Ketamine’s Expanding Role in Chronic Pain and Opioid-Sparing Therapy

As the search for alternatives to traditional opioid therapy continues amid the ongoing opioid crisis, ketamine has emerged as a promising selection for patients with difficult-to-manage chronic and acute pain conditions. In an emerging analysis on low-dose ketamine, findings indicate reductions in opioid requirements and improvements in analgesia across use for postoperative pain, chronic neuropathic pain, and opioid-tolerant patient populations.¹ While prior data associates ketamine with anesthesia and procedural sedation, the agent is increasingly being incorporated into multimodal pain management strategies for patients with limited therapeutic options.

What Is Ketamine, and Why Is It Important in Pain Management?

Ketamine is a dissociative anesthetic that primarily acts as an N-methyl-D-aspartate (NMDA) receptor antagonist.² Through blocking NMDA receptor activity, ketamine may reduce central sensitization, hyperalgesia, and amplification of pain signaling pathways associated with chronic pain syndromes.³ In contrast to traditional opioids, ketamine does not essentially depend upon μ-opioid receptor activation to produce analgesia, leading it to be an attractive opioid-sparing strategy in pain management.

In 1970, ketamine was initially approved by the FDA as an anesthetic agent and has since been reviewed for multiple off-label indications, including chronic neuropathic pain, complex regional pain syndrome, perioperative pain, cancer-related pain, and refractory migraine disorders.²˒⁴ In both inpatient and outpatient settings, low-dose ketamine infusions have become increasingly utilized for patients who have not adequately responded to standard analgesic regimens.

The evolving interest in ketamine is occurring alongside continued concerns in regard to opioid-related adverse effects, dependence, and overdose risk. Although there has been a decline in opioid prescribing in recent years, overdose deaths involving synthetic opioids remain a major public health concern, according to the CDC.⁵ This has resulted in clinicians increasingly exploring multimodal approaches that can reduce opioid exposure while maintaining adequate pain control.

Ketamine for Chronic Pain

Earlier this year, a review published in Pain Management discussed ketamine’s expanding role in both acute and chronic pain management.¹ The discussion emphasized that low-dose ketamine infusions displayed potential benefits in opioid-tolerant patients and individuals with treatment-resistant neuropathic pain conditions. Furthermore, the review also emphasizes ketamine’s potential utility in reducing opioid-induced hyperalgesia, a phenomenon in which prolonged opioid exposure paradoxically increases pain sensitivity.

Additional data further evaluates ketamine in perioperative and postoperative pain management protocols. The American Society of Regional Anesthesia and Pain Medicine consensus guidelines state that ketamine-containing multimodal analgesic regimens may reduce postoperative opioid requirements and improve pain scores in select surgical populations.³ These data continue to develop interest in incorporating ketamine into enhanced recovery after surgery protocols and hospital opioid stewardship initiatives.

Similarly, ketamine has also gained traction in oncology and palliative care settings, particularly in patients with refractory cancer pain who have exhausted conventional therapies.⁴ Low-dose ketamine may provide analgesic benefit while potentially limiting escalation of high-dose opioid therapy in these circumstances. Despite this, experts caution that patient selection, monitoring, and institutional protocols remain critical due to the association with adverse effects such as dissociation, hallucinations, hypertension, tachycardia, and nausea upon ketamine administration.²

Despite these optimal findings, additional large-scale randomized controlled trials are still required to better define optimal dosing strategies, treatment duration, long-term safety, and patient populations most likely to benefit from ketamine therapy.¹

REFERENCES

1. Duong HG, Pulskamp TG, Berlau DJ. Ketamine for acute and chronic pain: beyond anaesthesia. Pain Manag. 2026;16(5):523-533. doi:10.1080/17581869.2026.2627884

2. Ketalar (ketamine hydrochloride) injection. FDA. July 2018. Accessed May 11, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016812s040lbl.pdf

3. 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. Reg Anesth Pain Med. 2018;43(5):521-546. doi:10.1097/AAP.0000000000000808

4. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol. 2012;30(29):3611-3617. doi:10.1200/JCO.2012.42.1081

5. About prescription opioids. CDC. June 10, 2025. Accessed May 11, 2026. https://www.cdc.gov/overdose-prevention/about/prescription-opioids.html