Ketamine*

The NMDA-glutamate receptor is a calcium channel closely involved in the development of central sensitization of dorsal horn neurons, which transmit pain signals (Figure).⁴x4Richens, A. The basis of the treatment of epilepsy: neuropharmacology. in: M. Dam (Ed.) A practical approach to epilepsy. Pergamon Press, Oxford; 1991: 75–85Google ScholarSee all References At normal resting membrane potentials, the channel is blocked by magnesium and is inactive.⁵x5Mayer, M.L., Westbrook, G.L., and Guthrie, P.B. Voltage-dependent block for Mg²⁺ of NMDA responses in spinal cord neurones. Nature. 1984; 309: 261–263

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Ketamine is a dissociative anesthetic that has analgesic properties in subanesthetic doses.³x3Visser, E. and Schug, S.A. The role of ketamine in pain management. Biomed Pharmacother. 2006; 60: 341–348

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In some countries, both the racemic mixture and the S-enantiomer are commercially available for clinical use; in the USA, only the racemic mixture is marketed. Because of its greater affinity and selectivity for the NMDA-receptor, the S-enantiomer (parenterally) is about 4 times more potent an analgesic than the R-enantiomer, and twice as potent as the racemic mixture.¹⁰x10Øye, I., Hustveit, O., Maurset, A. et al. The chiral forms of ketamine as probes for NMDA receptor function in humans. in: T. Kameyama, T. Nabeshima, E.F. Domino (Eds.) NMDA receptor related agents: Biochemistry, pharmacology and behavior. 1991. NPP Books, Ann Arbor; 1991: 381–389Google ScholarSee all References^{, 11}x11White, P.F., Ham, J., Way, W.L., and Trevor, A.J. Pharmacology of ketamine isomers in surgical patients. Anesthesiology. 1980; 52: 231–239

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Ketamine has other actions, some of which also may contribute to its analgesic effect. These include interactions with other calcium and sodium channels, dopamine receptors, cholinergic transmission, and noradrenergic and serotoninergic re-uptake (intact descending inhibitory pathways are necessary for analgesia), together with opioid-like and anti-inflammatory effects.¹⁵x15Meller, S. Ketamine: relief from chronic pain through actions at the NMDA receptor?. Pain. 1996; 68: 435–436

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The analgesic effects of ketamine have been utilized in a wide range of clinical settings using various regimens and routes of administration.

Postoperative analgesia: Two systematic reviews of 37 RCTs of subanesthetic doses of ketamine as an adjunct to opioid-based postoperative analgesia concluded that:

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  IV and ED ketamine reduce opioid requirements and possibly chronic post-surgical pain

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  CIVI (typically 120–600 microgram/kg/h) is best for surgery associated with high opioid requirements, although a single IV dose (typically 150 microgram–1 mg/kg) may suffice for minor surgery

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  adding ketamine to IV patient-controlled analgesia (PCA) is not effective.¹⁸x18Subramaniam, K., Subramaniam, B., and Steinbrook, R.A. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg. 2004; 99: 482–495

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  | Google ScholarSee all References^{, 19}x19Bell, R.F., Dahl, J.B., Moore, R.A., and Kalso, E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006; ()

  PubMed

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Chronic non-cancer pain: A review of subanesthetic doses of ketamine for chronic non-cancer pain (mostly neuropathic but also ischemic, fibromyalgia, post-whiplash, etc.) identified 29 RCTs and concluded that:

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  ketamine provides relief

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  undesirable effects can limit its use

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  because of a lack of data, long-term use should be restricted to a controlled trial.²⁰x20Bell, R.F. Ketamine for chronic non-cancer pain. Pain. 2009; 141: 210–214

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There is RCT evidence of benefit in complex regional pain syndrome type 1.²¹x21Sigtermans, M.J., van Hilten, J.J., Bauer, M.C. et al. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009; 145: 304–311

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Cancer pain: A systematic review of ketamine as an adjunct to opioids in cancer pain found only two studies of sufficient quality,²³x23Yang, C.Y., Wong, C.S., Chang, J.Y., and Ho, S.T. Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain. Can J Anaesth. 1996; 43: 379–383

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Miscellaneous: Ketamine can provide analgesia during painful procedures, e.g., change of burns dressings.⁵⁰x50Richardson, P. and Mustard, L. The management of pain in the burns unit. Burns. 2009; 35: 921–936

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“Burst” ketamine: There is some evidence that short-term “burst” treatment with ketamine may have relatively long-term benefit in both cancer and non-cancer pain. For example, in patients taking regular strong opioids for ischemic limb pain, a single 4 h IV infusion of ketamine 600 microgram/kg reduced opioid requirements during a week of observation.⁵⁴x54Mitchell, A.C. and Fallon, M.T. A single infusion of intravenous ketamine improves pain relief in patients with critical limb ischaemia: results of a double blind randomised controlled trial. Pain. 2002; 97: 275–281

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There is increasing concern about the potential for urinary tract toxicity with ketamine (see Box A). Thus, in patients with a prognosis of months to years, it is probably best to first try a “burst” approach and limit the long-term regular use of ketamine to situations where this fails. Even then, after 2–3 weeks of satisfactory analgesia with regular ketamine, an attempt can be made to tail off the ketamine over several weeks. Although this may fail and the dose may need to be increased again, for some patients benefit persists without ketamine for weeks to months, or with a smaller maintenance dose.⁵⁷x57Fallon M. Personal communication, 2010.Google ScholarSee all References

PO ketamine undergoes extensive first-pass hepatic metabolism mainly to norketamine (via CYP3A4).⁵⁸x58Hijazi, Y. and Boulieu, R. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos. 2002; 30: 853–858

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Ketamine causes tachycardia and intracranial hypertension. After anesthetic use, most patients experience vivid dreams, misperceptions, hallucinations and alterations in body image and mood as emergent (psychotomimetic) phenomena, i.e., as the effects of a bolus dose wear off. These occur to a lesser extent with the subanesthetic analgesic doses given PO or CSCI, and generally can be controlled by concurrent administration of a benzodiazepine (e.g., diazepam, midazolam) or haloperidol.²⁴x24Mercadante, S., Arcuri, E., Tirelli, W., and Casuccio, A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage. 2000; 20: 246–252

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

Bioavailability: 93% IM; 45% nasal; 30% SL; 30% PR; and 20% PO.⁶²x62Chong, C.C., Schug, S., Page-Sharp, M., and Ilett, K. Bioavailability of ketamine after oral or sublingual administration. [abstract]. Pain Med. 2006; 7: 469

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

Time to peak plasma concentration: no data SC; 30 min PO; 1 h norketamine.⁶⁴x64Grant, I.S., Nimmo, W.S., and Clements, J.A. Pharmacokinetics and analgesic effects of IM and oral ketamine. Br J Anaesth. 1981; 53: 805–810

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Plasma half-life: 1–3 h IM; 3 h PO; 12 h norketamine.⁶⁵x65Domino, E.F., Domino, S.E., Smith, R.E. et al. Ketamine kinetics in unmedicated and diazepam premedicated subjects. Clin Pharmacol Ther. 1984; 36: 645–653

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Duration of action: 30min–2 h IM; 4–6 h PO, sometimes longer.⁶⁶x66Rabben, T., Skjelbred, P., and Oye, I. Prolonged analgesic effect of ketamine, an N-methyl-D-aspartate receptor inhibitor, in patients with chronic pain. J Pharmacol Exp Ther. 1999; 289: 1060–1066

PubMed

Current or past history of psychiatric disorder; epilepsy, glaucoma, hypertension, heart failure, ischemic heart disease and a history of cerebrovascular accidents.⁶⁷x67Ward, J. and Standage, C. Angina pain precipitated by a continuous subcutaneous infusion of ketamine. J Pain Symptom Manage. 2003; 25: 6–7

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Plasma concentration increased by diazepam. CYP3A4 inhibitors, e.g., clarithromycin, ketoconazole, increase plasma concentrations of ketamine and reduce those of norketamine, but the clinical relevance of this is unclear.⁶⁸x68Hagelberg, N.M., Peltoniemi, M.A., Saari, T.I. et al. Clarythromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ketamine. Eur J Pain. 2009; 16: 625–629Google ScholarSee all References

For full list, see manufacturers' PI.

Generally dose-related. Occur in about 40% of patients when given CSCI; less PO: psychotomimetic phenomena (euphoria, dysphasia, blunted affect, psychomotor retardation, vivid dreams, nightmares, impaired attention, memory and judgement, illusions, hallucinations, altered body image), delirium, dizziness, diplopia, blurred vision, nystagmus, altered hearing, hypertension, tachycardia, hypersalivation, nausea and vomiting, erythema and pain at injection site. Urinary tract toxicity (see Box A).

When used at higher doses in anesthesia, tonic-clonic movements are very common (>10%); however, these have not been reported after PO use or with the lower parenteral doses used for analgesia.

Ketamine can be abused (or diverted) and careful monitoring is essential.

Because of concerns around urinary tract toxicity (see Box A), consider using ketamine long-term only if a “burst” approach has failed (see Pharmacology).

Dose recommendations vary considerably but ketamine is often started in a low dose PO (see below). An oral solution can be compounded by a local pharmacy (Box B). Alternatively, patients can be supplied with vials of ketamine and 1 mL graduated syringes. Two needles (one as an air vent) should be inserted in the stopper of the vial to facilitate withdrawing the ketamine; sterility is not necessary for PO administration.

In some centers, an initial test dose is given to assess tolerability and efficacy. The prophylactic concurrent administration of a benzodiazepine or an antipsychotic is also routine in some but not all centers, where it is reserved for more select circumstances (see below). Long-term success, i.e., both pain relief and tolerable undesirable effects, varies from <20% to about 50%.³¹x31Kannan, T.R., Saxena, A., Bhatnagar, S., and Barry, A. Oral ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients. J Pain Symptom Manage. 2002; 23: 60–65

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Ketamine (generic)

Injection 50 mg/mL, 10 mL vial=$7; 100 mg/mL, 5 mL vial=$11.

Ketalar^® (Pfizer)

Injection 10 mg/mL, 20 mL vial=$18; 50 mg/mL, 10 mL vial=$33; 100 mg/mL, 5 mL vial=$33.

Although use as an analgesic is off-label, ketamine injection can be prescribed both in hospitals and in the community.