Oral Ketamine for Chronic Pain: Towards an Evidence-Based Dosing Regimen

Given the clinical urgency of the ongoing opioid crisis, alternative oral analgesics, like ketamine, are increasingly relevant. However, clinical trials and systematic reviews of oral ketamine for chronic cancer-related and non-cancer pain have employed a variety of dosing regimens. This key heterogeneity across studies may prove confusing to clinicians seeking to translate this literature into clinical practice. The present review sought to identify gaps in dosing regimens and adverse events reported in this literature.

A comprehensive search of MEDLINE, EMBASE, and PUBMED databases was conducted from January 1965 to July 2022 to identify studies on oral ketamine's analgesic effects upon chronic pain. Data regarding ketamine dosage, inter-dose interval, pain relief, and adverse events were extracted. Only studies employing a range of 0.5 mg/kg BID-QID, or equivalent dosing, were included for benefit and risk analysis. Among 1556 initially identified studies, screening processes removed 17 duplicates, leaving 1539 for abstract review and 27 articles for data extraction. Due to dosing and study design inconsistencies, only 5 studies met criteria for quantitative analysis.

Mean pain scores were determined to be 7.72/10 at the onset of treatment and 3.2/10 after 30-90 days of treatment. A simple linear regression analysis demonstrated a correlation between average pain scores and treatment duration (R-square=0.76).

Oral ketamine benefits chronic pain, which may include allodynia and/or hyperalgesia, as deduced from various levels of evidence. Our evaluation suggests that oral ketamine has potential efficacy comparable to opioids for hyperalgesia and allodynia, and is generally well tolerated for chronic pain. Oral ketamine 0.5 mg/kg, when dosed 3 times daily for 7-90 days, can achieve efficacy with an acceptable safety profile. This dosage regimen helps inform a need for standardized, evidence-based oral ketamine dosing for clinical care and future research when used as a component of a multimodal regimen for chronic cancer and non-cancer pain.