Journal of Pain & Palliative Care Pharmacotherapy. 2011;25:219230. Copyright 2011 Informa Healthcare USA, Inc.

. ISSN: 1536-0288 print / 1536-0539 online DOI: 10.3109/15360288.2011.589490

ARTICLE

Pharmacological Treatment of Opioid-Induced Hyperalgesia: A Review of the Evidence

Chitra Ramasubbu and Anita Gupta
A B STRA CT
Opioids are commonly used to treat moderate to severe pain. Opioid-induced hyperalgesia is a paradoxical response to opioid agonists resulting in an increased perception of pain rather than an antinociceptive effect. Even though there is a debate regarding its clinical relevance, it is becoming a challenge in both acute and chronic pain settings. The study of opioid-induced hyperalgesia is an emerging field with multiple challenges faced by investigators with regard to defining the diagnosis and characterizing the findings. The objective of this study was to review the preliminary evidence related to the treatment and management of opioid-induced hyperalgesia. Lack of data, small patient numbers, short-term follow-up, and variations in study design limited the review. With the literature on this subject being sparse, this study attempts to provide a preliminary look at the available data and to set the stage for an eventual meta-analysis. Case reports in the literature have shown success with various pharmacological interventions. Possible treatment regimens include ketamine, dextromethorphan, and nonsteroidal anti-inflammatory drugs (NSAIDs), opioid switching, amantadine, buprenorphine, 2 agonists, and methadone. These agents are briefly discussed in this paper. Further well-designed, placebo-controlled trials are needed to assess the effectiveness of the interventions investigated in this review. KEYWORDS Dextromethorphan, hyperalgesia, ketamine, nonsteroidal anti-inflammatory agents, opioid

BACKGROUND
Opioids have been recognized as the analgesic of choice in patients suffering from moderate to severe pain. In a clinical situation, it is common to escalate the dose of opioids to maintain adequate analgesia. Once disease progression and psychological processes are ruled out as the causes of pain, other causes of increased opioid requirement, which include opioidinduced hyperalgesia (OIH), opioid tolerance, physical dependence, addiction, and abuse (1), should be considered. Opioid-induced hyperalgesia (OIH) is a paradoxical response to opioid agonists resulting in an inChitra Ramasubbu, MD, is a Research Assistant and Anesthesiology Resident, Department of Anesthesiology and Critical Care, and Anita Gupta, DO, PharmD, is an Assistant Professor of Anesthesiology and Critical Care, Penn Pain Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Address correspondence to: Chitra Ramasubbu, MD, Department of Anesthesiology and Critical Care Medicine, University of Pennsylvania, 6 Dulles, 3400 Spruce Street, Philadelphia PA 19104, USA (E-mail: Chitra.ramasubbu@uphs.upenn.edu).

creased perception of pain rather than an antinociceptive effect (2). Even though there is a debate regarding its clinical relevance, it is becoming a challenge in both acute and chronic pain settings. OIH is broadly defined as a state of nociceptive sensitization caused by exposure to opioids (3). Clinical features of opioid-induced hyperalgesia include increasing sensitivity to pain stimuli (hyperalgesia), worsening pain despite increasing doses of opioids, pain that becomes more diffuse, and pain that extends beyond the distribution of preexisting pain. Opioidinduced hyperalgesia can occur at any dose of opioid, but is seen more commonly with high parenteral doses of opioids (4). Opioid tolerance is a phenomenon in which repeated exposure to an opioid results in a decreased therapeutic effect of the drug or need for a higher dose to maintain the same effect (4). The similar net effect makes the two phenomena difficult to distinguish in a clinical setting. Under chronic opioid treatment, a particular individuals requirement for dose escalation may be due to tolerance (desensitization of
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antinociceptive mechanisms), opioid-induced hyperalgesia (sensitization of pronociceptive mechanisms), or a combination of both. Identifying the development of hyperalgesia is of clinical importance, since patients receiving opioids to relieve pain may paradoxically experience more pain as a result of treatment. Development of opioid-induced hyperalgesia is mediated by neural mechanisms similar to those that generate neuropathic pain. These neural mechanisms involve N-methyl-D-aspartate (NMDA) receptor activation resulting in a central hyperactive state (5). Excitatory amino acids (EAAs) such as glutamate are mediators of this central sensitization resulting in a persistent hyperactive state. This causes an overall permanent imbalance between the excitatory and inhibitory neurons resulting in aberrant nerve activity (5). Mechanisms implicated in the development of opioid-induced hyperalgesia are sensitization of peripheral nerve endings, enhanced descending facilitation of nociceptive signal transmission, enhanced production of nociceptive neurotransmitters, and sensitization of second-order neurons to nociceptive neurotransmitters (6). The study of opioid-induced hyperalgesia is an emerging field with multiple challenges faced by investigators with regard to defining the diagnosis and characterizing the findings. With the literature on this subject being sparse, our study attempts to provide a preliminary look at the available data and to set the stage for an eventual meta-analysis. In this review we analyze various pharmacological treatment strategies and determine the evidence related to the use of these pharmacological therapies in the treatment of opioid-induced hyperalgesia. Several treatments have been utilized; however, the most common treatments include ketamine, dextromethorphan, and nonsteroidal anti-inflammatory drugs (NSAIDs). Multiple small studies and case reports in the literature have shown success with various pharmacological interventions. Such treatment regimens include opioid switching, amantadine, buprenorphine, 2 agonists, and methadone. These agents will be briefly discussed as well.

analgesics, opioid and hyperalgesia) and drug therapy (MeSH terms ketamine, dextromethorphan, anti-inflammatory agents, non-steroidal, cyclooxygenase inhibitors, and amantadine). The first domain search yielded 419 articles. Thirtytwo articles were obtained when combining MeSH term ketamine, 6 articles when combining MeSH term dextromethorphan, 24 articles when combining MeSH term anti-inflammatory agents, nonsteroidal and 4 articles when combining MeSH term amantadine to the first domain search. Studies were selected for inclusion in our systematic review if they met all of the following inclusion criteria: randomized controlled trials (RCTs) or meta-analysis of RCTs, interventions consisting of any drug therapy for patients with the diagnosis of opioid-induced hyperalgesia, and studies focusing on the human population. Two review authors independently screened the abstracts for eligibility for inclusion in this review. For the relevant abstracts chosen, the full paper was reviewed to determine whether therapies for opioidinduced hyperalgesia were discussed. Figure 1 is the PRISMA Flow Diagram described in the PRISMA statement is a graphical representation of the flow of citations reviewed in the course of the review.

RESULTS
After reviewing the full paper and searching the bibliographies of retrieved studies, 6 articles were appropriate for the ketamine group, 1 for dextromethorphan, 2 for NSAIDs, and 0 for amantadine. EMBASE was searched using a similar search strategy to PubMed. The EMBASE search yielded 50 results with the above criteria. No additional studies were obtained from the EMBASE search. The Cochrane Controlled Trials Register was searched with the text word Opioid-induced hyperalgesia. None of the papers obtained were relevant. The most common reason for exclusion was the study of something other than the treatment of opioid-induced hyperalgesia. Attempts were made to search for articles related to the use of opioid switching, buprenorphine, 2 agonists, and methadone in the treatment of opioidinduced hyperalgesia. Although small observational studies discussing improvement in pain with these regimens were available, no study elaborated on their roles in the treatment of opioid-induced hyperalgesia. The quality of evidence was stratified using the US Preventative Services Task Force ranking. Level I: Evidence obtained from at least one properly designed randomized controlled trial.
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METHODS
We conducted a review using PubMed, EMBASE, and Cochrane databases. References of the included studies were manually searched for additional relevant studies. The search engines dated back to 1966. Last search date was 14 January 2011. In PubMed, we combined the results of searches in two separate domains: opioid-induced hyperalgesia (MeSH terms

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FIGURE 1. Database search. From Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA Statement. PLoS Med 2009;6(6):e1000097.

Level II-1: Evidence obtained from well-designed controlled trials without randomization. Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group. Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic reTABLE 1. Characteristics of Included Studies Study design RCT RCT RCT RCT RCT RCT RCT RCT RCT No. of patients 90 14 10 13 34 75 40 15 90

sults in uncontrolled trials might also be regarded as this type of evidence. Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. Table 1 displays the characteristics of the included studies. The main therapy along with the duration of follow-up have

First author (Year) Xuerong (2008) Luginbuhl (2003) Angst (2003) Koppert (2003) Engelahardt (2008) Joly (2005) Compton (2008) Troster (2006) Xuerong (2008)

Duration of follow-up 48 hours 120 minutes 30 minutes 120 minutes 72 hours 48 hours 5 weeks 150 minutes 48 hours

Therapy Ketamine Ketamine Ketamine Ketamine Ketamine Ketamine Dextromethorphan Parecoxib Lornoxicam

Quality of study Level I Level I Level I Level I Level I Level I Level I Level I Level I

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been included. The quality of studies were ranked based on the US Preventative Services Task Force ranking.

DISCUSSION
NMDA Receptor Antagonists in the Treatment of Opioid-Induced Hyperalgesia
Ketamine in the Management of Opioid-Induced Hyperalgesia

The mechanism of action of ketamine is primarily the antagonism of the N-methyl-D-aspartate (NMDA) receptor. The NMDA receptor is a ligand-gated calcium channel with glutamate as its major endogenous agonist. The activation of the calcium channel is a major contributor to the wind-up phenomenon leading to central sensitization (7). Ketamine has been gaining more interest in the field of pain management. There are a considerable number of studies, including clinical trials, meta-analyses, and systemic reviews that have shown ketamine to have antihyperalgesic, antiallodynic, and tolerance-protective roles (8). Most recently, low-dose ketamine has been increasingly used in a wide range of acute and chronic pain settings. The earlier literature studying the basic mechanisms of opioid-induced hyperalgesia through NMDA-dependent pain facilitatory pathways were based on rat models (9). Repeated administration of ketamine simultaneously with fentanyl and morphine administration prevented early hyperalgesia (hours) as well as long-lasting hyperalgesia (days) (10). In humans, there is debate on whether small-dose ketamine reduces opioid consumption. Small-dose ketamine intraoperatively reduced intraoperative remifentanil use and postoperative morphine consumption in 50 patients undergoing abdominal surgery (11). However, intraoperative low-dose ketamine showed no reduction in morphine consumption at 24 and 48 hours in 31 patients undergoing major ear, nose, and throat (ENT) surgery (12). Ketamine in subanesthetic dose was shown to be effective in reducing morphine requirements in the first 24 hours after surgery. Ketamine also reduced postoperative nausea and vomiting. Adverse effects were mild or absent (13). In a randomized control trial of 10 cancer patients who were not responsive to morphine, a slow bolus of ketamine (0.25 or 0.50 mg/kg) was administered. Ketamine significantly reduced the pain intensity in almost all the patients at both dose levels (14).
Study Population. In all six ketamine studies included in our study the population was opioid na ve.

They were either healthy volunteers or patients undergoing surgery. No studies where available on cancer or noncancer patients who have been on large doses of opioids. Opioid Regimen During Intervention. In the patients who were undergoing surgery, Joly et al. (15) and Engelhardt et al. (16) maintained patients on remifentanil intraoperatively. Xuerong et al. (17) performed regional anesthesia along with fentanyl through the intravenous route. All the healthy volunteers in the rest of the studies were started on remifentanil infusions to achieve a hyperalgesic state. In studies using remifentanil, low-dose remifentanil in a dose ranging from 0.1 to 0.3 g/kg/min was used (16, 1820). Only one study (15) compared differences between large (0.4 g/kg/min) and small (0.1 g/kg/min) doses of remifentanil. In this study, ketamine prevented increase in postoperative hyperalgesia triggered by large-dose remifentanil only. Effects of Ketamine on Opioid-Induced Hyperalgesia. Out of the 6 RCTs, three studies showed no change in the hyperalgesic state with coadministration of low-dose ketamine (15, 16, 19). One study (15) showed ketamine to prevent hyperalgesia in large doses. Punctate hyperalgesia was reduced with no reduction in pain ratings at a ketamine dose of 5 g/kg in 13 healthy volunteers who were on lowdose remifentanil (18). Xuerong et al. (17) showed that a small dose of ketamine itself could not prevent postoperative morphine consumption, but it could prevent the increase of postoperative morphine consumption induced by intraoperative fentanyl administration. Because a spinal anesthetic with only bupivacaine was used for the study, it was possible to show that even small doses of intravenous fentanyl could increase postoperative opioid consumption. Hence the study concluded that in patients with opioid-induced hyperalgesia caused by fentanyl, response to ketamine was proven by pain scores. Interestingly, the dose of ketamine used for this study (15 g/kg/min) was higher than other studies (2 g/kg/min) (12, 13). However, the former study did report intraoperative and postoperative hallucinations. Joly et al. (15) studied the hypothesis that smalldose ketamine prevents hyperalgesia that occurs after relatively large dose of intraoperative remifentanil. Seventy-five patients undergoing major abdominal surgery were randomly assigned to small-dose remifentanil (0.1 g/kg/min), large-dose remifentanil (0.4 g/kg/min), or large-dose remifentanil with ketamine. Ketamine was initially given as a bolus of 0.5 mg/kg after induction, followed by an intraoperative infusion of 5 g/kg/min until skin closure and then 2 g/kg/min for 48 hours after. Hyperalgesia to von Frey hair stimulation adjacent to the
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surgical wound and morphine requirements were larger in the large-dose remifentanil group compared to the other two groups. Ketamine was able to prevent the increase in postoperative hyperalgesia triggered by a large dose of remifentanil only. Patients who received a large dose of remifentanil with ketamine had significantly less postoperative morphine requirements (reduction from 86 mg over a 48-hour period to 62 mg), with no increase in postoperative nausea and vomiting. Angst et al. (20) studied 10 healthy Caucasian volunteers with a mean age of 28 years. A four-occasion, double-blinded design study was conducted with parallel infusions of (S)-ketamine plus saline placebo, remifentanil plus saline placebo, (S)-ketamine plus remifentanil, and saline placebo plus saline placebo. Coadministration of the NMDA antagonist (S)ketamine with remifentanil abolished the extension of the hyperalgesic skin area that was observed with administration of remifentanil alone. The infusion of placebo/remifentanil resulted in a 130% increase of the hyperalgesic area once the remifentanil infusion was stopped. Such an increase was not observed if (S)-ketamine was coadministered with remifentanil or (S)-ketamine was administered alone. This study provides direct evidence for the occurrence of opioidassociated hyperalgesia in opioid-naive humans after brief opioid exposure.

In 50 patients scheduled for nonmalignant elective total abdominal hysterectomy, Ilkjaer et al. (27) measured morphine consumption over a 24-hour period. Patients who received oral dextromethorphan 150 mg 1 hour before surgery had a 30% reduction in morphine consumption from 0 to 4 hours after the operation (P = .02). No difference was observed from 5 to 24 hours postoperatively. There was no difference in the visual analog scale (VAS) scoring. Weinbroum et al. (28) found dextromethorphan at a dose of 90 mg to reduce postoperative analgesic consumption, pain intensity, and primary and secondary thermal hyperalgesia in 30 patients undergoing laparoscopic cholecystectomies or inguinal hernioplasty. In a randomized double-blinded study in 66 patients undergoing knee surgery (29), high-dose dextromethorphan (400 to 800 mg) showed a 29% reduction in morphine consumption with no difference in pain scores. The study concluded that dextromethorphan improved postoperative analgesia only marginally and is not clinically useful in the treatment of postoperative pain after knee surgery.
Study Population. One study was based on patients on chronic methadone. No studies available on acute settings. Opioid Regimen During Intervention. Patients on chronic methadone at a dose of 69 mg/day were started on high dose of dextromethorphan 480 mg over a 5-week period. Effects of Dextromethorphan on OpioidInduced Hyperalgesia. Compton et al. (30) was

Dextromethorphan in the Management of Opioid-Induced Hyperalgesia

Dextromethorphan is the D-isomer of the methyl ether derivative of levorphanol, which is an NMDA receptor antagonist. Dextromethorphan influences peripheral pain transmission at the level of the NMDA spinal receptors (21). Evidence still lacks regarding the use of dextromethorphan as an analgesic adjuvant in a clinical setting (22). Chia et al. (23) showed that a single dose of 5 mg/kg intravenous dextromethorphan premedication in patients who underwent intra-abdominal surgery reduced postoperative pain sensation and diclofenac requirement for the two study days. Henderson et al. (24) treated patients undergoing hysterectomy with 40 mg dextromethorphan preoperatively and three times daily for 24 hours after surgery with beneficial results. However, some studies showed the contrary. In children undergoing tonsillectomies, dextromethorphan at a dose of 0.5 to 1 mg/kg did not reduce pain scores or analgesic requirements during the 24-hour postoperative period (25). Grace et al. (26) demonstrated that 60 mg of dextromethorphan given the night before surgery in patients undergoing laparotomies did not reduce morphine requirements postoperatively.
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the only clinical trial studying the effect of NMDA antagonism in chronic methadone patients. The study concluded that for patients on methadone maintenance, the contribution of an NMDA-mediated excitatory mechanism to clinical opioid-induced hyperalgesia appeared negligible. No difference was found between groups on pain threshold and tolerance. Notably, dextromethorphan-induced changes significantly differed by gender, with women tending to show diminished tolerance for pain with therapy. These results support that chronic high-dose NMDA antagonism does not improve tolerance for pain in methadone maintained patients, although a gender effect on dextromethorphan response is suggested. Table 2 describes the opioid regimens of the patients, the NMDA receptor antagonist used to treat opioid-induced hyperalgesia and the duration of their follow-up. The final column includes the conclusions of the respective authors.

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Opioid regimen preintervention NMDA receptor antagonist/Dose Pain stimulus Surgical pain VAS 1, 3, 6, 12, Sedation, 24, and 48 dizziness, h postophallucinations, eratively itching 3, 20, and 120 min Sedation, pruritis, euphoria, dysphoria, nausea Follow-up Side effects Remarks Ketamine decreased postoperative morphine consumption induced by intraoperative fentanyl Remifentanil-induced hyperalgesia not prevented by ketamine Ketamine 15 g/kg/min Pain monitoring Spinal + Morphine fentanyl (3 g/kg) Pressure pain test Opioid regimen postintervention Ketamine 50 or 100 IM, transcutaRemifentanil Not measured ng/mL (target neous (target plasma electrical serum conconcentration) stimulation, centration pressure of 12 threshold ng/mL) Remifentanil Not Ketamine 23 Heat and (0.1 measured g/kg intradermal g/kg/min) electrical stimulation VAS 30 min after stopping second infusion Ketamine 5 g/kg Remifenanil Not measured (0.1 g/kg/min) Transcutaneous 010 numerical electrical scale stimulation 010 numerical scale Remifentanil Morphine (0.3 g/kg/min) Ketamine Bolus 0.5 Surgical pain mg/kg followed by 4 g/kg/min Every 15 min Hyperacusis, sedation from 0 to 120 min 24, 48, and N/V, pruritis, 72 h postpyrexia, operatively unpleasant dreams Sedation, pruritis, euphoria, dysphoria, nausea Hyperalgesic state from remifentanil infusion not observed on coadministration with (S)-ketamine (S)-ketamine abolished punctate hyperalgesia but did not reduce pain ratings Ketamine did not prevent the development of acute opioid hyperalgesia

TABLE 2.

Evidence Related to the Use of NMDA Receptor Antagonists in Treatment of Opioid-Induced Hyperalgesia

First author (Year) Patients

Xuerong (2008)

Luginbuhl (2003)

90 female patients undergoing TAH 14 healthy volunteers

Angst (2003)

10 healthy volunteers

Koppert (2003)

13 healthy volunteers

Engelahardt 34 adoles(2008) cents undergoing scoliosis repair Joly (2005) 75 patients undergoing abdominal surgery

Compton (2008)

Hallucinations, Ketamine prevented Ketamine Bolus 0.5 Surgical pain VAS verbal Before Remifentanil Morphine N/V, pruritus, increase in postoperative mg/kg followed rating surgery, 24 large dose diplopia, hyperalgesia triggered by by 24 g/kg/min scale, von and 48 h (0.4 sedation large dose remifentanil 48 h Frey hair postoperag/kg/min) only tively and small dose (0.1 g/kg/min) Chronic high-dose NMDA 40 Methadone Methadone Dextromethorphan Electrical Threshold 5 weeks 50% with antagonism does not methadone (average of 480 mg/day 5 stimulus, cold time (s) drowsiness, 31% improve tolerance for maintained 60 mg/day) weeks pressor with dizziness, pain in methadone patients 8% with maintained patients lethargy

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NSAIDs in the Management of Opioid-Induced Hyperalgesia

NSAIDs are increasingly being used for postoperative pain management as an adjunct to opioid analgesics. Parecoxib significantly reduced the areas of secondary hyperalgesia to pinprick and touch in 14 volunteers who underwent transdermal electrical stimulation (31). NSAIDs are known to induce analgesia mainly by inhibition of cyclooxygenase (COX). Prostaglandins stimulate glutamate release from astrocytes and spinal cord dorsal horns. Enhanced sensitivity to prostaglandin E in spinal segments plays an early pathogenic role in experimental neuropathic pain (32). An important element regarding the analgesic mechanism of COX inhibitors is that they may act by suppressing a peripheral inflammatory component and thus reversing peripheral sensitization of the primary afferent. In spite of this emphasis on a peripheral action, several lines of evidence suggest that these agents activity may be considerably more complex. Some data suggest that NSAIDs have a central action even when administered peripherally (33). Pain stimulus activates excitatory neurotransmitters including substance P and glutamate. This produces increased intracellular calcium, which in turns activates multiple intracellular enzymes including phospholipase A2 (34). This event leads to increase in free arachidonic acid, which enters the cyclooxygenase cascade, leading to the formation of prostaglandins. Although most studies on central sensitization focus on spinal mechanisms, there are also important supraspinal mechanisms involved in prostaglandin-induced hyperalgesia (35). The antinociceptive effect of supraspinal NSAIDs related to COX inhibition is consistent with the extensive distribution of COX-like immunoreactivity in several structures that have been implicated in descending inhibition of spinal nociceptive transmission.

Effects of NSAIDs on Opioid-Induced Hyperalgesia

Study Population

The study population in both the studies was opioid na ve. They were either healthy volunteers or patients undergoing surgery. No studies were available on cancer or noncancer patients who have been on larger doses of opioids.

Troster et al. (36) studied the modulation of remifentanil-induced hyperalgesia by parecoxib. Adequate timing appeared to have clinical importance for the antihyperalgesic effect of cyclooxygenase-2 inhibitors. Interestingly, only early treatment with parecoxib 30 minutes before application of remifentanil significantly diminished the enlarged hyperalgesic areas after cessation of the remifentanil infusion, whereas upon parallel application, parecoxib was ineffective. This would suggest that the interaction of opioids and COX inhibitors underlying inhibition of opioid-induced hyperalgesia is an early event and depends on whether prostaglandins have already sensitized the nociceptive system. Xuerong et al. (17) concluded that patients who received lornoxicam did not show sparing of opioid consumption postoperatively. Lornoxicam did not have a direct preemptive effect. But it significantly diminished the acute opioid-induced hyperalgesia caused by fentanyl. Lornoxicam had the same effect as ketamine in preventing the increase of postoperative morphine consumption induced by intraoperative administration of fentanyl. Patients who received lornoxicam before fentanyl had the same cumulative postoperative morphine consumption as patients in the control group during the first 48 hours after surgery. The patients who received only lornoxicam had no sparing of postoperative morphine consumption compared with patients in the control group. Lornoxicam therefore did not have direct preemptive effects, but preventive administration of the lornoxicam significantly diminished the acute opioidinduced hyperalgesia caused by fentanyl. Neither of the above studies mentioned side effects related to NSAIDs. Most side effects were due to the opioids used. One of the reasons for the lack of side effects was its short-term use. Table 3 displays the opioid regimens of the patients, the NSAIDs used to treat opioid-induced hyperalgesia and the duration of their follow-up. The final column includes the conclusions of the respective authors.
Other Pharmacological Agents 2 Agonists in the Management of OpioidInduced Hyperalgesia. The analgesic properties

Opioid Regimen During Intervention

Short-acting opioids were used to induce hyperalgesia in both studies. Both studies had control groups without opioids and the opioid groups without the NSAID had higher pain rating scores.
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of 2 agonists are proposed to involve both peripheral and central mechanisms. Clonidine and dexmedetomidine are selective agonists of the 2 receptor. Intrathecal clonidine administration has been shown to suppress the spinal NMDA receptor phosphorylation in the spinal dorsal horn neurons (37). In addition to its central analgesic action, clonidine can induce peripheral antinociception by an

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Evidence Related to the Use of NSAIDs in Treatment of Opioid-Induced Hyperalgesia Opioid regimen preintervention Opioid regimen postintervention

TABLE 3. First author (Year)

Patients

NSAIDs dosage

Pain stimulus

Pain mon- Follow-up itoring Period Side effects

Remarks

Troster 15 healthy Remifenanil None (2006) male infusion volunteers

Xuerong 90 female (2008) patients undergoing TAH

Spinal + fentanyl IV (3 g/kg)

Morphine

None men- Preventive adQ 5 min Parecoxib 40 Transcutaneous Numeric tioned ministration for 30 electrical rating mg either of parecoxib min stimulation scale, prior to significantly infusion measurinfusion or diminished period ing parallel to the enlarged Q 15 areas of infusion hyperalgesic min pinprick areas after thereanalgecessation of after for sia the 150 min remifentanil infusion, whereas parallel administration of parecoxib did not. VAS 1, 3, 6, 12, None men- Patients who Lornoxicam Surgical tioned received stimulus scoring 24, and 8 mg IV lornoxicam 48 h intraoperaalone did postoptively not show eratively opioid sparing postoperatively. However, it prevented the increase of postoperative morphine consumption induced by intraoperative administration of fentanyl.

2 -adrenoreceptormediated local release of enkephalin-like substances (38). Clonidine at high concentrations may cause blockade of the C-fibers. Also it causes local vasoconstriction, which may result in higher concentrations of local anesthetic near the nerves (39). In 13 healthy volunteers (17), clonidine alone did not significantly attenuate pain or areas of hyperalgesia. However, when given in combination with remifentanil, clonidine attenuated postinfusion increase of pain ratings. Clonidine reduced the intensity of postinfusion hyperalgesia, but did not decrease it below control levels. Clonidine given intravenously did show not show analgesic effects in the study. However there are studies that

show 2 -receptor agonists reduce pain via intrathecal and epidural routes (40, 41). Coadministration of remifentanil and clonidine significantly increased the number of episodes with oxygen desaturation, which may limit the use of this combination for postoperative pain control. A case series (42) described 11 hospitalized patients with painful medical conditions who were treated with dexmedetomidine infusions after assessing for opioid-induced hyperalgesia using an algorithm. The case series showed a substantial reduction in baseline opioid doses in 7 out of the 11 patients. These cases support the clinical utility of 2 agonists such as dexmedetomidine during opioid dose reduction in patients with opioid-induced hyperalgesia.
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Buprenorphine in the Management of Opioid-Induced Hyperalgesia

Opioid Switching in the Management of Opioid-Induced Hyperalgesia

Buprenorphine is a partial opioid agonist with antagonist properties. It is a partial -receptor agonist and a - and -receptor antagonist (43). It is currently used for the treatment of opioid dependence in its sublingual form Suboxone. Its -receptor antagonism may contribute to its ability to possibly reduce opioidinduced hyperalgesia. In a study of 15 healthy volunteers who were started on intravenous and sublingual buprenorphine (44), buprenorphine exerted lasting antihyperalgesic effects in patients with mechanical injury to the site. However, there were no changes in the pain ratings in these patients. Nausea and vomiting was seen in 28% of the patients who were given intravenous buprenorphine. More studies are needed to see if this translates to improvement in the treatment of opioid-induced hyperalgesia.
Amantidine in the Management of Opioid-Induced Hyperalgesia

Amantidine is primarily used for the treatment of Parkinson disease and as an antiviral drug. Ketamine and dextromethorphan have been studied for their role as NMDA receptor antagonists. Evidence shows that amantidine is a noncompetitive NMDA receptor antagonist and may be useful in preventing opioid-induced hyperalgesia (45, 46). Amantidine may therefore decrease pain and analgesic requirements, possibly by preventing central sensitization. In 24 patients undergoing prostate resection (47), there was a 32% reduction in morphine consumption over a 48-hour period in the group who received amantadine the evening and 1 hour before surgery as well as post surgery.
Methadone in the Management of Opioid-Induced Hyperalgesia

Patients who have poor response to a certain opioid may benefit from the pharmacological practice of opioid switching. The rationale is based on the difference in the levels of tolerance induced by opioids and individual variability (51). A review of 15 retrospective studies and 15 prospective uncontrolled studies (52) showed morphine to be the first-line opioid and methadone to be the most frequently used secondline opioid for switching. The review found opioid switching to be useful in improving pain control and reducing opioid-related side effects. In one report (53), 18 patients were switched from fentanyl patches to methadone and 7 from methadone to fentanyl patches. A significant decrease in pain and symptom intensity was found within 24 hours of switching in 12 of the patients. A systematic review (54) of existing literature showed a clinical improvement in more than 50% of patients with chronic pain who had a poor response to one opioid. The evidence to support the practice of opioid switching is based on observational and uncontrolled studies only. Importantly, the opioid conversions should not be a mere calculation, but be a part of a comprehensive evaluation of pain. There are many conversion ratios reported in the literature and the final changes in regimen should be highly individualized (55).

Pharmacological Agents Used to Treat Acute Versus Chronic Opioid-Induced Hyperalgesia

The majority of the studies obtained through the search were short-term studies looking into the immediate postoperative period. Many of them had defined the use of intraoperative remifentanil as the cause of opioid-induced hyperalgesia. Shortacting opioids may be accompanied by hyperalgesia. Remifentanil has been shown to induce acute opioid tolerance (56); hence an increase in postoperative morphine consumption after remifentanil use may be explained by the occurrence of opioid withdrawal hyperalgesia (57). Noncancer chronic pain patients taking either methadone or morphine were similar to patients maintained on methadone for dependence therapy in that both groups exhibited increased sensitivity to certain experimental pain stimuli (48). Davis et al. (58) describes three forms of opioid-induced hyperalgesia. Most attention is paid to opioid-induced hyperalgesia (OIH) in the context of opioid maintenance therapy or withdrawal. A second form of OIH has been described in the setting of very high and escalating doses of opioids. The third form of OIH has been seen in animals with the administration of

Methadone is a synthetic opioid that is a - and receptor agonist as well as a NMDA receptor antagonist (48). Methadone is currently used in palliative care as a second-line agent in opioid rotation for the treatment of opioid resistance. Opioid switching in 17 cancer patients from transdermal fentanyl to oral methadone improved somatic pain in 80% of the patients (49). Neuropathic pain did not improve with the switch. High doses of methadone produce a effect that can overpower the drugs NMDA effect and result in increased pain. Patients with chronic pain managed on methadone and opioid addicts on methadone maintenance have shown to have increased sensitivity to some types of pain (50). This may limit its role in the treatment of opioidinduced hyperalgesia.
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Summary of Treatment Approaches for Opioid-Induced Hyperalgesia

TABLE 4.

Reduce or discontinue the current opioid Consider opioid switching Add a nonopioid adjuvant therapies such as acetaminophen and NSAIDs Add a NMDA receptor antagonist to the regimen Consider other pharmacological agents such as antidepressants, antiepileptics, and skeletal muscle relaxants to treat pain Consider regional/local anesthesia

ultra-low-dose opioids. The second form, mostly observed in cancer patients, is unlikely to be mediated through the opioid receptors and opioid antagonists may not alleviate the symptoms. Switching from a phenanthrene derivative such as morphine to a piperidine derivative (fentanyl) or methadone has been reported to attenuate the symptoms (59). NMDA receptor antagonists may play a role as a therapeutic adjuvant secondary to the NMDA receptormediated symptoms of this second form of OIH. However, there is a lack of randomized controlled trials studying the pharmacological treatment of opioid-hyperalgesia related to chronic opioid therapy. Table 4 summarizes the treatment approaches for opioid-induced hyperalgesia. These are suggestions and should be customized to meet the specific needs of the patients.

calculate such a measure because it is difficult to define such characteristics. Unfortunately, many of the included trials had methodological weaknesses that compromised their results, including a lack of standard case definition for opioid-induced hyperalgesia. Issues of optimal dose and form of administration were not resolved by these trials. The most common route of the administration was intravenous bolus or infusion.

CONCLUSION
It is crucial to be able to differentiate between clinically worsening pain, tolerance, and opioid-induced hyperalgesia because treatment of these conditions differ. It is clear that there is no ideal agent in the treatment of opioid-induced hyperalgesia. The management of opioid-induced hyperalgesia should always begin with an assessment of the patient for medical causes of the pain. If the problem persists after this has been addressed, opioid-induced hyperalgesia should be considered in any patient with increasing pain who is not responding to increasing opioids. The treatment strategy needs to be individualized based on the clinical scenario and the patients history and condition. Referral to pain and palliative care professionals is appropriate to help develop a management strategy. In general, treatment should include the following strategies: tapering or discontinuation of the current opioid regimen, opioid switching, adding a NMDA receptor antagonist such as ketamine and adding a nonopioid adjuvant such as NSAIDs. The approach is to be guided by the current state of evidence in combination with the goal of minimizing adverse effects. Other forms of analgesia, including regional techniques such as peripheral nerve blocks, epidurals, and local anesthesia, may be attempted if appropriate. There are several challenges in designing larger, well-designed, controlled trials to evaluate pharmacological interventions in this set of patients. The diagnosis of opioid-induced hyperalgesia in patients exposed to chronic opioids is more challenging, secondary to the complexity of its diagnosis. It may be valuable to initially examine pharmacological agents
Journal of Pain & Palliative Care Pharmacotherapy

CLINICAL DILEMMAS/LIMITATIONS
We were unable to perform a meta-analysis owing to the heterogeneity of the included studies. In many of these studies, we were unable to differentiate between opioid-induced hyperalgesia and tolerance. A direct cause-and-effect relationship between opioids and development of opioid-induced hyperalgesia cannot be demonstrated. The dilemma of opioid-induced hyperalgesia is usually seen in the opioid-tolerant patient who is unable to achieve adequate analgesia despite escalating doses of opioids. These patients no longer respond to opioid escalations and still have insufficient pain control even when being on multiple adjuvant therapies, including antidepressants, anticonvulsants, and anti-inflammatory agents. None of the studies included here assessed such a patient population. There are several important methodological issues in defining opioid-induced hyperalgesia that limit the interpretation of the data and generate controversies regarding the pharmacological management of opioid-induced hyperalgesia. One controversy is how to define opioid-induced hyperalgesia in the clinical setting, especially during short-term trials. It is difficult to interpret small changes in scale scores. Was the increased pain experienced really opioid-induced hyperalgesia? The trials did not present data needed to

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in an acute setting and use that as a guide for further investigations. Future interventions that are currently being studied in animal models include gabapentin and pregabalin.

REFERENCES
[1] Angst MS, Clark DJ. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006;104:570587. [2] Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain. 2002;100:213217. [3] Koppert W, Schmelz M. The impact of opioid-induced hyperalgesia for postoperative pain. Best Pract Res Clin Anaesthesiol. 2007;21:6583. [4] Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin J Pain. 2008;24:479496. [5] Chang G, Chen L, Mao J. Opioid tolerance and hyperalgesia. Med Clin North Am. 2007;91:199211. [6] Silverman SM. Opioid induced hyperalgesia: clinical implications for the pain practitioner. Pain Physician. 2009;12: 679684. [7] White PF, Way WL, Trevor AJ. Ketamineits pharmacology and therapeutic uses. Anesthesiology. 1982;56:119136. [8] Visser E, Schug SA. The role of ketamine in pain management. Biomed Pharmacother. 2006;60:341348. [9] Larcher A, Laulin JP, Celerier E, Le Moal M, Simonnet G. Acute tolerance associated with a single opiate administration: involvement of N-methyl-d-aspartate-dependent pain facilitatory systems. Neuroscience. 1998;84:583589. [10] Laulin JP, Maurette P, Corcuff JB, Rivat C, Chauvin M, Simonnet G. The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance. Anesth Analg. 2002;94:12631269. [11] Guignard B, Coste C, Costes H, et al. Supplementing desflurane-remifentanil anesthesia with small-dose ketamine reduces perioperative opioid analgesic requirements. Anesth Analg. 2002;95:103108. [12] Ganne O, Abisseror M, Menault P, et al. Low-dose ketamine failed to spare morphine after a remifentanil-based anaesthesia for ear, nose and throat surgery. Eur J Anaesthesiol. 2005;22:426430. [13] Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006;25(1):CD004603. [14] Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage. 2000;20:246252. [15] Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005;103:147155. [16] Engelhardt T, Zaarour C, Naser B, et al. Intraoperative lowdose ketamine does not prevent a remifentanil-induced increase in morphine requirement after pediatric scoliosis surgery. Anesth Analg. 2008;107:11701175. [17] Xuerong Y, Yuguang H, Xia J, Hailan W. Ketamine and lornoxicam for preventing a fentanyl-induced increase in postoperative morphine requirement. Anesth Analg. 2008;107:20322037. [18] Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schuttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology. 2003;99:152159.
C

[19] Luginbuhl M, Gerber A, Schnider TW, Petersen-Felix S, Arendt-Nielsen L, Curatolo M. Modulation of remifentanilinduced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg. 2003;96:726732. [20] Angst M, Koppert W, Pahl I, Clark D, Schmelz M. Short-term infusion of mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain. 2003;106:4957. [21] Church J, Lodge D, Berry SC. Differential effects of dextromethorphan and levorphanol on the excitation of rat spinal neurons by amino acids. Eur J Pharmacol. 1985;111: 185190. [22] Weinbroum AA, Rudick V, Paret G, Ben-Abraham R. The role of dextromethorphan in pain control. Can J Anesth. 2000;47:585596. [23] Chia YY, Liu K, Chow LH, Lee TY. The preemptive administration of intravenous dextromethorphan reduces postoperative morphine consumption. Anesth Analg. 1999;89:748752. [24] Henderson DJ, Withington BS, Wilson JA, Morrison LM. Perioperative dextromethorphan reduces postoperative pain after hysterectomy. Anesth Analg. 1999;89:399402. [25] Rose JB, Cuy R, Cohen DE, Schreiner MS. Preoperative oral dextromethorphan does not reduce pain or analgesic consumption in children after adenotonsillectomy. Anesth Analg. 1999;88:749753. [26] Grace RF, Power I, Umedaly H, et al. Preoperative dextromethorphan reduces intraoperative but not postoperative morphine requirements after laparotomy. Anesth Analg. 1998;87:11351138. [27] Ilkjaer S, Bach LF, Nielsen PA, Wernberg M, Dahl JB. Effect of preoperative oral dextromethorphan on immediate and late postoperative pain and hyperalgesia after total abdominal hysterectomy. Pain. 2000;86:1924. [28] Weinbroum AA, Gorodezky A, Niv D, Ben-Abraham R, Rudick V, Szold A. Dextromethorphan attenuation of postoperative pain and primary and secondary thermal hyperalgesia. Can J Anaesth. 2001;48:167174. [29] Wadhwa A, Clarke D, Goodchild CS, Young D. Large-dose oral dextromethorphan as an adjunct to patient-controlled analgesia with morphine after knee surgery. Anesth Analg. 2001;92:448454. [30] Compton PA, Ling W, Torrington MA. Lack of effect of chronic dextromethorphan on experimental pain tolerance in methadone-maintained patients. Addict Biol. 2008;13:393402. [31] Koppert W, Wehrfritz A, Korber N, et al. The cyclooxygenase isozyme inhibitors parecoxib and paracetamol reduce central hyperalgesia in human. Pain. 2004;108:14381453. [32] ORielly DD, Loomis CW. Increased expression of cyclooxygenase and nitric oxide isoforms, and exaggerated sensitivity to prostaglandin E2, in the rat lumbar spinal cord 3 days after L5L6 spinal nerve ligation. Anesthesiology. 2006;104:328337. [33] Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science; 257:12761279. [34] Breder CD, Smith WL, Raz A, et al. Distribution and characterization of cyclooxygenase immunoreactivity in the ovine brain. J Comp Neurol. 1992;322:409438. [35] Urban MO, Gebhart GF. 1999. Supraspinal contributions to hyperalgesia. Proc Natl Acad Sci USA. 1999;96:76877692. [36] Troster A, Sittl R, Singler B, Schmelz M, Schuttler J, Koppert W. Modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by parecoxib in humans. Anesthesiology. 2006;105:10161023. [37] Maze M, Tranquilli W. Alpha-2 adrenoceptor agonists: defining the role in clinical anesthesia. Anesthesiology. 1991;74:581605. [38] Roh DH, Kim HW, Yoon SY, et al. Intrathecal clonidine suppresses phosphorylation of the N-methyl-d-aspartate receptor

2011 Informa Healthcare USA, Inc.

230

C. Ramasubbu and A. Gupta

NR1 subunit in spinal dorsal horn neurons of rats with neuropathic pain. Anesth Analg. 2008;107:693700. Nakamura M, Ferreira SH. Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances. Eur J Pharmacol. 1988;146:223228. Milne B, Cervenko FW, Jhamandas K, Sutak M. Intrathecal clonidine: analgesia and effect on opiate withdrawal in the rat. Anesthesiology. 1985;62:3438. Eisenach JC, De Kock M, Klimscha W. Alpha (2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (19841995). Anesthesiology. 1996;85:655674. Belgrade M, Hall S. Dexmedetomidine infusion for the management of opioid-induced hyperalgesia. Pain Med. 2010;11:18191826. Johnson RE, Fudala PJ, Payne R. Buprenorphine: considerations for pain management. J Pain Symptom Manage. 2005;29:297326. Koppert W, Ihmsen H, Korber N, et al. Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model. Pain. 2005;118:1522. Kornhuber J, Weller M, Schoppmeyer K, Riederer P. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm Suppl. 1994;43:91104. Danysz W, Parsons CG, Kornhuber J, Schmidt WJ, Quack G. Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agentspreclinical studies. Neurosci Biobehav Rev. 1997;21:455468. Snijdelaar D, Koren G, Katz J. Effects of perioperative oral amantidine on postoperative pain and morphine consumption in patients after radical prostatectomy: results of a preliminary study. Anesthesiology. 2004;100:134141. Hay JL, White JM, Bochner F, Somogyi AA, Semple TJ, Rounsefell B. Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. J Pain. 2009;10:316322. [49] Ben tez-Rosario MA, Feria M, Salinas-Mart n A, Mart nezCastillo LP, Mart n-Ortega JJ. Opioid switching from transdermal fentanyl to oral methadone in patients with cancer pain. Cancer. 2004;101:28662873. [50] Bruera E, Sweeney C. Methadone use in cancer patients with pain: a review. J Palliat Med. 2002;5:127138. [51] Mercadante S. Opioid rotation in cancer pain: rationale and clinical aspects. Cancer. 1999;86:18561866. [52] Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev. 2004;(3): CD004847. [53] Mercadante S, Ferrera P, Villari P, Casuccio A. Rapid switching between transdermal fentanyl and methadone in cancer patients. J Clin Oncol. 2005;23:52295234. [54] Mercadante S, Bruera E. Opioid switching: a systematic and critical review. Cancer Treat Rev. 2006;32:304315. [55] Muller-Busch HC, Lindena G, Tietze K, Woskanjan J. Opioid switch in palliative care, opioid choice by clinical need and opioid availability. Eur J Pain. 2005;9:571579. [56] Gustorff B, Nahlik G, Hoerauf KH, Kress HG. The absence of acute tolerance during remifentanil infusion in volunteers. Anesth Analg. 2002;94:12231228. [57] Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000;93:409 417. [58] Davis MP, Shaiova LA, Angst MS. When opioids cause pain. J Clin Oncol. 2007;25:44974498. [59] Angst MS, Clark JD. Opioid induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006;104:570587.

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

RECEIVED 25 January 2011 ACCEPTED 13 May 2011

Journal of Pain & Palliative Care Pharmacotherapy

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