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


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




long-acting opioids, opioids, extended-release opioids, sustained-release opioids, pain managment, chronic noncancer pain, chronic pain


Opioid products, specifically long-acting (LA), extended-release (ER), and sustained-release (SR) formulations, are used for the treatment of a subset of patients with chronic noncancer pain (CNCP). This article will review the specific pharmacology and risks associated with specific LA, ER, and SR opioid formulations that have been used in the treatment of chronic pain. This article will not address the indications for, evidence for and against, or general controversy regarding the use of any form of long-term opioid therapy for the treatment of chronic nonmalignant pain (CNMP), as this has been presented in other published works.

Author Biographies

Paul A. Sloan, MD

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

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


Caldwell JR: Avinza—24-h sustained-release oral morphine therapy. Expert Opin Pharmacother. 2004; 5(2): 469-472.

Portenoy RK, Sciberras A, Eliot L, et al.: Steady-state pharmacokinetic comparison of a new, extended-release, once-daily morphine formulation, Avinza, and a twice-daily controlled-release morphine formulation in patients with chronic moderate-to-severe pain. J Pain Symptom Manage. 2002; 23(4): 292-300.

Adams EH, Chwiecko P, Ace-Wagoner Y, et al.: A study of AVINZA (morphine sulfate extended-release capsules) for chronic moderate-tosevere noncancer pain conducted under real-world treatment conditions—The ACCPT Study. Pain Pract. 2006; 6(4): 254-264.

Rauck RL, Bookbinder SA, Bunker TR, et al.: A randomized, open-label study of once-a-day AVINZA (morphine sulfate extended-release capsules) versus twice-a-day OxyContin (oxycodone hydrochloride controlled- release tablets) for chronic low back pain: The extension phase of the ACTION trial. J Opioid Manag. 2006; 2(6): 325-328, 331-323.

Rauck RL, Bookbinder SA, Bunker TR, et al.: The ACTION study: A randomized, open-label, multicenter trial comparing once-a-day extended-release morphine sulfate capsules (AVINZA) to twice-a-day controlled-release oxycodone hydrochloride tablets (OxyContin) for the treatment of chronic, moderate to severe low back pain. J Opioid Manag. 2006; 2(3): 155-166.

Panjabi SS, Panjabi RS, Shepherd MD, et al.: Extended-release, once-daily morphine (Avinza) for the treatment of chronic nonmalignant pain: Effect on pain, depressive symptoms, and cognition. Pain Med. 2008; 9(8): 985-993.

Caldwell JR, Rapoport RJ, Davis JC, et al.: Efficacy and safety of a once-daily morphine formulation in chronic, moderate-to-severe osteoarthritis pain: Results from a randomized, placebo-controlled, double-blind trial and an open-label extension trial. J Pain Symptom Manage. 2002; 23(4): 278-291.

King CR, Khabazian A: Avinza (morphine sulfate extended-release capsules). Clin J Oncol Nurs. 2003; 7(4): 458-460, 478.

Semenchuk MR: Avinza Elan. Curr Opin Investig Drugs. 2002; 3(9): 1369-1372.

Heiskanen T, Backman JT, Neuvonen M, et al.: Itraconazole, a potent inhibitor of P-glycoprotein, moderately increases plasma concentrations of oral morphine. Acta Anaesthesiol Scand. 2008; 52(10): 1319-1326.

Su W, Pasternak GW: The role of multidrug resistance-associated protein in the blood-brain barrier and opioid analgesia. Synapse. 2013; 67(9): 609-619.

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.

Groenendaal D, Freijer J, de Mik D, et al.: Population pharmacokinetic modelling of non-linear brain distribution of morphine: Influence of active saturable influx and P-glycoprotein mediated efflux. Br J Pharmacol. 2007; 151(5): 701-712.

Skarke C, Jarrar M, Erb K, et al.: Respiratory and miotic effects of morphine in healthy volunteers when P-glycoprotein is blocked by quinidine. Clin Pharmacol Ther. 2003; 74(4): 303-311.

Wandel C, Kim R, Wood M, et al.: Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter Pglycoprotein. Anesthesiology. 2002; 96(4): 913-920.

Drewe J, Ball HA, Beglinger C, et al.: Effect of P-glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine. Br J Clin Pharmacol. 2000; 50(3): 237-246.

Heiskanen T, Kalso E: Non-analgesic effects of opioids: Interactions between opioids and other drugs. Curr Pharm Des. 2012; 18(37): 6079- 6089.

Transdermal buprenorphine (Butrans) for chronic pain. Med Lett Drugs Ther. 2011; 53(1362): 31-32.

Plosker GL, Lyseng-Williamson KA: Buprenorphine 5, 10 and 20 mug/h transdermal patch: A guide to its use in chronic non-malignant pain. CNS Drugs. 2012; 26(4): 367-373.

Plosker GL: Buprenorphine 5, 10 and 20 mug/h transdermal patch: A review of its use in the management of chronic non-malignant pain. Drugs. 2011; 71(18): 2491-2509.

Pergolizzi JV Jr, Ben-Joseph R, Chang CL, et al.: US practitioner prescribing practices and patient characteristics of those newly treated with a buprenorphine transdermal patch system. Curr Med Res Opin. 2014; 30(8): 1579-1587.

Park I, Kim D, Song J, et al.: Buprederm, a new transdermal delivery system of buprenorphine: Pharmacokinetic, efficacy and skin irritancy studies. Pharm Res. 2008; 25(5): 1052-1062.

Brown SM, Holtzman M, Kim T, et al.: Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active. Anesthesiology. 2011; 115(6): 1251-1260.

Ohtani M, Kotaki H, Sawada Y, et al.: Comparative analysis of buprenorphine- and norbuprenorphine-induced analgesic effects based on pharmacokinetic-pharmacodynamic modeling. J Pharmacol Exp Ther. 1995; 272(2): 505-510.

Kress HG: Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain. 2009; 13(3): 219-230.

Chang Y, Moody DE: Glucuronidation of buprenorphine and norbuprenorphine by human liver microsomes and UDP-glucuronosyltransferases. Drug Metab Lett. 2009; 3(2): 101-107.

Huang W, Moody DE, McCance-Katz EF: The in vivo glucuronidation of buprenorphine and norbuprenorphine determined by liquid chromatography-electrospray ionization-tandem mass spectrometry. Ther Drug Monit. 2006; 28(2): 245-251.

Mistry M, Houston JB: Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. Drug Metab Dispos. 1987; 15(5): 710-717.

Kapil RP, Cipriano A, Michels GH, et al.: Effect of ketoconazole on the pharmacokinetic profile of buprenorphine following administration of a once-weekly buprenorphine transdermal system. Clin Drug Investig. 2012; 32(9): 583-592.

Dilmaghanian S, Gerber JG, Filler SG, et al.: Enantioselectivity of inhibition of cytochrome P450 3A4 (CYP3A4) by ketoconazole: Testosterone and methadone as substrates. Chirality. 2004; 16(2): 79- 85.

McCance-Katz EF, Moody DE, Morse GD, et al.: Interaction between buprenorphine and atazanavir or atazanavir/ritonavir. Drug Alcohol Depend. 2007; 91(2-3): 269-278.

Bruce RD, Altice FL: Three case reports of a clinical pharmacokinetic interaction with buprenorphine and atazanavir plus ritonavir. AIDS. 2006; 20(5): 783-784.

Ohtani M, Kotaki H, Nishitateno K, et al.: Kinetics of respiratory depression in rats induced by buprenorphine and its metabolite, norbuprenorphine. J Pharmacol Exp Ther. 1997; 281(1): 428-433.

Megarbane B, Hreiche R, Pirnay S, et al.: Does high-dose buprenorphine cause respiratory depression?: Possible mechanisms and therapeutic consequences. Toxicol Rev. 2006; 25(2): 79-85.

Suzuki T, Zaima C, Moriki Y, et al.: P-glycoprotein mediates brainto-blood efflux transport of buprenorphine across the blood-brain barrier. J Drug Target. 2007; 15(1): 67-74.

Alhaddad H, Cisternino S, Decleves X, et al.: Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood-brain barrier in mice. Crit Care Med. 2012; 40(12): 3215-3223.

Hassan HE, Myers AL, Coop A, et al.: Differential involvement of Pglycoprotein (ABCB1) in permeability, tissue distribution, and antinociceptive activity of methadone, buprenorphine, and diprenorphine: In vitro and in vivo evaluation. J Pharm Sci. 2009; 98(12): 4928-4940.

Megarbane B, Alhaddad H: P-glycoprotein should be considered as an additional factor contributing to opioid-induced respiratory depression in paediatrics: The buprenorphine example. Br J Anaesth. 2013; 110(5): 842.

Wang J, Cai B, Huang DX, et al.: Decreased analgesic effect of morphine, but not buprenorphine, in patients with advanced P-glycoprotein(+) cancers. Pharmacol Rep. 2012; 64(4): 870-877.

Al-Tawil N, Odar-Cederlof I, Berggren AC, et al.: Pharmacokinetics of transdermal buprenorphine patch in the elderly. Eur J Clin Pharmacol. 2013; 69(2): 143-149.

Boger RH: Renal impairment: A challenge for opioid treatment? The role of buprenorphine. Palliat Med. 2006; 20(suppl 1): s17-s23.

Simon N, Simon R: Adaptive enrichment designs for clinical trials. Biostatistics. 2013; 14(4): 613-625.

Miller K, Yarlas A, Wen W, et al.: Buprenorphine transdermal system and quality of life in opioid-experienced patients with chronic low back pain. Expert Opin Pharmacother. 2013; 14(3): 269-277.

Gordon A, Callaghan D, Spink D, et al.: Buprenorphine transdermal system in adults with chronic low back pain: A randomized, doubleblind, placebo-controlled crossover study, followed by an open-label extension phase. Clin Ther. 2010; 32(5): 844-860.

Steiner DJ, Sitar S, Wen W, et al.: Efficacy and safety of the seven-day buprenorphine transdermal system in opioid-naive patients with moderate to severe chronic low back pain: An enriched, randomized, double-blind, placebo-controlled study. J Pain Symptom Manage. 2011; 42(6): 903-917.

Landau CJ, Carr WD, Razzetti AJ, et al.: Buprenorphine transdermal delivery system in adults with persistent noncancer-related pain syndromes who require opioid therapy: A multicenter, 5-week run-in and randomized, double-blind maintenance-of-analgesia study. Clin Ther. 2007; 29(10): 2179-2193.

Uberall MA, Muller-Schwefe GH: Long-term treatment of chronic pain with low-dose 7-day buprenorphine transdermal patch. Observational data from elderly patients of pain relief and quality of life. MMW Fortschr Med. 2013; 155(suppl 3): 87-96.

Uberall MA, Muller-Schwefe GH: Low-dose 7-day transdermal buprenorphine in daily clinical practice—Perceptions of elderly patients with moderate non-malignant chronic pain. Curr Med Res Opin. 2012; 28(10): 1585-1595.

Karlsson J, Soderstrom A, Augustini BG, et al.: Is buprenorphine transdermal patch equally safe and effective in younger and elderly patients with osteoarthritis-related pain? Results of an age-group controlled study. Curr Med Res Opin. 2014; 30(4): 575-587.

Karlsson M, Berggren AC: Efficacy and safety of low-dose transdermal buprenorphine patches (5, 10, and 20 microg/h) versus prolonged-release tramadol tablets (75, 100, 150, and 200 mg) in patients with chronic osteoarthritis pain: A 12-week, randomized, open-label, controlled, parallel-group noninferiority study. Clin Ther. 2009; 31(3): 503-513.

Schutter U, Ritzdorf I, Heckes B: The transdermal 7-day buprenorphine patch—An effective and safe treatment option, if tramadol or tilidate/naloxone is insufficient. Results of a non-interventional study. MMW Fortschr Med. 2010; 152(suppl 2): 62-69.

Gallagher AM, Leighton-Scott J, van Staa TP: Utilization characteristics and treatment persistence in patients prescribed low-dose buprenorphine patches in primary care in the United Kingdom: A retrospective cohort study. Clin Ther. 2009; 31(8): 1707-1715.

James IG, O’Brien CM, McDonald CJ: A randomized, double-blind, double-dummy comparison of the efficacy and tolerability of low-dose transdermal buprenorphine (BuTrans seven-day patches) with buprenorphine sublingual tablets (Temgesic) in patients with osteoarthritis pain. J Pain Symptom Manage. 2010; 40(2): 266-278.

Wolff RF, Aune D, Truyers C, et al.: Systematic review of efficacy and safety of buprenorphine versus fentanyl or morphine in patients with chronic moderate to severe pain. Curr Med Res Opin. 2012; 28(5): 833-845.

Ripa SR, McCarberg BH, Munera C, et al.: A randomized, 14-day, double-blind study evaluating conversion from hydrocodone/acetaminophen (Vicodin) to buprenorphine transdermal system 10 mug/h or 20 mug/h in patients with osteoarthritis pain. Expert Opin Pharmacother. 2012; 13(9): 1229-1241.

Wolff RF, Reid K, di Nisio M, et al.: Systematic review of adverse events of buprenorphine patch versus fentanyl patch in patients with chronic moderate-to-severe pain. Pain Manag. 2012; 2(4): 351-362.

Holdsworth MT, Forman WB, Killilea TA, et al.: Transdermal fentanyl disposition in elderly subjects. Gerontology. 1994; 40(1): 32-37.

Canneti A, Luzi M, Di Marco P, et al.: Safety and efficacy of transdermal buprenorphine and transdermal fentanyl in the treatment of neuropathic pain in AIDS patients. Minerva Anestesiol. 2013; 79(8): 871-883.

Mercadante S, Porzio G, Ferrera P, et al.: Low doses of transdermal buprenorphine in opioid-naive patients with cancer pain: A 4-week, nonrandomized, open-label, uncontrolled observational study. Clin Ther. 2009; 31(10): 2134-2138.

Wen W, Lynch SY, Munera C, et al.: Application site adverse events associated with the buprenorphine transdermal system: A pooled analysis. Expert Opin Drug Saf. 2013; 12(3): 309-319.

Durand C, Alhammad A, Willett KC: Practical considerations for optimal transdermal drug delivery. Am J Health Syst Pharm. 2012; 69(2): 116-124.

Katz N, Sun S, Johnson F, et al.: ALO-01 (morphine sulfate and naltrexone hydrochloride) extended-release capsules in the treatment of chronic pain of osteoarthritis of the hip or knee: Pharmacokinetics, efficacy, and safety. J Pain. 2010; 11(4): 303-311.

Johnson FK, Ciric S, Boudriau S, et al.: The relative bioavailability of morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA(R)) and an extended release morphine sulfate capsule formulation (KADIAN(R)) in healthy adults under fasting conditions. Am J Ther. 2011; 18(1): 2-8.

Johnson FK, Stark JG, Bieberdorf FA, et al.: Relative oral bioavailability of morphine and naltrexone derived from crushed morphine sulfate and naltrexone hydrochloride extended-release capsules versus intact product and versus naltrexone solution: A single-dose, randomized- sequence, open-label, three-way crossover trial in healthy volunteers. Clin Ther. 2010; 32(6): 1149-1164.

Johnson F, Ciric S, Boudriau S, et al.: Food effects on the pharmacokinetics of morphine sulfate and naltrexone hydrochloride extended release capsules. Adv Ther. 2010; 27(11): 846-858.

Stauffer J, Setnik B, Sokolowska M, et al.: Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-dependent opioid users: A randomized, double-blind, placebo-controlled, crossover study. Clin Drug Investig. 2009; 29(12): 777-790.

Smith HS: Morphine sulfate and naltrexone hydrochloride extended release capsules for the management of chronic, moderate-to-severe pain, while reducing morphine-induced subjective effects upon tampering by crushing. Expert Opin Pharmacother. 2011; 12(7): 1111-1125.

Setnik B, Sommerville K, Goli V, et al.: Assessment of pharmacodynamics effects following oral administration of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules compared with crushed morphine sulfate controlled-release tablets and placebo in nondependent recreational opioid users. Pain Med. 2013; 14(8): 1173-1186.

Katz N, Hale M, Morris D, et al.: Morphine sulfate and naltrexone hydrochloride extended release capsules in patients with chronic osteoarthritis pain. Postgrad Med. 2010; 122(4): 112-128.

Webster LR, Brewer R, Wang C, et al.: Long-term safety and efficacy of morphine sulfate and naltrexone hydrochloride extended release capsules, a novel formulation containing morphine and sequestered naltrexone, in patients with chronic, moderate to severe pain. J Pain Symptom Manage. 2010; 40(5): 734-746.

Ruan X, Chen T, Gudin J, et al.: Acute opioid withdrawal precipitated by ingestion of crushed embeda (morphine extended release with sequestered naltrexone): Case report and the focused review of the literature. J Opioid Manag. 2010; 6(4): 300-303.

Jang DH, Rohe JC, Hoffman RS, et al.: Severe opioid withdrawal due to misuse of new combined morphine and naltrexone product (Embeda). Ann Emerg Med. 2010; 55(3): 303-304.

Schaeffer T: Abuse-deterrent formulations, an evolving technology against the abuse and misuse of opioid analgesics. J Med Toxicol. 2012; 8(4): 400-407.

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.

Kharasch ED, Hoffer C, Whittington D, et al.: Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine. Clin Pharmacol Ther. 2003; 74(6): 543-554.

Aquilante CL, Letrent SP, Pollack GM, et al.: Increased brain P-glycoprotein in morphine tolerant rats. Life Sci. 2000; 66(4): PL47-PL51.

Huwyler J, Drewe J, Gutmann H, et al.: Modulation of morphine-6- glucuronide penetration into the brain by P-glycoprotein. Int J Clin Pharmacol Ther. 1998; 36(2): 69-70.

Qi X, Evans AM, Wang J, et al.: Inhibition of morphine metabolism by ketamine. Drug Metab Dispos. 2010; 38(5): 728-731.

Fujita K, Ando Y, Yamamoto W, et al.: Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer. Cancer Chemother Pharmacol. 2010; 65(2): 251-258.

Darbari DS, van Schaik RH, Capparelli EV, et al.: UGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease. Am J Hematol. 2008; 83(3): 200-202.

Coffman BL, Rios GR, King CD, et al.: Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos. 1997; 25(1): 1-4.

Nicholson B, Ross E, Weil A, et al.: Treatment of chronic moderate-to-severe non-malignant pain with polymer-coated extended-release morphine sulfate capsules. Curr Med Res Opin. 2006; 22(3): 539-550.

Ross EL, Hahn K: KADIAN (morphine sulfate extended-release) capsules for treatment of chronic, moderate-to-severe, nonmalignant pain. Int J Clin Pract. 2008; 62(3): 471-479.

Nicholson B: Morphine sulfate extended-release capsules for the treatment of chronic, moderate-to-severe pain. Expert Opin Pharmacother. 2008; 9(9): 1585-1594.

Broomhead A, Kerr R, Tester W, et al.: Comparison of a once-aday sustained-release morphine formulation with standard oral morphine treatment for cancer pain. J Pain Symptom Manage. 1997; 14(2): 63-73.

Chen ML, Shah V, Patnaik R, et al.: Bioavailability and bioequivalence: An FDA regulatory overview. Pharm Res. 2001; 18(12): 1645-1650.

Williams RL, Patnaik RN, Chen ML: The basis for individual bioequivalence. FDA Population and Individual Bioequivalence Working Group. Eur J Drug Metab Pharmacokinet. 2000; 25(1): 13-17.

Bioavailability and bioequivalence requirements; abbreviated applications; proposed revisions—FDA. Proposed rule. Fed Regist. 1998; 63(223): 64222-64228.

Patnaik RN, Lesko LJ, Chen ML, et al.: Individual bioequivalence. New concepts in the statistical assessment of bioequivalence metrics. FDA Individual Bioequivalence Working Group. Clin Pharmacokinet. 1997; 33(1): 1-6.

Hagen NA, Thirlwell M, Eisenhoffer J, et al.: Efficacy, safety, and steady-state pharmacokinetics of once-a-day controlled-release morphine (MS Contin XL) in cancer pain. J Pain Symptom Manage. 2005; 29(1): 80-90.

Johnson F, Wagner G, Sun S, et al.: Effect of concomitant ingestion of alcohol on the in vivo pharmacokinetics of KADIAN (morphine sulfate extended-release) capsules. J Pain. 2008; 9(4): 330-336.

Sasaki J, Weil AJ, Ross EL, et al.: Effectiveness of polymer-coated extended-release morphine sulfate capsules in older patients with persistent moderate-to-severe pain: A subgroup analysis of a large, open-label, community-based trial. Curr Ther Res Clin Exp. 2007; 68(3): 137-150.

Villesen HH, Banning AM, Petersen RH, et al.: Pharmacokinetics of morphine and oxycodone following intravenous administration in elderly patients. Ther Clin Risk Manag. 2007; 3(5): 961-967.

Sear JW, Hand CW, Moore RA: Studies on morphine disposition: Plasma concentrations of morphine and its metabolites in anesthetized middle-aged and elderly surgical patients. J Clin Anesth. 1989; 1(3): 164-169.

Weil AJ, Nicholson B, Sasaki J: Factors affecting dosing regimens of morphine sulfate extended-release (KADIAN) capsules. J Opioid Manag. 2009; 5(1): 39-45.

Nicholson B, Ross E, Sasaki J, et al.: Randomized trial comparing polymer-coated extended-release morphine sulfate to controlled-release oxycodone HCl in moderate to severe nonmalignant pain. Curr Med Res Opin. 2006; 22(8): 1503-1514.

Armstrong SC, Cozza KL: Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: Theory and clinical reality, Part II. Psychosomatics. 2003; 44(6): 515-520.

Armstrong SC, Cozza KL: Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: Theory and clinical reality, Part I. Psychosomatics. 2003; 44(2): 167-171.

Uchaipichat V, Raungrut P, Chau N, et al.: Effects of ketamine on human UDP-glucuronosyltransferases in vitro predict potential drug-drug interactions arising from ketamine inhibition of codeine and morphine glucuronidation. Drug Metab Dispos. 2011; 39(8): 1324-1328.

Nelsen JL, Marraffa JM, Jones L, et al.: Management considerations following overdoses of modified-release morphine preparations. World J Emerg Med. 2010; 1(1): 75-76.

Finn JW, Walsh TD, MacDonald N, et al.: Placebo-blinded study of morphine sulfate sustained-release tablets and immediate-release morphine sulfate solution in outpatients with chronic pain due to advanced cancer. J Clin Oncol. 1993; 11(5): 967-972.

Thirlwell MP, Sloan PA, Maroun JA, et al.: Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer patients. Cancer. 1989; 63(11 suppl): 2275-2283.

Kaiko RF, Grandy RP, Oshlack B, et al.: The United States experience with oral controlled-release morphine (MS Contin tablets). Parts I and II. Review of nine dose titration studies and clinical pharmacology of 15-mg, 30-mg, 60-mg, and 100-mg tablet strengths in normal subjects. Cancer. 1989; 63(11 suppl): 2348-2354.

Eliot L, Butler J, Devane J, et al.: Pharmacokinetic evaluation of a sprinkle-dose regimen of a once-daily, extended-release morphine formulation. Clin Ther. 2002; 24(2): 260-268.

Allan L, Richarz U, Simpson K, et al.: Transdermal fentanyl versus sustained release oral morphine in strong-opioid naive patients with chronic low back pain. Spine. 2005; 30(22): 2484-2490.

Clark AJ, Ahmedzai SH, Allan LG, et al.: Efficacy and safety of transdermal fentanyl and sustained-release oral morphine in patients with cancer and chronic non-cancer pain. Curr Med Res Opin. 2004; 20(9): 1419-1428.

van Seventer R, Smit JM, Schipper RM, et al.: Comparison of TTSfentanyl with sustained-release oral morphine in the treatment of patients not using opioids for mild-to-moderate pain. Curr Med Res Opin. 2003; 19(6): 457-469.

Allan L, Hays H, Jensen NH, et al.: Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ. 2001; 322(7295): 1154-1158.

Ahmedzai S, Brooks D: Transdermal fentanyl versus sustained-release oral morphine in cancer pain: Preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group. J Pain Symptom Manage. 1997; 13(5): 254-261.

Tassain V, Attal N, Fletcher D, et al.: Long term effects of oral sustained release morphine on neuropsychological performance in patients with chronic non-cancer pain. Pain. 2003; 104(1-2): 389-400.

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

Wilkinson TJ, Robinson BA, Begg EJ, et al.: Pharmacokinetics and efficacy of rectal versus oral sustained-release morphine in cancer patients. Cancer Chemother Pharmacol. 1992; 31(3): 251-254.

Beer B, Rabl W, Libiseller K, et al.: Impact of slow-release oral morphine on drug abusing habits in Austria. Neuropsychiatr. 2010; 24(2): 108-117.

Lamb D, Roberts G: Starch and talc emboli in drug addicts’ lungs. J Clin Pathol. 1972; 25(10): 876-881.

Rubinstein AL, Carpenter DM, Minkoff JR: Hypogonadism in men with chronic pain linked to the use of long-acting rather than short-acting opioids. Clin J Pain. 2013; 29(10): 840-845.

Cicero TJ: Effects of exogenous and endogenous opiates on the hypothalamic-pituitary-gonadal axis in the male. Fed Proc. 1980; 39(8): 2551-2554.

Vuong C, Van Uum SH, O’Dell LE, et al.: The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev. 2010; 31(1): 98-132.

Ceccarelli I, De Padova AM, Fiorenzani P, et al.: Single opioid administration modifies gonadal steroids in both the CNS and plasma of male rats. Neuroscience. 2006; 140(3): 929-937.

Khanal A, Peterson GM, Castelino RL, et al.: Renal drug dosing recommendations: Evaluation of product information for brands of the same drug. Intern Med J. 2014; 44(6): 591-596.

Perrino PJ, Colucci SV, Apseloff G, et al.: Pharmacokinetics, tolerability, and safety of intranasal administration of reformulated OxyContin((R)) tablets compared with original OxyContin ((R)) tablets

in healthy adults. Clin Drug Investig. 2013; 33(6): 441-449.

Cicero TJ, Ellis MS, Surratt HL: Effect of abuse-deterrent formulation of OxyContin. N Engl J Med. 2012; 367(2): 187-189.

Carise D, Dugosh KL, McLellan AT, et al.: Prescription OxyContin abuse among patients entering addiction treatment. Am J Psychiatry. 2007; 164(11): 1750-1756.

Cicero TJ, Inciardi JA, Munoz A: Trends in abuse of Oxycontin and other opioid analgesics in the United States: 2002-2004. J Pain. 2005; 6(10): 662-672.

Mandema JW, Kaiko RF, Oshlack B, et al.: Characterization and validation of a pharmacokinetic model for controlled-release oxycodone. Br J Clin Pharmacol. 1996; 42(6): 747-756.

Benziger DP, Miotto J, Grandy RP, et al.: A pharmacokinetic/pharmacodynamics study of controlled-release oxycodone. J Pain Symptom Manage. 1997; 13(2): 75-82.

Benziger DP, Kaiko RF, Miotto JB, et al.: Differential effects of food on the bioavailability of controlled-release oxycodone tablets and immediate- release oxycodone solution. J Pharm Sci. 1996; 85(4): 407-410.

Reder RF, Oshlack B, Miotto JB, et al. Steady-state bioavailability of controlled-release oxycodone in normal subjects. Clin Ther. 1996; 18(1): 95-105.

Stambaugh JE, Reder RF, Stambaugh MD, et al. Double-blind, randomized comparison of the analgesic and pharmacokinetic profiles of controlled- and immediate-release oral oxycodone in cancer pain patients. J Clin Pharmacol. 2001; 41(5): 500-506.

Colucci RD, Swanton RE, Thomas GB, et al.: Relative variability in bioavailability of oral controlled-release formulations of oxycodone and morphine. Am J Ther. 2001; 8(4): 231-236.

Binsfeld H, Szczepanski L, Waechter S, et al.: A randomized study to demonstrate noninferiority of once-daily OROS® hydromorphone with twice-daily sustained-release oxycodone for moderate to severe chronic noncancer pain. Pain Pract. 2010; 10(5): 404-415.

Kampe S, Wolter K, Warm M, et al.: Clinical equivalence of controlled-release oxycodone 20 mg and controlled-release tramadol 200 mg after surgery for breast cancer. Pharmacology. 2009; 84(5): 276-281.

Afilalo M, Etropolski MS, Kuperwasser B, et al.: Efficacy and safety of tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: A randomized, double-blind, placebo- and active-controlled phase III study. Clin Drug Investig. 2010; 30(8): 489-505.

Gronlund J, Saari TI, Hagelberg NM, et al.: Effect of inhibition of cytochrome P450 enzymes 2D6 and 3A4 on the pharmacokinetics of intravenous oxycodone: A randomized, three-phase, crossover, placebo-controlled study. Clin Drug Investig. 2011; 31(3): 143-153.

Gronlund J, Saari TI, Hagelberg NM, et al.: Exposure to oral oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by inhibition of CYP2D6 alone. Br J Clin Pharmacol. 2010; 70(1): 78-87.

Hagelberg NM, Nieminen TH, Saari TI, et al.: Voriconazole drastically increases exposure to oral oxycodone. Eur J Clin Pharmacol. 2009; 65(3): 263-271.

Nieminen TH, Hagelberg NM, Saari TI, et al.: Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir. Eur J Clin Pharmacol. 2010; 66(10): 977-985.

Nieminen TH, Hagelberg NM, Saari TI, et al.: Grapefruit juice enhances the exposure to oral oxycodone. Basic Clin Pharmacol

Toxicol. 2010; 107(4): 782-788.

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.

Fudin J, Atkinson TJ: Personalized oxycodone dosing: Using pharmacogenetic testing and clinical pharmacokinetics to reduce toxicity risk and increase effectiveness. Pain Med. 2014; 15(5): 723-725.

Okura T, Hattori A, Takano Y, et al.: Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood-brain barrier transport of oxycodone. Drug Metab Dispos. 2008; 36(10): 2005-2013.

Bostrom E, Simonsson US, Hammarlund-Udenaes M: In vivo blood-brain barrier transport of oxycodone in the rat: Indications for active influx and implications for pharmacokinetics/pharmacodynamics. Drug Metab Dispos. 2006; 34(9): 1624-1631.

Kokki M, Valitalo P, Kuusisto M, et al.: Central nervous system penetration of oxycodone after intravenous and epidural administration. Br J Anaesth. 2014; 112(1): 133-140.

Mikus G, Klimas R: Contribution of oxycodone and its metabolites to the analgesic effect. Br J Anaesth. 2014; 112(5): 944-945.

Bostrom E, Hammarlund-Udenaes M, Simonsson US: Blood-brain barrier transport helps to explain discrepancies in in vivo potency between oxycodone and morphine. Anesthesiology. 2008; 108(3): 495-505.

Suzuki T, Ohmuro A, Miyata M, et al.: Involvement of an influx transporter in the blood-brain barrier transport of naloxone. Biopharm Drug Dispos. 2010; 31(4): 243-252.

Sadiq MW, Borgs A, Okura T, et al.: Diphenhydramine active uptake at the blood-brain barrier and its interaction with oxycodone in vitro and in vivo. J Pharm Sci. 2011; 100(9): 3912-3923.

Hassan HE, Myers AL, Lee IJ, et al.: Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel’s tissue distribution in Sprague Dawley rats. J Pharm Sci. 2007; 96(9): 2494-2506.

Bostrom E, Simonsson US, Hammarlund-Udenaes M: Oxycodone pharmacokinetics and pharmacodynamics in the rat in the presence of the P-glycoprotein inhibitor PSC833. J Pharm Sci. 2005; 94(5): 1060-1066.

Nakazawa Y, Okura T, Shimomura K, et al.: Drug-drug interaction between oxycodone and adjuvant analgesics in blood-brain barrier transport and antinociceptive effect. J Pharm Sci. 2010; 99(1): 467-474.

Zwisler ST, Enggaard TP, Noehr-Jensen L, et al.: The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes. Fundam Clin Pharmacol. 2010; 24(4): 517-524.

Zwisler ST, Enggaard TP, Noehr-Jensen L, et al.: The hypoalgesic effect of oxycodone in human experimental pain models in relation to the CYP2D6 oxidation polymorphism. Basic Clin Pharmacol Toxicol. 2009; 104(4): 335-344.

Hagelberg NM, Nieminen TH, Saari TI, et al.: Interaction of oxycodone and voriconazole—A case series of patients with cancer pain supports the findings of randomised controlled studies with healthy subjects. Eur J Clin Pharmacol. 2011; 67(8): 863-864.

Gronlund J, Saari TI, Hagelberg N, et al.: Miconazole oral gel increases exposure to oral oxycodone by inhibition of CYP2D6 and CYP3A4. Antimicrob Agents Chemother. 2011; 55(3): 1063-1067.

Saari TI, Gronlund J, Hagelberg NM, et al.: Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone. Eur J Clin Pharmacol. 2010; 66(4): 387-397.

Gronlund J, Saari T, Hagelberg N, et al.: Effect of telithromycin on the pharmacokinetics and pharmacodynamics of oral oxycodone. J Clin Pharmacol. 2010; 50(1): 101-108.

Nieminen TH, Hagelberg NM, Saari TI, et al.: Rifampin greatly reduces the plasma concentrations of intravenous and oral oxycodone. Anesthesiology. 2009; 110(6): 1371-1378.

Nieminen TH, Hagelberg NM, Saari TI, et al.: St John’s wort greatly reduces the concentrations of oral oxycodone. Eur J Pain. 2010; 14(8): 854-859.

Kokki M, Valitalo P, Rasanen I, et al.: Absorption of different oral dosage forms of oxycodone in the elderly: A cross-over clinical trial in patients undergoing cystoscopy. Eur J Clin Pharmacol. 2012; 68(10): 1357-1363.

Liukas A, Kuusniemi K, Aantaa R, et al.: Elimination of intravenous oxycodone in the elderly: A pharmacokinetic study in postoperative orthopaedic patients of different age groups. Drugs Aging. 2011; 28(1): 41-50.

Liukas A, Kuusniemi K, Aantaa R, et al.: Plasma concentrations of oral oxycodone are greatly increased in the elderly. Clin Pharmacol Ther. 2008; 84(4): 462-467.

Saari TI, Ihmsen H, Neuvonen PJ, et al.: Oxycodone clearance is markedly reduced with advancing age: A population pharmacokinetic study. Br J Anaesth. 2012; 108(3): 491-498.

Komatsu T, Kokubun H, Suzuki A, et al.: Population pharmacokinetics of oxycodone in patients with cancer-related pain. J Pain Palliat Care Pharmacother. 2012; 26(3): 220-225.

Naito T, Tashiro M, Ishida T, et al.: Cancer cachexia raises the plasma concentration of oxymorphone through the reduction of CYP3A but not CYP2D6 in oxycodone-treated patients. J Clin Pharmacol. 2013; 53(8): 812-818.

Naito T, Tashiro M, Yamamoto K, et al.: Impact of cachexia on pharmacokinetic disposition of and clinical responses to oxycodone in cancer patients. Eur J Clin Pharmacol. 2012; 68(10): 1411-1418.

Lalovic B, Phillips B, Risler LL, et al.: Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos. 2004; 32(4): 447-454.

Tallgren M, Olkkola KT, Seppala T, et al.: Pharmacokinetics and ventilatory effects of oxycodone before and after liver transplantation. Clin Pharmacol Ther. 1997; 61(6): 655-661.

Kirvela M, Lindgren L, Seppala T, et al.: The pharmacokinetics of oxycodone in uremic patients undergoing renal transplantation. J Clin Anesth. 1996; 8(1): 13-18.

Lee MA, Leng ME, Cooper RM: Measurements of plasma oxycodone, noroxycodone and oxymorphone levels in a patient with bilateral nephrectomy who is undergoing haemodialysis. Palliat Med. 2005; 19(3): 259-260.

Foral PA, Ineck JR, Nystrom KK: Oxycodone accumulation in a hemodialysis patient. South Med J. 2007; 100(2): 212-214.

Harris SC, Perrino PJ, Smith I, et al.: Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users. J Clin Pharmacol. 2014; 54(4): 468-477.

Coplan PM, Kale H, Sandstrom L, et al.: Changes in oxycodone and heroin exposures in the National Poison Data System after introduction of extended-release oxycodone with abuse-deterrent characteristics. Pharmacoepidemiol Drug Saf. 2013; 22(12): 1274-1282.

Havens JR, Leukefeld CG, DeVeaugh-Geiss AM, et al.: The impact of a reformulation of extended-release oxycodone designed to deter abuse in a sample of prescription opioid abusers. Drug Alcohol Depend. 2014; 139: 9-17.

Rossiter LF, Kirson NY, Shei A, et al.: Medical cost savings associated with an extended-release opioid with abuse-deterrent technology in the US. J Med Econ. 2014; 17(4): 279-287.

Buer LM, Havens JR, Leukefeld C: Does the new formulation of OxyContin(R) deter misuse? A qualitative analysis. Subst Use Misuse. 2014; 49(6): 770-774.

Cassidy TA, DasMahapatra P, Black RA, et al.: Changes in prevalence of prescription opioid abuse after introduction of an abuse-deterrent opioid formulation. Pain Med. 2014; 15(3): 440-451.

Anastassopoulos KP, Chow W, Tapia CI, et al.: Economic study on the impact of side effects in patients taking oxycodone controlled-release for noncancer pain. J Manag Care Pharm. 2012; 18(8): 615-626.

Nalamachu S: Opioid rotation with extended-release opioids: Where should we begin? Int J Gen Med. 2012; 5: 11-17.

Syrmis W, Good P, Wootton J, et al.: Opioid conversion ratios used in palliative care: Is there an Australian consensus? Intern Med J. 2014; 44(5): 483-489.

Mercadante S, Caraceni A: Conversion ratios for opioid switching in the treatment of cancer pain: A systematic review. Palliat Med. 2011; 25(5): 504-515.

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

Webster LR, Fine PG: Overdose deaths demand a new paradigm for opioid rotation. Pain Med. 2012; 13(4): 571-574.

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.

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

Smith K, Hopp M, Mundin G, et al.: Single- and multiple-dose pharmacokinetic evaluation of oxycodone and naloxone in an opioid agonist/ antagonist prolonged-release combination in healthy adult volunteers. Clin Ther. 2008; 30(11): 2051-2068.

Meissner W, Leyendecker P, Mueller-Lissner S, et al.: A randomized controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain. 2009; 13(1): 56-64.

Mercadante S, Giarratano A: Combined oral prolonged-release oxycodone and naloxone in chronic pain management. Expert Opin Investig Drugs. 2013; 22(1): 161-166.

Sykes NP: An investigation of the ability of oral naloxone to correct opioid-related constipation in patients with advanced cancer. Palliat Med. 1996; 10(2): 135-144.

Meissner W, Schmidt U, Hartmann M, et al.: Oral naloxone reverses opioid-associated constipation. Pain. 2000; 84(1): 105-109.

Liu M, Wittbrodt E: Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J Pain Symptom Manage. 2002; 23(1): 48-53.

Vondrackova D, Leyendecker P, Meissner W, et al.: Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release tablets in patients with moderate to severe chronic pain. J Pain. 2008; 9(12): 1144-1154.

Smith K, Hopp M, Mundin G, et al.: Naloxone as part of a prolonged release oxycodone/naloxone combination reduces oxycodone-induced slowing of gastrointestinal transit in healthy volunteers. Expert Opin Investig Drugs. 2011; 20(4): 427-439.

van Dorp E, Yassen A, Dahan A: Naloxone treatment in opioid addiction: The risks and benefits. Expert Opin Drug Saf. 2007; 6(2): 125-132.

Mundin GE, Smith KJ, Mysicka J, et al.: Validated in vitro/in vivo correlation of prolonged-release oxycodone/naloxone with differing dissolution rates in relation to gastrointestinal transit times. Expert Opin Drug Metab Toxicol. 2012; 8(12): 1495-1503.

Wahlstrom A, Persson K, Rane A: Metabolic interaction between morphine and naloxone in human liver. A common pathway of glucuronidation? Drug Metab Dispos. 1989; 17(2): 218-220.

Schulteis G, Chiang D, Archer C: Relative potency of the opioid antagonists naloxone and 6-alpha-naloxol to precipitate withdrawal from acute morphine dependence varies with time post-antagonist. Pharmacol Biochem Behav. 2009; 92(1): 157-163.

Leow KP, Smith MT, Watt JA, et al.: Comparative oxycodone pharmacokinetics in humans after intravenous, oral, and rectal administration. Ther Drug Monit. 1992; 14(6): 479-484.

Smith K, Hopp M, Mundin G, et al.: Low absolute bioavailability of oral naloxone in healthy subjects. Int J Clin Pharmacol Ther. 2012; 50(5): 360-367.

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.

Lowenstein O, Leyendecker P, Hopp M, et al.: Combined prolonged-release oxycodone and naloxone improves bowel function in patients receiving opioids for moderate-to-severe non-malignant chronic pain: A randomised controlled trial. Expert Opin Pharmacother. 2009; 10(4): 531-543.

Koopmans G, Simpson K, De Andres J, et al.: Fixed ratio (2:1) prolonged-release oxycodone/naloxone combination improves bowel function in patients with moderate-to-severe pain and opioid-induced constipation refractory to at least two classes of laxatives. Curr Med Res Opin. 2014: 30(11): 2389-2396.

Ahmedzai SH, Leppert W, Janecki M, et al.: Long-term safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate-to-severe chronic cancer pain. Support Care Cancer. 2014 (in press).

Davis M, Goforth HW, Gamier P: Oxycodone combined with opioid receptor antagonists: Efficacy and safety. Expert Opin Drug Saf. 2013; 12(3): 389-402.

Ahmedzai SH, Nauck F, Bar-Sela G, et al.: A randomized, doubleblind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain. Palliat Med. 2012; 26(1): 50-60.

Cuomo A, Russo G, Esposito G, et al.: Efficacy and gastrointestinal tolerability of oral oxycodone/naloxone combination for chronic pain in outpatients with cancer: An observational study. Am J Hosp Palliat Care. 2014 (in press).

Mercadante S, Ferrera P, Adile C: High doses of oxycodone-naloxone combination may provide poor analgesia. Support Care Cancer. 2011; 19(9): 1471-1472.

Holzer P, Ahmedzai SH, Niederle N, et al.: Opioid-induced bowel dysfunction in cancer-related pain: Causes, consequences, and a novel approach for its management. J Opioid Manag. 2009; 5(3): 145-151.

DePriest AZ, Miller K: Oxycodone/naloxone: Role in chronic pain management, opioid-induced constipation, and abuse deterrence. Pain Ther. 2014; 3(1): 1-15.

Tompkins DA, Lanier RK, Harrison JA, et al.: Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone. Psychopharmacology. 2010; 210(4): 471-480.

Severtson SG, Bartelson BB, Davis JM, et al.: Reduced abuse, therapeutic errors, and diversion following reformulation of extendedrelease oxycodone in 2010. J Pain. 2013; 14(10): 1122-1130.

Pappagallo M, Sokolowska M: The implications of tamper-resistant formulations for opioid rotation. Postgrad Med. 2012; 124(5): 101-109.

Nalamachu SR: Opioid rotation in clinical practice. Adv Ther. 2012; 29(10): 849-863.

Fredheim OM, Moksnes K, Borchgrevink PC, et al.: Clinical pharmacology of methadone for pain. Acta Anaesthesiol Scand. 2008; 52(7): 879-889.

Longshore D, Annon J, Anglin MD, et al.: Levo-alpha-acetylmethadol (LAAM) versus methadone: Treatment retention and opiate use. Addiction. 2005; 100(8): 1131-1139.

Ferrari A, Coccia CPR, Bertolini A, et al.: Methadone-metabolism, pharmacokinetics and interactions. Pharmacol Res. 2004; 6: 551-559.

Lynch ME: A review of the use of methadone for the treatment of chronic noncancer pain. Pain Res Manag. 2005; 10(3): 133-144.

Somogyi AA, Barratt DT, Coller JK: Pharmacogenetics of opioids. Clin Pharmacol Ther. 2007; 81(3): 429-444.

Brown R, Kraus C, Fleming M, et al.: Methadone: Applied pharmacology and use as adjunctive treatment in chronic pain. Postgrad Med J. 2004; 80(949): 654-659.

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.

Modesto-Lowe V, Brooks D, Petry N: Methadone deaths: Risk factors in pain and addicted populations. J Gen Intern Med. 2010; 25(4): 305-309.

Andrews CM, Krantz MJ, Wedam EF, et al.: Methadone-induced mortality in the treatment of chronic pain: Role of QT prolongation. Cardiol J. 2009; 16(3): 210-217.

Chan GM, Stajic M, Marker EK, et al.: Testing positive for methadone and either a tricyclic antidepressant or a benzodiazepine is associated with an accidental overdose death: Analysis of medical examiner data. Acad Emerg Med. 2006; 13(5): 543-547.

Chou R, Deyo R, Devine B, et al.: The effectiveness and risks of long-term opioid treatment of chronic pain. Evidence Report/Technology Assessment No. 218. AHRQ Publication No. 14-E005-EF. Rockville, MD: Agency for Healthcare Research and Quality, September 2014. Available at www.effectivehealthcare.ahrq.gov/reports/final.cfm. Accessed October 1, 2014.

Lichtenwalner MR, Mencken T, Tully R, et al.: False-positive immunochemical screen for methadone attributable to metabolites of verapamil. Clin Chem. 1998; 44(5): 1039-1041.

Lotsch J, Walter C, Parnham MJ, et al.: Pharmacokinetics of non-intravenous formulations of fentanyl. Clin Pharmacokinet. 2013; 52(1): 23-36.

Sloan PA, Moulin DE, Hays H: A clinical evaluation of transdermal therapeutic system fentanyl for the treatment of cancer pain. J Pain Symptom Mange. 1998; 16(2): 102-111.

Grond S, Radbruch L, Lehmann KA: Clinical pharmacokinetics of transdermal opioids: Focus on transdermal fentanyl. Clin

Pharmacokinet. 2000; 38(1): 59-89.

Jeal W, Benfield P: Transdermal fentanyl. A review of its pharmacological properties and therapeutic efficacy in pain control. Drugs. 1997; 53(1): 109-138.

Sloan PA: Transdermal pain management delivery system in the cancer patient. Home Health Care Consult. 2000; 7: 10-14.

Zernikow B, Michel E, Anderson B: Transdermal fentanyl in childhood and adolescence: A comprehensive literature review. J Pain. 2007; 8(3): 187-207.

Jenerowicz D, Polanska A, Olek-Hrab K, et al.: Skin hypersensitivity reactions to transdermal therapeutic systems-still an important clinical problem. Ginekol Pol. 2012; 83(1): 46-50.

FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. August 2014. Available at www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/UCM277916.pdf. Accessed October 1, 2014.

Niscola P, Scaramucci L, Vischini G, et al.: The use of major analgesics in patients with renal dysfunction. Curr Drug Targets. 2010; 11(6): 752-758.

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

Nelson L, Schwaner R: Transdermal fentanyl: Pharmacology and toxicology. J Med Toxicol. 2009; 5(4): 230-241.

Fentanyl patches: Preventable overdose [editorial]. Prescrire Int. 2010; 19(105): 22-25.

Voight I: Fatal overdose due to confusion of an transdermal fentanyl delivery system. Case Rep Crit Care. 2013; 2013: 1-3.

Hawley P: Case report of severe bradycardia due to transdermal fentanyl. Palliat Med. 2013; 27(8): 793-795.

Vadivelu N, Maria M, Jolly S, et al.: Clinical applications of oxymorphone. J Opioid Manag. 2013; 9(6): 439-452.

Sloan PA, Babul N: Extended-release opioids for the management of chronic non-malignant pain. Exp Opin Drug Deliv. 2006; 3: 489-497.

Chamberlin KW, Cottle M, Neville R, et al.: Oral oxymorphone for pain management. Ann Pharmacother. 2007; 41(7): 1144-1152.

Guay DR: Use of oral oxymorphone in the elderly. Consult Pharm. 2007; 22(5): 417-430.

Sloan PA, Barkin R: Oxymorphone and oxymorphone extended-release: A pharmcotherapeutic review. J Opioid Manag. 2008; 4: 251-254.

Matsumoto AK: Oral extended-release oxymorphone: A new choice for chronic pain relief. Exp Opin Pharmacother. 2007; 8(10): 1515-1527.

Prommer E: Oxymorphone: A review. Supp Care Cancer. 2006; 14: 109-115.

Sloan PA, Slatkin NE, Ahdieh H: Effectiveness and safety of oral extended-release oxymorphone for the treatment of cancer pain: A pilot study. Supp Care Cancer. 2005; 13: 57-65.

Sloan PA: Oxymorphone in the management of pain. Ther Clin Risk Manage. 2008; 4: 777-787.

Pergolizzi JV, Raffa RB, Gould E: Considerations on the use of oxymorphone in geriatric patients. Exp Opin Drug Saf. 2009; 8(5): 603-613.

Singla A, Sloan PA: Pharmacokinetic evaluation of hydrocodone/acetaminophen for pain management. J Opioid Manag. 2013; 9: 71-80.

U.S. Prescription drug sales grow slowly; hydrocodone most prescribed. Available at www.seekingalpha.com/article/128003-u-s-prescription-drug-sales-grow-slowly-hydrocodone-most-prescribed. Accessed October 10, 2014.

Prommer E: Hydrocodone: Does it have a role in palliative care? J Opioid Manag. 2010; 6(4): 295-299.

Melhem MR, Rubino CM, Farr SJ, et al.: Population pharmacokinetic analysis for hydrocodone following the administration of hydrocodone bitartrate extended-release capsules. Clin Pharmacokinet. 2013; 52: 907-917.

Kaplan HL, Busto UE, Baylon GJ, et al.: Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability. J Pharm Exp Ther. 1997; 281(1): 103-108.

Otton SV, Schadel M, Cheung SW, et al.: CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther. 1993; 54(5): 463-472.

Extended-release hydrocodone (Zohydro) for pain. Med Lett Drugs Ther. 2014; 56(1444): 45-46.

Rauck RL, Nalamachu S, Wild JE, et al.: Single-entity hydrocodone extended-release capsules in opioid-tolerant subjects with moderate-tosevere chronic low back pain: A randomized double-blind, placebocontrolled study. Pain Med. 2014; 15: 975-985.

Krashin D, Murinova N, Trescot AM: Extended-release hydrocodone-gift or curse? J Pain Res. 2013; 6: 53-57.

Sloan PA: Tapentadol for acute and chronic pain. Exp Opin Pharmacother. 2010; 11: 1783-1785.

Smith HS, Raffa RB, Pergolizzi JV, et al.: Combining opioid and adrenergic mechanisms for chronic pain. Postgrad Med. 2014; 126(4): 98-114.

Hartrick CT, Rozek RJ: Tapentadol in pain management: A mu-opioid receptor agonist and noradrenaline reuptake inhibitor. CNS Drugs. 2011; 25(5): 359-370.

Pierce DM, Shipstone E: Pharmacology update: Tapentadol for neuropathic pain. Am J Hospice Pall Med. 2012; 29(8): 663-666.

Zannikos PN, Smith JW, Stahlberg HJ, et al.: Pharmacokinetics evaluation of tapentadol extended-release tablets in healthy subjects. J Opioid Manag. 2013; 9(4): 291-300.

Mercadante S, Porzio G, Gebbia V: New opioids. J Clin Oncol. 2014; 32(16): 1671-1676.

Mercadante S, Porzio G, Aielli F, et al.: Opioid switching from and to tapentadol extended-release in cancer patients: Conversion ratio with other opioids. Curr Med Res Opin. 2013; 29(6): 661-666.

Hoy SM: Tapentadol extended release. Drugs. 2012; 72(3): 375-393.

Etropolski M, Lange B, Goldberg J, et al.: A pooled analysis of patient-specific factors and efficacy and tolerability of tapentadol

extended release treatment for moderate to severe chronic pain. J Opioid Manag. 2013; 9(5): 343-356.

Afilalo M, Morlion B: Efficacy of tapentadol ER for managing moderate to severe chronic pain. Pain Phys. 2013; 16(1): 27-40.

Taylor R, Pergolizzi JV, Raffa RB: Tapentadol extended release for chronic pain patients. Adv Ther. 2013; 30(1): 14-27.

Gregory TB: Hydromorphone: Evolving to meet the challenges of today’s health care environment. Clin Ther. 2013; 35(12): 2007-2027.

Bruera E, Sloan PA, Mount B, et al.: A randomized, double-blind, double-dummy, crossover trial comparing the safety and efficacy of oral sustained-release hydromorphone with immediate-release hydromorphone in patients with cancer pain. J Clin Oncol. 1996; 14(5): 1713-1717.

Goforth HW: Hydromorphone-OROS formulation. Expert Opin Pharmacother. 2010; 11(7): 1207-1214.

Conley R, Gupta SK, Sathyan G: Clinical spectrum of the osmotic-controlled release oral delivery system (OROS), an advanced oral delivery form. Curr Med Res Opin. 2006; 22(10): 1879-1892.

Guay DR: Oral hydromorphone extended-release. Consult Pharm. 2010; 25(12): 816-828.

Extended-release hydromorphone (Exalgo) for pain. Med Lett Drugs Ther. 2011; 1370: 62.

Lussier D, Richarz U, Finco G: Use of hydromorphone, with particular reference to the OROS formulation, in the elderly. Drugs Aging. 2010; 27(4): 327-335.

Reisfield GM, Wilson GR: The metamorphosis of hydromorphone. J Opioid Manag. 2005; 1(3): 139-145.

Wallace M, Rauck RL, Moulin D, et al.: Once-daily OROS hydromorphone for the management of chronic nonmalignant pain: A dose-conversion and titration study. Int J Clin Pract. 2007; 61(10): 1671-1676.

Moore KT, St-Fleur D, Marricco NC, et al.: A randomized study of the effects of food on the pharmacokinetics of once-daily extended-release hydromorphone in healthy volunteers. J Clin Pharmacol. 2011; 51(11): 1571-1579.




How to Cite

Sloan, MD, P. A., M. P. Davis, MD, FCCP, and P. Gamier, RN, BSN, CHPN. “Specific Pharmacology of Long-Acting, Extended-Release, and Sustained-Release Opioids for the Treatment of Chronic Nonmalignant Pain”. Journal of Opioid Management, vol. 10, no. 7, May 2023, doi:10.5055/jom.2014.0230.