Chronic pain is defined as pain that persists for more than three months beyond the time frame of healing. It stands as a pervasive health challenge, emerging as a primary contributor to years lost due to disability on a global scale, particularly in the United States. The escalating prevalence of chronic pain is intricately linked to the aging demographic, giving rise to a surge in cases encompassing both acute injuries and long-term health conditions.

Ketamine, developed in the 1960s and first used as an anesthetic agent in the early 1970s, is classified by the FDA as a drug with a wide margin of safety that is used for both acute and chronic pain (CNS Neurosci Ther 2013;19:370-80). Ketamine demonstrates efficacy in cases where standard treatments have proven ineffective. Notably, ketamine's analgesic effects can be observed even at subanesthetic doses, making it a valuable option for patients with opioid tolerance and who are at high risk of opioid-related respiratory depression.

Ketamine's effects include NMDA antagonism, reducing central sensitization and impacting learning, memory, and synaptic plasticity. It can reverse opioid tolerance and interacts with various receptors and sodium channels. Its anti-inflammatory actions, reducing cytokines like IL-6, contribute to its analgesic properties (CNS Neurosci Ther 2013;19:370-80; Health Psychol Res 2021;9:25535).

The bioavailability of ketamine is influenced by its route of administration and metabolism. It undergoes extensive hepatic metabolism primarily via microsomal enzymes, resulting in the formation of norketamine (CNS Neurosci Ther 2013;19:370-80). Ketamine can be administered via parenteral, oral, sublingual, transdermal, and intranasal routes (Table).

Table: The route of administration and metabolism of ketamine.

Table: The route of administration and metabolism of ketamine.
Table: The route of administration and metabolism of ketamine.

In 2018, consensus guidelines on the utilization of ketamine for acute and chronic pain management highlighted the potential of ketamine as an adjunct therapy for opioid-dependent/tolerant patients and aimed to curtail opioid usage during surgeries or in individuals with chronic conditions like sickle cell crises.

Except for complex regional pain syndrome, or CRPS, there is a lack of evidence supporting the use of ketamine for intermediate or long-term pain relief in these specific situations (Reg Anesth Pain Med 2018;43:456-66).

Neuropathic pain

Chronic neuropathic pain often presents with sensory loss in the affected area. While ketamine shows promise in reducing pain, clinicians must balance its benefits against potential side effects and the specific cause of the patient's neuropathic pain (Pain 2005;117:231-5).

Fibromyalgia

Both ketamine and midazolam improve pain scores for fibromyalgia, with no significant difference between them. This raises doubts about the suitability of ketamine as a fibromyalgia treatment (Eur J Pain 2011;15:942-9).

“Notably, ketamine's analgesic effects can be observed even at subanesthetic doses, making it a valuable option for patients with opioid tolerance and who are at high risk of opioid-related respiratory depression.”

CRPS

Studies indicate that low-dose ketamine effectively reduces pain scores in CRPS patients compared to placebo up to week 12. Despite potential side effects, its demonstrated efficacy suggests consideration when conventional treatments fail (Pain 2009;147:107-15). Orhurhu et al. note short-term analgesic benefits with I.V. ketamine for refractory chronic pain, but long-term benefits require further study for optimized patient selection and treatment protocols (Anesth Analg 2019;129:241-54).

There is burgeoning interest in the application of I.V. ketamine infusion, particularly in low doses. Its versatility is evident in addressing a spectrum of conditions, ranging from the management of acute pain in opioid-tolerant patients to the treatment of chronic noncancer pain, severe depression, and palliative care. Typically, low-dose ketamine is administered at levels below 1 mg/kg/hour or through bolus doses of less than 0.5 mg/kg, as outlined in the existing literature. Importantly, these doses are carefully calibrated to avoid inducing moderate sedation or general anesthesia (J Pain Res 2017;10:787-95).

To safely administer intravenous ketamine, facilities must have trained personnel and necessary equipment, including oxygen, airway devices, advanced airway equipment, and defibrillators, due to potential cardiorespiratory complications. The ASA Committee on Pain Medicine advises that patients undergoing ketamine treatment be overseen by a physician specialist well-versed in pain medicine as an integral component of a comprehensive multidisciplinary treatment regimen.

In 2019, the FDA granted approval for Spravato (esketamine) nasal spray to be used in conjunction with an oral antidepressant to treat depression in adults who have not found relief with other antidepressant medications. Administered by the patient under health care professional supervision in a certified medical facility, the nasal spray is not for take-home use and undergoes monitoring for at least two hours.

Formal research on ketamine's effectiveness and safety in chronic pain, especially with long-term oral use, is limited. Recommended starting doses for ketamine-naive patients include 0.5 mg/kg of racemic ketamine or 0.25 mg/kg of S-ketamine as a single oral dose, with adjustments as necessary. Despite the potential contribution of the pharmacologically active metabolite norketamine to its analgesic effect, the lack of robust evidence and suboptimal safety profile should lead to caution against routine oral ketamine use in chronic pain management. Its consideration as an adjunct therapy may be warranted in complex chronic pain cases where other treatments have failed (Eur J Pain 2010;14:466-72).

Ketamine acts as an NMDA receptor antagonist at lower doses for pain relief, but at higher doses it affects multiple receptors, including dopamine D2 and monoaminergic and opioid receptors. Its inhibition of monoamine transporters contributes to psychotomimetic effects. These complexities underscore its nuanced effects across dose ranges and receptor systems (Pain Rep 2018;3:e674).

Side effects include increased heart oxygen demand, raised intracranial pressure, hallucinations, dissociation, and distressing memories. Overdose can lead to loss of consciousness, respiratory depression, and severe psychotropic symptoms, especially with frequent or high doses, which is particularly risky for certain populations (Reg Anesth Pain Med 2018;43:521-46). Recreational use is linked to bladder issues like pain, epithelial damage, and ureter stenosis (Health Psychol Res 2022;10:38247).

Ketamine should be avoided in patients with severe or uncontrolled cardiovascular disease, severe liver disease, increased intracranial pressure, elevated intraocular pressure, pregnancy, and underlying psychiatric conditions associated with psychosis.

The evidentiary support for ketamine in the context of chronic pain exhibits variability contingent upon the specific condition and dosage parameters. Most studies scrutinizing ketamine's efficacy tend to be characterized by small sample sizes, lack of control groups, and inadequately implemented blinding methodologies. Larger-scale investigations encompassing a broader spectrum of conditions are evidently lacking.

Ketamine holds promise as a valuable tool in the management of chronic pain, particularly in cases refractory to traditional therapies. Concerns regarding adverse effects and the need for further research to establish its long-term efficacy and safety underscore the importance of caution and ongoing investigation. The landscape shifts when it comes to chronic noncancer pain, as evidence is exceedingly scarce, and safety data for long-term or repeated treatments are lacking.

Alexander Bautista, MD, MBA, FASA, ASA Committee on Pain Medicine, and Associate Professor, Department of Anesthesiology and Perioperative Medicine, University of Louisville, Louisville, Kentucky.

Alexander Bautista, MD, MBA, FASA, ASA Committee on Pain Medicine, and Associate Professor, Department of Anesthesiology and Perioperative Medicine, University of Louisville, Louisville, Kentucky.

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Steven Halle, MD, ASA Committee on Pain Medicine, and Associate Professor, Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

Steven Halle, MD, ASA Committee on Pain Medicine, and Associate Professor, Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

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Matthew Tan, MD, ASA Committee on Pain Medicine, and Interventional Pain Management Fellow, Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois.

Matthew Tan, MD, ASA Committee on Pain Medicine, and Interventional Pain Management Fellow, Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois.

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