What “neuropathic” means — the IASP definition
Not all chronic pain is the same. The International Association for the Study of Pain (IASP), the body that sets the global terminology for pain medicine, defines neuropathic pain as “pain caused by a lesion or disease of the somatosensory nervous system.” That is a precise way of saying the pain originates from damaged or diseased nerves themselves, not from injured tissue that nerves are simply reporting on.
Patients describe it differently than ordinary pain. The words that recur in clinic are burning, electric, shooting, stabbing, or a strange numb-but-painful quality. It can flare in response to light touch (allodynia) or feel disproportionate to anything you can point to on a scan. Common diagnoses include post-herpetic neuralgia (after shingles), diabetic peripheral neuropathy, post-surgical nerve pain, complex regional pain syndrome (CRPS), spinal cord injury pain, and radiculopathy.
What unifies these conditions is the underlying problem: the nervous system itself has changed. After nerve injury, the spinal cord and brain begin to amplify signals through a process called central sensitization. Receptors on dorsal horn neurons become hypersensitive. Pain processing networks rewire. Over months and years, the nervous system learns to produce pain even after the original injury has healed.
Why opioids underperform here
One of the most consistent findings in pain medicine is that opioids work better for acute tissue-injury pain than for established neuropathic pain. There is a mechanistic reason. Opioids act primarily at mu-opioid receptors, which dampen pain transmission from the periphery. They do almost nothing to interrupt the central wind-up phenomenon that drives nerve pain at the spinal cord and brain level.
This matters clinically in two ways. First, patients with severe neuropathic pain often end up on escalating opioid doses with diminishing returns and accumulating risk. Second, when the IASP and the U.S. FDA review the evidence, opioids are not first-line for most neuropathic pain syndromes. First-line options are typically gabapentinoids (gabapentin, pregabalin), certain antidepressants (duloxetine, tricyclics), and topical agents.
Ketamine is interesting precisely because it works on a different receptor system entirely. For a broader comparison of these two approaches, our piece on ketamine vs. opioids for chronic pain walks through the mechanistic differences in more depth.
The NMDA mechanism in plain English
The NMDA receptor sits on neurons throughout the spinal cord and brain. It is one of the gates through which the excitatory neurotransmitter glutamate triggers signaling. In ordinary conditions, this gate is well regulated. In chronic neuropathic pain, the regulation breaks down. NMDA receptors stay overactive. Each pain signal builds on the last in a process pain researchers call wind-up. The nervous system gets stuck in a louder version of itself.
Ketamine is a non-competitive NMDA-receptor antagonist. At the sub-anesthetic doses used for chronic pain, it binds inside the receptor channel and blocks excessive glutamate signaling without shutting down normal function. The clinical effect is twofold: an immediate reduction in pain transmission, and, with sustained dosing, a window in which the over-sensitized circuitry can begin to recalibrate. This is the same broad mechanism that underlies ketamine’s effect in other central-sensitization syndromes such as fibromyalgia and other chronic pain conditions.
An off-label note. Ketamine is FDA-approved as an anesthetic. Its use for neuropathic pain and other chronic pain syndromes is off-label, meaning it is prescribed based on the body of clinical research rather than a specific FDA pain indication. This is standard practice in pain medicine, and it is also the regulatory context patients should understand before starting.
Niesters’ review: short vs. prolonged infusions
The most-cited single source on ketamine for neuropathic pain remains the 2014 review by Niesters, Martini, and Dahan published in the British Journal of Clinical Pharmacology. The authors synthesized the available human data on low-dose ketamine across pain conditions and drew a useful distinction between two protocol families.
- Short infusions (typically a few hours) tend to produce strong analgesia during the infusion, with relief that fades over hours to days afterward. Useful, but limited.
- Prolonged infusions (4 to 14 days, often given inpatient or in repeated outpatient sessions) can produce analgesic effects that persist for up to three months in some patients. The longer dosing window appears to give the central nervous system more time to step out of the wind-up loop.
Niesters and colleagues were careful with the conclusions. The quality of the evidence varies by condition. The strongest signals were in CRPS and certain refractory neuropathic syndromes. They emphasized that ketamine is not a uniform fit for every pain type, and that the dose-response curve is real — more is not always better, and side effects rise with prolonged exposure. Even with those caveats, the BJCP review remains the most useful single reference for setting expectations about durability.
Low-dose ketamine produces strong analgesia in neuropathic pain states. Prolonged infusions over four to fourteen days can produce analgesic effects lasting up to three months. — Niesters M, Martini C, Dahan A. British Journal of Clinical Pharmacology, 2014.
Conditions with the strongest evidence
The IASP, the American Society of Regional Anesthesia and Pain Medicine (ASRA), the American Academy of Pain Medicine (AAPM), and the American Society of Anesthesiologists (ASA) jointly published consensus guidelines on the use of IV ketamine for chronic pain in 2018, led by Cohen and colleagues in Regional Anesthesia & Pain Medicine. That document remains a useful map of where the evidence is strongest.
The consensus guidelines reported moderate-quality evidence supporting IV ketamine for several specific neuropathic pain syndromes, including:
- Complex regional pain syndrome (CRPS), where multiple controlled trials show meaningful analgesia, particularly with multi-day protocols.
- Spinal cord injury pain, a notoriously difficult-to-treat neuropathic syndrome where ketamine has shown durable benefit in selected patients.
- Mixed neuropathic pain syndromes (post-herpetic, post-surgical, peripheral neuropathy) where conventional first-line therapies have failed or are poorly tolerated.
Evidence for non-neuropathic chronic pain (e.g., headache, ischemic pain) was rated weaker. The guidelines explicitly note that ketamine is not a substitute for comprehensive multimodal pain care — physical therapy, sleep, mood treatment, and medication review all still matter. The IASP’s broader position is consistent with this: ketamine is a useful tool in the pain physician’s kit, not a stand-alone solution.
What durability and re-treatment look like
Patients reasonably want to know how long relief lasts and what happens after it fades. Honest answer: it depends on the condition, the protocol, and the individual. Drawing from Niesters’ review and the ASRA/AAPM/ASA consensus, a few patterns recur.
- After a standard induction series (typically 4–6 sessions over two to three weeks), responders often report meaningful pain reduction lasting weeks rather than months.
- Higher-dose or longer-duration protocols, where clinically appropriate, can extend the analgesic window further, with the three-month figure from Niesters representing an upper bound rather than an average.
- Many patients return for periodic booster infusions to maintain benefit, on a schedule built around how their pain actually behaves rather than a fixed calendar.
- Roughly a third to half of patients in the published literature do not achieve meaningful response. Research suggests the strongest predictors of response are clear neuropathic features and a shorter duration since pain onset, but no clinical tool reliably identifies responders in advance.
Studies indicate that re-treatment in responders tends to remain effective over time, though the data on truly long-term durability are limited and most series follow patients for less than two years. We do not promise a permanent solution. Anyone telling you they can guarantee one for nerve pain is not being straight with you.
Realistic expectations from a Nashville clinic
If you are considering ketamine for neuropathic pain at Music City Ketamine, here is what that looks like in practice. Treatment begins with a thorough consultation. We review your diagnosis, imaging, prior treatments, current medications, and pain history, and we coordinate with your existing pain or neurology team where relevant. Not everyone is a candidate, and we will say so when that is the case.
For patients we do treat, sessions take place in a private treatment room with anesthesia-level monitoring — continuous pulse oximetry, blood pressure, and heart rate — the same standard described in our safety overview. Marla Peterson, CRNA, oversees every infusion and is on-site throughout. You will also meet our therapy dogs, Walter White and Wilma, who tend to take an interest. You will need a driver. Most patients resume normal activities the next day.
A few honest expectations to set:
- This is off-label. Ketamine is FDA-approved as an anesthetic; its use for neuropathic pain is off-label and based on the body of evidence summarized above.
- Not everyone responds. Even with careful candidate selection, a meaningful minority of patients do not get the relief they hoped for. We talk about that honestly before starting.
- Ketamine works alongside other care. It does not replace your gabapentinoid, your duloxetine, or your physical therapy. We coordinate, we do not displace.
- Cost. Insurance generally does not cover IV ketamine for off-label pain indications. Sessions at Music City Ketamine are $475 each, and we are transparent about that from the first call.
If you want to read more about how the broader chronic-pain program works, our chronic pain treatment overview and how it works pages cover the operational details. The point of this article is the evidence: there is a real, mechanistically coherent reason ketamine helps some people with neuropathic pain when other treatments have not. The evidence is meaningful, the durability is real for responders, and the limits are honest. That is the right frame to bring into a consultation.