IN this issue of Anesthesiology, Loftus et al.  1report findings from a study examining the utility of ketamine as an adjunct analgesic in controlling postoperative pain. Is this just another report on the perioperative use of ketamine addressing a question that has already been answered? We know this works, right? Considering that the population under study consisted of patients on long-term opioid therapy for chronic pain, the report may be worth a closer look.

The use of opioids for the control of chronic pain is now commonplace. Opioid prescriptions increased greatly over the past decade, hydrocodone/acetaminophen being the most commonly prescribed drug in the United States for the past several years by a substantial margin.2–5Once the province of the pain specialist, long-term opioid prescribing is now in the repertoire of most primary care physicians, and virtually all chronic pain management guidelines endorse the use of opioids at some point in chronic pain treatment algorithms. Few data are readily available to address quantitatively the assertion that an increasing percentage of patients receiving opioids, particularly in large amounts, come to our operating rooms for all types of surgeries, but it seems undeniable.

There is widespread belief among clinicians that patients receiving long-term opioid therapy present significant perioperative management problems. For example, opioid requirements are often greatly increased (on average about three times those of opioid-naive patients), although prediction of postoperative opioid needs for individual patients remains difficult.6–8Some have found postoperative pain scores to be worse despite the availability of acute pain management experts.8Perhaps most worrisome, but not well studied, is the notion that the therapeutic index of opioids might be narrowed, making these patients particularly vulnerable to serious side effects or inadequate pain control. Finally, opioid doses tend to be substantially higher, compared with preoperative levels, at the time of discharge from hospital. Dose reduction in this setting can be a complex undertaking. Although the real impact of these challenges remains uncertain, several authors have offered their opinions concerning how patients receiving long-term opioid therapy should be managed.9–12Most often, the interrelated opioid “maladaptations” of tolerance, opioid-induced hyperalgesia, and physical dependence are cited as the roots of specific management problems.

If we accept that patients receiving long-term opioid therapy are a population of special concern, we might then ask how we would rationally improve their postoperative pain management. Setting aside regional anesthesia, our analgesic trump card, we might opt to use adjunctive analgesics that would both reduce the impact of long-term opioid consumption and contribute to analgesia via  opioid-independent mechanisms. An ideal drug would reduce opioid tolerance, would attenuate opioid-induced hyperalgesia, and would have proven analgesic properties of its own. Ketamine and perhaps α-2 agonists such as dexmedetomidine may fill the bill. Both ketamine and dexmedetomidine have been advocated as adjuvants in the analgesic management of patients receiving long-term opioid therapy, although there are few data yet to support those recommendations.

The basic and clinical pharmacology of ketamine have been well studied. Although it has many potential sites of action, its N -methyl-d-aspartate receptor blocking properties are most frequently discussed. A large body of work in laboratory animals indicates that ketamine can block the development of opioid tolerance and opioid-induced hyperalgesia and reverse both phenomena, at least partly, when already present. Ketamine has specifically been noted to reduce opioid-induced exacerbations of incisional pain in animals.13Curiously, however, studies are mixed as to whether N -methyl-d-aspartate receptors strongly support sensitization after incision.14–16More broadly, the N -methyl-d-aspartate receptor is one of the best studied regulators of pain signaling; these receptors are expressed in various areas in the peripheral and central nervous systems controlling pain sensitization and neural plasticity in many acute and chronic pain states including inflammation, nerve injury, and cancer.

Many studies have examined ketamine as an adjunctive analgesic in the perioperative period. A recent metaanalysis of 37 trials in more than 2,200 patients indicated that ketamine likely reduces postoperative opioid requirements, at least during the first 24 h.17Several studies also reported nominally better pain control, although these observations were not borne out in the combined analysis. The use of ketamine was safe and accompanied by mild side effects, if any. The results of Loftus et al.  1(∼30% reduction in morphine consumption over the first 48 h and ∼25% reduction in visual analog scale pain score in the postoperative care unit) are similar in magnitude to those previously reported in opioid-naive patients. No attempt has been made to compare directly responses in opioid-naïve patients versus  those receiving long-term opioid therapy, leaving unresolved the question of whether ketamine is particularly efficacious in the latter group.

Although the results reported by Loftus et al.  1provide reassurance that the adjuvant analgesic effects of ketamine persevere in the perioperative period in patients receiving long-term opioid therapy, many questions remain. First, the dose and infusion duration of ketamine in this study were similar to those used by others for opioid-naive patients, but the infusion stopped at the end of surgery. Perhaps enhanced pain control would have been observed if the infusions were continued on the hospital wards. Second, laboratory studies provide the basis to suggest that persons exposed to higher doses of opioids might receive greater benefit from ketamine, a notion supported by an exploratory post hoc  analysis undertaken by Loftus et al.  1Whether ketamine is of particular benefit for patients receiving high doses of opioids certainly merits future study. Third, comparing particular benefits and potential disadvantages of various adjunct analgesics head-to-head, including ketamine, α-2-adrenrgic agonists such as dexmedetomidine, and perhaps gabapentin, would be useful for selecting optimal treatment strategies for this group of patients. Finally, we might wonder whether a reduction in opioid requirements translates into any safety or longer term benefits. Perhaps more aggressive postoperative opioid use is as efficacious and safe as introducing a second medication with its inherent risks and benefits. However, if the use of ketamine widens the therapeutic index for opioids or provides longer term benefits, such as a reduced incidence or severity of more prolonged postsurgical pain states, enthusiasm for ketamine might be higher. Indeed some evidence for reduced chronic (6 week) postoperative pain in the ketamine group was found in the present publication; future studies will be needed to determine whether these effects are sustained.

Loftus et al.  1have provided a valuable first effort in addressing a problem of growing importance. Many of us who have embraced the perioperative use of ketamine for patients receiving long-term opioid therapy may be comforted now that there are some actual data supporting such use. Refining our understanding of ketamine's particular value as an adjunct therapeutic in populations vulnerable to suboptimal pain control will be necessary and will allow us to target its use toward those patients who would truly benefit.

Loftus RW, Yeager MP, Clark JA, Brown JR, Abdu WA, Sengupta DK, Beach ML: Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients. Anesthesiology 2010; 113:639–46
Molina DK, Hargrove VM: What is the lethal concentration of hydrocodone? A comparison of postmortem hydrocodone concentrations in lethal and incidental intoxications. Am J Forensic Med Pathol 2010 Apr 19. [Epub ahead of print]
Joranson DE, Ryan KM, Gilson AM, Dahl JL: Trends in medical use and abuse of opioid analgesics. JAMA 2000; 283:1710–4
Gilson AM, Ryan KM, Joranson DE, Dahl JL: A reassessment of trends in the medical use and abuse of opioid analgesics and implications for diversion control: 1997–2002. J Pain Symptom Manage 2004; 28:176–88
Olsen Y, Daumit GL, Ford DE: Opioid prescriptions by U.S. primary care physicians from 1992 to 2001. J Pain 2006; 7:225–35
de Leon-Casasola OA, Myers DP, Donaparthi S, Bacon DR, Peppriell J, Rempel J, Lema MJ: A comparison of postoperative epidural analgesia between patients with chronic cancer taking high doses of oral opioids versus  opioid-naive patients. Anesth Analg 1993; 76:302–7
de Leon-Casasola OA: Postoperative pain management in opioid-tolerant patients. Reg Anesth 1996; 21:114–6
Rapp SE, Ready LB, Nessly ML: Acute pain management in patients with prior opioid consumption: A case-controlled retrospective review. Pain 1995; 61:195–201
Carroll IR, Angst MS, Clark JD: Management of perioperative pain in patients chronically consuming opioids. Reg Anesth Pain Med 2004; 29:576–91
Gordon D, Inturrisi CE, Greensmith JE, Brennan TJ, Goble L, Kerns RD: Perioperative pain management in the opioid-tolerant individual. J Pain 2008; 9:383–7
Mitra S, Sinatra RS: Perioperative management of acute pain in the opioid-dependent patient. Anesthesiology 2004; 101:212–27
Rozen D, DeGaetano NP: Perioperative management of opioid-tolerant chronic pain patients. J Opioid Manag 2006; 2:353–63
Gu X, Wu X, Liu Y, Cui S, Ma Z: Tyrosine phosphorylation of the N-methyl-D-aspartate receptor 2B subunit in spinal cord contributes to remifentanil-induced postoperative hyperalgesia: The preventive effect of ketamine. Mol Pain 2009; 5:76
Nagakura Y, Jones TL, Malkmus SA, Sorkin L, Yaksh TL: The sensitization of a broad spectrum of sensory nerve fibers in a rat model of acute postoperative pain and its response to intrathecal pharmacotherapy. Pain 2008; 139:569–77
Nishimura W, Muratani T, Tatsumi S, Sakimura K, Mishina M, Minami T, Ito S: Characterization of N-methyl-D-aspartate receptor subunits responsible for postoperative pain. Eur J Pharmacol 2004; 503:71–5
Zahn PK, Pogatzki-Zahn EM, Brennan TJ: Spinal administration of MK-801 and NBQX demonstrates NMDA-independent dorsal horn sensitization in incisional pain. Pain 2005; 114:499–510
Bell RF, Dahl JB, Moore RA, Kalso E: Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev 2006: CD004603