What it is treating

The NMDA receptor sits in the spinal cord and brain and is central to how pain signals get amplified over time. In complex regional pain syndrome, an initial injury — often minor, sometimes barely remembered — triggers a disproportionate and self-sustaining response: the limb becomes exquisitely sensitive, discolored, swollen, and painful out of proportion to what the tissue itself would explain. NMDA receptor activation is a major driver of that amplification, which is why blocking it with ketamine is one of the few interventions aimed directly at the central mechanism rather than only at the limb.

Three routes, all offered here

Which route, at what dose and how often, is a clinical decision built around severity, response and what you can tolerate — not a package deal, and not offered as a pre-set series.

The terrain of a sensitized nervous system

Central sensitization does not stay contained to the injured limb, and it does not run on NMDA activity alone. Chronic pain itself drives systemic inflammation that keeps the amplification loop running, and sleep in CRPS is frequently wrecked by a limb that burns at rest — two biological drivers reinforcing each other in a feedback loop ketamine alone cannot fully break. The isolation of living with a visibly abnormal limb, and the disbelief some patients report from people around them who cannot see an obvious injury, is the third, social driver keeping the nervous system on high alert. Ketamine turns down the amplifier. This practice pairs it with the same attention to sleep and nervous system arousal used across every chronic pain plan here, because a quieted receptor sitting in an otherwise unaddressed terrain tends not to stay quiet.

The evidence, honestly

A 2019 systematic review and meta-analysis of ketamine infusions for chronic pain broadly found modest, time-limited benefit across the pooled trials, with CRPS among the better-represented conditions. Two systematic reviews specific to CRPS — one from 2015, one from 2018 — both found real short-term pain reduction from ketamine infusion, and both flagged the same limitation: the underlying trials are small, use inconsistent dosing protocols, and rarely follow patients past a few months, which means the durability of relief beyond that window is genuinely not well established. The populations studied also skew toward patients who had already failed multiple other treatments, which is honestly close to who ends up on this page, but it means the numbers describe a refractory population specifically, not CRPS in general.

Intranasal ketamine sits between the two: absorbed quickly across the nasal mucosa, it reaches the central nervous system without an IV line, and its evidence base is the one built for the esketamine nasal spray and a smaller ketamine literature in neuropathic pain, which we read as supportive but still short of the infusion trials in size. We tell patients directly: the trial evidence supports trying this, especially after other approaches have not held, and it does not yet support promising a specific duration of relief. That gap gets filled by watching how your own nervous system responds, not by a number from a paper.

Monitoring

IV infusions are done with continuous blood pressure, heart rate and oxygen monitoring for the duration, because ketamine can raise blood pressure and heart rate and, at sub-anesthetic doses, can still produce dissociative effects — a floaty, detached feeling some patients find unpleasant. You will not drive yourself home after an infusion. Sublingual and intranasal use is monitored through follow-up visits rather than continuous monitoring, since the peak exposure is lower and the dose is smaller, but we still track blood pressure and ask directly about mood and dissociative symptoms at each check-in.

What happens on the day of an infusion

Who is not a candidate

Poorly controlled hypertension or significant cardiac disease is a concern for IV dosing specifically, given ketamine’s effect on blood pressure and heart rate. A history of psychosis or an active, unstable psychiatric condition is a serious caution, since dissociative effects can be genuinely distressing in that context. A history of substance use disorder involving ketamine or a similar agent needs an honest conversation before this is the right tool, not an automatic disqualification but a reason to go slower and monitor closer. Pregnancy is a contraindication for systemic dosing.

Risks, in plain language

During an IV infusion: elevated blood pressure and heart rate, nausea, and dissociative effects that resolve as the infusion ends and the drug clears. Bladder irritation has been reported with frequent, high-dose, long-term ketamine use, most documented in a recreational-use context rather than the supervised, dose-limited regimens used here, but it is worth telling you about. Sublingual and intranasal use can cause drowsiness, mild dissociation and, with the nasal route, transient nasal irritation; both carry meaningfully less systemic risk than an infusion.

Common questions

Related reading

• Complex regional pain syndrome
• Sympathetic nerve blocks
• Spinal cord stimulation
• Opioid stewardship
• Sleep, movement and behavior