Ketamine for a Limb That Burns After the Injury Healed: Why the Route Changes the Evidence

What this video covers

• What central sensitization means, and why the spinal NMDA wind-up model comes from animal recordings, not human measurement
• Why infusion holds the only controlled efficacy data, while the topical and sublingual dosing this practice often starts with has never been compared with placebo
• What the one controlled trial showed: a 100-hour inpatient S-ketamine infusion lowered pain through week 11, lost its edge at week 12, did not improve function, and caused psychomimetic effects in three of four patients
• Why a short outpatient infusion is not the treatment that was studied
• The topical evidence: 10 percent cream cut brushing and pinprick pain in 20 patients, with undetectable blood levels, unchanged touch thresholds and no lasting relief
• MEDICAL DISCLAIMER: This content is for educational purposes only and is not medical advice. It does not substitute for professional diagnosis or treatment. Always consult a licensed healthcare provider regarding your condition. Viewing this video does not establish a doctor-patient relationship.

There is a jar on the kitchen counter. White cream, a pharmacy label, a strength written by hand — ten percent ketamine. Beside it, a bottle of troches that dissolve under the tongue. And in the folder from the clinic, a printout of an infusion study. Nobody has told the person holding that jar that the paper on the counter and the jar on the counter have almost nothing to do with each other.

If a limb has burned since an injury that healed — the condition most charts call complex regional pain syndrome, and what many patients and older records still call reflex sympathetic dystrophy, or RSD — ketamine will come up eventually. This article explains why it comes up, what the controlled evidence actually shows, and why that evidence is different for every route the drug can take.

Ketamine is not one treatment — it is three that share a molecule

Ketamine can be given three ways in this setting: as a compounded topical cream rubbed on the painful skin, as a sublingual troche that dissolves under the tongue, and as an intravenous infusion. They share a molecule. They do not share an evidence base.

That matters more than it sounds. A patient is handed a jar and a bottle, then quoted an intravenous trial. Or booked for a short outpatient infusion and told that trial produced eleven weeks of relief. It did not. Each route has to be judged on the studies that were actually run on that route.

The rationale: NMDA receptors and spinal wind-up

The reason anyone reaches for an NMDA antagonist in a limb like this starts in a laboratory animal’s spinal cord, and you are entitled to know that before you consent to it.

In animal experiments, investigators record from dorsal horn neurons — the first relay station where pain signals from the body enter the spinal cord. Deliver repetitive painful input at one fixed intensity and the neuron’s output climbs anyway. Glutamate accumulates, the magnesium ion that plugs the NMDA receptor channel is expelled, calcium floods in, and the gain of the system rises. That escalation is called wind-up, and it is a component of what is broadly termed central sensitization.

Two honest qualifications belong with that paragraph. First, wind-up is measured with an electrode in an animal. It has not been measured in your spinal cord. It is inferred in patients — reasonably — when allodynia outlasts the injury by months and spreads beyond a single nerve’s territory. That is an inference, not a recording.

Second, ketamine is a non-competitive NMDA receptor antagonist: it blocks that channel. That is the entire mechanistic rationale for using it here. Rational is not the same as proven.

Why this produces the symptom you actually feel

Central sensitization is the reason the symptom is so strange to describe and so hard for other people to believe.

If the spinal relay has raised its gain, then input that should register as touch arrives at the brain labeled as pain. That is allodynia — a bedsheet, a sock, a breeze from a fan, the light drag of a shirt cuff becoming unbearable. It is also why hyperalgesia appears: a pinprick that should be a small, sharp, brief thing becomes disproportionate and lingering.

It explains the second thing patients describe: the pain no longer respects the map. A nerve injury produces pain in that nerve’s territory. When the spinal cord itself has changed, the burning spreads past those borders, which is exactly the pattern that makes a primary care visit go in circles.

And it explains the third: why physical therapy stalls. A limb that cannot tolerate contact cannot be worked on. The therapy that would restore movement requires touch, and touch is the symptom.

What the controlled evidence shows, route by route

Take the three routes in the order the evidence ranks them, which is not the order a clinic finds convenient.

Intravenous: where the controlled data live

Sigtermans and colleagues, publishing in Pain in 2009, randomized 60 patients with complex regional pain syndrome type 1 — median disease duration over seven years — to a 100-hour continuous inpatient infusion of individually titrated S(+)-ketamine or to placebo.

At week one, pain scored 2.7 out of 10 on ketamine against 5.5 on placebo. That separation held through week eleven and was lost at week twelve.

Now the two findings that get left out of the retelling. Treatment did not cause functional improvement — pain fell, function did not follow. And psychomimetic effects (dissociation and related mental-state changes) occurred in 76 percent of ketamine patients versus 18 percent on placebo. Roughly three of four felt dissociated.

So this is where the controlled data live — but it is one randomized trial in 60 patients, and it tested one specific intervention: a hundred hours, inpatient, S(+)-ketamine, individually titrated, monitored. The multi-society consensus guidance discussed further down is blunt that most of the literature supporting ketamine in chronic pain is small and methodologically limited, and this trial sits inside that literature. It is the best evidence on this page, not settled evidence. And a short outpatient infusion is not the treatment that was studied. Anything shorter is an extrapolation from that trial, and should be described that way.

Topical: a separate literature, measured over a single day

Finch, Knudsen and Drummond, also in Pain in 2009, ran a double-blind, placebo-controlled crossover trial of 10 percent ketamine cream in 20 patients with CRPS.

The cream reduced allodynia to light brushing and hyperalgesia to punctate stimulation, and plasma ketamine was undetectable an hour after application — meaning the effect was local, not systemic. But normal touch thresholds did not change, and durability was never measured. That trial tells you about the same day. It tells you nothing about the same month.

Sublingual: no controlled efficacy evidence in this condition

Sublingual ketamine has no controlled efficacy trial in complex regional pain syndrome. When it is used, that is a practice preference, not an evidence-led first choice — and you are entitled to hear it named that way before it is dispensed.

One boundary on the numbers

Every figure above was measured in complex regional pain syndrome. If what you have is refractory neuropathic pain without CRPS — post-herpetic neuralgia, painful diabetic neuropathy, a nerve injured during surgery — the mechanistic rationale carries over. The eleven weeks does not. A study that did not enroll you cannot report your result.

What the usual conversation misses

None of this is an argument against standard care, and none of it is a criticism of the physicians who deliver it. Membrane-stabilizing medications, sympathetic blocks and desensitization therapy are the steps that come first, and a diagnostic sympathetic blockade earns its place by answering whether the sympathetic system is participating at all. Ketamine enters the conversation only in the narrow situation where those steps have already been tried and have not been enough — that is the setting the studies on this page were run in, and the only setting this article is about.

Three things do get missed, though, and they are the reason this article exists.

The diagnosis is skipped. This diagnosis is made using the Budapest criteria and by exclusion. Deep vein thrombosis, cellulitis, occult fracture, radiculopathy, entrapment neuropathy and small fiber neuropathy all imitate it, and diagnostic sympathetic blockade helps answer whether the sympathetic system is involved. If the name has not been earned that way, what follows is not a treatment decision — it is a guess with a controlled substance attached.

Evidence is transferred between routes that never shared it. The infusion paper on the counter does not support the jar on the counter.

The regulatory status goes unsaid. Ketamine is approved as an anesthetic; every use described here is off-label. Compounded creams and troches are not FDA-evaluated for potency, sterility or effectiveness, and strength can vary by batch. And one word deserves precision: the trial drug was S(+)-ketamine — that is esketamine, the same molecule as the nasal spray approved for treatment-resistant depression. Same molecule, different product, different route, different indication. That approval says nothing about a painful limb.

What this means for evaluation and treatment

A responsible ketamine conversation is mostly a screening and consent conversation. The 2018 consensus guidance from the American Society of Regional Anesthesia and Pain Medicine, with the American Academy of Pain Medicine and the American Society of Anesthesiologists, is explicit: benefit varies by condition and dose, most supporting studies are small and methodologically limited, adverse events are relatively rare but risk rises with higher doses and more frequent treatments — and its monitoring standards cover intravenous use only. That phrase “relatively rare” has to be read alongside the infusion trial above, where psychomimetic effects were not rare at all.

In practice, that means:

• Name the diagnosis first, by Budapest criteria and exclusion, before any route is discussed.
• Screen before dosing. Cardiac, blood pressure, liver, psychiatric and substance-use screening comes first. Ketamine is not appropriate in uncontrolled hypertension, unstable coronary or cerebrovascular disease, raised intracranial or intraocular pressure, active psychosis, significant liver disease, active substance use disorder, or in pregnancy or breastfeeding.
• Expect real side effects. Beyond dissociation: sedation, dizziness, nausea, blurred vision, and a rise in blood pressure and heart rate. No driving and no legal or financial decisions on a dosing day; infusions require continuous vital-sign monitoring, resuscitation equipment on hand, and an adult driver.
• Respect the controlled-substance status. Ketamine is Schedule III, with genuine misuse and dependence risk. Take-home troches are limited in quantity and governed by a written treatment agreement, because a Schedule III drug in a kitchen drawer is a diversion risk whether or not anyone in the house intends one.
• Handle the cream as a drug, not a lotion. It transfers by touch. Wash hands after every application, keep treated skin covered, and keep the jar away from children and pets. A dose that is therapeutic on your forearm is not a dose anyone else should receive.
• Monitor for the long-exposure harms. Repeated or high-dose exposure carries ulcerative cystitis — sometimes severe and not always reversible — plus liver injury, so urinary symptoms and liver enzymes are monitored.
• Set a stop date on day one. Every trial should be time-limited, recorded as a trial, and stopped on the agreed date if it does not deliver.

If you want the procedural detail — how each route is prepared, screened for and monitored — see the ketamine therapy page for the three routes and their monitoring requirements.

A composite picture, not one person’s chart

The following is a composite — a picture assembled from many patients with this condition, not one person’s chart, offered as a practice observation rather than a trial result. Individual results vary.

A limb is injured, immobilized, healed on imaging, and then burns for a year. Sympathetic blocks help for hours. A membrane stabilizer works at a dose that makes thinking difficult. A therapist cannot begin, because contact is unbearable. Treatment starts where risk is lowest: compounded 10 percent cream to the allodynic skin, with the understanding — spoken and written — that its evidence covers a single day, not a season. A bedsheet becomes tolerable. That is not a cure, and it should not be called one. But it can buy enough contact tolerance for the therapist to begin.

What deserves emphasis is the honest limit on that story. It is an observation from practice, not a measured outcome, and none of the trial numbers above can be borrowed to support it. The one controlled infusion trial in this condition lowered pain and did not move function at all, and there is no trial showing that desensitization therapy changes the trajectory here. The narrower claim is the true one — a limb no one can touch cannot be worked on. A limb that can be touched can be.

Frequently asked questions

Key takeaways

• Ketamine blocks the NMDA receptor implicated in spinal wind-up and central sensitization — a rationale inferred from animal recordings and from your symptom pattern, not measured in your spinal cord.
• The evidence does not transfer between routes: intravenous holds the only controlled efficacy data in this condition — one 60-patient trial of a 100-hour inpatient infusion, relief through week eleven, no functional gain, psychomimetic effects in 76 percent — topical has a single-day sensory trial, and sublingual has none.
• Even that intravenous trial sits inside a literature the 2018 multi-society guidance calls small and methodologically limited, and what it studied was a 100-hour inpatient infusion, not the short outpatient version.
• Every use described here is off-label; compounded creams and troches are not FDA-evaluated for potency, sterility or effectiveness, and ketamine is a Schedule III controlled substance requiring screening, monitoring and a written treatment agreement.
• The diagnosis has to be earned first — Budapest criteria plus exclusion of DVT, cellulitis, occult fracture, radiculopathy, entrapment and small fiber neuropathy — before any route is a treatment decision.
• If burning, swelling and temperature change have outlasted the injury that caused them, get the diagnosis named, then ask which route the evidence actually supports.

Medically reviewed by Gurpreet Singh Padda, MD, MBA, MHP — Board Certified in Anesthesiology, Pain Medicine, Interventional Pain Management, Addiction Medicine, and Obesity Medicine. Last reviewed July 2026.

This article is educational and is not a substitute for evaluation, diagnosis, or treatment by a physician. Individual results vary. Do not start, stop, or change any medication without consulting your physician. To be evaluated at Padda Institute Center for Interventional Pain Management, call (314) 481-5000 or text (314) 886-5902.

References

1. Sigtermans MJ, van Hilten JJ, Bauer MCR, Arbous SM, Marinus J, Sarton EY, Dahan A. 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. PubMed
2. 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. PubMed
3. Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, Viscusi ER, Narouze S, Davis FN, Ritchie EC, Lubenow TR, Hooten WM. 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. PMID 29870458. PubMed

Dr. Gurpreet Singh Padda, MD, MBA, MHP