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Cancer pain management: Adjuvant analgesics (coanalgesics)

Russell K Portenoy, MD
Ebtesam Ahmed, PharmD, MS
Yair Y Keilson, MD
Section Editor
Janet Abrahm, MD
Deputy Editor
Diane MF Savarese, MD


Opioid therapy is the first-line approach for moderate or severe pain in populations with active cancer. However, the comprehensive management of pain in patients with cancer also requires expertise in the use of the nonopioid analgesics, such as acetaminophen (paracetamol), non-steroidal antiinflammatory agents (NSAIDs), and a group of drugs referred to as “adjuvant” analgesics or coanalgesics. The term “adjuvant analgesics” has been used to describe drugs that are marketed for indications other than pain, but are potentially useful as analgesics when added to opioid therapy in patients with chronic pain syndromes. In more recent years, some of these drugs have acquired approved indications for pain. (See "Cancer pain management with opioids: Optimizing analgesia" and "Cancer pain management: Use of acetaminophen and nonsteroidal antiinflammatory drugs".)

A stepwise approach to management of cancer pain that includes both opioid and nonopioid drugs has been codified in the World Health Organization’s (WHO) “analgesic ladder” approach to cancer pain management (figure 1) [1]:

Step 1, which represents mild to moderate cancer-related pain, suggests the use of acetaminophen or an NSAID, possibly combined with an adjuvant drug to provide additional analgesia, treat a side effect, or manage a coexisting symptom.

For patients with moderate or severe pain, and those who do not achieve adequate relief with acetaminophen or an NSAID alone, treatment with a step 2 opioid (conventionally used for moderate pain) or a step 3 opioid (conventionally used for severe pain) is appropriate. On both steps 2 and 3, the use of an acetaminophen or an NSAID should be considered, as well as other drugs (adjuvants) to enhance analgesia or treat side effects.

The analgesic ladder approach is not an evidence-based guideline, and its most important role in current practice has been to provide a framework for managing cancer pain that highlights the central importance of opioid drugs for patients with active disease, and the value of combination therapy, including the use of the adjuvant analgesics. (See "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'General principles of pain management'.)

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Literature review current through: Oct 2017. | This topic last updated: Mar 06, 2017.
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  1. World Health Organization. Cancer pain relief, 2nd, World Health Organization, Geneva 1996.
  2. Portenoy RK. Adjuvant analgesics in pain management. In: Textbook of Palliative Medicine, 4th, Hanks G, Cherny NI, Christakis N, Fallon M, Kaasa S, Portenoy RK (Eds), Oxford University Press, Oxford 2010. p.361.
  3. Mercadante S, Portenoy RK. Opioid poorly-responsive cancer pain. Part 3. Clinical strategies to improve opioid responsiveness. J Pain Symptom Manage 2001; 21:338.
  4. Kane CM, Mulvey MR, Wright S, et al. Opioids combined with antidepressants or antiepileptic drugs for cancer pain: Systematic review and meta-analysis. Palliat Med 2017; :269216317711826.
  5. Della Cuna GR, Pellegrini A, Piazzi M. Effect of methylprednisolone sodium succinate on quality of life in preterminal cancer patients: a placebo-controlled, multicenter study. The Methylprednisolone Preterminal Cancer Study Group. Eur J Cancer Clin Oncol 1989; 25:1817.
  6. Tannock I, Gospodarowicz M, Meakin W, et al. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol 1989; 7:590.
  7. Mercadante SL, Berchovich M, Casuccio A, et al. A prospective randomized study of corticosteroids as adjuvant drugs to opioids in advanced cancer patients. Am J Hosp Palliat Care 2007; 24:13.
  8. Popiela T, Lucchi R, Giongo F. Methylprednisolone as palliative therapy for female terminal cancer patients. The Methylprednisolone Female Preterminal Cancer Study Group. Eur J Cancer Clin Oncol 1989; 25:1823.
  9. Bruera E, Roca E, Cedaro L, et al. Action of oral methylprednisolone in terminal cancer patients: a prospective randomized double-blind study. Cancer Treat Rep 1985; 69:751.
  10. Bruera E, Moyano JR, Sala R, et al. Dexamethasone in addition to metoclopramide for chronic nausea in patients with advanced cancer: a randomized controlled trial. J Pain Symptom Manage 2004; 28:381.
  11. Paulsen O, Klepstad P, Rosland JH, et al. Efficacy of methylprednisolone on pain, fatigue, and appetite loss in patients with advanced cancer using opioids: a randomized, placebo-controlled, double-blind trial. J Clin Oncol 2014; 32:3221.
  12. Yennurajalingam S, Frisbee-Hume S, Palmer JL, et al. Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer. J Clin Oncol 2013; 31:3076.
  13. Basile A, Masala S, Banna G, et al. Intrasomatic injection of corticosteroid followed by vertebroplasty increases early pain relief rather than vertebroplasty alone in vertebral bone neoplasms: preliminary experience. Skeletal Radiol 2012; 41:459.
  14. Haywood A, Good P, Khan S, et al. Corticosteroids for the management of cancer-related pain in adults. Cochrane Database Syst Rev 2015; :CD010756.
  15. George R, Jeba J, Ramkumar G, et al. Interventions for the treatment of metastatic extradural spinal cord compression in adults. Cochrane Database Syst Rev 2008; :CD006716.
  16. Verdu B, Decosterd I, Buclin T, et al. Antidepressants for the treatment of chronic pain. Drugs 2008; 68:2611.
  17. Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain 1992; 49:205.
  18. Collins SL, Moore RA, McQuayHJ, Wiffen P. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage 2000; 20:449.
  19. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev 2007; :CD005454.
  20. Sindrup SH, Gram LF, Skjold T, et al. Concentration-response relationship in imipramine treatment of diabetic neuropathy symptoms. Clin Pharmacol Ther 1990; 47:509.
  21. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992; 326:1250.
  22. Sindrup SH, Bach FW, Madsen C, et al. Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial. Neurology 2003; 60:1284.
  23. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain 2004; 110:697.
  24. Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 2005; 119:5.
  25. Wernicke JF, Pritchett YL, D'Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 2006; 67:1411.
  26. Sindrup SH, Gram LF, Brøsen K, et al. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain 1990; 42:135.
  27. Sindrup SH, Bjerre U, Dejgaard A, et al. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther 1992; 52:547.
  28. Semenchuk MR, Sherman S, Davis B. Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology 2001; 57:1583.
  29. Semenchuk MR, Davis B. Efficacy of sustained-release bupropion in neuropathic pain: an open-label study. Clin J Pain 2000; 16:6.
  30. Wilson E, Lader M. A review of the management of antidepressant discontinuation symptoms. Ther Adv Psychopharmacol 2015; 5:357.
  31. Eisenach JC, DuPen S, Dubois M, et al. Epidural clonidine analgesia for intractable cancer pain. The Epidural Clonidine Study Group. Pain 1995; 61:391.
  32. Malanga GA, Gwynn MW, Smith R, Miller D. Tizanidine is effective in the treatment of myofascial pain syndrome. Pain Physician 2002; 5:422.
  33. Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesth Analg 2004; 98:153.
  34. Prommer E. Review article: dexmedetomidine: does it have potential in palliative medicine? Am J Hosp Palliat Care 2011; 28:276.
  35. Russo EB, Guy GW, Robson PJ. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers 2007; 4:1729.
  36. Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. J Pain 2008; 9:164.
  37. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ 2004; 329:253.
  38. Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005; 65:812.
  39. Johnson JR, Burnell-Nugent M, Lossignol D, et al. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage 2010; 39:167.
  40. Karst M, Salim K, Burstein S, et al. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 2003; 290:1757.
  41. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain 2008; 9:506.
  42. Wilsey B, Marcotte T, Deutsch R, et al. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 2013; 14:136.
  43. Bowles DW, O'Bryant CL, Camidge DR, Jimeno A. The intersection between cannabis and cancer in the United States. Crit Rev Oncol Hematol 2012; 83:1.
  44. Portenoy RK, Ganae-Motan ED, Allende S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain 2012; 13:438.
  45. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA 2015; 313:2456.
  46. Hill KP. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review. JAMA 2015; 313:2474.
  47. Andreae MH, Carter GM, Shaparin N, et al. Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data. J Pain 2015; 16:1221.
  48. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007; 68:515.
  49. GW Pharma, Ltd. A double-blind, randomized, placebo-controlled parallel group study of Sativex in the treatment of subjects with pain due to diabetic neuropathy. EU Clinical Trials Register . https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract-number:2004-002530-20. Accessed August 4, 2014.
  50. Langford RM, Mares J, Novotna A, et al. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. J Neurol 2013; 260:984.
  51. Nurmikko TJ, Serpell MG, Hoggart B, et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain 2007; 133:210.
  52. Selvarajah D, Gandhi R, Emery CJ, Tesfaye S. Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. Diabetes Care 2010; 33:128.
  53. Serpell M, Ratcliffe S, Hovorka J, et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain 2014; 18:999.
  54. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain 2008; 9:254.
  55. Frank B, Serpell MG, Hughes J, et al. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ 2008; 336:199.
  56. Pinsger M, Schimetta W, Volc D, et al. [Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain--a randomized controlled trial]. Wien Klin Wochenschr 2006; 118:327.
  57. Wissel J, Haydn T, Müller J, et al. Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain : a double-blind placebo-controlled cross-over trial. J Neurol 2006; 253:1337.
  58. Blake DR, Robson P, Ho M, et al. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford) 2006; 45:50.
  59. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009; 34:672.
  60. Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 2010; 182:E694.
  61. Furlow B. States and US Government spar over medical marijuana. Lancet Oncol 2012; 13:450.
  62. Montana Department of Health and Human Services. Montana Medical Marijuana Program. Data available online at http://www.dphhs.mt.gov/marijuanaprogram/ (Accessed on January 17, 2013).
  63. Colorado Department of Public Health and Environment. The ColoradoMedical Marijuana Registry. Data available online at http://www.cdphe.state.co.us.hs/medicalmarijuana/ (Accessed on January 17, 2013).
  64. Oregon Department of Human Services . The Oregon Medical Marijuana Program. Data available online at http://public.health.oregon.gov/diseasesconditions/chronicdisease/medicalmarijuanaprogram/Pages/index.aspx (Accessed on January 17, 2013).
  65. Nevada Department of Health and Human Services. Medical Marijuana Program. Data available online at http://health.nv.gov/BudgetDocuments/2012-2013/MMPWHITEPAPR_FY11.pdf.
  66. Wallace MS, Marcotte TD, Umlauf A, et al. Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. J Pain 2015; 16:616.
  67. Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med 2014; 370:2219.
  68. Owen KP, Sutter ME, Albertson TE. Marijuana: respiratory tract effects. Clin Rev Allergy Immunol 2014; 46:65.
  69. Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain 1999; 80:533.
  70. Barbano RL, Herrmann DN, Hart-Gouleau S, et al. Effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in diabetic polyneuropathy. Arch Neurol 2004; 61:914.
  71. Gammaitoni AR, Galer BS, Onawola R, et al. Lidocaine patch 5% and its positive impact on pain qualities in osteoarthritis: results of a pilot 2-week, open-label study using the Neuropathic Pain Scale. Curr Med Res Opin 2004; 20 Suppl 2:S13.
  72. Gammaitoni AR, Alvarez NA, Galer BS. Pharmacokinetics and safety of continuously applied lidocaine patches 5%. Am J Health Syst Pharm 2002; 59:2215.
  73. Stow PJ, Glynn CJ, Minor B. EMLA cream in the treatment of post-herpetic neuralgia. Efficacy and pharmacokinetic profile. Pain 1989; 39:301.
  74. Rowbotham MC, Davies PS, Fields HL. Topical lidocaine gel relieves postherpetic neuralgia. Ann Neurol 1995; 37:246.
  75. Jones VM, Moore KA, Peterson DM. Capsaicin 8% topical patch (Qutenza)--a review of the evidence. J Pain Palliat Care Pharmacother 2011; 25:32.
  76. Derry S, Lloyd R, Moore RA, McQuay HJ. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2009; :CD007393.
  77. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015; 14:162.
  78. Haanpää M, Cruccu G, Nurmikko TJ, et al. Capsaicin 8% patch versus oral pregabalin in patients with peripheral neuropathic pain. Eur J Pain 2016; 20:316.
  79. Sommer C, Cruccu G. Topical Treatment of Peripheral Neuropathic Pain: Applying the Evidence. J Pain Symptom Manage 2017; 53:614.
  80. Lin J, Zhang W, Jones A, Doherty M. Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials. BMJ 2004; 329:324.
  81. Hsieh LF, Hong CZ, Chern SH, Chen CC. Efficacy and side effects of diclofenac patch in treatment of patients with myofascial pain syndrome of the upper trapezius. J Pain Symptom Manage 2010; 39:116.
  82. Ho KY, Huh BK, White WD, et al. Topical amitriptyline versus lidocaine in the treatment of neuropathic pain. Clin J Pain 2008; 24:51.
  83. Dworkin RH, O'Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007; 132:237.
  84. Serpell MG, Neuropathic pain study group. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain 2002; 99:557.
  85. Caraceni A, Zecca E, Bonezzi C, et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol 2004; 22:2909.
  86. Frampton JE, Foster RH. Pregabalin: in the treatment of postherpetic neuralgia. Drugs 2005; 65:111.
  87. Dworkin RH, Corbin AE, Young JP Jr, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2003; 60:1274.
  88. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 2004; 110:628.
  89. Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev 2005; :CD005452.
  90. Vondracek P, Oslejskova H, Kepak T, et al. Efficacy of pregabalin in neuropathic pain in paediatric oncological patients. Eur J Paediatr Neurol 2009; 13:332.
  91. Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev 2009; :CD007076.
  92. Mishra S, Bhatnagar S, Goyal GN, et al. A comparative efficacy of amitriptyline, gabapentin, and pregabalin in neuropathic cancer pain: a prospective randomized double-blind placebo-controlled study. Am J Hosp Palliat Care 2012; 29:177.
  93. Rao RD, Michalak JC, Sloan JA, et al. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3). Cancer 2007; 110:2110.
  94. Toth C. Substitution of gabapentin therapy with pregabalin therapy in neuropathic pain due to peripheral neuropathy. Pain Med 2010; 11:456.
  95. Saif MW, Syrigos K, Kaley K, Isufi I. Role of pregabalin in treatment of oxaliplatin-induced sensory neuropathy. Anticancer Res 2010; 30:2927.
  96. Mańas A, Ciria JP, Fernández MC, et al. Post hoc analysis of pregabalin vs. non-pregabalin treatment in patients with cancer-related neuropathic pain: better pain relief, sleep and physical health. Clin Transl Oncol 2011; 13:656.
  97. Bennett MI, Laird B, van Litsenburg C, Nimour M. Pregabalin for the management of neuropathic pain in adults with cancer: a systematic review of the literature. Pain Med 2013; 14:1681.
  98. Keskinbora K, Pekel AF, Aydinli I. Gabapentin and an opioid combination versus opioid alone for the management of neuropathic cancer pain: a randomized open trial. J Pain Symptom Manage 2007; 34:183.
  99. Bennett MI. Effectiveness of antiepileptic or antidepressant drugs when added to opioids for cancer pain: systematic review. Palliat Med 2011; 25:553.
  100. Jongen JL, Huijsman ML, Jessurun J, et al. The evidence for pharmacologic treatment of neuropathic cancer pain: beneficial and adverse effects. J Pain Symptom Manage 2013; 46:581.
  101. Eisenberg E, River Y, Shifrin A, Krivoy N. Antiepileptic drugs in the treatment of neuropathic pain. Drugs 2007; 67:1265.
  102. Wiffen PJ, McQuay HJ, Moore RA. Carbamazepine for acute and chronic pain. Cochrane Database Syst Rev 2005; :CD005451.
  103. Wiffen PJ, Rees J. Lamotrigine for acute and chronic pain. Cochrane Database Syst Rev 2007; :CD006044.
  104. Nasreddine W, Beydoun A. Oxcarbazepine in neuropathic pain. Expert Opin Investig Drugs 2007; 16:1615.
  105. Bendaly EA, Jordan CA, Staehler SS, Rushing DA. Topiramate in the treatment of neuropathic pain in patients with cancer. Support Cancer Ther 2007; 4:241.
  106. Hugel H, Ellershaw JE, Dickman A. Clonazepam as an adjuvant analgesic in patients with cancer-related neuropathic pain. J Pain Symptom Manage 2003; 26:1073.
  107. Wymer JP, Simpson J, Sen D, et al. Efficacy and safety of lacosamide in diabetic neuropathic pain: an 18-week double-blind placebo-controlled trial of fixed-dose regimens. Clin J Pain 2009; 25:376.
  108. Tremont-Lukats IW, Challapalli V, McNicol ED, et al. Systemic administration of local anesthetics to relieve neuropathic pain: a systematic review and meta-analysis. Anesth Analg 2005; 101:1738.
  109. Challapalli V, Tremont-Lukats IW, McNicol ED, et al. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev 2005; :CD003345.
  110. Ben-Ari A, Lewis MC, Davidson E. Chronic administration of ketamine for analgesia. J Pain Palliat Care Pharmacother 2007; 21:7.
  111. Jackson K, Ashby M, Howell D, et al. The effectiveness and adverse effects profile of "burst" ketamine in refractory cancer pain: The VCOG PM 1-00 study. J Palliat Care 2010; 26:176.
  112. Jackson K, Ashby M, Martin P, et al. "Burst" ketamine for refractory cancer pain: an open-label audit of 39 patients. J Pain Symptom Manage 2001; 22:834.
  113. Prommer EE. Ketamine for pain: an update of uses in palliative care. J Palliat Med 2012; 15:474.
  114. Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage 2000; 20:246.
  115. Lauretti GR, Lima IC, Reis MP, et al. Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology 1999; 90:1528.
  116. Yang CY, Wong CS, Chang JY, Ho ST. Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain. Can J Anaesth 1996; 43:379.
  117. Lauretti GR, Gomes JM, Reis MP, Pereira NL. Low doses of epidural ketamine or neostigmine, but not midazolam, improve morphine analgesia in epidural terminal cancer pain therapy. J Clin Anesth 1999; 11:663.
  118. Salas S, Frasca M, Planchet-Barraud B, et al. Ketamine analgesic effect by continuous intravenous infusion in refractory cancer pain: considerations about the clinical research in palliative care. J Palliat Med 2012; 15:287.
  119. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol 2012; 30:3611.
  120. Ishizuka P, Garcia JB, Sakata RK, et al. Assessment of oral S+ ketamine associated with morphine for the treatment of oncologic pain. Rev Bras Anestesiol 2007; 57:19.
  121. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev 2012; 11:CD003351.
  122. Quibell R, Fallon M, Mihalyo M, et al. Ketamine. J Pain Symptom Manage 2015; 50:268.
  123. Jackson K, Franco M, William L, et al. Ketamine and cancer pain: the reports of my death have been greatly exaggerated. J Clin Oncol 2013; 31:1373.
  124. Okamoto Y, Tsuneto S, Tanimukai H, et al. Can gradual dose titration of ketamine for management of neuropathic pain prevent psychotomimetic effects in patients with advanced cancer? Am J Hosp Palliat Care 2013; 30:450.
  125. Chizh BA, Headley PM. NMDA antagonists and neuropathic pain--multiple drug targets and multiple uses. Curr Pharm Des 2005; 11:2977.
  126. Yomiya K, Matsuo N, Tomiyasu S, et al. Baclofen as an adjuvant analgesic for cancer pain. Am J Hosp Palliat Care 2009; 26:112.
  127. Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol 2012; 13:e58.
  128. Porta-Sales J, Garzón-Rodríguez C, Llorens-Torromé S, et al. Evidence on the analgesic role of bisphosphonates and denosumab in the treatment of pain due to bone metastases: A systematic review within the European Association for Palliative Care guidelines project. Palliat Med 2017; 31:5.
  129. Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev 2012; :CD003474.
  130. Hoskin P, Sundar S, Reczko K, et al. A Multicenter Randomized Trial of Ibandronate Compared With Single-Dose Radiotherapy for Localized Metastatic Bone Pain in Prostate Cancer. J Natl Cancer Inst 2015; 107.
  131. Hendriks LE, Hermans BC, van den Beuken-van Everdingen MH, et al. Effect of Bisphosphonates, Denosumab, and Radioisotopes on Bone Pain and Quality of Life in Patients with Non-Small Cell Lung Cancer and Bone Metastases: A Systematic Review. J Thorac Oncol 2016; 11:155.
  132. Cleeland CS, Body JJ, Stopeck A, et al. Pain outcomes in patients with advanced breast cancer and bone metastases: results from a randomized, double-blind study of denosumab and zoledronic acid. Cancer 2013; 119:832.
  133. Martin M, Bell R, Bourgeois H, et al. Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid. Clin Cancer Res 2012; 18:4841.
  134. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010; 28:5132.
  135. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377:813.
  136. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011; 29:1125.
  137. Patrick DL, Cleeland CS, von Moos R, et al. Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents. Support Care Cancer 2015; 23:1157.
  138. Vadhan-Raj S, von Moos R, Fallowfield LJ, et al. Clinical benefit in patients with metastatic bone disease: results of a phase 3 study of denosumab versus zoledronic acid. Ann Oncol 2012; 23:3045.
  139. Martinez-Zapata MJ, Roque I, Figuls M, Alonso-Coello P. Calcitonin for metastatic bone pain. Cochrane Database Syst Rev 2012.
  140. Frech EJ, Adler DG. Endoscopic therapy for malignant bowel obstruction. J Support Oncol 2007; 5:303.