Skip to main content
SpringerLink
Log in

Efficacy and Tolerability of Oral Compared with Sublingual Ketamine Lozenges as Rescue Analgesics in Adults for Acute Pain: The OSKet Trial

  • Short Communication
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background and Objective

Ketamine is an N-methyl-D-aspartate receptor (NMDA) antagonist used widely as an intravenous analgesic for treatment of acute pain. Its use as oral and sublingual analgesics is not well studied. This study aims to compare the clinical efficacy and tolerability of oral (PO) versus sublingual (SL) ketamine lozenges in adult patients with moderate-to-severe breakthrough pain.

Methods

The study had a randomized, double-blind crossover design in 23 inpatients requiring ketamine as rescue analgesics when pain scores exceeded 4/10 on the Numerical Rating Scales. Each participant received either SL 50 mg ketamine lozenge and PO placebo lozenge or SL placebo lozenge and PO 50 mg ketamine lozenge in two treatment periods with a minimum 24-h washout. Pain scores and adverse effects were documented half hourly for the first 2 h, then one hourly for the next 2 h after treatment. The time to first effect and time to meaningful pain relief were recorded. Patients reported their satisfaction and a global impression of change (GIC) at the end of each treatment period. Data were analysed using random effects regression models.

Results

Sixteen subjects completed both days, 7 completed 1 day. Time to first effect was 13.1 min PO versus 6.6 min SL (p = 0.069), time to meaningful pain relief was 29.4 min PO versus 10.8 min SL (p = 0.02). Pain scores were not significantly different at all time points post-treatment. Satisfaction and GIC scores were similar for both groups. Overall, adverse events occurred more often with SL administration (p = 0.02).

Conclusions

Sublingual administration of ketamine led to a faster onset of pain relief (but also a higher adverse event rate), but in all other aspects treatment with ketamine given sublingually and orally produced similar analgesic effects.

ACTRN: ACTRN12621000240842, 08/03/2021, retrospectively registered.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Persson J. Ketamine in pain management. CNS Neurosci Ther. 2013;19:396–402.

    Article  CAS  Google Scholar 

  2. Bell RF. Ketamine for chronic non-cancer pain. Pain. 2009;141:210–4.

    Article  CAS  Google Scholar 

  3. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J of Clin Pharmacol. 2014;77–2:357–67.

    Article  Google Scholar 

  4. Noppers I, Niesters M, Aarts L, Smith T, Sarton E, Dahan A. Ketamine for the treatment of chronic non-cancer pain. Expert Opin Pharmacother. 2010;11:2417–29.

    Article  CAS  Google Scholar 

  5. Jouguelet-Lacoste J, La Colla L, Chelly J. The use of intravenous infusion or single dose of low-dose ketamine for postoperative analgesia: a review of current literature. Pain Med. 2015;16:383–403.

    Article  Google Scholar 

  6. Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011;58:911–23.

    Article  Google Scholar 

  7. Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database of Systematic Reviews 2013;(7). Art. No.: CD008307.

  8. Mercandante S, Arcure E, Ferrera P, Villari P, Mangione S. Alternative treatments of breakthrough pain in patients receiving spinal analgesics for Cancer pain. J Pain Symptom Manag. 2005;30:485–91.

    Article  Google Scholar 

  9. Bredlau AL, Tahnku 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;14:1505–17.

    Article  Google Scholar 

  10. Cvrcek P. Side effects of ketamine in long-term treatment of neuropathic pain. Pain Med. 2008;9:253–7.

    Article  Google Scholar 

  11. Zhao J, Wang Y, Wang D. The effect of ketamine infusion in the treatment of complex regional pain syndrome: a systemic review and meta-analysis. Curr Pain Headache Rep. 2018;22(2):12.

    Article  Google Scholar 

  12. Connolly SB, Prager JP, Harden RN. A systematic review of ketamine for complex regional pain syndrome. Pain Med. 2015;16(5):943–69.

    Article  Google Scholar 

  13. Soto E, Stewart DR, Mannes AJ, Ruppert SL, Baker K, Zlott D, Handel D, Berger AH. Oral ketamine in the palliative care setting: a review of the literature and case report of a patient with neurofibromatosis type 1 and glomus tumor-associated complex regional pain syndrome. Am J Hosp Palliat Care. 2012;29:308–17.

    Article  Google Scholar 

  14. Marchetti F, Coutaux A, Bellanger A, Magneux C, Bourgeois P, Mion G. Efficacy and safety of oral ketamine for the relief of intractable chronic pain: a retrospective 5-year study of 51 patients. Eur J Pain. 2015;19(7):984–93.

    Article  CAS  Google Scholar 

  15. Tawfic QA. A review of the use of ketamine in pain management. J Opioid Manag. 2013;9(5):379–88.

    Article  Google Scholar 

  16. Bell RF, Kalso EA. Ketamine for pain management. Pain Rep. 2018;3(5):e674.

    Article  Google Scholar 

  17. Sleigh J, Harvey M, Voss L, Denny B. Ketamine—more mechanisms of action than just NMDA blockade. Trends Anaesth Crit Care. 2014;4:76–81.

    Article  Google Scholar 

  18. Chong C, Schug SA, Page-Sharp M, Jenkins B, Illett KF. Development of sublingual/oral formulation of ketamine for use in neuropathic pain: preliminary findings from a three-way randomized, crossover study. Clin Drug Investig. 2009;29:317–24.

    Article  CAS  Google Scholar 

  19. Rolan P, Lim S, Sunderland V, Liu Y, Molnar V. The absolute bioavailability of racemic ketamine from a novel sublingual formulation. Br J Clin Pharmacol. 2014;77:1011–6.

    Article  CAS  Google Scholar 

  20. Yanagihara Y, Ohtani M, Kariya S, Uchino K, Hiraishi T, Ashizawa N, Aoyama T, Yamamura Y, Yamada Y, Iga T. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos. 2003;24:37–43.

    Article  CAS  Google Scholar 

  21. Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clin Pharmacokinet. 2016;55:1059–77.

    Article  CAS  Google Scholar 

  22. Ebert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM. Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol. 1997;333:99–104.

    Article  CAS  Google Scholar 

  23. Shimoyama M, Shimoyama N, Gorman AL, Elliott KJ, Inturrisi CE. Oral ketamine is antinociceptive in the rat formalin test: role of the metabolite, norketamine. Pain. 1999;81:85–93.

    Article  CAS  Google Scholar 

  24. Olefsen E, Noppers I, Niesters M, Kharasch E, Aarts L, Sarton E, Dahan A. Estimation of the contribution of norketamine to ketamine-induced acute pain relief and neurocognitive impairment in healthy volunteers. Anaesthesiology. 2012;117:353–64.

    Article  Google Scholar 

  25. Singh NS, Zarate CA Jr, Moaddel R, Bernier M, Wainer IW. What is hydroxynorketamine and what can it bring to neurotherapeutics? Expert Rev Neurother. 2014;14:1239–42.

    Article  CAS  Google Scholar 

  26. Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6.

    Article  CAS  Google Scholar 

  27. Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, Viscusi ER, Narouze S, Davis FN, Ritchie EC, Lubenow TR, Hooten WM. 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):521–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Clements JA, Nimmo WA, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci. 1982;71:539–42.

    Article  CAS  Google Scholar 

  29. Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgious P, Perreira EFR, Albuquerque EX, Thomas CJ, Zarate CA, Gould TD. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018;70:621–60.

    Article  CAS  Google Scholar 

  30. Schewenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, Narouze S, Bhatia A, Davis FN, Hooten WM, Cohen SP. Consensus guidelines on the use of intravenous ketamine infusions for acute pain management and pain medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43:456–66.

    Google Scholar 

Download references

Acknowledgements

We would like to acknowledge Ms Susan March, for assisting with data collection; Mr Richard Parson, for statistical analysis of results.

Author information

Authors and Affiliations

  1. Department of Anaesthesia and Pain, Royal Perth Hospital, GPO Box X2213, Perth, WA, 6847, Australia

    Chui C. Chong

  2. Emeritus Professor and Honorary Senior Research Fellow, Anaesthesiology and Pain Medicine, Medical School, University of Western Australia, Royal Perth Hospital, Level 4 MRF Building, GPO Box X2213, Perth, WA, 6847, Australia

    Stephan A. Schug

Authors
  1. Chui C. Chong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephan A. Schug
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chui C. Chong.

Ethics declarations

Funding

University of Western Australia, Discipline of Anaesthesiology and Pain Medicine, Level 4 MRF Building, Royal Perth Hospital, GPO BOX X2213 Perth WA 6847 Australia.

Conflict of interest

Dr. Chui Chong: None. Prof S. Schug: The Anaesthesiology Unit of the University of Western Australia (and Professor Schug personally since his retirement in October 2019) has received research and travel funding, speaking and consulting honoraria from Eli Lilly, Grunenthal, Indivior, Jansseen, Mundipharma, Pfizer, Phosphagenics, iXBiopharma, Seqirus, Xgene, Biogen, Luye Pharma and Foundry within the last 5 years. None of this funding was related to this study.

Ethic approval

All procedures in this study were in accordance with the 1964 Helsinki Declaration (and its amendments), and overseen by Royal Perth Hospital Human Research Ethic Committee

Consent to participate

Informed consent was obtained from all individual participants included in this study.

Consent for publication

Not applicable.

Data transparency

The datasets generated during and/or analysed during the current study can be made available from the corresponding author on reasonable request within 5 years of publication.

Code availability

All data generated or analysed during the current study are included in this published article.

Authors’ contributions

Study design and ethics approval obtained by SS. CC recruited subjects and collected data. Data analysed and paper written by CC and SS.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 149 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chong, C.C., Schug, S.A. Efficacy and Tolerability of Oral Compared with Sublingual Ketamine Lozenges as Rescue Analgesics in Adults for Acute Pain: The OSKet Trial. Clin Drug Investig 41, 817–823 (2021). https://doi.org/10.1007/s40261-021-01066-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-021-01066-x

Search

Navigation