Pregabalin for neuropathic pain
Clinical bottom line
For a maximum daily dose of pregabalin in a dose-titration in neuropathic pain the NNT for pregabalin compared with placebo was about 4.
Reference
Straube et al. Enriched enrollment: definition and effects of enrichment and dose in trials of pregabalin and gabapentin in neuropathic pain. A systematic review. British Journal of Clinical Pharmacology 2008 DOI: 10.1111/j.1365-2125.2008.03200.x
Study
The review examined both pregabalin and gabapentin. Few trials with gabapentin had useful efficacy outcomes approximating at least 50% pain relief over baseline. Only the results of pregabalin trials are examined here.
- Date review completed: July 2007
- Number of trials included: 9
- Number of patients: 2512
- Control group: placebo
- Main outcomes: at least 50% pain relief
The review used the following definitions to categorise trials, based on the degree of enrichment that various strategies might be expected to attain. These definitions assumed that clinically effective doses are used.
- Complete enriched enrollment (CEE) would occur in two circumstances. One would be the inclusion criterion of all participants responding to the test drug or a closely related drug with similar mechanism of action, within a clinical trial or with a satisfactory response in clinical practice. Another would be the exclusion criterion of non-response to the test drug or a closely related drug, and when all participants had been exposed to the drug.
- Partial enriched enrollment (PEE) was defined as the exclusion from the study of any previous non-responders to the study drug or a similar drug, but where not all participants were known to have been exposed. This measure leads to an unknown degree of enrichment of responders to the study drug.
- All other forms of enrollment were defined as non-enriched enrollment (NEE) when no statement of inclusion or exclusion of patients could be interpreted as enriching the population to drug responders.
Results
Pregabalin trials used PEE (1,342 patients) and NEE (1,088 patients). Trials examined efficacy in painful diabetic neuropathy, postherpetic neuralgia, and (in one trial) fibromyalgia. Trials were of high quality, and generally lasted 12 weeks.
There was no difference between results for the two strategies, at whatever maximum dose titration was used (Figure 1). The maximum degree of enrichment was estimated as 12% of patients randomised in those using a PEE strategy.
Figure 1: Percentage of patients with at least 50% pain relief with PEE and NEE at increasing maximum doses of pregabalin
There was a significant dose response with pregabalin depending upon the maximum dose allowed:
- For 150 mg the NNT compared with placebo was 14 (7.3 to 150).
- For 300 mg the NNT compared with placebo was 6.1 (4.4 to 9.5).
- For 600 mg the NNT compared with placebo was 3.8 (3.2 to 4.7).
There was also dose response for patient global impression of change and lack of efficacy withdrawal. Adverse events (adverse event withdrawal, somnolence, dizziness) were more frequent at higher doses of pregabalin, again in a dose dependent manner.
Comment
This review defines enrichment in a useful way, and demonstrates a significant dose response for efficacy and adverse events for pregabalin, mainly in "classic" neuropathic pain trials. It shows the wisdom of dose-titration.