Vol 14, No 3 (2020)
Review paper
Published online: 2020-08-17
Ketamine — a unique adjuvant drug in pain treatment
1
Palliat Med Pract 2020;14(3):192-197.
Abstract
Ketamine is an anaesthetic with unique properties. Synthesised for the first time in the early 1960s, it causes
dissociative anaesthesia, sedation, amnesia, and analgesia. Due to hallucinogenic effects, the use of the
drug was significantly reduced in the 1980s. At present, ketamine is used to treat acute and chronic pain,
especially pain resistant to other pain management methods. Ketamine can be effective in the treatment
of chronic neuropathic pain syndromes, prevention of secondary hyperalgesia in burn injuries, treatment
of muscle pain in patients with fibromyalgia, metastatic bone pain and treatment of pain caused by oral
mucositis.
Keywords: ketaminepainadjuvantanalgesia
References
- Domino EF, Chodoff P, Corssen G. Pharmacologic effects of Ci–581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965; 6: 279–291.
- Pribish A, Wood N, Kalava A. A Review of Nonanesthetic Uses of Ketamine. Anesthesiol Res Pract. 2020; 2020: 5798285.
- Quibell R, Prommer EE, Mihalyo M, et al. Ketamine*. J Pain Symptom Manage. 2011; 41(3): 640–649.
- Aroni F, Iacovidou N, Dontas I, et al. Pharmacological aspects and potential new clinical applications of ketamine: reevaluation of an old drug. J Clin Pharmacol. 2009; 49(8): 957–964.
- Li L, Vlisides PE. Ketamine: 50 Years of Modulating the Mind. Front Hum Neurosci. 2016; 10: 612.
- Michelet D, Brasher C, Horlin AL, et al. Ketamine for chronic non-cancer pain: A meta-analysis and trial sequential analysis of randomized controlled trials. Eur J Pain. 2018; 22(4): 632–646.
- Walters MK, Farhat J, Bischoff J, et al. Ketamine as an Analgesic Adjuvant in Adult Trauma Intensive Care Unit Patients With Rib Fracture. Ann Pharmacother. 2018; 52(9): 849–854.
- Sleigh J, Harvey M, Voss L, et al. Ketamine – More mechanisms of action than just NMDA blockade. Trends in Anaesthesia and Critical Care. 2014; 4(2-3): 76–81.
- Liu FL, Chen TL, Chen RM. Mechanisms of ketamine-induced immunosuppression. Acta Anaesthesiol Taiwan. 2012; 50(4): 172–177.
- De Kock M, Loix S, Lavand'homme P. Ketamine and peripheral inflammation. CNS Neurosci Ther. 2013; 19(6): 403–410.
- Koizuka S, Obata H, Sasaki M, et al. Systemic ketamine inhibits hypersensitivity after surgery via descending inhibitory pathways in rats. Can J Anaesth. 2005; 52(5): 498–505.
- Gordh T, Karlsten R, Kristensen J. Intervention with spinal NMDA, adenosine, and NO systems for pain modulation. Ann Med. 1995; 27(2): 229–234.
- Davis WD, Davis KA, Hooper K. The Use of Ketamine for the Management of Acute Pain in the Emergency Department. Adv Emerg Nurs J. 2019; 41(2): 111–121.
- Backonja M, Arndt G, Gombar KA, et al. Response of chronic neuropathic pain syndromes to ketamine: a preliminary study. Pain. 1994; 56(1): 51–57.
- Laskowski K, Stirling A, McKay WP, et al. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011; 58(10): 911–923.
- Remérand F, Le Tendre C, Baud A, et al. The early and delayed analgesic effects of ketamine after total hip arthroplasty: a prospective, randomized, controlled, double-blind study. Anesth Analg. 2009; 109(6): 1963–1971.
- Mak P, Broadbear JH, Kolosov A, et al. Long-Term Antihyperalgesic and Opioid-Sparing Effects of 5-Day Ketamine and Morphine Infusion ("Burst Ketamine") in Diabetic Neuropathic Rats. Pain Med. 2015; 16(9): 1781–1793.
- McGuinness SK, Wasiak J, Cleland H, et al. A systematic review of ketamine as an analgesic agent in adult burn injuries. Pain Med. 2011; 12(10): 1551–1558.
- Mercadante S, Villari P, Ferrera P, et al. Opioid switching and burst ketamine to improve the opioid response in patients with movement-related pain due to bone metastases. Clin J Pain. 2009; 25(7): 648–649.
- Graven-Nielsen T, Aspegren Kendall S, Henriksson KG, et al. Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain. 2000; 85(3): 483–491.
- 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 Physician. 2010; 13(3): 245–249.
- Nikolajsen L, Hansen CL, Nielsen J, et al. The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. Pain. 1996; 67(1): 69–77.
- Eide PK, Jørum E, Stubhaug A, et al. Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain. 1994; 58(3): 347–354.
- 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.
- Becerra L, Schwartzman RJ, Kiefer RT, et al. CNS Measures of Pain Responses Pre- and Post-Anesthetic Ketamine in a Patient with Complex Regional Pain Syndrome. Pain Med. 2015; 16(12): 2368–2385.
- 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.
- Sigtermans M, Noppers I, Sarton E, et al. An observational study on the effect of S+-ketamine on chronic pain versus experimental acute pain in Complex Regional Pain Syndrome type 1 patients. Eur J Pain. 2010; 14(3): 302–307.
- Pomeroy JL, Marmura MJ, Nahas SJ, et al. Ketamine Infusions for Treatment Refractory Headache. Headache. 2017; 57(2): 276–282.
- Moisset X, Clavelou P, Lauxerois M, et al. Ketamine Infusion Combined With Magnesium as a Therapy for Intractable Chronic Cluster Headache: Report of Two Cases. Headache. 2017; 57(8): 1261–1264.
- Singh V, Shteamer J, Lowe J, et al. Central sensitization and its role in chronic pain: What can ketamine do? Indian Journal of Pain. 2020; 34(1): 3.
- Singh V, Gillespie TW, Harvey RD. Intranasal Ketamine and Its Potential Role in Cancer-Related Pain. Pharmacotherapy. 2018; 38(3): 390–401.
- Frey TM, Florin TA, Caruso M, et al. Effect of Intranasal Ketamine vs Fentanyl on Pain Reduction for Extremity Injuries in Children: The PRIME Randomized Clinical Trial. JAMA Pediatr. 2019; 173(2): 140–146.
- Afridi SK, Giffin NJ, Kaube H, et al. A randomized controlled trial of intranasal ketamine in migraine with prolonged aura. Neurology. 2013; 80(7): 642–647.
- Kaube H, Herzog J, Käufer T, et al. Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology. 2000; 55(1): 139–141.
- Yanagihara Y, Ohtani M, Kariya S, et al. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos. 2003; 24(1): 37–43.
- Zhu MM, Zhou QH, Zhu MH, et al. Effects of nebulized ketamine on allergen-induced airway hyperresponsiveness and inflammation in actively sensitized Brown-Norway rats. J Inflamm (Lond). 2007; 4: 10.
- Ehieli E, Yalamuri S, Brudney CS, et al. Analgesia in the surgical intensive care unit. Postgrad Med J. 2017; 93(1095): 38–45.
- Patanwala AE, Martin JR, Erstad BL. Ketamine for Analgosedation in the Intensive Care Unit: A Systematic Review. J Intensive Care Med. 2017; 32(6): 387–395.
- Drapkin J, Masoudi A, Butt M, et al. Administration of Nebulized Ketamine for Managing Acute Pain in the Emergency Department: A Case Series. Clin Pract Cases Emerg Med. 2020; 4(1): 16–20.
- Romero TRL, Galdino GS, Silva GC, et al. Ketamine activates the L-arginine/Nitric oxide/cyclic guanosine monophosphate pathway to induce peripheral antinociception in rats. Anesth Analg. 2011; 113(5): 1254–1259.
- Fischer M, Glanz D, Urbatzka M, et al. Keratinocytes: a source of the transmitter L-glutamate in the epidermis. Exp Dermatol. 2009; 18(12): 1064–1066.
- Zhao P, Barr TP, Hou Q, et al. Voltage-gated sodium channel expression in rat and human epidermal keratinocytes: evidence for a role in pain. Pain. 2008; 139(1): 90–105.
- Radtke C, Vogt PM, Devor M, et al. Keratinocytes acting on injured afferents induce extreme neuronal hyperexcitability and chronic pain. Pain. 2010; 148(1): 94–102.
- Stanos SP. Topical agents for the management of musculoskeletal pain. J Pain Symptom Manage. 2007; 33(3): 342–355.
- Archer DF, Cullins V, Creasy GW, et al. The impact of improved compliance with a weekly contraceptive transdermal system (Ortho Evra) on contraceptive efficacy. Contraception. 2004; 69(3): 189–195.
- Carlton SM, Hargett GL, Coggeshall RE. Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci Lett. 1995; 197(1): 25–28.
- Coggeshall RE, Carlton SM. Ultrastructural analysis of NMDA, AMPA, and kainate receptors on unmyelinated and myelinated axons in the periphery. J Comp Neurol. 1998; 391(1): 78–86, doi: 10.1002/(sici)1096-9861(19980202)391:1<78::aid-cne7>3.3.co;2-8.
- Gupta A, Devi LA, Gomes I. Potentiation of μ-opioid receptor-mediated signaling by ketamine. J Neurochem. 2011; 119(2): 294–302.
- Moaddel R, Abdrakhmanova G, Kozak J, et al. Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors. European Journal of Pharmacology. 2013; 698(1-3): 228–234.
- Murrough JW. Ketamine as a novel antidepressant: from synapse to behavior. Clin Pharmacol Ther. 2012; 91(2): 303–309.
- Schnoebel R, Wolff M, Peters SC, et al. Ketamine impairs excitability in superficial dorsal horn neurones by blocking sodium and voltage-gated potassium currents. Br J Pharmacol. 2005; 146(6): 826–833.
- 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.
- Liu FL, Chen TL, Chen RM. Mechanisms of ketamine-induced immunosuppression. Acta Anaesthesiol Taiwan. 2012; 50(4): 172–177.
- Kopsky DJ. Keppel Hesselink JM, Bhaskar A. at al. Analgesic effects of topical ketamine. Minerva Anestesiol. 2015; 81(4): 440–449.
- Rabi J, Minori J, Abad H, et al. Topical Ketamine 10% for Neuropathic Pain in Spinal Cord Injury Patients: An Open-Label Trial. Int J Pharm Compd. 2016; 20(6): 517–520.
- Slatkin NE, Rhiner M. Topical ketamine in the treatment of mucositis pain. Pain Med. 2003; 4(3): 298–303.
- Middela S, Pearce I. Ketamine-induced vesicopathy: a literature review. Int J Clin Pract. 2011; 65(1): 27–30.
- Tobias JD, Leder M. Procedural sedation: A review of sedative agents, monitoring, and management of complications. Saudi J Anaesth. 2011; 5(4): 395–410.
- Wampole CR, Smith KE. Beyond Opioids for Pain Management in Adult Critically Ill Patients. J Pharm Pract. 2019; 32(3): 256–270.
- Erstad BL, Patanwala AE. Ketamine for analgosedation in critically ill patients. J Crit Care. 2016; 35: 145–149.
- 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.
- Mallick F, McCullumsmith CB. Ketamine for Treatment of Suicidal Ideation and Reduction of Risk for Suicidal Behavior. Curr Psychiatry Rep. 2016; 18(6): 61.
