Remifentanil and Opioid-Induced Hyperalgesia
Myron Yaster MD, Lynne Maxwell MD and Mark Crawford MD
General of the American Armies John J. Pershing once said of the men and women of World War I that, “Time will not dim the glory of their deeds.” It is up to us to make those words true, especially this November on the 11th hour of the 11th day….
In 2006, Mark Crawford and colleagues at Toronto’s Hospital for Sick Children published the first paper linking the use of remifentanil with acute opioid tolerance and opioid induced hyperalgesia.1 Today’s PAAD, from the same institution is another look at this issue but with different results. It’s a perfect PAAD topic because it also gives us the opportunity to review acute opioid tolerance, remifentanil, the anesthetic management of adolescent idiopathic posterior spine fusion surgery, and why results may differ between prospective and retrospective studies. Finally, Mark is an old and very dear friend and colleague and I’ve reached out and asked him to join us in this PAAD. Myron Yaster MD
Original article
Calvin Lo, Stephanie Schwindt, Richa Sharma, Rebecca Dubé, David Faraoni, Benjamin E Steinberg, Stephen Brown. Association Between Intraoperative Remifentanil Dosage and Postoperative Opioid Consumption in Adolescent Idiopathic Spine Surgery: A Retrospective Cohort Study. Anesth Analg. 2021 Oct 1;133(4):984-990. PMID: 33555691
The surgical correction of adolescent idiopathic scoliosis has always fascinated us. It is unique surgery in that the anesthetic plan is built around neurometric monitoring rather than the typical patient needs for surgery. Thus, increasingly it is a TIVA and remifentanil based anesthetic, with institutional biased intraoperative use of longer acting opioids like methadone or intrathecal morphine, NMDA antagonists like ketamine, methadone, and propofol, and non-opioid analgesics like acetaminophen. Persistent and prolonged postoperative pain is common following spine surgery and as many of 40% of patients may have chronic post-surgical pain (see Nov 2 PAAD, “Why Do I Still Hurt? A Primer on Chronic Post-Surgical Pain”).2,3 In the immediate postoperative period, moderate to severe pain is common and maybe made worse by the intraoperative use of remifentanil through the process of acute opioid tolerance or opioid-induced hyperalgesia.1
What is acute opioid tolerance or opioid-induced hyperalgesia? Essentially, it means that opioids may produce rapid tolerance and may produce more pain when stopped than if they were not used at all. The underlying molecular biology of this phenomenon is well understood. Laura Bohn and colleagues have been studying the interaction of the G-protein coupled, mu-opioid receptor, the NMDA receptor, beta arrestins and tolerance for more than 20 years.4,5 Indeed, this research has led to the development of biased ligands which theoretically produce analgesia with less tolerance and respiratory depression.6 Essentially, opioids that bind rapidly and tightly to the mu receptor like remifentanil and NMDA receptor agonists increase phosphorylated beta-arrestins which will produce the rapid development of tolerance by basically permanently inactivating the mu receptor. Drugs that block the NMDA receptor may prevent or minimize this, hence the use of ketamine, methadone, and/or propofol. One of the surprises to us in this article is that propofol is an NMDA antagonist.7,8
Ok, so what did the authors find in this retrospective study? Unlike the papers from Crawford et al. and from Yu et al.9 who found that remifentanil infusion rates > 0.25 mcg/kg/min were associated with higher postoperative opioid consumption, this paper “did not demonstrate an association between total intraoperative remifentanil dose and cumulative opioid consumption through 72 hours following surgery in the context of a multimodal analgesia regimen”. Thus, it did not produce hyperalgesia!
To be honest, we are unsure how to completely square this circle. The authors speculate that propofol as an NMDA antagonist may have prevented opioid induced hyperalgesia and may make the use of other NMDA antagonists like ketamine “superfluous”. We are not so sure. Because this was a retrospective and non-randomized study like Crawford’s study, (they did not have a “no remifentanil” group) they may have missed the hyperalgesia. Additionally, all randomized controlled trials have specific design elements within the trial. For example, the use of adjuvants (e.g., dexmedetomidine, ketamine, and acetaminophen) and the timing and dosing of their administration are specified and not up to the intraoperative team. Retrospective trials don’t do that. It is possible that amount and timing of adjuvant drugs and the analgesic drugs that may have been used in the PACU may have disguised the effects of remifentanil on hyperalgesia. Finally, in the current study PACU opioid requirements were not included in the first 24 hour analysis of opioid consumption and this likely affected the results as well.
Lo et al. conclude: “The effect of coanalgesic adjuvants on remifentanil-induced OIH/AOT, the impact on functional outcomes such as ambulation, and long-term effects of intraoperative remifentanil on chronic pain require further study. Well-designed prospective trials dedicated to answering these questions are needed to optimize and refine pain management for these patients.” We couldn’t agree more!
Myron Yaster MD, Lynne Maxwell MD and Mark Crawford MD
References
1. Crawford MW, Hickey C, Zaarour C, Howard A, Naser B: Development of acute opioid tolerance during infusion of remifentanil for pediatric scoliosis surgery. Anesth.Analg. 2006; 102: 1662-1667
2. Ocay DD, Li MMJ, Ingelmo P, Ouellet JA, Pagé MG, Ferland CE: Predicting Acute Postoperative Pain Trajectories and Long-Term Outcomes of Adolescents after Spinal Fusion Surgery. Pain Res Manag 2020; 2020: 9874739
3. Chidambaran V, Ding L, Moore DL, Spruance K, Cudilo EM, Pilipenko V, Hossain M, Sturm P, Kashikar-Zuck S, Martin LJ, Sadhasivam S: Predicting the pain continuum after adolescent idiopathic scoliosis surgery: A prospective cohort study. Eur J Pain 2017; 21: 1252-1265
4. Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT: Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 1999; 286: 2495-2498
5. Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG: Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 2000; 408: 720-723
6. Pantouli F, Grim TW, Schmid CL, Acevedo-Canabal A, Kennedy NM, Cameron MD, Bannister TD, Bohn LM: Comparison of morphine, oxycodone and the biased MOR agonist SR-17018 for tolerance and efficacy in mouse models of pain. Neuropharmacology 2021; 185: 108439
7. Bandschapp O, Filitz J, Ihmsen H, Berset A, Urwyler A, Koppert W, Ruppen W: Analgesic and antihyperalgesic properties of propofol in a human pain model. Anesthesiology 2010; 113: 421-8
8. Qiu Q, Sun L, Wang XM, Lo ACY, Wong KL, Gu P, Wong SCS, Cheung CW: Propofol produces preventive analgesia via GluN2B-containing NMDA Receptor/ERK1/2 Signaling Pathway in a rat model of inflammatory pain. Mol Pain 2017; 13: 1744806917737462
9. Yu EH, Tran DH, Lam SW, Irwin MG: Remifentanil tolerance and hyperalgesia: short-term gain, long-term pain? Anaesthesia 2016; 71: 1347-1362