Treatment with pregabalin (Lyrica), an anticonvulsant also approved for several forms of chronic pain, was associated with an increased risk for opioid-related death when co-prescribed with opioids, Canadian researchers reported.
Among some 6,500 residents of Ontario with opioid prescriptions — including 1,417 who subsequently died from an opioid-related cause — concomitant exposure to pregabalin and opioids was associated with significantly increased odds of opioid-related death compared with exposure to opioids alone (adjusted OR 1.68, 95% CI 1.19-2.36), reported Tara Gomes, MHSc, PhD, of the Institute for Clinical Evaluative Sciences (ICES) and St. Michael’s Hospital in Toronto, and colleagues.
A high dose of pregabalin (defined as >300 mg/d) was associated with substantially increased odds of opioid-related death relative to no pregabalin exposure (adjusted OR 2.51, 95% CI 1.24-5.06). A low or moderate dose (≤300 mg/d) was associated with relatively lower, but still significantly increased, odds of opioid-related death (adjusted OR 1.52, 95% CI 1.04-2.22), they wrote in the
Annals of Internal Medicine.
Pregabalin and opioids may lead to a potentially life-threatening interaction similar to
one previously observed with gabapentin (Neurontin) and opioids, the researchers suggested.
Pregabalin can be sedating and may augment central nervous system (CNS) depression in patients receiving opioids. “There is an important drug interaction between opioids and pregabalin that can lead to increased risk of fatal overdose, particularly at high doses of pregabalin,” Gomes told MedPage Today. “Clinicians should consider carefully whether to prescribe opioids and pregabalin together. If they decide that both medications are clinically appropriate, they should start with low doses and monitor their patients closely.”
New prescribing patterns “as healthcare practitioners begin to explore new pain management paradigms” in response to the opioid crisis may have led to this increase, observed Douglas Throckmorton, MD, and Janet Woodcock, MD, both of the FDA in Silver Spring, Maryland, in an
accompanying editorial.
“These drugs are approved to treat certain forms of neuropathic pain and seizures, and pregabalin is approved to treat fibromyalgia. Increased clinical use, much of which seems to be for painful conditions beyond the approved indications, has recently been linked to higher rates of misuse and abuse,” they wrote.
FDA reports suggest the number of patients receiving gabapentinoids with opioid analgesics or benzodiazepines has increased, with more than half of patients concurrently dispensed both a gabapentinoid and an opioid analgesic, added Throckmorton and Woodcock. “Clinicians who may seek to minimize opioid dosing by co-prescribing alternative medications could thus be inadvertently introducing new risks,” they said.
Because more than half of Ontario residents who start pregabalin therapy also are prescribed an opioid, this research has important clinical implications, Gomes noted.
“Currently the product monograph for pregabalin does not include a warning regarding its use with opioids,” she said. “In contrast, this warning does exist for gabapentin, another drug within this class. Given this emerging evidence, regulators should consider requiring a similar warning for pregabalin.”
From a regulatory perspective, more research about the consequences of combining CNS-active drugs is needed, Throckmorton and Woodcock noted. “The U.S. Food and Drug Administration is implementing processes to support such work and engaging in initiatives to determine what changes, if any, are needed to address the labeling concerns raised by Gomes and colleagues,” they wrote.
“As we move forward in this work, we need to keep in mind that both gabapentinoids and opioids have an appropriate role in pain management,” they noted. “As we work to better understand potential interactions, we also need to try to avoid inadvertently increasing prescription drug use or abuse through future regulatory actions.”
The study included Ontario residents, ages 15 to 105, who received publicly-funded opioid prescriptions from August 1997 to December 2016. The 1,417 who died of opioid-related causes (cases) were matched by age, sex, and other characteristics to 5,097 surviving individuals also receiving opioids (controls). Case patients were more likely to have recently been prescribed other CNS depressants, receive more medications annually, and have more comorbidities than control participants. Statistical results reflected multivariable adjustment.
The study was supported by the Ontario Ministry of Health and Long-Term Care.
Gomes and co-authors disclosed relevant relationships with Lundbeck, Indivior, Mundipharma, Opiant, D&A Pharma, BioProject, Kinnov Therapeutics, Novartis, Eli Lilly, Novo Nordisk, Allergan, and Celgene.
Throckmorton is the deputy center director for regulatory programs at the FDA Center for Drug Evaluation and Research (CDER). Woodcock is the CDER director. They disclosed no relevant relationships with industry.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Primary Source
Annals of Internal Medicine
Secondary Source
Annals of Internal Medicine
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