Prof Chris Maher

The 17^th October issue of the limbic ran a feature on the Robertson et al trial (1) that encouraged use of gabapentin and pregabalin for chronic sciatica. This conclusion is not supported by the trial and conflicts with the other available evidence (2-4). We are concerned that uncritical acceptance of the authors’ conclusion will encourage inappropriate use of these two medicines, both of which have significant safety issues associated with them.

Inspection of the trial registry (ACTRN12613000559718) reveals that what was reported in the JAMA Neurology publication is very different to what was originally specified. While originally registered as a two-arm trial of 200 people with funding from Pfizer, the report in JAMA Neurology describes an 18 person cross-over trial with no drug company funding. Over time the study design, sample size, and outcomes have repeatedly changed but this is not revealed to readers of JAMA Neurology. We are deeply concerned by this lack of transparency. The publication reveals additional concerns about trial conduct. For example the first author was unblinded, missing data were handled inappropriately and there are no outcomes beyond the treatment period.

The trial’s design only allows the authors to make inferences about comparative effectiveness of the two medicines; not to declare that both are efficacious. The benefit of gabapentin over pregabalin is marginally statistically significant for pain (p =0.035) but less than the authors specified as a clinically important difference of 0.9 points on a 0-10 pain scale. While there was no evidence of important benefit, 12 of the 18 participants experienced adverse events.

Results of the trial should also be interpreted in light of the potential serious harms of gabapentin or pregabalin, which include misuse, increased suicidality and intentional poisoning (5-7). Given the lack of important benefit within their trial and the evidence of harm we are dismayed by the authors advocacy of these two medicines for sciatica.

Prof Chris Maher, The University of Sydney

A/Prof Christine Lin, The University of Sydney

Prof Rachelle Buchbinder, Monash University, Cabrini Institute

Prof Andrew McLachlan, The University of Sydney

COI: authors CM, CL and AMc are authors on the Enke review (2) and the Mathieson trial (4). The Mathieson trial (4) received study medicines at no cost from Pfizer but the investigators retained autonomy over its design, conduct, analysis and reporting.

References

1. Robertson K et al. Effect of Gabapentin vs Pregabalin on Pain Intensity in Adults WIth Chronic Sciatica A Randomized Clinical Trial. JAMA Neurology 2018 Oct 15 [Epub ahead of print]
2. Enke O et al. Anticonvulsants for low back pain: A systematic review and meta-analysis. CMAJ 2018 190: E786–93.
3. Shanthanna H et al. Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta-analysis of randomized controlled trials. PLOS Medicine 2017: 14: e1002369
4. Mathieson S et al. Trial of pregabalin for acute and chronic sciatica. New England Journal of Medicine 2017 376: 1111-1120.
5. Chiappini S et al. A decade of gabapentinoid misuse: an analysis of the European Medicines Agency’s ‘suspected adverse drug reactions’ database. CNS Drugs 2016 30: 647-654.
6. Arana A et al. Suicide-related events in patients treated with antiepileptic drugs. New England Journal of Medicine 2010 363: 542-551.
7. Cairns R et al. Rising pregabalin use and misuse in Australia: trends in utilization and intentional poisonings. Addiction 2018 Aug 18 [Epub ahead of print]