American Journal of Therapeutics 22, e62–e74 (2015) Remifentanil—Acute Opioid Tolerance and Opioid-Induced Hyperalgesia: A Systematic Review Sang Hun Kim, MD, PhD,1,2* Nicoleta Stoicea, MD, PhD,2 Suren Soghomonyan, MD, PhD,2 and Sergio D. Bergese, MD2,3 The use of opioids may seem to be a double-edged sword; they provide straight analgesic and antihyperalgesic effects initially, but subsequently are associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) that have been reported in experimental studies and clinical observations. It has been suggested that opioids can induce an acute tolerance and hyperalgesia in dose- and/or time-dependent manners even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management in clinical anesthesia and in the intensive care units because of its rapid onset and offset. We reviewed articles analyzing AOT and/or OIH by remifentanil and focused on the following issues: (1) evidence of remifentanil inducing AOT and/or OIH and (2) importance of AOT and/or OIH in considering the reduction of remifentanil dosage or adopting preventive modulations. Twenty-four experimental and clinical studies were identified using electronic searches of MEDLINE (PubMed, Ovid, Springer, and Elsevier). However, the development of AOT and OIH by remifentanil administration remains controversial. There is no sufficient evidence to support or refute the existence of OIH in humans. Keywords: remifentanil, opioid-induced hyperalgesia, opioid tolerance, intraoperative, postoperative INTRODUCTION Studies on pharmacokinetic and pharmacodynamic of remifentanil showed that remifentanil increases analgesia and respiratory depression in a dose-dependent manner.1–5 However, after discontinuing administration of the drug, these effects disappear rapidly because of the extremely short elimination half-life 1 Department of Anesthesiology and Pain Medicine, School of Medicine, Chosun University, Gwangju, Korea; and Departments of 2Anesthesiology and 3Neurological Surgery, Ohio State University Medical Center, Columbus, OH. Supported by a research fund from Chosun University, 2012, and in collaboration with Division of Neuroanesthesia, Department of Anesthesiology, Ohio State University Wexner Medical Center. The authors have no conflicts of interest to declare. *Address for correspondence: Department of Anesthesiology and Pain Medicine, School of Medicine, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju 501-759, Korea. E-mail: ksh3223@Chosun.ac.kr (9.5 6 4 minutes). The context-sensitive half-time and terminal elimination half-life of remifentanil are shortest among other opioids after 3-hour infusion.4 Therefore, remifentanil can be given in high doses throughout surgery without the risk of delayed postoperative recovery or respiratory depression. Because of its rapid onset and offset, remifentanil has been used in clinical anesthesia as an induction and maintenance agent, and postoperative pain management in the intensive care units. Most of the studies conducted with remifentanil showed cardiovascular responses during perioperative manipulations. Perioperative use of remifentanil during laryngoscopy and tracheal intubation suggested that a bolus of remifentanil of 1 mg/kg was more effective than 0.5 mg/kg in reducing the pressor response to intubation. Also, a less decrease in systolic arterial pressure was noticed compared with the dose 1.25 mg/kg, resulting in a more rapid return to baseline values of heart rate and arterial pressure.6,7 However, while the cardiovascular responses reaches a peak 1–2 minutes after laryngoscopy and intubation, and usually subsides 1075–2765 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. www.americantherapeutics.com Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Remifentanil-Induced Tolerance and Hyperalgesia within 5–6 minutes,8 the context-sensitive half-time of bolus remifentanil is only 3.2 minutes.1,4 Therefore, remifentanil bolus alone is not enough to attenuate the responses and the use of a bolus-infusion regimen is required.6 The commonly accepted and recommended dose of remifentanil is 1 mg/kg followed by an infusion of 0.5–1 mg$kg21$min21 for induction of anesthesia or 0.05–2.0 mmg$kg21$min21 for maintenance of anesthesia.9–11 In postoperative period, remifentanil continuous infusion (CI) can be used for controlling the pain, and the final remifentanil infusion rates have been reported as 0.05–0.26 mg$kg21$min21 for satisfactory analgesia after surgery.11–15 Common concerns regarding the use of opioids are potential detrimental side effects, physical dependence, and addiction. However, recently, an additional concern has risen that these opioids can induce an acute tolerance and hyperalgesia in dose- and/or time-dependent manner even when used within clinically accepted doses. They provide straight analgesic and antihyperalgesic effects originally, but subsequently are associated with expression of hyperalgesia.16 Therefore, the use of opioids may seem to be a double-edged sword. In other words, patients receiving opioids to control their pain somewhat paradoxically may become more sensitive to pain as a direct result of opioid therapy. Therefore, a review of literature was carried out to analyze acute tolerance and/or postoperative hyperalgesia induced by remifentanil using electronic searches of MEDLINE (PubMed, Ovid, Springer, and Elsevier). The objective was to address the following issues: (1) what is the definition of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH)? (2) what mechanisms contribute to AOT and OIH? (3) Is it true that remifentanil may induce the acute tolerance and hyperalgesia? and (4) Are AOT and OIH significant enough to consider reducing the dose of remifentanil or adopting preventive modulations? DEFINITION OF AOT AND OIH The use of opioids can be associated not only with tolerance but also with hyperalgesia. Before we discuss AOT and OIH, we have to understand the definitions of AOT and OIH. OIH is defined as a state of nociceptive sensitization, which is characterized by a paradoxical response, whereby a patient receiving opioids for pain treatment might have an increased sensitivity to painful stimuli.16,17 Although controlled preclinical experiments have defined OIH in animals as a decrease in pain threshold from baseline after chronic administration of www.americantherapeutics.com e63 opioids,18 there is still no accepted operational definition of OIH among researchers in human clinical trials; hyperalgesia is defined as decrease in either pain threshold or pain tolerance after chronic opioid exposure.19 Pain threshold is the lowest intensity of stimulation at which pain is experienced, and pain tolerance is the amount of pain from a given stimulus a person can handle before seeking relief. OIH often is confused with opioid tolerance and allodynia because of the manifestations of similar symptoms. Allodynia is the pain due to a stimulus that normally does not provoke pain (eg, neuropathy, fibromyalgia) and can be treated with opioids, nonopioid analgesics, or surgical intervention. AOT is defined as an increase in the dose required maintaining adequate analgesia in patients receiving opioid medication for the treatment of pain in clinical settings.16,17 AOT, unlike OIH, can be overcome by increasing the dosage. Increasing the dosage only worsens the pain, and consequently, pain is reduced by reducing or eliminating the opioid. Clinical data indicate that early postoperative pain scores and subsequent greater demand of opioids could be attributed to tolerance, whereas the greater requirement for opioids at a later recovery stage could be associated with OIH after high-dose remifentanil anesthesia. Furthermore, some authors used the term tolerance in their articles on OIH when referring to increase opioid consumption and shorten time to the first postoperative analgesic requirement.20 CELLULAR MECHANISMS OF AOT AND OIH The underlying mechanism of AOT and OIH is still unclear. The AOT is likely to involve multiple mechanisms, such as decoupling from transduction systems, antianalgesia systems, and alterations of the N-methylD-aspartate (NMDA) receptor and its intracellular second messenger systems.21 OIH also may be explained by multiple mechanisms, including activation of central NMDA nociceptive systems,22,23 extensive internalization and thereby inactivation of m-opioid receptors,24 upregulation of the cyclic adenosine monophosphate pathway,25 and spinal dynorphin release.26,27 Thus, OIH may reflect similar mechanisms. Among the potential mechanisms leading to AOT and OIH, NMDA pain-facilitator processes seem to play a key role.22,23,28,29 Experimental studies performed in animals and humans have shown that NMDA receptor antagonists, such as ketamine, inhibit central sensitization and prevent OIH.29–32 Multiple studies demonstrated that OIH was blocked by pretreatment with NMDA receptor antagonists,28,29,33,34 American Journal of Therapeutics (2015) 22(3) Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. e64 which may be useful adjuncts to morphine to control postoperative pain after opioid-based anesthesia. Zhao and Joo35 also presented that clinically relevant concentrations of remifentanil induce rapid persistent increases in NMDA responses, which reflect the development of remifentanil-induced hyperalgesia and tolerance. However, there were controversial results in human study. Some authors suggested that the remifentanil-induced hyperalgesia was prevented by small-dose ketamine.31,32,36,37 Other authors suggested that NMDA antagonists did not prevent the remifentanil-induced hyperalgesia.38 Koppert et al37 documented that ketamine did not reduce the elevated pain ratings after infusion, although it abolished the remifentanil-induced hyperalgesia. And then, they suggested that there might be different mechanisms of antianalgesia and secondary hyperalgesia. Luginbuhl et al38 suggested that AOT and remifentanil-induced hyperalgesia were not affected by ketamine and depended on the type of nociceptive stimulus; it might be explained by an alternative mechanism, such as internalization of m-opioid receptors in spinal interneurons that are induced by remifentanil, but not by morphine or endogenously released opioids.24 Extensive internalization and thereby inactivation of m-opioid receptors by remifentanil would leave fewer functional receptors in the postinfusion period. This might explain transient inhibition of analgesic effects of endogenous opioids, correlated with remifentanil’s very short half-life. It would also exhibit the absence of postinfusion antianalgesia when opioids with longer half-life are tested in the same experimental mode.39 CONTROVERSIAL RESULTS ON DEVELOPMENT OF AOT AND OIH BY REMIFENTANIL Recently, many studies have focused on the development of acute tolerance and hyperalgesia after using opioids based on idea that OIH might be a potential risk factor for the development of chronic pain after surgery (Table 1).48–50 However, there is no information regarding dose-dependent induction of tolerance and hyperalgesia after infusing remifentanil and other opioids. Most authors have suggested that the higher dose of opioids induce the higher tolerance and/or hyperalgesia. OIH was observed either to follow analgesia and lasted long after opioid exposure ended29,30,51 or during continuous opioid exposure.27,33 It has been reported that high intraoperative doses of opioids not only increase postoperative pain scores and acute morphine consumption but also American Journal of Therapeutics (2015) 22(3) Kim et al induce significant nociceptive threshold changes, defined as AOT and hyperalgesia.21,31,36,52–55 The circumstances under which OIH may occur are also not yet entirely understood but may include high doses, long-term treatment, or abrupt changes in concentrations.56 Celerier et al29 showed that fentanyl injection was associated with sustained lowering of the nociceptive threshold below baseline value, and the higher the fentanyl dose used, the more pronounced was the fentanyl-induced hyperalgesia. Laulin et al33 reported that repeated once-daily heroin injections induced a gradual lowering of the nociceptive threshold, which progressively masked a sustained heroin analgesic functional effect, which is suggested as opiate tolerance. If all types of opioids have been shown to induce such a dose-dependent hypersensitivity, exposure to short-acting opioids, such as remifentanil, seems more likely to be responsible for postoperative high pain scores, high morphine consumption, and hypersensitivity to pain.21,31,57,58 A relatively large-dose of intraoperative remifentanil has been shown to induce postoperative hyperalgesia more rapidly and more frequently as compared with longer-acting opioids.36,59,60 These results are in agreement with the clinical observation of increased postoperative pain and morphine requirement.21,32,61 As a sole agent, remifentanil, as many articles suggest, could induce AOT and/or OIH. In the view of AOT, studies performed in animals and human volunteers showed that an acute analgesic opioid tolerance developed a couple of hours after the initiation of remifentanil administration through CI.34,62–64 Aguado et al34 mentioned that the acute tolerance was induced by remifentanil infusion alone in the dose-dependent manner, and its effect was observed approximately 1.5 hours later in the rat model. Remifentanil of 0.3 mg$kg21$min21 induced AOT within the first few hours in a rabbit model.62 A study performed by Vinik and Kissin,63 which was neither placebo controlled nor blinded, replicated these findings in healthy human volunteers. They suggested that acute tolerance was profound and developed very rapidly, and remifentanil of 0.1 mg$kg21$min21 resulted in the maximum analgesic effect in 60–90 minutes, and then began to decline despite the constant-rate infusion, eventually reaching 1/4 of the peak value after 3 hours of infusion, measuring by cold thermal and mechanical noxious stimulation. Gomez de Segura et al64 suggested that intraoperative remifentanil infusion induced a rapid acute tolerance revealed by diminished remifentanil efficacy in reducing the sevoflurane minimum alveolar concentration within 90 minutes or less, and increased opioid doses required to maintain intraoperative analgesia during sevoflurane anesthesia. www.americantherapeutics.com Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Remifentanil-Induced Tolerance and Hyperalgesia e65 Table 1. Clinical research using remifentanil on acute opioid tolerance and opioid-induced hyperalgesia. In high-dose remifentanil group Study No. Protocol of remifentanil patient infusion Crawford et al40 30 Guignard et al21 Joly et al36 50 Schmidt et al41 Song et al42 42 Angst et al43 36 Cortinez et al44 Hansen et al45 Lahtinen et al46 Yeom et al47 60 50 56 39 90 60 0.28 mg$kg21$min21 vs. intermittent morphine injection 0.3 vs. 0.1 mg$kg21$min21 0.4 vs. 0.05 mg$kg21$min21 0.4 vs. 0.1 mg$kg21$min21 0.2 vs. 0.05 mg$kg21$min21 0.0 and 2.4 ng/mL, vs. 0.8 and 3.2 ng/mL, or vs. 1.6 and 4.0 ng/mL 0.23 vs. 0.1 mg$kg21$min21 0.40 mg$kg21$min21 vs. saline 0.3 mg$kg21$min21 vs. saline 0.16 vs. 0.03 mg$kg21$min21 Postoperative pain score AOT OIH Yes No examination 30% greater NS Yes Yes 85% greater 50% higher No examination No examination No examination No Yes Greater NS Yes No examination NS Yes NS NS No examination No examination No examination No examination No NS NS NS NS No examination No NS NS NS NS No No No No A small number of clinical studies have looked at OIH in the setting of acute perioperative opioid exposure. A series of studies in patients undergoing surgery suggested that exposure to a high rather than to a low intraoperative opioid dose was associated with opioid consumption and/or increased pain in the postoperative period.21,36,52,65 A feasible explanation for these findings is either the development of acute tolerance on the rescue opioids for controlling the postoperative pain or a possible OIH in patients exposed to a high intraoperative opioid dose.16 Guignard et al21 suggested that AOT as well as OIH might be induced by the acute exposure to large doses of opioids. They assigned the patients to 2 anesthetic regimens: desflurane was kept constant at 0.5 minimum alveolar concentrations and a remifentanil infusion was titrated to autonomic responses (remifentanil group); or remifentanil kept constant at 0.1 mg$kg21$min21 and desflurane titrated to autonomic responses (desflurane group). The patients received 0.3 6 0.2 mg$kg21$min21 of the intraoperative remifentanil, in remifentanil group, required morphine significantly earlier and needed nearly twice more morphine in the first 24 www.americantherapeutics.com Postoperative opioid consumption postoperative hours than those in the desflurane group. Furthermore, higher pain scores were observed in the remifentanil group despite higher morphine requirement. Joly et al36 showed that remifentanil of 0.4 mg$kg21$min21 triggered the larger hyperalgesia as well as the larger morphine consumption for 48 postoperative hours, compared with remifentanil of 0.05 mg$kg21$min21 in patients undergoing major abdominal surgery, in their randomized double-blind study. In prospective, randomized, double-blind study, they suggested that remifentanil of mean 0.28 mg$kg21$min21 was associated with the development of clinically relevant AOT, in patients who underwent the general anesthesia using propofol infusion.40 However, they could not demonstrate the significant increase of postoperative pain scores, although cumulative morphine consumption was more in remifentanil group than that in morphine group. Studies on OIH in human volunteers have been performed to determine the effect of a short-term opioid infusion on an experimental skin lesion rendered hyperalgesia before starting the drug infusion,31,37,38,57,58,66 and the effects of opioid antagonist precipitated withdrawal on cold American Journal of Therapeutics (2015) 22(3) Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. e66 pressor pain in volunteers after acute physical opioid dependence.67,68 Several investigators observed significant enlargement of the area of mechanical hyperalgesia induced by transdermal electrical stimulation after 30–90 minutes of exposure to remifentanil, and it was related directly to the infusion duration and the opioid dose.31,37,57,58,66 This aggravation was observed up to 4 hours after stopping the remifentanil infusion, but was no longer evident when assessed on the subsequent day.58 They also observed the increased pain score as well as the decreased pain threshold by dosedependent manner after the discontinuation of opioids.31,57,58 Contrasting with results obtained in experimental hyperalgesic skin, heat pain sensitivity in normal skin was not different before and after remifentanil exposure.31,58 Pain sensitivity to cold pressor pain also was accessed in a model of acute physical opioid dependence, when withdrawal was precipitated with the opioid antagonist naloxone after a single injection of morphine or hydromorphone.67,68 They showed that sensitivity to cold pressor pain was significantly increased after injection of naloxone. It means that OIH may be triggered if opioid effect is suddenly disappeared or reversed. Finally, hyperalgesia can be induced by pressure-evoked pain after a short-term infusion of remifentanil in volunteers.38 However, these investigators exposed volunteers to significantly higher nociceptive input during remifentanil than during saline placebo administration. It cannot be excluded that postinfusion hyperalgesia resulted from more intense noxious stimulation during the remifentanil infusion rather than the opioid administration itself. Taken together, these findings provide that the OIH can develop differently for different types of pain.16 However, although many studies have indicated that both acute tolerance and hyperalgesia could be induced by using opioids, some studies have shown controversial results on acute tolerance and/or hyperalgesia in humans.43–47,69,70 Gustorff et al,69 in randomized, placebo-controlled, double-blinded, crossover study, suggested that there was no evidence of development of acute tolerance in volunteers assessed by thermal (heat and cold) and electrical current quantitative sensory testing (QST) during the infusion of remifentanil of 0.08 mg$kg21$min21 for 3 hours. Angst et al43 also documented that 3-hour infusion of remifentanil of up to 4.0 ng/mL was not associated with the development of significant tolerance to analgesic in placebo-controlled double-blind study. Patient-controlled analgesia using remifentanil targetcontrolled infusion (TCI) did not show any evidence of rapid development of acute tolerance.70 Cortinez et al44 suggested that remifentanil-based anesthesia American Journal of Therapeutics (2015) 22(3) Kim et al (0.23 6 0.10 mg$kg21$min21; average duration, 116 minutes) did not induce the AOT when compared with sevoflurane-based anesthesia in patients undergoing elective gynecologic surgery. Hansen et al45 investigated how remifentanil of 0.4 mg$kg21$min21 intraoperatively affected postoperative pain and opioid consumption after major abdominal surgery. In a double-blind study, they indicated that no significant differences could be observed between the groups after 2 hours postoperatively. Although the authors of the study did find a significant increase in visual analog scale score in the remifentanil group compared with placebo during the immediate postoperative period that is, suggestive of OIH, this difference was no longer significant 2 hours after surgery or during the remainder of the 24-hour observation period. A prospective, randomized, double-blind study showed that 3-hour infusion of remifentanil of 0.3 mg$kg21$min21 did not increase postoperative pain or opioid consumption in cardiac surgery patients who underwent sufentanil/propofol-based general anesthesia.46 Yeom et al47 suggested that remifentanil did not seem to cause AOT and hyperalgesia in patients undergoing spinal fusion, although the infusion rate of remifentanil was higher in propofol-based anesthesia (averaging 0.16 mg$kg21$min21) than that in sevoflurane-based anesthesia (averaging 0.03 mg$kg21$min21) for a short period of time (averaging 225 and 216 minutes, respectively). SUGGESTED DOSES OF REMIFENTANIL INDUCING AOT AND OIH In general, most of the articles documented that AOT and OIH were induced when remifentanil was infused at $0.1 mg$kg21$min21 and after stopping infusion of opioids.21,31,36,43,55,57,63,69,71 Cabanero et al55 suggested that remifentanil induced dose-dependent pronociceptive effects, and calculated ED50s of 1.7 (95% confidence interval, 1.3–2.1) and 1.26 (1.0–1.6) mg$kg21$min21 for thermal and mechanical hyperalgesia, respectively, in a mouse model. During infusion of remifentanil, acute tolerance was documented that it was profound and developed very rapidly when remifentanil was infused continuously at 0.1 mg$kg21$min21.63,71 Whereas in a placebo-controlled and double-blind study, they suggested that infusion of remifentanil at a rate of 0.08 mg$kg21$min21 could not induce tolerance to analgesic opioid effects in the cold pressor test and in models of electrical and heat pain.69 After stopping infusion of remifentanil, www.americantherapeutics.com Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Remifentanil-Induced Tolerance and Hyperalgesia Angst et al31 documented that the mechanical hyperalgesia was enlarged within 30 minutes of stopping a 90-minute infusion with remifentanil of 0.1 mg$kg21$min21. Koppert et al57 also suggested that mechanical hyperalgesia was more profound after discontinuation of remifentanil when administered at a rate of 0.10 mg$kg21$min21 but not at a rate of 0.05 mg$kg21$min21. When compared with different doses of remifentanil, the patients receiving the intraoperative remifentanil of 0.3 6 0.2 mg$kg21$min21 required morphine significantly earlier, and needed nearly twice more morphine in the first 24 postoperative hours than remifentanil kept constant at 0.1 mg$kg21$min21. Higher pain scores were observed in the remifentanil group despite higher morphine requirement.21 Joly et al36 suggested that large dose of remifentanil (0.4 mg$kg21$min21) triggered a larger hyperalgesia as well as a larger morphine consumption compared with small doses of remifentanil (0.05 mg$kg21$min21) for 48 postoperative hours. Therefore, acute tolerance of rescue opioids as well as OIH might be induced by the acute exposure to large doses of opioids. In several reports, the authors infused remifentanil as well as other opioids using CI mode. However, recently TCI mode has been recommended for achieving more precise effectiveness because TCI mode has been shown not only to improve intraoperative hemodynamic stability but also to decrease intraoperative remifentanil requirements.72,73 In studies on AOT and hyperalgesia, although most authors have used the CI mode, there are a few reports using the TCI mode.43,58,74,75 Hood et al58 showed that areas of hyperalgesia continuously enlarged 4 hours after remifentanil (targeted concentration of 3.1 6 1.2 ng/mL) was stopped, to 180% 6 47%. Shin et al74 suggested that remifentanil using TCI at 4 ng/mL induced the more increased cumulative morphine consumption and postoperative hyperalgesia than that at 1 ng/mL during sevoflurane anesthesia. This result is similar with that of previous studies using CI mode, higher dose of opioid, and higher development of AOT and OIH. Angst et al43 also suggested that target remifentanil concentrations corresponding to infusion rates of 0.65 and 1.3 mg$kg21$min21 did not induce tolerance in any of their pain models. There are reports assuming which rate is closely fit with TCI rate. A bolus of remifentanil 1 mg/kg followed by infusion 0.2 mg$kg21$min21 will produce stable plasma concentrations of 4–5 ng/mL within a few minutes.72 The infusion rate for remifentanil 0.1 mg$kg21$min21 can achieve a stable plasma concentration ranging between 2.7 and 2.9 ng/mL during the infusion.31 Remifentanil concentrations of 1.6 and 3.2 ng/mL correspond to steady-state concentrations achieved when infusing remifentanil at a constant www.americantherapeutics.com e67 rate of about 0.065 and 0.13 mg$kg21$min21.71 Such rates are commonly used in a clinical setting to provide analgesia during surgery. Therefore, according to these references, $0.1 mg$kg21$min21 using CI mode and $2.7 ng/mL using TCI mode seem to be sufficient to develop hyperalgesia. FACTORS THAT LEAD TO DISCREPANCIES REGARDING AOT AND OIH The clinical relevance of above-mentioned results is questionable, and there are some limitations in negative results concerning AOT and OIH (Table 2). These discrepancies can be explained by multiple methodological issues, including the administrated dose and duration of opioids administration, the different infusion mode, the coadministrated anesthetic drug’s effect, method assessing pain sensitivity, and the repetitive and potentially tissue damaging nature of the stimuli used to determine the threshold during opioid infusion.16,18,46,78 First, we can explain these discrepant results by differences in exposed opioid doses and administration duration. Studies reporting positive results have shown that acute tolerance to opioid-mediated analgesia develops in dose-dependent fashion and only becomes evident when total opioid exposure is quite high, which was supported by many animal and clinical research. The nonsignificant increase of postoperative pain and opioid consumption in studies reporting negative results may be noticed because of lower total intraoperative opioid exposure when compared with the positive results,21,44,79 suggesting a dose-dependent effect of opioids on the development of OIH. Acute tolerance is typically investigated during CI over 2–3 hours, whereas hyperalgesia is usually assessed within 1 hour postinfusion.21,23,32,34,62,64,80–82 Cabanero et al55 agreed that remifentanil induced dose-dependent pronociceptive effects for thermal and mechanical hyperalgesia, which lasted longer with higher doses, but they suggested that the duration of infusion did not alter the pronociceptive effects of remifentanil. This negative result might be explained by the shorter exposed duration, just over 30 or 60 minutes, than the positive results. In the recent animal study, they showed that intravenous remifentanil infusion alone induced transient hyperalgesia associated with the duration of exposure to remifentanil.82 Although 30-minute remifentanil infusion did not induce hyperalgesia, 120-minute remifentanil infusion induced the hyperalgesia regardless of dose. However, hyperalgesia was not sustained more than 60 minutes. Other study also documented that American Journal of Therapeutics (2015) 22(3) Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. e68 Kim et al Table 2. Factors that lead to discrepancies regarding AOT and OIH by remifentanil. Study Crawford et al40 Guignard et al21 Joly et al36 Schmidt et al41 Shin et al74 Song et al42 Vinik and Kissin63 Yalcin et al76 Angst et al43 Cortinez et al44 Echevarria et al77 Gustorff et al69 Hansen et al45 Lahtinen et al46 Schraag et al70 Yeom et al47 Exposed time (min) Observed time QST Anesthetics N2O Infusion mode 460 24 h X Propofol [173 or 91 (R) mg$kg21$min21] No CI 260 24 h X Desflurane [0.7 or 0.5 (R) MAC] No CI 270 70 245 110 240 48 h 90 min 24 h 48 h — O O X O X Desflurane [0.8 (SD) or 0.5 (LD) MAC] Isoflurane [0.62 (SD) or 0.52 (LD) MAC] Sevoflurane or propofol Sevoflurane (1.6 vol%) — No No No No — CI CI TCI CI CI 71 180 100 182 48 h — 24 h 18 h O X X X Desflurane, 0.5 MAC No Sevoflurane [1.75% (SD) or 0.5% (LD)] Propofol No No Yes (50%) Yes (70%) CI TCI CI CI 180 223 180 — 24 h 48 h O X X — Sevoflurane [1.0 or 0.8 (R) MAC] Propofol — — — CI CI CI 360 240 — 48 h X X Propofol Propofol (2–4 mg$kg21$h21) or sevoflurane — Yes (50%) TCI CI LD, large-dose group; MAC, minimal alveolar concentration; R, remifentanil group; SD, small-dose group. remifentanil-induced hyperalgesia started from 2 hours after surgery and reached its peak at 24–48 hours after surgery.83 Also, it is not sufficient to explain the cause of these discrepancies by using the dose and duration of remifentanil infusion. Although some authors used remifentanil infusion rate that was enough to develop hyperalgesia, they have reported the negative results on development of hyperalgesia after CI. It can be partially explained by the effect of coadministrated anesthetic drugs, such as propofol, sevoflurane, and nitrous oxide, which might affect the development of AOT and/or OIH. In a clinical case report, Fodale et al84 suggested that the development of AOT due to remifentanil was not encountered when it was coadministered with propofol or sevoflurane, which produced an inhibiting effect at NMDA receptors neutralizing the remifentanil stimulation on these receptors. However, sevoflurane has only a minimal inhibitory effect on NMDA receptors,85 which are considered to be involved in the development of opioid-related hypersensitivity.86 Relatively low sevoflurane concentrations (1.0%) reverse OIH, but there was the lack of effect of sevoflurane concentrations of 1.0% and 1.5% to oppose American Journal of Therapeutics (2015) 22(3) hyperalgesia after high-dose opioids.85,87 Shin et al74 also suggested that remifentanil-induced hyperalgesia was not apparent during propofol anesthesia compared with the effect produced during sevoflurane anesthesia, although dosage was increased from 1.0 to 4.0 ng/mL. This results can be supported by several observations; propofol inhibits the NMDA subtype of the glutamate receptor,88,89 which is one of the potential mechanisms that induced the OIH. Recent evidence suggests that propofol may have some modulatory effect on OIH, possibly through interactions with gamma-aminobutyric acid (GABA-A) receptors at the supraspinal level.90,91 Specifically, propofol was shown to have analgesic effects at subhypnotic doses, and it delayed the onset of antianalgesia after remifentanil infusion in a small clinical study of healthy human volunteers.90 However, it actually aggravated postremifentanil infusion secondary hyperalgesia in the intradermal electrical stimulation pain model, suggesting a facilitation of pronociceptive pathways, possibly through modulation of descending inhibition by receptor binding to the GABA-A ionophore.91 The clinical significance of these findings, especially in higher dosages used in the intraoperative setting, remains to be www.americantherapeutics.com Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Remifentanil-Induced Tolerance and Hyperalgesia studied. In addition, some authors ignored the impact that nitrous oxide might have against the AOT and hyperalgesia.44,47 Echevarria et al77 reported that the group using the 70% nitrous oxide with remifentanil of 0.3 mg$kg21$min21 showed a greater decreased mechanical threshold than the group without nitrous oxide at postoperative 12–18 hours, although the postoperative pain scores and cumulative morphine consumption was similar between the groups. Lee et al79 suggested that 70% nitrous oxide showed comparable effect on the postoperative opioid consumption similar to remifentanil at mean 0.17 mg$kg21$min21. Next, different infusion mode also can influence the development of acute tolerance and hyperalgesia, although they have an equipotential effect on the pain control. TCI has been shown not only to improve intraoperative hemodynamic stability but also to decrease intraoperative remifentanil requirements.72,73 Interestingly, Richebe et al75 evaluated whether the use of TCI mode also would lead to decrease in early postoperative period hyperalgesia after cardiac surgery. They suggested that an infusion of intraoperative remifentanil using TCI mode (target: 7 ng/mL) reduced postoperative hyperalgesia, compared with that using CI mode (0.3 mg$kg21$min21), and this decrease in postoperative hyperalgesia was sustained and lasted throughout the first postoperative week. The conclusion of the study was supported by the difference of intraoperative infused total remifentanil dose, which was greater in CI than in TCI group, despite the initial expectation that TCI of remifentanil at 7 ng/mL was equivalent to a CI rate at 0.3 mg$kg21$min21.72,92 Then, when nociceptive thresholds are repeatedly measured in a situation in which protective withdrawal reflexes are impaired or abolished by opioid administration, the possibility of cumulative tissue injury manifesting as AOT or OIH should be carefully excluded.93 This is especially likely to occur with repetitive testing protocols. In the study by Luginbuhl et al,38 they exposed volunteers to significantly higher nociceptive input during remifentanil versus during saline placebo administration. It cannot be excluded that postinfusion hyperalgesia resulted from more intense noxious stimulation during the remifentanil infusion rather than the opioid administration itself. However, Ishii et al80 documented that neither acute tolerance nor hyperalgesia was observed even in the setting when they used a tapered remifentanil infusion to rapidly attain maximum analgesic effect of remifentanil and tried to minimize the repetitive and potentially tissue damaging nature of the stimuli. Finally, it remains unclear whether OIH contributed to increased postoperative opioid requirements and/or pain in studies exposing patients to high intraoperative www.americantherapeutics.com e69 opioid doses because pain sensitivity was not formally assessed before and after surgery. As noted previously in this review, the need for dose escalation to maintain analgesia can be owing to the development of analgesic tolerance, OIH, or simultaneous expression of both phenomena. No causal relationship between acute perioperative opioid exposure and development of OIH can be established without direct measurement of pain sensitivity. If patients have a comorbidity affecting sensory thresholds preoperatively, this condition could distort postoperative measures on OIH. The German Network on Neuropathic Pain established a standardized QST protocol to investigate the somatosensory thresholds in healthy subjects and in patients with neuropathic pain.94 Reference values from healthy subjects could be used to establish normal sensory functioning in patients before anesthesia. In a clinical setting, this direct measure could be used for distinguishing between OIH and AOT, because of clinical importance, as AOT can be overcome by dose increase, while OIH may be aggravated by the same intervention. Without direct measures to assess hyperalgesia, such as QST, the results are not easy to distinguish from acute tolerance.63 Clinical studies examining remifentanil-induced hyperalgesia by QST showed that at a relatively high-dose remifentanil decreased the pain threshold.36,41,42,69,76 These studies used remifentanil infusions at clinically standard rates, and all of them showed clear hyperalgesia either shortly after discontinuing infusion or 1 and 2 days postoperatively. However, most studies confirmed the reality of this phenomenon using indirect evidence, such as greater postoperative pain and morphine consumptions instead of using QST.21,95 Therefore, we think that a further study is needed to reveal the development of AOT and OIH using QST. IMPORTANCE OF AOT AND/OR OIH IN CONSIDERING THE REDUCTION OF REMIFENTANIL DOSAGE AND ADOPTING PREVENTIVE MODULATIONS Of note, 41% of all surgical patients still experience moderate-to-severe acute postoperative pain and that 24% experience inadequate pain relief.96 According to previously mentioned reports, when opioid is used alone with high infusion rate, the OIH may be seen during 1–5 hours after stopping infusion and can last anywhere from 2 to 10 days.21,29,53,97,98 In a recent cohort study on postoperative remifentanil-induced hyperalgesia, its incidence was reported 16.1% of American Journal of Therapeutics (2015) 22(3) Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. e70 patients undergoing general anesthesia with remifentanil and whose length of operative incision was less than 4 cm.99 They also suggested that the relevant influencing factors were age less than 16 years, operative duration of above 2 hours, and more than 30 mg/kg of remifentanil. Increased pain sensitivity has been increasingly recognized as a paradoxical and undesirable effect of opioid, OIH, to combat surgical pain, and nociception.37 The presence of hyperalgesia in the acute postoperative period is likely to increase the amount of pain experienced. This, in turn, potentially increases the effects that carry the risk of more complications, impaired mobilization, prolonged hospital stay, and many other undesirable outcomes after surgery. More pain frequently results in more analgesia use, leading to an increase in analgesia-associated side effects, well documented for opioids and respiratory, gastrointestinal, and urologic function. Hyperalgesia itself may make opioid analgesic titration more difficult. Eventually, hyperalgesia and increased pain in the postoperative period is now considered a major candidate mechanism for the development of chronic pain.48–50 It has recently been highlighted that chronic pain as a direct result of surgery is more common than previously recognized.48 Therefore, less postoperative hyperalgesia results in better acute postoperative pain control,36 and interventions associated with alterations of postoperative hyperalgesia are also associated with changes in acute postoperative pain outcomes.21,95 However, there is a lack of good-quality clinical research in this area, despite the fairly extensive basic science evidence. In a structured evidence-based review for all levels of evidence on OIH in humans,18 10 hypotheses have been used to test for the possibility of OIH. Among them, 3 hypotheses are of interest: (1) opioid infusion in normal volunteers or chronic pain patients will decrease pain threshold and/or tolerance; (2) opioid infusion in normal volunteers will increase secondary hyperalgesia as measured by allodynia or hyperalgesia; and (3) perioperative opioids will increase postoperative pain and/or opioid requirements. They suggested that there was no sufficient evidence to support or refute the existence of OIH in humans except in the case of normal volunteers receiving opioid infusions. There was consistent evidence that opioid infusion in normal volunteers induced either an increase in secondary hyperalgesia or allodynia, and there was inconsistent evidence on pain threshold and tolerance in normal volunteers or chronic pain patients although the threshold decreased with opioid infusion. They also documented that using opioid in perioperative period increased the postoperative pain or opioid requirements with inconsistent evidence. American Journal of Therapeutics (2015) 22(3) Kim et al There are some questions regarding the importance of the drug use to prevent AOT and OIH in postoperative patients and whether the assessment of OIH at immediate postoperative period is suitable. Clinical studies assessing the preventive effect of drugs on OIH in the immediate postoperative period showed that the clinical benefit is either absent,77 limited to a moderate opioid-sparing effect,36,74 or a slight reduction in pain scores.42,74 According to these results, Martinez and Fletcher19 suggested that the immediate postoperative period may not be the optimal period to detect the preventive effects on OIH, although additional clinical data need to confirm it. Furthermore, Simonnet and Rivat56 suggested that OIH should be considered as a normal adaptive response counteracting the perturbations caused by administration of analgesic opioids. However, it is tempting to speculate that the long-lasting hyperalgesia induced by endogenous or exogenous opioids may still facilitate learning processes and memorization of drives so that environmental changes which might lead to pain may be better avoided. From a medical viewpoint, OIH after a first opioid administration is not a passive response but it might be considered as the first step of an active process leading to pain sensitization. This suggests that opioids have reinforced a nociceptive memory, which could contribute to pain chronicization. CONCLUSIONS Current experimental and clinical data generally support the development of AOT and OIH in specific settings, such as acute remifentanil exposure in human volunteer and postsurgical pain cohorts, when remifentanil was infused at $0.1 mg$kg21$min21 either alone or with inhalation anesthetics. Therefore, in these situations, clinicians need to be cautious for the possibility of the development of AOT and OIH, which may impair treatment of pain or even aggravate preexisting pain. Clinicians should suspect manifestation of OIH when opioid treatment effect seems to decline in the absence of disease progression, with unexplained pain reports or allodynia unassociated with the site of injury. According to the previous reported results, coadministrated anesthetic drugs, such as propofol and nitrous oxide, and using of TCI model seem to be helpful to modulate the development of the AOT and OIH. However, there are no sufficient data to support evidence of modulatory effect of them. Finally, we also cannot find any strong consistent evidence to support the need to reduce the dose of remifentanil or apply the modalities for preventing the www.americantherapeutics.com Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Remifentanil-Induced Tolerance and Hyperalgesia AOT and the OIH. Consequently, further studies will need to investigate whether remifentanil induce the AOT and the OIH after general anesthesia using propofol, nitrous oxide, or TCI mode through high-quality prospective trials. And the development of the AOT and the OIH should be evaluated with direct measures, such as QST. It is also important to investigate if remifentanil-induced hyperalgesia may contribute to the development of chronic pain, and if this contribution can be attenuated or even reversed through pharmacologic modulation. REFERENCES 1. Glass PS, Hardman D, Kamiyama Y, et al. 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