Response to Ketamine Article

Dear Editor:

I am really disappointed that the article about the ketamine study¹ was accepted for publication. After reading the article many practitioners with little experience with ketamine will come away with the impression that it is not a useful agent for alleviating pain. The authors themselves acknowledged in their discussion that the patients were under-dosed (0.5 mg/kg/day for all patients=1.25 mg/h=30 mg per day). Most of the literature suggests a starting dose of 0.1–0.2 mg/kg/h, so for a 60-kg patient the dose is 6–12 mg/h=72–144 mg/day±weight adjustment. Our ketamine protocol at the San Diego Hospice and The Institute for Palliative Medicine recommends the latter dosing strategy, and our clinical experience has been positive.

The description “randomized, double-blind, placebo-controlled trial” gives far too much weight to a small study for which the authors were “totally blind” to the appropriate dosing (in effect, both arms were placebo-treated due to under-dosing).

I have attached an approach to the dosing of ketamine with a list of references in the hope that future researchers will use this as a starting point.

References

1. Salas S, Frasca M, Planchet-Barraud B, Burucoa B, Pascal M, Lapiana J, Hermet R, Castany C, Ravallec F, Laundou A, Auquier P, Duffaud F, Baumstarck K: Ketamine analgesic effect by continuous intravenous infusion in refractory cancer pain: considerations about the clinical research in palliative care. J Palliat Med 2012;15:287–293.

Ketamine

Ketamine is a dissociative anesthetic that has analgesic properties in subanesthetic doses. Ketamine is a potent NMDA-receptor-channel blocker, binding to the phencyclidine site when the channels are open in the activated state. It is available clinically as a racemic mixture. Compared to the R-enantiomer, the S-enantiomer has greater affinity and selectivity for the NMDA receptor and is more potent. Ketamine has other actions which may also contribute to its analgesic effect, including interactions with other calcium and sodium channels, cholinergic transmission, noradrenergic and serotonergic reuptake inhibition, and μ, δ, and κ opioid-like effects. Ketamine has a wide therapeutic range making overdose difficult. The LD₅₀ in animals is ∼100 times the average IV human dose and 20 times the average IM human dose used for anesthesia.

Plasma half-life: 1–3 h (ketamine); 12 h (norketamine)

Onset of action: 5 min IM; 15–30 min SC; 30 min PO

Duration of action: 30 min–2 h IM; 4–12 h PO; may be given by CSCI or IV for continuous action

Metabolism: Extensive first-pass metabolism to norketamine.

Norketamine is one-third as potent as ketamine as an anesthetic, and equipotent as an analgesic (Palliative Care Formulary, 2002). Serum norketamine levels after oral ketamine administration are 2 to 3 three times higher than after parenteral ketamine use. The peak analgesic effect of oral ketamine corresponds with the peak serum level of norketamine (NK), not ketamine (K). The K:NK ratio after prolonged infusion equals 3:1. K:NK after chronic PO dosing equals 3:2–3, almost 1:1.

Less than 10% of ketamine is excreted unchanged, half in the feces and half renally. Long-term use of ketamine leads to hepatic enzyme induction and enhanced ketamine metabolism.

Dosing and Administration:

Ketamine is both water- and lipid-soluble, allowing convenient dosing by a variety of routes: PO, PR, SC, CSCI, IM, IV drip and bolus, and transdermal. Use of intranasal solutions and powders has also been reported.

PO: Starting dose: 10–25 mg q 8 h (intervals of q 4–12 have been reported). Increase up to 0.5–1 mg/kg q 8 h. Maximum reported dose is 200 mg q 6 h.

Transdermal: 5–15% in PLO; often combined with ketoprofen 10% and lidocaine 5% (compounded dosage form).

SC: 10–25 mg (0.2–0.5 mg/kg) intermittent; commonly used for painful wound debridement and dressing changes.

CSCI: Recommend dosage titration: Starting at 0.1–0.2 mg/kg/h. Loading dosing has been reported, but may increase psychomimetic side effects. Maximum reported dose: 3.6 g/24 h. Monitor and assess pain and vital signs; reassure patients they may experience a dream-like feeling. Continue titration and monitoring until satisfactory pain relief or undesirable side effects occur. Small doses of an anti-sialagogue or a benzodiazepine may be necessary to control excessive secretions and dysphoric feelings.

Relative Contraindications:

Listed as relative contraindications derived from the anesthesia literature, which uses ∼10–20 times higher dosing

• Severe CV disease, such as angina, heart failure, or malignant hypertension (increased BP, CO, HR)

• Intraocular pressure pathology (increased IOP pathology reported in animals, not reproducible in subsequent human studies)

• Previous psychotic illness (case reports of successful use in schizophrenia in the literature)

• Hyperthyroidism or thyroid medication use (case reports of HTN and SVT)

• Porphyria (no clinical evidence of worsening porphyria, but does elevate serum porphyric markers)

• H/O CVA (small case series of patients with known intracranial CSF obstruction experienced increased ICP)

Undesirable Effects: Psychotomimetic phenomena (euphoria, dysphoria, blunted affect, psychomotor retardation, vivid dreams, nightmares, poor concentration, illusions, hallucinations, altered body image), delirium, dizziness, diplopia, blurred vision, nystagmus, altered hearing. Erythema and pain at injection site. Side effects less frequent with PO use.

References:

Annetta MG, Iemma D, Garisto C, et al.: Ketamine: new indication for an old drug. Curr Drug Targets 2005;6:789–794.

Bell RF, et al.: Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review. (Cochrane review). Acta Anaesthesiol Scand 2005;49:1405–1428.

Chung WJ, Pharo GH: Successful use of ketamine infusion in the treatment of intractable cancer pain in outpatient. J Pain Symptom Manage 2007;33:2–5. (Letter to the editor)

Correll, GE, et al.: Subanesthetic ketamine infusion therapy: A retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med 2004;5:263–275.

DeKock M, et al.: “Balanced analgesia” in the perioperative period. Is there any place for Ketamine? Pain 2001;92:373–380.

Dyck JB, Wallace MS, Lu JQ, Rossi SS, Yaksh TL: Pharmacokinetics of lidocaine administered by computer-controlled infusion pump in humans. Eur J Pain 1997;1:141–148.

Goldberg ME, et al.: Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Pain Physician 2005;8:175–179.

Hijazi Y, et al.: Pharmacokinetics and hemodynamics of ketamine in intensive care patients with brain or spinal cord injury. Br J Anesthesia 2003;90:155–160.

Hocking G, et al.: Ketamine in chronic pain management: an evidence based review. Anesth Analgesia 2003;97:1730–1739.

Leung A, Wallace MS, Ridgeway B, Yaksh T: Concentration-effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain. Pain 2001;91:177–187.

Okon T: Ketamine: an introduction for the pain and palliative medicine physician. Pain Physician 2007;10:493–500.

Visser E, Schug SA: The role of ketamine in pain management. Biomed Pharmacother 2006;60:341–348.

Wallace MS, Braun JC, Schulteis G: Post-delivery of alfentanil and ketamine has no effect on intradermal capsaicin induced pain and hyperalgesia. Clin J Pain 2003;18:373–379.

Wallace MS, Dyck JB, Rossi SS, Yaksh TL: Computer-controlled lidocaine infusion for the evaluation of neuropathic pain after peripheral nerve injury. Pain 1996;66:69–77.

Wallace MS, Ridgeway BM, Leung AY, Gerayli A, Yaksh TL: Concentration-effect relationship of intravenous lidocaine on the allodynia of complex regional pain syndrome types I and II. Anesthesiology 2000;92:75–83.

Webster LR, Walker MJ: Safety and efficacy of prolonged outpatient ketamine infusions for neuropathic pain. Am J Therapeutics 2006;13:300–305.

White M, et al.: Pharmakokinetics of S(+) ketamine derived from target controlled infusion. Br J Anesthesia 2006;96:330–334.