Oral Ketamine Prescription Guidelines
Oral ketamine should be reserved for specialist use in refractory pain or treatment-resistant depression, with prescribing limited to palliative care, pain management, or psychiatric specialists due to lack of commercially available oral formulations, significant psychotomimetic risks, and limited evidence for this route compared to parenteral administration.
Current Clinical Position
Pain Management Context
Oral ketamine is NOT a first-line or routine analgesic and should only be considered by specialists when other therapeutic options have failed in complex chronic pain patients 1.
The Journal of the American Geriatrics Society explicitly states that ketamine use is currently restricted to specialists in palliative care, pain management, and emergency medicine due to serious adverse effects (psychotomimetic experiences, hypertension) and lack of experience with commercially available oral formulations 1.
The National Comprehensive Cancer Network found limited data for ketamine in cancer pain, with a double-blind randomized controlled trial showing no significant difference between ketamine and placebo for cancer pain management 1.
Treatment-Resistant Depression Context
Oral ketamine shows therapeutic potential for treatment-resistant depression with accumulating evidence from case reports, case series, and three randomized controlled trials demonstrating efficacy 2, 3.
Oral ketamine has demonstrated effectiveness in severe depression, depression with suicidal ideation, and as an augmentation agent with conventional antidepressants 2.
Meta-analysis shows oral ketamine has a pooled effect size of g = 0.633 at 21-28 days for treatment-resistant depression 3.
Dosing Strategies
Bioavailability Considerations
- Only 20-25% of oral ketamine reaches systemic circulation, requiring approximately 2.0-2.5 mg/kg oral dosing to achieve equivalence to intravenous administration 2, 4.
Pain Management Dosing
Starting dose for ketamine-naive patients: 0.5 mg/kg racemic ketamine or 0.25 mg/kg S-ketamine as a single oral dose 5.
Increase by the same amount if required, typically administered 3-4 times daily for continuous analgesic effect 5.
Reported dose ranges in clinical practice: 0.25 to 7 mg/kg per occasion, or fixed doses from 50 mg to 300 mg per occasion 2, 4.
When converting from parenteral to oral ketamine, maintain the same daily dosage initially, then slowly titrate based on clinical effect and adverse effects 5.
The oral injection fluid formulation can be administered orally 5.
Depression Management Dosing
Weight-based dosing has ranged from 0.25 to 7.0 mg/kg per session 4.
Fixed dosing has ranged from 25 mg to 300 mg per session 4.
Dosing strategies include both one-size-fits-all approaches and individualized dose discovery processes 4.
Safety Profile and Monitoring Requirements
Adverse Effects
Psychotomimetic effects (dysphoria, nightmares, hallucinations) are the primary concern, especially at higher doses and with prolonged use 1, 6.
Co-administration with benzodiazepines minimizes psychotomimetic effects 6, 7.
Sedation is the predominant side effect across multiple studies 6.
Hypertension risk requires cardiovascular monitoring 1.
Monitoring Requirements
Continuous cardiac monitoring and pulse oximetry during administration 6.
Regular assessment of sedation level, respiratory status, and hemodynamics 6, 7.
Monitor for nausea and vomiting, particularly in patients with gastrointestinal conditions 7.
Contraindications
- Absolute contraindications include: uncontrolled cardiovascular disease, pregnancy, active psychosis, severe liver dysfunction, and high intracranial/ocular pressure 7, 8.
Clinical Evidence Quality
Pain Management Evidence
The evidence base for oral ketamine in chronic pain is predominantly descriptive (case reports and case series) without consistent dose-response relationships 5.
A quarter-century of experience supports oral ketamine use for acute and chronic pain in children and adults, though formal research remains limited 2.
Lack of robust efficacy evidence and poor safety profile do not support routine use in chronic pain management 5.
Depression Evidence
Three randomized controlled trials support efficacy in treatment-resistant depression, with dropout rates and reasons similar between ketamine and control arms 2.
Maintenance ketamine treatment (including oral route) appears effective in sustaining antidepressant effects, with tachyphylaxis, cognitive impairment, addiction, and serious renal/urinary problems appearing uncommon 9.
The literature on oral ketamine remains thin, requiring more investigation regarding pharmacokinetics, physiologic effects, abuse potential, and comparative efficacy to other routes 4.
Practical Prescribing Considerations
Route Comparison
Oral administration is less effective than local infiltration for pain management 6.
Subcutaneous administration provides similar analgesia to IV route, while intramuscular route lacks analgesic efficacy 6.
Intravenous ketamine remains the best-studied approach, though oral ketamine is the most practical for outpatient maintenance treatment 2.
Treatment Duration and Frequency
For depression, dosing schedules have included multiple daily dosing, daily dosing, and intermittent dosing 2.
Maintenance treatment strategies are necessary due to transient antidepressant effects 9.
Allow sufficient time for absorption and peak effect before considering supplementation 8.
Critical Caveats
The use of oral ketamine for depression must be considered experimental until higher quality studies become available 4.
No commercially available oral formulation exists, constraining broader use 1.
The pharmacologically active metabolite norketamine contributes to analgesic effects of oral ketamine 5.
Direct comparative studies between different formulations and routes of delivery are needed to inform treatment decisions 3.
Practitioners must be able to identify and rescue patients from unintended deep sedation or general anesthesia 8.