Ketamine

Ketamine hydrochloride is a Schedule III (CIII) controlled substance and an arylcyclohexylamine dissociative anesthetic. The FDA-approved reference product is Ketalar injection. There is no FDA-approved oral or topical ketamine product. Esketamine, the S-enantiomer, is a separate FDA-approved nasal spray (Spravato) available only under a REMS. Lake Hills Pharmacy compounds ketamine topical cream and rapid dissolve tablets as a 503A pharmacy on patient-specific prescriptions.

Ketalar is FDA labeled as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation, for induction of anesthesia before other general anesthetics, and as a supplement to other anesthetic agents. Prescribers use compounded topical and oral ketamine preparations for pain. In October 2023 FDA warned about potential risks of compounded ketamine, including oral forms, used for psychiatric disorders without monitoring.

Ketamine is a noncompetitive NMDA receptor antagonist that blocks the channel pore and reduces glutamate signaling, producing dissociation, analgesia and amnesia. It also acts on opioid, monoaminergic, muscarinic and sodium channels, and causes indirect sympathomimetic stimulation through catecholamine release.

Bioavailability is about 93% intramuscularly, about 45 to 50% intranasally, and about 16 to 30% by oral or sublingual routes because of first-pass metabolism. Absorption from topical preparations is low and variable. Ketamine is N-demethylated mainly by CYP3A4 and CYP2B6 to the active metabolite norketamine, then hydroxylated, conjugated and excreted in urine. Elimination half-life is about 2.5 hours.

• Patients in whom a significant elevation of blood pressure would be a serious hazard.
• Known hypersensitivity to ketamine or any component of the preparation.

• Abuse, misuse and dependence: ketamine is CIII. It is used illicitly for dissociative effects and has been used to facilitate sexual assault. Tolerance, psychological dependence and withdrawal (craving, anxiety, fatigue) are reported with repeated use. Assess risk, limit quantities and monitor for misuse.
• Hemodynamic effects: transient rises in blood pressure and heart rate; use caution in hypertension, coronary disease, heart failure, aneurysm and thyrotoxicosis.
• Emergence and psychiatric reactions: vivid dreams, hallucinations, confusion, and delirium; psychiatric events can persist for days to weeks. Use caution with a history of psychosis.
• Respiratory depression and airway: risk increases with high doses, rapid administration and other CNS depressants. Hypersalivation and laryngospasm can occur.
• Liver injury: recurrent use is associated with cholestatic hepatobiliary dysfunction. Cystitis: chronic use is associated with lower urinary tract symptoms, ulcerative or hemorrhagic cystitis and reduced bladder capacity.
• Increased intracranial and intraocular pressure, and impaired driving or machine operation after doses. Repeated or prolonged anesthetic exposure in children under 3 years or in the third trimester may affect brain development.

• CNS depressants (opioids, benzodiazepines, barbiturates, alcohol, sedating antihistamines): additive sedation and respiratory depression; prolonged recovery.
• Theophylline and aminophylline: lowered seizure threshold.
• Sympathomimetics, vasopressin, MAO inhibitors and psychostimulants: increased blood pressure and heart rate.
• CYP3A4 and CYP2B6 inhibitors may increase, and inducers may decrease, ketamine exposure.

Common: dissociation, dizziness, sedation, diplopia, nystagmus, nausea and vomiting, raised blood pressure and heart rate, and emergence reactions. Also reported: hypersalivation, tonic-clonic-like movements, rash and injection-site pain, liver enzyme elevation, and urinary tract symptoms with chronic use. Topical use: local irritation and erythema.

Safe use during pregnancy, labor and delivery has not been established, and repeated anesthetic exposure in the third trimester may affect fetal brain development. Limited data describe ketamine in breast milk; an alternative is generally preferred during breastfeeding, and use is a prescriber decision.

Blood pressure and heart rate, mental status, signs of misuse or diversion, urinary symptoms, and baseline and periodic liver tests (including alkaline phosphatase and GGT) with recurrent dosing. Check the state prescription monitoring program as required.

• Ketalar (ketamine hydrochloride) Injection Prescribing Information.
• Spravato (esketamine) Nasal Spray Prescribing Information, Janssen Pharmaceuticals.
• U.S. Food and Drug Administration. FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders (October 2023).
• Lexicomp Drug Information, Wolters Kluwer.