Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Prevention and management of side effects in patients receiving opioids for chronic pain

Russell K Portenoy, MD
Zankhana Mehta, MD
Ebtesam Ahmed, PharmD, MS
Section Editor
Janet Abrahm, MD
Deputy Editor
Diane MF Savarese, MD


Opioids represent a mainstay for treatment of severe chronic pain in patients with active cancer or other serious chronic illnesses. Although the side effect liability of these drugs is significant and they are inherently associated with the serious problems of drug abuse and addiction, experience in the management of cancer pain indicates that they can potentially be used safely and effectively for all types of pain (ie, somatic, visceral, neuropathic). (See "Cancer pain management with opioids: Optimizing analgesia" and "Cancer pain management: General principles and risk management for patients receiving opioids".)

The term “chronic non-cancer pain” is ill defined but generally understood to apply to common types of musculoskeletal pain syndromes, such as arthritis and low back pain, and to headache. The long-term use of opioid drugs for these conditions is more controversial. For patients with chronic non-cancer pain, the decision to begin opioid therapy must be weighed carefully. (See "Use of opioids in the management of chronic non-cancer pain" and "Overview of the treatment of chronic non-cancer pain".)

A trial of an opioid for long-term use may be considered when:

Other alternative therapies have not provided sufficient pain relief and

Pain is adversely affecting a patient’s function and/or quality of life and

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Oct 06, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Grunkemeier DM, Cassara JE, Dalton CB, Drossman DA. The narcotic bowel syndrome: clinical features, pathophysiology, and management. Clin Gastroenterol Hepatol 2007; 5:1126.
  2. Clemens KE, Klaschik E. Management of constipation in palliative care patients. Curr Opin Support Palliat Care 2008; 2:22.
  3. Candrilli SD, Davis KL, Iyer S. Impact of constipation on opioid use patterns, health care resource utilization, and costs in cancer patients on opioid therapy. J Pain Palliat Care Pharmacother 2009; 23:231.
  4. 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 Manag 2009; 5:137.
  5. 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; 13:737.
  6. 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; 13:254.
  7. van Seventer R, Smit JM, Schipper RM, et al. Comparison of TTS-fentanyl with sustained-release oral morphine in the treatment of patients not using opioids for mild-to-moderate pain. Curr Med Res Opin 2003; 19:457.
  8. Wong JO, Chiu GL, Tsao CJ, Chang CL. Comparison of oral controlled-release morphine with transdermal fentanyl in terminal cancer pain. Acta Anaesthesiol Sin 1997; 35:25.
  9. Tassinari D, Sartori S, Tamburini E, et al. Transdermal fentanyl as a front-line approach to moderate-severe pain: a meta-analysis of randomized clinical trials. J Palliat Care 2009; 25:172.
  10. Tassinari D, Sartori S, Tamburini E, et al. Adverse effects of transdermal opiates treating moderate-severe cancer pain in comparison to long-acting morphine: a meta-analysis and systematic review of the literature. J Palliat Med 2008; 11:492.
  11. Ahmedzai SH, Nauck F, Bar-Sela G, et al. 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; 26:50.
  12. Mearin F, Lacy BE, Chang L, et al. Bowel Disorders. Gastroenterology 2016.
  13. Candy B, Jones L, Goodman ML, et al. Laxatives or methylnaltrexone for the management of constipation in palliative care patients. Cochrane Database Syst Rev 2011; :CD003448.
  14. Bharucha AE, Pemberton JH, Locke GR 3rd. American Gastroenterological Association technical review on constipation. Gastroenterology 2013; 144:218.
  15. Tarumi Y, Wilson MP, Szafran O, Spooner GR. Randomized, double-blind, placebo-controlled trial of oral docusate in the management of constipation in hospice patients. J Pain Symptom Manage 2013; 45:2.
  16. Teuri U, Vapaatalo H, Korpela R. Fructooligosaccharides and lactulose cause more symptoms in lactose maldigesters and subjects with pseudohypolactasia than in control lactose digesters. Am J Clin Nutr 1999; 69:973.
  17. Argoff CE, Brennan MJ, Camilleri M, et al. Consensus Recommendations on Initiating Prescription Therapies for Opioid-Induced Constipation. Pain Med 2015; 16:2324.
  18. 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; 12:371.
  19. 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; 108:1566.
  20. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 2008; 358:2332.
  21. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study. J Pain 2011; 12:554.
  22. 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; 283:367.
  23. Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. J Support Oncol 2009; 7:39.
  24. Anissian L, Schwartz HW, Vincent K, et al. Subcutaneous methylnaltrexone for treatment of acute opioid-induced constipation: phase 2 study in rehabilitation after orthopedic surgery. J Hosp Med 2012; 7:67.
  25. Rauck R, Peppin J, Israel R, et al.. Oral methylnaltrexone for the treatment of opioid induced constipation in patients with noncancer pain. Gastroenterology 2012; 142 (suppl1):S160.
  26. Dutka J, Lowe SS, Michaud M, Watanabe S. Long-term use of methylnaltrexone for the management of constipation in advanced cancer. J Support Oncol 2009; 7:177.
  27. Webster LR, Michna E, Khan A, et al. Long-Term Safety and Efficacy of Subcutaneous Methylnaltrexone in Patients with Opioid-Induced Constipation and Chronic Noncancer Pain: A Phase 3, Open-Label Trial. Pain Med 2017; 18:1496.
  28. Rauck R, Slatkin NE, Stambler N, et al. Randomized, Double-Blind Trial of Oral Methylnaltrexone for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain. Pain Pract 2017; 17:820.
  29. Webster L, Peppin J, Harper J, Israel R. (480) Oral methylnaltrexone does not negatively impact analgesia in patients with opioid-induced constipation and chronic noncancer pain. J Pain 2016; 17:S94.
  30. Yuan CS, Foss JF. Oral methylnaltrexone for opioid-induced constipation. JAMA 2000; 284:1383.
  31. Centeno C, Carranza O, Zuriarrain Y, et al. A prospective study of methylnaltrexone for opioid-induced constipation in advanced illness: should we use it or not? J Pain Symptom Manage 2013; 46:e1.
  32. Slatkin NE, Lynn R, Su C, et al. Characterization of abdominal pain during methylnaltrexone treatment of opioid-induced constipation in advanced illness: a post hoc analysis of two clinical trials. J Pain Symptom Manage 2011; 42:754.
  33. Watkins JL, Eckmann KR, Mace ML, et al. Utilization of methylnaltrexone (relistor) for opioid-induced constipation in an oncology hospital. P T 2011; 36:33.
  34. Chey WD, Webster L, Sostek M, et al. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med 2014; 370:2387.
  35. Hale ME, Wild J, Reddy J, et al. Efficacy and Safety of Naldemedine for the treatment of opioid-induced constipation in subjects with chronic non-cancer pain receiving opioid therapy: results from two Phase 3 clinical trials (abstract 598). Data presented at the 2016 Digestive Disease Week, San Diego, CA, May 21, 2016. Abstract available online at http://www.gastrojournal.org/article/S0016-5085(16)30515-7/pdf (Accessed on March 30, 2017).
  36. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/208854Orig1s000ltr.pdf (Accessed on March 30, 2017).
  37. Katakami N, Harada T, Murata T, et al. Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer. J Clin Oncol 2017; 35:3859.
  38. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/EMEA-001893-PIP01-15/pip_001533.jsp&mid=WC0b01ac058001d129 (Accessed on March 30, 2017).
  39. Culpepper-Morgan JA, Inturrisi CE, Portenoy RK, et al. Treatment of opioid-induced constipation with oral naloxone: a pilot study. Clin Pharmacol Ther 1992; 52:90.
  40. Sykes NP. An investigation of the ability of oral naloxone to correct opioid-related constipation in patients with advanced cancer. Palliat Med 1996; 10:135.
  41. Jansen JP, Lorch D, Langan J, et al. A randomized, placebo-controlled phase 3 trial (Study SB-767905/012) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain. J Pain 2011; 12:185.
  42. Paulson DM, Kennedy DT, Donovick RA, et al. Alvimopan: an oral, peripherally acting, mu-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction--a 21-day treatment-randomized clinical trial. J Pain 2005; 6:184.
  43. Alvimopan prescribing information available online at http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=77a67dc6-35d3-48ff-9d18-292d4d442f70 (Accessed on October 15, 2014).
  44. 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; 24:3503.
  45. 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; 10:531.
  46. Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J Pain Symptom Manage 2002; 23:48.
  47. 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; 13:56.
  48. Sanders M, Jones S, Löwenstein O, et al. New Formulation of Sustained Release Naloxone Can Reverse Opioid Induced Constipation Without Compromising the Desired Opioid Effects. Pain Med 2015; 16:1540.
  49. Cryer B, Katz S, Vallejo R, et al. A randomized study of lubiprostone for opioid-induced constipation in patients with chronic noncancer pain. Pain Med 2014; 15:1825.
  50. Jamal MM, Adams AB, Jansen JP, Webster LR. A randomized, placebo-controlled trial of lubiprostone for opioid-induced constipation in chronic noncancer pain. Am J Gastroenterol 2015; 110:725.
  51. Dimidi E, Christodoulides S, Fragkos KC, et al. The effect of probiotics on functional constipation in adults: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr 2014; 100:1075.
  52. Davis M, Gamier P. New Options in Constipation Management. Curr Oncol Rep 2015; 17:55.
  53. Lacy BE, Schey R, Shiff SJ, et al. Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial. PLoS One 2015; 10:e0134349.
  54. Kurita GP, Sjøgren P, Ekholm O, et al. Prevalence and predictors of cognitive dysfunction in opioid-treated patients with cancer: a multinational study. J Clin Oncol 2011; 29:1297.
  55. Reissig JE, Rybarczyk AM. Pharmacologic treatment of opioid-induced sedation in chronic pain. Ann Pharmacother 2005; 39:727.
  56. Rozans M, Dreisbach A, Lertora JJ, Kahn MJ. Palliative uses of methylphenidate in patients with cancer: a review. J Clin Oncol 2002; 20:335.
  57. Wilwerding MB, Loprinzi CL, Mailliard JA, et al. A randomized, crossover evaluation of methylphenidate in cancer patients receiving strong narcotics. Support Care Cancer 1995; 3:135.
  58. Bruera E, Miller MJ, Macmillan K, Kuehn N. Neuropsychological effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain. Pain 1992; 48:163.
  59. Bruera E, Chadwick S, Brenneis C, et al. Methylphenidate associated with narcotics for the treatment of cancer pain. Cancer Treat Rep 1987; 71:67.
  60. Stone P, Minton O. European Palliative Care Research collaborative pain guidelines. Central side-effects management: what is the evidence to support best practice in the management of sedation, cognitive impairment and myoclonus? Palliat Med 2011; 25:431.
  61. Bruera E, Brenneis C, Paterson AH, MacDonald RN. Use of methylphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer. J Pain Symptom Manage 1989; 4:3.
  62. Cox JM, Pappagallo M. Modafinil: a gift to portmanteau. Am J Hosp Palliat Care 2001; 18:408.
  63. Webster L, Andrews M, Stoddard G. Modafinil treatment of opioid-induced sedation. Pain Med 2003; 4:135.
  64. Prommer E. Modafinil: is it ready for prime time? J Opioid Manag 2006; 2:130.
  65. Kreeger L, Duncan A, Cowap J. Psychostimulants used for opioid-induced drowsiness. J Pain Symptom Manage 1996; 11:1.
  66. Mercadante S, Serretta R, Casuccio A. Effects of caffeine as an adjuvant to morphine in advanced cancer patients. A randomized, double-blind, placebo-controlled, crossover study. J Pain Symptom Manage 2001; 21:369.
  67. Slatkin NE, Rhiner M, Bolton TM. Donepezil in the treatment of opioid-induced sedation: report of six cases. J Pain Symptom Manage 2001; 21:425.
  68. Bruera E, Strasser F, Shen L, et al. The effect of donepezil on sedation and other symptoms in patients receiving opioids for cancer pain: a pilot study. J Pain Symptom Manage 2003; 26:1049.
  69. Wiffen PJ, Derry S, Moore RA. Impact of morphine, fentanyl, oxycodone or codeine on patient consciousness, appetite and thirst when used to treat cancer pain. Cochrane Database Syst Rev 2014; :CD011056.
  70. Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 2001; 19:2542.
  71. McDonald PP, Graham M, Clayton A, et al. Regular subcutaneous bolus morphine via an indwelling cannula for pain from advanced cancer. Palliat Med 1991; 5:323.
  72. De Conno F, Ripamonti C, Saita L, et al. Role of rectal route in treating cancer pain: a randomized crossover clinical trial of oral versus rectal morphine administration in opioid-naive cancer patients with pain. J Clin Oncol 1995; 13:1004.
  73. Babul N, Provencher L, Laberge F, et al. Comparative efficacy and safety of controlled-release morphine suppositories and tablets in cancer pain. J Clin Pharmacol 1998; 38:74.
  74. Bruera E, Fainsinger R, Spachynski K, et al. Clinical efficacy and safety of a novel controlled-release morphine suppository and subcutaneous morphine in cancer pain: a randomized evaluation. J Clin Oncol 1995; 13:1520.
  75. Laugsand EA, Kaasa S, Klepstad P. Management of opioid-induced nausea and vomiting in cancer patients: systematic review and evidence-based recommendations. Palliat Med 2011; 25:442.
  76. Keeley PW. Nausea and vomiting in people with cancer and other chronic diseases. BMJ Clin Evid 2009; 2009.
  77. McNicol E, Horowicz-Mehler N, Fisk RA, et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain 2003; 4:231.
  78. Hardy J, Daly S, McQuade B, et al. A double-blind, randomised, parallel group, multinational, multicentre study comparing a single dose of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o. in the treatment of opioid-induced nausea and emesis in cancer patients. Support Care Cancer 2002; 10:231.
  79. Sussman G, Shurman J, Creed MR, et al. Intravenous ondansetron for the control of opioid-induced nausea and vomiting. International S3AA3013 Study Group. Clin Ther 1999; 21:1216.
  80. Chung F, Lane R, Spraggs C, et al. Ondansetron is more effective than metoclopramide for the treatment of opioid-induced emesis in post-surgical adult patients. Ondansetron OIE Post-Surgical Study Group. Eur J Anaesthesiol 1999; 16:669.
  81. Okamoto Y, Tsuneto S, Matsuda Y, et al. A retrospective chart review of the antiemetic effectiveness of risperidone in refractory opioid-induced nausea and vomiting in advanced cancer patients. J Pain Symptom Manage 2007; 34:217.
  82. Ferris FD, Kerr IG, Sone M, Marcuzzi M. Transdermal scopolamine use in the control of narcotic-induced nausea. J Pain Symptom Manage 1991; 6:389.
  83. Eisele JH Jr, Grigsby EJ, Dea G. Clonazepam treatment of myoclonic contractions associated with high-dose opioids: case report. Pain 1992; 49:231.
  84. Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain 2009; 25:170.
  85. Rhodin A, Stridsberg M, Gordh T. Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment. Clin J Pain 2010; 26:374.
  86. McWilliams K, Simmons C, Laird BJ, Fallon MT. A systematic review of opioid effects on the hypogonadal axis of cancer patients. Support Care Cancer 2014; 22:1699.
  87. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, 6th, American Pain Society, Glenview, IL 2008.
  88. Fine P, Portenoy RK. Opioid analgesia. New York: McGraw Hill, 2004. http://www.stoppain.org/pcd/content/forpros/opioidbook.asp (Accessed on April 21, 2011).
  89. Quigley C. Opioids in people with cancer-related pain. BMJ Clin Evid 2008; 2008.
  90. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on February 27, 2016).
  91. American Academy of Hospice and Palliative Medicine www.aahpm.org/certification/index.html (Accessed on April 21, 2011).
  92. Ganesh A, Maxwell LG. Pathophysiology and management of opioid-induced pruritus. Drugs 2007; 67:2323.
  93. Hermens JM, Ebertz JM, Hanifin JM, Hirshman CA. Comparison of histamine release in human skin mast cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology 1985; 62:124.
  94. Warner MA, Hosking MP, Gray JR, et al. Narcotic-induced histamine release: a comparison of morphine, oxymorphone, and fentanyl infusions. J Cardiothorac Vasc Anesth 1991; 5:481.
  95. Ko MC, Song MS, Edwards T, et al. The role of central mu opioid receptors in opioid-induced itch in primates. J Pharmacol Exp Ther 2004; 310:169.
  96. Zylicz Z, Smits C, Krajnik M. Paroxetine for pruritus in advanced cancer. J Pain Symptom Manage 1998; 16:121.
  97. Tarcatu D, Tamasdan C, Moryl N, Obbens E. Are we still scratching the surface? A case of intractable pruritus following systemic opioid analgesia. J Opioid Manag 2007; 3:167.
  98. Friedman JD, Dello Buono FA. Opioid antagonists in the treatment of opioid-induced constipation and pruritus. Ann Pharmacother 2001; 35:85.
  99. Yuan CS, Foss JF, O'Connor M, et al. Efficacy of orally administered methylnaltrexone in decreasing subjective effects after intravenous morphine. Drug Alcohol Depend 1998; 52:161.
  100. Verhamme KM, Sturkenboom MC, Stricker BH, Bosch R. Drug-induced urinary retention: incidence, management and prevention. Drug Saf 2008; 31:373.
  101. Chen YP, Chen SR, Pan HL. Systemic morphine inhibits dorsal horn projection neurons through spinal cholinergic system independent of descending pathways. J Pharmacol Exp Ther 2005; 314:611.
  102. Meyboom RH, Brodie-Meijer CC, Diemont WL, van Puijenbroek EP. Bladder dysfunction during the use of tramadol. Pharmacoepidemiol Drug Saf 1999; 8 Suppl 1:S63.
  103. Marret E, Kurdi O, Zufferey P, Bonnet F. Effects of nonsteroidal antiinflammatory drugs on patient-controlled analgesia morphine side effects: meta-analysis of randomized controlled trials. Anesthesiology 2005; 102:1249.
  104. Rømsing J, Møiniche S, Mathiesen O, Dahl JB. Reduction of opioid-related adverse events using opioid-sparing analgesia with COX-2 inhibitors lacks documentation: a systematic review. Acta Anaesthesiol Scand 2005; 49:133.
  105. Wang J, Pennefather S, Russell G. Low-dose naloxone in the treatment of urinary retention during extradural fentanyl causes excessive reversal of analgesia. Br J Anaesth 1998; 80:565.
  106. Malinovsky JM, Lepage JY, Karam G, Pinaud M. Nalbuphine reverses urinary effects of epidural morphine: a case report. J Clin Anesth 2002; 14:535.
  107. Mao J, Sung B, Ji RR, Lim G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 2002; 22:8312.
  108. Vanderah TW, Suenaga NM, Ossipov MH, et al. Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. J Neurosci 2001; 21:279.
  109. Mao J. Opioid-induced abnormal pain sensitivity. Curr Pain Headache Rep 2006; 10:67.
  110. Bannister K, Dickenson AH. Opioid hyperalgesia. Curr Opin Support Palliat Care 2010; 4:1.
  111. Tompkins DA, Campbell CM. Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon? Curr Pain Headache Rep 2011; 15:129.
  112. Fishbain DA, Cole B, Lewis JE, et al. Do opioids induce hyperalgesia in humans? An evidence-based structured review. Pain Med 2009; 10:829.
  113. Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin J Pain 2008; 24:479.
  114. Eisenberg E, Suzan E, Pud D. Opioid-induced hyperalgesia (OIH): a real clinical problem or just an experimental phenomenon? J Pain Symptom Manage 2015; 49:632.
  115. Arout CA, Edens E, Petrakis IL, Sofuoglu M. Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations. CNS Drugs 2015; 29:465.
  116. Induru RR, Davis MP. Buprenorphine for neuropathic pain--targeting hyperalgesia. Am J Hosp Palliat Care 2009; 26:470.