Perioperative gabapentinoids: Deflating the bubble (2024)

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Prescription of gabapentin and pregabalin in the perioperative period has becomeincreasingly common, if not de rigueur. These gabapentinoids havebecome ubiquitous components of protocols for early recovery after surgery andmulti-modal analgesia. Neither is approved by the US Food and Drug Administration (FDA)for preventing or treating surgical pain, but their use is predicated on widespreadbelief in their benefit, including pain reduction and opioid-sparing, as well as lack ofside effects and risks. Nevertheless, these longstanding beliefs have recently beenchallenged.

In this issue of Anesthesiology, Verret and colleagues report asystematic review and meta-analysis of perioperative gabapentinoids for the managementof postoperative acute pain.¹ Theanalysis comprised 281 randomized clinical trials involving 24,682 adults, comparinggabapentinoids to placebo or another analgesic regimen or usual care, when initiatedbetween 1 week before and 12 hours after elective or emergent surgery under any type ofanesthesia. The primary outcome was pain 6, 12, 24, 48, and 72 hours after surgery. Theresults were statistically significant but clinically unimportant less postoperativepain at all primary time points (3–10% less), no difference in the proportion ofpatients achieving ‘appreciable’ analgesia, no difference in subacute pain(postoperative weeks 4–12), and no effect on chronic postoperative pain (3 monthsor longer), for both gabapentin and pregabalin, regardless of when administered.Gabapentinoids were associated with statistically lower but clinically unimportant lesspostoperative opioid use (8 mg morphine equivalent at 24hr). They were associated withless postoperative nausea and vomiting but more adverse effects, including dizziness andvisual disturbances. The authors concluded that these data do not support the routineuse of pregabalin or gabapentin for the management of postoperative pain in adults.

The article by Verret et al¹ iscommended to every practitioner who prescribes perioperative gabapentinoids, and tothose entrusted to author institutional protocols for early recovery after surgery ormulti-modal analgesia. The analysis was well-executed, the number of patients robust,the quality of evidence properly evaluated, the results clearly presented, and theconclusions well-supported and unambiguous. This article is entirely consistent withprevious reports,^2–6 but also brings forth additional information. Thenew analysis evaluated a broad surgical population, a long duration of outcomes,included additional trials, and, importantly, assessed minimally important clinicaldifferences rather than just statistical differences.

We are then left to ask, how did we get here, and where should we go?

Evidence of benefit

Gabapentin was approved by the FDA in 1993 for treatment of seizures andsubsequently in 2002 for postherpetic neuralgia - the only pain indication.Pregabalin was FDA-approved in 2004 for neuropathic pain (diabetic neuropathy andpostherpetic neuralgia), then fibromyalgia (2007), and spinal cord injuryneuropathic pain (2012). Both drugs bind to the α₂δ subunitof voltage-gated calcium channels in the spinal cord and peripheral nerves, decreaseexcitatory neurotransmitter release from activated nociceptors, inhibit ascendingpain transmission, activate descending inhibitory pathways, and prevent hyperalgesiaand central sensitization. They differ only in their pharmaco*kinetics. Neither drugis FDA-approved for treating or preventing surgical pain.

The early time course of perioperative gabapentinoid use was one ofenthusiastic implementation. An early study used a single preoperative dose,evaluated patients for only 4 hr postoperatively, and reported substantially (50%)less pain during movement and morphine consumption. An accompanying editorialheralded gabapentin as “a welcome addition to the anesthesiologist’spharmacopoeia of ‘coanalgesics’”, and interest mushroomed.Within just a few years, numerous studies appeared, and preoperative gabapentinoidswere celebrated as reducing pain scores, opioid requirements, and opioid-relatedside effects in the first 24hr after surgery with few adverse effects, deemed“promising”, and perhaps the long sought after “protectivepremedication” or “preemptive analgesic”. These remarkableeffects were attributed to and “fit with” leading theories at thetime, including prevention of central sensitization, inhibition of excitatoryneurotransmitter release in the spinal cord, synergy with opioids, and prevention ofopioid tolerance. What could be better? A groundswell of interest and exponentialuse of perioperative gabapentinoids ensued. They were evaluated for“preventive analgesia”, and associated with moderate-to-largedifferences in chronic postsurgical pain. Enthusiasm for perioperativegabapentinoids swelled further, including higher doses, dosing earlier (day beforesurgery), and dosing longer (weeks) postoperatively. Perioperative gabapentinoid usewas enthusiastically adopted, and became widespread and often routine.

In addition to the attractive and welcomed messages about benefits ofperioperative gabapentinoids, the proliferation of routine use may relate to otherfactors, coincident events, and trends in anesthesia and surgical practice: 1) Earlypublished reports of gabapentinoid benefit were largely devoid of data on adverseeffects and risk, and subsequent reviews had rosy descriptions of benefit orunsupported extrapolation; 2) The national epidemic of oral opioid overprescribingfor chronic pain and accompanying addiction and overdose, promptinganesthesiologists and surgeons to seek alternatives to opioids; 3) An even moreaggressive response by some anesthesiologists leading to a concept of“reducing or avoiding all perioperative opioids” (i.e.“opioid-free anesthesia”);^7,8 4) Early recoveryafter surgery protocols, which initially recognized the influence of excess opioidson gut motility and recovery, and then in some cases evolved to a similar approachof “avoiding all opioids”; 5) Adoption of “multimodalanalgesia” as a concept, but with uncritical widespread implementation ofpolypharmacy regimens whose clinical effectiveness and particularly adverse effectprofile were insufficiently tested or evidenced;⁹ 6) Spillover of widespread gabapentinoid use for outpatientpain to perioperative use; 7) Relatively small numbers of pharmacologic targets anddrugs available for acute perioperative pain, juxtaposed with earnest practitionerdesires to “do something”; and 8) Professional society guidelineswhich recommend gabapentinoids.^10,11 Whether any aggressive or illegalpharmaceutical marketing of gabapentinoids (as had occurred earlier withParke-Davis) influenced their perioperative use is not known.⁶

Recent years have seen a reversal of fortune for perioperativegabapentinoids, brought about by improved clinical research and its synthesis intoinformative and actionable evidence.^1–5 Compared withplacebo, patients receiving perioperative gabapentinoids sometimes have pain and/oropioid consumption that is less, statistically, but small in magnitude (a fewpercentage points less pain and sparing only a few mg of opioid) and short-lived(often only a day), but not clinically meaningful and not preventing chronicpostsurgical pain or opioid use.

Many placebo-controlled perioperative studies were designed to be single- ordouble-blinded, yet this is nearly impossible because gabapentinoids are sedating,and both patients and research staff may easily know who received active drug.Sedation alone might have a “placebo effect” with regard to pain.Indeed, in a seminal, well-designed, and important investigation, an active placebo(lorazepam) was used instead of an inactive placebo, to truly blind patients andresearch staff. The result was that gabapentin did not affect either pain resolutionor opioid cessation.¹² Thus withan active placebo, any evidence of gabapentin benefit evaporated.

Evidence of risk

Clinical studies must evaluate both analgesia and all relevant side effects.Gabapentinoids have well-described and frequent side effects. Because they bind tothe α2δ subunit of voltage-gated calcium channels, which are richlyexpressed in the cerebellum and hippocampus, they cause dizziness, balancedisorders, ataxia, visual disturbances, sedation, somnolence, and cognitiveimpairment. Early gabapentinoid studies focused on analgesia, but not side effects.In retrospect, however, there were early and clear yet underappreciated signals ofside effects, most notably dizziness and sedation. Years later, it is now clear thatperioperative gabapentinoids are associated with a greater risk of sedation,dizziness, and visual disturbances.^1–3 It is perhapsparadoxical that enhanced recovery protocols, which endeavor to avoid these verycomplications of sedation, somnolence, and cognitive impairment which can delayrecovery, can advocate the routine use of gabapentinoids. More importantly,pregabalin use was associated with a nearly 3-fold greater relative risk of seriousadverse events (life threatening; resulting in death, disability, or significantloss of function; causing hospital admission or prolongedhospitalization).⁵ Day ofsurgery gabapentinoid use was associated with dose-dependent increased odds ofpostoperative pulmonary complications (respiratory failure, pneumonia, reintubation,pulmonary edema, noninvasive ventilation, invasive mechanical ventilation) and ICUadmission, and without decreased opioid requirements or length of stay.

Multimodal analgesia is predicated on favorable pharmacodynamic interactionswhereby benefits of combination therapy exceeds the risks, either by synergisticanalgesia but only additive toxicity, or additive analgesia with sub-additive ordiminished toxicity. Pregabalin plus opioids caused greater postoperative sedation,dizziness, visual disturbances, and confusion, than opioids alone. Among the adverseeffects of postoperative analgesics, most dangerous is respiratory depression.Gabapentinoids, when combined with opioids, confer even greater respiratory riskthan opioids alone. Pregabalin plus remifentanil caused additive analgesia but worse(potentiated) remifentanil ventilatory depression.¹³ Perioperative gabapentinoid use wasassociated with greater postoperative respiratory depression, noninvasiveventilation, and naloxone use (as high as 6-fold greater).^14,15 Ina general population, concomitant gabapentinoid use substantially increases risks ofopioid-related death.

It is now unmistakable that perioperative gabapentinoids have clinicallysignificant adverse effects. Patient safety has emerged as a broader gabapentinoidconcern. FDA now recognizes and has issued warnings about adverse respiratoryeffects of gabapentinoids.^16,17 FDA now requires updates togabapentinoid labeling to include new warnings of potential respiratory depression,and is requiring new clinical trials, particularly in combination with opioids, toassess respiratory depression.

Evidence and action

It is now clear that over the past two decades, evidence of benefit fromroutine perioperative administration of gabapentinoids has diminished, whileevidence of harm has increased. If any potential benefits exist in “specialpopulations”, published reports have yet to identify the benefits or thepopulations. Anesthesiologists and surgeons prescribe perioperative gabapentinoidsbecause they believe they reduce acute postoperative pain, opioid use, and chronicpostoperative pain. However their expectations of meaningful clinical benefit arenot supported. The conclusion reaffirmed by Verret and colleagues in this issue ofAnesthesiology,¹ andreached by others before,^5,15 is that routine use ofperioperative gabapentinoids for treatment of postoperative pain in adults is notsupported. Furthermore, conducting even more clinical trials to evaluate analgesicbenefits of gabapentinoids on acute postoperative pain is very unlikely to provideany new evidence.¹ The goodintentions which led to routine gabapentinoid use should be redirected to lead theway out. The French Society of Anaesthesia and Intensive Care Medicine now statesthat gabapentinoids should not be used systematically, or in outpatientsurgery.¹⁸ Other societiesshould follow. As the weight of evidence has shifted, and the risk-benefit balancetilted away from benefit, evidence-based practice impels revising if not eliminatingthe routine use of perioperative gabapentinoids in adults.

Key citations are included in this version. A version with full citations isprovided as Supplemental DigitalContent ( ).

Supplementary Material

Sources of financial support:

National Institutes of Health (Bethesda, Maryland) grant No. R01 DA042985(EDK) and Department of Veterans Affairs grant No. I01 BX000881 (JDC)

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