The risky rise of gabapentinoids

There are reasons to worry about these opioid alternatives.

Every clinician wants to prescribe opioids judiciously, but is the solution to use other pain medications more, even in the absence of adequate evidence?

Gabapentin and pregabalin, known more broadly as gabapentinoids, are now among the most commonly prescribed medications in the country, with gabapentin ranking as the 10th most commonly prescribed medication in 2016, according to national prescribing data. Use of gabapentinoids in the U.S. tripled from 2002 to 2015, according to a research letter published in February 2018 by JAMA Internal Medicine.

Image by Getty Images
Image by Getty Images

The increase is “both in response to the epidemic of opioid use disorder and our decrease in prescribing opioids in an effort to find something in our ‘toolbox’ that might help patients with chronic pain and in response to the pharmaceutical industry,” said Theresa E. Vettese, MD, FACP, associate professor of medicine in the division of general medicine and geriatrics at Emory University School of Medicine in Atlanta.

However, the FDA-approved indications for gabapentinoids and pain are fairly limited. Gabapentin is approved to treat postherpetic neuralgia, and pregabalin is approved to treat postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy or spinal cord injury, and fibromyalgia.

Thus, off-label use is common. “There's a lot of uncertainty about what it can do to help with different types of pain, and there is a perception that it has few serious side effects, so it becomes an easy drug to consider prescribing . . . someone to help with their pain if you're reluctant about prescribing an opioid,” said geriatrician Michael A. Steinman, MD, FACP, professor of medicine at the University of California, San Francisco.

The drugs are mostly prescribed outside the hospital, but the effects are felt inside. In a recent study of more than 4,000 hospitalized patients in Canada, one in eight had been prescribed gabapentinoids before admission, with only 17% of prescriptions being for approved indications, according to results published in the September Journal of Hospital Medicine. When the off-label use was specified, it was most commonly for neuropathic pain unrelated to diabetes, musculoskeletal pain, and patients with diabetes with no documented history of neuropathic pain.

The results confirm hospitalists' experience. “That's probably not far from what we would see in terms of admission medication reconciliation,” said Christopher W. Goodman, MD, clinical assistant professor of internal medicine at the University of South Carolina School of Medicine in Columbia. In recent years, he has noticed more gabapentinoids, particularly gabapentin, appearing on patients' med lists in both inpatient and outpatient settings. “Sometimes you could kind of guess why it was being used, and then sometimes it wasn't clear at all.”

Inspired by these experiences, Dr. Goodman and Allan S. Brett, MD, FACP, sounded alarm bells in an August 2017 perspective published in the New England Journal of Medicine. “We believe there are several reasons to be concerned about this trend,” such as an insufficient amount of evidence to support the efficacy of gabapentinoids' off-label uses outside of the perioperative setting, they wrote. The drugs may have a reputation for being safe, “but that can bely the potential for harm,” said Dr. Goodman.

Risks vs. benefits

Gabapentinoids wouldn't generally be started in the hospital unless there was a compelling indication, but unnecessary use can cause real harms during and after admission, experts said.

First, despite the hypothesis that gabapentinoid prescriptions are increasing in response to the opioid epidemic, concomitant use of the two classes is common. For example, in the Journal of Hospital Medicine study, about 28% of gabapentinoid users were also taking opioids, compared to 12% of nonusers, and 10% were receiving an opioid and a benzodiazepine.

One explanation for this is that gabapentin might be seen as an opioid-sparing drug—in other words, if you start gabapentin, you can decrease the dose of the opioid even if you don't stop it, or avoid further dose increases, Dr. Steinman said. It could also be prescribed with the intention of weaning the person off opioids altogether, although that may never end up happening, he said.

Such coprescription can be deadly. The risk of opioid-related death is 49% higher when gabapentin is coprescribed with opioids compared to opioid prescription alone, according to a study published in October 2017 by PLOS Medicine. That's because one of the biggest risks of gabapentinoids is sedation, said Dr. Goodman. “They seem to augment the effect of opioids so that all the typical adverse events are heightened, and that's really the larger concern,” he said.

The median age of gabapentinoid users in the Journal of Hospital Medicine study was 71 years, which was troubling to senior author Emily G. McDonald, MD, MSc, assistant professor of medicine at McGill University Health Centre in Montreal. “A lot of the patients that I look after on the medical unit are older, sicker people with lots of other medical problems,” she said. “I think they're probably at the greatest risk of harm from these medications.”

In the updated Beers Criteria for potentially inappropriate medication use in older adults, published in the April Journal of the American Geriatrics Society, new recommendations include avoiding the use of opioids concurrently with gabapentinoids, except when transitioning from the former to the latter.

In addition to interacting with sedatives, gabapentinoids can also increase the risk of falls and can cause dizziness, confusion and fogginess, and fluid retention, noted Dr. McDonald. In older adults, any medication that can act on the brain has the potential to lead to adverse outcomes, particularly in those with a risk of cognitive impairment or other memory problems, Dr. Steinman said. “We're always cautious about prescribing these medications,” he said.

In some cases, though, gabapentinoids can be the right choice. Dr. Steinman noted that some of his patients take gabapentin and have seemed to respond well. “It's not unreasonable to consider its use for other forms of neuropathic pain” that do not have FDA approval, “but there's just less concrete evidence,” he said. Dr. McDonald noted that some trials have actually shown the medications not to be beneficial for certain conditions, such as chronic low back pain.

The problem is that nuances in how people experience pain lead to clinicians making educated guesses about what might help, sometimes without follow-up, said Dr. Steinman, also a staff physician at the San Francisco VA Medical Center. “What often happens is people get started on these drugs, they may or may not have a benefit, and then the people just continue these drugs indefinitely, even if they're not helping,” he said.

Clinicians are strapped for viable options to treat pain. While nonpharmacologic interventions like acupuncture and massage can give the benefits of treatment without substantial harms, they aren't easy to prescribe, said Dr. Steinman. As for medications, NSAIDs and acetaminophen have limited evidence themselves, and NSAIDs have their share of notable complications, said Dr. Goodman. “Then you get past that, and the evidence is less robust for the other options,” he said, “so you're left with some tough risk-benefit decision making.”

When to deprescribe

The decision to deprescribe these medicines in the hospital setting is another tricky balancing act. “I generally caution a humility to hospitalists in trying to change lots of medications that are used for chronic use because there might be a whole context to that person's use which is unknown to the hospitalist,” said Dr. Steinman. “You can end up doing more harm than good.”

This advice pertains to both stopping and starting medications used to treat chronic conditions. “The exception to that rule is if you see a drug that is obviously causing harm, in which case it's perfectly reasonable and appropriate to stop it,” said Dr. Steinman.

Dr. Goodman agreed. “I feel like hospitalizations are kind of a double-edged sword in terms of how to think about medicines,” presenting both a good opportunity to review medication regimens and a possibility of confusing patients and leading to medication discrepancies at discharge, he said. However, in general, the appropriateness of prescribed sedatives should be reviewed on every hospitalization, Dr. Goodman said.

As a hospitalist, Dr. Vettese said she deprescribes gabapentinoids if a patient is admitted with adverse effects and/or the risks clearly outweigh any potential benefits. An example would be an elderly patient with orthostatic hypotension and falls, delirium, and oversedation, she said, adding that she makes sure to include her reasoning in the discharge summary and educate the patient and family.

In some cases, people are hospitalized with a complication that may even be related to the medication, particularly falls and heart failure exacerbations, said Dr. McDonald. “These are two prime triggers. . . . I'd like to see hospitalists initiate a conversation about the gabapentinoid, saying, ‘Would you be interested in coming down on this [dosage] and maybe coming off of it?’”

However, for patients who are stable and on gabapentinoids for a nonindicated reason, Dr. Vettese said she does not deprescribe but instead tries to call the patient's primary care physician and discuss at discharge. “I will be the first person to say that this is easier in my role as a physician with expertise in pain management but would be more difficult if I wasn't,” she said.

Dr. Steinman agreed that raising the issue with a patient's primary clinician is easier said than done. Some outpatient doctors may not even get the chance to thoroughly read a dense discharge summary, he said. “That's why having patients be involved and activated to ask those questions themselves is so important.”

If you're concerned (but not quite sure) that a gabapentinoid may be causing more harm than good, there are a couple of ways to start the conversation with a patient. Dr. Steinman suggested telling the patient to ask her outpatient physician if she really needs the drug at her next appointment.

Dr. McDonald's approach is to go through med lists, asking patients if they know their medications and what they were prescribed for.

“Then I ask them if they know which ones are helping, and if they are not so sure and they're maybe not having any benefit from the medication, that makes it easier [to deprescribe],” she said. She is currently involved in a project of the Canadian Deprescribing Network to create a tool to help physicians have conversations with their patients about discontinuing gabapentinoids.

For patients who want to discontinue the medication, this process may take only a couple of minutes, whereas others might take longer and may need to continue the discussion with their outpatient doctors, Dr. McDonald said. “But I think you can have the conversation pretty quickly to initiate it, and it's going to be more successful than never having initiated a conversation at all.”