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. doi: 10.2165/00044011-200929050-00004.


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 25 mg of ketamine was formulated and manufactured in a hospital pharmacy setting. Stability was assessed by high-performance liquid chromatography (HPLC) during storage at 25 degrees C or 2-8 degrees 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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Administration, Sublingual
  • Adult
  • Aged
  • Analgesics / administration & dosage*
  • Analgesics / adverse effects
  • Analgesics / pharmacokinetics
  • Area Under Curve
  • Biological Availability
  • Chromatography, High Pressure Liquid
  • Chronic Disease
  • Cross-Over Studies
  • Drug Stability
  • Drug Storage
  • Excitatory Amino Acid Antagonists / administration & dosage
  • Excitatory Amino Acid Antagonists / adverse effects
  • Excitatory Amino Acid Antagonists / pharmacokinetics
  • Female
  • Humans
  • Ketamine / administration & dosage*
  • Ketamine / adverse effects
  • Ketamine / analogs & derivatives
  • Ketamine / pharmacokinetics
  • Male
  • Middle Aged
  • Neuralgia / drug therapy*
  • Temperature


  • Analgesics
  • Excitatory Amino Acid Antagonists
  • Ketamine
  • norketamine