Archive \ Volume.16 2025 Issue 4

Efficacy of Oral and Sublingual Ketamine Formulations for Analgesia: A Systematic Review and Meta-Analysis

Pamela D Moore , Raj Boopathy , Kinam Park*✉
  1. Institute for Psycholinguistics and Digital Health, United States of America.
  2. Department of Psychiatry, NYU Grossman School of Medicine, New York University, New York, United States of America.
  3. University of California, San Francisco, United States of America.

Abstract

This study aimed to perform a systematic review and meta-analysis evaluating the efficacy of oral and sublingual ketamine for pain relief. A comprehensive literature search was performed across four databases: MEDLINE, CINAHL, Embase, and Web of Science. Randomized controlled trials were selected that examined oral or sublingual ketamine for pain control in either inpatient or outpatient environments, relative to any other oral or sublingual treatment, including placebo. 21 studies were incorporated into the systematic review, all involving oral ketamine, with one study directly contrasting oral and sublingual forms. Among these, 12 trials addressed oral ketamine for procedural pain, where 10 demonstrated that oral ketamine outperformed the comparator in alleviating procedural discomfort. 2 trials assessed oral ketamine for postoperative pain, both indicating a decreased need for rescue analgesics versus placebo. 5 trials explored oral ketamine for chronic pain, yielding varied outcomes. The other 2 studies consisted of one evaluating different oral ketamine dosages and the other comparing oral versus sublingual administration. 15 studies qualified for the meta-analysis. Of these, 7 studies compared oral ketamine with placebo and revealed that oral ketamine significantly outperformed placebo in pain reduction (P < 0.01). The remaining eight compared oral ketamine with other oral agents, including methadone, codeine, midazolam, and dexmedetomidine, and found no notable advantage for oral ketamine in pain mitigation (P = 0.18). Findings indicate that oral ketamine serves as an efficacious analgesic option, particularly in procedural contexts.


Downloads: 64
Views: 450

How to cite:
Vancouver
Moore PD, Boopathy R, Park K. Efficacy of Oral and Sublingual Ketamine Formulations for Analgesia: A Systematic Review and Meta-Analysis. Arch Pharm Pract. 2025;16(4):1-11. https://doi.org/10.51847/Y02YjbkVsm
APA
Moore, P. D., Boopathy, R., & Park, K. (2025). Efficacy of Oral and Sublingual Ketamine Formulations for Analgesia: A Systematic Review and Meta-Analysis. Archives of Pharmacy Practice, 16(4), 1-11. https://doi.org/10.51847/Y02YjbkVsm

Download Citation
References
  1. Schug SA, Palmer GM, Scott DA, Alcock M, Halliwell R, Mott JF. Acute pain management: scientific evidence. Melbourne, Australia: Australian and New Zealand College of Anaesthetists; 2020.
  2. Keating L, Smith S. Acute pain in the emergency department: the challenges. Rev Pain. 2011;5(3):13–7.
  3. Vos T, Lim SS, Abbafati C, Abbas KM, Abbasi M, Abbasifard M, et al. Global burden of 369 diseases and injuries in 204 countries and territories: a systematic analysis for the global burden of disease study 2019. Lancet. 2020;396(10258):1204–22.
  4. Therapeutic Guidelines. Pain and analgesia. In: Therapeutic Guidelines. Melbourne: Therapeutic Guidelines Limited; 2023.
  5. United Nations Office on Drugs and Crime. Executive summary: conclusions and policy implications. In: World Drug Report 2019. Vienna: United Nations; 2019.
  6. Bell RF, Kalso EA. Ketamine for pain management. Pain Rep. 2018;3(5):e674.
  7. Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database Syst Rev. 2013;2013(7):CD008307.
  8. Guichard L, Hirve A, Demiri M, Martinez V. Opioid-induced hyperalgesia in patients with chronic pain: a systematic review of published cases. Clin J Pain. 2021;38(1):49–57.
  9. Yanagihara Y, Ohtani M, Kariya S, Uchino K, Hiraishi T, Ashizawa N, 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.
  10. Chong C, Schug SA, Page-Sharp M, Jenkins B, Ilett KF. Development of a sublingual/oral formulation of ketamine for use in neuropathic pain: preliminary findings from a three-way randomized, crossover study. Clin Drug Investig. 2009;29(5):317–24.
  11. Blonk MI, Koder BG, Bemt PMLA, Huygen FJPM. Use of oral ketamine in chronic pain management: a review. Eur J Pain. 2010;14(5):466–72.
  12. Riccardi A, Guarino M, Serra S, Spampinato MD, Vanni S, Shiffer D, et al. Narrative review: low-dose ketamine for pain management. J Clin Med. 2023;12(9):3256.
  13. Faculty of Pain Medicine of the Royal College of Anaesthetists. Ketamine. London: Faculty of Pain Medicine of the Royal College of Anaesthetists; 2023. Available from: https://fpm.ac.uk/opioids-aware-other-medicines/ketamine. Accessed 2024 Feb 1.
  14. US Food and Drug Administration (FDA). FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders United States. Washington: FDA; 2023. Available from: https://www.fda.gov/drugs/human-drug-compounding/fda-warns-patients-and-health-care-providers-about-potential-risks-associated-compounded-ketamine. Accessed 2023 Nov 3.
  15. Therapeutic Goods Administration. Australian Register of Therapeutic Goods Australia (ARTG). Canberra: Commonwealth of Australia; 2023. Available from: https://www.tga.gov.au/resources/artg?keywords=ketamine. Accessed 2023 Nov 3.
  16. Oh S, Kingsley K. Efficacy of ketamine in pediatric sedation dentistry: a systematic review. Compend Contin Educ Dent. 2018;39(5):e1–4.
  17. Rosenblat JD, Carvalho AF, Li M, Lee Y, Subramanieapillai M, McIntyre RS. Oral ketamine for depression: a systematic review. J Clin Psychiatry. 2019;80(3):18r12475.
  18. Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al. Cochrane handbook for systematic reviews of interventions. Version 6.3. London: Cochrane; 2022.
  19. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
  20. Chong CC, Schug SA. Efficacy and tolerability of oral compared with sublingual ketamine lozenges as rescue analgesics in adults for acute pain: the OSKet trial. Clin Drug Investig. 2021;41(9):817–23.
  21. Ezike H, Odiakosa M. Oral ketamine for wound care procedures in adult patients with burns. South Afr J Anaesth Analg. 2011;17(3):242–8.
  22. Bagheri M, Soltani AE, Qorbani M, Sureda A, Faghihi T. Efficacy and safety of low dose oral ketamine for controlling pain and distress during intravenous cannulation in children: a double-blind, randomized, placebo-controlled trial. Korean J Pain. 2022;35(3):311–8.
  23. Barkan S, Breitbart R, Brenner-Zada G, Feldon M, Assa A, Toledano M, et al. A double-blind, randomised, placebo-controlled trial of oral midazolam plus oral ketamine for sedation of children during laceration repair. Emerg Med J. 2014;31(8):649–53.
  24. Bozorgi F, Gholikhatir I, Mousavi SJ, Rahiminejad M, Lali A. A comparison of oral midazolam and ketamine with oral midazolam and promethazine in paediatric sedation. Med Stud. 2021;37(1):33–41.
  25. Humphries Y, Melson M, Gore D. Superiority of oral ketamine as an analgesic and sedative for wound care procedures in the pediatric patient with burns. J Burn Care Rehabil. 1997;18(1):34–6.
  26. Kaviani N, Khademi A, Ebtehaj I, Mohammadi Z. The effect of orally administered ketamine on requirement for anesthetics and postoperative pain in mandibular molar teeth with irreversible pulpitis. J Oral Sci. 2011;53(4):461–5.
  27. Kundra P, Velayudhan S, Krishnamachari S, Gupta SL. Oral ketamine and dexmedetomidine in adults’ burns wound dressing—a randomized double blind cross over study. Burns. 2013;39(6):1150–6.
  28. Majidinejad S, Kajbaf A, Khodadoostan M, Dolatkhah S, Kajbaf MH, Adibi P, et al. Ketamine administration makes patients and physicians satisfied during gastro-enteric endoscopies. J Res Med Sci. 2015;20(9):860–4.
  29. Modekwe VI, Ugwu JO, Ekwunife OH, Osuigwe AN, Orakwe JC, Awachie DS, et al. A randomised controlled trial on the efficacy and safety of oral ketamine in neonatal circumcision. J Clin Diagn Res. 2021;15(1):PC01–4.
  30. Norambuena C, Yañez J, Flores V, Puentes P, Carrasco P, Villena R. Oral ketamine and midazolam for pediatric burn patients: a prospective, randomized, double-blind study. J Pediatr Surg. 2013;48:629–34.
  31. Qureshi FA, Mellis PT, McFadden MA. Efficacy of oral ketamine for providing sedation and analgesia to children requiring laceration repair. Pediatr Emerg Care. 1995;11(2):93–7.
  32. Rubinstein O, Barkan S, Breitbart R, Berkovitch S, Toledano M, Weiser G, et al. Efficacy of oral ketamine compared to midazolam for sedation of children undergoing laceration repair: a double-blind, randomized, controlled trial. Medicine (Baltimore). 2016;95(26):e3984.
  33. Singh C, Pandey RK, Saksena AK, Chandra G. A comparative evaluation of analgo-sedative effects of oral dexmedetomidine and ketamine: a triple-blind, randomized study. Paediatr Anaesth. 2014;24(12):1252–9.
  34. Heidari SM, Saghaei M, Hashemi SJ, Parvazinia P. Effect of oral ketamine on the postoperative pain and analgesic requirement following orthopedic surgery. Acta Anaesthesiol Taiwan. 2006;44(4):211–5.
  35. Sakata RK, Issy AM, Garcia JBS, Martins DC, Memória EV. No effect of 10 mg of oral S(+)-ketamine combined with morphine on postoperative analgesia. Acute Pain. 2007;9(3):153–8.
  36. Fallon MT, Wilcock A, Kelly CA, Paul J, Lewsley LA, Norrie J, et al. Oral ketamine vs placebo in patients with cancer-related neuropathic pain: a randomized clinical trial. JAMA Oncol. 2018;4(6):870–2.
  37. Haines DR, Gaines SP. N of 1 randomised controlled trials of oral ketamine in patients with chronic pain. Pain. 1999;83(2):283–7.
  38. Ishizuka P, Garcia JBS, Sakata RK, Issy AM, Mülich SL. Assessment of oral S+ ketamine associated with morphine for the treatment of oncologic pain. Rev Bras Anestesiol. 2007;57:19–31.
  39. Jafarinia M, Afarideh M, Tafakhori A, Arbabi M, Ghajar A, Noorbala AA, et al. Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: a double-blind, randomized, controlled trial. J Affect Disord. 2016;204:1–8.
  40. Rigo FK, Trevisan G, Godoy MC, Rossato MF, Dalmolin GD, Silva MA, et al. Management of neuropathic chronic pain with methadone combined with ketamine: a randomized, double blind, active-controlled clinical trial. Pain Physician. 2017;20(3):207–15.
  41. Oliveira Filho GLR, Castilhos CM, Kriegl JP, Bianchi GN. Oral preanesthetic medication in children comparison between midazolam alone and in combination with ketamine: a systematic review and meta-analysis. Braz J Anesthesiol. 2023;73(4):477–90.
  42. Nowacka A, Borczyk M. Ketamine applications beyond anesthesia – a literature review. Eur J Pharmacol. 2019;860:172547.
  43. Bredlau AL, Thakur R, Korones DN, Dworkin RH. Ketamine for pain in adults and children with cancer: a systematic review and synthesis of the literature. Pain Med. 2013;14(10):1505–17.

 

 

 


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.