Pain, distress, and opioid use in chronic pain patients undergoing ketamine infusions.
Abstract
Pain is a primary contributor to the global burden of disability (Cohen et al., 2021), and chronic pain is estimated to be experienced by approximately 30% of the global population, reflecting substantial economic impact (Cohen et al., 2021; Deloitte Access Economics, 2019; Goldberg & McGee, 2011). While opioids are generally effective for chronic pain treatment (Busse et al., 2018; Chou et al., 2020; Jones et al., 2018), they have significant limitations, such as potential for diversion (Florence et al., 2016; Prakash et al., 2023), high risks of tolerance, dependence, and overdose (Pathan & Williams, 2012; Chang et al., 2018), and dangerous withdrawal syndromes (Chang et al., 2018; Rudolf et al., 2018). Given these limitations, the need for novel pain management approaches is evident. Ketamine, a glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist, is one such approach that has demonstrated promising results in the management of chronic pain. Ketamine has been suggested to exhibit the potential to address the limitations of opioids through treatment characteristics such as sustained efficacy (chronic pain reduction up to 50 days) using low-dose infusions (20 - 30 mg/h over 4 - 5 days; Dahan et al., 2011; Sigtermans et al., 2009). While ketamine is used recreationally, it does not appear to have the same level of abuse liability as opioids (Campbell & Lobo, 2022; Simmler et al., 2022), whilst intermittent retreatment, made possible by sustained analgesic effects, could also prevent the development of dependence (Davies et al., 2022; Dong et al., 2019). Moreover, withdrawal syndromes following ketamine administration do not exhibit potentially life-threatening physical symptoms like those of opioids (Israel et al., 2021). Ketamine also appears to affect opioid consumption with intraoperative ketamine infusions having been shown to reduce both postoperative opioid requirements, and subjective pain ratings in opioid-dependent patients in a variety of surgical contexts (Haliloglu et al., 2016; Kaur et al., 2015; Loftus et al., 2010; Nielsen et al., 2017; Suppa et al., 2012). Ketamine has also been used to demonstrate rapid and sustained antidepressant effects, lasting up to 1 – 2 weeks post-infusion, or longer with repeat treatment (Murrough et al., 2013; Hossein et al., 2025), potentially addressing some of the limitations of other antidepressants. However, placebo effects are important to consider, as blinding participants is challenging due to ketamine’s psychoactive effects (Heifets et al., 2024). In at least one fully blinded study, no significant antidepressant benefits were observed (Lii et al., 2023). Overall, however, results regarding ketamine’s potential efficacy for treating depression remain promising (Alnefeesi et al., 2022; Han et al., 2015; Hossein et al., 2025; Loo et al., 2023; Murrough et al., 2013). One nasally administered formulation of ketamine, Spravato (32.3 mg esketamine hydrochloride per 2 actuations), has been FDA and TGA approved for the treatment of depression (Therapeutic Goods Administration, 2021; U.S. Food and Drug Administration, 2019), whilst an intravenous formulation, NRX-100, is under current review (Grunebaum et al., 2017; U.S. Food and Drug Administration, 2025). Thus, studies have demonstrated promising early evidence for the use of ketamine in addressing both chronic pain and depressive mood – which are frequently comorbid (Armbrecht et al., 2020; Hooten, 2016; Roughan et al., 2021) with the potential to reduce the use of opioids for pain. However, most existing evidence is derived from randomised control trials (RCTs) – most of which have focused on pain or mood effects of ketamine rather than their combination, with little evidence from real-world clinical contexts. The diversity within real-world patient populations may not be fully captured by existing RCTs. There is also minimal evidence of demographics and characteristics that predict positive responses to ketamine treatment. The aim of this project is to evaluate the outcomes of chronic pain, emotional distress, and opioid use associated with ketamine infusions in a real-world setting, testing the following research questions: 1) In a real-world clinical context, what treatment outcomes are associated with ketamine infusions? and 2) What demographic and clinical variables predict pain and distress relief in ketamine-treated chronic pain patients? It was hypothesised that patients receiving ketamine would show a) reductions from baseline in self-reported pain; b) reductions in self-reported pain interference; c) promotions in pain self-efficacy; d) reductions in self-reported emotional distress; and e) reductions in use of prescription opioids. No specific hypotheses were made about demographic or clinical predictors of outcome in this population. References: Alnefeesi, Y., Chen-Li, D., Krane, E., Jawad, M. Y., Rodrigues, N. B., Ceban, F., Di Vincenzo, J. D., Meshkat, S., Ho, R. C. M., Gill, H., Teopiz, K. M., Cao, B., Lee, Y., McIntyre, R. S., & Rosenblat, J. D. (2022). Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis. Journal of psychiatric research, 151, 693–709. https://doi.org/10.1016/j.jpsychires.2022.04.037 Armbrecht, E., Shah, A., Schepman, P., Shah, R., Pappadopulos, E., Chambers, R., Stephens, J., Haider, S., & McIntyre, R. S. (2020). Economic and humanistic burden associated with noncommunicable diseases among adults with depression and anxiety in the United States. Journal of medical economics, 23(9), 1032–1042. https://doi.org/10.1080/13696998.2020.1776297 Busse, J. W., Wang, L., Kamaleldin, M., Craigie, S., Riva, J. J., Montoya, L., … Guyatt, G. H. (2018). Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis. JAMA: the Journal of the American Medical Association, 320(23), 2448–2460. https://doi.org/10.1001/jama.2018.18472 Campbell, R., & Lobo, M. K. (2022). A short burst of reward curbs the addictiveness of ketamine. Nature, 608(7922), 271–272. https://doi.org/10.1038/d41586-022-01948-w Chang, D. C., Klimas, J., Wood, E., & Fairbairn, N. (2018). A Case of Opioid Overdose and Subsequent Death After Medically Supervised Withdrawal: The Problematic Role of Rapid Tapers for Opioid Use Disorder. Journal of Addiction Medicine, 12(1), 80–83. https://doi.org/10.1097/ADM.0000000000000359 Chou, R., Hartung, D., Turner, J., Blazina, I., Chan, B., Levander, X., … Pappas, M. (2020). Opioid Treatments for Chronic Pain. Agency for Healthcare Research and Quality (US). Cohen, S. P., Vase, L., & Hooten, W. M. (2021). Chronic pain: an update on burden, best practices, and new advances. The Lancet (British Edition), 397(10289), 2082–2097. https://doi.org/10.1016/S0140-6736(21)00393-7 Dahan, A., Olofsen, E., Sigtermans, M., Noppers, I., Niesters, M., Aarts, L., … Sarton, E. (2011). Population pharmacokinetic–pharmacodynamic modeling of ketamine-induced pain relief of chronic pain. European Journal of Pain, 15(3), 258–267. https://doi.org/10.1016/j.ejpain.2010.06.016 Davies, S. J., Rudoler, D., de Oliveira, C., Huang, A., Kurdyak, P., & Iaboni, A. (2022). Comparative safety of chronic versus intermittent benzodiazepine prescribing in older adults: A population-based cohort study. Journal of Psychopharmacology, 36(4), 460–469. https://doi.org/10.1177/02698811211069096 Deloitte Access Economics (2019). The Cost of Pain in Australia. https://www.deloitte.com/au/en/services/economics/analysis/cost-pain-australia.html Dong, J., Min, S., Qiu, H., Chen, Q., & Ren, L. (2019). Intermittent administration of low dose ketamine can shorten the course of electroconvulsive therapy for depression and reduce complications: A randomized controlled trial. Psychiatry research, 281, 112573. https://doi.org/10.1016/j.psychres.2019.112573 Florence, C. S., Zhou, C., Luo, F., & Xu, L. (2016). The Economic Burden of Prescription Opioid Overdose, Abuse, and Dependence in the United States, 2013. Medical Care, 54(10), 901–906. https://doi.org/10.1097/MLR.0000000000000625 Grunebaum, M. F., Ellis, S. P., Keilp, J. G., Moitra, V. K., Cooper, T. B., Marver, J. E., Burke, A. K., Milak, M. S., Sublette, M. E., Oquendo, M. A., & Mann, J. J. (2017). Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial. Bipolar disorders, 19(3), 176–183. https://doi.org/10.1111/bdi.12487 Goldberg, D. S., & McGee, S. J. (2011). Pain as a global public health priority. BMC Public Health, 11, 770. https://doi.org/10.1186/1471-2458-11-770 Haliloglu, M., Ozdemir, M., Uzture, N., Cenksoy, P. O., & Bakan, N. (2016). Perioperative low-dose ketamine improves postoperative analgesia following Cesarean delivery with general anesthesia. The Journal of Maternal-Fetal & Neonatal Medicine: The Official Journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 29(6), 962–966. https://doi.org/10.3109/14767058.2015.1027190 Han, Y., Chen, J., Zou, D., Zheng, P., Li, Q., Wang, H., Li, P., Zhou, X., Zhang, Y., Liu, Y., & Xie, P. (2016). Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies. Neuropsychiatric disease and treatment, 12, 2859–2867. https://doi.org/10.2147/NDT.S117146 Heifets, B., Lii, T., Smith, A., Flohr, J., Nyongesa, C., Cianfichi, … Schatzberg, A. (2024). Clinical Outcomes and Biomarkers From a Randomized Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients. Biological Psychiatry, 95(10), S47. https://doi.org/10.1016/j.biopsych.2024.02.117 Hooten W. M. (2016). Chronic Pain and Mental Health Disorders: Shared Neural Mechanisms, Epidemiology, and Treatment. Mayo Clinic proceedings, 91(7), 955–970. https://doi.org/10.1016/j.mayocp.2016.04.029 Hossein, S., Rengasamy, M., Uzamere, A., Spotts, C., Howland, R. H., Wallace, M. L., Mathew, S. J., & Price, R. B. (2025). Effects of ketamine on individual symptoms and symptom networks of depression in a randomised controlled trial of ketamine for treatment-resistant depression. The British journal of psychiatry: the journal of mental science, 1–10. Advance online publication. https://doi.org/10.1192/bjp.2024.276 Israel, J. E., St Pierre, S., Ellis, E., Hanukaai, J. S., Noor, N., Varrassi, G., … Kaye, A. D. (2021). Ketamine for the Treatment of Chronic Pain: A Comprehensive Review. Health Psychology Research, 9(1), 25535. https://doi.org/10.52965/001c.25535 Jones, M. R., Viswanath, O., Peck, J., Kaye, A. D., Gill, J. S., & Simopoulos, T. T. (2018). A Brief History of the Opioid Epidemic and Strategies for Pain Medicine. Pain and Therapy, 7(1), 13–21. https://doi.org/10.1007/s40122-018-0097-6 Kaur, S., Saroa, R., & Aggarwal, S. (2015). Effect of intraoperative infusion of low-dose ketamine on management of postoperative analgesia. Journal of Natural Science, Biology, and Medicine, 6(2), 378–382. https://doi.org/10.4103/0976-9668.160012 Lii, T. R., Smith, A. E., Flohr, J. R., Okada, R. L., Nyongesa, C. A., Cianfichi, L. J., … Heifets, B. D. (2023). Randomized trial of ketamine masked by surgical anesthesia in patients with depression. Nature Mental Health, 1(11), 876–886. https://doi.org/10.1038/s44220-023-00140-x Loftus, R. W., Yeager, M. P., Clark, J. A., Brown, J. R., Abdu, W. A., Sengupta, D. K., & Beach, M. L. (2010). Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology, 113(3), 639. https://doi.org/10.1097/ALN.0b013e3181e90914 Loo, C., Glozier, N., Barton, D., Baune, B. T., Mills, N. T., Fitzgerald, P., Glue, P., Sarma, S., Galvez-Ortiz, V., Hadzi-Pavlovic, D., Alonzo, A., Dong, V., Martin, D., Nikolin, S., Mitchell, P. B., Berk, M., Carter, G., Hackett, M., Leyden, J., Hood, S., … Rodgers, A. (2023). Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial. The British journal of psychiatry: the journal of mental science, 223(6), 533–541. https://doi.org/10.1192/bjp.2023.79 Nielsen, R. V., Fomsgaard, J. S., Siegel, H., Martusevicius, R., Nikolajsen, L., Dahl, J. B., & Mathiesen, O. (2017). Intraoperative ketamine reduces immediate postoperative opioid consumption after spinal fusion surgery in chronic pain patients with opioid dependency: a randomized, blinded trial. Pain, 158(3), 463–470. https://doi.org/10.1097/j.pain.0000000000000782 Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. E., Perez, … Mathew, S. J. (2013). Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial. The American Journal of Psychiatry, 170(10), 1134–1142. https://doi.org/10.1176/appi.ajp.2013.13030392 Pathan, H., & Williams, J. (2012). Basic opioid pharmacology: an update. British Journal of Pain, 6(1), 11–16. https://doi.org/10.1177/2049463712438493 Prakash, S., Gu, Y., & Previti, M. (2023). Quantitative Survey on Prevalence of Prescription Pain Medications and Stimulants Use in Young Adults. Substance Abuse: Research and Treatment, 17, 11782218231162827. https://doi.org/10.1177/11782218231162827 Roughan, W. H., Campos, A. I., García-Marín, L. M., Cuéllar-Partida, G., Lupton, M. K., Hickie, I. B., Medland, S. E., Wray, N. R., Byrne, E. M., Ngo, T. T., Martin, N. G., & Rentería, M. E. (2021). Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness. Frontiers in psychiatry, 12, 643609. https://doi.org/10.3389/fpsyt.2021.643609 Rudolf, G., Walsh, J., Plawman, A., Gianutsos, P., Alto, W., Mancl, L., & Rudolf, V. (2018). A novel non-opioid protocol for medically supervised opioid withdrawal and transition to antagonist treatment. The American Journal of Drug and Alcohol Abuse, 44(3), 302–309. https://doi.org/10.1080/00952990.2017.1334209 Sigtermans, M. J., Van Hilten, J. J., Bauer, M. C., Arbous, M. S., Marinus, J., Sarton, E. Y., & Dahan, A. (2009). Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain, 145(3), 304-311. https://doi.org/10.1016/j.pain.2009.06.023 Simmler, L. D., Li, Y., Hadjas, L. C., Hiver, A., van Zessen, R., & Lüscher, C. (2022). Dual action of ketamine confines addiction liability. Nature: International Weekly Journal of Science, 608(7922), 368–373. https://doi.org/10.1038/s41586-022-04993-7 Suppa, E., Valente, A., Catarci, S., Zanfini, B. A., & Draisci, G. (2012). A study of low-dose S-ketamine infusion as ‘preventive’ pain treatment for cesarean section with spinal anesthesia: benefits and side effects. Minerva Anestesiol, 78(7), 774–781. Therapeutic Goods Administration. (2021). Spravato. https://tga.gov.au/resources/auspmd/spravato U.S. Food and Drug Administration (2019). SPRAVATO (esketamine) CIII nasal spray: Full prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf U.S. Food and Drug Administration (2025, June 17). FDA to issue new Commissioner’s National Priority Vouchers to companies supporting U.S. national interests [Press release]. Retrieved August 15, 2025, U.S. from Food and Drug Administration.
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