Open Access Open Access  Restricted Access Subscription or Fee Access

Oxymorphone and oxymorphone extended release: A pharmacotherapeutic review

Paul Alexander Sloan, MD, Robert L. Barkin, PharmD, MBA

Abstract


The treatment of chronic pain remains an enormous challenge in the United States. Opioid analgesics are an important component of pharmacotherapy for chronic pain and have proven efficacy in the management of cancer and noncancer chronic pain. The newest addition to oral opioid pharmacotherapy is oral oxymorphone, a semisynthetic opioid agonist that is now available in oral immediate-release (IR) and extended-release (ER) formulations. This review discusses the pharmacology, pharmacokinetics, pharmacodynamics, pharmacotherapeutics, and clinical use of oral oxymorphone IR and ER formulations for the management of moderate to severe pain for different types of patients in a variety of settings. Two published studies evaluated the efficacy and safety of oxymorphone IR in patients with moderate to severe postoperative pain and demonstrated that it provides rapid and effective analgesia and is generally well tolerated. Six published randomized controlled trials and three published open-label studies evaluated the efficacy and safety of oxymorphone ER for chronic cancer or noncancer pain. These trials found analgesic efficacy and tolerability comparable to that provided by morphine controlled release (CR) or oxycodone CR; treatment effects with oxymorphone ER were durable for treatment periods of 12 weeks at the same dose or up to 1 year with little dose escalation. Titrated doses of oxymorphone ER were effective and generally well tolerated in both opioid-experienced and opioid-naïve patients. Aspects of oxymorphone metabolism and limited protein binding may simplify treatment in certain populations.

Keywords


opioids, analgesics, pain management, oxymorphone, pharmacokinetics, pharmacodynamics

Full Text:

PDF

References


American Pain Foundation: Pain facts and figures. Available at http://www.painfoundation.org/page.asp?file=Newsroom/ PainFacts.htm. Accessed March 6, 2008.

AGS Panel on Persistent Pain in Older Persons: The management of persistent pain in older persons. J Am Geriatr Soc. 2002; 50(6 suppl):S205-S224.

World Health Organization: Cancer Pain Relief. Geneva, Switzerland: WHO Office of Publication, 1996.

Sloan P, Babul N: Extended-release opioids for the management of chronic non-malignant pain. Expert Opin Drug Deliv. 2006; 3(4): 489-497.

American Pain Society: Guideline for the Management of Pain in Osteoarthritis, Rheumatoid Arthritis and Juvenile Chronic Arthritis. Chicago, IL: American Pain Society, 2002.

Coluzzi F, Pappagallo M: Opioid therapy for chronic noncancer pain: Practice guidelines for initiation and maintenance of therapy. Minerva Anestesiol. 2005; 71(7/8): 425-433.

Vallerand AH: The use of long-acting opioids in chronic pain management. Nurs Clin North Am. 2003; 38(3): 435-445.

Airaksinen O, Brox JI, Cedraschi C, et al.: Chapter 4. European guidelines for the management of chronic nonspecific low back pain. Eur Spine J. 2006; 15 (suppl 2): S192-S300.

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.

Sloan P, Hamann S: Ultra low-dose opioid antagonists to enhance opioid analgesia. J Opioid Manage. 2006; 2(5): 295-304.

Nielsen CK, Ross FB, Shahrdad L, et al.: Oxycodone and morphine have distinctly different pharmacological profiles: Radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain. 2007; 132: 289-300.

Lotsch J, Geisslinger G: Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers. Pharmacogenomics J. 2006; 6(3): 200-210.

Lotsch J, Skarke C, Liefhold J, et al.: Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives. Clin Pharmacokinet. 2004; 43(14): 983-1013.

Pan L, Xu J, Yu R, et al.: Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene, Oprm. Neuroscience. 2005; 133(1): 209-220.

Pan YX, Xu J, Mahurter L, et al.: Identification and characterization of two new human mu opioid receptor splice variants, hMOR-1O and hMOR-1X. Biochem Biophys Res Commun. 2003; 301(4): 1057-1061.

Pasternak DA, Pan L, Xu J, et al.: Identification of three new alternatively spliced variants of the rat mu opioid receptor gene: Dissociation of affinity and efficacy. J Neurochem. 2004; 91(4): 881-890.

Clarke S, Kitchen I: Opioid analgesia: new information from gene knockout studies. Curr Opin Anaesthesiol. 1999; 12(5): 609-614.

Ravert HT, Bencherif B, Madar I, et al.: PET imaging of opioid receptors in pain: progress and new directions. Curr Pharm Des. 2004; 10(7): 759-768.

Grilo RM, Bertin P, Scotto di Fazano C, et al.: Opioid rotation in the treatment of joint pain. A review of 67 cases. Joint Bone Spine. 2002; 69(5): 491-494.

Mercadante S, Bruera E: Opioid switching: A systematic and critical review. Cancer Treat Rev. 2006; 32(4): 304-315.

Quang-Cantagrel ND, Wallace MS, Magnuson SK: Opioid substitution to improve the effectiveness of chronic noncancer pain control: A chart review. Anesth Analg. 2000; 90(4): 933-937.

Barkin RL, Iusco AM, Barkin SJ: Opioids used in primary care for the management of pain: A pharmacologic, pharmacotherapeutic, and pharmacodynamic overview. In Boswell MV CB (ed.): Weiner’s Pain Management: A Practical Guide for Clinicians, 7th ed. New York: Taylor & Francis, 2006.

Weiss U: Derivatives of morphine. I. 14-hydroxydihydromorphine. Am J Chem Soc. 1955; 77: 5891-5892.

O’Neil MJ, ed: The Merck Index, 13 ed. Whitehouse Station, NJ: Merck & Co., 2001.

Poyhia R, Seppala T: Liposolubility and protein binding of oxycodone in vitro. Pharmacol Toxicol. 1994; 74(1): 23-27.

Fand I, Sinatra R: Whole body autoradiographic localization of C[14] labeled morphine and nalorphine. Anat Rec. 1978; 190: 392-393.

Kadian® (morphine sulfate sustained release capsules). Full Prescribing Information. Piscataway, NJ: Alpharma, 2004.

OxyContin® (oxycodone HCl controlled-release tablets). Full Prescribing Information, Purdue Pharma L.P., Stamford, CT, 2005.

OPANA® ER (oxymorphone hydrochloride extended-release tablets). Full Prescribing Information, Endo Pharmaceuticals Inc, Chadds Ford, PA, 2007.

Hermens JM, Ebertz JM, Hanifin JM, et al.: Comparison of histamine release in human skin mast cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology. 1985; 62(2): 124-129.

Metzger TG, Paterlini MG, Ferguson DM, et al.: Investigation of the selectivity of oxymorphone- and naltrexone-derived ligands via site-directed mutagenesis of opioid receptors: exploring the “address” recognition locus. J Med Chem. 2001; 44(6): 857-862.

Ross FB, Smith MT: The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated. Pain. 1997; 73(2): 151-157.

Leighton GE, Hill RG, Hughes J: Effects of 5-HT and alpha 1 adrenoceptor antagonists on kappa opioid-induced sedation. Pharmacol Biochem Behav. 1988; 31(4): 899-904.

Kieffer BL, Gaveriaux-Ruff C: Exploring the opioid system by gene knockout. Prog Neurobiol. 2002; 66(5): 285-306.

Knoll AT, Meloni EG, Thomas JB, et al.: Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. J Pharmacol Exp Ther. 2007; 323(3): 838-845.

Fichna J, Staniszewska R, Poels J, et al.: Mu-opioid receptor ligands lack receptor subtype selectivity in the aequorin luminescence- based calcium assay. Chem Biol Drug Des. 2007; 70(3): 247-253.

Wolozin BL, Pasternak GW: Classification of multiple morphine and enkephalin binding sites in the central nervous system. Proc Natl Acad Sci U S A. 1981; 78(10): 6181-6185.

Pasternak GW: Multiple opiate receptors: déjà vu all over again. Neuropharmacology. 2004; 47: 312-323.

Watanabe H, Nakayama D, Ito K, et al.: A Tyr-W-MIF-1 analog containing D-Pro2 acts as a selective mu2-opioid receptor antagonist in the mouse. J Pharmacol Exp Ther. 2005; 312(3): 1075-1081.

Pasternak GW: Opiate, enkephalin, and endorphin analgesia: relations to a single subpopulation of opiate receptors. Neurology. 1981; 31(10): 1311-1315.

Gintzler AR, Pasternak GW: Multiple mu receptors: Evidence for mu2 sites in the guinea pig ileum. Neurosci Lett. 1983; 39(1): 51-56.

OPANA¨ (oxymorphone hydrochloride). Full Prescribing Information, Endo Pharmaceuticals Inc., Chadds Ford, PA, 2007.

Adams MP, Ahdieh H: Single- and multiple-dose pharmacokinetic and dose-proportionality study of oxymorphone immediate-release tablets. Drugs R D. 2005; 6(2): 91-99.

Adams MP, Ahdieh H: Pharmacokinetics and doseproportionality of oxymorphone extended release and its metabolites: results of a randomized crossover study. Pharmacotherapy. 2004; 24(4): 468-476.

Aqua K, Gimbel J, Singla N, et al.: Efficacy and tolerability of oxymorphone immediate release for acute postoperative pain after abdominal surgery: a randomized, double-blind, activeand placebo-controlled, parallel-group trial. Clin Ther. 2007; 29(6): 1000-1012.

Gimbel J, Ahdieh H: The efficacy and safety of oral immediaterelease oxymorphone for postsurgical pain. Anesth Analg. 2004; 99(5): 1472-1477.

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

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.

Leow KP, Smith MT, Williams B, et al.: Single-dose and steadystate pharmacokinetics and pharmacodynamics of oxycodone in patients with cancer. Clin Pharmacol Ther. 1992; 52(5): 487-495.

Adams M, Pieniaszek HJ, Jr, Gammaitoni AR, et al.: Oxymorphone extended release does not affect CYP2C9 or CYP3A4 metabolic pathways. J Clin Pharmacol. 2005; 45(3): 337-345.

American Academy of Pain Medicine, American Pain Society, American Society of Addiction Medicine: Definitions related to the use of opioids for the treatment of pain: A consensus document from the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine. Glenview, IL: 2001.

Reisfield GM, Bertholf R, Barkin RL, et al.: Urine drug test interpretation: what do physicians know? J Opioid Manag. 2007; 3(2): 80-86.

Matsumoto AK, Babul N, Ahdieh H: Oxymorphone extended-release tablets relieve moderate to severe pain and improve physical function in osteoarthritis: results of a randomized, double-blind, placebo- and active-controlled phase III trial. Pain Med. 2005; 6(5): 357-366.

Kivitz A, Ma C, Ahdieh H, et al.: A 2-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase III trial comparing the efficacy of oxymorphone extended release and placebo in adults with pain associated with osteoarthritis of the hip or knee. Clin Ther. 2006; 28: 352-364.

Gabrail NY, Dvergsten C, Ahdieh H: Establishing the dosage equivalency of oxymorphone extended release and oxycodone controlled release in patients with cancer pain: A randomized controlled study. Curr Med Res Opin. 2004; 20(6): 911-918.

Hale ME, Dvergsten C, Gimbel J: Efficacy and safety of oxymorphone exte nded release in chronic low back pain: results of a randomized, double-blind, placebo- and active-controlled phase III study. J Pain. 2005; 6(1): 21-28.

Hale ME, Ahdieh H, Ma T, et al.: Efficacy and safety of OPANA ER (oxymorphone extended release) for relief of moderate to severe chronic low back pain in opioid-experienced patients: A 12-week, randomized, double-blind, placebocontrolled study. J Pain. 2007; 8(2): 175-184.

Katz J, Rauck R, Ahdieh H, et al.: A 12-week randomized placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain. Curr Med Res Opin. 2007; 23(1): 117-128.

Sloan P, Slatkin N, Ahdieh H: Effectiveness and safety of oral extended-release oxymorphone for the treatment of cancer pain: A pilot study. Support Care Cancer. 2005; 13(1): 57-65.

McIlwain H, Ahdieh H: Safety, tolerability, and effectiveness of oxymorphone extended release for moderate to severe osteoarthritis pain: a one-year study. Am J Ther. 2005; 12(2): 106-112.

Ahdieh H, Kerwin R, Yuen F: Low dose titration with oxymorphone extended release to achieve effective long-term treatment of moderate to severe pain in opioid-naive patients. Presented at: American Academy of Physician Assistants 34th Annual Physician Assistant Conference; May 27-June 1, 2006; San Francisco, CA.

Kalso E, Edwards JE, Moore RA, et al.: Opioids in chronic non-cancer pain: Systematic review of efficacy and safety. Pain. 2004; 112(3): 372-380.

Adams D, Royal M, Jenson MG, et al.: Retrospective assessment of frequency of dosing of sustained release opiate preparations. Presented at American Pain Society 21st Scientific Meeting, March 14-17, 2002; Baltimore, MD. American Pain Society 2002 Abstract Database. Available at http://www.ampainsoc.org/db2/ abstract/view?poster_id=1088. Accessed December 6, 2005.




DOI: https://doi.org/10.5055/jom.2008.0018

Refbacks

  • There are currently no refbacks.