Non-opioid antinociceptive drugs : risk of respiratory depression and death related to concomitant use of gabapentinoids in addition to opioids

ABSTRACT

Introduction

Respiratory depression and opioid-related death are reported when opioids are associated with gabapentinoids. Meta-analyses of randomized clinical trials investigating efficacy and safety of such association failed to assess these risks because of the lack of data. The aim of this systematic review was to investigate the risk of respiratory depression or death during this combination in the scientific literature, including case reports or series, observational studies, and clinical trials.

Areas covered

PubMed®, Web of Science®, Embase®, and Google Scholar® were searched from their inception to December 2021, for original articles in English, French, and German. Data synthesis was done on a narrative approach by type of articles.

Expert opinion

The review included 25 articles (4 case reports, 2 cross-sectional, 3 case–control, 14 cohort studies, and 2 clinical trials). Respiratory depression or opioid-related death and co-exposure to gabapentinoids were associated in perioperative setting/chronic pain (odds ratios around 1.3) and in opioid maintenance treatment (hazard ratio 3.4). These findings are in agreement with experimental studies showing that a single dose of gabapentinoid may reverse opioid respiratory tolerance. Because the combination gabapentinoids–opioids is highly prevalent in all clinical context, all health care professionals and patients must be aware of this risk.

KEYWORDS:

• Pregabalin
• gabapentin
• opioids
• respiratory depression
• all-cause death
• drug-related death

Article highlights

• Despite the lack of evidence to support their efficacy in treating most pain conditions, gabapentinoids (gabapentin and pregabalin) are frequently used with opioids to improve the analgesic effect. In parallel, concerns over gabapentinoids’ safety, including respiratory depression in combination with opioids have raised in the recent years.

• This article reviews the scientific literature including case reports, observational studies, and clinical trials in order to characterize and quantify the risk of respiratory depression or death during this combination and to identify in which clinical situations they occur.

• Twenty-five articles were identified covering perioperative context, chronic pain, and patients treated by opioid agonists. In almost all the studies, a statistically significant association with respiratory depression, overdose, or drug-related death was reported, even with a single dose of gabapentinoid.

• Both gabapentin and pregabalin are involved. The level of risk is higher in the chronic pain context than in a perioperative setting, potentially as a reflect of a more improper use of both opioids and gabapentinoids. For patients with opioid addiction and treated with opioid agonists, the information to quantify the risk in case of therapeutic use or misuse remains scarce.

• Considering the reappraisal of the clinical benefit in terms of morphine sparing and the prevention of chronic pain of the gabapentinoids, health professional must be aware of these risks in any category of patients and settings and not only for high doses or misuse of gabapentinoids and opioids. Further investigations related to the potential of the reversal of opioid tolerance are needed.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

Conception and design: M Lapeyre-Mestre and M Tambon. Literature searching: M Lapeyre-Mestre and M Tambon. Studies selection and data extraction: B Montarnal and M Tambon. Data analysis and interpretation: all authors. Drafting of the article: M Lapeyre-Mestre. Critical revision for important intellectual content and final approval of the article: all authors.

Additional information

Funding

This paper was not funded.