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Emerging Trends in Pain Medication Management: Back to the Future: A Focus on Ketamine

close up of gloved hands filling a syringe


Providers face many challenges when faced with pain management. Pain is complex, difficult to understand and diagnose, and especially enigmatic to manage. The discovery of nonopioid agents for pain management has become particularly important considering the ongoing opioid epidemic. This review is focused on revisiting ketamine, an agent that has historically been used for anesthesia, in new ways to manage pain. Ketamine has unique pharmacologic properties that may prevent the development of pain as well as reduce chronic pain. This has led to the use of ketamine for perioperative analgesia as well as chronic pain syndromes. In select patients with pain refractory to other treatment modalities, ketamine may provide much needed relief.

In the midst of the opioid epidemic in the United States, the pressure on primary care providers to decrease opioid prescribing continues to intensify. Responsible and compassionate providers are in desperate need of alternative treatment options for severe pain syndromes. One emerging trend has been a significant increase in ketamine infusions in outpatient clinics. Several studies have highlighted the efficacy and safety of repeated ketamine infusions in ambulatory patients.1, 2 While facility protocols vary, patients report every 2-4 weeks for repeat infusions, and many have reported significant relief. Currently, there are more than 20 clinics across 12 states advertising for ketamine infusions for either pain or depression.3 Ketamine used in ambulatory settings is off-label but not illegal, and generally requires facilities to create limited-use protocols for subanesthetic doses of ketamine to be infused in the outpatient setting where monitoring requirements are decreased. To highlight why ketamine is such an attractive option for refractory pain conditions, we present a brief review of ketamine’s history and pharmacotherapy.

Ketamine is Food and Drug Administration approved for induction of anesthesia prior to other general anesthetic agents, sole anesthetic agent for procedures not requiring skeletal muscle relaxation, and to supplement low-potency anesthetic agents.4 Ketamine was synthesized in the early 1960s as a safer alternative to phencyclidine. Phencyclidine, also known as PCP, was initially thought to be suitable for anesthesia, but a high incidence of prolonged emergence delirium rendered the compound unsuitable for use in humans. Researchers hypothesized that an agent with a shorter duration of action would reduce delirious effects, and a series of PCP derivatives were synthesized by Dr. Calvin Lee Stevens, PhD. On August 3, 1964, Guenter Corssen, MD and Edward F. Domino, MD administered the PCP derivative now known as ketamine to the first human subject at Jackson Prison in Michigan. The researchers described dreamlike or disconnected effects in patients administered ketamine, leading to the classification of ketamine as a dissociative anesthetic.5 These dissociative properties and emergence of alternative agents has limited the use of ketamine for modern-day anesthesia. Newer studies utilizing subanesthetic doses show promise for ketamine as an analgesic agent.

Mechanism of Action

Ketamine is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that reduces the neurotransmission of glutamate, the primary excitatory neurotransmitter in the central nervous system.6 The reduction of excitatory neurotransmission reduces pain sensation transmission, resulting in an analgesic effect. Ketamine may have other central and peripheral sites of action including opioid receptors, voltage-gated sodium and potassium channels, serotonin and dopamine reuptake, and nitric oxide pathways5, 6, 7 Ketamine rapidly crosses the blood–brain barrier, corresponding to a quick onset for anesthesia or acute analgesia.4, 5, 8 Ketamine is susceptible to drug–drug interactions by cytochrome enzyme inhibitors, but cytochrome enzyme inducers have limited effects because hepatic clearance is already high prior to enzyme induction.7 Ketamine has been studied in a variety of administration routes, including intravenous (IV), intramuscular (IM), subcutaneous (SC), oral, rectal, nasal, transdermal, epidural, and intrathecal. Currently, only the injectable form of ketamine is Food and Drug Administration approved for use in the United States, and ketamine for oral administration must be compounded. However, ongoing clinical trials researching oral ketamine are promising for the development and approval of oral ketamine preparations in the future. Ketamine may have a role in both preventing the development of pain and reducing chronic pain, which has led to the use of ketamine for perioperative analgesia as well as chronic pain syndromes.

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-Meredith W. Crumb, PharmD, BCPS, Candace Bryant, PharmD, BCPS, Timothy J. Atkinson, PharmD, BCPS, CPE

This article originally appeared in the August issue  of The American Journal of Medicine.

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