{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T05:58:05Z","timestamp":1773381485124,"version":"3.50.1"},"reference-count":121,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Opioid-induced hyperalgesia (OIH) is a paradoxical effect of opioids that is not consensually recognized in clinical settings. We conducted a revision of clinical and preclinical studies and discuss them side by side to provide an updated and renewed view on OIH. We critically analyze data on the human manifestations of OIH in the context of chronic and post-operative pain. We also discuss how, in the context of cancer pain, though there are no direct evidence of OIH, several inherent conditions to the tumor and chemotherapy provide a substrate for the development of OIH. The review of the clinical data, namely in what concerns the strategies to counter OIH, emphasizes how much OIH rely mechanistically on the existence of \u00b5-opioid receptor (MOR) signaling through opposite, inhibitory\/antinociceptive and excitatory\/pronociceptive, pathways. The rationale for the maladaptive excitatory signaling of opioids is provided by the emerging growing information on the functional role of alternative splicing and heteromerization of MOR. The crossroads between opioids and neuroinflammation also play a major role in OIH. The latest pre-clinical data in this field brings new insights to new and promising therapeutic targets to address OIH. In conclusion, although OIH remains insufficiently recognized in clinical practice, the appropriate diagnosis can turn it into a treatable pain disorder. Therefore, in times of scarce alternatives to opioids to treat pain, mainly unmanageable chronic pain, increased knowledge and recognition of OIH, likely represent the first steps towards safer and efficient use of opioids as analgesics.<\/jats:p>","DOI":"10.3390\/jcm11206161","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T22:19:53Z","timestamp":1666217993000},"page":"6161","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Knowing the Enemy Is Halfway towards Victory: A Scoping Review on Opioid-Induced Hyperalgesia"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6320-2468","authenticated-orcid":false,"given":"Tiago J.","family":"Sampaio-Cunha","sequence":"first","affiliation":[{"name":"Department of Biomedicine, Unit of Experimental Biology, Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal"},{"name":"i3S\u2013Institute for Research & Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"IBMC-Institute for Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6797-2558","authenticated-orcid":false,"given":"Isabel","family":"Martins","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Unit of Experimental Biology, Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal"},{"name":"i3S\u2013Institute for Research & Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"IBMC-Institute for Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.36076\/ppj.2011\/14\/145","article-title":"A comprehensive review of opioid-induced hyperalgesia","volume":"14","author":"Lee","year":"2011","journal-title":"Pain Physician"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.neuroscience.2016.06.029","article-title":"Opioid-induced hyperalgesia: Cellular and molecular mechanisms","volume":"338","author":"Roeckel","year":"2016","journal-title":"Neuroscience"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1097\/00000542-200603000-00025","article-title":"Opioid-induced hyperalgesia: A qualitative systematic review","volume":"104","author":"Angst","year":"2006","journal-title":"Anesthesiology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/SPC.0b013e328335ddfe","article-title":"Opioid hyperalgesia","volume":"4","author":"Bannister","year":"2010","journal-title":"Curr. Opin. Support. Palliat. Care"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1097\/AJP.0000000000000994","article-title":"Opioid-induced Hyperalgesia in Patients With Chronic Pain: A Systematic Review of Published Cases","volume":"38","author":"Guichard","year":"2021","journal-title":"Clin. J. Pain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1097\/AJP.0000000000000814","article-title":"Attitudes Towards and Management of Opioid-induced Hyperalgesia: A Survey of Chronic Pain Practitioners","volume":"36","author":"Kum","year":"2020","journal-title":"Clin. J. Pain"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Vargas-Schaffer, G., Paquet, S., Neron, A., and Cogan, J. (2020). Opioid Induced Hyperalgesia, a Research Phenomenon or a Clinical Reality? Results of a Canadian Survey. J. Pers. Med., 10.","DOI":"10.3390\/jpm10020027"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.jpainsymman.2014.07.005","article-title":"Opioid-Induced Hyperalgesia (OIH): A Real Clinical Problem or Just an Experimental Phenomenon?","volume":"49","author":"Eisenberg","year":"2015","journal-title":"J. Pain Symptom Manag."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0304-3959(03)00276-8","article-title":"Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal","volume":"106","author":"Angst","year":"2003","journal-title":"Pain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1093\/bja\/aeu137","article-title":"Opioid-induced hyperalgesia in patients after surgery: A systematic review and a meta-analysis","volume":"112","author":"Fletcher","year":"2014","journal-title":"Br. J. Anaesth."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e114","DOI":"10.1016\/j.bja.2018.09.019","article-title":"Evidence of opioid-induced hyperalgesia in clinical populations after chronic opioid exposure: A systematic review and meta-analysis","volume":"122","author":"Higgins","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.neuroscience.2018.11.051","article-title":"Systemic Morphine Produces Dose-dependent Nociceptor-mediated Biphasic Changes in Nociceptive Threshold and Neuroplasticity","volume":"398","author":"Ferrari","year":"2019","journal-title":"Neuroscience"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"593842","DOI":"10.3389\/fpsyt.2021.593842","article-title":"The Effects of Low Dose Naltrexone on Opioid Induced Hyperalgesia and Fibromyalgia","volume":"12","author":"Jackson","year":"2021","journal-title":"Front. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Toljan, K., and Vrooman, B. (2018). Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization. Med. Sci., 6.","DOI":"10.3390\/medsci6040082"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10540","DOI":"10.1073\/pnas.92.23.10540","article-title":"Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance\/dependence during chronic cotreatment","volume":"92","author":"Crain","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wang, H.Y., Frankfurt, M., and Burns, L.H. (2008). High-affinity naloxone binding to filamin a prevents mu opioid receptor-Gs coupling underlying opioid tolerance and dependence. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001554"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1213\/ANE.0000000000002500","article-title":"Opioids for the Treatment of Chronic Pain: Mistakes Made, Lessons Learned, and Future Directions","volume":"125","author":"Ballantyne","year":"2017","journal-title":"Anesth. Analg."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Grelz, H., Fischer, M.R., Priouzifard, M., Midl\u00f6v, P., and Ringqvist, \u00c5. (2022). Prevalence of long-term opioid therapy in a chronic non-cancer pain population attending a university-based tertiary pain clinic in Sweden. A cross-sectional study. J. Rehabil. Med., 54.","DOI":"10.2340\/jrm.v54.1981"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1097\/FTD.0000000000000789","article-title":"Is Europe Facing an Emerging Opioid Crisis Comparable to the U.S.?","volume":"43","author":"Pierce","year":"2021","journal-title":"Ther. Drug Monit."},{"key":"ref_20","first-page":"158","article-title":"Impact of chronic pain on primary care across Europe","volume":"28","year":"2014","journal-title":"J. Pain Palliat. Care Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2844","DOI":"10.1016\/j.pain.2013.08.022","article-title":"A population-based study on chronic pain and the use of opioids in Portugal","volume":"154","author":"Azevedo","year":"2013","journal-title":"Pain"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.jpain.2018.12.007","article-title":"Effectiveness of Opioids for Chronic Noncancer Pain: A Two-Year Multicenter, Prospective Cohort Study with Propensity Score Matching","volume":"20","author":"Veiga","year":"2019","journal-title":"J. Pain"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1093\/pm\/pny275","article-title":"A Two-Year Prospective Multicenter Study of Opioid Therapy for Chronic Noncancer Pain: Prescription Trends and Predictors","volume":"20","author":"Veiga","year":"2019","journal-title":"Pain Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2058738419838383","DOI":"10.1177\/2058738419838383","article-title":"The neuropathic pain: An overview of the current treatment and future therapeutic approaches","volume":"33","author":"Cavalli","year":"2019","journal-title":"Int. J. Immunopathol. Pharm."},{"key":"ref_25","first-page":"Cd006605","article-title":"Long-term opioid management for chronic noncancer pain","volume":"2010","author":"Noble","year":"2010","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1080\/J354v19n01_09","article-title":"Opioid side effects, addiction, and anti-inflammatory medications","volume":"19","author":"Fishman","year":"2005","journal-title":"J. Pain Palliat. Care Pharmacother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/ejp.970","article-title":"European Pain Federation position paper on appropriate opioid use in chronic pain management","volume":"21","author":"Christrup","year":"2017","journal-title":"Eur. J. Pain"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s40122-021-00348-8","article-title":"Opioid Taper is Associated with Improved Experimental Pain Tolerance in Patients with Chronic Pain: An Observational Study","volume":"11","author":"Compton","year":"2022","journal-title":"Pain Ther."},{"key":"ref_29","first-page":"197","article-title":"Clinical utility of the cold pressor test: Evaluation of pain patients, treatment of opioid-induced hyperalgesia and fibromyalgia with low dose naltrexone","volume":"26","author":"Oaks","year":"2018","journal-title":"Discov. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1016\/S0140-6736(19)30352-6","article-title":"Transition from acute to chronic pain after surgery","volume":"393","author":"Glare","year":"2019","journal-title":"Lancet"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/B978-0-7020-4086-3.00033-3","article-title":"Fibromyalgia","volume":"119","author":"Sumpton","year":"2014","journal-title":"Handb. Clin. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"g6380","DOI":"10.1136\/bmj.g6380","article-title":"Opioids for low back pain","volume":"350","author":"Deyo","year":"2015","journal-title":"Bmj"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/ejp.1328","article-title":"Why mu-opioid agonists have less analgesic efficacy in neuropathic pain?","volume":"23","author":"Maldonado","year":"2019","journal-title":"Eur. J. Pain"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s11916-003-0013-5","article-title":"Opioid resistance in chronic daily headache: A synthesis of ideas from the bench and bedside","volume":"7","author":"Biondi","year":"2003","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/head.12223","article-title":"Clinical aspects of medication overuse headaches","volume":"54","author":"Lake","year":"2014","journal-title":"Headache"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/papr.12613","article-title":"Influence of Morphine and Naloxone on Pain Modulation in Rheumatoid Arthritis, Chronic Fatigue Syndrome\/Fibromyalgia, and Controls: A Double-Blind, Randomized, Placebo-Controlled, Cross-Over Study","volume":"18","author":"Hermans","year":"2018","journal-title":"Pain Prcatice"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1111\/j.1526-4637.2011.01276.x","article-title":"Longitudinal observation of changes in pain sensitivity during opioid tapering in patients with chronic low-back pain","volume":"12","author":"Wang","year":"2011","journal-title":"Pain Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1111\/j.1526-4637.2009.00613.x","article-title":"Fibromyalgia symptoms are reduced by low-dose naltrexone: A pilot study","volume":"10","author":"Younger","year":"2009","journal-title":"Pain Med."},{"key":"ref_39","first-page":"Cd012033","article-title":"Perioperative intravenous ketamine for acute postoperative pain in adults","volume":"12","author":"Brinck","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.brainresbull.2014.12.001","article-title":"Inhibition of DOR prevents remifentanil induced postoperative hyperalgesia through regulating the trafficking and function of spinal NMDA receptors in vivo and in vitro","volume":"110","author":"Wang","year":"2015","journal-title":"Brain Res. Bull."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e648","DOI":"10.1097\/PR9.0000000000000648","article-title":"Linking opioid-induced hyperalgesia and withdrawal-associated injury site pain: A case report","volume":"3","author":"Rieb","year":"2018","journal-title":"Pain Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1097\/FBP.0000000000000559","article-title":"Opioid system modulation of cognitive affective bias: Implications for the treatment of mood disorders","volume":"31","author":"Varastehmoradi","year":"2020","journal-title":"Behav. Pharm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1097\/j.pain.0000000000001458","article-title":"Kappa opioid signaling in the central nucleus of the amygdala promotes disinhibition and aversiveness of chronic neuropathic pain","volume":"160","author":"Navratilova","year":"2019","journal-title":"Pain"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"696515","DOI":"10.3389\/fpain.2021.696515","article-title":"Monoaminergic and Opioidergic Modulation of Brainstem Circuits: New Insights Into the Clinical Challenges of Pain Treatment?","volume":"2","author":"Tavares","year":"2021","journal-title":"Front. Pain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1097\/j.pain.0000000000000633","article-title":"Endogenous opioidergic dysregulation of pain in fibromyalgia: A PET and fMRI study","volume":"157","author":"Schrepf","year":"2016","journal-title":"Pain"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/j.pain.2012.02.028","article-title":"Analgesic tolerance without demonstrable opioid-induced hyperalgesia: A double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain","volume":"153","author":"Chu","year":"2012","journal-title":"Pain"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1111\/ner.13345","article-title":"One-Year Results of Prospective Research Study Using 10 kHz Spinal Cord Stimulation in Persistent Nonoperated Low Back Pain of Neuropathic Origin: Maiden Back Study","volume":"24","author":"Baranidharan","year":"2021","journal-title":"Neuromodulation"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s40463-019-0352-9","article-title":"Opioid prescribing practices following elective surgery in Otolaryngology-Head & Neck Surgery","volume":"48","author":"Biskup","year":"2019","journal-title":"J. Otolaryngol.-Head Neck Surg."},{"key":"ref_49","first-page":"581","article-title":"Clinical uses of fentanyl, sufentanil, and alfentanil","volume":"10","author":"Clotz","year":"1991","journal-title":"Clin. Pharm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1111\/anae.14582","article-title":"Analgesic impact of intra-operative opioids vs. opioid-free anaesthesia: A systematic review and meta-analysis","volume":"74","author":"Frauenknecht","year":"2019","journal-title":"Anaesthesia"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1016\/S0140-6736(19)30428-3","article-title":"Inappropriate opioid prescription after surgery","volume":"393","author":"Neuman","year":"2019","journal-title":"Lancet"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"Es9","DOI":"10.36076\/ppj.2012\/15\/ES9","article-title":"Opioid epidemic in the United States","volume":"15","author":"Manchikanti","year":"2012","journal-title":"Pain Physician"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1097\/MLR.0000000000001663","article-title":"Impacts of Initial Prescription Length and Prescribing Limits on Risk of Prolonged Postsurgical Opioid Use","volume":"60","author":"Young","year":"2022","journal-title":"Med. Care"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.suc.2021.09.003","article-title":"Multimodal Analgesia in the Era of the Opioid Epidemic","volume":"102","author":"Nicholas","year":"2022","journal-title":"Surg. Clin. N. Am."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1097\/ALN.0000000000003572","article-title":"Perioperative Opioid Administration","volume":"134","author":"Shanthanna","year":"2021","journal-title":"Anesthesiology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jor.2021.05.001","article-title":"Preoperative opioid use correlates with worse patient-reported outcomes two years after elective shoulder surgery","volume":"25","author":"McCurdy","year":"2021","journal-title":"J. Orthop."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e831","DOI":"10.1097\/PR9.0000000000000831","article-title":"Predicting poor postoperative acute pain outcome in adults: An international, multicentre database analysis of risk factors in 50,005 patients","volume":"5","author":"Schnabel","year":"2020","journal-title":"Pain Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1097\/EJA.0000000000000197","article-title":"Hyperalgesia induced by low-dose opioid treatment before orthopaedic surgery: An observational case-control study","volume":"32","author":"Hina","year":"2015","journal-title":"Eur. J. Anaesthesiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1097\/ALN.0b013e3181e9092d","article-title":"Ketamine for managing perioperative pain in opioid-dependent patients with chronic pain: A unique indication?","volume":"113","author":"Angst","year":"2010","journal-title":"Anesthesiology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/S0140-6736(19)30430-1","article-title":"Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia","volume":"393","author":"Colvin","year":"2019","journal-title":"Lancet"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"110652","DOI":"10.1016\/j.jclinane.2022.110652","article-title":"Perioperative ketamine for postoperative pain management in patients with preoperative opioid intake: A systematic review and meta-analysis","volume":"78","author":"Lipke","year":"2022","journal-title":"J. Clin. Anesth."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4097\/kjae.2013.64.1.19","article-title":"Effect of oral pregabalin on opioid-induced hyperalgesia in patients undergoing laparo-endoscopic single-site urologic surgery","volume":"64","author":"Lee","year":"2013","journal-title":"Korean J. Anesth."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1093\/bja\/aex174","article-title":"Low-dose buprenorphine infusion to prevent postoperative hyperalgesia in patients undergoing major lung surgery and remifentanil infusion: A double-blind, randomized, active-controlled trial","volume":"119","author":"Mercieri","year":"2017","journal-title":"Br. J. Anaesth."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1053\/j.jvca.2011.03.185","article-title":"Target-controlled dosing of remifentanil during cardiac surgery reduces postoperative hyperalgesia","volume":"25","author":"Pouquet","year":"2011","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_65","first-page":"3596","article-title":"The influence of dexmedetomidine on remifentanil-induced hyperalgesia and the sex differences","volume":"16","author":"Qiu","year":"2018","journal-title":"Exp. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"238","DOI":"10.4097\/kjae.2011.61.3.238","article-title":"Effects of intraoperative low dose ketamine on remifentanil-induced hyperalgesia in gynecologic surgery with sevoflurane anesthesia","volume":"61","author":"Hong","year":"2011","journal-title":"Korean J. Anesth."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.2147\/JPR.S221131","article-title":"Remifentanil-Induced Secondary Hyperalgesia Is Not Prevented By Preoperative Acetazolamide Administration In Patients Undergoing Total Thyroidectomy: A Randomized Controlled Trial","volume":"12","author":"Contreras","year":"2019","journal-title":"J. Pain Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"476","DOI":"10.4097\/kjae.2015.68.5.476","article-title":"Effect of intraoperative infusion of ketamine on remifentanil-induced hyperalgesia","volume":"68","author":"Choi","year":"2015","journal-title":"Korean J. Anesth."},{"key":"ref_69","first-page":"w13195","article-title":"The ED50 and ED95 of ketamine for prevention of postoperative hyperalgesia after remifentanil-based anaesthesia in patients undergoing laparoscopic cholecystectomy","volume":"141","author":"Hang","year":"2011","journal-title":"Swiss Med. Wkly."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"222","DOI":"10.4097\/kjae.2014.66.3.222","article-title":"Comparison of effects of intraoperative esmolol and ketamine infusion on acute postoperative pain after remifentanil-based anesthesia in patients undergoing laparoscopic cholecystectomy","volume":"66","author":"Lee","year":"2014","journal-title":"Korean J. Anesth."},{"key":"ref_71","first-page":"e94498","article-title":"A High Dose of Fentanyl May Accelerate the Onset of Acute Postoperative Pain","volume":"9","year":"2019","journal-title":"Anesth. Pain Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1097\/ALN.0b013e31821f6545","article-title":"Pregabalin suppresses spinal neuronal hyperexcitability and visceral hypersensitivity in the absence of peripheral pathophysiology","volume":"115","author":"Bannister","year":"2011","journal-title":"Anesthesiology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"E8","DOI":"10.3171\/2019.1.FOCUS18645","article-title":"Opioid-free anesthesia within an enhanced recovery after surgery pathway for minimally invasive lumbar spine surgery: A retrospective matched cohort study","volume":"46","author":"Soffin","year":"2019","journal-title":"Neurosurg. Focus"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1136\/rapm-2018-100217","article-title":"Fentanyl versus remifentanil-based TIVA for pediatric scoliosis repair: Does it matter?","volume":"44","author":"Kars","year":"2019","journal-title":"Reg. Anesth. Pain Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3389\/fnana.2017.00051","article-title":"Reticular Formation and Pain: The Past and the Future","volume":"11","author":"Martins","year":"2017","journal-title":"Front. Neuroanat."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0301-0082(01)00025-9","article-title":"The medullary dorsal reticular nucleus as a pronociceptive centre of the pain control system","volume":"66","author":"Lima","year":"2002","journal-title":"Prog. Neurobiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"287","DOI":"10.3389\/fncel.2019.00287","article-title":"Neuropathic Pain Induced Alterations in the Opioidergic Modulation of a Descending Pain Facilitatory Area of the Brain","volume":"13","author":"Costa","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.bbi.2017.08.018","article-title":"Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in male rats","volume":"72","author":"Grace","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1744-8069-8-19","article-title":"Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in mice","volume":"8","author":"Liu","year":"2012","journal-title":"Mol. Pain"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/j.neuroscience.2010.02.011","article-title":"Possible involvement of toll-like receptor 4\/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences","volume":"167","author":"Hutchinson","year":"2010","journal-title":"Neuroscience"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.neuroscience.2018.01.048","article-title":"Differential Spinal and Supraspinal Activation of Glia in a Rat Model of Morphine Tolerance","volume":"375","author":"Jokinen","year":"2018","journal-title":"Neuroscience"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"E3441","DOI":"10.1073\/pnas.1602070113","article-title":"Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation","volume":"113","author":"Grace","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1097\/WNR.0000000000001018","article-title":"Upregulation of P2X2 and P2X3 receptors in rats with hyperalgesia induced by heroin withdrawal","volume":"29","author":"Leng","year":"2018","journal-title":"Neuroreport"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1124\/jpet.120.000004","article-title":"Chronic Morphine-Induced Changes in Signaling at the A(3) Adenosine Receptor Contribute to Morphine-Induced Hyperalgesia, Tolerance, and Withdrawal","volume":"374","author":"Doyle","year":"2020","journal-title":"J. Pharm. Exp."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.neuropharm.2009.07.012","article-title":"Opiate-induced hypernociception and chemokine receptors","volume":"58","author":"White","year":"2010","journal-title":"Neuropharmacology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.bbi.2010.12.014","article-title":"CXCR4 signaling mediates morphine-induced tactile hyperalgesia","volume":"25","author":"Wilson","year":"2011","journal-title":"Brain Behav. Immun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1097\/j.pain.0000000000001888","article-title":"Activation of sphingosine-1-phosphate receptor subtype 1 in the central nervous system contributes to morphine-induced hyperalgesia and antinociceptive tolerance in rodents","volume":"161","author":"Doyle","year":"2020","journal-title":"Pain"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1111\/imm.13172","article-title":"The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain","volume":"159","author":"Pawlik","year":"2020","journal-title":"Immunology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"eaaw6471","DOI":"10.1126\/scitranslmed.aaw6471","article-title":"Anti-PD-1 treatment impairs opioid antinociception in rodents and nonhuman primates","volume":"12","author":"Wang","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"101570","DOI":"10.1016\/j.isci.2020.101570","article-title":"PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia","volume":"23","author":"Jiang","year":"2020","journal-title":"Iscience"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1126\/science.1211726","article-title":"Erasure of a spinal memory trace of pain by a brief, high-dose opioid administration","volume":"335","author":"Benrath","year":"2012","journal-title":"Science"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"53","DOI":"10.5607\/en.2014.23.1.53","article-title":"Attenuated Glial K(+) Clearance Contributes to Long-Term Synaptic Potentiation Via Depolarizing GABA in Dorsal Horn Neurons of Rat Spinal Cord","volume":"23","author":"Lee","year":"2014","journal-title":"Exp. Neurobiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.neuroscience.2017.12.002","article-title":"Enhanced Activities of \u03b4 Subunit-containing GABA(A) Receptors Blocked Spinal Long-term Potentiation and Attenuated Formalin-induced Spontaneous Pain","volume":"371","author":"Liu","year":"2018","journal-title":"Neuroscience"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"116","DOI":"10.3389\/fphar.2014.00116","article-title":"It\u2019s MORe exciting than mu: Crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system","volume":"5","author":"Chartoff","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1744806917704769","DOI":"10.1177\/1744806917704769","article-title":"Activation of spinal alpha-7 nicotinic acetylcholine receptor shortens the duration of remifentanil-induced postoperative hyperalgesia by upregulating KCC2 in the spinal dorsal horn in rats","volume":"13","author":"Gu","year":"2017","journal-title":"Mol. Pain"},{"key":"ref_96","first-page":"524","article-title":"Evaluating off-label uses of acetazolamide","volume":"75","author":"Elefritz","year":"2018","journal-title":"Bull. Am. Soc. Hosp. Pharm."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1097\/ALN.0000000000003412","article-title":"Shift of \u00b5-opioid Receptor Signaling in the Dorsal Reticular Nucleus Is Implicated in Morphine-induced Hyperalgesia in Male Rats","volume":"133","author":"Costa","year":"2020","journal-title":"Anesthesiology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1124\/pr.112.007138","article-title":"Mu opioids and their receptors: Evolution of a concept","volume":"65","author":"Pasternak","year":"2013","journal-title":"Pharm. Rev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/jnr.21466","article-title":"Axogenic effect of estrogen in male rat hypothalamic neurons involves Ca(2+), protein kinase C, and extracellular signal-regulated kinase signaling","volume":"86","author":"Gorosito","year":"2008","journal-title":"J. Neurosci. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1097\/ALN.0000000000000749","article-title":"Increased noradrenergic neurotransmission to a pain facilitatory area of the brain is implicated in facilitation of chronic pain","volume":"123","author":"Martins","year":"2015","journal-title":"Anesthesiology"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"107519","DOI":"10.1016\/j.pharmthera.2020.107519","article-title":"Replacement of current opioid drugs focusing on MOR-related strategies","volume":"210","author":"Busserolles","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.3389\/fphar.2018.01240","article-title":"Heteromerization Modulates mu Opioid Receptor Functional Properties in vivo","volume":"9","author":"Ugur","year":"2018","journal-title":"Front. Pharm."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Gaborit, M., and Massotte, D. (2021). Therapeutic potential of opioid receptor heteromers in chronic pain and associated comorbidities. Br. J. Pharm.","DOI":"10.1111\/bph.15772"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-018-0090-5","article-title":"Heteromerization of \u03bc-opioid receptor and cholecystokinin B receptor through the third transmembrane domain of the \u03bc-opioid receptor contributes to the anti-opioid effects of cholecystokinin octapeptide","volume":"50","author":"Yang","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"Es93","DOI":"10.36076\/ppj.2012\/15\/ES93","article-title":"Opioids and neuropathic pain","volume":"15","author":"Smith","year":"2012","journal-title":"Pain Physician"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Rowan, M.P., Bierbower, S.M., Eskander, M.A., Szteyn, K., Por, E.D., Gomez, R., Veldhuis, N., Bunnett, N.W., and Jeske, N.A. (2014). Activation of mu opioid receptors sensitizes transient receptor potential vanilloid type 1 (TRPV1) via \u03b2-arrestin-2-mediated cross-talk. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093688"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1007\/s10571-020-00973-5","article-title":"Mu Opioids Induce Biased Signaling at the Full-Length Seven Transmembrane C-Terminal Splice Variants of the mu Opioid Receptor Gene, Oprm1","volume":"41","author":"Narayan","year":"2021","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"21211","DOI":"10.1074\/jbc.M113.458687","article-title":"Stabilization of the \u03bc-opioid receptor by truncated single transmembrane splice variants through a chaperone-like action","volume":"288","author":"Xu","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/syn.10277","article-title":"Functional analysis of MOR-1 splice variants of the mouse mu opioid receptor gene Oprm","volume":"51","author":"Bolan","year":"2004","journal-title":"Synapse"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.pharep.2016.03.003","article-title":"Opioid-induced redistribution of 6TM and 7TM \u03bc opioid receptors: A hypothesized mechanistic facilitator model of opioid-induced hyperalgesia","volume":"68","author":"Wang","year":"2016","journal-title":"Pharm. Rep."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Oladosu, F.A., Conrad, M.S., O\u2019Buckley, S.C., Rashid, N.U., Slade, G.D., and Nackley, A.G. (2015). Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135711"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/npp.2011.155","article-title":"The mu-opioid receptor and the NMDA receptor associate in PAG neurons: Implications in pain control","volume":"37","author":"Berrocoso","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.gene.2018.03.081","article-title":"Association between MDR(1)\/CYP3A4\/OPRM(1) gene polymorphisms and the post-caesarean fentanyl analgesic effect on Chinese women","volume":"661","author":"Zhang","year":"2018","journal-title":"Gene"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1188\/17.CJON.294-296","article-title":"Opioid-Induced Hyperalgesia: Clinical Implications for Advanced Practice Nurses in Oncology","volume":"21","author":"Guastella","year":"2017","journal-title":"Clin. J. Oncol. Nurs."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s11916-017-0613-0","article-title":"New Cancer Pain Treatment Options","volume":"21","author":"Candido","year":"2017","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"173","DOI":"10.5055\/jom.2008.0023","article-title":"Ketamine for acute and subacute pain in opioid-tolerant patients","volume":"4","author":"Chazan","year":"2008","journal-title":"J. Opioid Manag."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/s13063-019-3303-x","article-title":"Evaluation of intravenous lidocaine in head and neck cancer surgery: Study protocol for a randomized controlled trial","volume":"20","author":"Omar","year":"2019","journal-title":"Trials"},{"key":"ref_118","first-page":"1413","article-title":"Role of Spinal Cord \u03b1(2)-Adrenoreceptors in Noradrenergic Inhibition of Nociceptive Transmission During Chemotherapy-Induced Peripheral Neuropathy","volume":"13","author":"Ribeiro","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1111\/ejn.14614","article-title":"Serotoninergic pain modulation from the rostral ventromedial medulla (RVM) in chemotherapy-induced neuropathy: The role of spinal 5-HT3 receptors","volume":"51","author":"Martins","year":"2020","journal-title":"Eur. J. Neurosci."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1097\/ALN.0b013e31820efb19","article-title":"5-hydroxytryptamine type 3 receptor modulates opioid-induced hyperalgesia and tolerance in mice","volume":"114","author":"Liang","year":"2011","journal-title":"Anesthesiology"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"e010664","DOI":"10.1136\/bmjopen-2015-010664","article-title":"Risk factors for persistent and new chronic opioid use in patients undergoing total hip arthroplasty: A retrospective cohort study","volume":"6","author":"Inacio","year":"2016","journal-title":"BMJ Open"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/20\/6161\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:57:23Z","timestamp":1760144243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/20\/6161"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,19]]},"references-count":121,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["jcm11206161"],"URL":"https:\/\/doi.org\/10.3390\/jcm11206161","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,19]]}}}