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In our November 2017 What's New in the Patient Safety World column “” we highlighted a study ( ) which found that among patients receiving prescription opioids, concomitant treatment with gabapentin was associated with a substantial increase in the risk of opioid-related death. We noted that study only looked at use of gabapentin. It did not evaluate those using pregabalin, the precursor of gabapentin that is more widely prescribed for certain types of chronic pain in the US. We suggested this may represent an opportunity of clinical decision support tools (in either CPOE or e-prescribing systems) to alert prescribers when an opioid is being started in a patient who is already receiving gabapentin or vice versa.
Since then, Gomes and colleagues () also looked at the combination of pregabalin and opioids. They conducted a population-based, nested case–control study of over 6500 Ontario residents eligible for public drug coverage who received prescription opioids between 1 August 1997 and 31 December 2016. They found that 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). High dose of pregabalin (>300 mg/d) was associated with substantially increased odds of opioid-related death relative to no pregabalin exposure (adjusted OR 2.51) and 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).
In the accompanying editorial (gabapentinoids with opioid analgesics or benzodiazepines has increased and more than half of patients concurrently dispensed both a gabapentinoid and an opioid analgesic. They suggest that clinicians who may seek to minimize opioid dosing by co-prescribing alternative medications might thus be inadvertently introducing new risks.), FDA officials Douglas Throckmorton and Janet Woodcock note the number of patients receiving
But it’s not just in the Canada and the US that risks associated with pregabalin have garnered attention. A study from Sweden () looked at coprescribing in patients taking opioids. They found that pregabalin prescriptions (hazard ratio 2.82) so called “Z-drug” (HR 1.60) were associated with overdose death. And, in the sensitivity analysis, all categories of sedatives, including benzodiazepines, were significantly associated with overdose death in opioid users.
A recent study from Australia () found that rates of pregabalin misuse‐related “ambulance attendances” in Victoria increased markedly over the past 6 years (increasing from 0.28 cases per 100 000 population in the first half of 2012 to 3.32 cases per 100 000 in the second half of 2017). The attendance rate correlated strongly with prescription rates in Australia.
Furthermore, 49% were for people with a history that may have contraindicated prescribing pregabalin. Pregabalin was frequently misused with other sedatives (68%), particularly benzodiazepines (37%). 39% were associated with suicide attempts. People who misused pregabalin with other sedatives more frequently presented with moderate to severe impairments of consciousness, but the frequency of suicide attempts was similar whether other sedatives were concurrently used or not.
The authors urge that caution is required when prescribing pregabalin for people taking other sedatives and suggest that limiting the dispensing of this drug may reduce the risks associated with its misuse.
And recent articles from the Australian lay press (, ) raise the question about possible addiction, note it’s being misused by drug users and traded on the black market. Apparently, euphoria as a side effect has led to recreational use of pregabalin. They also note possible links to suicidal ideation.
A 2014 review of pregabalin safety found safety issues were uncommon ( It did acknowledge the risk of a withdrawal syndrome abrupt discontinuation. It also mentioned potential for abuse of pregabalin has been described.). The most commonly noted adverse effects were sedation, dizziness, peripheral edema and dry mouth.
But a more recent systematic review of gabapentinoid (pregabalin and gabapentin) abuse () found that increasing numbers of patients are self-administering higher than recommended doses to achieve euphoric highs. In the general population, a 1.6% prevalence of gabapentinoid abuse was observed, whereas prevalence ranged from 3% to 68% among opioid abusers. Risk factors for gabapentinoid abuse include a history of substance abuse, particularly opioids, and psychiatric co-morbidities. While effects of excessively high doses are generally non-lethal, gabapentinoids are increasingly being identified in post-mortem toxicology analyses.
Practitioners also need to be aware of possible withdrawal effects when gabapentin or pregabalin are discontinued or reduced. Both gabapentin and pregabalin appear on ISMP’s list of drugs for which there is a credible signal related to withdrawal effects (). ISMP also noted the only discussion in the prescribing information for pregabalin and gabapentin was a brief mention that anti-epileptic drugs should not be discontinued abruptly due to an increased risk of seizures.
The 2014 safety review of pregabalin (similar to alcohol or benzodiazepine withdrawal. Such withdrawal symptoms can persist for 1–2 days should gabapentinoids be abruptly discontinued.) noted that, when pregabalin discontinuation is planned, a gradual tapering should occur. An abrupt discontinuation of pregabalin has uncommonly been linked to development of a syndrome
Pregabalin has been very helpful in our management of many patients with chronic pain. Most of us have regarded it as a drug with a relatively good safety profile and an alternative to analgesics that have riskier safety profiles. But, as use of pregabalin has skyrocketed, these reports of potential adverse effects and unexpected consequences are appearing.
Pregabalin has been one of the top 10 prescribed drugs in recent years, buoyed by extensive direct-to-consumer advertising (also a top 10 advertised drug). Spending on advertising for pregabalin was $20 million per month until the spending was reduced to $3.8 million in anticipation of expiration of its patent at the end of 2018 ().
Prescribers need to be aware that concomitant use of pregabalin and opioids or sedating agents may be dangerous. We need to use our CPOE and e-prescribing systems to alert prescribers when such combinations are in play.
Gomes T, Juurlink DN, Antoniou T, et al. Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case–control study. PLOS Medicine 2017; Published: October 3, 2017
Gomes T, Greaves S, van den Brink W, et al. Pregabalin and the Risk for Opioid-Related Death: A Nested Case–Control Study. Ann Intern Med 2018; 21 August 2018
Throckmorton DC, Woodcock J. Combined Gabapentinoid and Opioid Use: The Consequences of Shifting Prescribing Trends. Ann Intern Med 2018; 21 August 2018
Abrahamsson T, Berge J, Öjehagen A, Håkansson A. Benzodiazepine, z-drug and pregabalin prescriptions and mortality among patients in opioid maintenance treatment—A nation-wide register-based open cohort study. Drug and Alcohol Dependence 2017; 174(1): 58-64
Crossin R, Scott D, Arunogiri S, et al. Pregabalin misuse‐related ambulance attendances in Victoria, 2012–2017: characteristics of patients and attendances. Med J Aust 2019; 210 (2): 75-79
Mannix L, Dow A. Popular pain drug linked to rise in overdoses, suicides. The Sydney Morning Herald (Australia) 2018; 26 November 2018
Mannix L. This popular drug is linked to addiction and suicide. Why do doctors keep prescribing it? The Age (Australia) 2018; 18 December 2018
Toth C. Pregabalin: latest safety evidence and clinical implications for the management of neuropathic pain. Ther Adv Drug Saf 2014; 5(1): 38-56.
Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. Drugs 2017; 77: 403-426
ISMP (Institute for Safe Medication Practices). QuarterWatch™ (2016 Annual Report) Part I: Consumers at Risk from Drug Withdrawal Symptoms. ISMP Medication Safety Alert! Acute Care Edition 2017; July 13, 2017
Bulik BS. Goodbye to Lyrica ads? Big TV spender drops off top 10 list in October, FiercePharma 2018; November 5, 2018