Opioidinduced hyperalgesia OIH is defined as a state of nociceptive sensitization caused - PDF document

Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain loss of opioid efficacy in some patients. Findings of the clinical prevalence of OIH are not available. However, several observational, cross-sectional, and prospective controlled trials have examined the Comprehensive Pain Medicine Pompano Beach 'L; Pain Relief Centers Conover NC; ACMI Pain Care AlgonRuin IL; and Pain Management Center of Paducah Paducah ,: Dr Lee is Director of Centers for Pain Management Tifton GA Dr Silverman is Medical Director of Comprehensive Louisville Louisville ,: Address correspondence: Marion O Lee MD Centers for Pain Management  ,ennedy Road Suite B Tifton Ga  here was no external funding in the preparation of this Conflict of interest: None Pain Physician: March/April 2011; 14:145-161 146 www.painphysicianjournal.com 2.0 HISTORICAL ONSIDERATIONS As early as the 19th century, OIH was observed in patients receiving morphine for pain. It was recognized that a potent analgesic such as morphine could actu - ally result in an increase in pain and was observed by Albutt in 1870 (18). Albutt described that, “At such times I have certainly felt it a great responsibility to say that pain, which I know is an evil, is less injurious than morphia, which may be an evil.” It was questioned that, “Does morphia tend to encourage the very pain it pretends to relieve? In addition, Albutt stated that, “Experience is needed” and, “. . . in the cases in ques - tion, I have much reason to suspect that a reliance upon hypodermic morphia only ended in that curious state of perpetuated pain.” In addition, Rossbach (19) in 1880 noted that, “when dependence on opioids finally becomes an ill - ness of itself, opposite effects like restlessness, sleep disturbance, hyperesthesia, neuralgia, and irritability become manifest.” Accumulating evidence suggests that the adminis - tration of opioid analgesics leads not only to analgesia, but may also lead to a paradoxical sensitization to nox - ious stimuli (20). This phenomenon is referred to as OIH. Among the more important human studies document - ing this effect are those demonstrating hyperalgesia in former opioid addicts maintained on methadone when compared with matched controls not receiving metha - done or other opioids (21-23). In the early to mid 2000 period, studies had focused toward the toxic effects of opioid metabolites, causative of OIH, such as morphine-3-glucoronide, with central nervous system (CNS) effects of irritability and allodynia (24-26). In addition, hydromorphone 3-glucuronide was also shown to have toxic activity in rats (27). Further, OIH was reported to result only from the phenanthrene class of drugs. However, OIH has been demonstrated with drugs of different classes to include, but not be limited to, methadone and the phenanthrene class, and has been demonstrated in acute opioid administration in the synthetic class to include the piperidines, but not with oxymorphone (24,28-30). 3.0 ERMINOLOGY Tolerance and sensitization have been described to have similarities; however, tolerance is a pharmacologic concept which occurs when there is a progressive lack of response to a drug, thus requiring increased dos - ing, which can occur with a variety of drugs not limited to opioids (15). In addition, tolerance might not only T he use of opioids for the treatment of chronic non-cancer pain has escalated in recent years, making them one of the most commonly prescribed medications in the United States (1-4). However, this escalation has many problems. Among those problems are a lack of evidence supporting their long-term effectiveness, misuse and abuse of prescription opioids, and multiple adverse events associated with long-term opioid use, including opioid- induced hyperalgesia (OIH) (1-17). Chronic opioid therapy could paradoxically induce or sensitize patients to acute pain, a condition termed “opi - oid-induced hyperalgesia” (14,15). Even though direct and indirect experiments from animals and patients shows the evidence for opioid-induced analgesia, the clinical impli - cations of this phenomenon continue to be unclear. How - ever, the implications are that patients on high doses of long-term opioid pharmacotherapy can suffer exquisite acute pain after surgery, but more importantly, escalating doses in chronic opioid therapy might cause OIH by induc - ing a vicious cycle of increasing dosage and anxiety, both for physician and patient (17). Consequently, as Chapman et al (4) pointed out, the answers to multiple questions are lacking, including the proportion of patients with OIH who receive opioid therapy, the propensities of patients to develop OIH, the preferential effect on certain types of acute or chronic pain, dose relationship and prevalence of OIH, and the duration and prevalence of OIH. Further, there are no well-known strategies which are effective in preventing, reversing, or managing OIH. Apart from the paucity of literature on OIH and various related factors, systematic reviews are lack - ing on this subject. Consequently, this comprehensive review is undertaken to evaluate OIH and address the prevalence of OIH; analyze various factors leading to OIH with types of pain, and the relationship between opioid dosage, and identification of acute painful con - ditions secondary to OIH; and effective strategies for preventing, reversing, or managing OIH. 1.0 ET This is a narrative review of the literature from 1966 through November 2010 including reports, systematic re - views, all types of studies, and other literature concerning OIH. The data was collected by doing a search of PubMed, EMBASE, Cochrane Reviews, and a manual search of all pertinent references in the literature. The keywords used were opioid-induced hyperalgesia, allodynia, opioid with - drawal, addiction, opioid or opiate tolerance, neuropathic pain, chemically induced pain, and hyperpathia. www.painphysicianjournal.com 147 Opioid-Induced Hyperalgesia develop to the analgesia provided by opioids, but also adverse events might develop, which are seen with mul - tiple drugs including opioid administration such as pru - ritus, nausea, sedation, and respiratory depression. Other differences between tolerance and sensitiza - tion include that tolerance is characterized by decreas - ing efficacy of the drug, which can be overcome by increasing the dose; whereas OIH cannot be overcome by increasing the dosage since it is a form of pain sen - sitization induced by the drug which occurs within the CNS. In fact, increasing the dosage would only worsen the pain and conversely, pain is improved by reducing or eliminating the opioid. OIH is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is char - acterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain might ac - tually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain the loss of opioid efficacy in some cases. Significant evidence has been accumulating con - cerning the mechanism and pathophysiology of OIH in the literature. 4.1 Basic Science Evidence In a systematic review, Angst and Clark (14) re - viewed the majority of publications available describ - ing OIH in various animal models. Following this, they described a model for OIH that considers this process to be neurobiologically multifactorial. It seems that, in general, neurobiologic systems that respond to opioids acutely in such a manner as to provide analgesia, might change over time in such a way as to enhance nocicep - tion, especially in the setting of declining opioid doses (14,15). The best investigated sites of such plasticity in - clude peripheral effects, spinal effects, and supraspinal effects. Mao (31) has documented the occurrence of OIH in laboratory animals. He compared dose response effects before and after administration of an opioid. A progres - sive reduction in baseline nociceptive pain thresholds were illustrated with intrathecal morphine administra - tion (32), with fentanyl boluses (33), and with repeated heroin administration (34). Thus, the concept that de - sensitization can be present with concurrent or repeat administration of opioids has been demonstrated. Many laboratories have reported mechanical allo - dynia and/or thermal hyperalgesia after the acute ad - ministration of opioids like heroin and fentanyl (33,35), the chronic administration of intrathecal morphine (36,37), the local peripheral administration of mor - phine (38), or the chronic administration of systematic opioids of several types (39-41). Pronociceptive effects of remifentanil in a mouse model of post surgical pain were demonstrated (42). In this model of incisional pain, remifentanil induced pronociceptive effects, which were dose dependent but unaltered by the duration of administration. In ad - dition, a second surgery performed on the same site and experimental conditions induced greater post-op - erative hyperalgesia that was enhanced when remifen - tanil was used as an anesthetic. 4.2 Clinical Evidence Similar to basic science evidence, supporting clini - cal evidence has also been established (14,21,30,43-55). Clinical OIH has been described after intraoperative remifentanil infusion (30), in patients with detoxifica - tion from high dose opioids with improvement in pain (43), and increased pain sensitivity with methadone (21). Further, there have been a host of experimental studies in human volunteers in anecdotal reports of in - creased pain sensitivity induced or observed with con - comitant use of opioids. These studies and the mecha - nisms of OIH have been extensively reviewed (14). A prospective trial in which long-acting morphine was given to participants with chronic low back pain demonstrated measurable hyperalgesia within one month of beginning therapy (44). An observational study in patients with non-cancer chronic pain, taking either methadone or morphine, compared with a con - trol group, indicated that patients with chronic pain managed with opioids and methadone-maintained patients were hyperalgesic when assessed by the cold pressor test, but not by the electrical stimulations test (45). In a review of OIH (46), the findings reinforced the opinion that the development of OIH is based on confounders including the pain modality tested, route of drug administration, and specific opioid in question, specifically in normal human volunteers receiving acute morphine infusions. In another systematic evidence-based structured review of OIH (47), the strongest evidence came from opioid infusion studies in normal volunteers as mea - sured by secondary hyperalgesia. The authors con - www.painphysicianjournal.com 151 Opioid-Induced Hyperalgesia after injection of acute physical opioid dependence . It also has been shown that there is a reduction in physical pain sensitivity in response to social exclusion and social encounters (110). Enhanced central thermal nociception has been reported in mildly depressed non- patients and transiently sad healthy individuals. 5.4 In Chronic Pain Patients OIH is critical in managing chronic opioid therapy (22,40,44,50,54,111,112). Hooten et al (111) evaluated associations between heat pain perception and opioid dose among patients with chronic pain undergoing opi - oid tapering in a prospective evaluation. Their cohort included 109 patients using opioids who were admit - ted to an outpatient multidisciplinary rehabilitation program that incorporates opioid tapering. They used a standardized quantitative sensory test (QST) method of levels. Standardized values of heat pain perception were obtained one day following program admis - sion and following completion of the opioid taper at program dismissal. The results showed that a greater baseline morphine equivalent dose was associated with lower or more hyperalgesic values. The dose dependent association retained significance after adjusting for pain severity, pain duration, and pain diagnosis. Taper - ing of greater morphine equivalent doses was associ - ated with lower values. The association retained signifi - cance after adjusting for pain severity, pain duration, pain diagnosis, opioid withdrawal symptoms, and time between completion of the taper and performance of the dismissal QST. Hay et al (45), in an observational report, indicated that patients with chronic pain management with opi - oids, and methadone-maintained patients were hyper - algesic when assessed by the cold pressor test. However, there was no allodynia. Cohen et al (49) evaluated 355 patients on a steady regimen of analgesic medications and scheduled for an interventional procedure, and who were treated with a standard subcutaneous injection of lidocaine prior to a full dose of local anesthetic. The results showed that both opioid dose and duration of treatment di - rectly correlated with pain intensity and unpleasant - ness scores compared with patients not receiving opioid treatment. Patients receiving opioid therapy were more likely to rate the standardized pain stimulus as being more unpleasant than painful. They concluded that the results of this study bolster preclinical and experimental pain models demonstrating enhanced pain perception in patients receiving opioid therapy. In addition, other human data suggests that the short-term infusion of opioids like the µ-opioid receptor agonist remifentanil, followed by abrupt cessation, exacerbates preexisting hyperalgesia (35,51,54). In contrast to the clinical and experimental evi - dence, some studies have shown that oral opioid ad - ministration of “commonly used” doses of oral opioids does not result in abnormal pain sensitivity beyond that of patients receiving non-opioid analgesia (55). In con - trast, another study (7) further illustrated that OIH is present in the opioid addict population. Further, they also concluded that detoxification from opioids does not reset pain perception for at least one month. 5.5 With Administration of Very Low Dose Opioids A limited amount of direct human data directly sup - ports the notion that low opioid doses cause hyperalge - sia (15). In fact, one of the only studies to examine this question demonstrated biphasic effects of morphine in a subset of former opioid addicts given morphine (113). In addition, the question has been approached from another angle and the results have illustrated that the inclusion of very low doses of opioid antagonists might reduce postoperative opioid consumption (114,115). However, the findings have not been reproduced by others (116,117). In contrast, the animal data appear to be more definitive in the heightened nociceptive sensitization (one-thousandth of the systemic analgesic dose) after single dose morphine in arthritic rats (118). There is no clinical application for extremely low dose opioids. 5.6 In Patients Administered Very High Dose Opioids OIH more commonly has been seen in patients re - ceiving high opioid doses, rather than low or moderate doses. There are multiple case reports and some stud - ies; however, there has not been any systematic evidence (15). The majority of the reports involve the systemic or intrathecal administration of morphine, raising the pos - sibility that metabolites, such as morphine-3-glucuronide that is known to cause neuroexcitation, could contribute to hyperalgesia (119-121). Chu et al (15) report that con - trary to the low dose OIH phenomenon, high dose OIH does not seem to be modified by opioid receptors; rather it is influenced by 2 non-opioid receptor systems: glycine and the spinal cord NMDA receptor system (122-126). This is based on the information that opioid antagonists do not efficiently reduce the OIH of high dose opioids, Pain Physician: March/April 2011; 14:145-161 152 www.painphysicianjournal.com and the stereospecificity of high dose OIH does not fit the specificity for binding to opioid receptors (15). One non-opioid receptor system contributing to these ef - fects is glycine. The intrathecal injection of glycine was dose-dependent for reversing allodynia caused by the intrathecal administration of high doses of morphine (126). Further, studies have focused on the spinal cord NMDA receptor system as mediating the hyperalgesia and allodynia effects of large doses of morphine (125). 6.1 Diagnosis Lack of effectiveness might be seen with the ad - ministration of opioids for chronic pain more commonly than anticipated and reported. Common traditional so - lutions to this include opioid rotation, reduction of the administered dose, or detoxification to manage OIH. However, a major dilemma faces the pain practitioner in the diagnosis of OIH and differentiating it from toler - ance. Thus, it is a challenge to distinguish between the two since treatment of each is quite different. In addi - tion, the clinician must be able to distinguish among OIH, progression of the disease process, interval injury, and clinical exacerbation of preexisting pain. There are features that differentiate OIH from increases in preexisting pain, disease progression, in - creased activity, increased demands, increased stress, and interval injury. In contrast, OIH typically produces diffuse pain, less defined in quality, which extends to other areas of distribution from preexisting pain. Fur - ther, OIH mimics opioid withdrawal including pain, since the neurobiology of both is similar (32). Further, OIH has been demonstrated clinically by inducing changes in pain threshold, tolerability, and distribution pattern in opioid-maintained former addicts (21). Finally, if the preexisting pain is undertreated or a pharmacologic tolerance exists, then an increase in opioid dose will result in reduction of pain. Conversely, OIH would be worsened with increasing opioid dosage. 6.2 Modulation of Opioid-Induced Hyperalgesia Even though precise molecular mechanisms respon - sible for the development of OIH are just beginning to be understood, preclinical models implicate the gluta - minergic system and pathologic activation of NMDA receptors in the development of central sensitization. Consequently, clinical work in attenuating or prevent - ing the expression of OIH has primarily focused on ma - nipulation of the glutaminergic system, either through direct or indirect modulation of the NMDA receptor. However, the clinical efficacy and significance of these approaches has not been evaluated in large prospective clinical trials. The NMDA receptor is composed of several differ - ent subunits (NR1, NR2A-D, and sometimes NR3A/B) that are differentially expressed in various regions of the brain and during development (15,127). Further, the subunit expression of individual NMDA receptors can affect their binding sensitivity to neuromodulators and function (128). However, multiple drugs available have variable and undetermined effectiveness. The first generation NMDARAs, such as ketamine and dextro - methorphan, have limited clinical utility in some pa - tients precisely because of these reasons. 6.2.1 Ketamine Even though ketamine binds to many different receptor sites, it is known to be an uncompetitive an - tagonist of the phencyclidine binding site of NMDA re - ceptor, where its primary anesthetic effects are thought to occur (129). While its role as a clinical anesthetic has been limited (130), its role as NMDA receptor in chronic neuropathic pain has been expanding (131-136). Meta-analyses of studies examining perioperative low-dose ketamine in conjunction with opioid admin - istration yielded opposing results (49,137-145). Fur - ther, a systematic review failed to show any significant evidence that ketamine improves the effectiveness of opioid therapy in cancer pain. However, ketamine has been shown to be significantly beneficial in patients who require large amounts of opioid medications or exhibit some degree of opioid tolerance. Human exper - imental pain studies have shown that administration of S-ketamine abolishes remifentanil-induced aggravation of hyperalgesia induced by intradermal electrical stimu - lation (50,51). In addition, the findings were corrobo - rated in the post-surgical patient population. In summary, there is some evidence to show that perioperative administration of low-dose ketamine might modulate the expression of OIH or analgesic tolerance and that it reduces postoperative wound hy - peralgesia after acute intraoperative opioid exposure. However, the clinical significance of these benefits still needs to be demonstrated in larger prospective studies and in chronic pain populations. 6.2.2 Methadone Methadone has been shown to have weak NMDA Opioid-Induced Hyperalgesia www.painphysicianjournal.com 155 ACKNOWLEDGMENTS The authors wish to thank Sekar Edem for assis - tance in the search of the literature, Bert Fellows, MA, and Tom Prigge, MA for manuscript review, and Tonie M. Hatton and Diane E. Neihoff, transcriptionists, for their assistance in preparation of this manuscript. We would like to thank the editorial board of Pain Physician for review and criticism in improving the manuscript. 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:- Jensen ,B Lonsdorf TB Schalling M ,oseL E Ingvar M Increased sensitiv ity to thermal pain following a single opiate dose is in¿uenced by the COMT val  met polymorphism PLoS One Lotta T 7idgren J Tilgmann C Ulmanen I Melnn , JulLunen I TasLinen J ,inet ics of human soluble and membrane- bound catechol O-methyltransferase: A revised mechanism and description of the thermolabile variant of the en[yme ;ubieta J, Heit[eg MM Smith :R Buel ler JA 9u , 9u ,oeppe R Stohler  COMT valmet geno type affects mu-opioid neurotransmit ter responses to a pain stressor Tan H: Chen 2 Goldberg TE Mattay 7S Meyer-Lindenberg A 8einberg er DR Callicott JH Catechol-O-methyl transferase valmet modulation of prefrontal parietal striatal brain sys tems during arithmetic and temporal transformations in worLing memory Neurosci Drabant EM Hariri AR Meyer-Lin denberg A Muno[ ,E Mattay 7S ,o lachana BS Egan M' 8einberger DR Catechol O-methyltransferase val met genotype and neural mecha nisms related to affective arousal and regulation Arch Gen Psychiatry DiatchenLo L NacLley AG Slade GD Bhalang , Belfer I Max MB Goldman D Maixner 8 Catechol-O-methyltrans ferase gene polymorphisms are associ ated with multiple pain-evoLing stimu Pain Petrovic P Ingvar M Imaging cognitive modulation of pain processing Pain Basbaum A 'ields HL Endogenous pain control mechanisms: Review and Ann Neurol ; :- ,im H Neubert J, San Miguel A 9u , ,rishnaraKu R, Iadarola MJ Gold man D Dionne RA Genetic in¿uence on variability in human acute exper imental pain sensitivity associated with gender ethnicity and psychologi cal temperament Pain ; :- Coghill RC McHaf¾e JG :en :' Neural correlates of interindividual differenc es in the subKective experience of pain PNAS Chu L' Dairmont J ;amora A, :oung CA Angst MS The endogenous opioid system is not involved in modulation of opioid-induced hyperalgesia Pain Dunbar SA Pulai IJ Repetitive opi oid abstinence causes progressive hy peralgesia sensitive to N-methyl-D-as partate receptor blocLade in the rat Pharmacol Exp Ther ; :- Dunbar SA ,aramov IG BuerLle H The effect of spinal ibuprofen on opi oid withdrawal in the rat Anesth Analg Johnston IN Milligan ED 8ieseler- 'ranL J 'ranL MG ;apata 7 Campisi J Langer S Martin D Green P 'leshner M Leinwand L Maier S' 8atLins LR A role for proin¿ammatory cytoLines and fractalLine in analgesia tolerance and subseRuent pain facilitation induced by chronic intrathecal morphine J Neu rosci Compton MA Cold-pressor pain toler ance in opiate and cocaine abusers: Pain Physician: March/April 2011; 14:145-161 158 www.painphysicianjournal.com Correlates of drug type and use status J Pain Symptom Manage ; :- Ossipov MH Lai J ,ing T 7anderah T8 Malan TP Jr Hruby 7J Porreca ' Anti nociceptive and nociceptive actions of J Neurobiol 9ie J: Herman DS Stiller CO Gardell LR Ossipov MH Lai J Porreca ' 7an derah T8 CholecystoLinin in the ros tral ventromedial medulla mediates opioid-induced hyperalgesia and anti nociceptive tolerance J Neurosci ; Schall U ,atta T Pries E ,lzppel A Gastpar M Pain perception of intra venous heroin users on maintenance therapy with levomethadone copsychiatry Dyer ,R 'oster DJ 8hite JM Somo gyi AA Menelaou A Bochner ' Steady- state pharmacoLinetics and pharmaco dynamics in methadone maintenance patients: Comparison of those who do and do not experience withdrawal and concentration-effect relationships Pharmacol Ther Chia :: Liu , 8ang JJ ,uo MC Ho ST Intraoperative high dose fentan yl induces postoperative fentanyl tol erance Can J Anaesth ; : - Cortrne[ LI Brandes 7 Muvo[ HR Guer rero ME Mur M No clinical evidence of acute opioid tolerance after remifen tanil-based anaesthesia Br J Anaesth Lee LH Irwin MG Lui S, Intraopera tive remifentanil infusion does not in crease postoperative opioid consump tion compared with  nitrous oxide Hansen EG Duedahl TH RŸmsing J Hil sted ,L Dahl JB Intra-operative remi fentanil might in¿uence pain levels in the immediate postoperative period af ter maKor abdominal surgery Acta An Trzster A Sittl R Singler B Schmel[ M Schttler J ,oppert 8 Modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by parecox ib in humans ; ,oppert 8 Dern S, Sittl R Albrecht S Schttler J Schmel[ M A new model of electrically evoLed pain and hyper algesia in human sLin: The effects of intravenous alfentanil S  -Letamine and lidocaine ; Luginbhl M Gerber A Schnider T8 Petersen-'elix S Arendt-Nielsen L Cu ratolo M Modulation of remifentanil- induced analgesia hyperalgesia and tolerance by small-dose Letamine in Anesth Analg ; :- Compton P Miotto , Elashoff D Pre cipitated opioid withdrawal across acute physical dependence induction Pharmacol Biochem Behav Compton P Athanasos P Elashoff D 8ithdrawal hyperalgesia after acute opioid physical dependence in nonad dicted humans: A preliminary study Pain BorsooL T, MacDonald G Mildly neg ative social encounters reduce physi cal pain sensitivity Pain ; :- Hooten 8M Mantilla CB Sandroni P Townsend CO Associations between heat pain perception and opioid dose among patients with chronic pain un dergoing opioid tapering Pain Med Piverua-Shuhaibar L 7illalobos N Del gado N Rubio MA Suare[-Roca H En hanced Central Thermal Nociception in Mildly Depressed Nonpatients and Transiently Sad Healthy SubKects Pain Andrews HL The effect of opiates on the pain threshold in post addicts Clin Invest Joshi GP Duffy L Chehade J 8esevich J GaKraK N Johnson ER Effects of pro phylactic nalmefene on the incidence of morphine-related side effects in pa tients receiving intravenous patient- controlled analgesia Gan TJ Ginsberg B Glass PS 'ortney J Jhaveri R Perno R Opioid-sparing ef fects of a low-dose infusion of nalox one in patient-administered morphine ; :- Cepeda MS Africano JM ManriRue AM 'ragoso 8 Carr DB The combination of low dose of naloxone and morphine in PCA does not decrease opioid reRuire ments in the postoperative period Pain Cepeda MS Alvare[ H Morales O Carr DB Addition of ultralow dose naloxone to postoperative morphine PCA: Un changed analgesia and opioid reRuire ment but decreased incidence of opi Pain ,ayser 7 Besson JM Guilbaud G Par adoxical hyperalgesic effect of exceed ingly low doses of systemic morphine in an animal model of persistent pain 'reundµs adKuvant-induced arthritic rats  Brain Res Hemstapat , Monteith GR Smith D Smith MT Morphine-- glucuronideµs neuro-excitatory effects are mediat ed via indirect activation of N-methyl- D-aspartic acid receptors: Mechanistic studies in embryonic cultured hippo campal neurones Anesth Analg ; Smith MT Neuroexcitatory effects of morphine and hydromorphone: Evi dence implicating the -glucuronide Clin Exp Pharmacol Physi 8right A8 Mather LE Smith MT Hy dromorphone--glucuronide: A more potent neuro-excitant than its structur al analogue morphine--glucuronide 8oolf CJ Intrathecal high dose mor phine produces hyperalgesia in the rat Brain Res :aLsh TL Harty GJ Pharmacology of the allodynia in rats evoLed by high dose intrathecal morphine J Pharma col Exp Ther :aLsh TL Harty GJ Onofrio BM High dose of spinal morphine produce a nonopiate receptor-mediated hyper esthesia: clinical and theoretic impli ; :° SaLurada T 8atanabe C OLuda , Sugiyama A Moriyama T SaLurada C Tan-No , SaLurada S Intrathecal high dose morphine induces spinally-me diated behavioral responses through NMDA receptors Brain Res Mol Brain Res Hara N Minami T OLuda-AshitaLa E Sugimoto T SaLai M OnaLa M Mori H Imanishi T Shingu , Ito S Character i[ation of nociceptin hyperalgesia and allodynia in conscious mice Br J Phar Chen HS Lipton SA The chemical bi ology of clinically tolerated NMDA re ceptor antagonists J Neurochem ; Goebel DJ Poosch MS NMDA recep tor subunit gene expression in the rat brain: A Ruantitative analysis of endog enous mRNA levels of NRCom NRA NRB NRC NRD and NRA Brain Opioid-Induced Hyperalgesia www.painphysicianjournal.com 159 Res Mol Brain Res Sloan TB Anesthetics and the brain Anesthesiol Clin North America ; Annetta MG Iemma D Garisto C Ta fani C Proietti R ,etamine: New indi cations for an old drug Curr Drug Tar Smith HS ,etamine-induced urologic insult ,IUI  Pain Physician ; : ,apural L ,apural M Bensitel T Ses sler DI Opioid-sparing effect of intra venous outpatient Letamine infusions appears short-lived in chronic-pain pa tients with high opioid reRuirements Pain Physician Goldberg ME TorKman MC Schwart[ man RJ Mager DE 8ainer I8 Phar macodynamic pro¾les of Letamine R - and S - with -day inpatient infusion for the treatment of complex regional pain syndrome Pain Physician ; Nama S Meenan DR 'rit[ 8T The use of sub-anesthetic intravenous Let amine and adKuvant dexmedetomidine when treating acute pain from CRPS Pain Physician Amr :M Multi-day low dose Letamine infusion as adKuvant to oral gabapen tin in spinal cord inKury related chronic pain: A prospective randomi[ed dou ble blind trial Pain Physician ; OLon T ,etamine: An introduction for the pain and palliative medicine physi Pain Physician Elia N Tramor MR ,etamine and post operative pain°a Ruantitative system atic review of randomised trials Pain De ,ocL M Lavandµhomme P 8ater loos H ´´Balanced analgesiaµµ in the perioperative period: Is there a place Pain Stubhaug A BreiviL H Eide P, ,reunen M 'oss A Mapping of punctuate hy peralgesia around a surgical incision demonstrates that Letamine is a pow erful suppressor of central sensiti[a tion to pain following surgery Acta An Subramaniam , Subramaniam B SteinbrooL RA ,etamine as adKu vant analgesic to opioids: A Ruantita tive and Rualitative systematic review Bell R' Eccleston C ,also E ,etamine as adKuvant to opioids for cancer pain A Rualitative systematic review J Pain Symptom Manage Bell R' Low-dose subcutaneous Let amine infusion and morphine toler Pain 8einbroum AA A single small dose of postoperative Letamine provides rap id and sustained improvement in mor phine analgesia in the presence of morphine-resistant pain Anesth Analg Eilers H Philip LA BicLler PE Mc,ay 8R Schumacher MA The reversal of fentanyl induced tolerance by adminis tration of ´´small-doseµµ Letamine Joly 7 Richebe P Guignard B 'letcher D Maurette P Sessler DI Chauvin M Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose Letamine Callahan RJ Au JD Paul M Liu C :ost CS 'unctional inhibition by methadone of N-methyl-D-aspartate receptors ex pressed in 9enopus oocytes: Stereo speci¾c and subunit effects SKŸgren P Jensen NH Jensen TS Disap pearance of morphine induced hyper algesia after discontinuing or substi tuting morphine with other opioid ag Pain SKŸgren P Thunedborg LP Christrup L Hansen SH 'ranLs J Is development of hyperalgesia allodynia and myoclonus related to morphine metabolism during long-term administration Six case his Acta Anaesthesiol Scand ; Lawlor P 8alLer P Bruera E Mitchell S Severe opioid toxicity and somati[a tion of psychosocial distress in a can cer patient with a bacLground of chem ical dependence J Pain Symptom Man Mercadante S Arcuri E Hyperalgesia and opioid switching Am J Hosp Palliat Care Axelrod DJ Reville B Using methadone to treat opioid-induced hyperalgesia and refractory pain J Opioid Manag Chung ,S Carson S Glassman D 7adi velu N Successful treatment of hydro morphone-induced neurotoxicity and hyperalgesia Conn Med ; :- ;immermann C Seccareccia D Booth CM Cottrell 8 Rotation to metha done after opioid dose escalation: How should individuali[ation of dosing oc J Pain Palliat Care Pharmacother Mercadante S 'errera P 7illari P Arcuri E Hyperalgesia: An emerging iatrogen ic syndrome J Pain Symptom Manage Galer BS Lee D Ma T Nagle B Schla ghecL TG MorphiDex morphine sul fatedextromethorphan hydrobromide combination in the treatment of chron ic pain: Three multicenter randomi[ed double-blind controlled clinical tri als fail to demonstrate enhanced opi oid analgesia or reduction in tolerance Pain Singler B Trzster A Manering N Scht tler J ,oppert 8 Modulation of remi fentanil-induced postinfusion hyperal gesia by propofol Anesth Analg ; 8ang 2: Cao JL ;eng :M Dai TJ GAB AA receptor partially mediated propo fol-induced hyperalgesia at superspi nal level and analgesia at spinal cord level in rats Acta Pharmacol Sin ; Baba H ,ohno T Moore ,A 8oolf CJ Direct activation of rat spinal dorsal horn neurons by prostaglandin E Neurosci OµRielly DD Loomis C8 Increased ex pression of cyclooxygenase and nitric oxide isoforms and exaggerated sen sitivity to prostaglandin E in the rat lumbar spinal cord  days after L-L spinal nerve ligation Anesthesiology Malmberg AB :aLsh TL Hyperalgesia mediated by spinal glutamate or sub stance P receptor blocLed by spinal cy clooxygenase inhibition ; :aLsh TL Malmberg AB Spinal actions of NSAIDS in blocLing spinally mediat ed hyperalgesia: The role of cyclooxy genase products Agents Actions Suppl Powell ,J HosoLawa A Bell A SutaL M Milne B 2uirion R Jhamandas , Comparative effects of cyclo-oxygen ase and nitric oxide synthase inhibi tion on the development and reversal of spinal opioid tolerance Br J Pharma 8ong CS Hsu MM Chou R Chou :: Tung CS Intrathecal cyclooxygenase inhibitor administration attenuates morphine antinociceptive tolerance in rats Pain Physician: March/April 2011; 14:145-161 160 www.painphysicianjournal.com ManchiLanti L ManchiLanti ,N Pam pati 7 Cash ,A Prevalence of side ef fects of prolonged low or moderate dose opioid therapy with concomitant ben[odia[epine andor antidepressant therapy in chronic non-cancer pain Pain Physician 'alco 'JE Erhart S 8argo B8 Bryce DA Atluri S Datta S HayeL SM Sys tematic review of diagnostic utility and therapeutic effectiveness of cervical facet Koint interventions Pain Physi Datta S Lee M 'alco 'JE Bryce DA HayeL SM Systematic assessment of diagnostic accuracy and therapeutic utility of lumbar facet Koint interven Pain Physician ; :- ManchiLanti L Dunbar EE 8argo B8 Shah R7 Derby R Cohen SP System atic review of cervical discography as a diagnostic test for chronic spinal pain Pain Physician ManchiLanti L Glaser S 8olfer L Derby R Cohen SP Systematic review of lum bar discography as a diagnostic test for chronic low bacL pain Pain Physician Conn A Buenaventura R Datta S Abdi S Diwan S Systematic review of cau dal epidural inKections in the manage ment of chronic low bacL pain Pain Parr AT Diwan S Abdi S Lumbar inter laminar epidural inKections in manag ing chronic low bacL and lower extrem ity pain: A systematic review Pain Phy Benyamin RM Singh 7 Parr AT Conn A Diwan S Abdi S Systematic review of the effectiveness of cervical epidur als in the management of chronic necL Pain Physician Buenaventura RM Datta S Abdi S Smith HS Systematic review of ther apeutic lumbar transforaminal epidu ral steroid inKections Pain Physician Helm S HayeL S Benyamin RM ManchiLanti L Systematic review of the effectiveness of thermal annu lar procedures in treating discogen ic low bacL pain Pain Physician ; Smith HS Chopra P Patel 7B 'rey ME Rastogi R Systematic review on the role of sedation in diagnostic spinal interventional techniRues Pain Physi 'rey ME ManchiLanti L Benyamin RM Schult[ DM Smith HS Cohen SP Spi nal cord stimulation for patients with failed bacL surgery syndrome: A sys tematic review Pain Physician ; Epter RS Helm S HayeL SM Benyamin RM Smith HS Abdi S Systematic re view of percutaneous adhesiolysis and management of chronic low bacL pain in post lumbar surgery syndrome Pain Patel 7B ManchiLanti L Singh 7 Schul t[ DM HayeL SM Smith HS Systematic review of intrathecal infusion systems for long-term management of chronic non-cancer pain Pain Physician ; Rupert MP Lee M ManchiLanti L Dat ta S Cohen SP Evaluation of sacroili ac Koint interventions: A systematic ap praisal of the literature Pain Physician HayeL SM Helm S Benyamin RM Singh 7 Bryce DA Smith HS Effective ness of spinal endoscopic adhesioly sis in post lumbar surgery syndrome: A systematic review Pain Physician Hirsch JA Singh 7 'alco 'JE Benya min RM ManchiLanti L Automated percutaneous lumbar discectomy for the contained herniated lumbar disc: A systematic assessment of evidence Pain Physician Singh 7 ManchiLanti L Benyamin RM Helm S Hirsch JA Percutaneous lum bar laser disc decompression: A sys tematic review of current evidence Pain Physician Singh 7 Benyamin RM Datta S 'alco 'JE Helm S ManchiLanti L Systemat ic review of percutaneous lumbar me chanical disc decompression utili[ing DeLompressor� Pain Physician ; ManchiLanti L Derby R Benyamin RM Helm S Hirsch JA A systematic review of mechanical lumbar disc decompres sion with nucleoplasty Pain Physician Gerges 'J Lipsit[ SR NedelKLovic SS A systematic review on the effective ness of the nucleoplasty procedure for discogenic pain Pain Physician ; ManchiLanti L Boswell M7 Singh 7 Benyamin RM 'ellows B Abdi S Bue naventura RM Conn A Datta S Derby R 'alco 'JE Erhart S Diwan S HayeL SM Helm S Parr AT Schult[ DM Smith HS 8olfer LR Hirsch JA Comprehen sive evidence-based guidelines for in terventional techniRues in the manage ment of chronic spinal pain Pain Physi ManchiLanti L Datta S Derby R 8olf er LR Benyamin RM Hirsch JA A criti cal review of the American Pain Society clinical practice guidelines for interven tional techniRues: Part  Diagnostic in terventions Pain Physician ; : ManchiLanti L Datta S Gupta S Mung lani R Bryce DA 8ard SP Benyamin RM Sharma ML Helm II S 'ellows B Hirsch JA A critical review of the Ameri can Pain Society clinical practice guide lines for interventional techniRues: Part  Therapeutic interventions Pain ManchiLanti L 'alco 'JE Boswell M7 Hirsch JA 'acts fallacies and politics of comparative effectiveness research: Part  Basic considerations Pain Phy ManchiLanti L 'alco 'JE Boswell M7 Hirsch JA 'acts fallacies and politics of comparative effectiveness research: Part  Implications for intervention al pain management Pain Physician Benyamin RM Datta S 'alco 'JE A per fect storm in interventional pain man agement: Regulated but unbalanced Pain Physician ManchiLanti L Singh 7 Boswell M7 Interventional pain management at crossroads: The perfect storm brewing for a new decade of challenges Pain ManchiLanti L Singh 7 Cash ,A Pam pati 7 Datta S Management of pain of post lumbar surgery syndrome: One- year results of a randomi[ed double- blind active controlled trial of ¿uoro scopic caudal epidural inKections Pain ManchiLanti L Cash ,A McManus CD Pampati 7 Singh 7 Benyamin RM The preliminary results of a comparative ef fectiveness evaluation of adhesiolysis and caudal epidural inKections in man aging chronic low bacL pain second ary to spinal stenosis: A randomi[ed eRuivalence controlled trial Pain Phy ManchiLanti L Singh 7 Cash ,A Pam pati 7 Datta S A comparative effective ness evaluation of percutaneous ad hesiolysis and epidural steroid inKec tions in managing lumbar post surgery Opioid-Induced Hyperalgesia www.painphysicianjournal.com 161 syndrome: A randomi[ed eRuivalence controlled trial Pain Physician ; ManchiLanti L Singh 7 'alco 'JE Cash ,A Pampati 7 Evaluation of lumbar facet Koint nerve blocLs in managing chronic low bacL pain: A randomi[ed double-blind controlled trial with a -year follow-up Int J Med Sci ; ManchiLanti L Singh 7 'alco 'JE Cash ,A 'ellows B Comparative outcomes of a -year follow-up of cervical me dial branch blocLs in management of chronic necL pain: A randomi[ed dou ble-blind controlled trial Pain Physi ManchiLanti L Boswell M7 Singh 7 Derby R 'ellows B 'alco 'JE Datta S Smith HS Hirsch JA Comprehensive review of neurophysiologic basis and diagnostic interventions in manag ing chronic spinal pain Pain Physician ManchiLanti L Boswell M7 Datta S 'el lows B Abdi S Singh 7 Benyamin RM 'alco 'JE Helm S HayeL S Smith HS Comprehensive review of therapeutic interventions in managing chronic spi nal pain Pain Physician ; :E- ManchiLanti L Cash ,A McManus CD Pampati 7 Benyamin RM A preliminary report of a randomi[ed double-blind active controlled trial of ¿uoroscop ic thoracic interlaminar epidural inKec tions in managing chronic thoracic pain Pain Physician ManchiLanti L Singh 7 'alco 'JE Cash ,A Pampati 7 'ellows B Compara tive effectiveness of a one-year follow- up of thoracic medial branch blocLs in management of chronic thoracic pain: A randomi[ed double-blind active controlled trial Pain Physician ; ManchiLanti L Singh 7 'alco 'JE Cash ,A Pampati 7 Evaluation of the effec tiveness of lumbar interlaminar epidu ral inKections in managing chronic pain of lumbar disc herniation or radiculitis: A randomi[ed double-blind controlled Pain Physician ManchiLanti L Cash ,A Pampati 7 8argo B8 Malla : Cervical epidural inKections in chronic discogenic necL pain without disc herniation or radic ulitis: Preliminary results of a random i[ed double-blind controlled trial Pain Physician ManchiLanti L Cash ,A McManus CD Pampati 7 Benyamin RM Preliminary results of a randomi[ed double-blind controlled trial of ¿uoroscopic lum bar interlaminar epidural inKections in managing chronic lumbar discogenic pain without disc herniation or radic Pain Physician ; :E- ManchiLanti L Cash ,A Pampati 7 8argo B8 Malla : The effectiveness of ¿uoroscopic cervical interlaminar epidural inKections in managing chronic cervical disc herniation and radiculitis: Preliminary results of a randomi[ed double-blind controlled trial Pain Phy Smith HS Deer TR Staats PS Singh 7 Sehgal N Cordner H Intrathecal drug delivery Pain Physician ; :S- ManchiLanti L CBT for low-bacL pain in primary care ; :- Lamb SE Hansen ; Lall R Castelnuo vo E 8ithers EJ Nichols 7 Potter R Un derwood MR; BacL SLills Training Trial Investigators Group cognitive behav ioural treatment for low-bacL pain in primary care: A randomised controlled trial and cost-effectiveness analysis Hill JC 'oster NE Hay EM Cognitive behavioural therapy shown to be an ef fective and low cost treatment for sub acute and chronic low-bacL pain im proving pain and disability scores in a pragmatic RCT Evid Based Med ; Davis A Inturrisi C blocLs morphine tolerance and Methyl-D-aspartate-induced hyper J Pharmacol Exp Ther 7orobeychiL : Chen L Bush MC Mao J Improved opioid analgesic effect fol lowing opioid dose reduction Pain Johnson RE 'udala PJ Payne R Bu prenorphine: Considerations for pain J Pain Symptom Man ,oppert 8 Ihmsen H ,orber N 8ehr frit[ A Sittl R Schmel[ M Different pro ¾les of buprenorphine induced analge sia and antihyperalgesia in a human Pain