Friday, April 8, 2011

Antiepileptic Drugs for Fibromyalgia Reviewed

Fibromyalgia syndrome (FMS) is a difficult-to-treat chronic pain condition with relatively few specifically approved and effective pharmacotherapies. A recent review examined the relative benefits and harms of pregabalin, the only antiepileptic FDA approved for fibromyalgia, and the antiseizure medication gabapentin in the treatment of FMS. However, the evidence supporting their efficacy was somewhat disappointing.

Writing in the Journal of Pain, researchers from the Oregon Health & Science University, School of Medicine, Portland, Oregon, report conducting an extensive literature search for studies of any antiepileptic drug compared with placebo or another antiepileptic agent in a randomized controlled trial (RCT) or observational study [Siler et al. 2011]. Only 8 studies were discovered matching those inclusion criteria: 7 of pregabalin (Lyrica®) that included 2,964 subjects total, and 1 trial of gabapentin (eg, Neurontin® and generics) that enrolled 150 participants. Populations studied included predominantly women aged 47 to 50 years.

Short-term (8-14 weeks), response rates with both drugs at various doses, and reducing mean pain scores by 30% from baseline, were modestly greater than placebo — pregabalin 26% to 50%; gabapentin up to a 51%; compared with 19% to 35% response rates with placebo. [Note: these data are taken from body text of article, which differs from the abstract.] Study withdrawals due to adverse events were significantly greater in pregabalin groups compared with placebo, with relative risks increasing as dose was increased. Gabapentin had similar drop-out rates but not statistically different from placebo (possibly due to the small sample size in this trial).

Compared with placebo, both drugs had greater rates of side effects. Dizziness, headache, somnolence, and edema were the most commonly reported adverse events for both drugs. Dizziness was most common with pregabalin (38%), while headache (27%) was more prevalent with gabapentin. Additionally, weight gain was more common with pregabalin than placebo, whereas sedation and light-headedness occurred more often with gabapentin than placebo.

A follow-up analysis found that about 25% of the pain relief associated with pregabalin was significantly correlated with combined improvements in anxiety and depression. Examination of the impact of other factors such as age, race, gender, and socioeconomic status on the benefits or harms associated with pregabalin or gabapentin was not possible due to narrow inclusion criteria and limited reporting in the studies.

There were important methodological differences between the pregabalin and gabapentin trials and, without head-to-head clinical studies, the authors state it is not possible to conclude if pregabalin or gabapentin is superior. While it appeared that gabapentin was slightly more efficacious, the drug incurred significantly higher rates of headache than pregabalin and it was studied in only a single, small-scale RCT.

The authors believe that results of their review indicate that pregabalin and gabapentin can be used for the treatment of fibromyalgia with moderate benefits in the short-term. However, clinicians must be cautious not to generalize these results to other, unstudied antiepileptic drugs, and the limitations of this evidence with regard to the populations included, durations studied, and the potentials for important differences in adverse effect profiles between the drugs should be taken into account.

COMMENTARY: In a prior UPDATES article [here], we discussed comparisons of pregabalin with duloxetine (Cymbalta®) and milnacipran (Savella®) — both of which are selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants and FDA-approved for treating FMS. All 3 drugs were found to have short-term (up to 6 months) efficacy; although they differed in their adverse effect profiles, with pregabalin appearing to be most advantageous except in patients with depressed mood. There were some limitations of the trials and none compared all 3 drugs head-to-head.

In the present review by Siler and colleagues, the internal validity of the included RCTs was judged as being rather low. This was due to unclear methods of blinding, allocation concealment, and randomization. While the gabapentin trial was government funded, the pregabalin RCTs were supported by the pharmaceutical manufacturer. All of these factors can engender significant bias in research studies, as discussed in our recent UPDATES article on “Making Sense of Pain Research: Part 3” [here].

Both pregabalin and gabapentin were better than placebo in reducing pain in the short-term; however, in absolute terms the magnitude of beneficial effects were limited, with half of patients (at most) experiencing a 30% decrease in pain (while up to one-third had a similar response with placebo). The authors note that the Numbers-Needed-to-Treat, or NNTs, for both drugs were not impressive; specifically, for every 5 patients treated with gabapentin or 8 patients treated with pregabalin (rather than placebo) for 8 to 14 weeks, 1 additional patient would have a response of at least a 30% improvement in symptoms. According to Siler et al., NNTs of 2 to 4 are considered favorable for drug therapies [although their reference source for this assumption is unclear].

Of pregabalin responders, beneficial effects dissipated over time and only about one-third continued to have response at 6 months. While this rate of continued response was better than for those who were switched to placebo, it is still disappointing, the authors believe, considering the long-term duration of FMS symptoms in most patients.

The authors further note that, from an evidence-based medicine perspective, the major components in assessing strength of evidence are: 1) precision of estimates, 2) directness and consistency of evidence, 3) risk of bias, and 4) magnitude of effect. They believe that the overall body of evidence in their review would merit only a low strength of evidence ranking. Furthermore, the clinical applicability (external validity) of the studies was limited by the short duration of all clinical trials and the selective patient population.

A benchmark for therapeutic success in studies to date of antidepressant and antiepileptic agents for FMS appears to be a 30% improvement in symptoms. We have previously described in an UPDATE [here] that 30% to 36% improvements in pain are generally considered by patients as being moderate, with 50% or greater improvements deemed more desirable. This helps to explain why multidrug therapies that combine to increase improvement are commonplace in patients with FMS.

Indeed, Siler and colleagues recommend that better, longer-term comparative trials are needed, which adopt a more “pragmatic” design. That is, including large numbers of patients, with a wide variety of baseline symptoms and comorbidity, and taking multiple medications. However, such “real world” trials can be extremely difficult to construct, conduct, and interpret. And, as we have noted before, pharmacotherapy is only one piece of the puzzle when it comes to successful management of FMS, which often benefits more from multimodal approaches as part of a comprehensive pain management program.

REFERENCE: Siler AC, Gardner H, Yanit K, Tera Cushman, McDonagh M. Systematic Review of the Comparative Effectiveness of Antiepileptic Drugs for Fibromyalgia. J Pain. 2011(Apr);12(4):407-415 [abstract here].