Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia


  • Lucy Chen, MD
  • Michael Sein, MD
  • Trang Vo, BA
  • Shihab Amhmed, MD
  • Yi Zhang, MD
  • Kristin St Hilaire, BA, PhD
  • Mary Houghton, BA
  • Jianren Mao, MD, PhD



opioid, opioid tolerance, opioid-induced hyperalgesia, pain, primary care


Opioid analgesics are commonly used to manage moderate to severe pain. However, the long-term use of opioids could lead to opioid tolerance (OT) and opioid-induced hyperalgesia (OIH). Distinguishing OIH from OT would impact the practice of opioid therapy because opioid dose adjustment may differentially influence OT and OIH. Currently, there are no standard criteria of OT versus OIH causing considerable ambiguity in clinical interpretation and management of these conditions. The authors designed a practitioner-based survey consisting of 20 targeted questions. Answering these questions would require responders' actual clinical experiences with opioid therapy. The survey was conducted between 2011 and 2012 through direct mails or e-mails to 1,408 physicians who are currently practicing in the United States. The authors find that certain clinical characteristics (eg, increased pain despite opioid dose escalation) are often used by practitioners to make differential diagnosis of OT and OIH despite some overlap in their clinical presentation. A key difference in clinical outcome is that OT and OIH could be improved and exacerbated by opioid dose escalation, respectively. Our survey results revealed a significant knowledge gap in some responders regarding differential diagnosis and management of OT and OIH. The results also identified several issues, such as opioid dose adjustment and clinical comorbidities related to OT and OIH, which require future patient-based studies.

Author Biographies

Lucy Chen, MD

MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Michael Sein, MD

MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Trang Vo, BA

MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Shihab Amhmed, MD

MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Yi Zhang, MD

MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Kristin St Hilaire, BA, PhD

MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Mary Houghton, BA

MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Jianren Mao, MD, PhD

MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.


Ballantyne JC, Mao J: Opioid therapy for chronic pain. N Engl J Med. 2003; 349(20): 1943-1953. DOI:

Ballantyne JC: Opioid analgesia: Perspectives on right use and utility. Pain Physician. 2007; 10(3): 479-491. DOI:

Angst MS, Phillips NG, Drover DR, et al.: Pain sensitivity and opioid analgesia: A pharmacogenomic twin study. Pain. 2012; 153(7): 1397-1409. DOI:

He L, Kim JA, Whistler JL: Biomarkers of morphine tolerance and dependence are prevented by morphine-induced endocytosis of a mutant mu-opioid receptor. FASEB J. 2009; 23(12): 4327-4334. DOI:

Ravindranathan A, Joslyn G, Robertson M, et al.: Functional characterization of human variants of the mu-opioid receptor gene. Proc Natl Acad Sci USA. 2009; 106(26): 10811-10816. DOI:

Lee M, Silverman SM, Hansen H, et al.: A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011; 14(2): 145-161. DOI:

Low Y, Clarke CF, Huh BK: Opioid-induced hyperalgesia: A review of epidemiology, mechanisms and management. Singapore Med J. 2012; 53(5): 357-360.

Bianchi E, Norcini M, Smrcka A, et al.: Supraspinal gbetagamma- dependent stimulation of PLCbeta originating from G inhibitory protein-mu opioid receptor-coupling is necessary for morphine induced acute hyperalgesia. J Neurochem. 2009; 111(1): 171-180. DOI:

Bianchi E, Galeotti N, Menicacci C, et al.: Contribution of G inhibitory protein alpha subunits in paradoxical hyperalgesia elicited by exceedingly low doses of morphine in mice. Life Sci. 2011; 89(25-26): 918-925. DOI:

Celerier E, Gonzalez JR, Maldonado R, et al.: Opioid-induced hyperalgesia in a murine model of postoperative pain: Role of nitric oxide generated from the inducible nitric oxide synthase. Anesthesiology. 2006; 104(3): 546-555. DOI:

Chen Y, Yang C, Wang ZJ: Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia. J Neurosci. 2010; 30(1): 38-46. DOI:

Cui W, Li Y, Li S, et al.: Systemic lidocaine inhibits remifentanil-induced hyperalgesia via the inhibition of cPKCgamma membrane translocation in spinal dorsal horn of rats. J Neurosurg Anesthesiol. 2009; 21(4): 318-325. DOI:

Esmaeili-Mahani S, Shimokawa N, Javan M, et al.: Low-dose morphine induces hyperalgesia through activation of G alphas, protein kinase C, and L-type Ca2+ channels in rats. J Neurosci Res. 2008; 86(2): 471-479. DOI:

Ghelardini C, Galeotti N, Vivoli E, et al.: Molecular interaction in the mouse PAG between NMDA and opioid receptors in morphine-induced acute thermal nociception. J Neurochem. 2008; 105(1): 91-100. DOI:

Gu X, Wu X, Liu Y, et al.: Tyrosine phosphorylation of the N-methyl-d-aspartate receptor 2B subunit in spinal cord contributes to remifentanil-induced postoperative hyperalgesia: The preventive effect of ketamine. Mol Pain. 2009; 5: 76. DOI:

Gupta LK, Gupta R, Tripathi CD: N-methyl-d-aspartate receptor modulators block hyperalgesia induced by acute low-dose morphine. Clin Exp Pharmacol Physiol. 2011; 38(9): 592-597. DOI:

Liang DY, Li X, Clark JD: 5-Hydroxytryptamine type 3 receptor modulates opioid-induced hyperalgesia and tolerance in mice. Anesthesiology. 2011; 114(5): 1180-1189. DOI:

Mao J, Sung B, Ji RR, et al.: Chronic morphine induces downregulation of spinal glutamate transporters: Implications in morphine tolerance and abnormal pain sensitivity. J Neurosci. 2002; 22(18): 8312-8323. DOI:

Mao J, Sung B, Ji RR, et al.: Neuronal apoptosis associated with morphine tolerance: Evidence for an opioid-induced neurotoxic mechanism. J Neurosci. 2002; 22(17): 7650-7661. DOI:

Mao J: Opioid-induced abnormal pain sensitivity. Curr Pain Headache Rep. 2006; 10(1): 67-70. DOI:

Minville V, Fourcade O, Girolami JP, et al.: Opioid-induced hyperalgesia in a mice model of orthopaedic pain: Preventive effect of ketamine. Br J Anaesth. 2010; 104(2): 231-238. DOI:

Rivat C, Vera-Portocarrero LP, Ibrahim MM, et al.: Spinal NK-1 receptor-expressing neurons and descending pathways support fentanyl-induced pain hypersensitivity in a rat model of postoperative pain. Eur J Neurosci. 2009; 29(4): 727-737. DOI:

Ruiz-Medina J, Ledent C, Valverde O: GPR3 orphan receptor is involved in neuropathic pain after peripheral nerve injury and regulates morphine-induced antinociception. Neuropharmacology. 2011; 61(1-2): 43-50. DOI:

Simonin F, Schmitt M, Laulin JP, et al.: RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioidinduced tolerance associated with hyperalgesia. Proc Natl Acad Sci USA. 2006; 103(2): 466-471. DOI:

Van Elstraete AC, Sitbon P, Mazoit JX, et al.: Protective effect of prior administration of magnesium on delayed hyperalgesia induced by fentanyl in rats. Can J Anaesth. 2006; 53(12): 1180-1185. DOI:

Vanderah TW, Ossipov MH, Lai J, et al.: Mechanisms of opioid-induced pain and antinociceptive tolerance: Descending facilitation and spinal dynorphin. Pain. 2001; 92(1-2): 5-9. DOI:

Vardanyan A, Wang R, Vanderah TW, et al.: TRPV1 receptor in expression of opioid-induced hyperalgesia. J Pain. 2009; 10(3): 243-252. DOI:

Vera-Portocarrero LP, Zhang ET, King T, et al.: Spinal NK-1 receptor expressing neurons mediate opioid-induced hyperalgesia and antinociceptive tolerance via activation of descending pathways. Pain. 2007; 129(1-2): 35-45. DOI:

Zhao M, Joo DT: Enhancement of spinal N-methyl-daspartate receptor function by remifentanil action at delta-opioid receptors as a mechanism for acute opioid-induced hyperalgesia or tolerance. Anesthesiology. 2008; 109(2): 308-317. DOI:

Zhou HY, Chen SR, Chen H, et al.: Opioid-induced longterm potentiation in the spinal cord is a presynaptic event. J Neurosci. 2010; 30(12): 4460-4466. DOI:

Wei X, Wei W: Role of gabapentin in preventing fentanyl-and morphine-withdrawal-induced hyperalgesia in rats. J Anesth. 2012; 26(2): 236-241. DOI:

Liang DY, Liao G, Lighthall GK, et al.: Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence. Pharmacogenet Genomics. 2006; 16(11): 825-835. DOI:

Liang DY, Liao G, Wang J, et al.: A genetic analysis of opioid-induced hyperalgesia in mice. Anesthesiology. 2006; 104(5): 1054-1062. DOI:

Wilson NM, Jung H, Ripsch MS, et al.: CXCR4 signaling mediates morphine-induced tactile hyperalgesia. Brain Behav Immun. 2011; 25(3): 565-573. DOI:

Mao J: Opioid-induced abnormal pain sensitivity: Implications in clinical opioid therapy. Pain. 2002; 100(3): 213-217. DOI:

Chang G, Chen L, Mao J: Opioid tolerance and hyperalgesia. Med Clin North Am. 2007; 91(2): 199-211. DOI:

Chou R: 2009 clinical guidelines from the American Pain Society and the American Academy of Pain Medicine on the use of chronic opioid therapy in chronic noncancer pain: What are the key messages for clinical practice? Pol Arch Med Wewn. 2009; 119(7-8): 469-477. DOI:

Chou R, Fanciullo GJ, Fine PG, et al.: Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009; 10(2): 113-130. DOI:

Chapman CR, Lipschitz DL, Angst MS, et al.: Opioid pharmacotherapy for chronic non-cancer pain in the united states: A research guideline for developing an evidence-base. J Pain. 2010; 11(9): 807-829. DOI:

Chen L, Vo T, Seefeld L, et al.: Lack of correlation between opioid dose adjustment and pain score change in a group of chronic pain patients. J Pain. 2013; 14(4): 384-392. DOI:

Upshur CC, Luckmann RS, Savageau JA: Primary care provider concerns about management of chronic pain in community clinic populations. J Gen Intern Med. 2006; 21(6): 652-655. DOI:

Upshur CC, Bacigalupe G, Luckmann R: “They don't want anything to do with you”: Patient views of primary care management of chronic pain. Pain Med. 2010; 11(12): 1791-1798. DOI:

Bhamb B, Brown D, Hariharan J, et al.: Survey of select practice behaviors by primary care physicians on the use of opioids for chronic pain. Curr Med Res Opin. 2006; 22(9): 1859-1865. DOI:

Mahowald ML, Singh JA, Majeski P: Opioid use by patients in an orthopedics spine clinic. Arthritis Rheum. 2005; 52(1): 312-321. DOI:

Chen L, Malarick C, Seefeld L, et al.: Altered quantitative sensory testing outcome in subjects with opioid therapy. Pain.

; 143(1-2): 65-70.

Anand KJ, Willson DF, Berger J, et al.: Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics. 2010; 125(5): e1208-e1225. DOI:

Arnold JH, Truog RD, Orav EJ, et al.: Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology. 1990; 73(6): 1136-1140. DOI:

Arnold JH, Truog RD, Scavone JM, et al.: Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J Pediatr. 1991; 119(4): 639-643. DOI:

Ceger P, Kuhn CM: Opiate withdrawal in the neonatal rat: Relationship to duration of treatment and naloxone dose. Psychopharmacology (Berl). 2000; 150(3): 253-259. DOI:

Buntin-Mushock C, Phillip L, Moriyama K, et al.: Agedependent opioid escalation in chronic pain patients. Anesth Analg. 2005; 100(6): 1740-1745. DOI:

Sagheer MA, Khan MF, Sharif S: Association between chronic low back pain, anxiety and depression in patients at a tertiary care centre. J Pak Med Assoc. 2013; 63(6): 688-690.

Kroenke K, Outcalt S, Krebs E, et al.: Association between anxiety, health-related quality of life and functional impairment in primary care patients with chronic pain. Gen Hosp Psychiatry. 2013; 35(4): 359-365. DOI:

Kim H, Chen L, Lim G, et al.: Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. J Clin Invest. 2012; 122(8): 2940-2954. DOI:

Fine PG, Portenoy RK, Ad Hoc Expert Panel on Evidence Review and Guidelines for Opioid Rotation: Establishing “best practices” for opioid rotation: Conclusions of an expert panel. J Pain Symptom Manage. 2009; 38(3): 418-425. DOI:

Davis MP: Twelve reasons for considering buprenorphine as a frontline analgesic in the management of pain. J Support Oncol. 2012; 10(6): 209-219. DOI:

Chindalore VL, Craven RA, Yu KP, et al.: Adding ultralowdose naltrexone to oxycodone enhances and prolongs analgesia: A randomized, controlled trial of oxytrex. J Pain. 2005; 6(6): 392-399. DOI:

Webster LR: Oxytrex: An oxycodone and ultra-low-dose naltrexone formulation. Expert Opin Investig Drugs. 2007; 16(8): 1277-1283. DOI:

Webster LR, Fine PG: Review and critique of opioid rotation practices and associated risks of toxicity. Pain Med. 2012; 13(4): 562-570. DOI:

Von Korff M, Kolodny A, Deyo RA, et al.: Long-term opioid therapy reconsidered. Ann Intern Med. 2011; 155(5): 325-328. DOI:

Khan MI, Walsh D, Brito-Dellan N: Opioid and adjuvant analgesics: Compared and contrasted. Am J Hosp Palliat Care. 2011; 28(5): 378-383. DOI:

Kapural L, Kapural M, Bensitel T, et al.: Opioid-sparing effect of intravenous outpatient ketamine infusions appears short-lived in chronic-pain patients with high opioid requirements. Pain Physician. 2010; 13(4): 389-394. DOI:

Prommer EE: Ketamine for pain: An update of uses in palliative care. J Palliat Med. 2012; 15(4): 474-483. DOI:

Raffa RB, Pergolizzi JV Jr: Opioid-induced hyperalgesia: Is it clinically relevant for the treatment of pain patients? Pain Manag Nurs. 2013; 14(3): e67-e83. DOI:

Ma JF, Huang ZL, Li J, et al.: Cohort study of remifentanilinduced hyperalgesia in postoperative patients. Zhonghua Yi Xue Za Zhi. 2011; 91(14): 977-979.

Pohl M, Smith L: Chronic pain and addiction: Challenging co-occurring disorders. J Psychoactive Drugs. 2012; 44(2): 119-124. DOI:

Modesto-Lowe V, Girard L, Chaplin M: Cancer pain in the opioid-addicted patient: Can we treat it right? J Opioid Manag. 2012; 8(3): 167-175. DOI:

Pud D, Cohen D, Lawental E, et al.: Opioids and abnormal pain perception: New evidence from a study of chronic opioid addicts and healthy subjects. Drug Alcohol Depend. 2006; 82(3): 218-223. DOI:

Fishbain DA, Lewis JE, Gao J: Are psychoactive substance (opioid)-dependent chronic pain patients hyperalgesic? Pain Pract. 2011; 11(4): 337-343. DOI:

Suzan E, Eisenberg E, Treister R, et al.: A negative correlation between hyperalgesia and analgesia in patients with chronic radicular pain: Is hydromorphone therapy a doubleedged sword? Pain Physician. 2013; 16(1): 65-76. DOI:

Hay JL, White JM, Bochner F, et al.: Hyperalgesia in opioidmanaged chronic pain and opioid-dependent patients. J Pain. 2009; 10(3): 316-322. DOI:

Compton P, Charuvastra VC, Ling W: Pain intolerance in opioid-maintained former opiate addicts: Effect of long-acting maintenance agent. Drug Alcohol Depend. 2001; 63(2): 139-146. DOI:

Vinik HR, Kissin I: Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg. 1998; 86(6): 1307-1311. DOI:

Mao J, Price DD, Mayer DJ: Mechanisms of hyperalgesia and morphine tolerance: A current view of their possible interactions. Pain. 1995; 62(3): 259-274. DOI:

Devulder J: Hyperalgesia induced by high-dose intrathecal sufentanil in neuropathic pain. J Neurosurg Anesthesiol. 1997; 9(2): 146-148. DOI:

Sjogren P, Jensen NH, Jensen TS: Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists. Pain. 1994; 59(2): 313-316. DOI:

Vorobeychik Y, Chen L, Bush MC, et al.: Improved opioid analgesic effect following opioid dose reduction. Pain Med. 2008; 9(6): 724-727. DOI:

Wilson GR, Reisfield GM: Morphine hyperalgesia: A case report. Am J Hosp Palliat Care. 2003; 20(6): 459-461. DOI:

Atluri S, Akbik H, Sudarshan G: Prevention of opioid abuse in chronic non-cancer pain: An algorithmic, evidence based approach. Pain Physician. 2012; 15(3 Suppl): ES177-ES189. DOI:

Manchikanti L, Abdi S, Atluri S, et al.: American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part I—Evidence assessment. Pain Physician. 2012; 15(3 Suppl): S1-S65. DOI:



How to Cite

Chen, MD, L., M. Sein, MD, T. Vo, BA, S. Amhmed, MD, Y. Zhang, MD, K. St Hilaire, BA, PhD, M. Houghton, BA, and J. Mao, MD, PhD. “Clinical Interpretation of Opioid Tolerance Versus Opioid-Induced Hyperalgesia”. Journal of Opioid Management, vol. 10, no. 6, Nov. 2014, pp. 383-9, doi:10.5055/jom.2014.0235.