Values are numbers of citations. FDA indicates US Food and Drug Administration.
eTable 1. Randomized Controlled Trials of Gabapentin for Outpatient Treatment of Off-label Painful Conditions, Excluding Cancer Pain and Headache
eTable 2. Randomized Controlled Trials of Pregabalin for Outpatient Treatment of Off-label Painful Conditions, Excluding Cancer Pain and Headache
eTable 3. Off-label Painful Outpatient Conditions for Which Gabapentinoid Studies With No Controls or With Nonrandomized Comparisons Have Been Published, Excluding Cancer Pain and Headache
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Goodman CW, Brett AS. A Clinical Overview of Off-label Use of Gabapentinoid Drugs. JAMA Intern Med. Published online March 25, 2019179(5):695–701. doi:10.1001/jamainternmed.2019.0086
The gabapentinoid drugs gabapentin and pregabalin were originally developed as antiseizure drugs but now are prescribed mainly for treatment of pain. For gabapentin, the only pain-related indication approved by the US Food and Drug Administration (FDA) is postherpetic neuralgia. For pregabalin, FDA-approved indications related to pain are limited to postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy or spinal cord injury, and fibromyalgia. Despite these limited indications, gabapentin and pregabalin are widely prescribed off-label for various other pain syndromes. Such use is growing, possibly because clinicians are searching increasingly for alternatives to opioids.
This report summarizes the limited published evidence to support off-label gabapentinoid uses, describes clinical cases in which off-label use is problematic, and notes how review articles and guidelines tend to overstate gabapentinoid effectiveness.
Clinicians who prescribe gabapentinoids off-label for pain should be aware of the limited evidence and should acknowledge to patients that potential benefits are uncertain for most off-label uses.
The pharmacologic management of pain is challenging, particularly given the current opioid crisis. As government initiatives are setting restrictions on opioid prescribing,1 clinicians are turning to alternative medications for treatment of pain. Acetaminophen is often ineffective for moderate to severe pain, and nonsteroidal anti-inflammatory drugs are problematic or contraindicated in many patients with complex medical conditions. Increasingly, clinicians are prescribing the gabapentinoid drugs (gabapentin and pregabalin) to fill this void in pain management.2,3 However, gabapentinoid drugs have been approved by the US Food and Drug Administration (FDA) for treatment of only a limited number of pain syndromes, and a substantial proportion of gabapentinoid use is off-label (ie, for indications that are not FDA approved).
To prescribe gabapentinoids responsibly, clinicians should be familiar with the published evidence that addresses off-label use of these drugs. In this Special Communication, our primary objective is to provide an overview of randomized clinical trials that have examined the efficacy of gabapentinoids for treatment of painful conditions outside of FDA-approved indications and to present cases that illustrate potentially problematic off-label use of gabapentinoids. To provide additional perspective, we also briefly review the approval and marketing history of gabapentinoids, the presentation of gabapentinoid effectiveness for off-label use in practice guidelines and review articles, and recent concern about gabapentinoid misuse.
Gabapentin (brand-name Neurontin; Pfizer) was initially approved by the FDA in 1993 for treatment of seizures. At roughly the same time, the manufacturer began marketing the drug for off-label treatment of pain.4-6 However, the drug was eventually FDA approved for only one pain indication (postherpetic neuralgia) in 2002. In 2004, the company paid a penalty for improper marketing of Neurontin for off-label uses.4 Examination of internal documents from the manufacturer revealed that results of clinical trials examining off-label use of gabapentin, mainly for neuropathic pain, bipolar disorder, and migraine prophylaxis, were manipulated to magnify the drug’s perceived effectiveness.5,6 In 2004, gabapentin became available as a generic drug.
Pregabalin is available in the United States only as brand-name Lyrica (Pfizer). It was approved in 2004 for treatment of seizures and for treatment of postherpetic neuralgia and diabetic neuropathy. It was subsequently approved for treatment of fibromyalgia (in 2007) and pain associated with spinal cord injury (in 2012). In 2009, the manufacturer paid a settlement to the US government for misleading and illegal promotion of Lyrica for off-label indications, and a settlement was paid in 2012 to 33 US states.7,8 Currently, Lyrica is promoted in direct-to-consumer advertisements for 2 of its FDA-approved indications (painful diabetic neuropathy and fibromyalgia).
Despite FDA approval only for these specific indications, the use of gabapentinoids has tripled over the past 15 years; that increase is especially prominent in patients for whom opioids and benzodiazepines are also prescribed and in patients with numerous comorbidities.2 For gabapentin, it is implausible that its approved indications (seizures and postherpetic neuralgia) account for these observations. Rather, the accelerating use of gabapentinoids likely reflects a substantial increase in off-label prescribing for pain syndromes that are not FDA-approved indications, in part to substitute for opioids. Between 2013 and 2017, numbers of gabapentin prescriptions increased from 44 million to 68 million annually, and gabapentin was the 10th most commonly prescribed medication in 2017 in the United States.9 Pregabalin (available exclusively as Lyrica) ranked sixth in nondiscounted spending for brand-name drugs in 2017; between 2013 and 2017, nondiscounted spending for pregabalin increased from $2.4 billion to $4.9 billion. The only drugs with higher nondiscounted spending were 3 biologic treatments for autoimmune diseases (adalimumab, etanercept, and infliximab), the antiviral combination ladipasvir-sofosbuvir for hepatitis C, and the diabetes drug sitagliptin phosphate.9
To review the clinical research that informs off-label use of gabapentinoids for outpatient treatment of pain, we conducted a search of the PubMed database in September 2018. We used the search word pain in conjunction with each of the 2 drugs (gabapentin and pregabalin) and applied the filter clinical trial; we excluded studies that addressed cancer pain and headache.
Results of this search are summarized in the Figure. The gabapentin search yielded 362 citations. Fifty-four studies, 34 of which were randomized controlled trials (18 placebo-controlled), addressed outpatient noncancer pain syndromes for which gabapentin is not FDA approved. The pregabalin search yielded 315 citations. Thirty studies, 20 of which were randomized clinical trials (12 placebo-controlled), addressed outpatient noncancer pain syndromes for which pregabalin is not FDA approved. We also searched published systematic reviews of gabapentinoids and found 4 additional placebo-controlled trials (all involving gabapentin). We excluded studies in which most participants had FDA-approved indications.
Table 1 and Table 2 summarize double-blind, randomized clinical trials in which gabapentinoids were compared with placebo; given the subjective nature of pain and the prominent placebo response to treatment of pain, these studies merit the most attention. Numbers of participants ranged from 7 to 421; more than half of the studies had less than 100 participants. Trial durations varied substantially but generally ranged from 4 to 12 weeks. Because almost all studies reported the mean response to pain on a 0 to 10 scale as the primary outcome, those outcomes are listed in Tables 1 and 2. Research suggests that the minimal clinically important difference in pain on 0 to 10 scales depends somewhat on the clinical condition and the baseline level of pain, but absolute differences of 1 point or less are usually considered below the threshold of clinical importance.44 A more detailed presentation of the literature search is available online: eTable 1 and eTable 2 in the Supplement list all randomized clinical trials (both placebo-controlled and open-label) that met our search criteria, and eTable 3 in the Supplement lists pain syndromes for which nonrandomized or uncontrolled studies have been published.
Several findings are noteworthy. First, for gabapentin treatment of painful diabetic neuropathy (a common condition for which gabapentin is prescribed off-label), the evidence is mixed at best. Among 5 trials, 2 (including the largest and longest-duration trial) showed no benefit,10,13 and 2 showed improvement of only about 1 point on 0 to 10 scales compared with placebo.11,12 A recent Cochrane review estimated that roughly 6 patients with painful diabetic neuropathy would require treatment with gabapentin to provide “substantial benefit” for 1 patient.45
Second, there were few studies of gabapentinoids for nondiabetic neuropathies; studies were either negative or yielded statistically significant mean differences less than 1 point on 0 to 10 scales compared with placebo. The aforementioned Cochrane review concludes that, aside from postherpetic neuralgia (for which gabapentin is approved) and diabetic neuropathy, the evidence to support gabapentin therapy for other types of neuropathic pain “is very limited.”45
Third, the evidence does not support gabapentinoid therapy for low back pain or radiculopathy. In the largest study (a placebo-controlled trial of pregabalin for sciatica), the drug was ineffective.36
Fourth, fibromyalgia is an FDA-approved indication for pregabalin but not gabapentin; however, gabapentin is often prescribed off-label for fibromyalgia, presumably because it is substantially less expensive. In the sole placebo-controlled trial of gabapentin for fibromyalgia, the mean difference in pain was only 0.9 on a 0 to 10 scale.27 Notably, this difference is similar to the mean differences in the trials that resulted in pregabalin’s FDA approval for fibromyalgia.46
Fifth, both gabapentin and pregabalin are FDA approved for treatment of postherpetic neuralgia, defined as neuropathic pain persisting at least 3 months after acute herpes zoster. However, 2 placebo-controlled studies31,38 examined the efficacy of these drugs for acute zoster pain, and both were negative.
Sixth, Tables 1 and 2 summarize that a small number of placebo-controlled gabapentinoid trials have been performed for various other pain syndromes. With few exceptions, the drugs were either ineffective or associated with small analgesic effects that were statistically significant but of questionable clinical importance.
Four other aspects of the gabapentinoid trials are notable. First, many studies examined various secondary outcomes beyond pain relief; those findings generally paralleled the pain outcomes. Second, the time frame covered by patients’ pain scores varied (eg, ranging from the previous 24 hours to the previous 7 days). Third, dosing regimens varied across the trials. Fourth, in addition to reporting the mean pain scores, some studies also noted the proportions of participants whose pain response exceeded a given threshold. Such outcomes are instructive because they identify whether some participants have clinically meaningful responses, even when average responses are not clinically important, and they allow calculation of numbers needed to treat to benefit 1 person; however, such threshold outcomes were not reported consistently.
In the Box, we describe 6 representative cases that we have encountered during the past year and that illustrate common problematic issues in off-label prescribing of gabapentinoids; we are clinically active in both inpatient and outpatient settings, and we see such cases repeatedly. In cases 1 and 2 (treatment of acute herpes zoster and acute sciatica, respectively), gabapentinoids were prescribed despite evidence from placebo-controlled trials (as summarized in Tables 1 and 2) that they are ineffective for these conditions. In cases 3 and 4, nonspecific lower body pain is labeled as neuropathic to justify gabapentin prescribing, even when there is little clinical evidence for neuropathy. Cases 4 and 5 illustrate failure to appreciate the adverse effects of gabapentinoids, particularly when they are prescribed to older patients at risk for harms associated with polypharmacy. Case 6 illustrates rote prescribing of gabapentinoids to patients with diabetic neuropathy, even when the patient’s discomfort is minimal and no treatment is necessary.
Case 1. A 65-year-old woman develops an acute painful dermatomal rash, diagnosed as shingles at an urgent care clinic on a weekend. She is given pregabalin for pain. On a follow-up visit to her primary care physician a week later, she continues to have substantial pain.
Comment: Two double-blind, placebo-controlled trials (one with gabapentin31 and the other with pregabalin38) have examined the efficacy of these drugs for acute zoster pain; these drugs were ineffective in both trials. Both drugs have some demonstrated efficacy only for postherpetic neuralgia, defined as pain lasting more than 3 months after acute herpes zoster.
Case 2. A 55-year-old man is seen with acute severe low back pain that radiates to the left lower leg. His primary care physician starts naproxen and provides a limited supply of hydrocodone for as-needed use. When the leg pain further intensifies during the ensuing week, magnetic resonance imaging is performed and shows a large extruded disc compressing the S1 nerve root. The patient is referred to a spine surgeon, who immediately adds gabapentin.
Comment: Because radicular pain secondary to herniated disc is considered “neuropathic,” compressive neuropathic pain (as occurs with herniated disc) is often regarded as analogous to noncompressive neuropathic pain (as occurs with diabetic neuropathy or postherpetic neuralgia) in its response to gabapentinoids. However, gabapentinoids have been largely ineffective in placebo-controlled trials of patients with sciatica.15,16,36
Case 3. An 82-year-old nondiabetic man with hypertension and compensated heart failure is admitted to the hospital because of somnolence, lethargy, and several recent falls. He is taking 12 medications, including an antidepressant, a “muscle relaxant” (cyclobenzaprine hydrochloride), an opioid (tramadol hydrochloride), and pregabalin. An outpatient problem list includes diagnoses of chronic back pain, hip and knee osteoarthritis, and vague leg pain labeled as neuropathy. The patient and his wife are not sure of the specific indication for which pregabalin was originally prescribed, and they do not recall that any symptoms improved after it was initiated.
Comment: Gabapentinoids are sometimes prescribed to treat generalized pain that is multifactorial and nonspecific. Their effectiveness in such cases is unproven, and their use may be especially problematic as a component of polypharmacy in elderly patients.
Case 4. A 68-year-old man has had chronic bilateral weight-bearing foot pain for several years. He does not have diabetes or other disorders associated with neuropathy but does have bunions, metatarsalgia, plantar calluses, and excessive pronation. Although a detailed neurological examination reveals no evidence of motor or sensory neuropathy, a clinician suggests that the pain might be neuropathic and prescribes pregabalin.
Comment: Clinicians sometimes apply the diagnostic label neuropathy to justify gabapentinoids for patients like this one. Foot pain is often multifactorial and related to biomechanical or structural abnormalities. Although a patient could coincidentally have both biomechanical abnormalities and an idiopathic neuropathy with normal neurological examination (eg, a “small-fiber neuropathy”), no studies support gabapentinoid therapy for such patients.
Case 5. A 75-year-old woman has been receiving gabapentin for diabetic neuropathic pain for more than a year. The dose has been titrated up to 1200 mg 3 times daily; the patient believes that “it might be helping a bit.” During an acute visit to another physician for an unrelated problem, the patient notes that dizziness during the past year has caused her to limit activity. She has mentioned this symptom to her primary physician on several occasions, but the gabapentin has not been considered as a possible cause.
Comment: Because evidence for the efficacy of gabapentin in diabetic neuropathy is mixed in placebo-controlled trials,10-14 the balance of benefit and harm must be weighed carefully. Underappreciation of common adverse effects, such as dizziness, may result in overall harms outweighing benefits.
Case 6. A medical resident sees a 50-year-old man with long-standing type 2 diabetes who describes, for the first time, tingling in his feet bilaterally. In presenting the case to his attending physician, the resident proposes starting gabapentin “for neuropathy,” even though the tingling is not painful and is not interfering with the patient’s activity.
Comment: Some clinicians appear to prescribe gabapentinoids almost reflexively when they diagnose diabetic neuropathy, even when patients are not bothered by it. Therefore, some patients infer incorrectly that the drug is being initiated to alter the natural history of the neuropathy.
The wording in many guidelines and review articles reinforces an inflated view of gabapentinoid effectiveness or fails to distinguish carefully between evidence-based and non–evidence-based recommendations. In part, this problem may reflect how the term neuropathic pain is interpreted. Neuropathic pain is defined by the International Association for the Study of Pain as “[p]ain caused by a lesion or disease of the somatosensory nervous system.”47 Many clinicians likely conceptualize neuropathic pain in a similarly nonspecific way that includes conditions ranging from localized anatomical pathology (eg, nerve root compression from disc herniation) to systemic disorders with neuropathic effects (eg, diabetes). One unintended effect of the broad definition might be to create a mistaken perception that an effective drug for one type of neuropathic pain is effective for all neuropathic pain, regardless of underlying etiology or mechanism.
In particular, the evidence cited to support the general use of gabapentinoids in neuropathic pain is often extrapolated inappropriately from studies conducted exclusively in patients with diabetic neuropathy or postherpetic neuralgia. For example, a recent clinical synopsis on gabapentin for chronic neuropathic pain presents specific data only for postherpetic neuralgia and painful diabetic neuropathy but concludes generally that “[i]n patients with neuropathic pain…gabapentin is associated with a greater likelihood of achieving substantial or moderate pain relief vs placebo.”48(p818) Another example is the 2016 guideline on opioid prescribing from the US Centers for Disease Control and Prevention, which states broadly that gabapentin and pregabalin are first-line drugs for neuropathic pain, without further detail or specification.49 In a popular online clinical decision support resource, gabapentinoids are listed as first-line drugs for initial treatment of neuropathic pain, without further specification.50
Even for treatment of diabetic neuropathy (for which pregabalin is FDA approved and gabapentin is off-label), guideline conclusions tend to exaggerate effectiveness. For example, the text of the 2011 American Academy of Neurology guideline on treatment of painful diabetic neuropathy notes that for 4 studies of pregabalin “the effect size was small relative to placebo”51(p1759) and that for 2 studies of gabapentin one showed “a small effect” and the other showed “no effect.”51(p1760) Nevertheless, the authors conclude that “[b]ased on consistent Class I evidence, pregabalin is established as effective” and “[b]ased on one Class I study, gabapentin is probably effective”51(p1760)
A systematic review of practice guidelines on management of general neuropathic pain (ie, not targeted to diabetic, postherpetic, or other specified neuropathies) supports our observations.52 The authors conclude that recommendations across guidelines consistently recommended gabapentinoids as first-line agents but that the overall quality of these guidelines was poor.52
Gabapentin is often assumed to be interchangeable with pregabalin. Their mechanisms of action are thought to be similar because of their structural similarity. However, their pharmacokinetics vary considerably. Pregabalin is absorbed faster than gabapentin (with peak concentrations noted within 1 hour), and bioavailability is higher for pregabalin.53 Their metabolism is similar, with half-lives around 6 hours.53 Unfortunately, published direct comparisons between the 2 drugs in double-blind studies of patients with chronic noncancer pain are virtually nonexistent.
In the United States, the costs of generic gabapentin and the only available pregabalin product (Lyrica) differ dramatically; depending on the dose, cash prices range from a few dollars monthly for gabapentin to several hundred dollars monthly for pregabalin. Given the differences in cost, substitution of gabapentin for pregabalin when only pregabalin is FDA approved for a given disorder is understandable and often reasonable; however, clinicians should be aware that the evidence to support interchangeability is limited.
Two additional formulations of gabapentin have been designed and marketed. One is a sustained-release preparation (Gralise; Depomed Inc) that is FDA approved only for postherpetic neuralgia. The other is a prodrug (gabapentin encarbil; Horizant) with better bioavailability than standard gabapentin; this formulation is FDA approved only for restless legs syndrome and postherpetic neuralgia. Cash prices of these drugs approach $500 to $1000 per month.
Meta-analyses consistently show a substantial incidence of dizziness, somnolence, and gait disturbance in patients who take gabapentinoids, with dose-dependent effects.45,54 The number needed to harm for each adverse effect has ranged from roughly 3 to 11; as many as 1 in 3 recipients of higher-dose gabapentinoids will experience somnolence or dizziness.45,54 In the recent large sciatica trial, the prevalence of dizziness was 40% with pregabalin (vs 13% with placebo).36 In a prospective study of first-time pregabalin users, dizziness and somnolence were reported by 25% and 14% of patients, respectively.55 Whether gabapentin and pregabalin differ meaningfully in incidence of adverse effects is unclear.
Evidence of misuse of gabapentinoids is accumulating and likely related to the opioid epidemic. A recent review article reported an overall population prevalence of gabapentinoid “misuse and abuse” as high as 1%, with substantially higher prevalence noted among patients with opioid use disorders.56 The higher prevalence among patients with opioid use disorders may relate to the reported augmentation of euphoria.56 This trend is troubling, particularly because concomitant use of opioids and gabapentinoids is associated with increased odds of opioid-related death.57 Whether these concerns apply to patients receiving long-term prescribed opioid therapy is unclear.
Reports from law enforcement agencies corroborate growing diversion activity and street value for gabapentinoids. Some states are reclassifying gabapentinoids as controlled substances or mandating reporting to prescription drug monitoring programs, and the FDA is considering regulatory action.58,59 The influence of the opioid crisis on gabapentinoid misuse is likely mixed. On the one hand, the medical community and public are more aware of substance misuse generally, which may limit the consequences of gabapentinoid misuse. On the other hand, the prevalence of adults with opioid prescriptions or substance use disorders remains high, and the prevalence of gabapentinoid prescribing is rising concurrently.
The evidence to support off-label gabapentinoid use for most painful clinical conditions is limited. For some conditions, no well-performed controlled trials exist. For others, one or several placebo-controlled studies have been published, but results have generally shown the drugs to be either ineffective or only modestly and inconsistently effective.
This lack of compelling published evidence should be considered in the context of the problematic marketing history of gabapentin and pregabalin. Despite documentation that these drugs were promoted improperly for off-label treatment of pain, the recent rapid increase in prescribing of gabapentinoids suggests a persisting sense among clinicians that gabapentinoids are highly effective pain medications, particularly for any pain deemed as neuropathic. Guidelines and review articles have contributed to this perception by often uncritical extrapolation from FDA-approved indications to off-label use. Although direct-to-consumer marketing of pregabalin clearly denotes fibromyalgia and diabetic neuropathy as the target conditions, advertisements may result in perceptions that the drug is a pain medication generally. In our view, some clinicians are labeling nonspecific pain as neuropathic to justify gabapentinoid prescribing.
Mandates to reduce opioid use for patients with chronic noncancer pain have compelled clinicians to substitute nonopioid alternatives. Gabapentinoids have become frequent first-line alternatives in patients with chronic pain from whom opioids are being withheld or withdrawn, as well as in patients with acute pain who traditionally received short courses of low-dose opioid. Growing misuse of gabapentinoids is especially problematic in patients who also obtain opioids either illicitly or from prescribers.
Comprehensive management of pain in primary care settings is difficult; it requires time and resources that are frequently unavailable. Many patients with chronic pain have limited or no access to high-quality pain practices or to nonpharmacologic interventions, such as cognitive behavior therapy. Judicious therapeutic trials of gabapentinoids are justified in patients with selected off-label pain syndromes when at least modest evidence of efficacy exists. However, in such cases, clinicians should advise patients that the proposed gabapentinoid use is off-label and that adverse effects, such as dizziness and somnolence, are common. The drugs should be discontinued when patients perceive little or no benefit. Finally, guidelines, review articles, and point-of-care resources should more explicitly note the limited evidence supporting gabapentinoid use for off-label indications and should resist promoting gabapentinoid use for any pain labeled as neuropathic.
Accepted for Publication: January 11, 2019.
Corresponding Author: Christopher W. Goodman, MD, Department of Medicine, University of South Carolina School of Medicine, Two Medical Park, Ste 502, Columbia, SC 29203 (email@example.com).
Published Online: March 25, 2019. doi:10.1001/jamainternmed.2019.0086
Author Contributions: Drs Goodman and Brett had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Both authors.
Acquisition, analysis, or interpretation of data: Both authors.
Drafting of the manuscript: Both authors.
Critical revision of the manuscript for important intellectual content: Both authors.
Administrative, technical, or material support: Goodman.
Conflict of Interest Disclosures: None reported.
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