale for the effectiveness of pramipexole

"It was the disproportionate RLS in FMS [patients] that began to point to this therapy," Dr. Holman says, adding that some researchers believe that the essence of RLS is relevant to FMS. The RLS Foundation in Rochester, Minnesota, estimates that about 20% to 40% of the FM population also has RLS. "The hippocampal inhibition of autonomic arousal appears primary," Dr. Holman says. Some research suggests that disturbed stage four sleep leads to FMS symptoms and that autonomic arousal at night fragments sleep. "The hippocampus inhibits autonomic arousal, [and] dopamine₃ receptors control hippocampus function," Dr. Holman explains.

"Much work remains, but hopefully researchers will continue to report how hippocampal function applies to FMS," he says. "Currently, I hope to repeat the study using sleep studies to document sleep stage architecture improvement." Dr. Holman adds that now "we are completing a cost analysis of FMS care to measure the economic benefits of effective treatment of FMS with dopamine agonists."

Pramipexole improves pain, function

In the single-center, double-blind, placebo-controlled study of 60 FM patients, patients received either pramipexole (Mirapex; Boehringer Ingelheim) or placebo for 14 weeks. The drug was initiated at 0.25 mg, titrated to 4.5 mg for the last 3 weeks, and then tapered to 0 mg during week 15. The study medication was taken by mouth each evening.

Patients were allowed to take concomitant medications, including narcotic analgesics, antiepileptics, nonsteroidal anti-inflammatory drugs, and selective serotonin reuptake inhibitors during the study period as long as the dosage had been stable for at least 6 weeks prior to the study.

At week 14, the mean decrease in pain from baseline, as assessed by the visual analog scale (VAS), was 36% and 9.4% in the pramipexole and placebo groups, respectively (P = 0.008). Moreover, 42% of patients in the pramipexole group achieved at least a 50% reduction in VAS scores compared with 14% in the placebo arm (P = 0.03). Overall, 82% of patients taking pramipexole noted some improvement in pain compared with 57% of those in the placebo group (P = 0.04). Other scales that measure FM and mental symptoms, such as the Hamilton Depression Inventory and the Multidimensional Health Assessment Questionnaire, also improved in the pramipexole arm.

No study participants withdrew due to side effects of the study medication. The most common adverse effects were weight loss and nausea. Interestingly, patients did not suffer from any of the side effects seen in patients taking this medication for Parkinson's disease, including hallucinations.

May be of value in the subset of FM patients with RLS

"This looks like a promising treatment," says Daniel J. Clauw, MD, professor of medicine in the division of rheumatology at the University of Michigan in Ann Arbor, Michigan. "As with any new therapy, it will be interesting to see if these results are replicated by others. I think it's possible, if not likely, that a subset of people with FM will respond well to these drugs, and the challenge clinically is to identify that subset."

This challenge is similar to that seen both with other drugs that are used off-label and those that will become available, as none of them work in all FM patients. "It's not a homogenous disorder," says Dr. Clauw, director of the Chronic Pain and Fatigue Research Center at University of Michigan. "But the subset of people with FM and RLS would be a logical subset to start [dopamine agonist treatment] with."

When asked by CIAOMed if he would try pramipexole in such patients, Dr. Clauw says he may well try it off-label in patients with RLS and FM. After that, he says he would want to determine if it improved RLS or had a "more global beneficial effect on FM. If so, then I might expand and look at it as second- or third-line therapy for FM."

While no one drug is approved for the treatment of FM, several are now in the pipeline, he says. For example, the gabapentinoid pregabalin and the serotonin/norepinephrine reuptake inhibitors (SNRIs) duloxetine and milnacipran are all in various stages of clinical trials.

"This will be extremely important, not just because there will be additional drugs to prescribe, but because the companies that get the drugs approved will do massive education campaigns to teach people about FM," Dr. Clauw says. "My own personal view is that even with existing therapies, if physicians had a better idea of how to use them and how to combine drug and nondrug treatments, we could make most FM patients much better and they could lead a normal life."

However, Dr. Clauw adds, most physicians do not know how to use drugs in FM, pointing out that the doses of trycyclic antidepressants used in FM are much lower than those for depression, and many physicians do not adhere to this. "In FM, you must start at a low dose and go up slowly," he tells CIAOMed. "Some doctors may know that some antidepressants are effective in FM, but they prescribe a selective serotonin reuptake inhibitor, instead of [SNRIs], which have been shown to be more effective in FM," he explains. "The new drugs might be a little better than the existing drugs, but the huge advantage will be the education programs, teaching physicians how the compounds should be used, what FM is, and how to manage it," Dr. Clauw says.

Caution urged in interpretation

Leslie J. Crofford, MD, professor of internal medicine and chief of rheumatology at the University of Kentucky College of Medicine in Lexington, Kentucky, tells CIAOMed that it is plausible that dopaminergic pathways could be involved in FMS, but it has not been proven. However, she says, "I do think that further study of this approach is warranted."

Dr. Crofford echoes some of the study authors' comments regarding the limitations of this trial. "First, patients were typically on many other drugs that act centrally, and there is little information about how they may affect dopaminergic systems, though undoubtedly these systems interact," she says. Moreover, "the doses used in this study are huge compared with the doses used for RLS and even Parkinson's disease-the authors really have no information as to what these doses are doing in the brains of humans."

Reference:

Holman AJ, Myers RR. A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum. 2005;52:2495-2505.