Anesthesiology 2006; 104:570–87 © 2006 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Opioid-induced Hyperalgesia A Qualitative Systematic Review Martin S. Angst, M.D.,* J. David Clark, M.D., Ph.D.† Opioids are the cornerstone therapy for the treatment of an all-inclusive and current overview of a topic that may moderate to severe pain. Although common concerns regard- be difficult to grasp as a whole because new evidence ing the use of opioids include the potential for detrimental side accumulates quickly and in quite distinct research fields. effects, physical dependence, and addiction, accumulating evi- dence suggests that opioids may yet cause another problem, As such, a comprehensive review may serve as a source often referred to as opioid-induced hyperalgesia. Somewhat document. However, a systematic review also uses a paradoxically, opioid therapy aiming at alleviating pain may framework for presenting information, and such a frame- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/104/3/570/360792/0000542-200603000-00025.pdf by guest on 01 October 2021 render patients more sensitive to pain and potentially may work may facilitate and clarify future communication by aggravate their preexisting pain. This review provides a com- clearly delineating various entities or aspects of OIH. prehensive summary of basic and clinical research concerning opioid-induced hyperalgesia, suggests a framework for organiz- Finally, a systematic review aims at defining the status ing pertinent information, delineates the status quo of our quo of our knowledge concerning OIH, a necessary task knowledge, identifies potential clinical implications, and dis- to guide future research efforts and to identify potential cusses future research directions. clinical implications. For the purpose of this review, it is important to point OPIOIDS are the cornerstone therapy for alleviating out that OIH occurs in several distinct settings charac- moderate to severe pain. Whereas opioids have long terized by the opioid dose administered and the pattern been used for alleviating acute and cancer-related pain, of administration. Most work reported OIH during ongo- they recently have gained significant popularity for the ing (maintenance) therapy or withdrawal from opioids. treatment of chronic nonmalignant pain. Today, opioids Other bodies of literature documented OIH while admin- are second only to nonsteroidal antiinflammatory drugs istering either very high or very low opioid doses. Al- in terms of prescription frequency for chronic pain.1 though the opioid dose offers a convenient way to cat- Common concerns regarding the use of opioids are the egorize different types of OIH, it is less certain to what potential for detrimental side effects, physical depen- degree these phenomenological differences are mirrored dence, and addiction. However, recent research sug- by distinct mechanisms. Nevertheless, in this review we gests that opioids may yet cause another problem, often use separate sections to discuss OIH in the context of (1) referred to as opioid-induced hyperalgesia (OIH). Pa- maintenance dosing and withdrawal, (2) at very high or tients receiving opioids to control their pain somewhat escalating doses, and (3) at ultra-low doses. Each section paradoxically may become more sensitive to pain as a is divided further into a human and animal/basic science direct result of opioid therapy. That is, the use of opioids data subsection. At the end of each section, we draw may be a double-edged sword. They provide straight conclusions and outline potential clinical implications. analgesic and antihyperalgesic effects initially, but sub- The review ends with a discussion of future research sequently are associated with the expression of hyperal- directions. gesia likely reflecting upregulation of compensatory pronociceptive pathways. Several recent articles have reviewed and highlighted Literature Search important aspects of OIH, which reflects the growing Strategy interest and rapidly expanding body of literature regard- The three major databases, PubMed, BIOSIS, and Psy- 2–5 ing this phenomenon. The aim of this article is to cInfo, were searched for identifying articles pertinent to provide a comprehensive and systematic review of the OIH. PubMed, BIOSIS, and PsycInfo index publications literature pertinent to OIH. The primary intent of such relating to human health, the biologic and biomedical an undertaking is to provide the interested reader with sciences, and the field of psychology, respectively. The search included all work published between the incep- * Assistant Professor, Department of Anesthesia, Stanford University School of tion of a database (PubMed, 1966; BIOSIS, 1969; Psy- Medicine, Stanford, California; † Associate Professor, Department of Anesthesia, cInfo, 1887) and September 2004. Stanford University School of Medicine, Stanford, California, and Veterans Affairs Palo Alto Health Care System, Palo Alto, California. PubMed. Ideally, a search in PubMed using the mesh Received from the Department of Anesthesia, Stanford University School of terms hyperalgesia/chemically induced AND analge- Medicine, Stanford, California. Submitted for publication April 22, 2005. Ac- sics, opioid would have retrieved most of the relevant cepted for publication September 19, 2005. Support was provided solely from institutional and/or departmental sources. articles. However, such a search missed important arti- Address correspondence to Dr. Angst: Department of Anesthesia, Stanford cles when comparing results with an a priori index of all University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5117. [email protected]. Individual article reprints may be purchased through the relevant articles known to the authors. A more complex Journal Web site, www.anesthesiology.org. search accounting for variations in indexing was neces- Anesthesiology, V 104, No 3, Mar 2006 570 OPIOID-INDUCED HYPERALGESIA 571 sary to retrieve most of the pertinent articles without fects. Other articles were excluded because they re- listing an abundance of irrelevant publications. The final ported data obtained in nonmammalian species (lizards), search in PubMed was based on four “hedges” of free- hyperalgesia as a consequence of abstinence from en- text terms and medical subject headings. Hedges one dogenous opioids, or antianalgesic rather than hyperal- and two, and hedges three and four were combined for gesic treatment effects (attenuation of analgesic effects the search. Title rather than title/abstract searches were rather than increased sensitivity to pain). used to minimize retrieval of irrelevant citations. The The 139 articles included in this review were supple- hedges were as follows: mented by an additional 41 publications. These 41 arti- cles were added because they were either identified by ● Hedge 1 (induced hyperalgesia): hyperalgesia/chemi- the authors as containing relevant data when they re- cally induced [mesh] OR hyperalgesia/etiology OR an- viewed references cited in retrieved manuscripts, or tianalges* OR ((allodyni* [ti] OR hyperesthesi* [ti] OR these articles provided important background informa- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/104/3/570/360792/0000542-200603000-00025.pdf by guest on 01 October 2021 hyperalg* [ti]) AND (produc* [ti] OR elicit* [ti] OR tion indirectly related to OIH. Specifically, 18 manu- cause* [ti] OR trigger* [ti] OR refer* [ti] OR induc* scripts provided additional data relevant for the discus- [ti])); sion of hyperalgesia associated with the exogenous ● Hedge 2 (opioids): opioid* [ti] OR opiate* [ti] OR administration of opioids (2 manuscripts in nonmammal morphine [ti] OR fentanyl [ti]) OR analgesics, opioid species but of particular interest), 7 articles reported [pa] OR “opioid-related disorders”[mesh] OR “recep- analgesic effects in the context of opioid-antagonist ad- tors, opioid”[mesh] OR “analgesics, opioid”[mesh]; ministration, 8 articles documented mechanisms poten- ● Hedge 3 (drug tolerance or withdrawal): (toler* [ti] OR tially related to OIH but without testing for the expres- withdrawal [ti] OR adapt* [ti]) OR “substance with- sion of OIH, 7 manuscripts were reviews of topics drawal syndrome”[mesh] OR “drug tolerance”[mesh] pertinent to the discussion of OIH, and 1 reference OR “adaptation, physiologic”[mesh]; referred to a diagnostic guidebook. The 157 articles ● Hedge 4 (increased sensitivity to pain or sensation): reporting OIH in the context of exogenous opioid ad- hyperalgesia [mesh] OR hyperalges* OR allodyni* OR ministration consist of 120 animal and 37 human studies. hyperesthesi*. Biosis. Variability in indexing required combing three OIH during Maintenance and Withdrawal hedges: Human Studies ● Hedge 1 (title search): ((opiate* OR opioid* OR heroin Brief Historical Perspective. For more than a cen- OR fentanyl OR morphine) AND (antianalges* OR allo- tury, clinical reports have listed hyperesthesia or an dyni* OR hyperesthesi* OR hyperalg*)) NOT (antihy- increased sensitivity to pain as one of the symptoms peralges* OR “anti hyperalges*”)); associated with opioid withdrawal. In an essay dating ● Hedge 2 (subject search): hyperalgesia AND drug-in- back to 1880, Rossbach wrote, “[W] hen dependence on duced; opioids finally becomes an illness of itself, opposite ef- ● Hedge 3 (subject search): ((hyperalgesia AND (opiate* fects like restlessness, sleep disturbance, hyperesthesia, OR opioid*)). neuralgia and irritability become manifest.”6