Opioid-induced Hyperalgesia...opioid-induced hyperalgesia, suggests a framework for organiz-ing pertinent information, delineates the status quo of our knowledge, identiﬁes potential

Anesthesiology 2006; 104:570–87 © 2006 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Opioid-induced Hyperalgesia

A Qualitative Systematic ReviewMartin S. Angst, M.D.,* J. David Clark, M.D., Ph.D.†

Opioids are the cornerstone therapy for the treatment ofmoderate to severe pain. Although common concerns regard-ing the use of opioids include the potential for detrimental sideeffects, physical dependence, and addiction, accumulating evi-dence suggests that opioids may yet cause another problem,often referred to as opioid-induced hyperalgesia. Somewhatparadoxically, opioid therapy aiming at alleviating pain mayrender patients more sensitive to pain and potentially mayaggravate their preexisting pain. This review provides a com-prehensive summary of basic and clinical research concerningopioid-induced hyperalgesia, suggests a framework for organiz-ing pertinent information, delineates the status quo of ourknowledge, identifies potential clinical implications, and dis-cusses future research directions.

OPIOIDS are the cornerstone therapy for alleviatingmoderate to severe pain. Whereas opioids have longbeen used for alleviating acute and cancer-related pain,they recently have gained significant popularity for thetreatment of chronic nonmalignant pain. Today, opioidsare second only to nonsteroidal antiinflammatory drugsin terms of prescription frequency for chronic pain.1

Common concerns regarding the use of opioids are thepotential for detrimental side effects, physical depen-dence, and addiction. However, recent research sug-gests that opioids may yet cause another problem, oftenreferred to as opioid-induced hyperalgesia (OIH). Pa-tients receiving opioids to control their pain somewhatparadoxically may become more sensitive to pain as adirect result of opioid therapy. That is, the use of opioidsmay be a double-edged sword. They provide straightanalgesic and antihyperalgesic effects initially, but sub-sequently are associated with the expression of hyperal-gesia likely reflecting upregulation of compensatorypronociceptive pathways.

Several recent articles have reviewed and highlightedimportant aspects of OIH, which reflects the growinginterest and rapidly expanding body of literature regard-ing this phenomenon.2–5 The aim of this article is toprovide a comprehensive and systematic review of theliterature pertinent to OIH. The primary intent of suchan undertaking is to provide the interested reader with

an all-inclusive and current overview of a topic that maybe difficult to grasp as a whole because new evidenceaccumulates quickly and in quite distinct research fields.As such, a comprehensive review may serve as a sourcedocument. However, a systematic review also uses aframework for presenting information, and such a frame-work may facilitate and clarify future communication byclearly delineating various entities or aspects of OIH.Finally, a systematic review aims at defining the statusquo of our knowledge concerning OIH, a necessary taskto guide future research efforts and to identify potentialclinical implications.

For the purpose of this review, it is important to pointout that OIH occurs in several distinct settings charac-terized by the opioid dose administered and the patternof administration. Most work reported OIH during ongo-ing (maintenance) therapy or withdrawal from opioids.Other bodies of literature documented OIH while admin-istering either very high or very low opioid doses. Al-though the opioid dose offers a convenient way to cat-egorize different types of OIH, it is less certain to whatdegree these phenomenological differences are mirroredby distinct mechanisms. Nevertheless, in this review weuse separate sections to discuss OIH in the context of (1)maintenance dosing and withdrawal, (2) at very high orescalating doses, and (3) at ultra-low doses. Each sectionis divided further into a human and animal/basic sciencedata subsection. At the end of each section, we drawconclusions and outline potential clinical implications.The review ends with a discussion of future researchdirections.

Literature Search

StrategyThe three major databases, PubMed, BIOSIS, and Psy-

cInfo, were searched for identifying articles pertinent toOIH. PubMed, BIOSIS, and PsycInfo index publicationsrelating to human health, the biologic and biomedicalsciences, and the field of psychology, respectively. Thesearch included all work published between the incep-tion of a database (PubMed, 1966; BIOSIS, 1969; Psy-cInfo, 1887) and September 2004.

PubMed. Ideally, a search in PubMed using the meshterms hyperalgesia/chemically induced AND analge-sics, opioid would have retrieved most of the relevantarticles. However, such a search missed important arti-cles when comparing results with an a priori index of allrelevant articles known to the authors. A more complexsearch accounting for variations in indexing was neces-

* Assistant Professor, Department of Anesthesia, Stanford University School ofMedicine, Stanford, California; † Associate Professor, Department of Anesthesia,Stanford University School of Medicine, Stanford, California, and Veterans AffairsPalo Alto Health Care System, Palo Alto, California.

Received from the Department of Anesthesia, Stanford University School ofMedicine, Stanford, California. Submitted for publication April 22, 2005. Ac-cepted for publication September 19, 2005. Support was provided solely frominstitutional and/or departmental sources.

Address correspondence to Dr. Angst: Department of Anesthesia, StanfordUniversity School of Medicine, 300 Pasteur Drive, Stanford, CA [email protected]. Individual article reprints may be purchased through theJournal Web site, www.anesthesiology.org.

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sary to retrieve most of the pertinent articles withoutlisting an abundance of irrelevant publications. The finalsearch in PubMed was based on four “hedges” of free-text terms and medical subject headings. Hedges oneand two, and hedges three and four were combined forthe search. Title rather than title/abstract searches wereused to minimize retrieval of irrelevant citations. Thehedges were as follows:

● Hedge 1 (induced hyperalgesia): hyperalgesia/chemi-cally induced [mesh] OR hyperalgesia/etiology OR an-tianalges* OR ((allodyni* [ti] OR hyperesthesi* [ti] ORhyperalg* [ti]) AND (produc* [ti] OR elicit* [ti] ORcause* [ti] OR trigger* [ti] OR refer* [ti] OR induc*[ti]));

● Hedge 2 (opioids): opioid* [ti] OR opiate* [ti] ORmorphine [ti] OR fentanyl [ti]) OR analgesics, opioid[pa] OR “opioid-related disorders”[mesh] OR “recep-tors, opioid”[mesh] OR “analgesics, opioid”[mesh];

● Hedge 3 (drug tolerance or withdrawal): (toler* [ti] ORwithdrawal [ti] OR adapt* [ti]) OR “substance with-drawal syndrome”[mesh] OR “drug tolerance”[mesh]OR “adaptation, physiologic”[mesh];

● Hedge 4 (increased sensitivity to pain or sensation):hyperalgesia [mesh] OR hyperalges* OR allodyni* ORhyperesthesi*.

Biosis. Variability in indexing required combing threehedges:

● Hedge 1 (title search): ((opiate* OR opioid* OR heroinOR fentanyl OR morphine) AND (antianalges* OR allo-dyni* OR hyperesthesi* OR hyperalg*)) NOT (antihy-peralges* OR “anti hyperalges*”));

● Hedge 2 (subject search): hyperalgesia AND drug-in-duced;

● Hedge 3 (subject search): ((hyperalgesia AND (opiate*OR opioid*)).

PsycInfo. A simple search using a single and fairlybroad hedge was sufficient:

● Hedge: hyperalgesia AND (kw: Opiate* Or kw: Opi-oid*).

ResultsThe search retrieved 869 citations. Based on the pre-

established criteria that only peer-reviewed original arti-cles published in English were considered for this re-view, a total of 213 citations were excluded (123meeting abstracts, 24 letters, 46 reviews, 3 meetingnotes, 9 book chapters, 5 articles not in English, 3 pat-ents). Of the remaining 656 articles, 139 were includedin this review, because they reported data relevant forthe discussion of hyperalgesia associated with the exog-enous administration of opioids (OIH). Most of the other517 articles were excluded because they reported opi-oid-mediated antinociceptive and antihyperalgesic ef-

fects. Other articles were excluded because they re-ported data obtained in nonmammalian species (lizards),hyperalgesia as a consequence of abstinence from en-dogenous opioids, or antianalgesic rather than hyperal-gesic treatment effects (attenuation of analgesic effectsrather than increased sensitivity to pain).

The 139 articles included in this review were supple-mented by an additional 41 publications. These 41 arti-cles were added because they were either identified bythe authors as containing relevant data when they re-viewed references cited in retrieved manuscripts, orthese articles provided important background informa-tion indirectly related to OIH. Specifically, 18 manu-scripts provided additional data relevant for the discus-sion of hyperalgesia associated with the exogenousadministration of opioids (2 manuscripts in nonmammalspecies but of particular interest), 7 articles reportedanalgesic effects in the context of opioid-antagonist ad-ministration, 8 articles documented mechanisms poten-tially related to OIH but without testing for the expres-sion of OIH, 7 manuscripts were reviews of topicspertinent to the discussion of OIH, and 1 referencereferred to a diagnostic guidebook. The 157 articlesreporting OIH in the context of exogenous opioid ad-ministration consist of 120 animal and 37 human studies.

OIH during Maintenance and Withdrawal

Human StudiesBrief Historical Perspective. For more than a cen-

tury, clinical reports have listed hyperesthesia or anincreased sensitivity to pain as one of the symptomsassociated with opioid withdrawal. In an essay datingback to 1880, Rossbach wrote, “[W] hen dependence onopioids finally becomes an illness of itself, opposite ef-fects like restlessness, sleep disturbance, hyperesthesia,neuralgia and irritability become manifest.”6 Six decadeslater, Himmelsbach gave a comprehensive description ofthe opioid abstinence syndrome and stated that “achingreferred to the bones, joints, and muscles is probably themost common symptom of withdrawal.”7 Today, painsymptoms are part of the criteria used for diagnosingopioid withdrawal.8 Although strictly observational innature, these clinical reports provide early cues for asignificant alteration of pain modulating neuronal sys-tems as a consequence of opioid therapy.

Recent Evidence. During the last decade, several clin-ical scientists became interested in exploring OIH as aconsequence of withdrawal and/or maintenance ther-apy. In contrast to early work in the field of addiction,recent studies focused on OIH in the context of painmanagement. The renewed interest in OIH was triggeredby dozens of animal studies conducted since the early1970s suggesting that administration of opioids paradox-ically may increase the sensitivity to pain and potentiallymay aggravate preexisting pain. This quite disturbing

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prospect triggered a series of controlled clinical trialsexamining expression and potential clinical impact ofOIH in humans.

Evidence so far suggests that OIH does develop inhumans and may have important clinical implications.Data supporting this notion has been collected in threedistinct experimental settings: (1) in former opioid ad-dicts maintained on methadone, (2) in patients undergo-ing surgery, and (3) in human volunteers tested in ex-perimental pain paradigms. These studies are discussedin more detail in the following paragraphs.

Former Opioid Addicts Maintained on Methadone.Different clinical investigators have measured pain sen-sitivity in former opioid addicts with aid of the coldpressor test and an electrical and/or a pressure painmodel.9–15 Results of these studies are summarized intable 1 and suggest that former opioid addicts main-tained on a stable dose of methadone are more sensitiveto cold pressor pain than former opioid addicts notmaintained on methadone or healthy controls.9–13 Hy-peralgesia to electrical stimulation was less pronouncedor not detectable at all, suggesting that OIH developsdifferentially for different types of pain.9,12,14 Similarly,hyperalgesia to mechanical pressure was not detected.15

It is noteworthy that the two studies reporting negativeresults for electrically and mechanically evoked painmeasured the pain threshold, which is less sensitive thanthe pain tolerance for detecting OIH.9,12

Findings in former opioid addicts maintained on meth-adone are compatible with the concept that hyperalgesiawas caused by chronic opioid therapy. However, thecited studies were cross-sectional rather than prospec-tive in design and do not allow establishing a cause-and-effect relationship. It can not be excluded that formeropioid addicts receiving methadone maintenanceseemed to be relatively hyperalgesic because increased

pain sensitivity may predispose to both becoming anaddict and requiring methadone to prevent relapse afterdetoxification. The fact that current users of both sub-stances, an opioid or cocaine, are more sensitive to coldpressor pain than former users of either drug is compat-ible with this latter view.11

Patients Undergoing Surgery. Two controlled studiesreported aggravated postoperative pain despite in-creased postoperative opioid consumption in patientsreceiving a high rather than a low systemic opioid doseduring surgery.16,17 Similarly, a study of women under-going cesarean section under spinal anesthesia docu-mented increased postoperative opioid consumption ifintrathecal opioids rather than saline placebo was in-jected before the surgery.18 In contrast, a fourth studyfailed to detect increased pain or exaggerated opioidconsumption in the postoperative period if patients hadreceived a high rather than a low systemic opioid doseduring surgery.19 This study explored the same opioidanalgesic in a similar patient population as Guignard etal.,16 who reported positive findings. However, the in-traoperative opioid dose administered to patients in thehigh-dose group was approximately 3.4 times higher inthe study by Guignard et al. (infusion rate and duration),suggesting dose dependency of the observed phenome-non (table 2).17–19

The finding of increased postoperative pain and post-operative opioid consumption in patients receiving ahigh rather than a low intraoperative opioid dose iscompatible with the view that OIH developed in thesepatients. Alternatively, these patients may have experi-enced acute tolerance to analgesic opioid effects. Al-though it is tempting to speculate that increased post-operative pain despite augmented opioid consumptionpoints toward OIH, no firm conclusions can be drawn.Differentiation between OIH and tolerance requires a

Table 1. Studies in Former Opioid Addicts Maintained on Methadone

Methadone Pain

ReferenceNo. Study Population (n) Daily dose (mg)* Duration (mo)* Test Threshold Tolerance Remarks

11 43 patients receivingmethadone; 26 patients notreceiving methadone

— — CPP — 42%2† Similar findings in current andformer cocaine users

15 42 patients; 16 controls 0.7 � 025 (mg/kg) 3–56 PP ND —14 18 patients; 10 controls 7.5–130 6–120 EP ND‡ —10 60 patients; 60 controls 66 � 20 �1 CPP — 53%2‡13 18 patients; 18 controls 66 � 21 �1 CPP — 56%2‡12 16 patients; 16 controls 62 � 6 4–120 CPP 43%2§ 74%2§ At peak plasma concentration,

EP ND 15%2 no hyperalgesia for EP and57%2 for CPP

9 4 patients; 4 controls 81 � 25 9–96 CPP 34%2§ 76%2§ At peak plasma concentration,EP ND ND 56%2 for CPP

* Mean � SD or range. † Time of testing relative to time of drug intake not specified. ‡ Measurements obtained within 2 h of drug administration.§ Measurements obtained at trough plasma concentrations.

— � no data available;2 � decrease compared with controls; CPP � cold pressure pain evoked by ice-water immersion of hand; EP � electrically inducedpain at earlobe; ND � no difference; PP � blunt pressure pain evoked on middle phalanx of digit.

572 M. S. ANGST AND J. D. CLARK


method directly assessing pain sensitivity. Implementa-tion of such a method into a clinical trial is difficult andhas not yet been attempted.

Experimental Pain Studies in Human Volunteers.Two sets of experiments have been performed to docu-ment OIH in human volunteers. A first set explored theeffect of a short-term opioid infusion on an experimentalskin lesion rendered hyperalgesic before starting thedrug infusion.20–23 A second set explored the effects ofopioid antagonist precipitated withdrawal on cold pres-sor pain in volunteers made acutely dependent on opi-oids.24

Several investigators observed aggravation of preexist-ing mechanical hyperalgesia after a 30- to 90-min infu-sion with the ultra–short-acting opioid agonist remifen-tanil. Aggravation was reflected by a 1.4- to 2.2-foldenlargement of the hyperalgesic skin area comparedwith preinfusion measurements, and the magnitude ofthis effect was related directly to the infusion durationand the opioid dose.20–22,25 Aggravation of preexistinghyperalgesia was observed up to 4 h after stopping theremifentanil infusion, but was no longer evident whenassessed on the subsequent day.21 These changes areconsistent with an expanded area of secondary hyperal-gesia thought to be the result of enhanced nociceptivesignal processing at the level of the spinal cord. Twostudies also assessed the effect of remifentanil exposureon heat pain sensitivity.20,21 Contrasting with resultsobtained in hyperalgesic skin, heat pain sensitivity innormal skin was not different before and after remifen-tanil exposure, suggesting that OIH develops differen-tially for different types of pain. Two studies docu-mented that coadministration of ketamine abolishedremifentanil-induced aggravation of preexisting hyperal-gesia, thereby implying an N-methyl-D-aspartate (NMDA)receptor-dependent underlying mechanism.20,22 Finally,one report suggested that coadministration of the �-2-receptor agonist clonidine attenuated remifentanil-in-duced aggravation of preexisting hyperalgesia.22

A single study examined pain sensitivity to cold pres-sor pain in a model of acute physical opioid dependencein a small number of human volunteers. Two to 4 h after

a single injection of morphine or hydromorphone, with-drawal was precipitated with the intravenous adminis-tration of the opioid antagonist naloxone. Subjective andobjective signs of withdrawal became evident in all sub-jects and were accompanied by a significantly increasedsensitivity to cold pressor pain.24,26

Finally, a single study reported hyperalgesia to pres-sure-evoked pain after a short-term infusion of remifen-tanil in volunteers.27 However, these investigators ex-posed volunteers to significantly higher nociceptiveinput during remifentanil than during saline placeboadministration. It can not be excluded that postinfusionhyperalgesia resulted from more intense noxious stimu-lation during the remifentanil infusion rather than theopioid administration itself.

In summary, studies in human volunteers involving theshort-term administration of opioids provide the onlycurrently available direct evidence for the existence ofOIH in humans using models of secondary hyperalgesiaand cold pressor pain.

Small and Anecdotal Reports. Our search also re-vealed a series of isolated reports perhaps consistentwith OIH in patients. In the first, a patient underwentthree separate withdrawal episodes while being evalu-ated and treated for chronic back and radicular pain withan intrathecal morphine pump.28 Withdrawal signs andsymptoms included fever, vomiting, diarrhea, disturbedsense of smell, and ataxia. Painful paresthesias to brushon all four extremities also were noted. In the secondstudy, investigators compared the analgesic effects ofmorphine between human volunteers and pain patientson chronic opioid therapy. This provided the first quan-titative evidence for OIH.29 The authors observed thatstudy patients undergoing withdrawal had a significantlylower tolerance to heat-evoked pain (outside the 95%confidence interval) compared with healthy volunteers.Last, a single report by Seymour et al.30 described en-hanced pain after third molar extraction in patientsgiven regular doses of dihydrocodeine after surgery, al-though other reports documented modest analgesic ef-fectiveness of dihydrocodeine for postoperative pain.31

Table 2. Studies in Patients Undergoing Surgery

Intraoperative Data

Postoperative Data(High vs. Low

Intraoperative Opioid Dose)

Reference No. Surgery Opioid Dose Opioid Use Pain Remarks

18 Cesarean section Fentanyl IT 0 vs. 25 �g 60%1 ND n � 60; 23-h observation17 Hysterectomy Fentanyl IV 1 vs. 22 �g/kg 120%1 30%1 n � 60; 16-h observation16 Colectomy Remifentanil IV 0.1 vs. 0.3 �g · kg�1 · min–1

for 260 min85%1 50%1 n � 50; 24-h observation

19 Gynecologic Remifentanil IV 0.1 vs. 0.23 �g · kg�1 · min–1

for 100 minND ND n � 60; 24-h observation

IT � intrathecal; IV � intravenous; ND � not different.



Table 3. Animal Studies Reporting Opioid-induced Hyperalgesia during Maintenance and Withdrawal

Investigator(s), yr Reference Animal Route Drug Nociceptive Test Mechanism(s) Explored

Aley and Levine, 1995 50 Rat ID DAMGO MechanicalAley and Levine, 1997 51 Rat ID DAMGO Mechanical AC, calcium, PKCAley and Levine, 1997 52 Rat ID DAMGO Mechanical PKCAley and Levine, 1997 53 Rat ID DAMGO MechanicalArts et al., 1991 54 Mouse ICV Morphine Thermal DynorphinBederson et al., 1990 142 Rat IV Morphine Thermal RVM (on cell/off cell activity)Bie et al., 2003 143 Rat IV Morphine Thermal NRM (�1-adrenergic receptor)Bie, 2003 144 Rat IP Morphine Thermal NRM (�-opioid receptor)Burdin et al., 1992 145 Rat PAG Morphine Electrical PAG (opioid modulation)

Celerier et al., 1999 38 Rat SCMorphine

Mechanical NMDA receptorFentanyl

Celerier et al., 2000 43 Rat SC Fentanyl Mechanical NMDA receptorCelerier et al., 2001 37 Rat SC Heroin Mechanical NMDA receptor

Celerier et al., 2004 39 Mouse SC FentanylMechanical

PKC�Chemical

Christensen and Kayser, 2000 146 Rat SC Morphine MechanicalColpaert et al., 2002 147 Rat SC Morphine MechanicalCrain and Shen, 2004 136 Rat SC Morphine Thermal Neuraminidase/GM1

gangliosideDavies et al., 2003 49 Mouse SC Morphine MechanicalDoerr and Kristal, 1991 148 Rat IP Morphine Thermal Amniotic fluidDunbar and Pulai, 1998 60 Rat IT Morphine Thermal NMDA receptorDunbar et al., 2000 65 Rat IT Morphine Thermal CyclooxygenaseDunbar and Karamian, 2003 100 Rat IT Morphine Thermal EAA release, NMDA receptorEkblom et al., 1993 149 Rat IV Morphine ThermalGaleotti et al., 2002 150 Mouse Oral Morphine Thermal Caffeine, indomethacin,

prochlorperazine

Gardell et al., 2002 76 Rat SC MorphineMechanical

DynorphinThermal

Grilly et al., 1981 151 Rat SC Morphine ElectricalGrilly et al., 1986 152 Rat SC Morphine ElectricalHarris et al., 2004 153 Rat IP Morphine ThermalHeinzen and Pollack, 2004 154 Rat IV Morphine Electrical NOSHendrie, 1985 137 Rat Oral Morphine Thermal AdrenocorticotropinHendrie, 1989 155 Mouse IP Morphine Thermal Endogenous opioid systemHoffmann et al., 1998 156 Rat SC Morphine Thermal Genetic factorsIbuki et al., 1997 45 Rat IT Morphine Thermal NMDA receptor, EAAJohnston et al., 2004 66 Rat IT Morphine Thermal Cytokines

Kang et al., 2002 157 Rat FentanylThermal

Cyclooxygenase activityMechanical

Kaplan and Fields, 1991 158 Rat RVM,IV

Morphine Thermal RVM

Kayan and Mitchell, 1968 159 Cat SC Morphine ElectricalKayan et al., 1971 32 Rat SC Morphine ThermalKest et al., 2002 160 Mouse SC Morphine Thermal Genetic factorsKhasar et al., 1995 55 Rat ID DAMGO Thermal ACKim et al., 1990 161 Rat IV Morphine ThermalKim and Siegel, 2001 162 Rat IV Morphine Thermal CholecystokininKissin et al., 2000 163 Rat IV Alfentanil Mechanical NMDA receptorLane et al., 2004 164 Rat PAG Morphine Thermal PAGLarcher et al., 1998 165 Rat SC Heroin Mechanical NMDA receptorLaulin et al., 1999 40 Rat SC Heroin Mechanical NMDA receptorLaulin et al., 2002 42 Rat SC Fentanyl Mechanical NMDA receptorLi et al., 2001 36 Rat SC Morphine Thermal, mechanical,

incisionEndogenous opioid system

Li et al., 2001 46 Mouse SCMorphine Thermal, mechanical,

chemicalNMDA, NOS and HO

receptorsFentanylLi and Clark, 2002 35 Mouse SC Morphine Thermal, mechanical,

ITneurotransmitters

Glutamate, substance P

Liang et al., 2003 73 Mouse SC Morphine Thermal, mechanical HO systemManning et al., 1996 166 Rat SC Morphine Thermal NMDA receptorMao et al., 1994 48 Rat IT Morphine Thermal NMDA receptor, non-NMDA

glutamate receptor, PKC(continued)



Animal StudiesEarly Studies: OIH as a Measure of Physical De-

pendence. For more than three decades, it has beenrecognized that systemic administration of opioids torodents can lead to a hyperalgesic response during with-drawal. Early studies documented that such hyperalgesiacan be observed after precipitating withdrawal with theinjection of an opioid antagonist as well as during spon-taneous withdrawal after cessation of opioid administra-tion.32–34 The objective of these studies was to examinewhether the hyperalgesic response was useful as a quan-titative measure of opioid dependence. They did notemphasize the potential impact of OIH on pain manage-ment. This not only may reflect the primary researchfocus of the investigators on questions relating to addic-tion rather than pain management, but also may reflect amore restricted medical use of opioids for the treatmentof chronic pain at that time.

The Mechanistic Exploration of OIH. More recentinvestigations have focused on OIH as a phenomenonrelevant to clinical pain management. Many animal stud-ies describing various aspects of the pharmacology, bio-chemistry, and functional neuroanatomy of this phenom-enon were identified in our literature search. The

phenomenon of OIH as it is studied during consistentopioid dosing or after abrupt discontinuation of opioidadministration can be described in terms of several di-mensions, including the nociceptive modality renderedhyperalgesic, the time course of hyperalgesia, the opioidreceptor system implicated, and the neuroanatomicalstructures and signaling pathways involved. Table 3 pro-vides a comprehensive listing of all studies describingOIH in rodent model systems. Excluded from this tableare studies specifically addressing the phenomenon ofassociative hyperalgesia and studies examining hyperal-gesia in the context of administering �-opioid receptoragonists. These types of hyperalgesia reflect specialentities and are addressed in separate sections of thisreview.

Nociceptive Methods. The increased pain sensitivityinduced by exposure to opioids has been demonstratedin many different nociceptive assays. Table 3 lists thesemethods separately for each study. Although all assaysusing heat, mechanical stimuli, or chemical irritants re-lied on the activation of peripheral nociceptors, therewas a single study demonstrating OIH after nociceptivestimulation at the level of the spinal cord via intrathecalneurotransmitter injections.35 Examining the data of all

Table 3. (continued)

Investigator(s), yr Reference Animal Route Drug Nociceptive Test Mechanism(s) Explored

Mao et al., 2002 62 Rat IT Morphine Thermal Glutamate transporters,NMDA receptor

McNally and Akil, 2002 167 Rat SC Morphine Thermal Corticotropin-releasinghormone

Milne et al., 1985 168 Rat SC Morphine ThermalOhnishi et al., 1990 169 Mouse SC Morphine Chemical Calcium ion channelPlesan et al., 1999 170 Rat SC Morphine Thermal NMDA receptorRaghavendra et al., 2002 171 Rat SC Morphine Thermal, mechanical Glia/cytokinesRaghavendra et al., 2003 75 Rat SC Morphine Thermal, mechanical Glia/cytokinesRaghavendra et al., 2004 172 Rat SC Morphine Thermal, mechanical Glia/cytokinesRivat et al., 2002 44 Rat SC Fentanyl Chemical NMDA receptorSalimov et al., 1993 173 Mouse SC Morphine Thermal Alcohol deprivationSchmidt and Way, 1980 174 Mouse SC Morphine Thermal CalciumShen and Crain, 2001 175 Mouse SC Morphine Thermal Cholera toxinSweitzer et al., 2004 176 Mouse SC Morphine Thermal, mechanicalSweitzer et al., 2004 71 Mouse SC Morphine Thermal PKCTilson et al., 1973 33 Rat IP Morphine ElectricalTislon and Reech, 1974 177 Rat SC Morphine Electrical p-chlorophenylalanineVanderah et al., 2000 64 Rat IT DAMGO Thermal, mechanical DynorphinVanderah et al., 2001 47 Rat SC Morphine Thermal, mechanical RVMVonVoigtlander and Lewis,

198334 Mouse SC Morphine,

penta-zocine,ethylketo-cyclazocine,nalbu-phine,butorphanol

Chemical

Welin et al., 1994 178 Rat SC Morphine MechanicalWilcox et al., 1979 179 Rat SC Morphine ElectricalYu et al., 1997 180 Rat IT Morphine Thermal, mechanicalZeitz et al., 2001 70 Mouse SC Morphine Chemical PKC

AC � adenylate cyclase; DAMGO � Tyr-D-Ala-Gly-(me) Phe-Gly-ol; EAA � excitatory amino acids; HO � heme oxygenase; ICV � intracerebroventricular; ID �intradermal; IP � intraperitoneal; IT � intrathecal; IV � intravenous; NMDA � N-methyl-D-aspartate; NOS � nitric oxide synthase; NRM � nucleus raphe magnus;PAG � periaqueductal gray; PKC � phosphokinase C; RVM � rostral ventral medulla; SC � subcutaneous.



these studies suggests variable susceptibility of differentpain signaling pathways to express OIH. Probably bestdocumented is a greater susceptibility of pathways acti-vated by mechanical (punctuated pressure) rather thanthermal (heat) noxious stimuli.

Few studies have attempted to go beyond assays usingbrief noxious stimuli to better mimic clinical pain. Vir-tually lacking are investigations examining the potentialimpact of OIH in models of chronic pain. One study useda hind paw incision, a model of postsurgical pain. Ani-mals chronically treated with morphine experiencedmuch more marked hyperalgesia in response to the hindpaw incision than opioid-naı̈ve animals.36 Findings ofthis study fit well with human data suggesting that pa-tients receiving a high rather than a low intraoperativeopioid dose experience increased pain after surgery de-spite higher postoperative opioid consumption.16–18

Time Course. Two fundamental patterns characteriz-ing the onset and resolution of OIH can be distinguished.The first is observed after the acute administration of anopioid, that is, the systemic administration of one to fourrelatively high opioid doses within 1 h. Morphine, her-oin, and fentanyl have been administered acutely to miceand rats and evoked a consistent, biphasic, and dose-dependent response. Intense antinociceptive effectswere followed by a 2- to 3-h period of mechanical hy-peralgesia.37–42 However, one of these studies demon-strated prolonged hyperalgesia that lasted up to 5daysafter a very high dose of fentanyl.43 A second experimentadministering a similarly high dose of fentanyl beforeinjecting carrageenan into the hind paw demonstratedthat hyperalgesia associated with hind paw inflammationwas prolonged from 2 to 10 days.44 Thus acute opioidadministration typically has evoked a transient hyperal-gesic response lasting for hours, except for some in-stances of prolonged hyperalgesia lasting for days. Theduration of acute OIH clearly is related to the opioiddose.

More commonly investigators have exposed animals toopioids on a more chronic time course (3–12 days) viarepeated subcutaneous injections, implantation of sub-cutaneous opioid containing pellets or pumps, or inter-mittent administration or continuous infusions throughindwelling intrathecal catheters. If animals were givenopioids by continuous techniques, antinociception typ-ically was measurable for the first day, which was fol-lowed by a loss of this effect or even by a hyperalgesicstate during ongoing drug administration.36,45–47 Ani-mals given repeated systemic or intrathecal boluses ofopioids developed progressive hyperalgesia to thermal ormechanical stimuli over the course of several days.37,48

Where studied, the time course of resolution of OIH wassimilar to the time course of its development.36,37,46,49

Of particular interest is a study by Celerier et al.37

documenting that animals with normal noxious sensitiv-ity after recovering from OIH expressed recurrent and

robust hyperalgesia if challenged with a single bolus ofeither drug, an opioid agonist or antagonist. These find-ings have two important implications. First, animals ap-parently recovered from OIH remained sensitized to thehyperalgesic effects of opioids. Second, this sensitizationmost likely was opposed by an endogenous opioidergicsystem, because the injection of an opioid antagonistunmasked hyperalgesia. This implies that OIH resolvedbecause of upregulated inhibitory pathways opposingactivity of sensitized excitatory pathways rather than thedesensitization of excitatory pathways. According to thisconcept, resolution of OIH occurred at a new equilib-rium of high neuronal activity between excitatory andinhibitory pathways (fig. 1). It is conceivable that anequilibrium achieved at a high level of neuronal activityis prone to derangements, which in a clinical contextmay translate into increased vulnerability to pain.

Site of Action and Signaling Systems. Studies examin-ing OIH can be characterized by the route of opioidadministration. Because drugs are distributed differentlyafter peripheral, intrathecal, or systemic administration,interpretation can be made about potential mechanismsunderlying observed OIH. This section of the manuscriptsummarizes studies investigating signaling systems medi-ating OIH because anatomical site and signaling systemsoften have been explored within the same set of exper-iments. Figure 2 provides a diagram summarizing theneuroanatomical sites implicated in the expression ofOIH.

Fig. 1. A model of the neuroadaptive changes underlying ex-pression and recovery of opioid-induced hyperalgesia (OIH)has been suggested by Celerier et al.37 Antinociceptive (whitebars) and pronociceptive (black bars) systems are in balance ata low level of neuronal activity before the exposure to opioids.Pronociceptive systems become upregulated as a result of opi-oid exposure, which is reflected by the development of OIH.Upregulation of antinociceptive systems is associated with thediscontinuation of opioid exposure, which results in the offsetof OIH. However, recovery from OIH is the result of a newequilibrium between pronociceptive and antinociceptive sys-tems that occurs at high level of neuronal activity. The high-level balance between pronociceptive and antinociceptive sys-tems may be prone to derangements, which in a clinical contextmay build the basis for a long-term vulnerability to pain. FromCelerier et al.37; used with permission, copyright 2001 by theSociety for Neuroscience.



Peripheral administration. Opioids have been ad-ministered locally in very small volumes to rodent hindpaw tissue. In a series of studies, it was demonstratedthat the repeated local injection of the selective �-opioidagonist Tyr-D-Ala-Gly-(me) Phe-Gly-ol (DAMGO) fol-lowed by the local administration of the opioid antago-nist naloxone caused mechanical hyperalgesia.50–55 Thishyperalgesic state seemed to be dependent on proteinkinase C activity as well as the activation of guanosinetriphosphate binding proteins.51,55

Spinal administration. Mao et al.48 conducted oneof the earliest and most complete studies examining therole of the spinal cord in the genesis of OIH. Rats receiv-ing intrathecal morphine for 8 days developed thermalhyperalgesia in association with antinociceptive toler-ance, suggesting similar underlying mechanisms. Theexcitatory amino acid (EAA) neurotransmitter and recep-tor system was implicated because coadministration ofthe NMDA receptor antagonist MK-801 or the non-NMDA EAA-receptor antagonist 6-cyano-7-nitroquinoxa-line-2,3-dione with intrathecal morphine fully or partiallyblocked the development of OIH and tolerance. A criti-cal role of the intracellular messenger phosphokinase C(PKC) for developing OIH and tolerance was suggestedby the fact that both phenomena were prevented by thePKC inhibitor GM1 ganglioside. Studies in a culturedneuronal cell line also suggested a modulating role ofGM1 ganglioside in opioid-related neuroplasticity.56 Maoet al.57–59 demonstrated that the EAA receptor and neu-rotransmitter systems not only are relevant for hyperal-gesia observed in conjunction with opioid administra-tion, but also for hyperalgesia associated with chronicpain states.

Dunbar et al.60 demonstrated independently thatNMDA receptor antagonists reduce thermal hyperalgesiacaused by intrathecal morphine administration. An in-

creased content of EAA in spinal cord tissue has beenverified directly in the context of chronic intrathecalmorphine administration.61 An increased availability ofspinal EAA may be caused in part by a decreased activityof spinal glutamate transport systems associated withintrathecal opioid administration.62 Spinal injection ofthe EAA glutamate but also of the neurokinin-1 agonistsubstance P in mice chronically exposed to morphineevoked an exaggerated pain response.46 Others havedemonstrated increased expression of several primaryneurotransmitters in dorsal root ganglion neurons whenchronically exposed to opioids.63 Therefore, OIH hasbeen linked to enhanced EAA availability and receptorsensitivity in spinal cord tissue, although other neuro-transmitter systems may play a role as well.

Vanderah et al.64 demonstrated that chronic intrathe-cal administration of the selective �-opioid receptor ag-onist DAMGO enhanced spinal expression of dynorphinand suggested that the release of dynorphin was a criti-cal step in propagating OIH. Spinal prostaglandins maybe of some importance, because intrathecal administra-tion of the cyclooxygenase inhibitor ibuprofen reversedhyperalgesia associated with opioid antagonist precipi-tated withdrawal.65 Finally, spinal cytokines (interleukin1�) and chemokines (fractalkine) may be relevant for thedevelopment of OIH.66 The role of neuronal systemsother than the EAA system and likely interactions be-tween relevant neuronal systems in the expression ofOIH are not yet well understood and need further clar-ification.

Experiments discussed so far used behavioral data tosupport a role of the spinal cord in the genesis of OIH.However, studies using c-fos protein immunocytochem-istry to quantify neuronal activity have been consistentwith the view that chronic exposure to morphine cansensitize neurons in the dorsal horn of the spinal cord.Opioid antagonists precipitated not only physical signsof withdrawal in rats chronically exposed to morphine,but also increased c-fos expression in sensory neurons ofthe spinal cord.67,68 Injection of noxious formalin intothe hind paw also resulted in an accentuated expressionof c-fos in the spinal cord if rats had been chronicallytreated with morphine.69 Li et al.35 found a similarlyenhanced expression of spinal c-fos in response to nox-ious mechanical stimulation if mice had been chronicallyexposed to morphine.

Systemic administration. The systemic delivery ofopioids has been used most often to study OIH in ani-mals. Much of the work centered on the EAA system, andthe NMDA receptor in particular. Results are consistentwith those obtained after intrathecal opioid administra-tion. The systemic administration of the NMDA receptorantagonist MK-801, or ketamine, reversed opioid-in-duced thermal and mechanical hyperalgesia after acute(one injection or multiple injections on a single day) andchronic opioid administration (5 days continuous-

Fig. 2. Neuroanatomical sites and mechanisms implicated in thedevelopment of opioid-induced hyperalgesia during mainte-nance therapy and withdrawal. (1) Sensitization of peripheralnerve endings. (2) Enhanced descending facilitation of nocicep-tive signal transmission. (3) Enhanced production and releaseas well as diminished reuptake of nociceptive neurotransmit-ters. (4) Sensitization of second-order neurons to nociceptiveneurotransmitters. Figure 2 does not illustrate all potentialmechanisms underlying opioid-induced hyperalgesia, butrather depicts those that have been more commonly studied.DRG � dorsal root ganglion; RVM � rostral ventral medulla.



ly).37,38,40–44,46 A role for the intracellular messengerPKC has been suggested by several groups. Administra-tion of an opioid evoked OIH in wild-type mice but notin mice lacking the PKC-� gene.39,70 Also, Sweitzer et al.used selective PKC antagonists to demonstrate a role forboth PKC-� and PKC-� for the expression of hyperalgesiaduring morphine withdrawal in rat pups.71

Other mechanisms have been implicated in OIH.Blocking the monoxide signaling systems heme oxygen-ase and nitric oxide synthase reversed OIH in micechronically treated with morphine.46 Similar to the EAA-system, both of the monoxide signaling systems alsohave been implicated in opioid tolerance, and the linkbetween NMDA receptor activation and enhanced NOSactivity supporting opioid tolerance has received signif-icant attention.72–74 Both the heme oxygenase and nitricoxide synthase systems are also involved in modulatingchronic pain states, again suggesting that similar path-ways mediate hyperalgesia observed in OIH and chronicpain. Although probably underappreciated for their rolesin nociceptive neurotransmission, glial cells in the spinalcord become activated and produce enhanced levels ofcytokines in rats rendered hyperalgesic with systemicmorphine treatment.75

One set of studies suggested involvement of the brain-stem in OIH.47,76 Experiments used stereotactic injec-tions of local anesthetics into the rostral ventromedialmedulla or surgical lesioning of the dorsolateral funicu-lus to demonstrate that descending pain facilitating path-ways play a role in the genesis of OIH. These pathwaysmay trigger the release of dynorphin and calcitonin gene-related peptide at the level of the spinal cord. Consider-ing the results of all the studies examining differentanatomical sites and structures for their involvement inOIH, it is most likely that relevant changes occur atmultiple levels of the nervous system, including thebrainstem nuclei, spinal cord neurons, glia, and primaryafferent neurons.

It should be recognized that the doses of morphineused in the aforementioned studies were generally farhigher than those used in the management of pain inhumans. Also, the period of exposure generally wasquite short compared with common human scenarios.This raises the possibility that the mechanisms responsi-ble for rodent OIH are different to some extent fromthose responsible for the phenomena in humans.

Opioid Receptor Subtypes. Many different �-opioidreceptor agonists elicit OIH. Most investigators adminis-tered morphine, but, as summarized in table 3, othersexplored opioids included heroin, fentanyl, DAMGO,pentazocine, nalbuphine, and butorphanol. Some ofthese compounds, like fentanyl and DAMGO, show se-lectivity for the �-opioid receptor, whereas others areless selective for various opioid receptor subtypes. How-ever, CXBK mice, a strain expressing �-opioid receptorsat a very low density, did not develop OIH in a protocol

rendering wild-type mice hyperalgesic.46 This suggeststhat the �-opioid receptor system plays a relevant role inthe development of OIH.

Exogenous administration or enhanced endogenousrelease of �-opioid receptor agonists can result in bothhyperalgesic and antinociceptive effects.77 Factors deter-mining the net effect of �-agonist administration arecomplex, incompletely understood, and likely includethe site of drug administration and the nociceptivemethod tested. Given the scope of this review, studiespredominantly reporting on the hyperalgesic effects of�-agonist are briefly discussed in the next paragraph.

Intrathecal lumbar injections of �-agonists resulted inthermal and mechanical hyperalgesia and aggravated al-lodynia in dogs, guinea pigs, and rats tested in models ofacute and chronic pain.78–80 Microinjections of �-ago-nists into the rat brain stem caused heat hyperalgesia atthe mesencephalic tegmentum but antinociception atthe lower medulla.81 Blocking the endogenous �-agonistdynorphin at the level of the mesencephalic tegmentumenhanced antinociception, suggesting that tonic noci-ceptive facilitation mediated by �-receptor originatesfrom this site.82,83 A role for �-receptor–mediated med-ullary hyperalgesia also was suggested by experimentsinjecting �-agonist into the forth ventricle of rats.84 Fi-nally, a single study reported heat hyperalgesia after theperipheral, subcutaneous administration of dynorphin inrats.85

Contrary to the biphasic, analgesic-hyperalgesic tem-poral response observed after administering �-opioidagonists, the response elicited by �-opioid agonistsseems to be monophasic, that is, either analgesic orhyperalgesic. Although the �-opioid receptor is a likelycandidate for triggering events leading to OIH, it is en-tirely possible that �-opioid receptors play a role in themanifestation of OIH. The increased expression and re-lease of spinal dynorphin during chronic exposure to�-opioid agonists recently has been cited as a mecha-nism supporting OIH in rats.64,76

Associative Hyperalgesia. Although most of the workinvestigating mechanisms supporting OIH has been bio-chemical in its orientation, several laboratories have fo-cused on learning and conditioning as factors contribut-ing to the expression of OIH. These studies wereconducted pursuant to the hypothesis that animals asso-ciate opioid injections and opioid effects with environ-mental cues. As a consequence of such association, ani-mals express a conditioned drug response that istriggered by environmental cues and typically antago-nizes the original opioid effect. According to this con-cept, OIH in the setting of repetitive dosing can beviewed as a conditioned drug response opposing antino-ciceptive opioid effects. Although reasonable consensusexists about the role of a conditioned drug response inthe development of antinociceptive opioid tolerance, itis less clear whether a conditioned drug response con-



tributes to the expression of OIH. Data from severalstudies support this concept.86–92 However, other stud-ies found no evidence for the development of associativehyperalgesia.93–96 Several investigators pointed out thatthe specific drug administration algorithm and nocicep-tive assay may be decisive factors determining whetherassociative hyperalgesia is expressed.86,97,98 Mechanismsunderlying associative hyperalgesia are poorly under-stood, although one study suggested that NMDA recep-tors may mediate it.99

Based on existing animal data, it remains controversialwhether an associative hyperalgesic component signifi-cantly contributes to the expression of OIH. In fact, moststudies exploring OIH were not designed to clarify thisquestion because they neither systematically excludednor intentionally provided environmental clues to con-trol for an associative component.

OIH versus Tolerance to Analgesic Effects. Exposureto opioids can result in a need to increase the dose overtime to maintain a desired analgesic effect. Typically, thishas been attributed to the development of tolerance.However, dose escalation can also be expected as aresult of OIH. Pharmacologically, tolerance is character-ized by a loss of drug potency or a right-shift of the doseversus effect relationship, while OIH is characterized byincreased pain sensitivity or a downward-shift of thedose versus effect relationship. Figure 3 illustrates whyboth of these pharmacologically distinct phenomenashare the same net effect on dose requirements. Mech-anistically, tolerance reflects a desensitization of antino-ciceptive pathways to opioids, whereas hyperalgesia in-volves a sensitization of pronociceptive pathways. Sucha distinction is not trivial and becomes relevant whenattempting to overcome a loss of treatment effect. Tol-erance may be addressed by increasing the opioid dose,whereas the same intervention may result in aggravatedpain in case of OIH. Furthermore, some of the mecha-nisms underlying the two phenomena may be distinctand amenable to different preventive or therapeuticstrategies.

Tolerance and OIH can be demonstrated and distin-guished in animal behavioral studies by measuring base-line pain sensitivity and antinociceptive potency of anopioid over time. In a clinical setting, distinguishing thetwo phenomena is much more challenging and often isimpossible. The assumption that the two conditions arelikely to coexist is probably safe, because both involvestimulation of opioid receptors and share some neuro-transmitter and receptor systems, including dynorphin,PKC, NMDA receptors, nitric oxide synthase, hemoxy-genase, and others. However, two sets of observationssuggest that OIH and tolerance may not contribute instrict proportion to a loss of treatment effect or the needfor dose escalation. First, intermittent administration ofthe opioid-receptor antagonist naloxone during ongoing,intrathecal administration of morphine in rats aggravated

OIH, whereas the degree of opioid tolerance remainedunaffected.100 Second, experiments using repeated her-oin administration in rats suggested that there was onlyan apparent loss of antinociceptive potency over time,which was no longer present when accounting forchanges in baseline pain sensitivity. In other words,these experiments documented a lowered noxiousthreshold to mechanical stimulation with repeated her-oin injections but maintained antinociceptive potency ofheroin when considering relative rather than absolutechanges of the mechanical pain threshold in response todrug administration.37 Although OIH and tolerance mayshare certain mechanistic components, the relative ex-pression of both phenomena may vary depending on theopioid treatment protocol and the nociceptive assayused.

Considerations and RecommendationsAbove, we addressed OIH as it has been most com-

monly explored in laboratory and clinical studies. Withrespect to rodent studies, many investigators using avariety of opioids, dosing schedules, routes of adminis-tration, and nociceptive paradigms have demonstratedhyperalgesia between opioid doses and during with-drawal. Studies in higher mammals are virtually lacking,thus creating uncertainty about how generalizable theseresults may be. The available human data are far morelimited in terms of the types of opioids administered,dosing schedules, and nociceptive paradigms used, al-though the results are compatible with the rodent find-ings. It is also important to recognize that most of thehuman studies provide only indirect evidence for OIH inclinically relevant settings. The few human studies sug-gesting a cause-and-effect relationship only demon-strated an aggravation of preexisting hyperalgesia byopioids.

Fig. 3. Tolerance and opioid-induced hyperalgesia (OIH) arepharmacologically distinct phenomena that share the same neteffect on dose requirements. Either condition necessitates doseescalation for maintaining a certain drug effect. If tolerance isexpressed, decreased drug potency is reflected by a right-shiftof the dose versus effect relationship (AC). If OIH is expressed,increased pain sensitivity is reflected by a downward shift ofthe dose versus effect relationship (AB). Both, tolerance, or OIHresult in a decreased effectiveness of a given drug dose (X).From Carroll et al.102; used with permission from The AmericanSociety of Regional Anesthesia and Pain Medicine, copyright2004 by Elsevier, Inc.



Based on the available evidence, we need to giveserious consideration to the possibility that OIH is asignificant consequence of opioid therapy in humans.Paradoxically, the aggressive treatment of pain with opi-oids may predispose patients to greater levels of pain atlater times. For example, patients chronically consumingopioids experience increased levels of postoperativepain despite consuming larger amounts of postoperativepain medications.101,102 In addition, there seems to be aprevailing belief that patients currently or formerly usingopioids display much heightened pain responses to mi-nor procedures like venipuncture. Conceivably, thelong-term use of opioids also may exacerbate rather thanameliorate chronic pain. The possibility of OIH limitingthe usefulness of opioids emphasizes the value of alter-native methods of pain control.

OIH with Dose Escalation and Ultra-highDoses

Human StudiesSevere allodynia, that is, pain evoked by stimuli, such

as touch, that normally are not painful, is a rare compli-

cation in patients treated for intractable pain with highand escalating opioid doses.103 Nine reports documentallodynia in 22 patients (table 4). In eight patients, allo-dynia was accompanied by myocloni. Taken together,these reports provide evidence that systemic orneuraxial administration of large doses of morphine canproduce a generalized tenderness of skin and soft tissuethat makes patients hurt when touched or gently moved.Escalating the morphine dose in patients already suffer-ing from opioid-induced allodynia typically aggravatedthe symptoms.104–106 Reducing the morphine dose orsubstituting for it with an alternative opioid (fentanyl,sufentanil, methadone, ketobemidone) alleviated orabolished observed allodynia.104,107–110

A few reports are not entirely consistent with thegeneral characteristics of high-dose, opioid-induced allo-dynia as outlined in the previous paragraph. Allodyniaafter typical rather than very high morphine doses wasreported in two patients.104,111 One patient experiencedcentral pain and segmental allodynia after intrathecalmorphine administration. It is possible that some formsof central pain are particularly sensitive to excitatoryopioid effects. The second patient had cancer-related

Table 4. Case Reports Documenting High-dose, Opioid-induced Allodynia/Hyperalgesia

Reference Opioid Route Dose Hyperalgesia (n) Remarks

104 M PO, IM, IV 60–300 mg/d PO; 150–960 mg/dIM; 20 g/d IV

Generalized allodynia, myocloni(1)

n � 4; cancer pain; substitutingmorphine with methadone,sufentanil, or ketobemidonereversed allodynia

105 M IV 175–200 mg/h Generalized allodynia (5),aggravated neuralgia (3),myocloni (4)

n � 8; cancer pain (described indetail, n � 2), dose escalationaggravated allodynia

106 M IT 37.5 mg/h Spontaneous pain, allodynia notreported

n � 1; cancer pain, 50-foldreduction of IT morphineresolved pain aggravation

107 M IT 80 mg/d Spontaneous pain and allodyniain dermatomes S5–T5,myocloni

n � 1; cancer pain, primary painT4–T7, dose reduction to 50mg/d reduced allodynia

108 M IV 600 mg/h Generalized allodynia, myocloni n � 1; cancer pain, substitutingmorphine with methadonereversed allodynia

109 M PO, IT 400 mg/d IV; 48 mg/d IT Generalized or lumbosacralsegmental allodynia, myocloni(1)

n � 3; cancer and nonmalignantpain (described in detail, n �2), dose reduction orsubstituting morphine withsufentanil, fentanyl, ormethadone reversed allodynia

110 M IV 105 mg/h Generalized allodynia n � 1; cancer pain in infant,reduction of morphineresolved allodynia

111 M IT 0.2 and 0.5 mg bolus Allodynia in dermatomes T6–T7 n � 1; central pain after spinalinjury, administration ofnaloxone did not reversehyperalgesia

112 M/MET IV/PO 200/75 mg/d; 90/90 mg/d Generalized allodynia n � 2; cancer pain, switchingsecond patient to methadonedid not reverse hyperalgesia

IT � intrathecal; IV � intravenous; M � morphine; Met � methadone; PO � per oral.



back pain and, for reasons currently unclear, experi-enced generalized allodynia after a dose of oral mor-phine. Second, allodynia was reported in two patientsreceiving escalating doses of methadone in combinationwith morphine.112 The relative contribution of metha-done for producing allodynia remains uncertain, partic-ularly when considering reports suggesting that substi-tuting morphine with methadone can abolish high-dose,morphine-induced allodynia.104,108,109 It should benoted that the possibility of spinal granulomas surround-ing the intrathecal catheters used to administer opioidsin some patients contributing to the observed segmentalhyperalgesia cannot be excluded.

Animal StudiesAnimal studies documented that administration of a

high opioid dose can evoke an allodynic/hyperalgesicstate and shed some light on potential underlying mech-anisms. Rats receiving intrathecal morphine at a dose 10times higher than that required to produce antinocicep-tion displayed a biting and scratching behavior and anextreme aversion to touch at dermatomes in close prox-imity to the subarachnoid injection site.113–115 A role forthe opioid-receptor system in mediating this allodynic/hyperalgesic state is unlikely because the phenomenonwas (1) not reversed by opioid-receptor antagonists, (2)not produced by all opioid agonists tested at a high dose,(3) evoked in a nonstereospecific fashion by variousenantiomers, and (4) not cross-tolerant with effectsknown to be mediated by opioid receptors.113–117

An intrathecal injection of strychnine produced anallodynic/hyperalgesic state quite similar to that ob-served after administering a high opioid dose.114 Strych-nine depresses glycinergic neuronal inhibition and elec-trophysiological evidence obtained in single-cellrecordings of the rodent spinal cord indicates that highopioid concentrations can act similarly.118,119 Intrathecalinjection of glycine dose-dependently attenuated allo-dynia evoked by a high opioid dose, further pointingtoward impaired glycinergic inhibitory control as anunderlying mechanism.117 Recent evidence suggests thatthe excitatory phenomena observed in conjunction witha high opioid dose are mediated by the NMDA receptorsystem.116,117

Considerations and RecommendationsFor practical reasons, it is important to consider work

suggesting that not all opioids produce an allodynic/hyperalgesic state when given at high doses.115 Yaksh etal.115 explored 33 opioid-related alkaloids in rats andconcluded that opioids need the following structuralcharacteristics to produce an allodynic/hyperalgesicstate: (1) phenantrene structure, (2) hydrogen at posi-tion 14, (3) ether bond, (4) one or no methyl group onthe nitrogen, and (5) free 3-OH position or glucuronide/sulfate conjugate in this position. Available clinical data

are consistent with the suggestion of Yaksh et al. Con-vincing clinical evidence for the development of high-dose, opioid-induced allodynia/hyperalgesia exists onlyfor the phenantrene morphine (table 4). Switching pa-tients to the piperidine derivatives fentanyl or sufentanilattenuated or abolished such allodynia/hyperalge-sia.104,109 In this context, two apparently contradictorycase reports are worth mentioning. The first report de-scribes the occurrence of acute hyperalgesia in a patientreceiving a 50-fold overdose of intravenous fentanyl.120

This report needs to be interpreted carefully, becausethe portrayed patient was confused and unresponsive toverbal commands at the time of showing signs of motorhyperactivity in response to touch and noise. It is ques-tionable whether observed behavior truly reflects pres-ence of allodynia/hyperalgesia. The second report de-scribes a patient with radiating neuropathic pain in herleft leg as a result of chronic arachnoiditis who experi-enced aggravated spontaneous burning pain in both legsafter intrathecal injection of sufentanil.121 However, thispatient did not experience measurable allodynia or hy-peralgesia, making the report of unclear relevance toOIH.

In summary, administration of very high doses of cer-tain opioids can produce allodynia and possibly hyper-algesia on rare clinical occasions. The allodynic/hyperal-gesic state is not reversed by opioid antagonists and canbecome aggravated when the dose of the causative opi-oid agonist is further escalated. As soon as a high-dose,opioid-induced allodynic/hyperalgesic state is sus-pected, dose reduction of the causative agent and/orsubstitution of the causative agent with an opioid agonistless likely to cause such symptoms are appropriate nextsteps aiming at attenuating or eliminating these symp-toms. In this regard, experimental evidence backed bylimited clinical data suggests that switching from aphenantrene (e.g., morphine) to a piperidine derivative(e.g., fentanyl or sufentanil) is a valid strategy.

OIH with Ultra-low Doses

Human StudiesAlthough several laboratories performed animal stud-

ies to explore whether ultra-low opioid doses exert hy-peralgesic effects, very little experimental work hasbeen carried out in humans. A single anecdotal reportdating back to the early 1940s was identified and de-scribes the inadvertent finding of a dose-dependent bi-phasic response to morphine in 7 of 57 studied formeraddicts. These seven patients became mildly hyperalge-sic to heat pain at the lowest morphine dose, but expe-rienced analgesia at higher doses.122

However, some human studies attempted to exploitthe idea that an ultra-low opioid dose causes excitatoryor hyperalgesic effects, which typically are overshad-owed by inhibitory effects exerted by higher opioid



doses. These studies tested the reverse concept, that is,whether an ultra-low dose of an opioid antagonist selec-tively could block excitatory opioid effects and, as aconsequence, augment analgesic opioid effects obtainedwith higher and clinically used doses. Early clinical stud-ies in humans indeed provide some support for the ideathat opioid antagonists may exert analgesic effects at lowdoses, while aggravating pain at higher doses.123 Twostudies in patients undergoing hysterectomy suggestedthat coadministration of a very low dose of an opioidantagonist reduced postoperative opioid consumptionor postoperative pain.124,125 However, subsequent stud-ies in patients undergoing surgery could not confirmthese findings, and it remains controversial whether co-administration of ultra-low doses of an opioid antagonistwith an opioid agonist augments opioid analgesia.126,127

Animal StudiesThe administration of �-opioid receptor agonists at

doses far below those predicted to be effective caused ahyperalgesic response in animals. Kayser et al.128 mea-sured the effects of systemic morphine in arthritic ratswhen administered a dose approximately 1000-foldlower than that typically used to study antinociceptiveeffects and demonstrated a paradoxically enhanced sen-sitivity to noxious pressure in the arthritic paw. Similarresults were obtained by Crain et al.129 using mice and athermal nociceptive test. In a paradigm measuring car-diovascular reactivity under anesthesia, a very low doseof the �-opioid receptor agonist sufentanil aggravatedthe hemodynamic response to noxious stimuli, furthersuggesting that systemic subanalgesic opioid doses maycause hyperalgesia.130 Finally, the opioid etorphine in-jected locally caused hyperalgesia at very low doses, butevoked an antinociceptive effect at higher doses.131 Botheffects were sensitive to antagonists, suggesting thatboth were mediated by opioid receptors.

Shen and Crain132 suggested that the naloxone-revers-ible hyperalgesic effects of ultra-low dose morphine maybe the result of bimodal effects on dorsal root ganglionopioid receptors. According to this theory, opioid recep-tors trigger an excitatory signaling cascade when ex-posed to very low opioid agonist concentrations butactivate inhibitory pathways when exposed to higheragonist concentrations. This concept is supported by theobservation that very low opioid antagonist concentra-tions produced antinociceptive effects, whereas higherantagonist concentrations caused hyperalgesia.133,134

The antinociceptive effects observed at very low opioidantagonist concentrations are likely mediated by opioidreceptors, because they showed cross-tolerance to theantinociceptive effects evoked by higher concentrationsof an opioid agonist.135 At a molecular level, GM1-gan-glioside has been implicated in mediating these excita-tory opioid effects.136

Considerations and RecommendationsAt this point, significant evidence in the animal litera-

ture suggests that rodents exposed to very low opioiddoses show signs of hyperalgesia, whereas larger dosesproduce antinociceptive effects. No controlled studieswere identified that directly examined whether very lowopioid doses cause hyperalgesia in humans. Studies inhumans providing some indirect evidence for an hyper-algesic effect of very low opioid doses explored thereversed hypothesis, that is, whether very low doses ofan opioid antagonists would provide enhanced postop-erative pain control. However, results of these studiesare conflicting.

The concept that ultra low doses of opioids causehyperalgesia may have some relevance to OIH as ob-served during periods of abstinence (see above). Presum-ably, very low opioid concentrations may still be presentin experiments testing animals and humans during absti-nence. A single report documenting that naloxone re-versed hyperalgesia as observed during opioid absti-nence in mice is compatible with this idea.137 However,naloxone enhanced the degree of OIH displayed by ratsin other paradigms.37 These latter studies are in line withthe many studies using naloxone to precipitate opioidwithdrawal and OIH. Although we cannot exclude somecontribution of low opioid concentrations to OIH duringperiods of abstinence, it is unlikely that this is a predom-inant mechanism.

The fundamental capacity of the opioid receptor sys-tem to elicit hyperalgesia is especially apparent in spe-cies inert to antinociceptive opioid effects. Such species,including the fowl and the mole-rat, display a mono-tonic, naloxone-reversible hyperalgesic response tothermal and chemical stimuli after opioid administra-tion.138–141 Thus, the overall effect of a given opioiddose is likely the composite response resulting fromactivation of opioid-dependent pronociceptive and an-tinociceptive systems.

General Implications and Future Directions

Administration of opioids typically results in analgesia.However, the opioid receptor system signals and modu-lates a multitude of effects, and under certain conditionsmediates hyperalgesia rather than analgesia. In this sys-tematic review, we divided opioid-induced hyperalgesiainto three major categories based on the opioid dose andfurther subdivided these categories by distinguishingvarious types of pain as well as route and pattern ofopioid administration. It can be reasonably concludedfrom the available literature that opioidergic mecha-nisms can counteract analgesia and enhance pain sensi-tivity. Such mechanisms have been identified as originat-ing in afferent neurons, in spinal cord tissue, and insupraspinal centers of the central nervous system. Al-



though opioids have enjoyed widespread use in themanagement of acute and cancer-related pain for manydecades, the increasingly popular use of opioids foralleviating chronic, nonmalignant pain stresses the im-portance of gaining a thorough understanding of poten-tial limitations of the clinical usefulness of these drugs.

It is clear from our systematic review of the literaturethat OIH in the context of maintenance therapy andperiods of withdrawal or abstinence has received themost attention. This is not particularly surprising, be-cause OIH in these settings may be clinically most rele-vant for a large number of patients. Particularly concern-ing is the possibility that chronic pain and painassociated with interventional procedures could beworsened by virtue of ongoing and possibly even acuteopioid therapy.

The body of laboratory data using behavioral assays isrobust, although human studies in this area are far lessnumerous. The animal studies predominantly provideevidence for sensitization to acute noxious stimuli afteracute and chronic opioid dosing. Lacking are animalstudies examining OIH in models of chronic pain. Hu-man studies have used patients and volunteers. Patientdata provide evidence for aggravation of postoperativepain in the setting of acute and chronic opioid adminis-tration. Increased sensitivity to acute experimental painalso was seen in patients receiving methadone mainte-nance therapy. Most data from human volunteer studiesdemonstrates exacerbation of secondary hyperalgesia af-ter short-term administration of short-acting opioids.Lacking are prospective studies exploring the possiblerole of OIH in exacerbating clinical pain states.

We believe that there are two primary areas on whichto focus future studies:

1. Mechanisms of OIH. Existing data suggest that periph-eral, spinal cord, and higher central nervous systemstructures may be involved in OIH, but many specificsare missing from our understanding. Such topics in-clude the sensitization of primary afferents, the over-all understanding of the neurotransmitter systems in-volved, the participating intracellular secondmessenger systems, and the genetic susceptibility toOIH. Ultimately, these mechanistic studies will needto be integrated into a model accounting for the likelycomplex interactions. Such a model would be usefulin developing strategies to optimize opioid therapy.

2. Clinical studies. Existing human data generally sup-port the existence of OIH in a few specific settings.Future studies will need to clarify the conditionsunder which OIH is expressed and its clinical signif-icance. Such studies would include evaluating theimpact of OIH on our ability to control chronic painwith opioids, exploring whether OIH may facilitatethe development of chronic pain, developing opioidadministration algorithms minimizing OIH, identify-

ing patients at particular risk for developing OIH, andevaluating approaches for reducing OIH after it isestablished.

As for ultra-high opioid doses, a series of case reportsindicates that certain opioids can produce allodynia andhyperalgesia particularly during rapid dose escalation.This condition is not reversed by administration of anopioid antagonist, but would be expected to respond toopioid dose reduction or rotation from a phenantrene(e.g., morphine) to a piperidine opioid derivative (e.g.,fentanyl). From the currently available literature, thereare no clear mechanistic commonalities between thehyperalgesia experienced during rapid opioid dose esca-lation and that experienced during opioid maintenanceor withdrawal. Although some animal studies exist, thereare no human studies prospectively exploring pain sen-sitization in humans during rapid opioid titration.

Although it has been observed that very low opioiddoses can cause hyperalgesia in rodents, the human dataare conflicting, and direct evidence for the existence ofthis condition in humans is lacking. Mechanistically, wedo not at present have sufficient information to (1)determine in which clinical situations the phenomenamay be relevant and (2) design clinical strategies to avoidany negative impact on pain control that this form ofhyperalgesia might have. Prospective human studiesclearly are required.

It needs to be recognized that our method of literaturesearch does impose some limitations on the forgoingdiscussion. Specifically, our search algorithm was de-signed to identify studies that measured OIH as a primaryendpoint. It is likely that studies reporting OIH as anincidental finding also were identified by the search.Although studies measuring OIH as a primary endpointand reporting negative results likely were captured aswell, studies providing incidental data suggesting ab-sence of OIH might have been missed.

In summary, clinicians need to be aware of the possi-bility that opioid therapy, particularly if aggressive innature, may cause heightened pain sensitivity and mayaggravate preexisting pain. It would seem reasonable todiscuss with patients the possible adverse impact of OIHwhen initiating opioid therapy. The disappearance ofopioid treatment effects, particularly if coupled with theunexplained expansion of pain complaints, may signalthe expression of OIH. In this setting, the use of alter-native analgesics and detoxification from opioids mayneed to be considered. Specific recommendations forthe management of patients at risk for OIH have beenmade by Carroll et al.102 Although these recommenda-tions were made in the context of perioperative paincontrol, many of them would be applicable to the man-agement of chronic pain patients receiving opioid ther-apy. Some of the relevant approaches would include theuse of multimodal analgesia, using caution when rapidly



titrating opioids, and avoiding periods of relative opioidabstinence. As our appreciation of the relevance of OIHimproves, more recommendations may become avail-able.

The authors thank Chris Stave, M.L.S., Lane Medical Library, Stanford Univer-sity Medical Center, Stanford, California, for his advice end expertise on perform-ing a systemic literature search.

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