They also note that gabapentinoids are associated with several common adverse effects. In a trial in which the efficacy of gabapentin for the treatment of sciatica was examined, dizziness was reported by 40% of participants administered the drug vs 13% of those receiving placebo.5 In another study, 25% and 14% of patients taking pregabalin for the first time reported experiencing dizziness and somnolence, respectively.6

Emerging evidence also shows significant rates of gabapentin misuse, especially in patients with opioid use disorder, underscoring the need for selective prescribing of these agents.7

“Our message is one of caution, not rejection. Some people with select conditions may find benefit, but the majority of those starting a gabapentinoid — even in FDA-approved conditions — will not,” Dr Goodman told Clinical Pain Advisor. “It is worth reminding clinicians that these drugs are not approved for all neuropathic pain— despite the common misconception that they are.”

Clinical Pain Advisor interviewed Matthias Behrends, MD, health science clinical professor in the department of anesthesia and perioperative care, medical director of inpatient pain services, and director of the acute pain service at the University of California San Francisco. 

Clinical Pain Advisor: What are your thoughts on off-label uses of gabapentin and pregabalin?

Dr Behrends: The authors of the paper made very valid observations. A lot of the off-label use of gabapentinoids is not supported by any evidence about their efficacy to treat some of the pain conditions that are regularly treated with gabapentinoids. Chronic noncancer pain is difficult to treat, and the use of gabapentinoids in the treatment of these chronic pain syndromes may reflect the hopes of providers to present a pharmacologic solution for a challenging and complex problem.

While the current lack of evidence for the beneficial effects of gabapentinoids for certain pain syndromes cannot not be interpreted as proof that these drug do not work for these indications, I do agree with the authors that the lack of supporting literature for an indication should result in careful consideration about whether these drugs should be prescribed. Ultimately, we need more quality clinical trials that test these drugs for the off-label indications most commonly seen.

Clinical Pain Advisor: Are there any points you would add regarding the off-label use of gabapentinoids for pain?

Dr Behrends: The authors make a compelling point that the increasing off-label use of gabapentinoids was the consequence of generalizations about their effects on neuropathic pain. Interestingly, the current discourse surrounding the critical reevaluation of gabapentinoids is also not free of these generalizations — resulting in statements that these drugs do not help, that they are dangerous, and that they are being abused. Again, things are a bit more complicated, and there are off-label indications that are supported by the literature.

The authors excluded from their analysis the use of gabapentinoids in the treatment of short-term perioperative pain. There is compelling scientific evidence that gabapentinoids do effectively reduce postsurgical pain, and can reduce opioid requirements and lower the incidence of persistent postsurgical pain.8 Any discussion about the off-label use of gabapentinoids would be incomplete without acknowledging the beneficial effects of these drugs for this indication, and generalizations about the lack of efficacy and dangers of gabapentinoids used off label may result in underutilization of what appears to be a potent preventive analgesic intervention.

Clinical Pain Advisor: What are the relevant treatment implications for clinicians?

Dr Behrends: The challenges seen in the treatment of chronic pain highlight the need for highly individualized treatments. The authors make a good argument that treating all conditions with a component of neuropathic pain with gabapentinoids as a knee jerk reaction is not appropriate. Prescribers must screen their patients for side effects and evaluate whether the therapy has resulted in any benefits for the patients. It happens too frequently that a therapy stays on a patient’s medication list indefinitely, putting them at risk for adverse events.

And, we may ultimately have to accept that we do not have a pharmacologic solution for every pain problem — especially since chronic pain responds better, in many cases, to behavioral therapy and physical therapy than to pharmacologic interventions. Maybe it is time to say goodbye to the paradigm that there is a pill for every problem.

Clinical Pain Advisor: What should be the focus of future studies regarding this topic?

Dr Behrends: We need well-conducted clinical trials that help us identify the pain syndromes that actually benefit from treatment with gabapentinoids. We need more information about the effects of short- vs long-term treatment with gabapentinoids. We have to better identify the patients at risk for adverse events and get a better understanding about the complex interactions between gabapentinoids and opioids.

Given the current paucity of good scientific data, we cannot come to a final conclusion regarding the effectiveness of off-label use of gabapentinoids. The authors of the paper should be commended, though, for promoting a critical discussion about the off-label use of gabapentinoids.

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References

1. Johansen ME. Gabapentinoid use in the United States 2002 through 2015. JAMA Intern Med. 2018;178(2):292-294.

2. Goodman CW, Brett AS. A clinical overview of off-label use of gabapentinoid drugs. JAMA Intern Med. 2019;179(5):695-701.

3. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA. 2016;315(15):1624-1645.

4. Bril V, England J, Franklin GM, et al; American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76(20):1758-1765.

5. Mathieson S, Maher CG, McLachlan AJ, et al. Trial of pregabalin for acute and chronic sciatica. N Engl J Med. 2017;376(12):1111-1120.

6. Härmark L, van Puijenbroek E, Straus S, van Grootheest K. Intensive monitoring of pregabalin: results from an observational, web-based, prospective cohort study in the Netherlands using patients as a source of information. Drug Saf. 2011;34(3):221-231.

7. Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. Drugs. 2017;77(4):403-426.

8. Imani F, Rahimzadeh P. Gabapentinoids: gabapentin and pregabalin for postoperative pain management. Anesth Pain Med. 2012;2(2):52-53.