Friday, June 4, 2010

Meds for Fibromyalgia Compared & Contrasted

The perfect medication for treating fibromyalgia syndrome has apparently yet to be discovered, as a recent systematic review comparing duloxetine, milnacipran, and pregabalin found. Each of these medications approved for fibromyalgia has particular strengths and weaknesses that may affect prescribing decisions and patient outcomes.

Researchers in Germany conducted a systematic review of available evidence comparing benefits and harms of the 3 FDA-approved drugs for the treatment of fibromyalgia syndrome (FMS): duloxetine (DLX; Cymbalta®, Lilly), milnacipran (MLN; Savella®, Forest Labs), and pregabalin (PGB; Lyrica®, Pfizer) [Hauser et al. 2010]. The authors searched MEDLINE, SCOPUS, Cochrane Central Register of Controlled Trials, and sought unpublished data from the databases of the FDA, U.S. National Institutes of Health, and industry through May 2009 for randomized controlled trials. Outcomes of interest were symptom reduction (pain, fatigue, sleep disturbance, depressed mood, health-related quality of life), and adverse events.

Based on their search, 17 high quality studies met inclusion criteria, enrolling 7,739 patients who were almost exclusively Caucasian females aged 48 to 50 years on average. Adjusted indirect comparisons indicated that the 3 medications were equivalent in terms of dropout rates due to adverse events, in providing at least 30% pain relief, and in improving health related quality of life (HRQOL) scores. Significant differences between the 3 drugs may be summarized as follows (and depicted in the table below):
  • In the various trials the 3 drugs were superior to placebo except DLX for fatigue, MLN for sleep disturbance, and PGB for depressed mood.

  • DLX and PGB were superior to MLN in reducing pain and sleep disturbances.

  • DLX was superior to PGB and MLN in reducing depressed mood.

  • PGB and MLN were superior to DLX in reducing fatigue.

  • The risk of headache and nausea was less with PGB compared with DLX and MLN.

  • The risk of diarrhea was less with MLN and PGB than with DLX.
FMS MedsCONCLUSIONS: This study by Hauser and colleagues was a very thorough first-of-its-kind attempt to compare all 3 FDA-approved drugs for FMS. Overall, the authors conclude that there is evidence for the short-term (up to 6 months) efficacy of DLX, MLN, and PGB. From the data, it might appear that PGB could be a first choice of therapy except when depressed mood is of primary concern. However, differences between the 3 agents in benefitting key symptoms of FMS and the differential occurrence of drug-specific adverse events (beyond headache, nausea, diarrhea as noted) can be relevant for the choice of medication or the combination of medications.

DLX and MLN are serotonin (5HT) and norepinephrine reuptake inhibitors, so there could be concerns regarding harmful serotonin syndrome, particularly with concomitant use of serotonergic drugs (including triptans), with drugs that impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. An FDA warning to this effect regarding MLN was issued last February [here]. In the case of DLX, its metabolism can be affected by inhibitors of CYP1A2 or CYP2D6 liver enzymes. Pregabalin is a structural analog of the neurotransmitter GABA and there can be a potential for convulsive activity in patients with seizure disorders. If administration of any of the 3 medications is abruptly stopped, there can be a discontinuation (withdrawal) syndrome. No drug-related deaths were reported with the 3 medications in any of the clinical trials; however, patients younger than age 18 and older than 70 were not included in the trials, so safety in these populations is undetermined.

It is important to note that all of the clinical trials had been sponsored by pharmaceutical firms as part of the approval process for their respective drugs and there may have been inherent biases. None of the studies compared all 3 drugs head-to-head; therefore, the findings of Hauser and colleagues result from indirect analyses that have methodological limitations. Finally, the authors provide an important reminder that “pharmacology is only one piece of the puzzle when it comes to successful management of FMS. Aerobic exercise, hydrotherapy, and multicomponent therapy have shown efficacy in alleviating fibromyalgic symptoms without harms, and can be offered to the patient either as [an] alternative or used adjunctively with pharmacological therapy.”

CONFLICT OF INTREST: None to declare; Pain Treatment Topics is not supported by nor has any relationship with any of the companies noted in this blogpost, and neither endorses nor specifically recommends any of the products mentioned.

REFERENCE: Hauser W, Petzke F, Sommer C. Comparative Efficacy and Harms of Duloxetine, Milnacipran, and Pregabalin in Fibromyalgia Syndrome. J Pain. 2010(June);11(6):505-521 [abstract here].