We reviewed several sources of data including case reports submitted to FDA or published in the medical literature, observational studies, human trials, and animal studies.

Gabapentinoids are increasingly being prescribed for medical uses, and misuse and abuse of these medications are growing. Between 2012 and 2016, the number of patients who filled a gabapentin prescription increased from 8.3 million to 13.1 million annually, and the number of patients who filled a pregabalin prescription increased from 1.9 million to 2.1 million annually.16 Gabapentinoids are commonly co-administered with opioids for prescribed medical uses and abused in combination with opioids. Data collected in 2016 from an office-based physician survey showed that 14 percent and 19 percent of patient encounters involving gabapentin and pregabalin, respectively, also involved opioids.17 Several small cross-sectional studies suggest that in the U.S. and Europe, approximately 15 percent to 26 percent of patients with opioid use disorder (OUD) concomitantly misuse or abuse gabapentin, and approximately 7 percent to 21 percent of patients with OUD concomitantly misuse or abuse pregabalin. However, these studies were small, so the prevalence estimates may not be generalizable to all populations of patients with OUD.17-22

We reviewed data from the FDA Adverse Event Reporting System (FAERS) database and the medical literature1-6 which show that respiratory depression can occur when gabapentinoids are administered in combination with opioids or other central nervous system (CNS) depressants or in patients with underlying respiratory impairment. A small number of reports were in patients only on gabapentinoids. A search of FAERS from January 1, 2012, to October 26, 2017, identified 49 cases of respiratory depression with gabapentinoids. Fifteen cases were reported with gabapentin and 34 cases with pregabalin. Ninety-two percent of the cases reported either a respiratory risk factor, including age-related loss of lung function, or the use of a CNS depressant. Twenty-four percent of the cases resulted in death (n=12). All 12 death cases reported at least one risk factor for developing respiratory depression or concomitant use of a CNS depressant.

Several small randomized trials of healthy volunteers showed that gabapentinoids alone and in combination with opioids depress respiratory function. Myhre et al.7 conducted a small randomized, double-blind, placebo-controlled cross-over trial in 12 healthy volunteers exposed to placebo, pregabalin alone, the opioid remifentanil alone, or a combination of pregabalin plus remifentanil. End-tidal CO2 rose with exposure to the drugs together in an additive way. Piovezan and colleagues8 carried out a small randomized, double-blind, placebo-controlled cross-over trial of eight healthy volunteers. The subjects were older non-obese men without sleep complaints or sleep apnea. Subjects were given a single dose of gabapentin or placebo followed by a sleep study. After a washout period, subjects were again given a single dose of treatment (crossing over to the alternate treatment) followed by another sleep study. The number of hourly apneic episodes during gabapentin exposure exceeded those during placebo exposure.

Observational studies suggest that patients exposed to preoperative gabapentinoids have an increased risk of postoperative respiratory depression compared to those not exposed to gabapentinoids preoperatively. A Mayo Clinic research group published a case-control study describing the relationship between preoperative gabapentin exposure and the risk of postoperative respiratory depression in more than 11,000 arthroplasty patients.9 They defined respiratory depression as apnea, hypopnea, oxyhemoglobin desaturation, or an episode of severe pain despite moderate to profound sedation (i.e., “pain-sedation” mismatch) during recovery in the postanesthesia care unit. In this study, when compared to patients not exposed to preoperative gabapentin, the risk of respiratory depression was increased 60 percent for patients using regional anesthesia (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.27, 2.02) and 47 percent for those using general anesthesia (OR 1.47, 95% CI 1.26, 1.70) when the preoperative anesthesia regimen included gabapentin doses greater than 300 mg. This same research group conducted another case-control study describing the relationship between preoperative gabapentin exposure and the risk of postoperative respiratory depression in more than 8,000 laparoscopy patients.10 Respiratory depression was defined as apnea, hypopnea, oxyhemoglobin desaturation, pain-sedation mismatch, naloxone administration, failure to extubate, need to reintubate, or non-invasive positive pressure ventilation (NIPPV) use in patients who were not previously prescribed such a device. In this study, preoperative gabapentin increased the risk of postoperative respiratory depression by 26 percent (OR 1.26, 95% CI 1.02, 1.58) compared to those not exposed to preoperative gabapentin.

Animal studies have shown that gabapentinoids can cause respiratory depression alone and in combination with opioids.12-14 Kozer and colleagues12 showed that rabbits given morphine after gabapentin had greater CO2 retention than rabbits given saline after gabapentin. Lyndon and colleagues13 studied the respiratory depressant effects of a high intraperitoneal dose of pregabalin with and without medium dose morphine in six mice. Pregabalin produced a dose-dependent decrease in respiration rate. A pregabalin bolus given alone depressed mouse minute ventilation to the same extent as a morphine bolus given alone. The respiratory depressant effects of morphine and pregabalin were additive, not multiplicative. Collectively, the published animal studies suggest that gabapentinoids have an independent dose-dependent depressive effect on respiration and can augment the respiratory depression caused by opioids.