Oral Ketamine as an Analgesic Therapy: Systematic Review of Randomized Clinical Trials

Background: Ketamine is a dissociative anesthetic with analgesic properties, traditionally administered intravenously. Its use in oral form is increasingly utilized and appealing for outpatient and palliative settings due to easier administration, but evidence for its safety and efficacy is limited. This review systematically evaluated randomized controlled trials of oral ketamine for pain management.

Design and Participants: Systematic review of six RCTs published between 1999 and 2022, included 479 adult participants from six countries. Pain types studied included cancer pain, neuropathic pain, burn-associated pain, inflammatory dental pain, and acute musculoskeletal pain.

Results

• Cancer pain: Mixed results; one trial showed opioid-sparing benefit, but the largest study (214 patients) found no difference versus placebo.
• Neuropathic pain: Oral ketamine was as effective as methadone in chronic neuropathic pain, particularly reducing allodynia.
• Dental pain: A 10 mg dose reduced anesthetic requirements, intraoperative pain, and postoperative analgesic use.
• Burn pain: Doses of 6 mg/kg provided optimal pain relief with fewer adverse effects; higher doses caused hallucinations and hypersalivation.
• Musculoskeletal pain: Oral ketamine alone was superior to aspirin plus ketamine for short-term relief. Adverse effects: Commonly reported but severity often under-described; included hallucinations, hypersalivation, dizziness, and nausea.
• Three trials comparing oral ketamine to other analgesics found no significant differences in pain relief.
• Two placebo-controlled trials showed mixed findings: one demonstrated reduced anesthetic use and intraoperative pain in dental patients, while another in neuropathic cancer pain found no difference from placebo.
• One trial in burn pain identified 6 mg/kg as the optimal dose balancing analgesia with side effects.
• Oral ketamine was as effective as methadone for refractory neuropathic pain.
  Adverse events (hallucinations, hypersalivation, dizziness, nausea) were common, though severity was inconsistently reported.

Commentary: This is the first systematic review of RCTs evaluating oral ketamine. The evidence is preliminary, limited by small sample sizes, heterogeneous pain types, and variable outcome measures. Oral ketamine may have an opioid-sparing role and benefit in select refractory neuropathic or burn-related pain, but results for cancer pain are disappointing. Safety concerns, including psychotropic side effects and potential misuse, remain barriers.Anecdotally, I have seen benefit to oral ketamin in my work, with the greatest benefit occurring after an IV infusion at subanesthetic dose and I am interested in new literature on this topic.

Bottom Line: Oral ketamine remains an investigational option. While it may be helpful for refractory neuropathic and burn pain, it has not shown benefit in cancer-related pain and carries significant risks. Until larger, high-quality trials clarify efficacy and safety, oral ketamine should be used cautiously and only under expert supervision.

Source: Umbacia MA, Calsina-Berna A, Hernández-Rico AN, Mendoza-Montenegro FA, Gallo-Hincapié JS, Ruiz Cadena LM, Martínez-Díaz MF, Del Castillo Visbal S, Correa-Morales JE. Oral Ketamine as an Analgesic Therapy: Systematic Review of Randomised Clinical Trials. Journal of Pain & Palliative Care Pharmacotherapy. 2025;39(3):353-362. doi:10.1080/15360288.2025.2496520.

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