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Review

CYP2D6 phenotypes and opioid metabolism: the path to personalized analgesia

, &
Pages 261-275 | Received 13 Aug 2021, Accepted 31 May 2022, Published online: 10 Jun 2022

References

  • NSW Government. Chronic pain management. [ updated Tuesday 23 Mar 2021; cited 8 Jul 2021]. Available from: https://www.health.nsw.gov.au/pharmaceutical/doctors/Pages/chronic-pain-medical-practitioners.aspx
  • Domenichiello AF, Ramsden CE. The silent epidemic of chronic pain in older adults. Progress in neuro-psychopharmacology & biological psychiatry. Eur J Pain. 2019 Jul 13;93:284–290.
  • Breivik H, Collett B, Ventafridda V, et al. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006 May;10(4):287–333.
  • Warner DF, Brown TH. Understanding how race/ethnicity and gender define age-trajectories of disability: an intersectionality approach. Soc Sci Med. 2011 Apr;72(8):1236–1248.
  • Miotto K, Cho AK, Khalil MA, et al. Trends in tramadol: pharmacology, metabolism, and misuse. Anesth Analg. 2017 Jan;124(1):44–51.
  • Tobias JD, Green TP, Coté CJ. Codeine: time to say “No.” Pediatrics. 2016 Oct;138(4).
  • Shah A, Hayes CJ, Martin BC. Factors influencing long-term opioid use among opioid naive patients: an examination of initial prescription characteristics and pain etiologies. J Pain. 2017 Nov;18(11):1374–1383.
  • Higgins C, Smith BH, Matthews K. Incidence of iatrogenic opioid dependence or abuse in patients with pain who were exposed to opioid analgesic therapy: a systematic review and meta-analysis. Br J Anaesth. 2018 Jun;120(6):1335–1344.
  • Schuchat A, Guy GP Jr., Dowell D. Prescription drug monitoring programs and opioid death rates-reply. Jama. 2017 Nov 28;318(20):2045.
  • Fernandes K, Martins D, Juurlink D, et al. High-dose opioid prescribing and opioid-related hospitalization: a population-based study. PloS one. 2016;11(12):e0167479.
  • Ko TM, Wong CS, Wu JY, et al. Pharmacogenomics for personalized pain medicine acta anaesthesiologica Taiwanica: official journal of the Taiwan Society of Anesthesiologists PloS one. 2016 Mar;54(1):24–30.
  • Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008 Mar;11(2 Suppl):S105–20.
  • Manchikanti L, Kaye AM, Knezevic NN, et al. Responsible, safe, and effective prescription of opioids for chronic non-cancer pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines. Pain Physician. 2017 Feb;20(2S):S3–S92.
  • Maani CV, Shah MA, Hansen JJ, et al. Translational advances in pain and anesthesia for cancer patients. J Surg Oncol. 2012 Apr 1 105(5):488–493.
  • Chou R, Deyo R, Devine B, et al. The effectiveness and risks of long-term opioid treatment of chronic pain. Evid Rep Technol Assess (Full Rep). 2014;218:1–219.
  • Kim KH, Seo HJ, Abdi S, et al. All about pain pharmacology: what pain physicians should know. Korean J Pain. 2020 Apr 1 33(2):108–120.
  • Graziani M, RJPr N. Gender difference in prescription opioid abuse: a focus on oxycodone and hydrocodone. J Surg Oncol. 2016;108:31–38.
  • Kaye AD, Garcia AJ, Hall OM, et al. Update on the pharmacogenomics of pain management. Pharmgenomics Pers Med. 2019;12:125–143.
  • Hartford C, Gjpp R. Fundamental considerations for genetically-guided pain management with opioids based on CYP2D6 and OPRM1 polymorphisms. J Surg Oncol. 2018;21(6):E611–E621. .
  • Samer CF, Daali Y, Wagner M, et al. Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. Mayo Clin Proc. 2010;160(4): 919–930
  • Xu F, Yin J, Xiong E, et al. COMT gene variants and beta-endorphin levels contribute to ethnic differences in experimental pain sensitivity. Mol Pain. 2020 Jan-Dec;16:1744806920908474.
  • Smith HS. Opioid metabolism. Mayo Clin Proc. 2009 Jul;84(7):613–624.
  • Batistaki C, Chrona E, Kostroglou A, et al. CYP2D6 basic genotyping of patients with chronic pain receiving tramadol or codeine. a study in a Greek cohort. Pain Med. 2020 Nov 1 21(11):3199–3204.
  • Smith DM, Weitzel KW, Cavallari LH, et al. Clinical application of pharmacogenetics in pain management. Per Med. 2018 Mar;15(2):117–126.
  • Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005;5(1):6–13.
  • Gaedigk A, Simon SD, Pearce RE, et al. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008 Feb;83(2):234–242.
  • Caudle KE, Sangkuhl K, Whirl-Carrillo M, et al. Standardizing CYP2D6 genotype to phenotype translation: consensus recommendations from the clinical pharmacogenetics implementation consortium and Dutch pharmacogenetics working group. Clin Transl Sci. 2020 Jan;13(1):116–124.
  • Samer CF, Lorenzini KI, Rollason V, et al. Applications of CYP450 testing in the clinical setting. Mol Diagn Ther. 2013 Jun;17(3):165–184.
  • FDA warns against use of codeine and tramadol in children and breastfeeding women. Med Lett Drugs Ther. 2017;59:86–88. May 22.
  • Eid RS, Gobinath AR, Galea LAM. Sex differences in depression: insights from clinical and preclinical studies. Prog Neurobiol. 2019 May;176:86–102.
  • Goetz TG, Becker JB, Mazure CM. Women, opioid use and addiction. FASEB J. 2021 Feb;35(2):e21303.
  • Lopes GS, Bielinski SJ, Moyer AM, et al. Sex differences in associations between cyp2d6 phenotypes and response to opioid analgesics. Pharmgenomics Pers Med. 2020;13:71–79.
  • Ershad M, Cruz MD, Mostafa A, et al. Opioid toxidrome following grapefruit juice consumption in the setting of methadone maintenance. J Addict Med. 2020 ;14(2):172–174.
  • Rodieux F, Vutskits L, Posfay-Barbe KM, et al. When the safe alternative is not that safe: tramadol prescribing in children. Front Pharmacol. 2018;9:148.
  • Burton AW, Cleeland CS. Cancer pain: progress since the WHO guidelines. Pain Pract. 2001 Sep;1(3):236–242.
  • Aklillu E, Herrlin K, Gustafsson LL, et al. Evidence for environmental influence on CYP2D6-catalysed debrisoquine hydroxylation as demonstrated by phenotyping and genotyping of Ethiopians living in Ethiopia or in Sweden. Pharmacogenetics. 2002 Jul;12(5):375–383.
  • Crews KR, Monte AA, Huddart R, et al. Clinical pharmacogenetics implementation consortium guideline for CYP2D6, OPRM1, and COMT genotypes and select opioid therapy. Clin Pharmacol Ther. 2021 Oct;110(4):888–896.
  • Söderberg Löfdal KC, Andersson ML, Gustafsson LL. Cytochrome P450-mediated changes in oxycodone pharmacokinetics/pharmacodynamics and their clinical implications. Drugs. 2013 May;73(6):533–543.
  • Sitasuwan P, Melendez C, Marinova M, et al. Degradation of opioids and opiates during acid hydrolysis leads to reduced recovery compared to enzymatic hydrolysis. J Anal Toxicol. 2016 Oct;40(8):601–607.
  • Dong H, Lu SJ, Zhang R, et al. Effect of the CYP2D6 gene polymorphism on postoperative analgesia of tramadol in Han nationality nephrectomy patients. Eur J Clin Pharmacol. 2015 Jun;71(6):681–686.
  • Baber M, Chaudhry S, Kelly L, et al. The pharmacogenetics of codeine pain relief in the postpartum period. Pharmacogenomics J. 2015 Oct;15(5):430–435.
  • Bastami S, Haage P, Kronstrand R, et al. Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose. Forensic Sci Int. 2014 May;238:125–132.
  • Tanaka H, Naito T, Sato H, et al. Impact of CYP genotype and inflammatory markers on the plasma concentrations of tramadol and its demethylated metabolites and drug tolerability in cancer patients. Eur J Clin Pharmacol. 2018 Nov;74(11):1461–1469.
  • Lane K, Dixon JJ, McKeown D, et al. Using tramadol to measure CYP2D6 metabolism in critically ill adults. Intensive Care Med. 2014 Aug;40(8):1177–1178.
  • Haage P, Kronstrand R, Josefsson M, et al. Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype. Pharmacol Res Perspect. 2018 Jul;6(4):e00419.
  • Yu H, Hong S, Jeong CH, et al. Development of a linear dual column HPLC-MS/MS method and clinical genetic evaluation for tramadol and its phase I and II metabolites in oral fluid. Arch Pharm Res. 2018 Mar;41(3):288–298.
  • Yu H, Choi M, Jang JH, et al. Development of a column-switching LC-MS/MS method of tramadol and its metabolites in hair and application to a pharmacogenetic study. Arch Pharm Res. 2018 May;41(5):554–563.
  • Arafa MH, Atteia HH. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6) are associated with long term tramadol treatment-induced oxidative damage and hepatotoxicity. Toxicol Appl Pharmacol. 2018 May 1; 346:37–44.
  • Fonseca S, Amorim A, Costa HA, et al. Sequencing CYP2D6 for the detection of poor-metabolizers in post-mortem blood samples with tramadol. Forensic Sci Int. 2016 Aug;265:153–159.
  • Frost J, Lokken TN, Helland A, et al. Post-mortem levels and tissue distribution of codeine, codeine-6-glucuronide, norcodeine, morphine and morphine glucuronides in a series of codeine-related deaths. Forensic Sci Int. 2016 May;262:128–137.
  • Prows CA, Zhang X, Huth MM, et al. Codeine-related adverse drug reactions in children following tonsillectomy: a prospective study. Laryngoscope. 2014 May;124(5):1242–1250.
  • Radford H, Simpson KH, Rogerson S, et al. A single site population study to investigate CYP2D6 phenotype of patients with persistent non-malignant pain. Medicina (B Aires). 2019 May 28;55(6).
  • Naito T, Takashina Y, Yamamoto K, et al. CYP3A5*3 affects plasma disposition of noroxycodone and dose escalation in cancer patients receiving oxycodone. J Clin Pharmacol. 2011 Nov;51(11):1529–1538.
  • Andreassen TN, Eftedal I, Klepstad P, et al. Do CYP2D6 genotypes reflect oxycodone requirements for cancer patients treated for cancer pain? A cross-sectional multicentre study. Eur J Clin Pharmacol. 2012 Jan;68(1):55–64.
  • Balyan R, Mecoli M, Venkatasubramanian R, et al. CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients. Pharmacogenomics. 2017 Mar;18(4):337–348.
  • Slanar O, Dupal P, Matouskova O, et al. Tramadol efficacy in patients with postoperative pain in relation to CYP2D6 and MDR1 polymorphisms. Bratisl Lek Listy. 2012;113(3):152–155.
  • Wu SB, Cai LN, Yang XH, et al. Impact of CYP2D6 polymorphisms on postoperative fentanyl analgesia in gastric cancer patients. Genet Test Mol Biomarkers. 2015 May;19(5):248–252.
  • Stauble ME, Moore AW, Langman LJ, et al. Hydrocodone in postoperative personalized pain management: pro-drug or drug? Clin Chim Acta. 2014 Feb 15;429:26–29.
  • Mactier H, McLaughlin P, Gillis C, et al. Variations in Infant CYP2B6 genotype associated with the need for pharmacological treatment for neonatal abstinence syndrome in infants of methadone-maintained opioid-dependent mothers. Am J Perinatol. 2017 Jul;34(9):918–921.
  • Solhaug V, EJSjop M. Individual variability in clinical effect and tolerability of opioid analgesics–Importance of drug interactions and pharmacogenetics. Am J Perinatol. 2017;17(1):193–200.
  • Wang Q, Zuo Z. Impact of transporters and enzymes from blood–cerebrospinal fluid barrier and brain parenchyma on CNS drug uptake. Am J Perinatol. 2018;14(9):961–972.
  • Zanger UM, Schwab MJP. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138(1):103–141.
  • St Sauver JL, Olson JE, Roger VL, et al. CYP2D6 phenotypes are associated with adverse outcomes related to opioid medications. Pharm Pers Med. 2017;10:217.
  • Zahari Z, RJDm I. Influence of cytochrome P450, family 2, Subfamily D, Polypeptide 6 (CYP2D6) polymorphisms on pain sensitivity and clinical response to weak opioid analgesics. Mayo Clin Proc. 2017;10:217.
  • D’empaire I, Guico-Pabia CJ, PP PS. Antidepressant treatment and altered CYP2D6 activity: are pharmacokinetic variations clinically relevant? J Psy Prac. 2011;17(5):330–339.
  • Yip V, Hawcutt D, Pirmohamed MJCP, et al. Pharmacogenetic markers of drug efficacy and toxicity. Cli Pharm Thera. 2015;98(1):61–70.
  • Vieira CMP, Fragoso RM, Pereira D, et al. Pain polymorphisms and opioids: an evidence based review. Mol Med Rep. 2019 Mar;19(3):1423–1434.
  • Monte AA, Heard KJ, Campbell J, et al. The effect of CYP2D6 drug-drug interactions on hydrocodone effectiveness. Acad Emerg Med. 2014 Aug;21(8):879–885.
  • de Leon J. Glucuronidation enzymes, genes and psychiatry. Int J Neuropsychopharmacol. 2003 Mar;6(1):57–72.
  • HSJTCjop S. The metabolism of opioid agents and the clinical impact of their active metabolites. Int J Neuropsychopharmacol. 2011;27(9):824–838.
  • Takeda S, Ishii Y, Iwanaga M, et al. Modulation of UDP-glucuronosyltransferase function by cytochrome P450: evidence for the alteration of UGT2B7-catalyzed glucuronidation of morphine by CYP3A4. Mol Pharm. 2005;67(3):665–672.
  • “Weak” opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine. Prescrire Int. 2016 Feb;25(168):45–50.
  • Zandonai T, Escorial M, Peiró AM. Codeine and tramadol use in athletes: a potential for abuse. Front Pharmacol. 2021;12:661781.
  • Jin J. Risks of codeine and tramadol in children. Jama. 2017 Oct 17; 318(15):1514.
  • Krantz M, Garcia J, PJIjoc M. Tramadol-associated pericarditis. Int J card. 2005;99(3):497–498.
  • Elkalioubie A, Allorge D, Robriquet L, et al. Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer. Eur J Clin Pharmacol. 2011 Aug;67(8):855–858.
  • Orliaguet G, Hamza J, Couloigner V, et al. A case of respiratory depression in a child with ultrarapid CYP2D6 metabolism after tramadol. Pediatrics. 2015 Mar;135(3):e753–5.
  • Smith DM, Weitzel KW, Elsey AR, et al. CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial. Genet Med. 2019 Aug;21(8):1842–1850.
  • Machado-Alba JE, Serna-Echeverri LS, Valladales-Restrepo LF, et al. Use of tramadol or other analgesics in patients treated in the emergency department as a risk factor for opioid use. Pain Res Manag. 2020;8847777. DOI: https://doi.org/10.1155/2020/8847777.
  • Saarikoski T, Saari TI, Hagelberg NM, et al. Effects of terbinafine and itraconazole on the pharmacokinetics of orally administered tramadol. Eur J Clin Pharmacol. 2015 Mar;71(3):321–327.
  • Schelde AB, Sørensen AMS, Hindsø M, et al. Sex and age differences among tramadol users in three Nordic countries. Dan Med J. 2020 Jul 1;67(7):A06190336.
  • Thorn CF, Klein TE, Altman RB. Codeine and morphine pathway. Pharmacogenet Genomics. 2009 Jul;19(7):556–558.
  • Poulsen L, Arendt-Nielsen L, Brosen K, et al. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther. 1996 Dec;60(6):636–644.
  • Volpe DA, McMahon Tobin GA, Mellon RD, et al. Uniform assessment and ranking of opioid mu receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol. 2011 Apr;59(3):385–390.
  • Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004 Dec 30 351(27):2827–2831.
  • VanderVaart S, Berger H, Sistonen J, et al. CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: a pilot study. Ther Drug Monit. 2011 Aug;33(4):425–432.
  • Shaw KD, Amstutz U, Jimenez-Mendez R, et al. Suspected opioid overdose case resolved by CYP2D6 genotyping. Ther Drug Monit. 2012 Apr;34(2):121–123.
  • Wu X, Yuan L, Zuo J, et al. The impact of CYP2D6 polymorphisms on the pharmacokinetics of codeine and its metabolites in Mongolian Chinese subjects. Eur J Clin Pharmacol. 2014 Jan;70(1):57–63.
  • Kelly LE, Rieder M, van den Anker J, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics. 2012 May;129(5):e1343–7.
  • Friedrichsdorf SJ, Nugent AP, Strobl AQ. Codeine-associated pediatric deaths despite using recommended dosing guidelines: three case reports. J Opioid Manag. 2013 Mar-Apr;9(2):151–155.
  • Sistonen J, Madadi P, Ross CJ, et al. Prediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers. Clin Pharmacol Ther. 2012 Apr;91(4):692–699.
  • European Medicines Agency. PRAC recommends restrictions on the use of codeine for cough and cold in children [ cited 4 Feb 2022]. Available from: https://www.ema.europa.eu/en/news/prac-recommends-restrictions-use-codeine-cough-cold-children
  • Van amsterdam J, van den Brink W. The misuse of prescription opioids: a threat for Europe? Curr Drug Abuse Rev. 2015;8(1):3–14.
  • Graziani M, Nisticò R. Gender difference in prescription opioid abuse: a focus on oxycodone and hydrocodone. Pharmacol Res. 2016 Jun;108:31–38.
  • Coluzzi F, Mattia C. Oxycodone Pharmacological profile and clinical data in chronic pain management. Minerva Anestesiol. 2005 Jul-Aug;71(7–8):451–460.
  • Elder NM, Atayee RS, Best BM, et al. Observations of urinary oxycodone and metabolite distributions in pain patients. J Anal Toxicol. 2014 Apr;38(3):129–134.
  • Samer CF, Daali Y, Wagner M, et al. Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. Br J Pharmacol. 2010 Jun;160(4):919–930.
  • de Leon J, Dinsmore L, Wedlund P. Adverse drug reactions to oxycodone and hydrocodone in CYP2D6 ultrarapid metabolizers. J Clin Psychopharmacol. 2003 Aug;23(4):420–421.
  • Stamer UM, Zhang L, Book M, et al. CYP2D6 genotype dependent oxycodone metabolism in postoperative patients. PloS one. 2013;8(3):e60239.
  • Trescot AM, Datta S, Lee M, et al. Opioid pharmacology. Pain Physician. 2008;11(2 Suppl):S133–53.
  • Barakat NH, Atayee RS, Best BM, et al. Urinary hydrocodone and metabolite distributions in pain patients. J Anal Toxicol. 2014 Sep;38(7):404–409.
  • Roulet L, Rollason V, Desmeules J, et al. Tapentadol versus tramadol: a narrative and comparative review of their pharmacological, efficacy and safety profiles in adult patients. Drugs. 2021 Jul;81(11):1257–1272.
  • Buynak R, Shapiro DY, Okamoto A, et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo-and active-controlled Phase III study. Int J Neuropsychopharmacol. 11(11):1787–1804.
  • CTJEoop H. Tapentadol immediate release for the relief of moderate-to-severe acute pain. Exp Opi Pharm. 2009;10(16):2687–2696.
  • Deodhar M, Turgeon J, Michaud V. Contribution of CYP2D6 functional activity to oxycodone efficacy in pain management: genetic polymorphisms, phenoconversion, and tissue-selective metabolism. Pharmaceutics. 2021 Sep 14; 13(9):1466.
  • Linares OA, Daly D, Linares AD, et al. Personalized oxycodone dosing: using pharmacogenetic testing and clinical pharmacokinetics to reduce toxicity risk and increase effectiveness. Pain Med (Malden, Mass.). 2014 May;155:791–806.
  • Khan MI, Walsh D, Brito-Dellan N. Opioid and adjuvant analgesics: compared and contrasted. Am J Hosp Palliat Care. 2011 Aug;28(5):378–383.
  • Richarz U, Jacobs A, Spina E. How frequently are contraindicated or warned against combinations of drugs prescribed to patients receiving long-term opioid therapy for chronic pain? Pharmacoepidemiol Drug Saf. 2012 May;21(5):453–462.
  • The Trustees of Indiana University. Drug interactions flockhart table ™: the trustees of Indiana University; [cited 2022 Feb 11]. Available from: https://drug-interactions.medicine.iu.edu/MainTable.aspx
  • Peiró AM. Pharmacogenetics in pain treatment. Adv Pharm (San Diego, Calif). 2018;83:247–273.
  • Shelton RC. Serotonin and norepinephrine reuptake inhibitors. Antidepressants: Springer; 2018. p. 145–180.
  • Alfaro CL, Lam YF, Simpson J, et al. CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations. J Clin Pharm. 2000;40(1):58–66.
  • Kapil RP, Friedman K, Cipriano A, et al. Effects of paroxetine, a CYP2D6 inhibitor, on the pharmacokinetic properties of hydrocodone after coadministration with a single-entity, once-daily, extended-release hydrocodone tablet. Clin Ther. 2015 Oct 1; 37(10):2286–2296.
  • Brown EE, Davies S. Potential for drug-drug interactions with adjunctive tramadol use in treatment of obsessive-compulsive disorder. Can J Psychiatry. 2016;61(5):308–309.
  • Cavallari LH, Jeong H, Bress A. Role of cytochrome P450 genotype in the steps toward personalized drug therapy. Pharmgenomics Pers Med. 2011;4:123–136.
  • Montané Jaime LK, Paul J, Lalla A, et al. Impact of CYP2D6 on venlafaxine metabolism in Trinidadian patients with major depressive disorder. Pharmacogenomics. 2018 Feb;19(3):197–212.
  • Karaca-Mandic P, Meara E, Morden NE. The growing problem of co-treatment with opioids and benzodiazepines. BMJ (Clinical research ed). 2017 Mar 14;356:j1224.
  • Lee J, Yoo HD, Bae JW, et al. Population pharmacokinetic analysis of tramadol and O-desmethyltramadol with genetic polymorphism of CYP2D6. Drug Des Devel Ther. 2019;13:1751–1761.
  • Ji B. Pharmacokinetics modeling and molecular modeling of drug-drug interactions between opioids and benzodiazepines. 2019;19(03):297–305. DOI: https://doi.org/10.1007/s40268-019-00282-3 .
  • Krakowski JC, Orebaugh SL. Opioids and benzodiazepines. basic clinical anesthesia. New York: Springer; 2015. p. 139–150.
  • Jones JD, Mogali S, Comer SD. Polydrug abuse: a review of opioid and benzodiazepine combination use. Drug Alcohol Depend. 2012 Sep 1;125(1–2):8–18.
  • Niles JK, Gudin J, Radcliff J, et al. The opioid epidemic within the COVID-19 pandemic: drug testing in 2020. Int J Neuropsychopharmacol. 24(S1):S-43-S–51.
  • McHugh RK, Geyer R, Karakula S, et al. Nonmedical benzodiazepine use in adults with alcohol use disorder: the role of anxiety sensitivity and polysubstance use. Am J Addict. 2018 Sep;27(6):485–490.
  • McHugh RK, Geyer RB, Chase AR, et al. Sex differences in benzodiazepine misuse among adults with substance use disorders. Addict Behav. 2021 Jan;112:106608.
  • Mathieson S, Lin CC, Underwood M, et al. Pregabalin and gabapentin for pain. BMJ (Clinical research ed). 2020 Apr 28;369:m1315.
  • Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010 Oct;49(10):661–669.
  • Perucca E. Clinically relevant drug interactions with antiepileptic drugs. B J clin pharm. 2006;61(3):246–255.
  • Lamy FR, Daniulaityte R, Barratt MJ, et al. Listed for sale: analyzing data on fentanyl, fentanyl analogs and other novel synthetic opioids on one cryptomarket. Clin Pharmacokinet. 2020;213:108115.
  • Degenhardt L, Grebely J, Stone J, et al. Global patterns of opioid use and dependence: harms to populations, interventions, and future action. Lancet (London, England). 2019;394(10208):1560–1579.
  • Treitler PC, Bowden CF, Lloyd J, et al. Perspectives of opioid use disorder treatment providers during COVID-19: adapting to flexibilities and sustaining reforms. J Sub Abu Treat. 2022;132:108514.
  • Lee JW, Aminkeng F, Bhavsar A, et al. The emerging era of pharmacogenomics: current successes, future potential, and challenges. Clinical Genetics. 2014;86(1):21–28.
  • Banerjee AK, Okun S, Edwards IR, et al. Patient-reported outcome measures in safety event reporting: PROSPER consortium guidance. Drug Safety. 2013;36(12):1129–1149.
  • Dagostino C, Allegri M, Napolioni V, et al. CYP2D6 genotype can help to predict effectiveness and safety during opioid treatment for chronic low back pain: results from a retrospective study in an Italian cohort. Pharmgenomics Pers Med. 2018;11:179–191.
  • Cheatle MD, Savage SR. Informed consent in opioid therapy: a potential obligation and opportunity. J Pain Sym Man. 2012;44(1):105–116.
  • Russell MD, Sofat NJ. Analgesics, opioids, and NSAIDs. Addict Behav. 2020;331.
  • Breivik H, Collett B, Ventafridda V, et al. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain (London, England). 2006;10(4): 287–333
  • Pieretti S, Di Giannuario A, Di Giovannandrea R, et al. Gender differences in pain and its relief. Annali dell’Istituto superiore di sanita. 2016;52(2):184–189.
  • Endendijk JJ, Groeneveld MG, JJAosb M. The gendered family process model: an integrative framework of gender in the family archives of sexual behavior. Per Soc Psy Bull . 2018;47(4):877–904.
  • McAnally HB. Opioid dependence: a clinical and epidemiologic approach. New York: Springer; 2017.
  • Martin CE, Scialli A, Terplan M. Addiction: sex and gender evidence in alcohol, tobacco use and nicotine addiction, and opioid use disorders. how sex and gender impact clinical practice. New York: Elsevier; 2021. p. 23–51.
  • A-M Y, Fukamachi K, Krausz KW, et al. Potential role for human cytochrome P450 3A4 in estradiol homeostasis. Endocrinology. 2005;146(7):2911–2919.
  • Shuldiner AR, Relling MV, Peterson JF, et al. The pharmacogenomics research network translational pharmacogenetics program: overcoming challenges of real-world implementation [Research Support, N.I.H., extramural research support, non-U.S. Gov’t]. Clin Pharmacol Ther. 2013 Aug;94(2):207–210.
  • Wilke RA, Xu H, Denny JC, et al. The emerging role of electronic medical records in pharmacogenomics [Research support N.I.H., Extramural review]. Clin Pharmacol Ther. 2011 Mar;89(3):379–386.
  • Peterson JF, Bowton E, Field JR, et al. Electronic health record design and implementation for pharmacogenomics: a local perspective [Research support, N.I.H., Extramural]. Genet Med. 2013 Oct;15(10):833–841.
  • Gottesman O, Kuivaniemi H, Tromp G, et al. The electronic medical records and genomics (eMERGE) Network: past, present, and future [Research support, N.I.H., Extramural research support, Non-U.S. Gov’t]. Genet Med. 2013 Oct;15(10):761–771.
  • Kullo IJ, Jarvik GP, Manolio TA, et al. Leveraging the electronic health record to implement genomic medicine. Genet Med. 2013 Apr;15(4):270–271.
  • CPIC. CPIC guideline for opioids based on genotype. [cited 2022 Feb 2]. Available from: https://cpicpgx.org/guidelines/guideline-for-codeine-and-cyp2d6/
  • PharmGKB. Gene reference materials for CYP2D6: pharmGKB; [cited 2016 Sep 16]. Available from: https://www.pharmgkb.org/page/cyp2d6RefMaterials
  • Pulley JM, Denny JC, Peterson JF, et al. Operational implementation of prospective genotyping for personalized medicine: the design of the vanderbilt PREDICT Project. Clin Pharmacol Ther. 2012 Jul;92(1):87–95.
  • Pratt VM, Cavallari LH, Del Tredici AL, et al. Recommendations for clinical CYP2D6 genotyping allele selection: a joint consensus recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and the European Society for Pharmacogenomics and Personalized Therapy. J mol diagn. 2021Sep; 239: 1047–1064
  • Nofziger C, Turner AJ, Sangkuhl K, et al. PharmVar GeneFocus: CYP2D6. Clin Pharmacol Ther. 2020 Jan;107(1):154–170.
  • Bosilkovska M, Samer CF, Deglon J, et al. Geneva cocktail for cytochrome p450 and P-glycoprotein activity assessment using dried blood spots. Clin Pharmacol Ther. 2014 Sep;96(3):349–359.
  • Dorado P, Gonzalez I, Naranjo ME, et al. Lessons from Cuba for global precision medicine: CYP2D6 genotype is not a robust predictor of CYP2D6 ultrarapid metabolism. OMICS. 2017 Jan;21(1):17–26.

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