Pramipexole in fibromyalgia offers hope to patients

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Pramipexole in fibromyalgia " offers hope to patients "

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Aug 16, 2005

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Zosia Chustecka

Renton, WA - A drug for Parkinson's disease, the dopamine agonist

pramipexole (Mirapex, Boehringer Ingelheim), " 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 Holman

and Robin Myers (Pacific Rheumatology Associates, Renton, WA) report in

the August 2005 issue of Arthritis & Rheumatism [1]. 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.

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