Ketamine may help with chronic pain because it blocks the NMDA receptor. This is a glutamate receptor in the spinal cord and brain. It keeps pain circuits turned up long after the first injury has healed. Ketamine is not an opioid. It does not act on opioid receptors. It works on the amplifier, not the volume knob. So it is used mainly for pain the nerves now drive on their own. It is not for pain from an ongoing structural problem.
That is the theory. The evidence is narrower. The best trials are in complex regional pain syndrome (CRPS, also called RSD). The effects are modest and often short-lived. A 2025 Cochrane review of 67 randomized trials rated the certainty of evidence across chronic pain as a whole low to very low.6
What is ketamine?
Ketamine is an anesthetic. At full doses it puts you under in a detached, dream-like state (dissociative anesthesia). Pain medicine uses far lower doses — often a tenth or less of that. At those doses it relieves pain while the patient stays awake and can talk. Its main action is blocking the NMDA receptor. It does not act on GABA receptors. That sets it apart from sedatives and benzodiazepines. The liver turns it into norketamine,1 which also blocks the NMDA receptor.10 In the United States it is a Schedule III controlled substance, FDA-approved as an anesthetic. For chronic pain, specialty consensus guidelines guide its use.2
How does ketamine treat chronic pain?
Wind-up in the dorsal horn
When a nerve in the body fires again and again, nerve cells in the spinal cord’s dorsal horn react harder to each identical signal. This is called wind-up. The NMDA receptor sits at the center of it. At rest, a magnesium ion plugs the channel. Steady firing pushes the magnesium out. The channel opens, and calcium flows in. That sets off changes that make the nerve cell more excitable and keep it that way.
Scale that up and you get central sensitization. The nervous system amplifies signals far beyond the input. In the clinic it looks like allodynia (pain from a bedsheet or a breeze). It looks like hyperalgesia (too much pain from a small poke). And pain spreads past the first injury. Once that state sets in, treating the tissue does not always fix the pain. The pain no longer tracks the tissue.
Why CRPS is the test case
CRPS is where this argument is strongest. Clinical and lab evidence tie CRPS to NMDA receptor activity and glial activation. The evidence suggests both play a part in how CRPS starts and keeps going.4 If the receptor keeps the pain going, blocking it should do more than mask pain. It should let the overactive circuit reset.
There is some evidence for that. Drug modeling in 60 CRPS-1 patients found pain relief lasting well after ketamine had left the blood. The estimated onset/offset half-life was about 11 days. The authors read this as ketamine starting a chain reaction that calmed the pain-boosting receptor systems, an effect that slowly wore off.5 Relief that fades over weeks, not hours, would set ketamine apart from a normal painkiller. But that reading rests on a model fitted to a single trial. It is not a repeated finding.
Does ketamine work for chronic pain? What the trials found
In the founding trial, 60 patients with CRPS-1 had been sick for a median of 7.4 years. They got a 4.2-day intravenous S(+)-ketamine infusion or placebo. Pain scores over 12 weeks were significantly lower with ketamine (more than chance would explain). The lowest score came at the end of week 1 (2.68 versus 5.45 on a 0-10 scale). By week 12 the gap was no longer significant. Neither group gained function. Mind-altering side effects hit 76% of the ketamine group versus 18% of placebo.3 A second double-blind trial dosed four hours a day for ten days, capped at 0.35 mg/kg/h. It reported significant drops across many pain measures, with none in the placebo group. Both groups also got clonidine and midazolam. So the test was ketamine plus add-ons against add-ons alone.4
Now the other side. A 2022 meta-analysis pooled 20 randomized trials in 818 adults with CRPS-1. Ketamine cut pain by about 8 points on a 0-100 scale. Bisphosphonates cut it by about 24. The authors’ first choice was bisphosphonates.7 Note how thin the ketamine number is: only 2 of those 20 trials tested ketamine, against 7 for bisphosphonates. A systematic review concluded that evidence for ketamine is emerging and that confirming trials are still needed.8
The broadest look is the 2025 Cochrane review. It pooled 67 randomized trials of NMDA blockers in chronic pain that was not from cancer or headache. It found no clear evidence that intravenous ketamine lowers pain in the near, short, or medium term. It rated that evidence low to very low certainty. And it found ketamine may raise side effects.6 Most of the studies were small. Blinding is hard when three quarters of the treatment group can tell they got something.
The fair reading: ketamine is a real option for severe pain driven by the nervous system that has failed better-proven treatments. But the effect is modest and time-limited. Anyone selling it as a general answer for chronic pain is ahead of the data.
Route matters more than most patients are told
“Ketamine therapy” means at least three treatments with different drug actions, evidence, and risks.
Intravenous
IV delivery skips the liver’s first pass. So blood levels are predictable. The dose can be adjusted in real time against effect and side effects. Nearly all the controlled trials used this route. This is where the evidence lives. It needs a monitored setting. The same dose control that makes it work also makes it possible to overshoot.
Sublingual
Swallowed ketamine is broken down heavily before it reaches the blood. One lozenge study looked at six chronic pain patients. The authors called the findings preliminary. Median bioavailability (the share that reaches the blood) was 24% by both mouth and under the tongue. Much of it was turned into norketamine on the first pass.10 A larger study of a 50 mg S-ketamine oral thin film in 20 volunteers found bioavailability of about 26%. Roughly 80% was turned into norketamine.11
That conversion is not pure loss, because norketamine is an active NMDA blocker. The sublingual route gives a different exposure, not just a weaker one. You get less of the parent drug, more of the active breakdown product, and a flatter curve. Note what those studies do and do not show. They measure how much drug reaches the blood, not whether pain gets better. On that second question, the Cochrane review found no clear benefit for oral ketamine.6
Topical
Topical ketamine is the odd one out. It may not work through the brain and spinal cord at all. In a double-blind, placebo-controlled crossover trial, 10% ketamine cream was put on the painful limb of 20 CRPS patients. It blocked allodynia to light brushing and hyperalgesia to pinprick. Yet blood ketamine stayed too low to detect. That points to an action at the pain nerve endings in the skin. Touch thresholds did not change. It cut the abnormal amplification without numbing the skin.9
That is an interesting result from one small crossover study. It should be weighed against the pooled evidence. The same Cochrane review found no clear evidence that topical ketamine lowers pain in the immediate or short term, at low to very low certainty.6
Sublingual and topical forms can be used on one limb or taken at home. They do not need the setup an infusion does. That is why they get used outside research. That is a practical argument, not an evidence-based one. Choosing a route is still a clinical judgment, not a settled question.
What happens during a ketamine infusion, and what are the risks?
A low-dose (subanesthetic) infusion is given while the patient is awake and monitored. Blood pressure and heart rate usually rise, because ketamine revs up the sympathetic nervous system. Patients often feel some mix of detachment, visual distortion, dizziness, nausea, and a dream-like state. These follow the dose and clear with the drug. Consensus guidelines note that most trials had few side effects. But higher doses and more frequent infusions carry more risk.2
Two harms come from repeat use, not a single dose. Repeated long infusions have caused drug-induced liver injury. In one series, six CRPS-1 patients got a second 100-hour infusion 16 days after the first. Three of them developed high liver enzymes. These returned to normal within two months after stopping.12 Heavy, sustained use — seen mainly in recreational users — can cause ulcerative cystitis and bladder scarring. Long-term abusers have had shrunken bladders and swollen kidneys (hydronephrosis).13 New urinary urgency, frequency, or pelvic pain during a course is a reason to stop and get checked, not to push through.
The consensus guidelines list relative contraindications. These are cases that call for caution or avoidance, not an outright ban. The list: poorly controlled heart disease, severe liver disease, and certain poorly controlled psychoses. Also high pressure in the skull or eye, pregnancy, and active substance abuse.2 A drug review states plainly that long-term pain relief in chronic pain has not been proven. Long-term safety questions remain open.1
Where ketamine fits
The CRPS trial that gave real pain relief gave no gain in function3 — pain came down, but the limb did not start working better on its own. That is why a course is a window, not a destination. It can lower the pain floor enough to make step-by-step movement bearable. Rehab is what changes function. In CRPS, pooled evidence favors bisphosphonates first,7 and sympathetic blockade, stellate ganglion blocks, and spinal cord stimulation each have their place. Ketamine belongs in the talk after simpler options, not instead of them.
If you are in the St. Louis area
Padda Institute, Center for Interventional Pain Management, offers intravenous ketamine infusion plus sublingual and topical forms. The route is chosen by diagnosis and tolerance. See ketamine therapy and complex regional pain syndrome treatment. Dr. Gurpreet Singh Padda, MD, MBA, MHP practices at 4477 Woodson Rd, Suite 100, St. Louis, MO 63134 and 12174 Natural Bridge Rd, St. Louis, MO 63044. Phone: (314) 481-5000.
Frequently asked questions
Does ketamine cure chronic pain?
No. In the strongest CRPS trial, the gap from placebo faded by week 12, and function did not improve.3 When it helps, it lowers pain for weeks, not for good. That can open room for rehab — one option among several under pain treatments.
Is ketamine an opioid?
No. Its main action is blocking the NMDA glutamate receptor, not switching on opioid receptors.1 It is a controlled substance and needs the same care as any controlled drug. But it is a different drug class from opioid painkillers. See the pain management physicians page.
How long does relief last after an infusion?
It varies widely. You cannot predict it for one person. Modeling in CRPS-1 patients estimated an onset/offset half-life of roughly 11 days, with relief lasting past the treatment period.5 Some patients get weeks. Some get very little. The choice to continue is based on measured response — part of the evaluation under CRPS treatment.
Is sublingual or topical ketamine as effective as an infusion?
They are not the same. And they are not just weaker versions of one thing. Under the tongue, roughly a quarter of the dose reaches the blood. Most of the rest turns into norketamine.1011 Topical ketamine seems to act on the skin itself, with blood levels too low to measure.9 Both have thinner evidence than infusion. Pooled analysis found no clear benefit for either oral or topical ketamine.6 They are used because they are practical for one limb or for dosing at home. See ketamine therapy.
Will I be sedated or put under?
No. Low-dose infusions are given while you are awake and monitored, not under general anesthesia. Dream-like, detached feelings are common. They follow the dose and fade as the drug clears.3 Have someone else drive. The same awake, monitored approach applies to other procedures here, including nerve blocks.
What should I try before considering ketamine?
For CRPS, pooled evidence favors bisphosphonates first,7 and sympathetic blockade has its own supporting trials.8 Depending on what is causing the pain, an epidural steroid injection may fit better. Start with a diagnosis-first evaluation: request an appointment or use the contact page.
Is ketamine a painkiller?
Yes, at the right dose. Ketamine is an anesthetic. But pain medicine uses much lower doses, often a tenth or less of an anesthetic dose. At those doses it relieves pain while you stay awake and able to talk. It is not an opioid. It works by blocking the NMDA receptor. That calms pain circuits that have been turned up in the spinal cord and brain.
What are the side effects of a ketamine infusion?
During an infusion, blood pressure and heart rate usually rise. Many people feel some mix of detachment, visual distortion, dizziness, nausea and a dream-like state. These follow the dose and clear as the drug leaves the body. Repeated, long infusions have caused liver injury. Heavy long-term use can damage the bladder. New urinary urgency, frequency or pelvic pain during a course means stop and get checked.
What guides ketamine use for chronic pain?
In the United States ketamine is a Schedule III controlled substance that is FDA-approved as an anesthetic. For chronic pain, specialty consensus guidelines guide its use. Those guidelines list cases that call for caution. These include poorly controlled heart disease, severe liver disease, pregnancy and active substance abuse.
Sources
- Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clinical Pharmacokinetics. 2016;55(9):1059-77. PMID 27028535
- 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 and Pain Medicine. 2018;43(5):521-546. PMID 29870458
- Sigtermans MJ, van Hilten JJ, Bauer MCR, et al. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009;145(3):304-311. PMID 19604642
- Schwartzman RJ, Alexander GM, Grothusen JR, et al. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009;147(1-3):107-15. PMID 19783371
- Dahan A, Olofsen E, Sigtermans M, et al. Population pharmacokinetic-pharmacodynamic modeling of ketamine-induced pain relief of chronic pain. European Journal of Pain. 2011;15(3):258-67. PMID 20638877
- Ferraro MC, Cashin AG, Visser EJ, et al. Ketamine and other NMDA receptor antagonists for chronic pain. Cochrane Database of Systematic Reviews. 2025;8:CD015373. PMID 40819842
- Fassio A, Mantovani A, Gatti D, et al. Pharmacological treatment in adult patients with CRPS-I: a systematic review and meta-analysis of randomized controlled trials. Rheumatology (Oxford). 2022;61(9):3534-3546. PMID 35104332
- Duong S, Bravo D, Todd KJ, Finlayson RJ, Tran DQ. Treatment of complex regional pain syndrome: an updated systematic review and narrative synthesis. Canadian Journal of Anaesthesia. 2018;65(6):658-684. PMID 29492826
- Finch PM, Knudsen L, Drummond PD. Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine. Pain. 2009;146(1-2):18-25. PMID 19703730
- Chong C, Schug SA, Page-Sharp M, Jenkins B, Ilett KF. Development of a sublingual/oral formulation of ketamine for use in neuropathic pain: Preliminary findings from a three-way randomized, crossover study. Clinical Drug Investigation. 2009;29(5):317-24. PMID 19366273
- Simons P, Olofsen E, van Velzen M, et al. S-Ketamine Oral Thin Film-Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine. Frontiers in Pain Research. 2022;3:946486. PMID 35899184
- Noppers IM, Niesters M, Aarts LPHJ, et al. Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases. Pain. 2011;152(9):2173-2178. PMID 21546160
- Castellani D, Pirola GM, Gubbiotti M, et al. What urologists need to know about ketamine-induced uropathy: A systematic review. Neurourology and Urodynamics. 2020;39(4):1049-1062. PMID 32212278
Dr. Gurpreet Singh Padda, MD, MBA, MHP
