Skip to main content
SpringerLink
Log in

Development of a Sublingual/Oral Formulation of Ketamine for Use in Neuropathic Pain

Preliminary Findings from a Three-Way Randomized, Crossover Study

  • Original Research Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background and objective: Enterally administered low-dose ketamine is being used increasingly to treat pain states. However, suitable oral or sublingual formulations are not available. The objective of the study was to develop a lozenge formulation of ketamine for use in patients with neuropathic pain, and to investigate its storage stability and bioavailability after oral or sublingual administration.

Methods: A lozenge containing 25mg of ketamine was formulated and manufactured in a hospital pharmacy setting. Stability was assessed by high-performance liquid chromatography (HPLC) during storage at 25°C or 2–8°C for up to 14 weeks. Bioavailability after both oral and sublingual administration was evaluated in six patients with chronic neuropathic pain. Ketamine and its metabolite norketamine in plasma were measured by HPLC.

Results: The lozenge formulation was chemically stable for at least 14 weeks. Oral and sublingual bioavailabilities [median (interquartile range)] were 24% (17–27%) and 24% (19–49%), respectively. There was substantial metabolism to norketamine for both routes. The mean norketamine/ketamine area under the plasma concentration-time curve from baseline to 8 hours ratios were 5 and 2.1 after oral or sublingual administration, respectively.

Conclusion: The ketamine lozenge showed acceptable storage stability. Bioavailability was sufficiently high and reproducible to support its use in routine pain management. There was extensive first-pass conversion to norketamine. Efficacy studies are warranted to evaluate sublingual and oral administration of our new lozenge formulation of ketamine in patients with chronic pain states. Investigation of the role of the metabolite norketamine, which is also an NMDA receptor antagonist, is particularly important because this may contribute significantly to clinical efficacy.

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

Table I
Fig. 1
Table II

Similar content being viewed by others

References

  1. Reich DL, Silvay G. Ketamine: an update on the 1st 25 years of clinical experience. Can J Anaesth 1989; 36: 186–97

    Article  PubMed  CAS  Google Scholar 

  2. Walker SM, Cousins MJ. Reduction in hyperalgesia and intrathecal morphine requirements by low-dose ketamine infusion. J Pain Symptom Manage 1997; 14: 129–33

    Article  PubMed  CAS  Google Scholar 

  3. Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence-based review. Anesth Analg 2003; 97: 1730–9

    Article  PubMed  CAS  Google Scholar 

  4. Sang CN. NMDA-receptor antagonists in neuropathic pain: experimental methods to clinical trials. J Pain Symptom Manage 2000; 19: S21–5

    Article  PubMed  CAS  Google Scholar 

  5. Price DD, Mayer DJ, Mao J, et al. NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance. J Pain Symptom Manage 2000; 19: S7–11

    Article  PubMed  CAS  Google Scholar 

  6. Sator-Katzenschlager S, Deusch E, Maier P, et al. The long-term antinociceptive effect of intrathecal S(+)-ketamine in a patient with established morphine tolerance. Anesth Analg 2001; 93: 1032–4

    Article  PubMed  CAS  Google Scholar 

  7. Eilers H, Philip LA, Bickler PE, et al. The reversal of fentanyl-induced tolerance by administration of “small-dose” ketamine. Anesth Analg 2001; 93: 213–4

    Article  PubMed  CAS  Google Scholar 

  8. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg 2004; 99: 482–95

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  10. Hijazi Y, Boulieu R. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos 2002; 30: 853–8

    Article  PubMed  CAS  Google Scholar 

  11. Kannan TR, Saxena A, Bhatnagar S, et al. Oral ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients. J Pain Symptom Manage 2002; 23: 60–5

    Article  PubMed  CAS  Google Scholar 

  12. Fitzgibbon EJ, Hall P, Schroder C, et al. Low dose ketamine as an analgesic adjuvant in difficult pain syndromes: a strategy for conversion from parenteral to oral ketamine. J Pain Symptom Manage 2002; 23: 165–70

    Article  PubMed  Google Scholar 

  13. Enarson MC, Hays H, Woodroffe MA. Clinical experience with oral ketamine. J Pain Symptom Manage 1999; 17: 384–6

    Article  PubMed  CAS  Google Scholar 

  14. Gross AS, Nicolay A, Eschalier A. Simultaneous analysis of ketamine and bupivacaine in plasma by high-performance liquid chromatography. J Chromatog B 1999; 728: 107–15

    Article  CAS  Google Scholar 

  15. Hijazi Y, Bolon M, Boulieu R. Stability of ketamine and its metabolites norketamine and dehydronorketamine in human biological samples. Clin Chem 2001; 47: 1713–5

    PubMed  CAS  Google Scholar 

  16. Thomann P. Non-compartmental analysis methods manual. In: Heinzel G, Woloszcak R, Thomann P, editors. TopFit 2.0 pharmacokinetic and pharmacodynamic data analysis system for the PC. Stuttgart: Gustav Fischer, 1993: 5–66

    Google Scholar 

  17. Heinzel G, Tanswell P. Compartmental analysis methods manual. In: Heinzel G, Woloszcak R, Thomann P, editors. Topfit 2.0 pharmacokinetic and pharmacodynamic data analysis system for the PC. Stuttgart: Gustav Fischer, 1993: 5–140

    Google Scholar 

  18. 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: 37–43

    Article  PubMed  CAS  Google Scholar 

  19. Hijazi Y, Bodonian C, Salord F, et al. Pharmacokinetic-pharmacodynamic modelling of ketamine in six neuro-traumatised intensive care patients. Clin Drug Invest 2003; 23: 605–9

    Article  CAS  Google Scholar 

  20. Yanagihara Y, Ohtani M, Matsumoto M, et al. Preparation of ketamine tablets for treatment of patients with neuropathic pain. Yakugaku Zasshi 1999; 119: 980–7

    PubMed  CAS  Google Scholar 

  21. Grant IS, Nimmo WS, Clements JA. Pharmacokinetics and analgesic effects of i.m. and oral ketamine. Br J Anaesth 1981; 53: 805–10

    Article  PubMed  CAS  Google Scholar 

  22. Ebert B, Mikkelsen S, Thorkildsen C, et al. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  24. Edwards SR, Mather LE. Tissue uptake of ketamine and norketamine enantiomers in the rat: indirect evidence for extrahepatic metabolic inversion. Life Sci 2001; 69: 2051–66

    Article  PubMed  CAS  Google Scholar 

  25. Bushnell TG, Craig J. Response of chronic neuropathic pain syndromes to ketamine: a role for norketamine [letter]? Pain 1995; 60: 115

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The study was funded by a project grant from the Australian and New Zealand College of Anaesthetists (ANZCA), Melbourne, Australia. The grant had no influence on the way the study was conducted.

The role of the Pharmacy of Royal Perth Hospital, Perth, Australia in the development of the lozenge and the editorial assistance of Falk Reinholz, University of Western Australia, Perth, Australia in the preparation and finalization of this manuscript are kindly acknowledged.

The authors have no conflicts of interest that are directly related to the content of this study.

Author information

Authors and Affiliations

  1. Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, Western Australia, Australia

    Chui Chong &  Stephan A. Schug

  2. Pharmacology and Anaesthesiology Unit, School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia

    Stephan A. Schug, Madhu Page-Sharp & Kenneth F. Ilett

  3. Pharmacy Department, Royal Perth Hospital, Perth, Western Australia, Australia

    Barry Jenkins

  4. Clinical Pharmacology and Toxicology Laboratory, PathWest Laboratory Medicine, Nedlands, Western Australia, Australia

    Kenneth F. Ilett

Authors
  1. Chui 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

  3. Madhu Page-Sharp
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Barry Jenkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenneth F. Ilett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephan A. Schug.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chong, C., Schug, S.A., Page-Sharp, M. et al. Development of a Sublingual/Oral Formulation of Ketamine for Use in Neuropathic Pain. Clin. Drug Investig. 29, 317–324 (2009). https://doi.org/10.2165/00044011-200929050-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00044011-200929050-00004

Keywords

Search

Navigation