Ketamine for Pain

Throughout the last 60 years, treatment for chronic pain has been following somewhat of a trial-and-error approach, with opioids, non-steroidal anti-inflammatory drugs, anticonvulsants, and antidepressants at the forefront of pain management.

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Ketamine, a versatile dissociative anesthetic drug, can be used as an alternative to traditional approaches at subanesthetic doses, demonstrating promising potential for treatment-resistant forms of chronic pain and catalyzing an upsurge of scientific interest in this compound. Aside from its efficacy, this increased interest is, at least partially, thought to be a result of ketamine's noninterference with patient functionality, in addition to its co-occurring antidepressant effects.

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In recent years, ketamine has been increasingly employed as an effective treatment for various chronic pain syndromes, particularly neuropathic pain conditions. Ketamine is thought to primarily exert its rapid-acting, potent analgesic effects by blocking N-methyl-D-aspartate (NMDA) receptors, offering patients some much sought-after relief. 

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NMDA receptors are ionotropic glutamate receptors that occupy spinal and supraspinal sites and aid in the transmission of messages from damaged tissue. Ketamine’s blockade of NMDA receptors helps to augment anti-nociceptive systems, thus blocking the detection of painful stimuli.

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It is probably also that ketamine’s analgesic action is mediated by temporary enhancement of the brain’s ability to form new connections between neurons and to modify and adapt its structure and function in response to experience. 

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The Analgesic Versatility of Ketamine 

Ketamine was first synthesized in 1962 by American organic chemist Calvin Lee Stevens of the pharmaceutical laboratory Parke-Davis while he was searching for a safer alternative to phencyclidine (PCP). Two years later, psychopharmacology pioneer Ed Domino identified ketamine’s anesthetic properties when he administered doses of 1.0 - 2.0 mg/kg to 20 volunteers from a prison population, determining that the drug was worthy of further pharmacological and clinical investigation.

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Since then, ketamine has displayed unique therapeutic versatility being used to treat a plethora of medical conditions, its practicality as a treatment for various chronic pain conditions principal among them. 

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When used in a controlled, therapeutic setting, ketamine can be an especially effective treatment for various types of pain, including chronic neuropathic pain, peripheral nerve injury, complex regional pain syndrome, chronic migraine, limb ischemia, fibromyalgia, spinal cord injury, and whiplash. 

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Ketamine for Chronic Pain

In 2010, Dutch scientist Ingeborg Noppers and colleagues analyzed thirty-six randomized controlled trials (RCTs) investigating ketamine's effect on chronic non-cancer pain, involving a total of 776 patients. In their review, entitled Ketamine for the treatment of chronic non-cancer pain, the authors concluded that the administration of long-term intravenous administration of ketamine produces up to a 50% reduction in chronic pain that lasts several months 

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Chronic neuropathic pain, triggered by lesions on the somatosensory nervous system most often as a consequence of disease, injury, infection, and loss of a limb, can cause unexpected, intense pain to occur in response to everyday environmental stimuli.

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According to a review published in the British Journal of Clinical Pharmacology on the risks and benefits of using ketamine to treat chronic pain, NMDA receptor antagonists, such as ketamine, act as a halting agent of these nociceptive signals to produce strong analgesia.

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The authors concluded that for the majority of treating physicians and, importantly, patients, the benefits outweigh the risks when it comes to the use of ketamine for pain, despite its link to a variety of inconvenient side effects, which may include nausea, vomiting, dissociative effects, headache, fatigue, and sedation.

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Use of Ketamine in Emergency and Perioperative Hospital Settings

In 2016, professors Eun Nam Lee and Jae Hoon Lee published a systematic review on the benefits of using ketamine as an alternative to traditional opioid analgesics for patients in an emergency department or pre-hospital setting. The researchers wished to research ketamine largely due to its ability to activate respiratory effort, and due to the undesirability of repeated administration of opioids, which poses possible threats of adverse side effects such as hypotension and hypoxemia. 

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To do so, they retrieved six RCTs that compared intravenous bolus ketamine with morphine or fentanyl in 438 patients over the age of 15. Assessing pain changes 30 minutes post-treatment, the authors concluded that routine use of ketamine was either equivalent to or more effective than fentanyl and morphine, and was associated with a reduced risk of cardiopulmonary side effects. Ketamine was also observed to have no side effects and results suggested that it may even help to reduce the side effects associated with traditional opioid medications.

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A 2006 review of the efficacy and tolerability of perioperatively-administered ketamine in the treatment or prevention of acute pain reported moderate or non-existent adverse effects, which had the knock-on effect of reducing postoperative nausea and vomiting. More importantly, perhaps, 73% of the RCTs included in this review found that perioperative subanesthetic doses of ketamine reduced pain intensity and patient reliability on opioids. 

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Ketamine for Cancer Pain

While evidence of ketamine’s clinical efficacy in treating cancer pain, where it is typically used as an adjuvant to opioid treatment, is limited, anecdotal reports and case studies are quite consistently suggestive of ketamine’s effectiveness as a meaningful management tool in treatment-resistant cancer pain.

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For instance, Kelly Jonkman and colleagues out of Leiden University Medical Center examined a total of sixteen open-label studies that investigated the efficacy of ketamine for cancer pain, and four RCTs that examined the effect of intravenous, subcutaneous, or oral ketamine on pain relief, relief of neuropathic symptoms or on opioid consumption.

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Their analysis of open-label studies is supportive of ketamine’s benefit in the treatment of terminal cancer pain, suggesting that it reduces opioid use and successfully alleviates pain symptoms. Interestingly, however, this runs contrary to the results of four RCTs that showed no clinically relevant benefit. 

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Experimental evidence of ketamine's ability to enhance endogenous pain inhibition and decrease pain hypersensitivity, resulting in higher levels of patient satisfaction, suggests that it may play an important role in the future treatment of this commonly experienced cancer symptom. The question of why RCTs fail to provide support for ketamine’s analgesic efficacy, while open-label and case studies continue to, makes for a fascinating and necessary avenue of scientific inquiry. 

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Ketamine for Pain: What’s Next?

Although more research on ketamine’s efficacy for pain is needed, the available evidence, presented above, demonstrates its promising potential as a pain treatment across a variety of conditions and treatment settings. 

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With more rigorous research in the pipeline for the coming years, current uncertainty surrounding the analgesic efficacy of responsibly administered ketamine will, hopefully, be cleared up. We could soon see this powerful, transdiagnostic molecule being utilized at the forefront of pain medicine. 

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