Prescription of Opioids and Gabapentinoids Associated With Subsequent Overdose, Especially at High Doses and in Combination

Gabapentinoid prescriptions have increased substantially over the last 2 decades, and there is increasing evidence of a heightened risk of overdose among patients prescribed these medications, especially in combination with opioids. This prospective cohort study evaluated the association between receipt of gabapentinoid and/or opioid medications* and overdose over 12 months. Participants (N = 71,000) were Medicare beneficiaries with a diagnosis of fibromyalgia, low back pain, neuropathy, or osteoarthritis who were newly prescribed either medication (or both) following a 6-month period without a prescription for either. Results were adjusted for sociodemographic markers, disability, a medical comorbidity index, co-occurring psychiatric disorders, benzodiazepine prescriptions, and healthcare access and utilization. People with previously diagnosed substance use disorder or overdose were excluded.

• Most patients received monotherapy (59% opioid-only and 27% gabapentinoid-only), while 14% received both medications.
• Compared with patients prescribed opioids only who had early medication discontinuation (i.e., discontinued within a month of initiation, 41% of the cohort), patients prescribed gabapentinoids alone—regardless of dose or duration—had a 40% increased risk of overdose over the 12-month follow-up. A similar overdose risk was observed in the group prescribed only low-dose opioid medications.
• Compared with the opioid-only early discontinuation group, receipt of low-dose opioid medications co-prescribed with both high- and low-dose gabapentinoids was associated with a 250% increased risk of overdose. Patients co-prescribed high-dose opioids and moderate-dose gabapentinoids saw a 7-fold risk increase.

* Opioid average daily doses defined as: low (< 50 morphine milligram equivalent [MME]), moderate (50–90 MME), and high (> 90 MME). Gabapentinoid standardized daily doses (SDD) defined as: low (< 2 SDD [i.e., gabapentin < 600 mg or pregabalin < 300 mg]), moderate (2–3 SDD [i.e., 600 ≤ gabapentin < 900 mg or 300 ≤ pregabalin < 450 mg]), and high (>3 SDD [i.e., gabapentin ≥ 900 mg or pregabalin ≥ 450 mg]).

Comments: This study provides evidence of heightened risk of overdose in a dose-dependent and additive manner following new prescriptions for gabapentinoid and opioid medications. This study should give clinicians significant pause when considering a new prescription for gabapentinoids, especially in combination with opioid medications, and when prescribing for an off-label application where evidence of benefit is limited at best.

Morgan Younkin, MD, MPH† and Darius A. Rastegar, MD

† Contributing Editorial Intern and Addiction Medicine Fellow, Boston Medical Center.

Reference: Zhou L, Bhattacharjee S, Kwoh CK, et al. Dual-trajectories of opioid and gabapentinoid use and risk of subsequent drug overdose among Medicare beneficiaries in the United States: a retrospective cohort study. Addiction. 2020 [Epub ahead of print]. doi: 10.1111/add.15189.