This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
Orthopaedic surgeons may not be at the forefront of dealing with nonoperative nerve pain, but many of our patients who are not candidates for surgery suffer from spine-related nerve pain in their limbs, such as sciatica. Both gabapentin (GBP, Neurontin) and pregabalin (PGB, Lyrica) are used to treat chronic sciatica (CS).
Gamma-aminobutyric acid (GABA) is an important pain-related neurotransmitter, although neither GBP nor PGB affect the GABA receptor. Instead, both drugs associate with the ligand of the auxiliary α2δ-1 and α2δ-2 subunits of certain voltage-dependent calcium channels in nerves. Among other uses, Neurontin is prescribed to treat diabetic peripheral neuropathy, and Lyrica is commonly used to treat fibromyalgia.
Investigators reporting in JAMA Neurology sought to help guide practitioners in the initial choice of drug. Eighteen patients with MRIs corroborating single-sided nerve-root sciatic pain of at least 3 months duration were evaluated in an interim analysis as part of a randomized, double-blind, double-dummy crossover trial of PGB vs GBP (8 weeks of exposure to each drug with a 1-week washout in between). The primary outcome was pain intensity measured with a 10-point visual analog scale (VAS) at baseline and 8 weeks. Secondary outcomes included disability as measured with the Oswestry Disability Index and the severity and frequency of adverse events.
Relative to baseline, both drugs showed significant VAS pain reductions and disability-score improvements, However, head-to-head, GBP showed superior VAS pain reduction (mean [SD], GBP: 1.72 [1.17] vs PGB: 0.94 [1.09]; P = 0.035), regardless of the order in which it was given. There were no between-drug differences in disability scores, but adverse events for PGB were more frequent (PGB, 31 [81%] vs GBP, 7 [19%]; P = 0.002), especially when PGB was taken first.
The authors conclude that GBP was superior with fewer and less severe adverse events, and they suggest that gabapentin should be commenced before PGB to permit optimal crossover of medicines.
Reference
Robertson K, Marshman LAG, Plummer D, Downs E. Effect of Gabapentin vs Pregabalin on Pain Intensity in Adults WIth Chronic Sciatica: A Randomized Clinical Trial. JAMA Neurol. 2018 Oct 15. doi: 10.1001/jamaneurol.2018.3077. [Epub ahead of print] PMID: 30326006
This post reflects the need to understand more basic science, particularly epidemiology and statistical method.
The original trial protocol was described as a superiority trial (1). The impact on an organisation and size of the study are significantly different compared to noninferiority trials (2). Remarkably the authors assert that the crossover technique reduced the estimated study population size by more than half (100 to 30, 38 if one includes a 20% dropout rate).
However, in this published article, the actual study size was 20 including the dropouts. It is unclear why an interim analysis in October 2018 was deemed necessary, since the protocol was only published 9 months earlier in January 2018, even though the trial actually started in 2016. The paper title did not make it clear that this was an interim analysis of an incomplete study.
Given the size (less than 2/3, after dropouts, of the planned study population), I don’t see how readers can make a reasonable conclusion when the study has not yet reached its planned recruitment size.
An even more important question is this: although the study claims both gabapentoids are effective in reducing pain (GBP more so than PGB), are they any better than placebos? The study did not look at this, but there is increasing evidence that neither is much better than placebo for sciatica (3,4).
In the current climate of big pharma’s influence over evidence-based medicine, doctors should not rely on headlines and abstracts to make conclusions. Although placebo-comparison studies are expensive, we should not assume they are not important or relevant.
If the lessons from arthroscopic meniscectomies, vertebroplasties, and arthroscopic shoulder decompression are to be learned, we should never forget the value of placebos, be they pills or procedures.
References
1. https://trialsjournal.biomedcentral.com/track/pdf/10.1186/s13063-017-2400-y
2. https://www.bmj.com/content/364/bmj.k5432/rr-0
3. https://www.nejm.org/doi/10.1056/NEJMoa1614292
4. https://doi.org/10.1503/cmaj.171333
I have tried both
Currently the P