Association of Gabapentinoids With the Risk of Opioid-Related Adverse Events in Surgical Patients in the United States

Abstract

IMPORTANCEThe use of gabapentinoids in multimodal postoperative analgesia is increasing; however, when coadministered with opioids, these drugs may potentiate central nervous system and respiratory depression.OBJECTIVE To evaluate the association between perioperative coadministration of gabapentinoids and opioids with inpatient opioid-related adverse events in surgical patients. DESIGN, SETTING, AND PARTICIPANTSThis cohort study used propensity score trimming, stratification, and weighting of adults admitted for a major surgery between October 2007 and December 2017 who were treated with opioids on the day of surgery and included in the Premier Research database. Data analysis was conducted from February to April 2020. EXPOSURE Gabapentinoids (gabapentin or pregabalin) coadministered with opioids starting the day of surgery vs opioid therapy without gabapentinoids. MAIN OUTCOMES AND MEASURESPrimary outcome was opioid overdose. Secondary outcomes included respiratory complications, unspecified adverse effects of opioid use, and a composite of these 3 outcomes. Patients were followed up for as long as 30 days from the day of surgery until deviation from the initial treatment regimen or discharge. RESULTSGabapentinoids with opioids were administered to 892 484 of 5 547 667 eligible admissions (16.1%; mean [SD] age, 63.5 [11.8] years; 353 315 [39.6%] men). Among the 4 655 183 patients who received opioids only, the mean (SD) age was 63.7 (14.7) years, and 1 913 284 (41.1%) were men. Overall, 441 overdose events were identified, with absolute risks of 1.4 per 10 000 patients with gabapentinoid exposure and 0.7 per 10 000 patients receiving opioids only. Following propensity score trimming, the cohort included 737 383 patients exposed to gabapentinoids and 3 002 480 patients receiving opioids only. The primary analysis yielded the adjusted hazard ratio of 1.95 (95% CI, 1.49-2.55), and the number needed to treat for an additional overdose to occur was 16 914 patients (95% CI, 11 556-31 537 patients). Adjusted hazard ratios for secondary outcomes were 1.68 (95% CI, 1.59-1.78) for respiratory complications, 1.77 (95% CI, 1.61-1.93) for unspecified adverse effects of opioids, and 1.70 (95% CI, 1.62-1.79) for the composite outcome. The results were consistent across sensitivity analyses and subgroups identified by key clinical factors. CONCLUSIONS AND RELEVANCEIn this real-world cohort study of patients who underwent major surgery, concomitant use of gabapentinoids with opioids was associated with increased risk of opioid overdose and other opioid-related adverse events; however, the absolute risk of adverse events was low.

Perioperative Pain Management and Opioid Stewardship: A Practical Guide

“…A third retrospective analysis found preoperative gabapentin exposure was associated with a 47% increase in odds of experiencing a postoperative respiratory event, though the vast majority of the studied population were administered doses exceeding 300 mg [190,191]. Gabapentinoids exhibit dose-dependent propensity to increase postoperative pulmonary complications, though combination with other multimodal agents may negate this risk, and the absolute risk of adverse events with perioperative gabapentinoids appears low [177,192,193]. Hence, adverse event risks of gabapentinoids can be substantially mitigated by using conservative doses (i.e., 300 mg gabapentin preoperatively), avoiding postoperative use in patients experiencing or at risk for sedation or dizziness, and/or avoiding entirely in high-risk patients.…”

Non-medical Use of Prescription Gabapentinoids (Gabapentin and Pregabalin) in Five European Countries

“…Pregabalin and gabapentin are usually prescribed with other pain medications, mainly with opioids; among 50–70% were reported in a recent paper ( 23 ). This combination could increase the risk for overdose death ( 30 ). Otherwise, the usefulness of the combination of pregabalin and opioids for the treatment of some kind of pain is not clear, as some researchers have described that pregabalin plus opioids was associated with more pain severity and higher oral doses of opioids; furthermore, pregabalin use was not associated with improvements on mental health symptoms ( 31 ).…”

Potential Adverse Consequences of Combination Therapy with Gabapentin and Pregabalin

“…Lastly, one more important point to consider in controlling the way these gabapentinoids are prescribed is their abuse and misuse potential [2,11,13]. Along with the abovementioned central adverse effects, these medications can be addictive, particularly in people with other addictions or when combined with other drugs of abuse particularly opioids [21], although the risk is low. Rare cases of overdose deaths have also been reported from gabapentin and pregabalin [22].…”