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Abstract
One of the main causes of misery and incapacity is chronic pain, which is frequently linked to psychological issues.
Psychedelic substances are drugs that can exert a psychological effect on patients.
Psychedelic drugs like lysergic acid diethylamide (LSD) and psilocybin, exert their action mainly via activation of the serotonin-2A (5-HT2A).1
In a trial to understand the actual mode of action of psychedelics in chronic pain setting; Joel Castellanos et al2 elaborated that, given the complexity of chronic pain, which is still not fully understood, a multitude of somatic and visceral afferent pain signals may strengthen specific neural circuits through peripheral and central sensitization, leading to the perception of both physical and emotional chronic pain experience. Consequently, psychedelics exert their influence on human nociceptive system modulation and serotonin pathway activation. Additionally, the alterations in functional connections (FC ) seen with psychedelic drugs use suggested a way that these agents could help reverse the changes in neural connections seen in chronic pain states.2
Psychedelics may have potential to alleviate pain secondary to a multitude of chronic painful conditions as concluded in an article that was published by Christopher L Robinson et al in March 2024.3 Mauro Cavarra et al. reported in a different survey conducted that same year, that individuals with fibromyalgia, sciatica, migraine, arthritis, and tension-type headaches can experience analgesic effects from psychedelics.4
Psychedelic substances have a generally favorable safety profile, particularly when contrasted with opioid analgesics. However, clinical evidence to date for their use in chronic pain management is limited and of low quality.2 Several studies and reports over the past 50 years have shown potential analgesic benefit in cancer pain, phantom limb pain and cluster headache as well.2 Given the current state of the opioid epidemics and limited efficacy of non-opioid analgesics, research on psychedelics as analgesics is gaining popularity in order to improve the lives of chronic pain patients.
Based on the previously provided information, can we add ketamine to the list of psychedelic drugs utilized for chronic pain management!!!!
The answer is YES!
Yes, ketamine is indeed considered a psychedelic drug. It was initially developed as a dissociative anesthetic drug, but has gained attention for its unique effects on perception, consciousness, and mood. When used in controlled settings, ketamine can induce hallucinations, dissociation, and altered states of consciousness. In clinical contexts, it’s also being explored for its potential in treating chronic pain, depression and and post traumatic stress disorder (PTSD).5 In the context of resistant depression cases in the west, ketamine clinics all of a sudden began to exhibit a ‘Trending’ attitude.
Since it first entered the pharmaceutical industry more than 50 years ago, ketamine has been used by pain specialists for more than 20 years to treat patients with chronic pain who are refractory, all without the benefit of strict guidelines. We are grateful to the American Society of Regional Anesthesia and Pain Medicine (ASRA), which brought up this matter and began drawing attention to the need for recommendations, as originally mentioned by Brian J. Marascalchi and Steve Cohen in their November 2018 newsletter.6 Shortly after, in collaboration with the American Society of Anesthesiologists, the American Academy of Pain Medicine, and the ASRA, Cohen and his colleagues released the first organized guidelines regarding the use of intravenous ketamine for chronic pain.7
Among a limited number of adequately structured systematic reviews we would mention a meta-analysis by Orhurhu V and his colleagues,8 another review by JE Israel et al.9 and a good review by Riccardi A.10 However we find all these are still not adequate.
NMDA receptor/ion channel complexes are sited peripherally and centrally within the nervous system. Ketamine is a phenylcyclidine derivative that acts primarily as a non-competitive antagonist of the NMDA receptor, although it also binds to many other sites in the peripheral and central nervous systems.11 Primarily, ketamine exhibits its analgesic, antidepressant, and cognitive effects via the NMDA receptors situated in the central nervous system. Ketamine has also been found to act on the; opioid receptors, γ-aminobutyric acid A (GABA-A) receptors, dopamine D2 receptors, nicotinic receptors, muscarinic cholinergic receptors, and a ligand of the serotonin 5-HT2A receptor.11 We highlight that ketamine acquires almost the same mode of action (serotonin receptors activation) like other psychedelic drugs.
In the chronic pain setting, ketamine was found to exert a good therapeutic effect in cases of Complex regional pain syndrome, fibromyalgia, chronic neuropathic pain, cancer pain and phantom limb pain.9
Given that ketamine is widely accessible and reasonably priced, physicians in countries with limited resources find it especially appealing for treating refractory patients because they are unable to pay for more expensive and advanced treatments like neuromodulation.
More structured guidelines are still required. But as Carl Sagan eloquently said, ‘Absence of Evidence is not Evidence of Absence.’
References
Kooijman NI, Willegers T, Reuser A, Mulleners WM, Kramers C, Vissers KCP, van der Wal SEI. Are psychedelics the answer to chronic pain: a review of current literature. Pain Pract. 2023 Apr;23(4):447-458. doi: 10.1111/papr.13203. Epub 2023 Jan 11. PMID: 36597700.
Castellanos JP, Woolley C, Bruno KA, et al. Chronic pain and psychedelics: a review and proposed mechanism of action. Regional Anesthesia & Pain Medicine 2020;45:486-494. doi: 10.1136/rapm-2020-101273.
Robinson CL, Fonseca ACG, Diejomaoh EM, D’Souza RS, Schatman ME, Orhurhu V, Emerick T. Scoping review: the role of psychedelics in the management of chronic pain. J Pain Res. 2024 Mar 11;17:965-973. doi: 10.2147/JPR.S439348. PMID: 38496341; PMCID: PMC10941794.
Cavarra M, Mason NL, Kuypers KPC, Bonnelle V, Smith WJ, Feilding A, Kryskow P, Ramaekers JG. Potential analgesic effects of psychedelics on select chronic pain conditions: A survey study. Eur J Pain. 2024 Jan;28(1):153-165. doi: 10.1002/ejp.2171. Epub 2023 Aug 20. PMID: 37599279.
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Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists Regional Anesthesia & Pain Medicine 2018;43:521-546. doi: 10.1097/AAP.0000000000000808.
Intravenous Ketamine Guidelines for Pain Management; ASRA newsletter,November2018
Orhurhu V, Orhurhu MS, Bhatia A, Cohen SP. Ketamine Infusions for Chronic Pain: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Anesth Analg. 2019 Jul;129(1):241-254. doi: 10.1213/ANE.0000000000004185. PMID: 31082965.
Israel JE, St Pierre S, Ellis E, Hanukaai JS, Noor N, Varrassi G, Wells M, Kaye AD. Ketamine for the Treatment of Chronic Pain: A Comprehensive Review. Health Psychol Res. 2021 Jul 10;B(1):25535. doi: 10.52965/001c.25535. PMID: 34746491; PMCID: PMC8567802.
Riccardi A, Guarino M, Serra S, Spampinato MD, Vanni S, Shiffer D, Voza A, Fabbri A, De Iaco F; Study and Research Center of the Italian Society of Emergency Medicine. Narrative Review: Low-Dose Ketamine for Pain Management. J Clin Med. 2023 May 2;12(9):3256. doi: 10.3390/jcm12093256. PMID: 37176696; PMCID: PMC10179418.
Niesters M, Aarts L, Sarton E, Dahan A. Influence of ketamine and morphine on descending pain modulation in chronic pain patients: a randomized placebo-controlled cross-over proof-of-concept study. Br J Anaesth. 2013 Jun;110(6):1010-6. doi: 10.1093/bja/aes578. Epub 2013 Feb 5. PMID: 23384733.