ARTICLE IN BRIEF
Increased prescribing of gabapentinoids for chronic pain management may be driven, in part, by the response to the opioid epidemic. Experts in chronic pain weigh the decisions and evidence for use of gabapentin or pregabalin.
Are efforts to solve one drug crisis helping to create another? That's the provocative question underlying an August 7 commentary in The New England Journal of Medicine that documents a dramatic rise over the past few years in the prescribing of gabapentin and pregabalin — an increase that comes as many doctors are pulling back on prescribing opioids amid what has been declared an opioid epidemic.
Increased prescribing of gabapentinoids for pain problems, involving many off-label uses, may reflect at least in part “a desire among clinicians to prescribe possibly safer alternatives to opioids,” the authors of the perspective piece wrote.
The article noted two trends from national prescribing data. In 2012, 39 million gabapentin (Neurontin) prescriptions were dispensed; by 2016, gabapentin prescriptions were up to 64 million, making it the tenth most commonly prescribed medication in the US. During the same period, non-discounted sales of pregabalin (Lyrica) more than doubled to $4.4 billion, earning it the number eight spot on a list of brand-name drugs that generate the most sales.
According to the article, the US Food and Drug Administration has approved gabapentinoids for several conditions involving nerve pain, including postherpetic neuralgia (gabapentin and pregabalin), fibromyalgia (pregabalin) and neuropathic pain associated with diabetes or spinal cord injuries (pregabalin). But the drugs have become popular for other painful conditions, including nondescript lower-back pain, sciatica, and osteoarthritis, even though evidence for such uses is lacking.
“We suspect that clinicians who are desperate for alternatives to opioids have lowered their threshold for prescribing gabapentinoids to patients with various types of acute, subacute, and chronic noncancer pain,” wrote Christopher Goodman, MD, and Allan Brett MD, of the department of medicine at the University of South Carolina School of Medicine.
Dr. Goodman, assistant professor of clinical internal medicine, told Neurology Today that he and his colleagues had noticed what seemed to be excessive prescribing of gabapentinoids for various types of pain by doctors in both hospital and outpatient settings. Their observations were based on national prescribing data.
“It is hard to know what the key driver is, but we zeroed in on the opioid epidemic as probably a key piece of what is going on,” Dr. Goodman said. Other likely factors in the surging use of gabapentinoids include an unmet need for effective pain-relief drugs; marketing efforts by drug manufacturers; and a bias on the part of both physicians and patients toward using medication rather than a more holistic approach to managing pain, he said.
“Writing a prescription and moving on is considerably easier and less stressful for clinicians,” the article noted. Some patients may view a doctor visit as a failure if they don't come away with a prescription, they said.
Dr. Goodman said that while gabapentinoids do not appear to have the same highly addictive qualities as opioids, they do have significant side effects including dizziness and somnolence, and some patients report a euphoric high.
The article noted that “evidence suggests that some patients misuse, abuse, or divert gabapentin and pregabalin,” though it also cautioned that “whether misuse and abuse of gabapentinoids will become an important public health issue remains to be seen.”
The authors acknowledged the quandary doctors face. “Patients in pain deserve empathy, understanding, time and attention,” the authors said, adding that some patients “may benefit from a therapeutic trial of gabapentin or pregabalin for off-label indications.”
But the authors also pointed out that while “we support efforts to limit opioid prescribing...we shouldn't assume that gabapentinoids are an effective approach for most pain syndromes or a routinely appropriate substitute for opioids.”
Independent experts interviewed by Neurology Today said the article speaks to the complexity of treating pain, the lack of effective treatments for some pain conditions, and the sheer scope of pain in the population.
Roy Freeman, MD, professor of neurology at Harvard Medical School and director of the Center for Autonomic and Peripheral Nerve Disorders at Beth Israel Deaconess Medical Center, cited a 2012 survey by the National Institutes of Health that found that 23 million Americans reported having daily chronic pain and another 25 million reported severe pain.
“Chronic pain is a huge unmet need and we suffer from a vacuum of safe and effective drugs to treat these conditions,” Dr. Freeman said, adding that it is not surprising gabapentinoids have become heavily relied on to help fill the void.
“Their widespread use reflects the relative safety of this class of drugs and the lack of safe drugs of proven efficacy to treat chronic pain.”
Dr. Freeman said: “It is reasonable to infer that these drugs, for which there is a strong body of evidence for treating nerve pain of various kinds, both central and peripheral, may work in other conditions that show pathophysiological similarities.”
Even absent clinical trial data, “it is possible these drugs may help some patients who have clinical features of neuropathic pain,” said Dr. Freeman. “In the same way that not every patient responds to a medication with proven efficacy for their condition, there are some patients who may respond to medications even though efficacy was not demonstrated in a clinical trial.”
From a scientific standpoint, “understanding the characteristics of these responder subgroups is an important area of current research in the pain field,” he said. For clinical practice, “given the lack of safe alternatives for treating some pain conditions, it may be reasonable to try a course of a gabapentinoid.”
CHRONIC BACK PAIN
One condition under scrutiny is chronic back pain. Harsha Shanthanna, MD, associate professor of anesthesiology and a physician researcher specializing in chronic pain at St. Joseph's Healthcare at McMaster University in Hamilton, Ontario, in Canada, recently conducted a meta-analysis of studies that assessed the use of either gabapentin or pregabalin for chronic low back pain (CLBP), which affects more than half of people during the course of their lifetime and often is due to a nonspecific cause. He and his colleges searched the medical literature through 2016 and found only eight randomized controlled trials.
“Existing evidence on the use of gabapentinoids in CLBP is limited and demonstrates a significant risk of adverse effects without any demonstrated benefits,” Dr. Shanthanna and colleagues reported on August 15 in PLOS Medicine. They said the use of the drugs for back pain “merits caution.”
Dr. Shanthanna told Neurology Today that more randomized controlled trials are needed to assess the use of gabapentin and pregabalin for back pain and other conditions.
“There is a lack of evidence but that doesn't mean there is a lack of efficacy,” he said. There may be a rationale for using the drugs in certain patients with chronic back and leg pain, but he said patients need to be followed up fairly quickly to determine that the dosing is appropriate and whether the drug should be continued based on the patient's report of any side effects, such as fuzzy thinking and dizziness, versus whether they are experiencing pain relief and improved function.
Dr. Shanthanna said doctors need to educate themselves about their appropriate use and the potential for patients to abuse the drugs, particularly if they have a history of opioid addiction.
Michael C. Rowbotham, MD, senior scientist and scientific director of the California Pacific Medical Center Research Institute, said many doctors understandably feel as though they can no longer prescribe opioids given all the reports on opioid abuse and addiction, but they still face a dilemma because there aren't a lot of treatment options for some pain conditions and other therapies also have potential risks.
Nonsteroidal anti-inflammatory drugs, for instance, are often seen as a safe alternative but they can have serious side effects, including stomach pain, gastrointestinal bleeding, and kidney damage, if taken at high doses for an extended period of time.
Dr. Rowbotham said non-pharmacological pain interventions such as nerve block injections and electrical nerve stimulation also have downsides. He thinks antidepressants are underutilized in pain management.
He said he agreed with a point made in the New England Journal of Medicine perspective piece that non-pharmacological interventions should be part of pain management, but he said many patients suffering from pain lack the time, energy or insurance coverage to seek out add-ons such as cognitive behavioral therapy, yoga, meditation or acupuncture.
“The [insurance] coverage is pretty bare,” he said.
THE PLACEBO EFFECT
Brian Wainger, MD, assistant professor of neurology and anesthesiology at Harvard Medical School and Massachusetts General Hospital, said it is not clear how much the increase in the use of gabapentinoids is directly due to avoidance of opioids and how much is due to other factors, such as marketing by drug manufacturers.
“In the clinic we prescribe the medicines frequently for multiple types of neuropathic pain such as neuropathy and often for radiculopathy,” he said.
While he agreed that gabapentinoids can cause side effects and have a possible risk for abuse, “I think the magnitude of the risk is much smaller than with opioids.”
Dr. Wainger said good data on the efficacy of pain medication are hard to come by, in part because medications are often tested against placebo, which has a surprisingly large effect. Even if the active drug shows an advantage, it may be not better than placebo.
Dr. Wainger said the placebo effect also influences clinical practice because patients may feel improvement in their pain simply because they are taking medication and expect benefit.
“Assessing a true benefit above placebo is hard to do outside of a formal clinical trial,” he said. “From the patient care perspective, it's important to focus on benefit, even if some component is placebo.”
He said asking specific questions about pain level and function can help doctors determine if gabapentin or pregabalin is helping.
This article was revised and republished to correct reporting errors. The original article inaccurately portrayed Dr. Freeman's relationship with Pfizer. Dr. Freeman is a scientific advisor to Pfizer and has a grant to investigate a biomarker for familial amyloid polyneuropathy. The editor apologizes for the error.