Opioid-induced Hyperalgesia: A Qualitative Systematic Review

Opioids are the cornerstone therapy for the treatment of moderate to severe pain. Although common concerns regarding the use of opioids include the potential for detrimental side effects, physical dependence, and addiction, accumulating evidence suggests that opioids may yet cause another problem, often referred to as opioid-induced hyperalgesia. Somewhat paradoxically, opioid therapy aiming at alleviating pain may render patients more sensitive to pain and potentially may aggravate their preexisting pain. This review provides a comprehensive summary of basic and clinical research concerning opioid-induced hyperalgesia, suggests a framework for organizing pertinent information, delineates the status quo of our knowledge, identifies potential clinical implications, and discusses future research directions.

[1]  H. Fields,et al.  Naloxone dose dependently produces analgesia and hyperalgesia in postoperative pain , 1979, Nature.

[2]  D. Carr,et al.  The combination of low dose of naloxone and morphine in PCA does not decrease opioid requirements in the postoperative period , 2002, Pain.

[3]  J. Schüttler,et al.  Naloxone provokes similar pain facilitation as observed after short-term infusion of remifentanil in humans , 2003, Pain.

[4]  M. Morgan,et al.  EHAVIORAL AND ELECTROPHYSIOLOGICAL EVIDENCE FOR OLERANCE TO CONTINUOUS MORPHINE ADMINISTRATION INTO HE VENTROLATERAL PERIAQUEDUCTAL , 2004 .

[5]  W. Ma,et al.  Expression of calcitonin gene-related peptide, substance P and protein kinase C in cultured dorsal root ganglion neurons following chronic exposure to mu, delta and kappa opiates , 2002, Neuroscience.

[6]  Z. Wiesenfeld‐Hallin,et al.  Genetic differences in morphine sensitivity, tolerance and withdrawal in rats , 1998, Brain Research.

[7]  B. Bie,et al.  Presynaptic Mechanism for Anti-Analgesic and Anti-Hyperalgesic Actions of κ-Opioid Receptors , 2003, The Journal of Neuroscience.

[8]  A. Basbaum,et al.  Contribution of sacral spinal cord neurons to the autonomic and somatic consequences of withdrawal from morphine in the rat , 1997, Brain Research.

[9]  J. Kessler,et al.  Kappa opioid receptors participate in nerve growth factor-induced hyperalgesia , 1995, Neuroscience.

[10]  W. Ling,et al.  Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent. , 2001, Drug and alcohol dependence.

[11]  S. Siegel,et al.  Evidence from rats that morphine tolerance is a learned response. , 1975, Journal of comparative and physiological psychology.

[12]  J. Fujimoto,et al.  Differential contribution of descending serotonergic and noradrenergic systems to central Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5 (DAMGO) and morphine-induced antinociception in mice. , 1991, The Journal of pharmacology and experimental therapeutics.

[13]  S. Mercadante,et al.  Hyperalgesia: an emerging iatrogenic syndrome. , 2003, Journal of pain and symptom management.

[14]  T. Jensen,et al.  Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine , 1993, Pain.

[15]  M. Davies,et al.  Dexmedetomidine fails to cause hyperalgesia after cessation of chronic administration. , 2003, Anesthesia and analgesia.

[16]  C. Wong,et al.  Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord. , 2000, British journal of anaesthesia.

[17]  W. Falls,et al.  Procedures that produce context-specific tolerance to morphine in rats also produce context-specific withdrawal. , 1989, Behavioral neuroscience.

[18]  E. Bruera,et al.  Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain , 1997, Pain.

[19]  D. Elashoff,et al.  Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study. , 2003, The journal of pain : official journal of the American Pain Society.

[20]  Jason M. White,et al.  Hyperalgesic responses in methadone maintenance patients , 2001, Pain.

[21]  K. Shen,et al.  Antagonists at excitatory opioid receptors on sensory neurons in culture increase potency and specificity of opiate analgesics and attenuate development of tolerance/dependence , 1994, Brain Research.

[22]  K. Shen,et al.  Cholera toxin-B subunit blocks excitatory opioid receptor-mediated hyperalgesic effects in mice, thereby unmasking potent opioid analgesia and attenuating opioid tolerance/dependence , 2001, Brain Research.

[23]  U. Schall,et al.  Pain perception of intravenous heroin users on maintenance therapy with levomethadone. , 1996, Pharmacopsychiatry.

[24]  E. Zhang,et al.  Dynorphin Promotes Abnormal Pain and Spinal Opioid Antinociceptive Tolerance , 2000, The Journal of Neuroscience.

[25]  J. Clark,et al.  Chronic pain prevalence and analgesic prescribing in a general medical population. , 2002, Journal of pain and symptom management.

[26]  F. Rowell,et al.  DIHYDROCODEINE-INDUCED HYPERALGESIA IN POSTOPERATIVE DENTAL PAIN , 1982, The Lancet.

[27]  A. Phillips,et al.  Associative factors in tolerance to analgesia produced by electrical stimulation in the brainstem. , 1990, Behavioral neuroscience.

[28]  T. Vanderah,et al.  Sustained Morphine Exposure Induces a Spinal Dynorphin-Dependent Enhancement of Excitatory Transmitter Release from Primary Afferent Fibers , 2002, The Journal of Neuroscience.

[29]  C. Rivat,et al.  Long-lasting Hyperalgesia Induced by Fentanyl in Rats: Preventive Effect of Ketamine , 2000, Anesthesiology.

[30]  H. Tilson,et al.  Hyperalgesia during withdrawal as a means of measuring the degree of dependence in morphine dependent rats , 2004, Psychopharmacologia.

[31]  S. Siegel,et al.  The role of cholecystokinin in conditional compensatory responding and morphine tolerance in rats. , 2001, Behavioral neuroscience.

[32]  T. Yaksh,et al.  Spinal amino acid release and repeated withdrawal in spinal morphine tolerant rats , 2003, British journal of pharmacology.

[33]  D. Price,et al.  Pain-related increases in spinal cord membrane-bound protein kinase C following peripheral nerve injury , 1992, Brain Research.

[34]  N. Salimova,et al.  Interaction between alcohol deprivation and morphine withdrawal in mice. , 1993, Drug and alcohol dependence.

[35]  J. C. Doerr,et al.  Amniotic-fluid ingestion enhances morphine analgesia during morphine tolerance and withdrawal in rats , 1991, Physiology & Behavior.

[36]  J. Eisenach,et al.  Intrathecal Ketorolac Reverses Hypersensitivity following Acute Fentanyl Exposure , 2002, Anesthesiology.

[37]  A. Basbaum,et al.  Reduced development of tolerance to the analgesic effects of morphine and clonidine in PKCγ mutant mice , 2001, Pain.

[38]  M. Nessly,et al.  Acute pain management in patients with prior opioid consumption: a case-controlled retrospective review , 1995, Pain.

[39]  R. Maldonado,et al.  Prevention of fentanyl-induced delayed pronociceptive effects in mice lacking the protein kinase Cγ gene , 2004, Neuropharmacology.

[40]  S. Kamerling,et al.  Possible medullary kappa hyperalgesic mechanism. I. A new potential role for endogenous opioid peptides in pain perception. , 1983, Life sciences.

[41]  A. Caraceni,et al.  Hyperalgesia and myoclonus with intrathecal infusion of high-dose morphine , 1991, Pain.

[42]  The role of contextual cues on counterirritation in the development process of analgesic tolerance to morphine. , 2002, Life sciences.

[43]  Peter A. Smith,et al.  Morphine-3 (cid:1) - D -glucuronide Suppresses Inhibitory Synaptic Transmission in Rat Substantia Gelatinosa , 2002 .

[44]  S. Maier,et al.  A Role for Proinflammatory Cytokines and Fractalkine in Analgesia, Tolerance, and Subsequent Pain Facilitation Induced by Chronic Intrathecal Morphine , 2004, The Journal of Neuroscience.

[45]  A. Basbaum,et al.  Spinal cord mechanisms of opioid tolerance and dependence: Fos-like immunoreactivity expression increases in subpopulations of spinal cord neurons during withdrawal , 1996, Neuroscience.

[46]  J. Levine,et al.  Mu-opioid agonist enhancement of prostaglandin-induced hyperalgesia in the rat: a G-protein beta gamma subunit-mediated effect? , 1995, Neuroscience.

[47]  R. Hinson,et al.  Conditional hyperalgesia is elicited by environmental signals of morphine. , 1981, Behavioral and neural biology.

[48]  G. Paxinos,et al.  Effects of an Infusion of Morphine into the Accumbens Nucleus upon Acquisition of Hypoalgesic and Fear Responses in Rats Exposed to a Heat Stressor , 1992, The Quarterly journal of experimental psychology. B, Comparative and physiological psychology.

[49]  J. Corcuff,et al.  Fentanyl Enhancement of Carrageenan-induced Long-lasting Hyperalgesia in Rats: Prevention by the N-methyl-d-aspartate Receptor Antagonist Ketamine , 2002, Anesthesiology.

[50]  R. A. Hughes,et al.  Morphine hyperalgesic effects on the formalin test in domestic fowl (Gallus gallus) , 1991, Pharmacology Biochemistry and Behavior.

[51]  A. Somogyi,et al.  Steady‐state pharmacokinetics and pharmacodynamics in methadone maintenance patients: Comparison of those who do and do not experience withdrawal and concentration‐effect relationships , 1999, Clinical pharmacology and therapeutics.

[52]  J. Schüttler,et al.  Differential Modulation of Remifentanil-induced Analgesia and Postinfusion Hyperalgesia by S-Ketamine and Clonidine in Humans , 2003, Anesthesiology.

[53]  J. Corcuff,et al.  The Role of Ketamine in Preventing Fentanyl-Induced Hyperalgesia and Subsequent Acute Morphine Tolerance , 2002, Anesthesia and analgesia.

[54]  H. Fields,et al.  Roles of α1- and α2-Adrenoceptors in the Nucleus Raphe Magnus in Opioid Analgesia and Opioid Abstinence-Induced Hyperalgesia , 2003, The Journal of Neuroscience.

[55]  Lars Arendt-Nielsen,et al.  Modulation of Remifentanil-Induced Analgesia, Hyperalgesia, and Tolerance by Small-Dose Ketamine in Humans , 2003, Anesthesia and analgesia.

[56]  C. Woolf.  Analgesia and hyperalgesia produced in the rat by intrathecal naloxone , 1980, Brain Research.

[57]  S. Heger,et al.  Morphine induced allodynia in a child with brain tumour. , 1999, BMJ.

[58]  M. Moal,et al.  Long‐lasting increased pain sensitivity in rat following exposure to heroin for the first time , 1998, The European journal of neuroscience.

[59]  M. Le Moal,et al.  Progressive Enhancement of Delayed Hyperalgesia Induced by Repeated Heroin Administration: A Sensitization Process , 2001, Journal of Neuroscience.

[60]  J. Deleo,et al.  Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats , 2004, Neuropsychopharmacology.

[61]  J. Levine,et al.  Opioid and adenosine peripheral antinociception are subject to tolerance and withdrawal , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[62]  M. Compton,et al.  Cold-pressor pain tolerance in opiate and cocaine abusers: correlates of drug type and use status. , 1994, Journal of pain and symptom management.

[63]  K. Shen,et al.  Acute thermal hyperalgesia elicited by low-dose morphine in normal mice is blocked by ultra-low-dose naltrexone, unmasking potent opioid analgesia , 2001, Brain Research.

[64]  S. Ho,et al.  Intraoperative high dose fentanyl induces postoperative fentanyl tolerance , 1999, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[65]  H. Tilson,et al.  The effects of p-chlorophenylalanine on morphine analgesia, tolerance and dependence development in two strains of rats , 1974, Psychopharmacologia.

[66]  D. Price,et al.  Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance , 1996, Pain.

[67]  L. Paalzow,et al.  Modeling of tolerance development and rebound effect during different intravenous administrations of morphine to rats. , 1993, The Journal of pharmacology and experimental therapeutics.

[68]  M. Angst,et al.  Opioid-Induced Hyperalgesia and Incisional Pain , 2001, Anesthesia and analgesia.

[69]  M. Kock,et al.  Questioning the cardiocirculatory excitatory effects of opioids under volatile anaesthesia. , 2004, British journal of anaesthesia.

[70]  G. Guilbaud,et al.  Cross-tolerance between analgesic low doses of morphine and naloxone in arthritic rats , 1987, Brain Research.

[71]  S. Tiffany,et al.  Associative morphine tolerance in the rat: examinations of compensatory responding and cross-tolerance with stress-induced analgesia. , 1989, Behavioral and neural biology.

[72]  L. Cox,et al.  Context-specific morphine tolerance on the paw-pressure and tail-shock vocalization tests: evidence of associative tolerance without conditioned compensatory responding , 1999, Psychopharmacology.

[73]  B. Blumenkopf,et al.  Comparison of subjective and objective analgesic effects of intravenous and intrathecal morphine in chronic pain patients by heat beam dolorimetry , 1989, Pain.

[74]  H. Akil,et al.  Role of corticotropin-releasing hormone in the amygdala and bed nucleus of the stria terminalis in the behavioral, pain modulatory, and endocrine consequences of opiate withdrawal , 2002, Neuroscience.

[75]  J. Levine,et al.  Dissociation of Tolerance and Dependence for Opioid Peripheral Antinociception in Rats , 1997, The Journal of Neuroscience.

[76]  J. Clark,et al.  Hyperalgesia during opioid abstinence: mediation by glutamate and substance p. , 2002, Anesthesia and analgesia.

[77]  Xiao-jun Xu,et al.  The development of morphine tolerance and dependence in rats with chronic pain , 1997, Brain Research.

[78]  T. Yaksh,et al.  High Doses of Spinal Morphine Produce a Nonopiate Receptormediated Hyperesthesia: Clinical and Theoretic Implications , 1986, Anesthesiology.

[79]  G. Lighthall,et al.  Heme oxygenase type 2 modulates behavioral and molecular changes during chronic exposure to morphine , 2003, Neuroscience.

[80]  J. Gewirtz,et al.  Potentiated startle and hyperalgesia during withdrawal from acute morphine: effects of multiple opiate exposures , 2004, Psychopharmacology.

[81]  R. F. Westbrook,et al.  Conditioned Tolerance to Morphine Hypoalgesia: Compensatory Hyperalgesia in the Experimental Group or Conditioned Hypoalgesia in the Control Group? , 1992, The Quarterly journal of experimental psychology. B, Comparative and physiological psychology.

[82]  Xiao-jun Xu,et al.  Genetic differences in the antinociceptive effect of morphine and its potentiation by dextromethorphan in rats , 1999, Neuroscience Letters.

[83]  J. Mao.  Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy , 2002, Pain.

[84]  C. Rivat,et al.  Opioid-induced hyperalgesia: abnormal or normal pain? , 2003, Neuroreport.

[85]  D. Carr,et al.  Addition of ultralow dose naloxone to postoperative morphine PCA: unchanged analgesia and opioid requirement but decreased incidence of opioid side effects , 2004, Pain.

[86]  N. Barbaro,et al.  Hyperalgesia during naloxone-precipitated withdrawal from morphine is associated with increased on-cell activity in the rostral ventromedial medulla. , 1990, Somatosensory & motor research.

[87]  G. Wilson,et al.  Morphine hyperalgesia: A case report , 2003, The American journal of hospice & palliative care.

[88]  T. Yaksh,et al.  Pharmacology of the allodynia in rats evoked by high dose intrathecal morphine. , 1988, The Journal of pharmacology and experimental therapeutics.

[89]  G. Rolly,et al.  A case of uncommon withdrawal symptoms after a short period of spinal morphine administration , 1996, Pain.

[90]  S. Maier,et al.  Route of morphine administration modulates conditioned analgesic tolerance and hyperalgesia , 1994, Pharmacology Biochemistry and Behavior.

[91]  C. Himmelsbach.  THE MORPHINE ABSTINENCE SYNDROME, ITS NATURE AND TREATMENT* , 1941 .

[92]  T. Kanui,et al.  Hyperalgesia following administration of morphine and pethidine in the root rat (Tachyoryctes splendens). , 1995, Journal of veterinary pharmacology and therapeutics.

[93]  N. Rawal,et al.  Clinical Experience of Long-Term Treatment with Epidural and Intrathecal Opioids: A Nationwide Survey , 1988 .

[94]  B. Milne,et al.  Intrathecal Clonidine: Analgesia and Effect on Opiate Withdrawal in the Rat , 1985, Anesthesiology.

[95]  D. Kooy,et al.  Hyperalgesia mediated by peripheral opiate receptors in the rat , 1985, Behavioural Brain Research.

[96]  Xiao-jun Xu,et al.  Treatment of chronic allodynia in spinally injured rats: effects of intrathecal selective opioid receptor agonists , 1998, Pain.

[97]  G. McNally,et al.  Effects of systemic, intracerebral, or intrathecal administration of an N-methyl-D-aspartate receptor antagonist on associative morphine analgesic tolerance and hyperalgesia in rats. , 1998, Behavioral neuroscience.

[98]  G. Guilbaud,et al.  Paradoxical hyperalgesic effect of exceedingly low doses of systemic morphine in an animal model of persistent pain (Freund's adjuvant-induced arthritic rats) , 1987, Brain Research.

[99]  C. Mitchell,et al.  Morphine-induced hyperalgesia in rats tested on the hot plate. , 1971, The Journal of pharmacology and experimental therapeutics.

[100]  C. Ghelardini,et al.  Indomethacin, caffeine and prochlorperazine alone and combined revert hyperalgesia in in vivo models of migraine. , 2002, Pharmacological research.

[101]  R. A. Hughes.  Codeine analgesic and morphine hyperalgesic effects on thermal nociception in domestic fowl , 1990, Pharmacology Biochemistry and Behavior.

[102]  W. Ling,et al.  Pain responses in methadone-maintained opioid abusers. , 2000, Journal of pain and symptom management.

[103]  S. Dunbar,et al.  The Effect of Spinal Ibuprofen on Opioid Withdrawal in the Rat , 2000, Anesthesia and analgesia.

[104]  J. Harro,et al.  Cholecystokinin receptor binding in morphine analgesia: Tolerance, withdrawal and abstinence , 1994, Neuropeptides.

[105]  D. M. Grilly,et al.  Acute morphine dependence: Effects observed in shock and light discrimination tasks , 2004, Psychopharmacology.

[106]  M. Moal,et al.  Evidence for opiate-activated NMDA processes masking opiate analgesia in rats , 1999, Brain Research.

[107]  S. Siegel,et al.  Drug-onset cues as signals: intraadministration associations and tolerance. , 1999, Journal of experimental psychology. Animal behavior processes.

[108]  W. Martin,et al.  Hyperalgesic and analgesic actions of morphine, U50-488, naltrexone, and (−)-lobeline in the rat brainstem , 1994, Pharmacology Biochemistry and Behavior.

[109]  Jason M. White,et al.  Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine , 2001, Pain.

[110]  J. Kendig,et al.  Mechanical allodynia and thermal hyperalgesia upon acute opioid withdrawal in the neonatal rat , 2004, Pain.

[111]  T. Jensen,et al.  Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists , 1994, Pain.

[112]  R. Hill,et al.  Intrathecal injection of a ϰ opioid agonist produces hyperalgesia in the guinea pig , 1988 .

[113]  D. M. Grilly,et al.  Morphine dependence in rats assessed in a shock discrimination task , 2004, Psychopharmacology.

[114]  P. Glass,et al.  Opioid‐sparing Effects of a Low‐dose Infusion of Naloxone in Patient‐administered Morphine Sulfate , 1997, Anesthesiology.

[115]  T. Yaksh,et al.  Effect of transient naloxone antagonism on tolerance development in rats receiving continuous spinal morphine infusion , 1997, Pain.

[116]  K. Tan-No,et al.  Intrathecal high-dose morphine induces spinally-mediated behavioral responses through NMDA receptors. , 2002, Brain research. Molecular brain research.

[117]  D. Elashoff,et al.  Precipitated opioid withdrawal across acute physical dependence induction methods , 2004, Pharmacology Biochemistry and Behavior.

[118]  J. Levine,et al.  Multiple Receptors Involved in Peripheral α2, μ, and A1 Antinociception, Tolerance, and Withdrawal , 1997, The Journal of Neuroscience.

[119]  P. Jenner,et al.  AMINES, ANTICONVULSANTS, AND EPILEPSY , 1975, The Lancet.

[120]  T. Kanui,et al.  Effects of pethidine, acetylsalicylic acid, and indomethacin on pain and behavior in the mole-rat , 1993, Pharmacology Biochemistry and Behavior.

[121]  J. Mogil,et al.  Genetic variation in morphine analgesic tolerance A survey of 11 inbred mouse strains , 2002, Pharmacology Biochemistry and Behavior.

[122]  P. Pauwels,et al.  Large-amplitude 5-HT1A receptor activation: a new mechanism of profound, central analgesia , 2002, Neuropharmacology.

[123]  E. Bradley,et al.  The Effect of Ketamine on Opioid-Induced Acute Tolerance: Can It Explain Reduction of Opioid Consumption with Ketamine-Opioid Analgesic Combinations? , 2000, Anesthesia and analgesia.

[124]  C. Hendrie.  Naloxone-sensitive hyperalgesia follows analgesia induced by morphine and environmental stimulation , 1989, Pharmacology Biochemistry and Behavior.

[125]  J. Levine,et al.  Different Mechanisms Mediate Development and Expression of Tolerance and Dependence for Peripheral μ-Opioid Antinociception in Rat , 1997, The Journal of Neuroscience.

[126]  M. Moal,et al.  Acute tolerance associated with a single opiate administration: involvement of N-methyl-d-aspartate-dependent pain facilitatory systems , 1998, Neuroscience.

[127]  S. Siegel,et al.  Intraadministration associations: conditional hyperalgesia elicited by morphine onset cues. , 2002, Journal of experimental psychology. Animal behavior processes.

[128]  P. Siddall,et al.  Allodynia after acute intrathecal morphine administration in a patient with neuropathic pain after spinal cord injury. , 2003, Anesthesia and analgesia.

[129]  D. Sessler,et al.  Acute Opioid Tolerance: Intraoperative Remifentanil Increases Postoperative Pain and Morphine Requirement , 2000, Anesthesiology.

[130]  T. Vanderah,et al.  Tonic Descending Facilitation from the Rostral Ventromedial Medulla Mediates Opioid-Induced Abnormal Pain and Antinociceptive Tolerance , 2001, The Journal of Neuroscience.

[131]  M. Angst,et al.  Management of Perioperative Pain in Patients Chronically Consuming Opioids , 2004, Regional Anesthesia & Pain Medicine.

[132]  J. Kendig,et al.  Exaggerated nociceptive responses on morphine withdrawal: roles of protein kinase C ε and γ , 2004, Pain.

[133]  E. Okuda‐Ashitaka,et al.  Characterization of nociceptin hyperalgesia and allodynia in conscious mice , 1997, British journal of pharmacology.

[134]  S. Eldabe,et al.  Does intrathecal fentanyl produce acute cross-tolerance to i.v. morphine? , 1997, British journal of anaesthesia.

[135]  E. Bruera,et al.  Severe opioid toxicity and somatization of psychosocial distress in a cancer patient with a background of chemical dependence. , 1997, Journal of pain and symptom management.

[136]  R. Lewis,et al.  A withdrawal hyperalgesia test for physical dependence: evaluation of mu and mixed-partial opioid agonists. , 1983, Journal of pharmacological methods.

[137]  F. Colpaert,et al.  Opioid hyperalgesia and tolerance versus 5-HT1A receptor-mediated inverse tolerance. , 2003, Trends in pharmacological sciences.

[138]  D. Lougson,et al.  Acute. , 2020, The Manchester medical gazette.

[139]  J. Mao,et al.  Chronic Morphine Induces Downregulation of Spinal Glutamate Transporters: Implications in Morphine Tolerance and Abnormal Pain Sensitivity , 2022 .

[140]  R. Moore,et al.  Single dose oral dihydrocodeine for acute postoperative pain , 2000 .

[141]  M. Rowbotham,et al.  Effect of Remifentanil on Pain and Secondary Hyperalgesia Associated with the Heat–Capsaicin Sensitization Model in Healthy Volunteers , 2001, Anesthesiology.

[142]  D. Price,et al.  Increases in protein kinase C gamma immunoreactivity in the spinal cord dorsal horn of rats with painful mononeuropathy , 1995, Neuroscience Letters.

[143]  V. Kayser,et al.  The development of pain-related behaviour and opioid tolerance after neuropathy-inducing surgery and sham surgery , 2000, PAIN.

[144]  H. Muñoz,et al.  No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. , 2001, British journal of anaesthesia.

[145]  J. Wesevich,et al.  Effects of prophylactic nalmefene on the incidence of morphine-related side effects in patients receiving intravenous patient-controlled analgesia. , 1999, Anesthesiology.

[146]  D. Price,et al.  Spatial patterns of increased spinal cord membrane-bound protein kinase C and their relation to increases in 14C-2-deoxyglucose metabolic activity in rats with painful peripheral mononeuropathy. , 1993, Journal of neurophysiology.

[147]  H. L. Andrews.  THE EFFECT OF OPIATES ON THE PAIN THRESHOLD IN POST-ADDICTS. , 1943, The Journal of clinical investigation.

[148]  E. Heinzen,et al.  Pharmacodynamics of morphine-induced neuronal nitric oxide production and antinociceptive tolerance development , 2004, Brain Research.

[149]  J. Devulder.  Hyperalgesia induced by high-dose intrathecal sufentanil in neuropathic pain. , 1997, Journal of neurosurgical anesthesiology.

[150]  M. Moal,et al.  Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain sensitivity , 1999, Neuroscience.

[151]  S. Maeda,et al.  Intracerebroventricular treatment of mice with pertussis toxin induces hyperalgesia and enhances 3H-nitrendipine binding to synaptic membranes: Similarity with morphine tolerance , 2004, Naunyn-Schmiedeberg's Archives of Pharmacology.

[152]  G. Guilbaud,et al.  Dose-dependent analgesic and hyperalgesic effects of systemic naloxone in arthritic rats , 1981, Brain Research.

[153]  C. Woolf.  Intrathecal high dose morphine produces hyperalgesia in the rat , 1981, Brain Research.

[154]  F. Graeff,et al.  Opioid mediation of the antiaversive and hyperalgesic actions of bradykinin injected into the dorsal periaqueductal gray of the rat , 1992, Physiology & Behavior.

[155]  W. Martin,et al.  Opioid and nicotinic analgesic and hyperalgesic loci in the rat brain stem. , 1992, The Journal of pharmacology and experimental therapeutics.

[156]  R. Moore,et al.  Single dose dihydrocodeine for acute postoperative pain. , 2000, The Cochrane database of systematic reviews.

[157]  H. G. R. Robinson,et al.  The Development of , 1965 .

[158]  S. Hansen,et al.  Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long‐term administration?: Six case histories , 1998, Acta anaesthesiologica Scandinavica.

[159]  Martin S Angst,et al.  Short-term infusion of the μ-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal , 2003, Pain.

[160]  J. Eisenach,et al.  Intravenous Remifentanil Produces Withdrawal Hyperalgesia in Volunteers with Capsaicin-Induced Hyperalgesia , 2003, Anesthesia and analgesia.

[161]  J. Deleo,et al.  The Role of Spinal Neuroimmune Activation in Morphine Tolerance/Hyperalgesia in Neuropathic and Sham-Operated Rats , 2002, The Journal of Neuroscience.

[162]  A. Basbaum,et al.  Formalin-evoked Fos expression in spinal cord is enhanced in morphine-tolerant rats , 1997, Brain Research.

[163]  S. Dunbar,et al.  Repetitive opioid abstinence causes progressive hyperalgesia sensitive to N-methyl-D-aspartate receptor blockade in the rat. , 1998, The Journal of pharmacology and experimental therapeutics.

[164]  Tat-Leang Lee,et al.  Role of nitric oxide in the induction and expression of morphine tolerance and dependence in mice , 1996, British journal of pharmacology.

[165]  C. Hendrie.  Opiate dependence and withdrawal— A new synthesis? , 1985, Pharmacology Biochemistry and Behavior.

[166]  M. Krank.  Conditioned hyperalgesia depends on the pain sensitivity measure. , 1987, Behavioral neuroscience.

[167]  R. Ledeen,et al.  Chronic opioid treatment of neuroblastoma X dorsal root ganglion neuron hybrid F11 cells results in elevated GM1 ganglioside and cyclic adenosine monophosphate levels and onset of naloxone‐evoked decreases in membrane K+ currents , 1995, Journal of neuroscience research.

[168]  N. Barbaro,et al.  Morphine analgesia and acute physical dependence: rapid onset of two opposing, dose-related processes , 1990, Brain Research.

[169]  D. Price,et al.  Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[170]  S. Dunbar,et al.  Periodic abstinence enhances nociception without significantly altering the antinociceptive efficacy of spinal morphine in the rat , 2003, Neuroscience Letters.

[171]  K. Shen,et al.  Neuraminidase inhibitor, oseltamivir blocks GM1 ganglioside-regulated excitatory opioid receptor-mediated hyperalgesia, enhances opioid analgesia and attenuates tolerance in mice , 2004, Brain Research.

[172]  J. Levine,et al.  Mu-opioid agonist enhancement of prostaglandin-induced hyperalgesia in the rat: A G-protein βγ subunit-mediated effect? , 1995, Neuroscience.

[173]  R. Macdonald,et al.  Opiate alkaloids antagonize postsynaptic glycine and GABA responses: Correlation with convulsant action , 1982, Brain Research.

[174]  E. Way,et al.  Hyperalgesic effects of divalent cations and antinociceptive effects of a calcium chelator in naive and morphine-dependent mice. , 1980, The Journal of pharmacology and experimental therapeutics.

[175]  H. Fields,et al.  Hyperalgesia during acute opioid abstinence: evidence for a nociceptive facilitating function of the rostral ventromedial medulla , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[176]  J. Sloan,et al.  Opioid and nicotinic medullary hyperalgesic influences in the decerebrated rat , 1988, Pharmacology Biochemistry and Behavior.

[177]  H. Fields,et al.  Roles of alpha1- and alpha2-adrenoceptors in the nucleus raphe magnus in opioid analgesia and opioid abstinence-induced hyperalgesia. , 2003, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[178]  M. Angst,et al.  A murine model of opioid-induced hyperalgesia. , 2001, Brain research. Molecular brain research.