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Cancer pain management: Adjuvant analgesics (coanalgesics)

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

INTRODUCTION

Opioid therapy is the first-line approach for moderate or severe pain in populations with active cancer. If opioid therapy by itself yields a good outcome (satisfactory analgesia and tolerable side effects) additional interventions for pain are not needed. Should the patient demonstrate a poor response to the opioid, however, therapy must be changed. This common scenario may be addressed in many ways, among which is the addition of another analgesic drug. In some cases, the use of a nonopioid analgesic, such as acetaminophen (paracetamol) or a nonsteroidal antiinflammatory drug (NSAIDs), is sufficient. In others, significant benefit may be obtained by the addition of a so-called “adjuvant analgesic” or coanalgesic. This topic review will cover the use of adjuvant analgesics in cancer pain management. Assessment of cancer pain, a review of specific cancer pain syndromes, clinical use and side effects of opioid analgesics, use of acetaminophen and NSAIDs in patients with cancer pain, and nonpharmacologic methods of cancer pain management are covered elsewhere. (See "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'General principles of pain management' and "Cancer pain management with opioids: Optimizing analgesia" and "Cancer pain management: Use of acetaminophen and nonsteroidal antiinflammatory drugs".)

DEFINITION OF AN ADJUVANT ANALGESIC

The term “adjuvant analgesic” was originally coined to refer to a small number of drugs that were marketed for indications other than pain but were found to be potentially useful as analgesics in patients receiving opioid therapy. Over the past three decades, the number, diversity, and uses of these drugs have increased dramatically, and several are now indicated as first-line therapy for certain types of pain [1]. As a result, the term “adjuvant analgesic” has become somewhat of a misnomer, but it is still commonly applied in the context of cancer pain. The term is used interchangeably with the term “coanalgesic” and can be used to denote any drug with a major clinical use other than pain that is used as an analgesic in selected circumstances.

Integration into cancer pain management — In the 1980s, the World Health Organization (WHO) described an “analgesic ladder” approach to the use of drugs for cancer pain (figure 1) [2]. This influential model included references to adjuvant drugs that may be used to provide additional analgesia, treat a side effects, or manage a coexisting symptom. Specifically:

Step 1 of the analgesic ladder approach, which is appropriate for mild to moderate cancer-related pain, suggests the use of acetaminophen or a nonsteroidal antiinflammatory drug (NSAID), combined, if needed, with an adjuvant drug.

Step 2, which is appropriate for moderate cancer-related pain and pain that has not responded to step 1 drugs, includes the use of an opioid conventionally used for moderate pain, plus an adjuvant drug if needed.

                                           
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Literature review current through: Nov 2017. | This topic last updated: Dec 11, 2017.
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References
Top
  1. 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.
  2. World Health Organization. Cancer pain relief, 2nd, World Health Organization, Geneva 1996.
  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. Verdu B, Decosterd I, Buclin T, et al. Antidepressants for the treatment of chronic pain. Drugs 2008; 68:2611.
  16. 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.
  17. 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.
  18. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev 2007; :CD005454.
  19. Woolf CJ, American College of Physicians, American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004; 140:441.
  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. Gallagher HC, Gallagher RM, Butler M, et al. Venlafaxine for neuropathic pain in adults. Cochrane Database Syst Rev 2015; :CD011091.
  27. 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.
  28. 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.
  29. Semenchuk MR, Sherman S, Davis B. Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology 2001; 57:1583.
  30. Semenchuk MR, Davis B. Efficacy of sustained-release bupropion in neuropathic pain: an open-label study. Clin J Pain 2000; 16:6.
  31. Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA 2013; 309:1359.
  32. Wilson E, Lader M. A review of the management of antidepressant discontinuation symptoms. Ther Adv Psychopharmacol 2015; 5:357.
  33. Eisenach JC, DuPen S, Dubois M, et al. Epidural clonidine analgesia for intractable cancer pain. The Epidural Clonidine Study Group. Pain 1995; 61:391.
  34. Malanga GA, Gwynn MW, Smith R, Miller D. Tizanidine is effective in the treatment of myofascial pain syndrome. Pain Physician 2002; 5:422.
  35. 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.
  36. Prommer E. Review article: dexmedetomidine: does it have potential in palliative medicine? Am J Hosp Palliat Care 2011; 28:276.
  37. Smith HS, Barton AE. Tizanidine in the management of spasticity and musculoskeletal complaints in the palliative care population. Am J Hosp Palliat Care 2000; 17:50.
  38. Semenchuk MR, Sherman S. Effectiveness of tizanidine in neuropathic pain: an open-label study. J Pain 2000; 1:285.
  39. 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.
  40. Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. J Pain 2008; 9:164.
  41. 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.
  42. 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.
  43. 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.
  44. 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.
  45. 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.
  46. Wilsey B, Marcotte T, Deutsch R, et al. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 2013; 14:136.
  47. 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.
  48. 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.
  49. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA 2015; 313:2456.
  50. Hill KP. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review. JAMA 2015; 313:2474.
  51. 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.
  52. Nugent SM, Morasco BJ, O'Neil ME, et al. The Effects of Cannabis Among Adults With Chronic Pain and an Overview of General Harms: A Systematic Review. Ann Intern Med 2017; 167:319.
  53. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007; 68:515.
  54. 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.
  55. Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 2010; 182:E694.
  56. Furlow B. States and US Government spar over medical marijuana. Lancet Oncol 2012; 13:450.
  57. 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).
  58. 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).
  59. 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).
  60. Nevada Department of Health and Human Services. Medical Marijuana Program. Data available online at http://health.nv.gov/BudgetDocuments/2012-2013/MMPWHITEPAPR_FY11.pdf.
  61. Wallace MS, Marcotte TD, Umlauf A, et al. Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. J Pain 2015; 16:616.
  62. Bonn-Miller MO, Loflin MJE, Thomas BF, et al. Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA 2017; 318:1708.
  63. Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med 2014; 370:2219.
  64. Owen KP, Sutter ME, Albertson TE. Marijuana: respiratory tract effects. Clin Rev Allergy Immunol 2014; 46:65.
  65. Patel S, Williams JW Jr, Wallace RB. What We Do (and Don't) Know About the Health Effects of Cannabis and Whether Marijuana Is Medicine. Ann Intern Med 2017; 166:747.
  66. National Academies of Sciences, Engineering, and Medicine.. Health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. National Academies Pr; Washington DC, 2017.
  67. Derry S, Wiffen PJ, Moore RA, Quinlan J. Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev 2014; :CD010958.
  68. Rowbotham MC, Davies PS, Fields HL. Topical lidocaine gel relieves postherpetic neuralgia. Ann Neurol 1995; 37:246.
  69. Gammaitoni AR, Alvarez NA, Galer BS. Pharmacokinetics and safety of continuously applied lidocaine patches 5%. Am J Health Syst Pharm 2002; 59:2215.
  70. Gabra BH, Abidi MH, Al-Khadimi Z, et al. Systemic absorption of topical lidocaine in a bone marrow transplant recipient with hepatic sinusoidal obstruction syndrome. Am J Health Syst Pharm 2011; 68:135.
  71. De Martin S, Orlando R, Bertoli M, et al. Differential effect of chronic renal failure on the pharmacokinetics of lidocaine in patients receiving and not receiving hemodialysis. Clin Pharmacol Ther 2006; 80:597.
  72. Stow PJ, Glynn CJ, Minor B. EMLA cream in the treatment of post-herpetic neuralgia. Efficacy and pharmacokinetic profile. Pain 1989; 39:301.
  73. Jones VM, Moore KA, Peterson DM. Capsaicin 8% topical patch (Qutenza)--a review of the evidence. J Pain Palliat Care Pharmacother 2011; 25:32.
  74. Derry S, Lloyd R, Moore RA, McQuay HJ. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2009; :CD007393.
  75. 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.
  76. 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.
  77. Sommer C, Cruccu G. Topical Treatment of Peripheral Neuropathic Pain: Applying the Evidence. J Pain Symptom Manage 2017; 53:614.
  78. Burness CB, McCormack PL. Capsaicin 8 % Patch: A Review in Peripheral Neuropathic Pain. Drugs 2016; 76:123.
  79. Derry S, Wiffen PJ, Kalso EA, et al. Topical analgesics for acute and chronic pain in adults - an overview of Cochrane Reviews. Cochrane Database Syst Rev 2017; 5:CD008609.
  80. Ho KY, Huh BK, White WD, et al. Topical amitriptyline versus lidocaine in the treatment of neuropathic pain. Clin J Pain 2008; 24:51.
  81. McCleane G. Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study. Br J Clin Pharmacol 2000; 49:574.
  82. Barton DL, Wos EJ, Qin R, et al. A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Support Care Cancer 2011; 19:833.
  83. Sandrini G, De Icco R, Tassorelli C, et al. Botulinum neurotoxin type A for the treatment of pain: not just in migraine and trigeminal neuralgia. J Headache Pain 2017; 18:38.
  84. Bach CA, Wagner I, Lachiver X, et al. Botulinum toxin in the treatment of post-radiosurgical neck contracture in head and neck cancer: a novel approach. Eur Ann Otorhinolaryngol Head Neck Dis 2012; 129:6.
  85. Wang L, Lei QS, Liu YY, et al. A case report of the beneficial effects of botulinum toxin type A on Raynaud phenomenon in a patient with lung cancer. Medicine (Baltimore) 2016; 95:e5092.
  86. Rostami R, Mittal SO, Radmand R, Jabbari B. Incobotulinum Toxin-A Improves Post-Surgical and Post-Radiation Pain in Cancer Patients. Toxins (Basel) 2016; 8.
  87. Dworkin RH, O'Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007; 132:237.
  88. Paice JA, Portenoy R, Lacchetti C, et al. Management of Chronic Pain in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2016; 34:3325.
  89. 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.
  90. 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.
  91. 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.
  92. Bennett MI. Effectiveness of antiepileptic or antidepressant drugs when added to opioids for cancer pain: systematic review. Palliat Med 2011; 25:553.
  93. 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.
  94. Toth C. Substitution of gabapentin therapy with pregabalin therapy in neuropathic pain due to peripheral neuropathy. Pain Med 2010; 11:456.
  95. Hepner S, Claxton R. Anti-epileptic drugs for pain #271. J Palliat Med 2013; 16:799.
  96. Wiffen PJ, Derry S, Moore RA, Kalso EA. Carbamazepine for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2014; :CD005451.
  97. Wiffen PJ, Derry S, Moore RA, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews. Cochrane Database Syst Rev 2013; :CD010567.
  98. Wiffen PJ, Rees J. Lamotrigine for acute and chronic pain. Cochrane Database Syst Rev 2007; :CD006044.
  99. Demant DT, Lund K, Vollert J, et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study. Pain 2014; 155:2263.
  100. Hearn L, Derry S, Moore RA. Lacosamide for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012; :CD009318.
  101. 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.
  102. Wiffen PJ, Derry S, Lunn MP, Moore RA. Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2013; :CD008314.
  103. Yajnik S, Singh GP, Singh G, Kumar M. Phenytoin as a coanalgesic in cancer pain. J Pain Symptom Manage 1992; 7:209.
  104. Hardy JR, Rees EA, Gwilliam B, et al. A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain. J Pain Symptom Manage 2001; 21:204.
  105. 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.
  106. Garzón-Rodríguez C, Casals Merchan M, Calsina-Berna A, et al. Lidocaine 5 % patches as an effective short-term co-analgesic in cancer pain. Preliminary results. Support Care Cancer 2013; 21:3153.
  107. 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.
  108. Buchanan DD, J MacIvor F. A role for intravenous lidocaine in severe cancer-related neuropathic pain at the end-of-life. Support Care Cancer 2010; 18:899.
  109. Ben-Ari A, Lewis MC, Davidson E. Chronic administration of ketamine for analgesia. J Pain Palliat Care Pharmacother 2007; 21:7.
  110. 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.
  111. 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.
  112. Prommer EE. Ketamine for pain: an update of uses in palliative care. J Palliat Med 2012; 15:474.
  113. 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.
  114. 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.
  115. 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.
  116. 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.
  117. 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.
  118. 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.
  119. 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.
  120. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev 2017; 6:CD003351.
  121. Quibell R, Fallon M, Mihalyo M, et al. Ketamine. J Pain Symptom Manage 2015; 50:268.
  122. 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.
  123. 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.
  124. Chizh BA, Headley PM. NMDA antagonists and neuropathic pain--multiple drug targets and multiple uses. Curr Pharm Des 2005; 11:2977.
  125. Yomiya K, Matsuo N, Tomiyasu S, et al. Baclofen as an adjuvant analgesic for cancer pain. Am J Hosp Palliat Care 2009; 26:112.
  126. 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.
  127. Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev 2012; :CD003474.
  128. 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.
  129. 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.
  130. 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.
  131. 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.
  132. 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.
  133. 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.
  134. 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.
  135. 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.
  136. 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.
  137. Van Poznak C, Somerfield MR, Barlow W. J Clin Oncol 2017; 35.
  138. Martinez-Zapata MJ, Roque I, Figuls M, Alonso-Coello P. Calcitonin for metastatic bone pain. Cochrane Database Syst Rev 2012.