Oxycodone/Naloxone: role in chronic pain management, opioid-induced constipation, and abuse deterrence

Anne Z DePriest, Katie Miller, Anne Z DePriest, Katie Miller

Abstract

The use of opioids in the treatment of chronic pain is widespread; the prevalence of specific opioids varies from country to country and depends on product availability, national formulary systems, and provider preferences. Patients often receive opioids for legitimate treatment of pain conditions, but on the opposite side of the spectrum, nonmedical use of opioids is a significant public health concern. Opioids are associated with several side effects, and constipation is the most commonly reported and persistent symptom. Unlike some adverse effects associated with opioid use, tolerance does not develop to constipation. Opioid-induced constipation (OIC) is the most prevalent patient complaint associated with opioid use and has been associated with declines in various quality of life measures. OIC can be extremely difficult for patients to tolerate and may prompt patients to decrease or discontinue opioid treatment. Current management strategies for OIC are often insufficient. A prolonged-release formulation of oxycodone/naloxone (OXN) has been investigated for the treatment of nonmalignant and cancer pain and mitigation of OIC, and evidence is largely favorable. Studies have demonstrated the capability of OXN to alleviate OIC while maintaining pain control comparable to oxycodone-only regimens. There is insufficient evidence for OXN efficacy for patients with mild OIC or patients maintained on high doses of opioids, and use in these populations is controversial. The reduction of costs associated with OIC may provide overall cost effectiveness with OXN. Additionally, the presence of naloxone may deter abuse/misuse by those seeking to misuse the formulation by modes of administration other than oral ingestion. Most studies to date have occurred in European countries, and phase 3 trials continue in the United States. This review will include current therapeutic options for pain and constipation, unique characteristics of OXN, evidence related to use of OXN and its place in therapy, discussion of opioid abuse/misuse, and various abuse-deterrent mechanisms, and areas of continuing research.

References

    1. Mercadante S. Prospects and challenges in opioid analgesia for pain management. Curr Med Res Opin. 2011;27(9):1741–1743. doi: 10.1185/03007995.2011.602057.
    1. Gras B, Magge S, Bloom A, Lembo A. Motility disorders of the colon and rectum. Curr Opin Gastroenterol. 2013;29(1):66–71. doi: 10.1097/MOG.0b013e32835a80e7.
    1. Sng BL, Schug SA. The role of opioids in managing chronic non-cancer pain. Ann Acad Med Singap. 2009;38(11):960–966.
    1. Higginson IJ, Gao W. Opioid prescribing for cancer pain during the last 3 months of life: associated factors and 9-year trends in a nationwide United Kingdom cohort study. J Clin Oncol. 2012;30(35):4373–4379. doi: 10.1200/JCO.2012.42.0919.
    1. Institute of Medicine (IOM) Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington, DC: The National Academies Press; 2011.
    1. 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. doi: 10.1517/13543784.2011.563236.
    1. Purdue Pharma. FDA accepts for review Purdue Pharma’s new drug application for Targiniq™ ER (oxycodone HCl/naloxone HCl controlled-release) tablets CII. Press release. 26 November 2013. . Accessed 2 Jan 2014.
    1. Ballantyne JC. Opioid analgesia: perspectives on right use and utility. Pain Physician. 2007;10(3):479–491.
    1. Clemens KE, Quednau I, Klaschik E. Bowel function during pain therapy with oxycodone/naloxone prolonged-release tablets in patients with advanced cancer. Int J Clin Pract. 2011;65(4):472–478. doi: 10.1111/j.1742-1241.2011.02634.x.
    1. 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.
    1. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs. 2003;63(7):649–671. doi: 10.2165/00003495-200363070-00003.
    1. Woolery M, Bisanz A, Lyons HF, Gaido L, Yenulevich M, Fulton S, et al. Putting evidence into practice: evidence-based interventions for the prevention and management of constipation in patients with cancer. Clin J Oncol Nurs. 2008;12(2):317–337. doi: 10.1188/08.CJON.317-337.
    1. Meissner W, Leyendecker P, Mueller-Lissner S, et al. A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain. 2009;13(1):56–64. doi: 10.1016/j.ejpain.2008.06.012.
    1. Swegle JM, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician. 2006;74(8):1347–1354.
    1. Bell T, Annunziata K, Leslie JB. Opioid-induced constipation negatively impacts pain management, productivity, and health-related quality of life: findings from the National Health and Wellness Survey. J Opioid Manage. 2009;5(3):137–144.
    1. Shook JE, Pelton JT, Hruby VJ, Burks TF. Peptide opioid antagonist separates peripheral and central opioid antitransit effects. J Pharmacol Exp Ther. 1987;243(2):492–500.
    1. Wirz S, Wittmann M, Schenk M, et al. Gastrointestinal symptoms under opioid therapy: a prospective comparison of oral sustained-release hydromorphone, transdermal fentanyl, and transdermal buprenorphine. Eur J Pain. 2009;13(7):737–743. doi: 10.1016/j.ejpain.2008.09.005.
    1. Holzer P. Non-analgesic effects of opioids: management of opioid-induced constipation by peripheral opioid receptor antagonists: prevention or withdrawal? Curr Pharm Des. 2012;18(37):6010–6020. doi: 10.2174/138161212803582388.
    1. Reimer K, Hopp M, Zenz M, et al. Meeting the challenges of opioid-induced constipation in chronic pain management—a novel approach. Pharmacology. 2009;83(1):10–17. doi: 10.1159/000165778.
    1. Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J Pain Symptom Manage. 2002;23(1):48–53. doi: 10.1016/S0885-3924(01)00369-4.
    1. Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg. 2001;182(5A Suppl):11S–18S. doi: 10.1016/S0002-9610(01)00782-6.
    1. Ishihara M, Ikesue H, Matsunaga H, et al. A multi-institutional study analyzing effect of prophylactic medication for prevention of opioid-induced gastrointestinal dysfunction. Clin J Pain. 2012;28(5):373–381. doi: 10.1097/AJP.0b013e318237d626.
    1. Miles CL, Fellowes D, Goodman ML, Wilkinson S. Laxatives for the management of constipation in palliative care patients. Cochrane Database Syst Rev. 2006;(4):CD003448.
    1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Adult Cancer Pain. V 2.2013. . Accessed 2 Jan 2014.
    1. Manara L, Bianchi G, Ferretti P, et al. Inhibition of gastrointestinal transit by morphine in rats results primarily from direct drug action on gut opioid sites. J Pharmacol Exp Ther. 1986;237(3):945–949.
    1. Mori T, Shibasaki Y, Matsumoto K, et al. Mechanisms that underlie µ-opioid receptor agonist-induced constipation: differential involvement of µ-opioid receptor sites and responsible regions. J Pharmacol Exp Ther. 2013;347(1):91–99. doi: 10.1124/jpet.113.204313.
    1. Parolaro D, Sala M, Gori E. Effect of intracerebroventricular administration of morphine upon intestinal motility in rate and its antagonism with naloxone. Eur J Pharmacol. 1977;46:329–338. doi: 10.1016/0014-2999(77)90227-8.
    1. Stewart JJ, Weisbrodt NW, Burks TF. Central and peripheral actions of morphine on intestinal transit. J Pharmacol Exp Ther. 1978;205(3):547–555.
    1. Porecca F, Cowan A, Raffa RB, et al. Ketazocines and morphine: effects on gastrointestinal transit after central and peripheral administration. Life Sci. 1983;32:1785–1790. doi: 10.1016/0024-3205(83)90843-3.
    1. Thorn SE, Wattwil M, Lindberg G, et al. Systemic and central effects of morphine on gastroduodenal motility. Acta Anaesthesiol Scand. 1996;40:177–186. doi: 10.1111/j.1399-6576.1996.tb04417.x.
    1. Iyer S, Davis KL, Candrilli S. Opioid use patterns and health care resource utilization in patients prescribed opioid therapy with and without constipation. Manag Care. 2010;19(3):44–51.
    1. Kwong WJ, Diels J, Kavanagh S. Costs of gastrointestinal events after outpatient opioid treatment for non-cancer pain. Ann Pharmacother. 2010;44(4):630–640. doi: 10.1345/aph.1M520.
    1. Gregorian RS, Jr, Gasik A, Kwong WJ, Voeller S, Kavanagh S. Importance of side effects in opioid treatment: a trade-off analysis with patients and physicians. J Pain. 2010;11(11):1095–1108. doi: 10.1016/j.jpain.2010.02.007.
    1. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113–130. doi: 10.1016/j.jpain.2008.10.008.
    1. Tack J. Current and future therapies for chronic constipation. Best Pract Res Clin Gastroenterol. 2011;25(1):151–158. doi: 10.1016/j.bpg.2011.01.005.
    1. Ford AC, Brenner DM, Schoenfeld PS. Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(10):1566–74; quiz 1575.
    1. Holzer P. Opioid antagonists for prevention and treatment of opioid-induced gastrointestinal effects. Curr Opin Anaesthesiol. 2010;23(5):616–622. doi: 10.1097/ACO.0b013e32833c3473.
    1. Wyeth Pharmaceuticals Inc. Relistor. Prescribing information. Philadelphia: Wyeth Pharmaceuticals Inc.; 2010.
    1. Yuan CS, Foss JF, O’Connor M, et al. Effects of enteric-coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time. Clin Pharmacol Ther. 2000;67(4):398–404. doi: 10.1067/mcp.2000.105037.
    1. Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial. JAMA. 2000;283(3):367–372. doi: 10.1001/jama.283.3.367.
    1. Cubist Pharmaceuticals, Inc. Entereg. Prescribing information. Lexington: Cubist Pharmaceuticals, Inc.; 2008.
    1. Ahmedzai SH, Boland J. Constipation in people prescribed opioids. Clin Evid. 2010;04:2407.
    1. Leppert W. The impact of opioid analgesics on the gastrointestinal tract function and the current management possibilities. Wspolczesna Onkol. 2012;16(2):125–131. doi: 10.5114/wo.2012.28792.
    1. Weinstein SH, Pfeffer M, Schor JM, Indindoli L, Mintz M. Metabolites of naloxone in human urine. J Pharm Sci. 1971;60(10):1567–1568. doi: 10.1002/jps.2600601030.
    1. Cubitt HE, Houston JB, Galetin A. Relative importance of intestinal and hepatic glucuronidation-impact on the prediction of drug clearance. Pharm Res. 2009;26(5):1073–1083. doi: 10.1007/s11095-008-9823-9.
    1. Napp Pharmaceuticals Limited. Targinact. Prescribing information. Cambridge: Napp Pharmaceuticals Limited; 2012.
    1. 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. doi: 10.1177/026921639601000208.
    1. Meissner W, Schmidt U, Hartmann M, Kath R, Reinhart K. Oral naloxone reverses opioid-associated constipation. Pain. 2000;84(1):105–109. doi: 10.1016/S0304-3959(99)00185-2.
    1. Kaufman PN, Krevsky B, Malmud LS, et al. Role of opiate receptors in the regulation of colonic transit. Gastroenterology. 1988;94(6):1351–1356.
    1. 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. doi: 10.1016/j.clinthera.2008.11.008.
    1. Müller-Lissner S, Leyendecker P, Hopp M, Ruckes C, Fleischer W, Reimer K. Oral prolonged release (PR) oxycodone/naloxone combination reduces opioid-induced bowel dysfunction (OIBD) in patients with severe chronic pain. Eur J Pain. 2007;11(Suppl 1):S82. doi: 10.1016/j.ejpain.2007.03.204.
    1. 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. doi: 10.1016/j.jpain.2008.06.014.
    1. 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. doi: 10.1185/03007990802584454.
    1. Löwenstein 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. doi: 10.1517/14656560902796798.
    1. Nadstawek J, Leyendecker P, Hopp M, et al. Patient assessment of a novel therapeutic approach for the treatment of severe, chronic pain. Int J Clin Pract. 2008;62(8):1159–1167. doi: 10.1111/j.1742-1241.2008.01820.x.
    1. Ahmedzai SH, Nauck F, Bar-Sela G, Bosse B, Leyendecker P, Hopp M. A randomized, double-blind, 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. doi: 10.1177/0269216311418869.
    1. Ueberall MA, Müller-Lissner S, Buschmann-Kramm C, Bosse B. The Bowel Function Index for evaluating constipation in pain patients: definition of a reference range for a non-constipated population of pain patients. J Int Med Res. 2011;39(1):41–50. doi: 10.1177/147323001103900106.
    1. Rentz AM, Yu R, Müller-Lissner S, Leyendecker P. Validation of the Bowel Function Index to detect clinically meaningful changes in opioid-induced constipation. J Med Econ. 2009;12(4):371–383. doi: 10.3111/13696990903430481.
    1. Foundation Rome. Guidelines—Rome III diagnostic criteria for functional gastrointestinal disorders. J Gastrointest Liver Dis. 2006;15(3):307–312.
    1. Sandner-Kiesling A, Leyendecker P, Hopp M, et al. Long-term efficacy and safety of combined prolonged-release oxycodone and naloxone in the management of non-cancer chronic pain. Int J Clin Pract. 2010;64(6):763–774. doi: 10.1111/j.1742-1241.2010.02360.x.
    1. Löwenstein O, Leyendecker P, Lux EA, et al. Efficacy and safety of combined prolonged-release oxycodone and naloxone in the management of moderate/severe chronic non-malignant pain: results of a prospectively designed pooled analysis of two randomised, double-blind clinical trials. BMC Clin Pharmacol. 2010;10:12. doi: 10.1186/1472-6904-10-12.
    1. Cloutier C, Taliano J, O’Mahony W, et al. Controlled-release oxycodone and naloxone in the treatment of chronic low back pain: a placebo-controlled, randomized study. Pain Res Manag. 2013;18(2):75–82.
    1. Kuusniemi K, Zollner J, Sjovall S, et al. Prolonged-release oxycodone/naloxone in postoperative pain management: from a randomized clinical trial to usual clinical practice. J Int Med Res. 2012;40(5):1775–1793. doi: 10.1177/030006051204000516.
    1. Davis M, Goforth HW, Gamier P. Oxycodone combined with opioid receptor antagonists: efficacy and safety. Expert Opin Drug Saf. 2013;12(3):389–402. doi: 10.1517/14740338.2013.783564.
    1. Lesaffre E. Superiority, equivalence, and non-inferiority trials. Bull NYU Hosp Jt Dis. 2008;66(2):150–154.
    1. Schutter U, Grunert S, Meyer C, Schmidt T, Nolte T. Innovative pain therapy with a fixed combination of prolonged-release oxycodone/naloxone: a large observational study under conditions of daily practice. Curr Med Res Opin. 2010;26(6):1377–1387. doi: 10.1185/03007991003787318.
    1. Hermanns K, Junker U, Nolte T. Prolonged-release oxycodone/naloxone in the treatment of neuropathic pain—results from a large observational study. Expert Opin Pharmacother. 2012;13(3):299–311. doi: 10.1517/14656566.2012.648615.
    1. Cuomo A, Russo G, Esposito G, Forte CA, Connola M, Marcassa C. Efficacy and gastrointestinal tolerability of oral oxycodone/naloxone combination for chronic pain in outpatients with cancer: an observational study. Am J Hosp Palliat Care. 2013. (Epub ahead of print).
    1. Lazzari M, Sabato AF, Caldarulo C, et al. Effectiveness and tolerability of low-dose oral oxycodone/naloxone added to anticonvulsant therapy for noncancer neuropathic pain: an observational analysis. Curr Med Res Opin. 2014;30(4):555–564. doi: 10.1185/03007995.2013.866545.
    1. Gatti A, Casali M, Lazzari M, et al. Prolonged-release oxycodone/naloxone in nonmalignant pain: single-center study in patients with constipation. Adv Ther. 2013;30(1):41–59. doi: 10.1007/s12325-012-0074-0.
    1. Comelon M, Wisloeff-Aase K, Raeder J, et al. A comparison of oxycodone prolonged-release vs. oxycodone + naloxone prolonged-release after laparoscopic hysterectomy. Acta Anaesthesiol Scand. 2013;57(4):509–517. doi: 10.1111/aas.12051.
    1. Ruetzler K, Blome CJ, Nabecker S, et al. A randomised trial of oral versus intravenous opioids for treatment of pain after cardiac surgery. J Anesth. 2013. (Epub ahead of print).
    1. Mercadante S, Ferrera P, Adile C. High doses of oxycodone-naloxone combination may provide poor analgesia. Support Care Cancer. 2011;19(9):1471–1472. doi: 10.1007/s00520-011-1205-x.
    1. Dunlop W, Uhl R, Khan I, Taylor A, Barton G. Quality of life benefits and cost impact of prolonged release oxycodone/naloxone versus prolonged release oxycodone in patients with moderate-to-severe non-malignant pain and opioid-induced constipation: a UK cost-utility analysis. J Med Econ. 2012;15(3):564–575. doi: 10.3111/13696998.2012.665279.
    1. Gálvez R, Provencio M, Sanz-Ortiz J, et al. Análisis económico de oxicodona LP/naloxona LP en el manejo del dolor intense y el estreñimiento asociado al tratamiento con opioids en España. Pharmacoeconomics – Spanish Research Articles. 2012;9(1):21–32.
    1. Rychlik R, Kiencke P, Kresimon J. Health services research on HRQ oL and pharmacoeconomics of low back pain patients treated with oxycodone/naloxone or other Step III opioids. Gesundh ökon Qual Manag. 2011;16:S10–S19. doi: 10.1055/s-0029-1246102.
    1. Rychlik R, Viehmann K, Daniel D, Kiencke P, Kresimon J. Pain management and costs of a combination of oxycodone + naloxone in low back pain patients. In: Racz G (ed) Pain management—current issues and opinions. 2012. ISBN: 978-953-307-813-7. . Accessed 8 Feb 2014.
    1. Gerlier L, Lamotte M, Van Megen Y. Treatment of moderate to severe pain with oxycodone/naloxone to reduce opioid-induced constipation: a cost-utility analysis in Belgium and the Netherlands (abstract PG115) Value Health. 2009;12(7):A348. doi: 10.1016/S1098-3015(10)74711-2.
    1. Australian Government Department of Health and Ageing Therapeutic Goods Administration. Australian Public Assessment Report for oxycodone hydrochloride/naloxone hydrochloride. Submission No: PM-2008-2938-1. May 2010. . Accessed 24 Dec 2013.
    1. Ishihara M, Iihara H, Okayasu S, et al. Pharmaceutical interventions facilitate premedication and prevent opioid-induced constipation and emesis in cancer patients. Support Care Cancer. 2010;18(12):1531–1538. doi: 10.1007/s00520-009-0775-3.
    1. Leppert W. Oxycodone/naloxone in the management of patients with pain and opioid-induced bowel dysfunction. Curr Drug Targets. 2014;15(1):124–135. doi: 10.2174/13894501113149990210.
    1. 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. doi: 10.5414/CP201646.
    1. Wilcock A. Prolonged-release naloxone can cause systemic opioid withdrawal. Eur J Pain. 2009;13(9):1001. doi: 10.1016/j.ejpain.2009.05.018.
    1. Compagnone C, Tagliaferri F, Ramelli A. Some concerns about the article: “High doses of oxycodone-naloxone combination may provide poor analgesia.”. Support Care Cancer. 2012;20(5):889–890. doi: 10.1007/s00520-011-1346-y.
    1. Mercadante S. Clarifications on oxycodone-naloxone combination in cancer pain management. Support Care Cancer. 2012;20(7):1351–1352. doi: 10.1007/s00520-012-1449-0.
    1. Kang JH, Lee GW, Shin SH, Bruera E. Opioid withdrawal syndrome after treatment with low-dose extended-release oxycodone and naloxone in a gastric cancer patient with portal vein thrombosis. J Pain Symptom Manage. 2013;46(2):e15–e17. doi: 10.1016/j.jpainsymman.2013.02.009.
    1. Trenkwalder C, Benes H, Grote L, et al. Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension. Lancet Neurol. 2013;12(12):1141–1150. doi: 10.1016/S1474-4422(13)70239-4.
    1. Centers for Disease Control and Prevention (CDC) CDC grand rounds: prescription drug overdoses—a U.S. epidemic. MMWR Morb Mortal Wkly Rep. 2012;61(1):10–13.
    1. Kirschner N, Ginsburg J, Sulmasy LS. Prescription drug abuse: a policy position paper from the American College of Physicians. Ann Intern Med. 2014;160(3):198. doi: 10.7326/M13-2209.
    1. Kirsh K, Peppin J, Coleman J. Characterization of prescription opioid abuse in the United States: focus on route of administration. J Pain Palliat Care Pharmacother. 2012;26(4):348–361. doi: 10.3109/15360288.2012.734905.
    1. Cicero TJ, Ellis MS, Surratt HL, Kurtz SP. Factors influencing the selection of hydrocodone and oxycodone as primary opioids in substance abusers seeking treatment in the United States. Pain. 2013;154(12):2639–2648. doi: 10.1016/j.pain.2013.07.025.
    1. Cassidy TA, Dasmahapatra P, Black RA, Wieman MS, Butler SF. Changes in prevalence of prescription opioid abuse after introduction of an abuse-deterrent opioid formulation. Pain Med. 2014;15(3):440–451. doi: 10.1111/pme.12295.
    1. Mercadante S, Craig D, Giarratano A. US Food and Drug Administration’s Risk Evaluation and Mitigation Strategy for extended-release and long-acting opioids: pros and cons, and a European perspective. Drugs. 2012;72(18):2327–2332. doi: 10.2165/11642230-000000000-00000.
    1. Stanos SP. Strategies to reduce the tampering and subsequent abuse of long-acting opioids: potential risks and benefits of formulations with physical or pharmacologic deterrents to tampering. Mayo Clin Proc. 2012;87(7):683–694. doi: 10.1016/j.mayocp.2012.02.022.
    1. Coplan PM, Kale H, Sandstrom L, Landau C, Chilcoat HD. 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. doi: 10.1002/pds.3522.
    1. Severtson SG, Bartelson BB, Davis JM, et al. Reduced abuse, therapeutic errors, and diversion following reformulation of extended-release oxycodone in 2010. J Pain. 2013;14(10):1122–1130. doi: 10.1016/j.jpain.2013.04.011.
    1. Tompkins DA, Lanier RK, Harrison JA, Strain EC, Bigelow GE. Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone. Psychopharmacology. 2010;210(4):471–480. doi: 10.1007/s00213-010-1838-3.
    1. Colucci S, Perrino P, Shram M, Bartlett C, Wang Y, Harris S. Abuse potential of oxycodone/naloxone solution administered intravenously in nondependent recreational drug users with moderate opioid experience (abstract). Presented at PAINWeek, September 2013. . Accessed 6 Feb 2014.
    1. Harris S, Perrino P, Shram M, Bartlett C, Colucci S, Wang Y. Abuse potential of oxycodone/naloxone (OXN) tablets administered intranasally in nondependent recreational drug users with moderate opioid experience (abstract). Presented at PAINWeek, September 2013. . Accessed 6 Feb 2014.
    1. Wang Y, Perrino P, Bartlett C, et al. Abuse potential of chewed or intact oxycodone/naloxone (OXN) tablets in methadone-stabilized, opioid-dependent subjects when administered orally (abstract). Presented at PAINWeek, September 2013. . Accessed 6 Feb 2014.
    1. Perrino P, Colucci S, Shram M, et al. Relative attractiveness of oxycodone/naloxone (OXN): comparative assessment of tampering potential and recreational drug user preferences for different opioid formulations (abstract). Presented at PAINWeek, September 2013. . Accessed 6 Feb 2014.

Source: PubMed

3
구독하다