Does the benefit of off-label Gabapentinoid use outweigh the harms?

Gabapentinoids, a class of medications including gabapentin (brand name Neurontin) and pregabalin (brand name Lyrica), are among the most prescribed for off-label uses. Gabapentinoids are with approved by the FDA to treat certain specific conditions, such as seizures and fibromyalgia, but 95% of prescriptions are for off-label uses such as low-back pain, post-operative pain, nerve injury, and other pain conditions. These significant off-label sales have made gabapentinoids into blockbuster drugs. In 2017 there were 68 million prescriptions written for gabapentin and $4.9 billion spent on pregabalin. 

If off-label gabapentinoid use is so prevalent for treating pain, it must be because the drug is so effective, right? Not exactly, as Dr. Christopher Goodman and Dr. Allen Brett of the University of South Carolina School of Medicine explain in a recent piece in JAMA Internal Medicine. Goodman and Brett present a summary of the published evidence on gabapentinoid effectiveness, with an emphasis on double-blind randomized controlled trials. They found that most double-blind RCTs of gabapentinoids show minimal pain relief for off-label uses — either no change compared to placebo, or change of less than 1 point on 10-point pain scale, which is not considered clinically meaningful. Additionally, the side effects of gabapentinoids can be serious; as many as one in three patients taking a high dose of gabapentinoids experience dizziness or sleepiness, which can lead to falls or other adverse events.

Given the limited effectiveness of off-label use and risk of adverse events, why are gabapentinoids so readily subscribed? Despite the bad press Pfizer weathered for their off-label marketing in the early 2000s, it appears the damage has already been done. While Pfizer reps may not be directly marketing gabapentinoids to doctors with “lavish weekends and trips to Florida and Hawaii,” they can still conduct post-marketing studies and use these as pseudo-marketing materials to try and show doctors that these drugs are appropriate for non-approved uses. Restrictions on prescribing opioids may also be driving clinicians to prescribe gabapentinoids for chronic pain in recent years. 

Specialty societies have also adopted enthusiasm for gabapentinoids. Goodman and Brett write that some specialty societies recommend gabapentinoids as the first line of treatment for general neuropathic pain, even though the evidence doesn’t support this claim. As other researchers have pointed out, guidelines often contain discrepancies between their conclusions of the evidence (finding a lack of quality evidence) and their overall recommendations (finding that a treatment is “reasonable” or “probably effective”). We would be interested to find out how conflicts of interest may shape the way these neuropathy guidelines are written…