From the Journals

Surge of gabapentinoids for pain lacks supporting evidence



Many clinicians are prescribing the gabapentinoid drugs pregabalin (Lyrica) and gabapentin (Neurontin) for off-label treatment of pain, despite a lack of supporting data or approval from the Food and Drug Administration, according to investigators.

Over the past 15 years, use of gabapentinoids has tripled, a level of growth that cannot be explained by prescriptions for approved indications, reported coauthors Christopher W. Goodman, MD, and Allan S. Brett, MD, of the University of South Carolina, Columbia. Instead, clinicians are turning to gabapentinoids, partly as an option to substitute for opioids, which now have greater prescribing restrictions as a result of the current opioid crisis.

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Although clinicians may cite guidelines that support off-label use of gabapentinoids for pain, the investigators warned that many of these recommendations stand on shaky ground.

“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 investigators wrote in a clinical review published online March 25 in JAMA Internal Medicine.

The investigators narrowed down 677 publications to 84 papers describing the use of gabapentinoids for outpatient noncancer pain syndromes for which they are not FDA approved; 54 for gabapentin and 30 for pregabalin. In the domain of analgesia, both agents are currently FDA-approved for postherpetic neuralgia, while pregabalin is additionally approved for pain associated with fibromyalgia and neuropathic pain from diabetic neuropathy and spinal cord injury. Indications in reviewed studies ranged broadly, from conditions somewhat related to those currently approved, such as unspecified neuropathy, to dissimilar conditions, such as chronic pancreatitis and burn injury.

The investigators summarized findings from randomized clinical trials while using case studies to illustrate potential problems with off-label use. In addition, they reviewed the history of gabapentinoids and sources of recommendations for off-label use, such as guidelines and previous review articles.

Six major findings were reported: (1) evidence supporting gabapentin for diabetic neuropathy pain is “mixed at best”; (2) evidence supporting gabapentin for nondiabetic neuropathies is very limited; (3) evidence does not support gabapentinoids for radiculopathy or low back pain; (4) gabapentin has minimal benefit for fibromyalgia pain, based on minimal evidence; (5) evidence does not support gabapentinoids for acute herpes zoster pain; and (6) in almost all studies for other painful indications, gabapentinoids were ineffective or “associated with small analgesic effects that were statistically significant but of questionable clinical importance.”

Case studies complemented this overview, highlighting related clinical dilemmas that the investigators encounter “repeatedly” during inpatient and outpatient care. Along with off-label use, such as gabapentinoid prescriptions for acute sciatica, the investigators reported cases in which neuropathy was diagnosed in place of nonspecific lower body pain to facilitate gabapentin prescription. They also described apparent disregard for risks of polypharmacy in prescriptions for elderly patients and rote use of gabapentinoids in patients with diabetic neuropathy who did not have sufficient discomfort to warrant prescription.

The investigators also cited a number of problems with the language of reviews and guidelines involving gabapentinoids.

“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,” they wrote, adding that clinicians may have misconceptions about neuropathic pain. “One unintended effect of the broad definition [of neuropathic pain] 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,” the investigators suggested.

Another facet of prescribing behavior could be explained in economic terms. Pregabalin, sold under the brand name Lyrica, is considerably more expensive than gabapentin; however, the investigators warned that the similarity of these agents does not equate with interchangeability, noting differences in bioavailability and rate of absorption.

“Unfortunately, published direct comparisons between the 2 drugs in double-blind studies of patients with chronic noncancer pain are virtually nonexistent,” the investigators wrote.

In addition to questionable effectiveness of gabapentinoids for off-label chronic noncancer pain syndromes, Dr. Goodman and Dr. Brett noted that the drugs produce a “substantial incidence of dizziness, somnolence, and gait disturbance.”

They also described a new trend of gabapentinoid abuse and diversion, which may not be surprising, considering that gabapentinoids are reported to augment opioid-induced euphoria.

“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,” the investigators wrote. “This trend is troubling, particularly because concomitant use of opioids and gabapentinoids is associated with increased odds of opioid-related death. Whether these concerns apply to patients receiving long-term prescribed opioid therapy is unclear.”

In the era of the opioid crisis, the investigators acknowledged that many clinicians have serious concerns about adequately treating chronic noncancer pain.

“Comprehensive management of pain in primary care settings is difficult. It requires time and resources that are frequently unavailable,” the investigators wrote. “Many patients with chronic pain have limited or no access to high-quality pain practices or to nonpharmacologic interventions, such as cognitive behavior therapy.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Goodman CW et al. JAMA Intern Med. 2019 Mar 25. doi: 10.1001/jamainternmed.2019.0086

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