Ketamine’s Utilization for Chronic Pain Management

Amit Aggarwal is an anesthesiology resident physician at The University of Texas Medical Branch in Galveston. He has a strong interest in pursuing a fellowship in interventional pain management. In the future, he desires to continue further research projects dedicated to both fields, with specific interests in nonopioid chronic pain management and new treatment modalities. 

Tiraj Parikh is an anesthesia resident at Wake Forest Baptist Medical Center in North Carolina. He is very interested in pursuing pain management. His research interests include education, differential diagnosis, and developing computer and mobile applications for these fields. He would like to continue further research on non-opiate pain management in the future

Ketamine, discovered in the 1960s, has been widely accepted as an anesthetic agent, sometimes used intraoperatively and in trauma settings. Ketamine is a phencyclidine derivative, which is a compound primarily classified as a hallucinogen¹ The mechanism of action is competitive antagonism of the N-methyl-D-aspartate (NMDA) receptor. This receptor responds to glutamate, an excitatory neurotransmitter, and is prominent primarily in the hippocampus and cerebral cortex.² The NMDA receptors are vital for synaptic plasticity and memory. This receptor is also involved in amplification of pain signals and with opioid tolerance.¹ Along with the NMDA receptor, ketamine also interacts with opioid receptors to suppress pain transmission, mainly at lower doses. 

Research studies show evidence of a dose-response relationship for ketamine use, primarily for analgesic effects.³ Recent articles have shown a new association between treatment of major depression and suicidal ideation with ketamine.¹ At lower doses, ketamine modulates the central sensory processing of pain for analgesic effects. It can be used as an adjuvant to opioid medications; however, paradoxically, ketamine can counteract opioid-induced hyperalgesia and decrease opioid tolerance.⁴ Higher doses of ketamine cause interaction with other receptors, including nicotinic, voltage-gated sodium channels, monoamine transporters and dopamine D2 receptors. By activating other receptors, patients typically have psychomimetic effects such as hallucinations, agitation, anxiety and euphoria. 

Ketamine is primarily administered intraoperatively, postoperatively for acute pain, and for chronic pain patients. Ketamine has multiple methods of delivery, with the intravenous method being most commonly used for ketamine infusions for chronic pain. Infusions can be given intermittently or continuously. Intermittent IV infusions typically start at 0.25 to 0.6 mg/kg per hour (maximum daily dose, 60 mg), whereas continuous IV infusions start at 0.05 to 0.15 mg/kg per hour (maximum dose, 30 mg per hour; not well established).⁵ Subcutaneous ketamine is given at 0.1 to 0.6 mg/kg, titrated to effect (maximum daily dose, 500 mg). Intrathecal ketamine has been shown to be efficacious in chronic pain, especially in the management of terminally ill cancer patients.⁶ Oral ketamine is less often considered for chronic pain, except in palliative care settings, and is initially administered at 0.5 mg/kg per day, in three to four divided doses, and then doses are titrated to effect with increments of 5 mg per dose (maximum daily dose, 800 mg).⁷ Unfortunately, there are no formal guidelines on the most effective dosage and method of administration for the use of ketamine for chronic pain, so more large-scale trials are necessary to produce more standardized care. 

Current Research
Along with the anesthetic component of ketamine for induction and maintenance, ketamine has been implemented for acute and chronic pain management by decreasing opioid-induced hyperalgesia and reversing central sensitization.⁸ Neuropathic pain has a particularly increased response to ketamine’s analgesic effects. When patients develop chronic pain, central sensitization occurs over time, which is defined by increased nociceptive responsiveness, with amplification of the pain signals and upregulation of dorsal horn NMDA receptors.⁸ Ketamine’s analgesic effects on the NMDA receptors also include anti-inflammatory actions. A 2016 study used ketamine in rabbits with osteoarthritis, with a significant response of decreasing pro-inflammatory mediators, including interleukin-10.⁹ Additionally, a different study showed that intraoperative ketamine administration reduced postoperative interleukin-6 levels.¹

Another common type of chronic pain that ketamine is used for is cancer-related neuropathic pain.¹⁰ Chemotherapy-induced neuropathy, specifically with paclitaxel, was studied in the early 2010s to determine ketamine’s efficacy in animal studies. Systemic injections of ketamine were found to mitigate thermal hyperalgesia in rats, with one study noting that male rats required a higher dose to reduce pain thresholds compared with female rats.10 A retrospective study in China, ranging from 2004 to 2018, showed that parenteral ketamine infusion in refractory cancer pain resulted in a favorable response to ketamine with the concurrent use of more than one co-analgesic, with the most common side effects being drowsiness, hypertension and nightmares.¹¹

Multiple studies from the 1990s to the 2010s indicate that for neuropathic pain, intrathecal administration of ketamine reduced mechanical allodynia the most, indicating that the spinal cord had the most NMDA receptors with effective responses. Common chronic pain syndromes for which ketamine has been used include complex regional pain syndrome (CRPS) at 22 mg per hour for four days or 0.35 mg/kg per hour for four hours for 10 consecutive days as an infusion, and spinal cord injuries, with one protocol using a total dose of 80 mg infused over five hours. Other neuropathic pain conditions, such as fibromyalgia, phantom limb pain, migraine headache and postherpetic neuralgia, have yet to undergo extensive research for finding proper ketamine dosing and administration. Treatments are primarily initiated with 80 mg of ketamine infused over at least two hours, with significant responses, but infusions should be adjusted clinically for doses and time.⁸

Ketamine has demonstrated a dose-dependent adverse effect profile.3 The most commonly reported psychomimetic effects include euphoria, dysphoria, dissociation, hallucination and anxiety.¹ Major sympathomimetic side effects include hypertension, tachycardia, increased pulmonary artery pressure and increased cardiac output, but most of these reactions are transient and only occur while ketamine is actively being administered.⁸ There are also psychiatric side effects which ketamine is most known for, including psychosis. Many genitourinary effects have also been seen in chronic ketamine abuse,¹² including urinary urgency/frequency, nocturia, hematuria and dysuria, although these studies were conducted mainly in subjects taking significantly higher doses than those given for chronic pain. Ketamine dependence and withdrawal are additional side effects that add another barrier to FDA approval for use in chronic pain.¹³ Recently, there was an addendum to the FDA recommendations stating that prior to starting ketamine (and intermittently while taking ketamine), it is important to test liver function, because studies have shown an increased risk for hepatobiliary dysfunction.¹⁴ Ketamine is metabolized by the cytochrome enzymes CYP3A4 and CYP2B6 in the liver, thus medications that inhibit and accelerate the rate of these enzymes may affect the pharmacokinetics of this drug.¹⁵ Interestingly, through inhibiting many UDP-glucuronosyltransferase enzymes, ketamine also plays a role in the metabolism of other opioid analogs, including morphine and codeine.¹⁶

Although there are many studies on the efficacy of ketamine for chronic pain, the number of randomized controlled trials with placebo testing is limited. Ketamine is not a first-line treatment for chronic pain, and so there are limited studies in which solely ketamine was given for chronic pain; thus, some confounding factors may affect these studies due to the use of ketamine as an adjunct treatment.

Future Studies
There is continuing research on the benefit of ketamine for treatment-resistant depression. A link between depression and chronic pain is known, and so treatment of the different facets of pain using a multimodal approach has shown promising results. Given that there is a large surge of interest in ketamine’s subanesthetic doses for antidepressant effects, further studies are being conducted, with meta-analyses and systematic reviews to strengthen ketamine’s claim for depression compared with placebo drugs and other medications. Research has been conducted for almost two decades now, with the latest discovery of intranasal esketamine as one of the first rapid-acting antidepressant medications in March 2019. Both IV ketamine and intranasal esketamine have demonstrated rapid improvement in patients with major depressive disorder and treatment-resistant depression, although effectiveness is of short duration with discontinuation of therapy.^17-18

Given ketamine’s high potential for abuse and concern about major side effects, the FDA required a risk evaluation and mitigation strategy for mandatory training for esketamine prescribing by healthcare providers and practitioners for specific healthcare settings.¹⁹ A 2022 systematic review that examined the benefit of ketamine in patients with concomitant depression and acute or chronic pain suggested future research comparing the effect of the different enantiomers of ketamine (racemic ketamine, arketamine and esketamine) for concomitant depression and chronic pain.²⁰ Ketamine has yet to be prescribed in an outpatient setting, with the exception of intrathecal chronic pain management. 

Conclusion
Ketamine has been extensively studied for many years and in multiple projects on its application in chronic pain management, with its optimal effects seen in patients through intrathecal administration for neuropathy. While the FDA has yet to approve ketamine infusions for chronic pain management and cancer-related neuropathy, long-term psychiatric effects continue to be studied, including improvement of depression. Further research may strengthen ketamine’s off-label uses, especially for comorbidities associated with chronic pain. 

References
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