Supportive Therapy in OncologySupportive Therapy in OncologyПоддерживающая терапия в онкологии3034-24733034-3178Publishing House ABV Press7010.17650/3034-2473-2025-2-3-65-75REVIEWSОБЗОРНЫЕ СТАТЬИReview ArticleOpioid-induced hyperalgesiaОпиоидиндуцированная гипералгезияhttps://orcid.org/0000-0002-2797-4740SpasovaArina P.СпасоваАрина Павловна
Russian Federation

MD, PhD, Associate Professor of the Department of Diagnostic Radiology and Radiotherapy with a course on Critical and Respiratory Medicine, Head of the course on Critical and Respiratory Medicine at the Department of Diagnostic Radiology and Radiotherapy with a course on Criticaland Respiratory Medicine, Associate Professor of the Center for Postgraduate Education of the Medical Institute, Head Anesthesiologist-Resuscitationist of the Ministry of Health and Social Development of the Republic of Karelia

д.м.н., доцент кафедры лучевой диагностики и лучевой терапии с курсом критической и респираторной медицины, заведующая курсом критической и респираторной медицины кафедры лучевой диагностики и лучевой терапии с курсом критической и респираторной медицины, доцент Центра постдипломного образования медицинского института, главный анестезиолог-реаниматолог Министерства здравоохранения и социального развития Республики Карелия

arina22@mail.ruhttps://orcid.org/0000-0002-0059-326XDorozhenkoAndrei М.ДороженкоАндрей М.
Russian Federation
arina22@mail.ruhttps://orcid.org/0000-0001-7195-6307RyazankinaAlla A.РязанкинаАлла Алексеевна
Russian Federation

MD, PhD, Researcher, Anesthesiologist-Resuscitationist

к.м.н., доцент, научный сотрудник, врач анестезиолог-реаниматолог

arina22@mail.ruhttps://orcid.org/0000-0001-6317-1243BaryshevaOl’ga Yu.БарышеваОльга Ю.
Russian Federation
arina22@mail.ruhttps://orcid.org/0009-0006-3490-3082BazarovaEkaterina N.БазароваЕкатерина Н.
Russian Federation
arina22@mail.ruPetrozavodsk State UniversityФГБОУ ВО «Петрозаводский государственный университет»V.A. Baranova Republican Clinical HospitalГБУЗ РК «Республиканская больница им. В. А. Баранова»N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Петрова» Минздрава России2512202523657527082025Copyright ©; 2025, Spasova A.P., Dorozhenko A.М., Ryazankina A.A., Barysheva O.Y., Bazarova E.N.Copyright ©; 2025, Спасова А.П., Дороженко А.М., Рязанкина А.А., Барышева О.Ю., Базарова Е.Н.2025Spasova A.P., Dorozhenko A.М., Ryazankina A.A., Barysheva O.Y., Bazarova E.N.Спасова А.П., Дороженко А.М., Рязанкина А.А., Барышева О.Ю., Базарова Е.Н.https://creativecommons.org/licenses/by/4.0https://stio.abvpress.ru/jour/article/view/70

The review is devoted to the problem of opioid-induced hyperalgesia – a paradoxical effect in which therapy with narcotic analgesics can increase existing pain. The review considers the epidemiology, risk factors, mechanisms of development, differential diagnostics, recommendations for assessment and measures aimed at stopping the phenomenon of opioid-induced hyperalgesia.

Обзор посвящен проблеме опиоидиндуцированной гипералгезии – парадоксальному эффекту, при котором терапия наркотическими анальгетиками может усиливать уже существующую боль. В обзоре рассматривается эпидемиология, факторы риска, механизмы развития, дифференциальная диагностика, рекомендации по оценке и меры, направленные на купирование феномена опиоид-индуцированной гипералгезии.

opioid hyperalgesiachronic cancer painquantitative sensory testingопиоидная гипералгезияхроническая онкологическая больколичественное сенсорное тестированиеKim S.H., Stoicea N., Soghomonyan S., Bergese S. D. Intraoperative use of remifentanil and opioid induced hyperalgesia/acute opioid tolerance: systematic review. Front Pharmacol 2014;5:108. DOI: 10.3389/FPHAR.2014.00108Ballantyne J.C. Opioids for chronic nonterminal pain. South Med J 2006;99:1245–55. DOI:10.1097/01.smj.0000223946.19256.17Rossbach M.J. Ueber die Gewoehnung an Gifte. Pflugers Archieve Gesamte Physiologie des Menschen 1880;21:213–25.Andrews H.L. The effect of opiates on the pain threshold in post-addicts. J Clin Invest 1943;22(4):511–6. DOI: 10.1172/JCI101420Kayan S., Woods L.A., Mitchell C.L. Morphine-induced hyperalgesia in rats tested on the hot plate. J Pharmacol Exp Ther 1971;177(3):509–13.Angst M.S. Clark J.D. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006;104(3):570–87. DOI: 10.1097/00000542-200603000-00025Waldron D., Levins K., Murphy D. et al. Reflecting on cancer pain as constant acute pain, not chronic pain. ‘Known knowns, known unknowns, unknown unknowns’. Curr Oncol Rep 2025;27(5):584–600. DOI: 10.1007/s11912-025-01642-wLow Y., Clarke C.F., Huh B.K. Opioid-induced hyperalgesia: a review of epidemiology, mechanisms and management. Singapore Med J 2012;53(5):357–60.Kaneria A. Opioid-induced hyperalgesia: when pain killers make pain worse. BMJ Case Rep 2014;1564. DOI:10.1136/bcr-2014-204551Weber L., Yeomans D.C., Tzabazis A. Opioid-induced hyperalgesia in clinical anesthesia practice: what has remained from theoretical concepts and experimental studies? Curr Opin Anaesthesiol 2017;30(4):458–65. doi: 10.1097/ACO.0000000000000485Kum E., Buckley N., De Leon-Casasola O. et al. Attitudes towards and management of opioid-induced hyperalgesia: a survey of chronic pain practitioners. Clin J Pain 2020;36(5):359–64. DOi:10.1097/AJP.0000000000000814Roeckel L.A., Le Coz G.M., Gaveriaux-Ruff C., Simonin F. Opioid-induced hyperalgesia: cellular and molecular mechanisms. Neuroscience 2016;338:160–82. DOI: 10.1016/j.neuroscience.2016.06.029Mao J. Opioid-induced hyperalgesia. Pain Clinical Updates 2008;16:1–4.Vergara F., Sardi N.F., Pescador A.C. et al. Contribution of mesolimbic dopamine and kappa opioid systems to the transition from acute to chronic pain. Neuropharmacology 2020;178:108226. DOI: 10.1016/j.neuropharm.2020.108226Peng B., Jiao Y., Zhang Y. et al. Bulbospinal nociceptive ON and OFF cells related neural circuits and transmitters. Front Pharmacol 2023;14:1159753. DOI: 10.3389/fphar.2023.1159753Sasaki M., Kamiya Y., Bamba K. et al. Serotonin plays a key role in the development of opioid-induced hyperalgesia in mice. J Pain 2021;22(6):715–29. DOI: 10.1016/j.jpain.2020.12.008Matthes H.W., Maldonado R., Simonin F. et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 1996;383(6603):819–23. DOI:10.1038/383819a0Zhu Y., King M.A., Schuller A.G.P. et al. Retention of supraspinal delta-like analgesia and loss of morphine tolerance in δ-opioid receptor knockout mice. Neuron 1999;24(1):243–52. DOI:10.1016/S0896-6273(00)80836-3Ikeda K., Kobayashi T., Kumanishi T. et al. Involvement of G-protein-activated inwardly rectifying K+ (GIRK) channels in opioid-induced analgesia. Neurosci Res 2000;38:113–6. DOI: 10.1016/S0168-0102(00)00144-9Bourinet E., Soong T.W., Stea A., Snutch T.P. Determinants of the G protein-dependent opioid modulation of neuronal calcium channels. Proc Natl Acad Sci USA 1996;93:1486–91. DOI: 10.1073/pnas.93.4.1486.Porreca F., Cowan A., Raffa R.B., Tal-larida R.J. Estimation in vivo of the receptor constants of morphine in naive and morphine-tolerant rats. Life Sci 1982;31(20-21):2355–8. DOI: 10.1016/0024-3205(82)90155-2Stein C. Opioid Receptors. Annu Rev Med 2016;67:433–51. PubMed DOI: 10.1146/annurev-med-062613-093100Wang X., Loram L.C., Ramos K. et al. Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc Natl Acad Sci USA 2012;109:6325–30. DOI: 10.1073/pnas.1200130109Watkins L.R., Hutchinson M.R., Rice K.C., Maier S.F. The “toll” of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol Sci 2009;30:581–91. DOI: 10.1016/j.tips.2009.08.002Liu Y.-C., Berta T., Liu T. et al. Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in mice. Molecular Pain 2012;8–19. DOI: 10.1186/1744-8069-8-19Zhou J., Ma R., Jin Y. et al. Molecular mechanisms of opioid tolerance: from opioid receptors to inflammatory mediators (review). Exp Ther Med 2021;22:1–8. DOI:10.3892/etm.2021.10437Celerier E., Laulin J.-P., Corcuff J.-B. et al. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: A sensitization process. J Neurosci 2001;21(11):4074–80. DOI: 10.1523/JNEUROSCI.21-11-04074.2001Li X., Angst M.S., Clark J.D. Opioid-induced hyperalgesia and incisional pain. Anesth Analg 2001;93:204–9. DOI: 10.1097/00000539-200107000-00040Célèrier E., Rivat C., Jun Y. et al. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology 2000;92:465–72. DOI:10.1097/00000542-200002000-00029Sampaio-Cunha T.J., Martins I. Knowing the enemy is halfway towards victory: a scoping review on opioid-induced hyperalgesia. J Clin Med 2022;11(20):6161. DOI: 10.3390/jcm11206161Wasserman R.A., Brummett C.M., Goesling J. et al. Characteristics of chronic pain patients who take opioids and persistently report high pain intensity. Reg Anesth Pain Med 2014;39(1):13–7. DOI: 10.1097/AAP.0000000000000024Martel M.O., Petersen K., Cornelius M. et al. Endogenous pain modulation profiles among individuals with chronic pain: relation to opioid use. J Pain 2019;20(4):462–71. DOI: 10.1016/j.jpain.2018.10.004Fletcher D., Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth 2014;112(6):991–1004. DOI: 10.1093/bja/aeu137Kosten T.R., George T.P. The neurobiology of opioid dependence: implications for treatment. Sci Pract Perspect 2002;1(1):13–20. DOI:10.1151/spp021113Rivet C., Ballantyne J. The dark side of opioids in pain management: basic science explains clinical observation. Pain Rep 2016;1(2):e570. DOI: 10.1097/PR9.0000000000000570Kosten T.R., O’Connor P.G. Management of drug and alcohol withdrawal. N Engl J Med 2003;348(18):1786–95. DOI: 10.1056/NEJMra020617Volkow N.D., Koob G.F., McLellan A.T. Neurobiologic Advances from the Brain Disease Model of Addiction. N Engl J Med 2016; 374(4):363–71. DOI: 10.1056/NEJMra1511480Ako T., Ørnskov M.P., Lykke C. et al. Prevalence of opi]oid misuse in patients with cancer: a systematic review and meta-analysis. Br J Cancer 2024;131:1014–20. DOI: 10.1038/s41416-024-02802-8Lewis C.E.S., Schutzer-Weissmann J., Farquhar-Smith P. Opioid use disorder in cancer patients. Curr Opin Support Palliat Care 2023;17(2):98–103. DOI: 10.1097/SPC.0000000000000640Compton P., Charuvastra V.C., Ling W. Pain intolerance in opioidmaintained former opiate addicts: effect of long-acting maintenance agent. Drug Alcohol Depend 2001;63(2):139–46. DOI: 10.1016/s0376-8716(00)00200-3Kawanaka R., Sakuma S., Kokubun H. et al. Effects of Intraoperative opioid administration on postoperative pain and pain threshold: a randomized controlled study J Clin Med 2022;11:5587. DOI: 10.3390/jcm11195587Higgins C., Smith B.H., Matthews K. Evidence of opioid-induced hyperalgesia in clinical populations after chronic opioid exposure: a systematic review and meta-analysis. Br J Anaesth 2019;122(6):e114–26. DOI: 10.1016/j.bja.2018.09.019Henry S.G., Paterniti D.A., Feng B. et al. Patients’ experience with opioid tapering: a conceptual model with recommendations for clinicians. J Pain 2019;20(2):181–91. DOI: 10.1016/j.jpain.2018.09.001Treillet E., Laurent S., Hadjiat Y. Practical management of opioid rotation and equianalgesia. J Pain Res 2018;11:2587–601. DOI: 10.2147/JPR.S170269Reddy A., Yennurajalingam S., Reddy S. et al. The opioid rotation ratio from transdermal fentanyl to “Strong” opioids in patients with cancer pain. J Pain Symptom Manage 2016;51(6):1040–5.Vanderah T.W., Gardell L.R, Burgess S.E. et al. Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. J Neurosci 2000;20(18):7074–9. DOI: 10.1523/JNEUROSCI.20-18-07074.2000Forero M., Chan P.S., Restrepo-Garces C.E. Successful reversal of hyperalgesia/myoclonus complex with lowdose ketamine infusion. Pain Pract 2012;12(2):154–8. DOI: 10.1111/j.1533-2500.2011.00475Hocking G., Cousins M.J. Ketamine in chronic pain management: an evidence-based review. Anesth Analg 2003;97(6):1730–9.Baba H., Kohno T., Moore K.A., Woolf C.J. Direct activation of rat spinal dorsal horn neurons by prostaglandin E2. J Neurosci 2001;21(5):1750–6. DOI: 10.1523/JNEUROSCI.21-05-01750.2001Yaksh T.L., Malmberg A.B. Spinal actions of NSAIDS in blocking spinally mediated hyperalgesia: The role of cyclooxygenase products. Agents Actions Suppl1993;41:89–100.Peng Y., Zang T., Zhou L. et al. COX-2 contributed to the remifentanil-induced hyperalgesia related to ephrinB/EphB signaling. Neurological Res 2019;41:519–27. DOI:10.1080/01616412.2019.1580459Bannister K., Sikandar S., Bauer C.S. et al. Pregabalin suppresses spinal neuronal hyperexcitability and visceral hypersensitivity in the absence of peripheral pathophysiology. Anesthesiology 2011;115:144–52. DOI:10.1097/ALN.0b013e31821f6545Chincholkar M. Analgesic mechanisms of gabapentinoids and effects in experimental pain models: a narrative review. Br J Anaesth 2018;120(6):1315–34. DOI: 10.1016/j.bja.2018.02.066Chizh B.A., Göhring M., Tröster A. et al. Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers. Br J Anaesth 2007;98:246–54. DOI:10.1093/bja/ael344Stoicea N., Russell D., Weidner G. et al. Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin. Front Pharmacol 2015;6:104. DOI: 10.3389/fphar.2015.00104Archambault L., Bertrand K., Martel M.O. et al. The current state of knowledge on care for co-occurring chronic pain and opioid use disorder: A scoping review. J Clin Nurs 2024;33(8):3056–76. DOI: 10.1111/jocn.17139Pertovaara A. Noradrenergic pain modulation. Prog Neurobiol 2006;80(2):53–83. DOI: 10.1016/j.pneurobio.2006.08.001Al-Hassan A., Weissman B., Chowdhury S. et al. Comparative efficacy of dexmedetomidine and remifentanil in reducing postoperative pain and opioid use: a systematic review cureus 2025;17(2):e79759. DOI: 10.7759/cureus.79759Lan J., Zheng J., Feng J., Peng W. Nrf2 mediates the antinociceptive activity of dexmedetomidine in an acute inflammatory visceral pain rat model by activating the NF-κB sensor. Cell Biochem Funct 2020;38(1):97–105. DOI: 10.1002/cbf.3456Silverman S.M. Opioid-induced hyperalgesia: clinical implications for the pain practitioner. Pain Phys 2009;12(3):679–84.