General Pharmacology of Long-Acting, Extended-Release, and Sustained-Release Opioids for the Treatment of Chronic Nonmalignant Pain

Mellar P. Davis, MD, FCCP; Pamela Gamier, RN, BSN, CHPN; Paul A. Sloan, MD

doi:10.5055/jom.2014.0229

Authors

Mellar P. Davis, MD, FCCP
Pamela Gamier, RN, BSN, CHPN
Paul A. Sloan, MD

DOI:

https://doi.org/10.5055/jom.2014.0229

Keywords:

long-acting opioids, pain management, opioids, extended-release opioids

Abstract

Both short-acting (SA) opioids and long-acting (LA) opioids have been used for chronic pain (defined as pain lasting >3 months). SA opioids have a duration of action ranging between 2 and 4 hours, result in rapidly fluctuating drug levels and are suitable for acute, unstable, intermittent, breakthrough, and procedure-related pain.

Author Biographies

Mellar P. Davis, MD, FCCP

Department of Solid Tumor Oncology, Cleveland Clinic, Taussig Cancer Institute, Cleveland, Ohio

Pamela Gamier, RN, BSN, CHPN

Department of Solid Tumor Oncology, Cleveland Clinic, Taussig Cancer Institute, Cleveland, Ohio

Paul A. Sloan, MD

Department of Anesthesiology, University of Kentucky Medical Center, Lexington, Kentucky

References

Rauck RL: What is the case for prescribing long-acting opioids over short-acting opioids for patients with chronic pain? A critical review. Pain Pract. 2009; 9(6): 468-479.

Davies AN: Breakthrough cancer pain. Curr Pain Headache Rep. 2014; 18(6): 420.

Davies AN, Dickman A, Reid C, et al.: The management of cancer-related breakthrough pain: Recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur J Pain. 2009; 13(4): 331-338.

McCarberg BH, Barkin RL: Long-acting opioids for chronic pain: Pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther. 2001; 8(3): 181-186.

Gourlay GK: Sustained relief of chronic pain. Pharmacokinetics of sustained release morphine. Clin Pharmacokinet. 1998; 35(3): 173-190.

Hill HF, Chapman CR, Saeger LS, et al.: Steady-state infusions of opioids in human. II. Concentration-effect relationships and therapeutic margins. Pain. 1990; 43(1): 69-79.

Hill HF, Saeger L, Bjurstrom R, et al.: Steady-state infusions of opioids in human volunteers. I. Pharmacokinetic tailoring. Pain. 1990; 43(1): 57-67.

Ferrell B, Wisdom C, Wenzl C, et al.: Effects of controlled-released morphine on quality of life for cancer pain. Oncol Nurs Forum. 1989; 16(4): 521-526.

Chary S, Goughnour BR, Moulin DE, et al.: The dose-response relationship of controlled-release codeine (Codeine Contin) in chronic cancer pain. J Pain Symptom Manage. 1994; 9(6): 363-371.

Arkinstall WW, Goughnour BR, White JA, et al.: Control of severe pain with sustained-release morphine tablets v. oral morphine solution. CMAJ. 1989; 140(6): 653-657, 661.

Caldwell JR, Hale ME, Boyd RE, et al.: Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus acetaminophen added to nonsteroidal anti-inflammatory drugs: A double blind, randomized, multicenter, placebo controlled trial. J Rheumatol. 1999; 26(4): 862-869.

Klepstad P, Dale O, Kaasa S, et al.: Influences on serum concentrations of morphine, M6G and M3G during routine clinical drug monitoring: A prospective survey in 300 adult cancer patients. Acta Anaesthesiol Scand. 2003; 47(6): 725-731.

Amabile CM, Bowman BJ: Overview of oral modified-release opioid products for the management of chronic pain. Ann Pharmacother. 2006; 40(7-8): 1327-1335.

Fine PG, Mahajan G, McPherson ML: Long-acting opioids and short-acting opioids: Appropriate use in chronic pain management. Pain Med. 2009; 10(suppl 2): S79-S88.

Chou R, Clark E, Helfand M: Comparative efficacy and safety of long-acting oral opioids for chronic non-cancer pain: A systematic review. J Pain Symptom Manage. 2003; 26(5): 1026-1048.

Carson S, Thakurta S, Low A, et al.: Drug Class Review: Long-Acting Opioid Analgesics: Final Update 6 Report. Portland (OR): Oregon Health & Science University, 2011.

Chou R, Carson S: Drug Class Review on Long-Acting Opioid Analgesics: Final Report Update 5. Portland (OR): Oregon Health & Science University, 2008.

Nuckols TK, Anderson L, Popescu I, et al.: Opioid prescribing: A systematic review and critical appraisal of guidelines for chronic pain. Ann Intern Med. 2014; 160(1): 38-47.

Pedersen L, Borchgrevink PC, Riphagen, II, et al.: Long- or short-acting opioids for chronic non-malignant pain? A qualitative systematic review. Acta Anaesthesiol Scand. 2014; 58(4): 390-401.

Kalso E, Allan L, Dellemijn PL, et al.: Recommendations for using opioids in chronic non-cancer pain. Eur J Pain. 2003; 7(5): 381-386.

Webster LR, Bath B, Medve RA, et al.: Randomized, double-blind, placebo-controlled study of the abuse potential of different formulations of oral oxycodone. Pain Med. 2012; 13(6): 790-801.

Jonsson T, Christrup LL, Hojsted J, et al.: Symptoms and side effects in chronic non-cancer pain: Patient report vs. systematic assessment. Acta Anaesthesiol Scand. 2011; 55(1): 69-74.

Ioannidis JP, Evans SJ, Gotzsche PC, et al.: Better reporting of harms in randomized trials: An extension of the CONSORT statement. Ann Intern Med. 2004; 141(10): 781-788.

Klepstad P, Kaasa S, Jystad A, et al.: Immediate- or sustained-release morphine for dose finding during start of morphine to cancer patients: A randomized, double-blind trial. Pain. 2003; 101(1-2): 193-198.

Salzman RT, Roberts MS, Wild J, et al.: Can a controlled-release oral dose form of oxycodone be used as readily as an immediate-release form for the purpose of titrating to stable pain control? J Pain Symptom Manage. 1999; 18(4): 271-279.

Weimer MB, Chou R: Research gaps on methadone harms and comparative harms: Findings from a review of the evidence for an American Pain Society and College on Problems of Drug Dependence clinical practice guideline. J Pain. 2014; 15(4): 366-376.

Chou R, Weimer MB, Dana T: Methadone overdose and cardiac arrhythmia potential: Findings from a review of the evidence for an American Pain Society and College on Problems of Drug Dependence clinical practice guideline. J Pain. 2014; 15(4): 338-365.

Chou R, Cruciani RA, Fiellin DA, et al.: Methadone safety: A clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014; 15(4): 321-337.

Mercadante S, Villari P, Ferrera P, et al.: Safety and effectiveness of intravenous morphine for episodic breakthrough pain in patients receiving transdermal buprenorphine. J Pain Symptom Manage. 2006; 32(2): 175-179.

Dasgupta N, Kramer ED, Zalman MA, et al.: Association between non-medical and prescriptive usage of opioids. Drug Alcohol Depend. 2006; 82(2): 135-142.

Edlund MJ, Martin BC, Russo JE, et al.: The role of opioid prescription in incident opioid abuse and dependence among individuals with chronic noncancer pain: The role of opioid prescription. Clin J Pain. 2014; 30(7): 557-564.

Martell BA, O’Connor PG, Kerns RD, et al.: Systematic review: Opioid treatment for chronic back pain: Prevalence, efficacy, and association with addiction. Ann Intern Med. 2007; 146(2): 116-127.

Banta-Green CJ, Merrill JO, Doyle SR, et al.: Measurement of opioid problems among chronic pain patients in a general medical population. Drug Alcohol Depend. 2009; 104(1-2): 43-49.

Boscarino JA, Rukstalis M, Hoffman SN, et al.: Risk factors for drug dependence among out-patients on opioid therapy in a large US healthcare system. Addiction. 2010; 105(10): 1776-1782.

Compton PA, Wu SM, Schieffer B, et al.: Introduction of a self-report version of the Prescription Drug Use Questionnaire and relationship to medication agreement noncompliance. J Pain Symptom Manage. 2008; 36(4): 383-395.

Saffier K, Colombo C, Brown D, et al.: Addiction Severity Index in a chronic pain sample receiving opioid therapy. J Subst Abuse Treat. 2007; 33(3): 303-311.

Cowan DT, Wilson-Barnett J, Griffiths P, et al.: A survey of chronic noncancer pain patients prescribed opioid analgesics. Pain Med. 2003; 4(4): 340-351.

Hojsted J, Nielsen PR, Guldstrand SK, et al.: Classification and identification of opioid addiction in chronic pain patients. Eur J Pain. 2010; 14(10): 1014-1020.

Fleming MF, Balousek SL, Klessig CL, et al.: Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain. 2007; 8(7): 573-582.

Mistry CJ, Bawor M, Desai D, et al.: Genetics of opioid dependence: A review of the genetic contribution to opioid dependence. Curr Psychiatry Rev. 2014; 10(2): 156-167.

Starrels JL, Becker WC, Alford DP, et al.: Systematic review: Treatment agreements and urine drug testing to reduce opioid misuse in patients with chronic pain. Ann Intern Med. 2010; 152(11): 712-720.

Turk DC, Swanson KS, Gatchel RJ: Predicting opioid misuse by chronic pain patients: A systematic review and literature synthesis. Clin J Pain. 2008; 24(6): 497-508.

Dunn KM, Saunders KW, Rutter CM, et al.: Opioid prescriptions for chronic pain and overdose: A cohort study. Ann Intern Med. 2010; 152(2): 85-92.

Gomes T, Mamdani MM, Dhalla IA, et al.: Opioid dose and drugrelated mortality in patients with nonmalignant pain. Arch Intern Med. 2011; 171(7): 686-691.

Bohnert AS, Ilgen MA, Ignacio RV, et al.: Risk of death from accidental overdose associated with psychiatric and substance use disorders. Am J Psychiatry. 2012; 169(1): 64-70.

Webster LR, Cochella S, Dasgupta N, et al.: An analysis of the root causes for opioid-related overdose deaths in the United States. Pain Med. 2011;12(suppl 2): S26-S35.

Siegler A, Tuazon E, Bradley O’Brien D, et al.: Unintentional opioid overdose deaths in New York City, 2005-2010: A place-based approach to reduce risk. Int J Drug Policy. 2014; 25(3): 569-574.

Hasegawa K, Brown DF, Tsugawa Y, et al.: Epidemiology of emergency department visits for opioid overdose: A population-based study. Mayo Clinic Proc. 2014; 89(4): 462-471.

Kuehn BM: Methadone overdose deaths rise with increased prescribing for pain. JAMA. 2012; 308(8): 749-750.

Mercado-Crespo MC, Sumner SA, Spelke MB, et al.: Notes from the field: Increase in fentanyl-related overdose deaths—Rhode Island, November 2013-March 2014. MMWR Morb Mortal Wkly Rep. 2014; 63(24): 531.

Sessler NE, Downing JM, Kale H, et al.: Reductions in reported deaths following the introduction of extended-release oxycodone (OxyContin) with an abuse-deterrent formulation. Pharmacoepidemiol Drug Saf. 2014 (in press).

Walley AY, Xuan Z, Hackman HH, et al.: Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: Interrupted time series analysis. BMJ. 2013; 346: f174.

Walley AY, Doe-Simkins M, Quinn E, et al.: Opioid overdose prevention with intranasal naloxone among people who take methadone. J Subst Abuse Treat. 2013; 44(2): 241-247.

Dahan A, Overdyk F, Smith T, et al.: Pharmacovigilance: A review of opioid-induced respiratory depression in chronic pain patients. Pain Physician. 2013; 16(2): E85-E94.

Jann M, Kennedy WK, Lopez G: Benzodiazepines: A major component in unintentional prescription drug overdoses with opioid analgesics. J Pharm Pract. 2014; 27(1): 5-16.

Panagiotou I, Mystakidou K: Non-analgesic effects of opioids: Opioids’ effects on sleep (including sleep apnea). Curr Pharm Des. 2012; 18(37): 6025-6033.

Rose AR, Catcheside PG, McEvoy RD, et al.: Sleep disordered breathing and chronic respiratory failure in patients with chronic pain on long term opioid therapy. J Clin Sleep Med. 2014; 10(8): 847-852.

Walker JM, Farney RJ, Rhondeau SM, et al.: Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med. 2007; 3(5): 455-461.

Weil JV, McCullough RE, Kline JS, et al.: Diminished ventilatory response to hypoxia and hypercapnia after morphine in normal man. N Engl J Med. 1975; 292(21): 1103-1106.

Bouillon T, Bruhn J, Radu-Radulescu L, et al.: A model of the ventilator depressant potency of remifentanil in the non-steady state. Anesthesiology. 2003; 99(4): 779-787.

Santiago TV, Edelman NH: Opioids and breathing. J Appl Physiol. 1985; 59(6): 1675-1685.

Kuo A, Wyse BD, Meutermans W, et al.: In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: No two opioids have the same profile. Br J Pharmacol. 2014 (in press).

Robinson RW, Zwillich CW, Bixler EO, et al.: Effects of oral narcotics on sleep-disordered breathing in healthy adults. Chest. 1987; 91(2): 197-203.

Chidambaran V, Mavi J, Esslinger H, et al.: Association of OPRM1 A118G variant with risk of morphine-induced respiratory depression following spine fusion in adolescents. Pharmacogenomics J. 2014 (in press).

Wheatley RG, Somerville ID, Sapsford DJ, et al.: Postoperative hypoxaemia: Comparison of extradural, i.m. and patient-controlled opioid analgesia. Br J Anaesth. 1990; 64(3): 267-275.

Madej TH, Wheatley RG, Jackson IJ, et al.: Hypoxaemia and pain relief after lower abdominal surgery: Comparison of extradural and patient-controlled analgesia. Br J Anaesth. 1992; 69(6): 554-557.

Barbour SJ, Vandebeek CA, Ansermino JM: Increased tidal volume variability in children is a better marker of opioid-induced respiratory depression than decreased respiratory rate. J Clin Monit Comput. 2004; 18(3): 171-178.

Bouillon T, Bruhn J, Roepcke H, et al.: Opioid-induced respiratory depression is associated with increased tidal volume variability. Eur J Anaesthesiol. 2003; 20(2): 127-133.

Boland J, Boland E, Brooks D: Importance of the correct diagnosis of opioid-induced respiratory depression in adult cancer patients and titration of naloxone. Clin Med. 2013; 13(2): 149-151.

Martin WR: Naloxone. Ann Intern Med. 1976; 85(6): 765-768.

Ngai SH, Berkowitz BA, Yang JC, et al.: Pharmacokinetics of naloxone in rats and in man: Basis for its potency and short duration of action. Anesthesiology. 1976; 44(5): 398-401.

Vizi ES, Foldes FF, Rich J, et al.: The structure-action relationship and kinetics of some naloxone and naltrexone derivatives. Pharma - cology. 1976; 14(1): 76-85.

Berkowitz BA: The relationship of pharmacokinetics to pharmacological activity: Morphine, methadone and naloxone. Clin Pharma - cokinet. 1976; 1(3): 219-230.

Olofsen E, van Dorp E, Teppema L, et al.: Naloxone reversal of morphine-and morphine-6-glucuronide-induced respiratory depression in healthy volunteers: A mechanism-based pharmacokinetic-pharmacodynamic modeling study. Anesthesiology. 2010; 112(6): 1417-1427.

van Dorp E, Yassen A, Sarton E, et al.: Naloxone reversal of buprenorphine-induced respiratory depression. Anesthesiology. 2006; 105(1): 51-57.

Yassen A, Olofsen E, van Dorp E, et al.: Mechanism-based pharmacokinetic-pharmacodynamic modelling of the reversal of buprenorphine-induced respiratory depression by naloxone: A study in healthy volunteers. Clin Pharmacokinet. 2007; 46(11): 965-980.

Goldfrank L, Weisman RS, Errick JK, et al.: A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med. 1986; 15(5): 566-570.

Sabzghabaee AM, Eizadi-Mood N, Yaraghi A, et al.: Naloxone therapy in opioid overdose patients: Intranasal or intravenous? A randomized clinical trial. Arch Med Sci. 2014; 10(2): 309-314.

De Schepper HU, Cremonini F, Park MI, et al.: Opioids and the gut: Pharmacology and current clinical experience. Neurogastroenterol Motil. 2004; 16(4): 383-394.

Mori T, Shibasaki Y, Matsumoto K, et al.: Mechanisms that underlie mu-opioid receptor agonist-induced constipation: Differential involvement of mu-opioid receptor sites and responsible regions. J Pharmacol Exp Ther. 2013; 347(1): 91-99.

Szigethy E, Schwartz M, Drossman D: Narcotic bowel syndrome and opioid-induced constipation. Curr Gastroenterol Rep. 2014; 16(10): 410.

Drossman D, Szigethy E: The narcotic bowel syndrome: A recent update. Am J Gastroenterol. 2014; 2(1): 22-30.

Davis MP: The opioid bowel syndrome: A review of pathophysiology and treatment. J Opioid Manag. 2005; 1(3): 153-161.

Kurlander JE, Drossman DA: Diagnosis and treatment of narcotic bowel syndrome. Nat Rev Gastroenterol Hepatol. 2014; 11(7): 410-418.

Tuteja AK, Biskupiak J, Stoddard GJ, et al.: Opioid-induced bowel disorders and narcotic bowel syndrome in patients with chronic noncancer pain. Neurogastroenterol Motil. 2010; 22(4): 424-430, e496.

Farmer AD, Ferdinand E, Aziz Q: Opioids and the gastrointestinal tract—A case of narcotic bowel syndrome and literature review. J Neurogastroenterol Motil. 2013; 19(1): 94-98.

Grover CA, Wiele ED, Close RJ: Narcotic bowel syndrome. J Emerg Med. 2012; 43(6): 992-995.

Wirz S, Nadstawek J, Elsen C, et al.: Laxative management in ambulatory cancer patients on opioid therapy: A prospective, open-label investigation of polyethylene glycol, sodium picosulphate and lactulose. Eur J Cancer Care. 2012; 21(1): 131-140.

Bouvy ML, Buurma H, Egberts TC: Laxative prescribing in relation to opioid use and the influence of pharmacy-based intervention. J Clin Pharm Ther. 2002; 27(2): 107-110.

Sykes N: Emerging evidence on docusate: Commentary on Tarumi et al. J Pain Symptom Manage. 2013; 45(1): 1.

Twycross R, Sykes N, Mihalyo M, et al.: Stimulant laxatives and opioid-induced constipation. J Pain Symptom Manage. 2012; 43(2): 306-313.

Larkin PJ, Sykes NP, Centeno C, et al.: The management of constipation in palliative care: Clinical practice recommendations. Palliat Med. 2008; 22(7): 796-807.

Cass LJ, Frederik WS: A clinical comparison of bulk and stimulant laxatives. J Lancet. 1955; 75(3): 105-108.

Connolly P, Hughes IW, Ryan G: Comparison of “Duphalac” and “irritant” laxatives during and after treatment of chronic constipation: A preliminary study. Curr Med Res Opin. 1974; 2(10): 620-625.

Dettmar PW, Sykes J: A multi-centre, general practice comparison of ispaghula husk with lactulose and other laxatives in the treatment of simple constipation. Curr Med Res Opin. 1998; 14(4): 227-233.

Simpson K, Leyendecker P, Hopp M, et al.: Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain. Curr Med Res Opin. 2008; 24(12): 3503-3512.

Sykes NP: Oral naloxone in opioid-associated constipation. Lancet. 1991; 337(8755): 1475.

Hellwig TR, Pottebaum AA: The role of methylnaltrexone in opioid-induced constipation. S D Med. 2013; 66(10): 425, 427.

Rauck RL: Treatment of opioid-induced constipation: Focus on the peripheral mu-opioid receptor antagonist methylnaltrexone. Drugs. 2013; 73(12): 1297-1306.

Bader S, Durk T, Becker G: Methylnaltrexone for the treatment of opioid-induced constipation. Expert Rev Gastroenterol Hepatol. 2013; 7(1): 13-26.

Cryer B, Katz S, Vallejo R, et al.: A randomized study of lubiprostone for opioid-induced constipation in patients with chronic noncancer pain. Pain Med. 2014 (in press).

Lubiprostone (Amitiza) for opioid-induced constipation. Med Lett Drugs Ther. 2013; 55(1418): 47-48.

Wong BS, Camilleri M: Lubiprostone for the treatment of opioidinduced bowel dysfunction. Expert Opin Pharmacother. 2011; 12(6): 983-990.

Sharma A, Jamal MM: Opioid induced bowel disease: A twenty-first century physicians’ dilemma. Considering pathophysiology and treatment strategies. Curr Gastroenterol Rep. 2013; 15(7): 334.

Azizi Z, Javid Anbardan S, Ebrahimi Daryani N: A review of the clinical manifestations, pathophysiology and management of opioid bowel dysfunction and narcotic bowel syndrome. Middle East J Dig Dis. 2014; 6(1): 5-12.

Sandgren JE, McPhee MS, Greenberger NJ: Narcotic bowel syndrome treated with clonidine. Resolution of abdominal pain and intestinal pseudo-obstruction. Ann Intern Med. 1984; 101(3): 331-334.

Bruera E, Brenneis C, Michaud M, et al.: Continuous Sc infusion of metoclopramide for treatment of narcotic bowel syndrome. Cancer Treat Rep. 1987; 71(11): 1121-1122.

Wong V, Sobala G, Losowsky M: A case of narcotic bowel syndrome successfully treated with clonidine. Postgrad Med J. 1994; 70(820): 138-140.

Pergolizzi JV Jr, Ma L, Foster DR, et al.: The prevalence of opioid-related major potential drug-drug interactions and their impact on health care costs in chronic pain patients. J Manag Care Pharm. 2014; 20(5): 467-476.

Chen LH, Hedegaard H, Warner M: Drug-poisoning deaths involving opioid analgesics: United States, 1999-2011. NCHS Data Brief. 2014; (166): 1-8.

Leung SY: Benzodiazepines, opioids and driving: An overview of the experimental research. Drug Alcohol Rev. 2011; 30(3): 281-286.

Zacny JP, Paice JA, Coalson DW: Separate and combined psychopharmacological effects of alprazolam and oxycodone in healthy volunteers. Drug Alcohol Depend. 2012; 124(3): 274-282.

Gudin JA, Mogali S, Jones JD, et al.: Risks, management, and monitoring of combination opioid, benzodiazepines, and/or alcohol use. Postgrad Med. 2013; 125(4): 115-130.

Jobski K, Schmid U, Behr S, et al.: 3-Year prevalence of alcoholrelated disorders in German patients treated with high-potency opioids. Pharmacoepidemiol Drug Saf. 2012; 21(10): 1125-1129.

Krajacic A, Tucker IG: Matrix formation in sustained release tablets: Possible mechanism of dose dumping. Int J Pharm. 2003; 251(1-2): 67- 78.

Fiske WD, Jobes J, Xiang Q, et al.: The effects of ethanol on the bioavailability of oxymorphone extended-release tablets and oxymorphone crush-resistant extended-release tablets. J Pain. 2012; 13(1): 90-99.

Lennernas H: Ethanol-drug absorption interaction: Potential for a significant effect on the plasma pharmacokinetics of ethanol vulnerable formulations. Mol Pharm. 2009; 6(5): 1429-1440.

Sathyan G, Sivakumar K, Thipphawong J: Pharmacokinetic profile of a 24-hour controlled-release OROS formulation of hydromorphone in the presence of alcohol. Curr Med Res Opin. 2008; 24(1): 297-305.

Browne B, Linter S: Monoamine oxidase inhibitors and narcotic analgesics. A critical review of the implications for treatment. Br J Psychiatry. 1987; 151: 210-212.

Gillman PK: Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth. 2005; 95(4): 434-441.

Park SH, Wackernah RC, Stimmel GL: Serotonin syndrome: Is it a reason to avoid the use of tramadol with antidepressants? J Pharm Pract. 2014; 27(1): 71-78.

Van Vugt DA, Meites J: Influence of endogenous opiates on anterior pituitary function. Fed Proc. 1980; 39(8): 2533-2538.

Iakobishvili Z, Cohen E, Garty M, et al.: Use of intravenous morphine for acute decompensated heart failure in patients with and without acute coronary syndromes. Acute Card Care. 2011; 13(2): 76-80.

Gray A, Goodacre S, Seah M, et al.: Diuretic, opiate and nitrate use in severe acidotic acute cardiogenic pulmonary oedema: Analysis from the 3CPO trial. QJM. 2010; 103(8): 573-581.

Korinek AM, Languille M, Bonnet F, et al.: Effect of postoperative extradural morphine on ADH secretion. Br J Anaesth. 1985; 57(4): 407-411.

Graham CA, Cattermole GN: Morphine should be abandoned as a treatment for acute cardiogenic pulmonary oedema. Emerg Med Australas. 2009; 21(2): 160.

Kao D, Bucher Bartelson B, Khatri V, et al.: Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011: An analysis of registry data. Ann Intern Med. 2013; 158(10): 735-740.

Farsi D, Mirafzal A, Hassanian-Moghaddam H, et al.: The correlation between prolonged corrected QT interval with the frequency of respiratory arrest, endotracheal intubation, and mortality in acute methadone overdose. Cardiovasc Toxicol. 2014; 14(4): 358-367.

Wolbrette D: Gender differences in the proarrhythmic potential of QT-prolonging drugs. Curr Womens Health Rep. 2002; 2(2): 105-109.

Byrne A, Stimmel B: Methadone and QTc prolongation. Lancet. 2007; 369(9559): 366; author reply 366-367.

Abramson DW, Quinn DK, Stern TA: Methadone-associated QTc prolongation: A case report and review of the literature. Primary Care Companion J Clin Psychiatry. 2008; 10(6): 470-476.

Krantz MJ, Martin J, Stimmel B, et al.: QTc interval screening in methadone treatment. Ann Intern Med. 2009; 150(6): 387-395.

Chang KC, Huang CL, Liang HY, et al.: Gender-specific differences in susceptibility to low-dose methadone-associated QTc prolongation in patients with heroin dependence. J Cardiovasc Electrophysiol. 2012; 23(5): 527-533.

Mujtaba S, Romero J, Taub CC: Methadone, QTc prolongation and torsades de pointes: Current concepts, management and a hidden twist in the tale? J Cardiovasc Dis Res. 2013; 4(4): 229-235.

Wang SC, Ho IK, Tsou HH, et al.: Functional genetic polymorphisms in CYP2C19 gene in relation to cardiac side effects and treatment dose in a methadone maintenance cohort. OMICS. 2013; 17(10): 519-526.

Anchersen K, Hansteen V, Gossop M, et al.: Opioid maintenance patients with QTc prolongation: Congenital long QT syndrome mutation may be a contributing risk factor. Drug Alcohol Depend. 2010; 112(3): 216-219.

Katchman AN, McGroary KA, Kilborn MJ, et al.: Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents. J Pharmacol Exp Ther. 2002; 303(2): 688-694.

Wedam EF, Bigelow GE, Johnson RE, et al.: QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007; 167(22): 2469-2475.

Fareed A, Patil D, Scheinberg K, et al.: Comparison of QTc interval prolongation for patients in methadone versus buprenorphine maintenance treatment: A 5-year follow-up. J Addict Dis. 2013; 32(3): 244-251.

Krantz MJ, Garcia JA, Mehler PS: Effects of buprenorphine on cardiac repolarization in a patient with methadone-related torsade de pointes. Pharmacotherapy. 2005; 25(4): 611-614.

Esses JL, Rosman J, Do LT, et al.: Successful transition to buprenorphine in a patient with methadone-induced torsades de pointes. J Interv Card Electrophysiol. 2008; 23(2): 117-119.

Baker JR, Best AM, Pade PA, et al.: Effect of buprenorphine and antiretroviral agents on the QT interval in opioid-dependent patients. Ann Pharmacother. 2006; 40(3): 392-396.

Zhou SF: Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet. 2009; 48(11): 689-723.

Zhou SF: Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part II. Clin Pharmacokinet. 2009; 48(12): 761-804.

Zahari Z, Ismail R: Influence of cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) polymorphisms on pain sensitivity and clinical response to weak opioid analgesics. Drug Metab Pharmacokinet. 2014; 29(1): 29-43.

Kirchheiner J, Schmidt H, Tzvetkov M, et al.: Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007; 7(4): 257-265.

Crews KR, Gaedigk A, Dunnenberger HM, et al.: Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014; 95(4): 376-382.

Stamer UM, Zhang L, Book M, et al.: CYP2D6 genotype dependent oxycodone metabolism in postoperative patients. PLoS One. 2013; 8(3): e60239.

Kummer O, Hammann F, Moser C, et al.: Effect of the inhibition of CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Eur J Clin Pharmacol. 2011; 67(1): 63-71.

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; 160(4): 919-930.

Susce MT, Murray-Carmichael E, de Leon J: Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. Prog Neuropsychopharmacol Biol Psychiatry. 2006; 30(7): 1356-1358.

Lurcott G: The effects of the genetic absence and inhibition of CYP2D6 on the metabolism of codeine and its derivatives, hydrocodone and oxycodone. Anesth Prog. 1998; 45(4): 154-156.

Samer CF, Daali Y, Wagner M, et al.: The effects of CYP2D6 and CYP3A activities on the pharmacokinetics of immediate release oxycodone. Br J Pharmacol. 2010; 160(4): 907-918.

Hutchinson MR, Menelaou A, Foster DJ, et al.: CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Clin Pharmacol. 2004; 57(3): 287-297.

Soderberg Lofdal KC, Andersson ML, Gustafsson LL: Cytochrome P450-mediated changes in oxycodone pharmacokinetics/pharmacodynamics and their clinical implications. Drugs. 2013; 73(6): 533-543.

Solassol I, Caumette L, Bressolle F, et al.: Inter- and intra-individual variability in transdermal fentanyl absorption in cancer pain patients. Oncol Rep. 2005; 14(4): 1029-1036.

Solassol I, Bressolle F, Caumette L, et al.: Inter- and intraindividual variabilities in pharmacokinetics of fentanyl after repeated 72-hour transdermal applications in cancer pain patients. Ther Drug Monit. 2005; 27(4): 491-498.

Feierman DE, Lasker JM: Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes. Role of CYP3A4. Drug Metab Dispos. 1996; 24(9): 932-939.

Kokubun H, Ebinuma K, Matoba M, et al.: Population pharmacokinetics of transdermal fentanyl in patients with cancer-related pain. J Pain Palliat Care Pharmacother. 2012; 26(2): 98-104.

Kapur BM, Hutson JR, Chibber T, et al.: Methadone: A review of drug-drug and pathophysiological interactions. Crit Rev Clin Lab Sci. 2011; 48(4): 171-195.

Campbell SD, Crafford A, Williamson BL, et al.: Mechanism of autoinduction of methadone N-demethylation in human hepatocytes. Anesth Anal. 2013; 117(1): 52-60.

Dickmann LJ, Isoherranen N: Quantitative prediction of CYP2B6 induction by estradiol during pregnancy: Potential explanation for increased methadone clearance during pregnancy. Drug Metab Dispos. 2013; 41(2): 270-274.

Bendayan R, Lee G, Bendayan M: Functional expression and localization of P-glycoprotein at the blood brain barrier. Microsc Res Tech. 2002; 57(5): 365-380.

Mercer SL, Coop A: Opioid analgesics and P-glycoprotein efflux transporters: A potential systems-level contribution to analgesic tolerance. Curr Top Med Chem. 2011; 11(9): 1157-1164.

Takashina Y, Naito T, Mino Y, et al.: Impact of CYP3A5 and ABCB1 gene polymorphisms on fentanyl pharmacokinetics and clinical responses in cancer patients undergoing conversion to a transdermal system. Drug Metab Pharmacokinet. 2012; 27(4): 414-421.

Hamabe W, Maeda T, Kiguchi N, et al.: Negative relationship between morphine analgesia and P-glycoprotein expression levels in the brain. J Pharmacol Sci. 2007; 105(4): 353-360.

Hassan HE, Mercer SL, Cunningham CW, et al.: Evaluation of the Pglycoprotein (Abcb1) affinity status of a series of morphine analogs: Comparative study with meperidine analogs to identify opioids with minimal P-glycoprotein interactions. Int J Pharm. 2009; 375(1-2): 48-54.

Mercer SL, Cunningham CW, Eddington ND, et al.: Opioids and efflux transporters. Part 3: P-glycoprotein substrate activity of 3-hydroxyladdition to meperidine analogs. Bioorg Med Chem Lett. 2008; 18(12): 3638-3640.

Cunningham CW, Mercer SL, Hassan HE, et al.: Opioids and efflux transporters. Part 2: P-glycoprotein substrate activity of 3- and 6-substituted morphine analogs. J Med Chem. 2008; 51(7): 2316-2320.

Kalvass JC, Olson ER, Cassidy MP, et al.: Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice: Assessment of unbound brain EC50,u and correlation of in vitro, preclinical, and clinical data. J Pharmacol Exp Ther. 2007; 323(1): 346-355.

Yousif S, Saubamea B, Cisternino S, et al.: Effect of chronic exposure to morphine on the rat blood-brain barrier: Focus on the P-glycoprotein. J Neurochem. 2008; 107(3): 647-657.

Letrent SP, Polli JW, Humphreys JE, et al.: P-glycoprotein-mediated transport of morphine in brain capillary endothelial cells. Biochem Pharmacol. 1999; 58(6): 951-957.

Letrent SP, Pollack GM, Brouwer KR, et al.: Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat. Drug Metab Dispos. 1999; 27(7): 827-834.

Henthorn TK, Liu Y, Mahapatro M, et al.: Active transport of fentanyl by the blood-brain barrier. J Pharmacol Exp Ther. 1999; 289(2): 1084-1089.

Fudin J, Fontenelle DV, Payne A: Rifampin reduces oral morphine absorption: A case of transdermal buprenorphine selection based on morphine pharmacokinetics. J Pain Palliat Care Pharmacother. 2012; 26(4): 362-367.

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; 21(5): 453-462.

Ashburn MA, Ogden LL, Zhang J, et al.: The pharmacokinetics of transdermal fentanyl delivered with and without controlled heat. J Pain. 2003; 4(6): 291-297.

Knotkova H, Fine PG, Portenoy RK: Opioid rotation: The science and the limitations of the equianalgesic dose table. J Pain Symptom Manage. 2009; 38(3): 426-439.