Cite as: Goordeen A, Zemmedhun G, Abd-Elsayed A, et al. Ketamine infusion and its role in chronic pain. ASRA Pain Medicine News 2022;47. https://doi.org/10.52211/asra080122.036

Introduction

Ketamine has been approved by the FDA for induction of general anesthesia, providing dose-dependent hypnosis that is characterized by dissociative amnesia, unresponsiveness, and potent analgesia while maintaining spontaneous respiration and protective airway reflexes. It also has been used off-label as an infusion for intraoperative pain control in chronic pain patients. It is a phencyclidine that influences multiple pathways in the central nervous system, its greatest effect being antagonism of the N-methyl-D-aspartate (NMDA) receptor. The NMDA receptor is a G protein-coupled ionotropic glutamate receptor present at spinal and supraspinal areas involved in nociceptive signal transmission.¹ Part of ketamine’s analgesic property can be explained by its ability to occupy some brain and spinal cord mu-opioid receptors. Its high lipid solubility allows for rapid awakening after bolus dosing due to its redistribution into inactive tissue sites. Hepatic metabolism results in the formation of active metabolite norketamine, which carries 20%-30% of its parent compound’s potency; this contributes to the lingering effects displayed after continuous ketamine infusions.

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In addition to induction and maintenance of anesthesia, evidence supports the use of ketamine in acute and chronic pain states, analgesia, and mood disorders. 

Studies have shown ketamine use to be beneficial in the treatment of chronic pain syndromes, particularly those with a neuropathic component.¹ Prolonged stimulation of nociceptive pathways in chronic pain leads to the upregulation and activation of dorsal horn NMDA receptors. This causes an amplification of pain signals sent to the brain, a phenomenon known as central sensitization. The inhibition of descending pain pathways as well as central anti-inflammatory effects account for ketamine’s strong analgesia.

Indications and Infusion Guidelines

In addition to induction and maintenance of anesthesia, evidence supports the use of ketamine in acute and chronic pain states, analgesia, and mood disorders. Its roles in the treatment of chronic pain are promoting the reversal of central sensitization and decreasing opioid-induced hyperalgesia for conditions such as phantom limb pain, migraine headache, complex regional pain syndrome (CRPS), fibromyalgia, traumatic spinal cord injury, and postherpetic neuralgia.¹ According to the American Society of Anesthesiologists (ASA) and American Society of Regional Anesthesia and Pain Medicine Practice Guidelines for Chronic Pain Management,² indications have the following evidenced-based dosing recommendations.

• CRPS, medium-term improvement (moderate evidence): 22 mg/h for 4 days or 0.35 mg/kg/h for 4 hours repeated in 10 consecutive days.
• Pain related to spinal cord injury, short-term improvement (weak evidence): Investigators used variable methods, one protocol used a total dose of 80 mg infused over 5 hours.
• Conditions such as mixed neuropathic pain, phantom limb pain, fibromyalgia, migraine headache, low back pain, ischemic pain, and postherpetic neuralgia have weak or no evidence supporting the immediate improvement of pain.

The discordance of literature available to date has made establishing a standard protocol challenging. Despite the heterogeneity, the practice guidelines recommend initiating therapy with 80 mg of ketamine infused over at least 2 hours, and, if subsequent therapies are indicated, dosing should be based on clinical response.²

Side Effects and Contraindications

The adverse effects associated with ketamine administration are dose-dependent and can be classified as either sympathomimetic or neuropsychiatric.¹ Increases in blood pressure, heart rate, cardiac output, and pulmonary artery pressure make it unsuitable for use in individuals with endocrine disorders, such as pheochromocytoma, and cardiovascular conditions, such as uncontrolled hypertension, unstable angina, or high-risk coronary artery disease. Although airway reflexes are typically preserved, aspiration in obtunded individuals can occur due to increased airway secretions and bronchodilation. Patients with elevated intraocular or intracranial pressure such as those with space-occupying intracranial lesions or head trauma are not candidates, as increases in intracranial pressure and cerebral blood flow may arise. There have been reported cases of transient reversible transaminitis resulting from ketamine exposure; therefore, use in those with severe liver disease is not advisable. It is important to note that most side effects (>95%) are transient and will resolve following discontinuation. Psychiatric effects and potential for abuse make employing therapy in those with preexisting psychosis, delirium, or substance abuse infeasible. Pretreatment with a benzodiazepine has been shown to decrease the incidence of ketamine-induced psychosis.

Monitoring

The ASA standard of monitoring for general anesthesia consists of oxygenation, ventilation, circulation, and temperature. Subanesthetic doses of ketamine, such as those used in infusion therapy, provide relatively stable hemodynamics with minor respiratory compromise in healthy individuals. It is recommended that heart rate, blood pressure, pulse oximetry, and level of consciousness be monitored during infusion treatments. Patients at high risk of adverse respiratory events should also have their end-tidal carbon dioxide continuously monitored. Due to the potential for cardiopulmonary sequela, personnel trained in airway management and advanced cardiac life support should be on site. The chronic pain and acute pain practice guidelines advise that those administering the infusion be trained in conscious sedation because the dosage used in the treatment of chronic pain is higher than that used for mood disorders.²

Legalities

The U.S. Drug Enforcement Administration (DEA) has listed ketamine as a schedule III controlled substance, meaning it has a low to moderate potential for abuse, psychological dependence, and physical dependence. As ketamine is a controlled substance, registration with the DEA is required for its administration. Regulatory boundaries including licensing and permits can be identified by evaluating local and state laws. Ketamine is currently FDA approved for the induction and maintenance of anesthesia. Concern associated with long-term dosing arises from cases of cognitive impairment and bladder dysfunction seen in rodents.³ There are no FDA regulations regarding off-label use for the management of chronic pain and psychiatric disorders. Off-label use is common and supported by evidence-based medicine. It is not required by law, but most guidelines recommend having a physician on call or in close proximity who can safely manage and secure the airway if the need arises. ⁴

Insurance and Cost

Neither federal nor private medical insurance providers cover the cost of ketamine infusion therapy for any disorders. Patients must pay out of pocket for treatment. Each treatment plan depends on the local market, the disorder being treated, and the number of infusion treatments needed. The average cost to the patient is anywhere between $415-$1,350 per infusion session depending on the length of the infusion and the dose used.⁵

Conclusion

Currently, there is no FDA-approved indication for using ketamine infusion as a treatment modality, but recent data has shown growing evidence for its efficacy in treating a wide range of psychiatric and chronic pain disorders. Unfortunately, there is no single consensus or guideline on the infusion dosage or the number of infusion treatments needed to treat any disorder. Given the high cost of each infusion treatment session and no insurance coverage, this treatment modality is only accessible to a few select patients. Due to the side effects of ketamine, the infusion sessions must be completed in a clinic setting with basic vital sign monitoring and with a physician capable of managing and securing the airway on call or nearby.

Ashley Goordeen, MD, is an anesthesiology specialist in the department of anesthesiology at the University of Texas Medical Branch in Galveston.

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Gelilla Zemmedhun, MD, is an anesthesiology specialist in the department of anesthesiology at the University of Texas Medical Branch in Galveston.

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Alaa Abd-Elsayed, MD, MPH, FASA, is an associate professor in the department of anesthesiology at the University of Wisconsin School of Medicine and Public Health in Madison.

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Michael Yolland, MD, is an anesthesiologist at the University of Texas Medical Branch in Galveston.

References

1. Fischer M, Abd-Elsayed A. Ketamine infusion therapy. In: Abd-Elsayed A. (ed.) Infusion Therapy. Springer, Cham; 2019. Available at: https://doi.org/10.1007/978-3-030-17478-1_2.
2. American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Practice guidelines for chronic pain management: an updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology 2010;112(4), 810-33. https://doi.org/10.1097/ALN.0b013e3181c43103 
3. Sun L, Lam W, Wong Y, et al. Permanent deficits in brain functions caused by long-term ketamine treatment in mice. Hum Exper Toxicol 2010;30(9):1287-96. https://doi.org/10.1177/0960327110388958
4. Wilkinson ST, Sanacora G. Considerations on the off-label use of ketamine as a treatment for mood disorders. JAMA 2017;318(9),793-4. https://doi.org/10.1001/jama.2017.10697 
5. Lone Star Infusion. About - Allison Wells, MD: Ketamine Infusion Therapy Houston, TX. (n.d.). Retrieved from https://www.lonestarinfusion.com/about. Accessed October 20, 2021.