Pharmacological Treatment of Opioid-Induced Hyperalgesia a Review of the Evidence

Journal of Pain & Palliative Care Pharmacotherapy. 2011;25:219–230.Copyright © 2011 Informa Healthcare USA, Inc.ISSN: 1536-0288 print / 1536-0539 onlineDOI: 10.3109/15360288.2011.589490

ARTICLE

Pharmacological Treatment of Opioid-InducedHyperalgesia: A Review of the Evidence

Chitra Ramasubbu and Anita Gupta

ABSTRACT

Opioids are commonly used to treat moderate to severe pain. Opioid-induced hyperalgesia is a paradoxicalresponse 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 chronicpain settings. The study of opioid-induced hyperalgesia is an emerging field with multiple challenges faced byinvestigators with regard to defining the diagnosis and characterizing the findings. The objective of this studywas 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. Withthe literature on this subject being sparse, this study attempts to provide a preliminary look at the available dataand to set the stage for an eventual meta-analysis. Case reports in the literature have shown success withvarious pharmacological interventions. Possible treatment regimens include ketamine, dextromethorphan, andnonsteroidal anti-inflammatory drugs (NSAIDs), opioid switching, amantadine, buprenorphine, α2 agonists, andmethadone. These agents are briefly discussed in this paper. Further well-designed, placebo-controlled trialsare 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 ofchoice in patients suffering from moderate to severepain. In a clinical situation, it is common to escalatethe dose of opioids to maintain adequate analgesia.Once disease progression and psychological processesare ruled out as the causes of pain, other causes ofincreased opioid requirement, which include opioid-induced hyperalgesia (OIH), opioid tolerance, physi-cal dependence, addiction, and abuse (1), should beconsidered.

Opioid-induced hyperalgesia (OIH) is a paradox-ical response to opioid agonists resulting in an in-

Chitra Ramasubbu, MD, is a Research Assistant and AnesthesiologyResident, Department of Anesthesiology and Critical Care, and AnitaGupta, DO, PharmD, is an Assistant Professor of Anesthesiology and Crit-ical Care, Penn Pain Medicine, University of Pennsylvania, Philadelphia,Pennsylvania, USA.

Address correspondence to: Chitra Ramasubbu, MD, Department ofAnesthesiology and Critical Care Medicine, University of Pennsylvania, 6Dulles, 3400 Spruce Street, Philadelphia PA 19104, USA (E-mail: [email protected]).

creased perception of pain rather than an antinoci-ceptive effect (2). Even though there is a debate re-garding its clinical relevance, it is becoming a chal-lenge in both acute and chronic pain settings. OIHis broadly defined as a state of nociceptive sensi-tization caused by exposure to opioids (3). Clini-cal features of opioid-induced hyperalgesia includeincreasing sensitivity to pain stimuli (hyperalgesia),worsening pain despite increasing doses of opioids,pain that becomes more diffuse, and pain that extendsbeyond the distribution of preexisting pain. Opioid-induced hyperalgesia can occur at any dose of opi-oid, but is seen more commonly with high parenteraldoses of opioids (4).

Opioid tolerance is a phenomenon in which re-peated exposure to an opioid results in a decreasedtherapeutic effect of the drug or need for a higherdose to maintain the same effect (4). The similar neteffect makes the two phenomena difficult to distin-guish in a clinical setting. Under chronic opioid treat-ment, a particular individual’s requirement for doseescalation may be due to tolerance (desensitization of

219

220 C. Ramasubbu and A. Gupta

antinociceptive mechanisms), opioid-induced hyper-algesia (sensitization of pronociceptive mechanisms),or a combination of both. Identifying the develop-ment of hyperalgesia is of clinical importance, sincepatients receiving opioids to relieve pain may para-doxically experience more pain as a result of treat-ment.

Development of opioid-induced hyperalgesia ismediated by neural mechanisms similar to thosethat generate neuropathic pain. These neural mecha-nisms involve N-methyl-D-aspartate (NMDA) recep-tor activation resulting in a central hyperactive state(5). Excitatory amino acids (EAAs) such as gluta-mate are mediators of this central sensitization re-sulting in a persistent hyperactive state. This causesan overall permanent imbalance between the ex-citatory and inhibitory neurons resulting in aber-rant nerve activity (5). Mechanisms implicated inthe development of opioid-induced hyperalgesia aresensitization of peripheral nerve endings, enhanceddescending facilitation of nociceptive signal transmis-sion, enhanced production of nociceptive neurotrans-mitters, and sensitization of second-order neurons tonociceptive neurotransmitters (6).

The study of opioid-induced hyperalgesia is anemerging field with multiple challenges faced byinvestigators with regard to defining the diagnosisand characterizing the findings. With the literatureon this subject being sparse, our study attemptsto provide a preliminary look at the available dataand to set the stage for an eventual meta-analysis.In this review we analyze various pharmacologi-cal treatment strategies and determine the evidencerelated to the use of these pharmacological thera-pies in the treatment of opioid-induced hyperalge-sia. Several treatments have been utilized; however,the most common treatments include ketamine, dex-tromethorphan, and nonsteroidal anti-inflammatorydrugs (NSAIDs). Multiple small studies and casereports in the literature have shown success withvarious pharmacological interventions. Such treat-ment regimens include opioid switching, amantadine,buprenorphine, α2 agonists, and methadone. Theseagents will be briefly discussed as well.

METHODS

We conducted a review using PubMed, EMBASE,and Cochrane databases. References of the includedstudies were manually searched for additional rele-vant 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 separatedomains: opioid-induced hyperalgesia (MeSH terms

“analgesics, opioid” and “hyperalgesia”) and drugtherapy (MeSH terms “ketamine,” “dextromethor-phan,” “anti-inflammatory agents, non-steroidal,”“cyclooxygenase inhibitors,” and “ amantadine”).The first domain search yielded 419 articles. Thirty-two articles were obtained when combining MeSHterm “ketamine,” 6 articles when combining MeSHterm “dextromethorphan,” 24 articles when com-bining MeSH term “anti-inflammatory agents, non-steroidal” and 4 articles when combining MeSH term“amantadine” to the first domain search.

Studies were selected for inclusion in our system-atic review if they met all of the following inclu-sion criteria: randomized controlled trials (RCTs) ormeta-analysis of RCTs, interventions consisting ofany drug therapy for patients with the diagnosis ofopioid-induced hyperalgesia, and studies focusing onthe human population.

Two review authors independently screened theabstracts for eligibility for inclusion in this review.For the relevant abstracts chosen, the full paper wasreviewed to determine whether therapies for opioid-induced hyperalgesia were discussed. Figure 1 is thePRISMA Flow Diagram described in the PRISMAstatement is a graphical representation of the flow ofcitations reviewed in the course of the review.

RESULTS

After reviewing the full paper and searching the bibli-ographies of retrieved studies, 6 articles were appro-priate for the ketamine group, 1 for dextromethor-phan, 2 for NSAIDs, and 0 for amantadine. EM-BASE was searched using a similar search strategyto PubMed. The EMBASE search yielded 50 resultswith the above criteria. No additional studies wereobtained from the EMBASE search. The CochraneControlled Trials Register was searched with the textword “Opioid-induced hyperalgesia.” None of the pa-pers obtained were relevant. The most common rea-son for exclusion was the study of something otherthan the treatment of opioid-induced hyperalgesia.

Attempts were made to search for articles relatedto the use of opioid switching, buprenorphine, α2 ag-onists, and methadone in the treatment of opioid-induced hyperalgesia. Although small observationalstudies discussing improvement in pain with theseregimens were available, no study elaborated on theirroles in the treatment of opioid-induced hyperalgesia.

The quality of evidence was stratified using the USPreventative Services Task Force ranking.

Level I: Evidence obtained from at least one properlydesigned randomized controlled trial.

Journal of Pain & Palliative Care Pharmacotherapy

Journal of Pain & Palliative Care Pharmacotherapy 221

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

Level II-1: Evidence obtained from well-designedcontrolled trials without randomization.

Level II-2: Evidence obtained from well-designedcohort or case-control analytic studies, preferablyfrom more than one center or research group.

Level II-3: Evidence obtained from multiple time se-ries with or without the intervention. Dramatic re-

sults in uncontrolled trials might also be regardedas this type of evidence.

Level III: Opinions of respected authorities, basedon clinical experience, descriptive studies, orreports of expert committees. Table 1 displays thecharacteristics of the included studies. The maintherapy along with the duration of follow-up have

TABLE 1. Characteristics of Included Studies

First author (Year) Study design No. of patients Duration of follow-up Therapy Quality of study

Xuerong (2008) RCT 90 48 hours Ketamine Level ILuginbuhl (2003) RCT 14 120 minutes Ketamine Level IAngst (2003) RCT 10 30 minutes Ketamine Level IKoppert (2003) RCT 13 120 minutes Ketamine Level IEngelahardt (2008) RCT 34 72 hours Ketamine Level IJoly (2005) RCT 75 48 hours Ketamine Level ICompton (2008) RCT 40 5 weeks Dextromethorphan Level ITroster (2006) RCT 15 150 minutes Parecoxib Level IXuerong (2008) RCT 90 48 hours Lornoxicam Level I

C© 2011 Informa Healthcare USA, Inc.


been included. The quality of studies were rankedbased on the US Preventative Services Task Forceranking.

DISCUSSION

NMDA Receptor Antagonists in the Treatmentof Opioid-Induced Hyperalgesia

Ketamine in the Management of Opioid-InducedHyperalgesiaThe mechanism of action of ketamine is primarily theantagonism of the N-methyl-D-aspartate (NMDA)receptor. The NMDA receptor is a ligand-gated cal-cium channel with glutamate as its major endoge-nous agonist. The activation of the calcium channelis a major contributor to the “wind-up” phenomenonleading to central sensitization (7). Ketamine hasbeen gaining more interest in the field of pain man-agement. There are a considerable number of studies,including clinical trials, meta-analyses, and systemicreviews that have shown ketamine to have antihyper-algesic, antiallodynic, and tolerance-protective roles(8). Most recently, low-dose ketamine has been in-creasingly used in a wide range of acute and chronicpain settings.

The earlier literature studying the basic mech-anisms of opioid-induced hyperalgesia throughNMDA-dependent pain facilitatory pathways werebased on rat models (9). Repeated administra-tion of ketamine simultaneously with fentanyl andmorphine administration prevented early hyperal-gesia (hours) as well as long-lasting hyperalgesia(days) (10). In humans, there is debate on whethersmall-dose ketamine reduces opioid consumption.Small-dose ketamine intraoperatively reduced in-traoperative remifentanil use and postoperativemorphine consumption in 50 patients undergoingabdominal surgery (11). However, intraoperativelow-dose ketamine showed no reduction in morphineconsumption at 24 and 48 hours in 31 patients un-dergoing major ear, nose, and throat (ENT) surgery(12). Ketamine in subanesthetic dose was shownto be effective in reducing morphine requirementsin the first 24 hours after surgery. Ketamine alsoreduced postoperative nausea and vomiting. Adverseeffects were mild or absent (13).

In a randomized control trial of 10 cancer patientswho were not responsive to morphine, a slow bolusof ketamine (0.25 or 0.50 mg/kg) was administered.Ketamine significantly reduced the pain intensity inalmost all the patients at both dose levels (14).

Study Population. In all six ketamine studies in-cluded in our study the population was opioid naıve.

They were either healthy volunteers or patients un-dergoing surgery. No studies where available on can-cer or noncancer patients who have been on largedoses of opioids.

Opioid Regimen During Intervention. In thepatients who were undergoing surgery, Joly et al.(15) and Engelhardt et al. (16) maintained patientson remifentanil intraoperatively. Xuerong et al. (17)performed regional anesthesia along with fentanylthrough the intravenous route. All the healthy vol-unteers in the rest of the studies were started onremifentanil infusions to achieve a hyperalgesic state.In studies using remifentanil, low-dose remifentanilin a dose ranging from 0.1 to 0.3 µg/kg/min was used(16, 18–20). Only one study (15) compared differ-ences between large (0.4 µg/kg/min) and small (0.1µg/kg/min) doses of remifentanil. In this study, ke-tamine prevented increase in postoperative hyperal-gesia triggered by large-dose remifentanil only.

Effects of Ketamine on Opioid-Induced Hyper-algesia. Out of the 6 RCTs, three studies showedno change in the hyperalgesic state with coadmin-istration of low-dose ketamine (15, 16, 19). Onestudy (15) showed ketamine to prevent hyperalge-sia in large doses. Punctate hyperalgesia was reducedwith no reduction in pain ratings at a ketamine dose of5 µg/kg in 13 healthy volunteers who were on low-dose remifentanil (18). Xuerong et al. (17) showedthat a small dose of ketamine itself could not preventpostoperative morphine consumption, but it couldprevent the increase of postoperative morphine con-sumption induced by intraoperative fentanyl admin-istration. Because a spinal anesthetic with only bupi-vacaine was used for the study, it was possible to showthat even small doses of intravenous fentanyl could in-crease postoperative opioid consumption. Hence thestudy concluded that in patients with opioid-inducedhyperalgesia caused by fentanyl, response to ketaminewas proven by pain scores. Interestingly, the doseof ketamine used for this study (15 µg/kg/min) washigher than other studies (2 µg/kg/min) (12, 13).However, the former study did report intraoperativeand postoperative hallucinations.

Joly et al. (15) studied the hypothesis that small-dose ketamine prevents hyperalgesia that occursafter relatively large dose of intraoperative remifen-tanil. Seventy-five patients undergoing major abdom-inal surgery were randomly assigned to small-doseremifentanil (0.1 µg/kg/min), large-dose remifentanil(0.4 µg/kg/min), or large-dose remifentanil with ke-tamine. Ketamine was initially given as a bolus of0.5 mg/kg after induction, followed by an intraop-erative infusion of 5 µg/kg/min until skin closureand then 2 µg/kg/min for 48 hours after. Hyperal-gesia to von Frey hair stimulation adjacent to the



surgical wound and morphine requirements werelarger in the large-dose remifentanil group comparedto the other two groups. Ketamine was able to pre-vent the increase in postoperative hyperalgesia trig-gered by a large dose of remifentanil only. Patientswho received a large dose of remifentanil with ke-tamine had significantly less postoperative morphinerequirements (reduction from 86 mg over a 48-hourperiod to 62 mg), with no increase in postoperativenausea and vomiting.

Angst et al. (20) studied 10 healthy Caucasian vol-unteers with a mean age of 28 years. A four-occasion,double-blinded design study was conducted with par-allel infusions of (S)-ketamine plus saline placebo,remifentanil plus saline placebo, (S)-ketamine plusremifentanil, and saline placebo plus saline placebo.Coadministration of the NMDA antagonist (S)-ketamine with remifentanil abolished the extensionof the hyperalgesic skin area that was observed withadministration of remifentanil alone. The infusion ofplacebo/remifentanil resulted in a 130% increase ofthe hyperalgesic area once the remifentanil infusionwas stopped. Such an increase was not observed if(S)-ketamine was coadministered with remifentanilor (S)-ketamine was administered alone. This studyprovides direct evidence for the occurrence of opioid-associated hyperalgesia in opioid-naive humans afterbrief opioid exposure.

Dextromethorphan in the Management ofOpioid-Induced HyperalgesiaDextromethorphan is the D-isomer of the methylether derivative of levorphanol, which is an NMDAreceptor antagonist. Dextromethorphan influencesperipheral pain transmission at the level of theNMDA spinal receptors (21). Evidence still lacks re-garding the use of dextromethorphan as an analgesicadjuvant in a clinical setting (22). Chia et al. (23)showed that a single dose of 5 mg/kg intravenous dex-tromethorphan premedication in patients who under-went intra-abdominal surgery reduced postoperativepain sensation and diclofenac requirement for the twostudy days. Henderson et al. (24) treated patientsundergoing hysterectomy with 40 mg dextromethor-phan preoperatively and three times daily for 24 hoursafter surgery with beneficial results. However, somestudies showed the contrary. In children undergoingtonsillectomies, dextromethorphan at a dose of 0.5to 1 mg/kg did not reduce pain scores or analgesicrequirements during the 24-hour postoperative pe-riod (25). Grace et al. (26) demonstrated that 60 mgof dextromethorphan given the night before surgeryin patients undergoing laparotomies did not reducemorphine requirements postoperatively.

In 50 patients scheduled for nonmalignant electivetotal abdominal hysterectomy, Ilkjaer et al. (27) mea-sured morphine consumption over a 24-hour period.Patients who received oral dextromethorphan 150 mg1 hour before surgery had a 30% reduction in mor-phine consumption from 0 to 4 hours after the op-eration (P = .02). No difference was observed from5 to 24 hours postoperatively. There was no differ-ence in the visual analog scale (VAS) scoring. Wein-broum et al. (28) found dextromethorphan at a doseof 90 mg to reduce postoperative analgesic consump-tion, pain intensity, and primary and secondary ther-mal hyperalgesia in 30 patients undergoing laparo-scopic cholecystectomies or inguinal hernioplasty. Ina randomized double-blinded study in 66 patients un-dergoing knee surgery (29), high-dose dextromethor-phan (400 to 800 mg) showed a 29% reduction inmorphine consumption with no difference in painscores. The study concluded that dextromethorphanimproved postoperative analgesia only marginally andis not clinically useful in the treatment of postopera-tive pain after knee surgery.

Study Population. One study was based on pa-tients on chronic methadone. No studies available onacute settings.

Opioid Regimen During Intervention. Patientson chronic methadone at a dose of 69 mg/day werestarted on high dose of dextromethorphan 480 mgover a 5-week period.

Effects of Dextromethorphan on Opioid-Induced Hyperalgesia. Compton et al. (30) wasthe only clinical trial studying the effect of NMDA an-tagonism in chronic methadone patients. The studyconcluded that for patients on methadone main-tenance, the contribution of an NMDA-mediatedexcitatory mechanism to clinical opioid-inducedhyperalgesia appeared negligible. No differencewas found between groups on pain threshold andtolerance. Notably, dextromethorphan-inducedchanges significantly differed by gender, with womentending to show diminished tolerance for pain withtherapy. These results support that chronic high-doseNMDA antagonism does not improve tolerance forpain in methadone maintained patients, althougha gender effect on dextromethorphan response issuggested. Table 2 describes the opioid regimens ofthe patients, the NMDA receptor antagonist used totreat opioid-induced hyperalgesia and the durationof their follow-up. The final column includes theconclusions of the respective authors.


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NSAIDs in the Management ofOpioid-Induced Hyperalgesia

NSAIDs are increasingly being used for postopera-tive pain management as an adjunct to opioid anal-gesics. Parecoxib significantly reduced the areas ofsecondary hyperalgesia to pinprick and touch in14 volunteers who underwent transdermal electricalstimulation (31).

NSAIDs are known to induce analgesia mainly byinhibition of cyclooxygenase (COX). Prostaglandinsstimulate glutamate release from astrocytes andspinal cord dorsal horns. Enhanced sensitivity toprostaglandin E in spinal segments plays an earlypathogenic role in experimental neuropathic pain(32). An important element regarding the analgesicmechanism of COX inhibitors is that they may actby suppressing a peripheral inflammatory componentand thus reversing peripheral sensitization of the pri-mary afferent. In spite of this emphasis on a periph-eral action, several lines of evidence suggest that theseagents activity may be considerably more complex.Some data suggest that NSAIDs have a central actioneven when administered peripherally (33). Pain stim-ulus activates excitatory neurotransmitters includingsubstance P and glutamate. This produces increasedintracellular calcium, which in turns activates multi-ple intracellular enzymes including phospholipase A2(34). This event leads to increase in free arachidonicacid, which enters the cyclooxygenase cascade, lead-ing to the formation of prostaglandins. Although moststudies on central sensitization focus on spinal mech-anisms, there are also important supraspinal mecha-nisms involved in prostaglandin-induced hyperalge-sia (35). The antinociceptive effect of supraspinalNSAIDs related to COX inhibition is consistent withthe extensive distribution of COX-like immunoreac-tivity in several structures that have been implicatedin descending inhibition of spinal nociceptive trans-mission.

Study PopulationThe study population in both the studies was opioidnaıve. They were either healthy volunteers or patientsundergoing surgery. No studies were available on can-cer or noncancer patients who have been on largerdoses of opioids.

Opioid Regimen During InterventionShort-acting opioids were used to induce hyperalge-sia in both studies. Both studies had control groupswithout opioids and the opioid groups without theNSAID had higher pain rating scores.

Effects of NSAIDs on Opioid-InducedHyperalgesiaTroster et al. (36) studied the modulation ofremifentanil-induced hyperalgesia by parecoxib. Ad-equate timing appeared to have clinical importancefor the antihyperalgesic effect of cyclooxygenase-2inhibitors. Interestingly, only early treatment withparecoxib 30 minutes before application of remifen-tanil significantly diminished the enlarged hyperal-gesic areas after cessation of the remifentanil infusion,whereas upon parallel application, parecoxib was in-effective. This would suggest that the interaction ofopioids and COX inhibitors underlying inhibition ofopioid-induced hyperalgesia is an early event and de-pends on whether prostaglandins have already sensi-tized the nociceptive system.

Xuerong et al. (17) concluded that patients whoreceived lornoxicam did not show sparing of opi-oid consumption postoperatively. Lornoxicam didnot have a direct preemptive effect. But it signifi-cantly diminished the acute opioid-induced hyperal-gesia caused by fentanyl. Lornoxicam had the sameeffect as ketamine in preventing the increase of post-operative morphine consumption induced by intra-operative administration of fentanyl. Patients whoreceived lornoxicam before fentanyl had the samecumulative postoperative morphine consumption aspatients in the control group during the first 48hours after surgery. The patients who received onlylornoxicam had no sparing of postoperative morphineconsumption compared with patients in the controlgroup. Lornoxicam therefore did not have direct pre-emptive effects, but preventive administration of thelornoxicam significantly diminished the acute opioid-induced hyperalgesia caused by fentanyl. Neither ofthe above studies mentioned side effects related toNSAIDs. Most side effects were due to the opioidsused. One of the reasons for the lack of side effectswas its short-term use. Table 3 displays the opioidregimens of the patients, the NSAIDs used to treatopioid-induced hyperalgesia and the duration of theirfollow-up. The final column includes the conclusionsof the respective authors.

Other Pharmacological Agentsα2 Agonists in the Management of Opioid-

Induced Hyperalgesia. The analgesic propertiesof α2 agonists are proposed to involve both pe-ripheral and central mechanisms. Clonidine anddexmedetomidine are selective agonists of the α2

receptor. Intrathecal clonidine administration hasbeen shown to suppress the spinal NMDA receptorphosphorylation in the spinal dorsal horn neurons(37). In addition to its central analgesic action, cloni-dine can induce peripheral antinociception by an



TABLE 3. Evidence Related to the Use of NSAIDs in Treatment of Opioid-Induced Hyperalgesia

Firstauthor(Year) Patients

Opioidregimenpreinter-vention

Opioidregimen

postinter-vention

NSAIDsdosage Pain stimulus

Pain mon-itoring

Follow-upPeriod Side effects Remarks

Troster(2006)

15 healthymalevolun-teers

Remifenanilinfusion

None Parecoxib 40mg eitherprior toinfusion orparallel toinfusion

Transcutaneouselectricalstimulation

Numericratingscale,measur-ingareas ofpinprickanalge-sia

Q 5 minfor 30mininfusionperiodQ 15minthere-after for150 min

None men-tioned

Preventive ad-ministrationof parecoxibsignificantlydiminishedthe enlargedhyperalgesicareas aftercessation oftheremifentanilinfusion,whereasparallel ad-ministrationof parecoxibdid not.

Xuerong(2008)

90 femalepatientsunder-goingTAH

Spinal +fentanylIV (3µg/kg)

Morphine Lornoxicam8 mg IVintraopera-tively

Surgicalstimulus

VASscoring

1, 3, 6, 12,24, and48 hpostop-eratively

None men-tioned

Patients whoreceivedlornoxicamalone didnot showopioidsparingpostopera-tively.However, itpreventedthe increaseof postoper-ativemorphineconsump-tion inducedby intraop-erativeadministra-tion offentanyl.

α2-adrenoreceptor–mediated local release ofenkephalin-like substances (38). Clonidine athigh concentrations may cause blockade of theC-fibers. Also it causes local vasoconstriction,which may result in higher concentrations of localanesthetic near the nerves (39).

In 13 healthy volunteers (17), clonidine alonedid not significantly attenuate pain or areas ofhyperalgesia. However, when given in combinationwith remifentanil, clonidine attenuated postinfusionincrease of pain ratings. Clonidine reduced theintensity of postinfusion hyperalgesia, but didnot decrease it below control levels. Clonidinegiven intravenously did show not show analgesiceffects in the study. However there are studies that

show α2-receptor agonists reduce pain via intrathecaland epidural routes (40, 41). Coadministration ofremifentanil and clonidine significantly increasedthe number of episodes with oxygen desaturation,which may limit the use of this combination forpostoperative pain control.

A case series (42) described 11 hospitalized pa-tients with painful medical conditions who weretreated with dexmedetomidine infusions after assess-ing for opioid-induced hyperalgesia using an algo-rithm. The case series showed a substantial reductionin baseline opioid doses in 7 out of the 11 patients.These cases support the clinical utility of α2 agonistssuch as dexmedetomidine during opioid dose reduc-tion in patients with opioid-induced hyperalgesia.



Buprenorphine in the Management ofOpioid-Induced HyperalgesiaBuprenorphine is a partial opioid agonist with antag-onist properties. It is a partial µ-receptor agonist anda κ- and δ-receptor antagonist (43). It is currentlyused for the treatment of opioid dependence in itssublingual form Suboxone. Its κ-receptor antagonismmay contribute to its ability to possibly reduce opioid-induced hyperalgesia. In a study of 15 healthy volun-teers who were started on intravenous and sublingualbuprenorphine (44), buprenorphine exerted lastingantihyperalgesic effects in patients with mechanicalinjury to the site. However, there were no changes inthe pain ratings in these patients. Nausea and vomit-ing was seen in 28% of the patients who were givenintravenous buprenorphine. More studies are neededto see if this translates to improvement in the treat-ment of opioid-induced hyperalgesia.

Amantidine in the Management ofOpioid-Induced HyperalgesiaAmantidine is primarily used for the treatment ofParkinson disease and as an antiviral drug. Ke-tamine and dextromethorphan have been studied fortheir role as NMDA receptor antagonists. Evidenceshows that amantidine is a noncompetitive NMDAreceptor antagonist and may be useful in prevent-ing opioid-induced hyperalgesia (45, 46). Amanti-dine may therefore decrease pain and analgesic re-quirements, possibly by preventing central sensiti-zation. In 24 patients undergoing prostate resection(47), there was a 32% reduction in morphine con-sumption over a 48-hour period in the group whoreceived amantadine the evening and 1 hour beforesurgery as well as post surgery.

Methadone in the Management ofOpioid-Induced HyperalgesiaMethadone is a synthetic opioid that is a µ- and δ-receptor agonist as well as a NMDA receptor an-tagonist (48). Methadone is currently used in pal-liative care as a second-line agent in opioid rota-tion for the treatment of opioid resistance. Opioidswitching in 17 cancer patients from transdermal fen-tanyl to oral methadone improved somatic pain in80% of the patients (49). Neuropathic pain did notimprove with the switch. High doses of methadoneproduce a µ effect that can overpower the drug’sNMDA effect and result in increased pain. Patientswith chronic pain managed on methadone and opioidaddicts on methadone maintenance have shown tohave increased sensitivity to some types of pain (50).This may limit its role in the treatment of opioid-induced hyperalgesia.

Opioid Switching in the Management ofOpioid-Induced HyperalgesiaPatients who have poor response to a certain opioidmay benefit from the pharmacological practice of opi-oid switching. The rationale is based on the differ-ence in the levels of tolerance induced by opioids andindividual variability (51). A review of 15 retrospec-tive studies and 15 prospective uncontrolled studies(52) showed morphine to be the first-line opioid andmethadone to be the most frequently used second-line opioid for switching. The review found opioidswitching to be useful in improving pain control andreducing opioid-related side effects. In one report(53), 18 patients were switched from fentanyl patchesto methadone and 7 from methadone to fentanylpatches. A significant decrease in pain and symptomintensity was found within 24 hours of switching in12 of the patients. A systematic review (54) of exist-ing literature showed a clinical improvement in morethan 50% of patients with chronic pain who had apoor response to one opioid. The evidence to supportthe practice of opioid switching is based on observa-tional and uncontrolled studies only. Importantly, theopioid 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 lit-erature and the final changes in regimen should behighly individualized (55).

Pharmacological Agents Used to Treat AcuteVersus Chronic Opioid-Induced Hyperalgesia

The majority of the studies obtained through thesearch were short-term studies looking into the im-mediate postoperative period. Many of them haddefined the use of intraoperative remifentanil asthe cause of opioid-induced hyperalgesia. Short-acting opioids may be accompanied by hyperalgesia.Remifentanil has been shown to induce acute opi-oid tolerance (56); hence an increase in postoperativemorphine consumption after remifentanil use may beexplained by the occurrence of opioid withdrawal hy-peralgesia (57).

Noncancer chronic pain patients taking eithermethadone or morphine were similar to patientsmaintained on methadone for dependence therapyin that both groups exhibited increased sensitivity tocertain experimental pain stimuli (48). Davis et al.(58) describes three forms of opioid-induced hyper-algesia. Most attention is paid to opioid-induced hy-peralgesia (OIH) in the context of opioid mainte-nance therapy or withdrawal. A second form of OIHhas been described in the setting of very high andescalating doses of opioids. The third form of OIHhas been seen in animals with the administration of



TABLE 4. Summary of Treatment Approaches for Opioid-Induced Hyperalgesia

• 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 ob-served in cancer patients, is unlikely to be mediatedthrough the opioid receptors and opioid antagonistsmay not alleviate the symptoms. Switching from aphenanthrene derivative such as morphine to a piperi-dine derivative (fentanyl) or methadone has been re-ported to attenuate the symptoms (59). NMDA re-ceptor antagonists may play a role as a therapeuticadjuvant secondary to the NMDA receptor–mediatedsymptoms of this second form of OIH. However,there is a lack of randomized controlled trials studyingthe pharmacological treatment of opioid-hyperalgesiarelated to chronic opioid therapy. Table 4 summa-rizes the treatment approaches for opioid-induced hy-peralgesia. These are suggestions and should be cus-tomized to meet the specific needs of the patients.

CLINICAL DILEMMAS/LIMITATIONS

We were unable to perform a meta-analysis owing tothe heterogeneity of the included studies. In many ofthese studies, we were unable to differentiate betweenopioid-induced hyperalgesia and tolerance. A directcause-and-effect relationship between opioids anddevelopment of opioid-induced hyperalgesia cannotbe demonstrated. The dilemma of opioid-induced hy-peralgesia is usually seen in the opioid-tolerant pa-tient who is unable to achieve adequate analgesia de-spite escalating doses of opioids. These patients nolonger respond to opioid escalations and still have in-sufficient pain control even when being on multipleadjuvant therapies, including antidepressants, anti-convulsants, and anti-inflammatory agents. None ofthe studies included here assessed such a patient pop-ulation.

There are several important methodological issuesin defining opioid-induced hyperalgesia that limit theinterpretation of the data and generate controver-sies regarding the pharmacological management ofopioid-induced hyperalgesia. One controversy is howto define opioid-induced hyperalgesia in the clinicalsetting, especially during short-term trials. It is diffi-cult to interpret small changes in scale scores. Was theincreased pain experienced really opioid-induced hy-peralgesia? The trials did not present data needed to

calculate such a measure because it is difficult to de-fine such characteristics. Unfortunately, many of theincluded trials had methodological weaknesses thatcompromised their results, including a lack of stan-dard case definition for opioid-induced hyperalgesia.Issues of optimal dose and form of administrationwere not resolved by these trials. The most commonroute of the administration was intravenous bolus orinfusion.

CONCLUSION

It is crucial to be able to differentiate between clini-cally worsening pain, tolerance, and opioid-inducedhyperalgesia because treatment of these conditionsdiffer. It is clear that there is no ideal agent in thetreatment of opioid-induced hyperalgesia. The man-agement of opioid-induced hyperalgesia should al-ways begin with an assessment of the patient for med-ical causes of the pain. If the problem persists afterthis has been addressed, opioid-induced hyperalgesiashould be considered in any patient with increasingpain who is not responding to increasing opioids. Thetreatment strategy needs to be individualized basedon the clinical scenario and the patient’s history andcondition.

Referral to pain and palliative care professionals isappropriate to help develop a management strategy.In general, treatment should include the followingstrategies: tapering or discontinuation of the currentopioid regimen, opioid switching, adding a NMDAreceptor antagonist such as ketamine and adding anonopioid adjuvant such as NSAIDs. The approachis to be guided by the current state of evidence incombination with the goal of minimizing adverse ef-fects. Other forms of analgesia, including regionaltechniques 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 pharma-cological interventions in this set of patients. Thediagnosis of opioid-induced hyperalgesia in patientsexposed to chronic opioids is more challenging, sec-ondary to the complexity of its diagnosis. It may bevaluable to initially examine pharmacological agents



in an acute setting and use that as a guide for furtherinvestigations. Future interventions that are currentlybeing studied in animal models include gabapentinand pregabalin.

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RECEIVED 25 January 2011ACCEPTED 13 May 2011


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