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It was January a year ago that we wrote about an FDA warning on gabapentinoids (see our January 2020 What's New in the Patient Safety World column “FDA Warning on Gabapentinoids”). In the past several years we had done a several columns on dangers of gabpentinoids, alone or in combination with opioids (see our What's New in the Patient Safety World columns for November 2017 “Bad Combination: Gabapentin and Opioids” and March 2019 “Gabapentin and Pregabalin on the Radar Screen”). So, it came as no surprise to us that the FDA has issued a warning about gabapeninoids (FDA 2019).
But most of the warnings about respiratory depression with gabapentinoids, often when used in combination with opioids, were the result of anecdotal reports and small case series. Then, in our February 25, 2020 Patient Safety Tip of the Week “More on Perioperative Gabapentinoids”, we discussed 2 studies by Duke University researchers from larger databases looking at the impact of gabapentinoids used in the perioperative period. Ohnuma et al. (Ohnuma 2019) analyzed data from a large administrative claims database, including 862,524 patients from 592 hospitals, who underwent elective primary THA or TKA between 2009 and 2014. They looked at the following drugs, alone or in combination, on the day of surgery for patients undergoing TKA or THA: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAID’s), gabapentinoids (gabapentin or pregabalin), or none of the three drugs.
Compared to none of the three drugs as the reference category, exposure to gabapentinoids was associated with increased odds of naloxone use after surgery (OR 2.11), noninvasive ventilation (OR, 1.45), invasive mechanical ventilation (OR 1.25), and ICU admission (OR 1.28). A similar increase was seen in analgesic combinations including gabapentinoids. The group receiving NSAID’s plus acetaminophen showed the most protective associations with naloxone use after surgery (OR 0.59), invasive mechanical ventilation (OR, 0.72), and ICU admission (OR 0.69), and was associated with the lowest opioid consumption on the day before discharge.
The authors conclude that preoperative gabapentinoids were associated with significant increased risk of postoperative opioid-related respiratory depression. It also failed to find benefits for gabapentinoids in terms of postoperative opioid consumption and LOS. They recommended reconsideration of routine use of preoperative gabapentinoids in the adult TKA and THA population.
The researchers also looked at 108,616 patients who underwent elective colorectal surgery across the 605 hospitals, 2% of whom received gabapentinoids on the day of surgery (Yan 2019). They found that use of gabapentinoids was associated with higher odds of noninvasive ventilation (OR 1.39) and receipt of naloxone after surgery (OR 1.70). There was no difference in invasive mechanical ventilation, opioid consumption, or LOS. They cite other small studies showing increased risk of postoperative respiratory depression and naloxone use in patients receiving gabapentinoids, which may be explained by an interaction between gabapentinoids and opioids.
Now, a new study (Bykov 2020) analyzed data from the large Premier Research database to assess use of perioperative gabapentinoids in relation to the risk of opioid-related adverse events in surgical patients. The study population included adults admitted for major surgery between October 2007 and December 2017 who were treated with opioids on the day of surgery. Overall, gabapentinoids with opioids were administered to 892,484 of 5 547 667 eligible admissions (16.1%). 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 adjusted hazard ratio for an overdose in those receiving gabapentinoids and opioids compared to those receiving opioids only was 1.95. But the absolute risk was small. To put it in perspective, the number needed to treat (NNT) for an additional overdose to occur was 16,914 patients. Adjusted hazard ratios for secondary outcomes were 1.68 for respiratory complications, 1.77 for unspecified adverse effects of opioids, and 1.70 for the composite outcome of the 3 outcomes. The results were consistent across sensitivity analyses and subgroups identified by key clinical factors.
In our attempts to reduce the use of perioperative opioids, the use of multimodal analgesia has been front and center. One component of many multimodal analgesia regimens has been gabapentinoids. The Bykov study is somewhat reassuring in that the absolute risk of untoward complications is small. The overall occurrence of adverse outcomes was very low, with overdoses occurring in less than 0.1% of patients. Yet, it does confirm that concomitant use of gabapentinoids almost doubles the risk of overdose and increased the risk of respiratory complications by about 70%. That certainly calls for careful consideration of when gabapentinoids should be used perioperatively and when they might be best avoided.
Others have questioned the risks and benefits of perioperative gabapentinoids. In our February 25, 2020 Patient Safety Tip of the Week “More on Perioperative Gabapentinoids” we discussed a systematic review and meta-analysis on perioperative use of gabapentinoids (Verret 2019) that found no clinically significant analgesic effect for the perioperative use of gabapentinoids, with low level of evidence, and an increased risk of adverse events with moderate level of evidence. The authors concluded that their results do not support the use of gabapentinoids for the management postoperative acute pain in adult patients.
Unfortunately, the studies from the large databases do not tell us what other risk factors may have contributed to the adverse events related to patients receiving gabapentinoids. Taking those risk factors into account might allow better selection of patients who might benefit from gabapentinoids without the risks of respiratory depression. For example, we might avoid using gabapentinoids in patients at risk for obstructive sleep apnea (OSA).
So, again, mixed messages from the Bykov study – the absolute risk from gabapentinioids is low but they do increase the risk of adverse events in those patients receiving opioids perioperatively.
Hospitals and ambulatory surgical centers should include a look at gabapentinoids in their analysis of events following surgery. Particularly in view of the Obnuma study mentioned above (Ohnuma 2019), they should also look to see if the intended rationale for use of gabapentinoids (to reduce the need for opioids) actually achieved that goal.
Some of our prior columns on safety issues with gabapentinoids:
FDA (US Food and Drug Administration). FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR)When used with CNS depressants or in patients with lung problems12-19-2019
OhnumaT, Raghunathan K, Ellis A, et al. Abstract S-344 Effects of Acetaminophen, NSAID’s, Gabapentinoids and Their Combinations on the Day of Surgery in Total Hip and Knee Arthroplasties. Anesthesia & Analgesia 2019; 128(5): 741
Yan R, Ohnuma T, Krishnamoorthy V, et al. Abstract S-353 Gabapentinoids on the Day of Colorectal Surgery Are Associated with Adverse Postoperative Respiratory Outcomes. Anesthesia & Analgesia 2019; 128(5): 760
Bykov K, Bateman BT, Franklin JM, Vine SM, Patorno E. Association of Gabapentinoids With the Risk of Opioid-Related Adverse Events in Surgical Patients in the United States. JAMA Netw Open 2020; 3(12): e2031647
Verret M, Lauzier F, Zarychanski R, et al. Perioperative Use of Gabapentinoids for the Management of Postoperative Acute Pain: A Systematic Review and Meta-analysis. 2019 annual meeting of the American Society of Anesthesiologists (ASA; abstract A2096).
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