Sublingual ketamine is safe and effective in treating chronic non-malignant pain

Sublingual ketamine is a safe, effective analgesic therapy for chronic non-malignant pain with no significant side effects or side effects associated with long-term treatment. This is evident from research 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 shown to be an effective treatment for chronic pain, especially in patients with opioid-induced hyperalgesia, chronic neuropathic pain, and complex regional pain syndrome.

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

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The study cohort comprised 29 patients from a tertiary pain service in the metropolitan region who received sublingual ketamine lozenges or lozenges between 2012 and 2019. The patients had previously undergone a comprehensive, multidisciplinary assessment of pain management and were given in-patient subcutaneous ketamine infusion as part of an opioid detox or central sensitivity management for chronic neuropathic pain.

All enrolled patients received a continuous subcutaneous ketamine infusion of 0.1 to 1.2 mg / kg / hour, titrated according to pain and tolerability, with a maximum daily dose of 500 mg. Patients who responded to these infusions were given ketamine lozenges or lozenges.

The initial dose of the lozenges was 25 mg three times a day, titrated for tolerance and effect of the patient. Patients had personal visits to the pain clinic every 3 months to review treatment.

Overall, the study population was heterogeneous and comprised 19 women and 10 men between the ages of 26 and 67 years. No statistically significant effects of gender on the measured endpoints were found.

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

Before the start of oral ketamine therapy, the duration of pain was between 24 and 600 months (mean 177 months; median 126 months). The oral ketamine dose also varied from 25 to 600 mg, divided into 3 doses (mean 216 mg / day; median 200 mg / day).

The reduction in the numerical pain rating scale (NPRS) ranged from 2 to 10 out of 10. Before starting ketamine therapy, the mean pain score was 8.71; after ketamine this value fell to 2.89 with a mean pain reduction of 5.82. A positive correlation was observed between the total daily ketamine dose and the NPRS reduction from baseline to the time of data collection. However, there was no correlation between the total daily dose and the frequency of side effects reported.

The duration of treatment with ketamine ranged from 2 to 89 months; 59% of patients reported persistent use of ketamine. There was no relationship between the duration of use and the frequency of side effects; this, the researchers said, indicated that prolonged sublingual ketamine use did not increase side effects. There was also no association between duration of use and NPRS, suggesting a sustained response to treatment.

No serious adverse events were reported. Side effects were self reported; 24% of patients reported side effects, 15% reported excessive daytime sleepiness, 9% lightheadedness or dizziness, 3% reported nightmares, and 3% reported dysphoria.

Of the 7 patients who reported side effects, only 2 stopped treatment because of these side effects. No reports of renal impairment, cystitis or hepatotoxicity have been noted.

The main reason for discontinuing oral ketamine therapy was the inability to obtain ongoing approval from the Australian Department of Health for sublingual ketamine in 2019; At that point, the regulatory body raised concerns about the lack of evidence of long-term use of ketamine. Other reasons for discontinuation included inability to afford therapy, drowsiness, loss of effectiveness, desire to have a child, and use of a spinal cord stimulator.

An associated reduction in opioid, gabapentinoid, and benzodiazepine use was noted in 59% of patients, and 39% of patients reported complete analgesic discontinuation.

The limitations of the study include its retrospective, non-randomized, and non-blinded nature; self-disclosure of side effects; the use of a subjective pain rating scale; and the use of medical records that may omit information. Researchers acknowledge that the study size is relatively small.

“Sublingual ketamine is safe and provides significant reductions in pain scores and other analgesics used to treat chronic non-malignant pain,” the researchers concluded. “It is indicated for various chronic pain conditions and has an excellent safety profile, with no connection between the frequency of side effects and the duration of therapy or the total daily dose.”

“The study also showed that the ‘safe’ dose can be higher than the previously proposed maximum of 1.5 mg / kg / dose or 5 mg / kg / day,” they added.


Maudlin B, Gibson SB, Aggarwal A. Long-term safety and effectiveness of sublingual ketamine lozenges / lozenges in the treatment of chronic non-malignant pain. Intern Med J. Published online June 6, 2021. doi: 10.1111 / img.15404

This article originally appeared on Clinical Pain Advisor

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