HPRHealth Psychology ResearchTBA2420-8124Health Psychology Research10.52965/001c.25535GeneralKetamine for the Treatment of Chronic Pain: A Comprehensive  Review https://healthpr.org/journal/HPR/9/1/10.52965/001c.25535E. IsraelJacob,PierreSamantha St,EllisEmily,S. HanukaaiJosephine,NoorNazir,VarrassiGiustino,WellsMarkus,D. KayeAlan2021912021-07-09Background Chronic pain significantly worsens the quality of life. Unlike neuropathic, musculoskeletal, postoperative pain, and cancer pain, chronic primary pain cannot be explained by an underlying disease or condition, making its treatment arduous. Objectives This manuscript intends to provide a comprehensive review of the use of ketamine as a treatment option for specific chronic pain conditions. Study Design A review article. Setting A review of the literature. Methods A search was done on PubMed for relevant articles. Results A comprehensive review of the current understanding of chronic pain and the treatment of specific chronic pain conditions with ketamine. Limitations Literature is scarce regarding the use of ketamine for the treatment of chronic pain. Conclusion First-line treatment for many chronic pain conditions includes NSAIDs, antidepressants, anticonvulsants, and opioids. However, these treatment methods are unsuccessful in a subset of patients. Ketamine has been explored in randomized controlled trials (RCTs) as an alternative treatment option, and it has been demonstrated to improve pain symptoms, patient satisfaction, and quality of life. Conditions highlighted in this review include neuropathic pain, fibromyalgia, complex regional pain syndrome (CRPS), phantom limb pain (PLP), cancer pain, and post-thoracotomy pain syndrome. This review will discuss conditions, such as neuropathic pain, fibromyalgia, complex regional pain syndrome, and more and ketamine’s efficacy and its supplementary benefits in the chronic pain patient population. As the opioid crisis in the United States continues to persist, this review aims to understand better multimodal analgesia, which can improve how chronic pain is managed.depression, post-thoracotomy pain syndrome, cancer pain, fibromyalgia, phantom limb syndrome, complex regional pain syndrome, neuropathic pain, ketamine, chronic pain

1. Treede RD, Rief W, Barke A, et al. A classification of chronic pain for ICD-11. Pain. 2015;156(6):1003-1007. doi:10.1097/j.pain.0000000000000160 2. Johannes CB, Le TK, Zhou X, Johnston JA, Dworkin RH. The Prevalence of Chronic Pain in United States Adults: Results of an Internet-Based Survey. J Pain. 2010;11(11):1230-1239. doi:10.1016/j.jpain.2010.07.002 3. Treede RD, Rief W, Barke A, et al. Chronic pain as a symptom or a disease: The IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11). Pain. 2019;160(1):19-27. doi:10.1097/j.pain.0000000000001384 4. Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010;85(3 Suppl):S3-S14. doi:10.4065/mcp.2009.0649 5. Nicholas M, Vlaeyen JWS, Rief W, et al. The IASP classification of chronic pain for ICD-11: Chronic primary pain. Pain. 2019;160(1):28-37. doi:10.1097/j.pain.0000000000001390 6. Dureja GP, Jain PN, Shetty N, et al. prevalence of chronic pain, impact on daily life, and treatment practices in India. Pain Pract. 2014;14(2):E51-E62. doi:10.1111/papr.12132 7. Van Hecke O, Torrance N, Smith BH. Chronic pain epidemiology and its clinical relevance. Br J Anaesth. 2013;111(1):13-18. doi:10.1093/bja/aet123 8. Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults — United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67(36):1001-1006. doi:10.15585/mmwr.mm6736a2 9. Zorina-Lichtenwalter K, Meloto CB, Khoury S, Diatchenko L. Genetic predictors of human chronic pain conditions. Neuroscience. 2016;338:36-62. doi:10.1016/j.neuroscience.2016.04.041 10. Mills SEE, Nicolson KP, Smith BH. Chronic pain: a review of its epidemiology and associated factors in population-based studies. Br J Anaesth. 2019;123(2):e273-e283. doi:10.1016/j.bja.2019.03.023 11. Wiesenfeld-Hallin Z. Sex differences in pain perception. Gend Med. 2005;2(3):137-145. doi:10.1016/s1550-8579(05)80042-7 12. Sachs-Ericsson N, Kendall-Tackett K, Hernandez A. Childhood abuse, chronic pain, and depression in the National Comorbidity Survey. Child Abuse Negl. 2007;31(5):531-547. doi:10.1016/j.chiabu.2006.12.007 13. Jank R, Gallee A, Boeckle M, Fiegl S, Pieh C. Chronic Pain and Sleep Disorders in Primary Care. Pain Res Treat. 2017;2017:9081802. doi:10.1155/2017/9081802 14. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32(1):1-32. doi:10.1146/annurev.neuro.051508.135531 15. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2-S15. doi:10.1016/j.pain.2010.09.030 16. Johnson MI. The physiology of the sensory dimensions of clinical pain. Physiotherapy. 1997;83(10):526-536. doi:10.1016/s0031-9406(05)65610-6 17. Fields HL, Basbaum AI, Heinricher MM. Central nervous system mechanisms of pain modulation. In: Wall and Melzack’s Textbook of Pain. Elsevier; 2006:125-142. https://doi.org/10.1016/b0-443-07287-6/50012-6 18. Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest. 2010;120(11):3779-3787. doi:10.1172/jci43766 19. Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: A review. Anesth Analg. 2003;97(4):1108-1116. doi:10.1213/01.ane.0000081061.12235.55 20. Carlton SM, Coggeshall RE. Inflammation-induced changes in peripheral glutamate receptor populations. Brain Res. 1999;820(1-2):63-70. doi:10.1016/s0006-8993(98)01328-6 21. Gaunitz C, Schüttler A, Gillen C, Allgaier C. Formalin-induced changes of NMDA receptor subunit expression in the spinal cord of the rat. Amino Acids. 2002;23(1-3):177-182. doi:10.1007/s00726-001-01253-3 22. Jansen KLR. A review of the nonmedical use of ketamine: Use, users and consequences. J Psychoactive Drugs. 2000;32(4):419-433. doi:10.1080/02791072.2000.10400244 23. Morris H, Wallach J. From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. Drug Test Anal. 2014;6(7-8):614-632. doi:10.1002/dta.1620 24. Kronenberg RH. Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration. J Pain Palliat Care Pharmacother. 2002;16(3):27-35. doi:10.1080/j354v16n03_03 25. Domino EF. Taming the ketamine tiger. Anesthesiology. 2010;113(3):678-684. doi:10.1097/aln.0b013e3181ed09a2 26. Schwenk ES, Viscusi ER, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):456-466. doi:10.1097/aap.0000000000000806 27. Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):521-546. doi:10.1097/aap.0000000000000808 28. Sanacora G, Frye MA, McDonald W, et al. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry. 2017;74(4):399-405. doi:10.1001/jamapsychiatry.2017.0080 29. Caddy C, Amit BH, McCloud TL, et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev. 2015;(9):CD011612. doi:10.1002/14651858.cd011612.pub2 30. Kim J, Farchione T, Potter A, Chen Q, Temple R. Esketamine for Treatment-Resistant Depression — First FDA-Approved Antidepressant in a New Class. N Engl J Med. 2019;381(1):1-4. doi:10.1056/nejmp1903305 31. Hirota K, Lambert DG. Ketamine: its mechanism(s) of action and unusual clinical uses. Br J Anaesth. 1996;77(4):441-444. doi:10.1093/bja/77.4.441 32. Furukawa H, Singh SK, Mancusso R, Gouaux E. Subunit arrangement and function in NMDA receptors. Nature. 2005;438(7065):185-192. doi:10.1038/nature04089 33. Monyer H, Sprengel R, Schoepfer R, et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science. 1992;256(5060):1217-1221. doi:10.1126/science.256.5060.1217 34. Niesters M, Aarts L, Sarton E, Dahan A. Influence of ketamine and morphine on descending pain modulation in chronic pain patients: A randomized placebo-controlled cross-over proof-of-concept study. Br J Anaesth. 2013;110(6):1010-1016. doi:10.1093/bja/aes578 35. Hirota K, Lambert DG. Ketamine: new uses for an old drug? Br J Anaesth. 2011;107(2):123-126. doi:10.1093/bja/aer221 36. Bruehl S. Complex regional pain syndrome. BMJ. 2015;351:h2730. doi:10.1136/bmj.h2730 37. Schwartzman RJ. New treatments for reflex sympathetic dystrophy. N Engl J Med. 2000;343(9):654-656. doi:10.1056/nejm200008313430911 38. Sigtermans MJ, van Hilten JJ, Bauer MCR, et al. ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009;145(3):304-311. doi:10.1016/j.pain.2009.06.023 39. Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: A double-blind placebo-controlled study. Pain. 2009;147(1-3):107-115. doi:10.1016/j.pain.2009.08.015 40. Lee JY, Choi SH, Park KS, et al. comparison of complex regional pain syndrome and fibromyalgia. Medicine. 2019;98(7):e14452. doi:10.1097/md.0000000000014452 41. Chinn S, Caldwell W, Gritsenko K. Fibromyalgia Pathogenesis and Treatment Options Update. Curr Pain Headache Rep. 2016;20(4):25. doi:10.1007/s11916-016-0556-x 42. Clauw DJ. Fibromyalgia. JAMA. 2014;311(15):1547. doi:10.1001/jama.2014.3266 43. Noppers I, Niesters M, Swartjes M, et al. Absence of long-term analgesic effect from a short-term S-ketamine infusion on fibromyalgia pain: a randomized, prospective, double-blind, active placebo-controlled trial. Eur J Pain. 2011;15(9):942-949. doi:10.1016/j.ejpain.2011.03.008 44. Scholz J, Finnerup NB, Attal N, et al. The IASP classification of chronic pain for ICD-11: chronic neuropathic pain. Pain. 2019;160(1):53-59. doi:10.1097/j.pain.0000000000001365 45. Jensen TS, Madsen CS, Finnerup NB. Pharmacology and treatment of neuropathic pains. Curr Opin Neurol. 2009;22(5):467-474. doi:10.1097/wco.0b013e3283311e13 46. Park HJ, Moon DE. Pharmacologic Management of Chronic Pain. Korean J Pain. 2010;23(2):99-108. doi:10.3344/kjp.2010.23.2.99 47. Vranken JH, Dijkgraaf MGW, Kruis MR, Van Dasselaar NT, Van Der Vegt MH. Iontophoretic administration of S(+)-ketamine in patients with intractable central pain: A placebo-controlled trial. Pain. 2005;118(1-2):224-231. doi:10.1016/j.pain.2005.08.020 48. Rigo FK, Trevisan G, Godoy MC, et al. Management of neuropathic chronic pain with methadone combined with ketamine: a randomized, double-blind, active-controlled clinical trial. Pain Phys. 2017;20(3):207-215. doi:10.36076/ppj.2017.215 49. Jabbour HJ, Naccache NM, Jawish RJ, et al. Ketamine and magnesium association reduces morphine consumption after scoliosis surgery: Prospective randomised double-blind study. Acta Anaesthesiol Scand. 2014;58(5):572-579. doi:10.1111/aas.12304 50. Jabbour H, Jabbour K, Abi Lutfallah A, et al. Magnesium and Ketamine Reduce Early Morphine Consumption After Open Bariatric Surgery: a Prospective Randomized Double-Blind Study. Obes Surg. 2020;30(4):11695-11019. doi:10.1007/s11695-019-04317-1 51. Pickering G, Pereira B, Morel V, et al. Ketamine and Magnesium for Refractory Neuropathic Pain: A Randomized, Double-blind, Crossover Trial. Anesthesiol. 2020;133(1):154-164. doi:10.1097/aln.0000000000003345 52. Amr YM. Multi-day low dose ketamine infusion as adjuvant to oral gabapentin in spinal cord injury-related chronic pain: A prospective, randomized, double-blind trial. Pain Phys. 2010;13(3):245-249. doi:10.36076/ppj.2010/13/245 53. Mitchell AC, Fallon MT. A single infusion of intravenous ketamine improves pain relief in patients with critical limb ischaemia: Results of a double-blind randomised controlled trial. Pain. 2002;97(3):275-281. doi:10.1016/s0304-3959(02)00033-7 54. International Association for the Study of Pain, Subcommittee on Taxonomy. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Pain Suppl. 1986;3:S1-S226. 55. Moyse DW, Kaye AD, Diaz JH, Qadri MY, Lindsay D, Pyati S. Perioperative ketamine administration for thoracotomy pain. Pain Phys. 2017;20(3):173-184. doi:10.36076/ppj.2017.184 56. Mendola C, Cammarota G, Netto R, et al. S(+)-ketamine for control of perioperative pain and prevention of post-thoracotomy pain syndrome: A randomized, double-blind study. Minerva Anestesiol. 2012;78(7). 57. Dualé C, Sibaud F, Guastella V, et al. Perioperative ketamine does not prevent chronic pain after thoracotomy. Eur J Pain. 2009;13(5):497-505. doi:10.1016/j.ejpain.2008.06.013 58. Deng G. Integrative Medicine Therapies for Pain Management in Cancer Patients. Cancer J. 2019;25(5):343-348. doi:10.1097/ppo.0000000000000399 59. 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(29):3611-3617. doi:10.1200/jco.2012.42.1081 60. 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(3):287-293. doi:10.1089/jpm.2011.0353 61. Flor H. Phantom-limb pain: characteristics, causes, and treatment. Lancet Neurol. 2002;1(3):182-189. doi:10.1016/s1474-4422(02)00074-1 62. Nikolajsen L, Ilkjaer S, Christensen JH, Krøner K, Jensen TS. Randomised trial of epidural bupivacaine and morphine in prevention of stump and phantom pain in lower-limb amputation. Lancet. 1997;350(9088):1353-1357. doi:10.1016/s0140-6736(97)06315-0 63. Hayes C, Armstrong-Brown A, Burstal R. Perioperative intravenous ketamine infusion for the prevention of persistent post-amputation pain: a randomized, controlled trial. Anaesth Intensive Care. 2004;32(3):330-338. doi:10.1177/0310057x0403200305 64. Bone M, Critchley P, Buggy DJ. Gabapentin in postamputation phantom limb pain: A randomized, double-blind, placebo-controlled, cross-over study. Reg Anesth Pain Med. 2002;27(5):481-486. doi:10.1053/rapm.2002.35169 65. Nikolajsen L, Finnerup NB, Kramp S, Vimtrup AS, Keller J, Jensen TS. A randomized study of the effects of gabapentin on postamputation pain. Anesthesiology. 2006;105(5):1008-1015. doi:10.1097/00000542-200611000-00023 66. Wu CL, Tella P, Staats PS, et al. Analgesic effects of intravenous lidocaine and morphine on postamputation pain: a randomized double-blind, active placebo-controlled, crossover trial. Anesthesiology. 2002;96(4):841-848. doi:10.1097/00000542-200204000-00010 67. Huse E, Larbig W, Flor H, Birbaumer N. The effect of opioids on phantom limb pain and cortical reorganization. Pain. 2001;90(1-2):47-55. doi:10.1016/s0304-3959(00)00385-7 68. Nikolajsen L, Hansen CL, Nielsen J, Keller J, Arendt-Nielsen L, Jensen TS. The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. Pain. 1996;67(1):69-77. doi:10.1016/0304-3959(96)03080-1 69. Ben Abraham R, Marouani N, Weinbroum AA. Dextromethorphan mitigates phantom pain in cancer amputees. Ann Surg Oncol. 2003;10(3):268-274. doi:10.1245/aso.2003.08.007 70. Nikolajsen L, Gottrup H, Kristensen AGD, Jensen TS. Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: a randomized, double-blinded, crossover study. Anesth Analg. 2000;91(4):960-966. doi:10.1097/00000539-200010000-00036 71. Maier C, Dertwinkel R, Mansourian N, et al. Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain – results of a randomized double-blinded, placebo-controlled trial. Pain. 2003;103(3):277-283. doi:10.1016/s0304-3959(02)00456-6 72. Wiech K, Kiefer RT, Tpfner S, et al. A Placebo-Controlled Randomized Crossover Trial of the N-Methyl-d-Aspartic Acid Receptor Antagonist, Memantine, in Patients with Chronic Phantom Limb Pain. Anesth Analg. Published online February 2004:408-413. doi:10.1213/01.ane.0000096002.53818.bd 73. Jaeger H, Maier C. Calcitonin in phantom limb pain: a double-blind study. Pain. 1992;48(1):21-27. doi:10.1016/0304-3959(92)90127-w 74. Eichenberger U, Neff F, Sveticic G, et al. Chronic phantom limb pain: The effects of calcitonin, ketamine, and their combination on pain and sensory thresholds. Anesth Analg. 2008;106(4):1265-1273. doi:10.1213/ane.0b013e3181685014 75. Berman RM, Cappiello A, Anand A, et al. Antidepressant Effects of Ketamine in Depressed Patients. Biol Psychiatry. 2000;47(4):351-354. doi:10.1016/s0006-3223(99)00230-9 76. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864. doi:10.1001/archpsyc.63.8.856 77. Schoevers RA, Chaves TV, Balukova SM, aan Het Rot M, Kortekaas R. Oral ketamine for the treatment of pain and treatment-resistant depression. Br J Psychiatry. 2016;208(2):108-113. doi:10.1192/bjp.bp.115.165498 78. Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-964. doi:10.1126/science.1190287 79. Aligeti S, Quinones M, Salazar R. Rapid Resolution of Suicidal Behavior and Depression With Single Low-Dose Ketamine Intravenous Push Even After 6 Months of Follow-Up. J Clin Psychopharmacol. 2014;34(4):533-535. doi:10.1097/jcp.0000000000000146 80. Juni A, Klein G, Kest B. Morphine hyperalgesia in mice is unrelated to opioid activity, analgesia, or tolerance: Evidence for multiple diverse hyperalgesic systems. Brain Res. 2006;1070(1):35-44. doi:10.1016/j.brainres.2005.11.054 81. Van Dorp ELA, Kest B, Kowalczyk WJ, et al. Morphine-6β-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans. Anesthesiology. 2009;110(6):1356-1363. doi:10.1097/aln.0b013e3181a105de 82. Barreveld AM, Correll DJ, Liu X, et al. ketamine decreases postoperative pain scores in patients taking opioids for chronic pain: Results of a prospective, randomized, double-blind study. Pain Med. 2013;14(6):925-934. doi:10.1111/pme.12086 83. Nielsen RV, Fomsgaard JS, Nikolajsen L, Dahl JB, Mathiesen O. Intraoperative S-ketamine for the reduction of opioid consumption and pain one year after spine surgery: A randomized clinical trial of opioid-dependent patients. Eur J Pain. 2019;23(3):455-460. doi:10.1002/ejp.1317 84. Pruskowski KA, Harbourt K, Pajoumand M, Chui SHJ, Reynolds HN. Impact of Ketamine Use on Adjunctive Analgesic and Sedative Medications in Critically Ill Trauma Patients. Pharmacother. 2017;37(12):1537-1544. doi:10.1002/phar.2042