Ketamine has been clinically available for almost five decades, classified by the U.S. Food and Drug Administration as an anesthetic induction agent in dosages ranging between 1 and 4.5 mg/kg. However, within the previous 20 years its use as a treatment in subanesthetic dosages for acute and chronic pain and depression has increased dramatically, which has contributed to a national shortage of ketamine.¹ Chronic pain and depression are inextricably intertwined, with the presence of one predisposing to the other. Consequently, many therapies effective for depression have also been shown to be effective for chronic pain, such as antidepressants, electroconvulsive therapy, and repetitive transcranial stimulation.² Ketamine is just the latest in a string of therapies to treat two of the leading causes of years lost to disability in the world.

The guidelines cover indications, contraindications, preprocedure testing and infusion monitoring, dosing guidelines, defining a positive treatment response, preventing and treating adverse effects, and the value of repeat infusions and postinfusion oral and nasal N-methyl-D-aspartate (NMDA) receptor antagonists, including but not limited to ketamine.

Despite ketamine’s popularity and longevity in clinical practice, extensive variations still exist in patient selection, dosing, and monitoring as a treatment for pain, depression, and to a lesser extent, post-traumatic stress disorder (PTSD). This is in part a predictable consequence of the drug being off-patent and widely available for an extended period of time. Likely no pharmaceutical company stands to benefit from an acute or chronic pain indication and therefore large-scale clinical trials and postmarketing surveillance are lacking.

The demand for guidelines to inform patient selection and standardization of treatment has come from multiple sources, including health insurance companies, government regulatory agencies, patient advocacy groups, and hospitals and other medical facilities. To answer those calls, ASRA, in conjunction with the American Academy of Pain Medicine (AAPM) and American Society of Anesthesiologists (ASA), published comprehensive guidelines on the use of ketamine for acute and chronic pain on June 5, 2018, in Regional Anesthesia and Pain Medicine.^1,3 The guidelines cover indications, contraindications, preprocedure testing and infusion monitoring, dosing guidelines, defining a positive treatment response, preventing and treating adverse effects, and the value of repeat infusions and postinfusion oral and nasal N-methyl-D-aspartate (NMDA) receptor antagonists, including but not limited to ketamine.

Ketamine is a chemical derivative of the illicit drug phencyclidine (PCP). PCP was used as early as 1958 as an anesthetic, but severe emergence delirium led to its being abandoned for use in humans.⁴ Ketamine was first administered to 20 volunteers from a prison population in 1964 for the purposes of general anesthesia, and shortly thereafter, subsequent studies used ketamine in subtherapeutic doses.⁵

Ketamine is postulated to be involved in signaling at more than 10 distinct receptor pathways. Primarily, ketamine exhibits its analgesic, antidepressant, and cognitive effects via the NMDA receptors situated in the central nervous system.^6,7 The binding of glutamate, the primary excitatory neurotransmitter, to NMDA receptors is blocked by ketamine, resulting in decreased neuronal activity. Ketamine has also been found to act on sodium and potassium channels, as well as opioid, γ-aminobutyric acid A (GABA-A), dopamine D2, nicotinic and muscarinic cholinergic, and a ligand of the serotonin 5-HT2A receptor, among others.^8-11

Because of ketamine’s involvement in numerous signaling pathways, a wide array of side effects may ensue, including cognitive, cardiovascular, and gastrointestinal effects.¹² The consensus guidelines for chronic pain therefore recommend as contraindications pregnancy, active psychosis, poorly controlled cardiovascular disease, severe hepatic disease (avoid), moderate hepatic disease (caution), elevated intracranial pressure, elevated intraocular pressure, and active substance abuse.³ In the acute pain guidelines, because many patients may present with a history of opioid dependence and acute pain is a more ‘urgent’ indication than chronic pain, active substance abuse is not considered a contraindication.¹

Clinical studies have examined the role of ketamine in multiple pain syndromes, including spinal cord injury pain, peripheral neuropathic pain, fibromyalgia, ischemic pain, cancer pain, headaches, and complex regional pain syndrome (CRPS). For mixed neuropathic pain, fibromyalgia, cancer pain, ischemic pain, headache, and spinal pain, the authors found weak or no evidence for immediate improvement in symptoms. However, in patients with CRPS, the authors concluded that intravenous ketamine may provide improvement for up to week 12 (moderate evidence); for spinal cord injury pain, they found weak evidence to support short-term improvement.³

For chronic pain, the evidence suggests that higher doses administered over longer time periods and more frequent dosing schedules provide greater benefit. The consensus guidelines recommend bolus doses of up to 0.35 mg/kg, infusions ranging from 0.5–2 mg/kg per hour (1 mg/kg per hour for acute pain), and a total dosage of at least 80 mg infused over a period of more than two hours.³

The authors assert that no testing prior to a ketamine infusion is necessary for healthy individuals. Patients who are catecholamine-depleted may experience an unmasking of ketamine’s direct negative inotropic effects. Therefore, in individuals with suspected or at high risk of cardiovascular disease, baseline echocardiogram testing should be used to rule out ischemic heart disease. Ketamine is metabolized in the liver and has infrequently been associated with elevated liver function tests at high doses. Thus, the authors recommended that individuals with liver dysfunction who are at risk of liver toxicity (eg, alcohol abuse, chronic hepatitis) or who are expected to receive high doses of ketamine at frequent intervals, baseline and postinfusion liver function tests be considered on a case-by-case basis.³

Patients receiving ketamine infusions have typically been refractory to other therapies. Based on this and studies performed in acute and chronic pain conditions, the authors concluded that objective measures of benefit (eg, 30% pain relief), in addition to satisfaction and comparable validated measures for different conditions (eg, Oswestry Disability Index for back pain, reduction in opioid usage), be used to designate a positive treatment response.³

One of the most difficult questions the authors wrestled with was the requirement for available personnel throughout the course of the infusion. Because of the high dosages employed; short-term risks including but not limited to aspiration, cardiovascular instability, and psychomimetic effects; and the fact that ketamine is considered a controlled substance, the guideline’s authors recommended that the supervising clinician have substantial clinical experience with ketamine, be advanced cardiac life support certified, and be equipped and certified to provide moderate sedation (eg, an anesthesiologist, critical care physician, emergency medicine doctor, pain management physician). The administering clinician, registered nurse, or physician’s assistant should also have completed formal training in the safe administration of moderate sedation. For infusion doses exceeding 1 mg/kg per hour or bolus doses greater than 0.35 mg/kg, a monitored setting containing resuscitative equipment and immediate access to rescue medications and personnel who can treat emergencies should be used. However, the authors cautioned that those dose ranges may vary from patient to patient.³

The extensive resources required to provide ketamine infusions have led many clinicians to explore alternative therapies for acute and chronic pain such as oral ketamine, intranasal ketamine, and other NMDA receptor antagonists. Based on limited studies, the authors concluded that oral ketamine, intranasal ketamine, or dextromethorphan could be used in lieu of serial infusions in short-term responders.³

Despite the dramatic increase in the use of ketamine for acute and chronic pain, many questions remain unanswered. These include whether ketamine can prevent the transition from acute to chronic pain; if significant tachyphylaxis occurs, reducing benefit with repeated administration; and how best to identify which individuals are likely to respond to treatment. To address those issues, practitioners should aim to perform large-scale clinical trials with long-term follow-up and to establish ketamine treatment–based registries.

References

1. Schwenk E, Viscusi ER, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for acute pain management from the American Society of Regional Anesthesia and Pain Medicine (ASRA), American Academy of Pain Medicine (AAPM) and the American Society of Anesthesiologists (ASA). Reg Anesth Pain Med. 2018;43(5):456–466. https://doi.org/10.1097/AAP.0000000000000806
2. Radvansky BM, Puri S, Sifonios AN, Eloy JD, Le V. Ketamine—a narrative review of its uses in medicine. Am J Ther. 2016;23: e1414–e1426. https://doi.org/10.1097/MJT.0000000000000257
3. Cohen SP, Bhatia A, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American Society of Regional Anesthesia and Pain Medicine (ASRA), the American Academy of Pain Medicine (AAPM), and the American Society of Anesthesiologists (ASA). Reg Anesth Pain Med. 2018;43(5):521–546. https://doi.org/10.1097/AAP.0000000000000808
4. Chopra K, Arora V. An intricate relationship between pain and depression: clinical correlates, coactivation factors and therapeutic targets. Expert Opin Ther Targets. 2014;18:159–176. https://doi.org/10.1517/14728222.2014.855720
5. Domino EF, Chodoff P, Corssen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965;6:279–291.
6. Greifenstein FE, DeVault M, Yoshitake J, Gajewski JE. A study of a 1-aryl cyclo hexyl amine for anesthesia. Anesth Analg. 1958;37:283–294.
7. Cohen SP, Liao W, Gupta A, Plunkett A. Ketamine in pain management. Adv Psychosom Med. 2011;30:139–161. https://doi.org/10.1159/000324071
8. Orser BA, Pennefather PS, MacDonald JF. Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors. Anesthesiology. 1997;86:903–917.
9. Niesters M, Aarts L, Sarton E, Dahan A. Influence of ketamine and morphine on descending pain modulation in chronic pain patients: a randomized placebo-controlled cross-over proof-of-concept study. Br J Anaesth. 2013;110:1010–1016. https://doi.org/10.1093/bja/aes578
10. Sinner B, Graf BM. Ketamine. Handb Exp Pharmacol. 2008;182:313–333. https://doi.org/10.1007/978-3-540-74806-9_15
11. Seeman P, Ko F, Tallerico T. Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. Mol Psychiatr 2005;10: 877–883. https://doi.org/10.1038/sj.mp.4001682
12. Sleigh J, Harvey M, Voss L, Denny B. Ketamine—more mechanisms of action than just NMDA blockade. Trends Anaesth Crit Care. 2014;4: 76–81. https://doi.org/10.1016/j.tacc.2014.03.002
13. Gorlin AW, Rosenfeld DM, Ramakrishna H. Intravenous sub-anesthetic ketamine for perioperative analgesia. J Anaesthesiol Clin Pharmacol. 2016;32:160–167. https://doi.org/10.4103/0970-9185.182085