Sublingual Ketamine Is Safe and Effective for Management of Chronic Nonmalignant Pain

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The researchers’ goal was to provide the initial evidence for the safety and efficacy of sublingual ketamine in patients with chronic nonmalignant pain.

Sublingual ketamine is a safe, effective analgesic therapy for chronic nonmalignant pain, with no significant side effects or adverse events associated with long-term treatment. This is according to research results published in the Internal Medicine Journal by Australian researchers.

Chronic pain can be complex and challenging for both patients and their families and caregivers. Sublingual ketamine has previously been demonstrated to be an efficacious treatment for chronic pain, particularly for patients with opioid-induced hyperalgesia, chronic neuropathic pain, and complex regional pain syndrome.

Currently, though, there are no published long-term safety data on ketamine use. The current researchers, therefore, conducted a retrospective case series study to provide “initial evidence” about the efficacy and safety of oral ketamine treatment; secondary goals of the study were to evaluate the reduction in use of other analgesics following sublingual ketamine use.

The study cohort included 29 patients from a metropolitan tertiary pain service who received sublingual ketamine troches or lozenges between 2012 and 2019. Patients had previously undergone a comprehensive, multidisciplinary pain management assessment and were admitted for inpatient subcutaneous ketamine infusion as part of opioid detoxification or central sensation management associated with chronic neuropathic pain.

All admitted patients underwent continuous subcutaneous ketamine infusion of 0.1 to 1.2 mg/kg/hour titrated based on pain and tolerability, with a maximum daily dose of 500 mg. Patients who responded to these infusions received ketamine troches or lozenges.

The initial dose of troches was 25 mg 3 times daily, titrated to patient tolerability and effect. Patients had in-person pain clinic visits every 3 months to review treatment.

Overall, the study population was heterogeneous and included 19 women and 10 men between 26 and 67 years of age. No statistically significant impacts of sex were noted on the measured outcomes.

Patient pain diagnoses included peripheral neuropathy, complex regional pain syndrome, chronic neuropathic pain, trigeminal neuralgia, fibromyalgia, spinal syrinx, spina bifida, and cauda equina.

Prior to initiating oral ketamine therapy, pain duration ranged between 24 and 600 months (mean, 177 months; median, 126 months). Oral ketamine dose also varied from 25 to 600 mg divided among 3 doses (mean, 216 mg/day; median, 200 mg/day).

The reduction in numerical pain rating scale (NPRS) ranged from 2 to 10 out of 10. Prior to initiation of any ketamine therapy, the mean pain score was 8.71; after ketamine, this score dropped to 2.89 with a mean pain reduction of 5.82. A positive correlation was observed between total daily ketamine dose and NPRS reduction from baseline to the time of data collection. There was, however, no correlation between total daily dose and the frequency of reported adverse effects.

Ketamine treatment duration ranged from 2 to 89 months; 59% of patients reported ongoing ketamine use. There was no relationship between duration of use and adverse effect frequency; this, the investigators noted, indicated that longer term sublingual ketamine use does not increase adverse effects. There was also no association between use duration and NPRS, indicating a sustained response to treatment.

No serious adverse events were reported. Adverse effects were self-reported; 24% of patients reported any adverse effects, 15% reported excessive daytime drowsiness, 9% reported lightheadedness or dizziness, 3% reported nightmares, and 3% reported dysphoria.

Of the 7 patients who reported adverse effects, only 2 discontinued treatment due to these effects. No reports of renal impairment, cystitis, or hepatotoxicity were noted.

The primary reason for discontinuation of oral ketamine therapy was the inability to obtain an ongoing Australian Government Department of Health authority approval of sublingual ketamine in 2019; at this time, the approving body indicated concerns about a lack of evidence for long-term ketamine use. Other reasons for discontinuation included an inability to afford the therapy, drowsiness, loss of efficacy, desire to conceive a child, and insertion of a spinal cord stimulator.

Associated reductions in the use of opioids, gabapentinoids, and benzodiazepines were experienced by 59% of patients, and a complete cessation of analgesic agents was reported by 39% of patients.

Study limitations include its retrospective, nonrandomized, and nonblinded nature; the self-report of adverse effects; the use of a subjective pain rating scale; and the use of medical record data, which may omit information. Researchers acknowledge that the study size is relatively small.

“Sublingual ketamine is safe and provides a substantial reduction in pain scores and other analgesic agents to use in chronic nonmalignant pain management,” the researchers concluded. “It is indicated in various chronic pain conditions and has an excellent safety profile, with no association between the frequency of adverse effects and duration of therapy or total daily dosages.”

“The study has also shown that the ‘safe’ does may be higher than the previously suggested maximum of 1.5 mg/kg/dose or 5 mg/kg/day,” they added.


Maudlin B, Gibson SB, Aggarwal A. Long term safety and efficacy of sub-lingual ketamine troches/lozenges in chronic non-malignant pain management. Intern Med J. Published online June 6, 2021. doi:10.1111/img.15404