What Makes Nerve Pain Different
Most pain works like an alarm system. You touch something hot, nociceptors fire, and you pull your hand back. The pain matches the threat, and it stops when the threat is gone. Neuropathic pain breaks that logic. The nerves themselves are damaged, and they keep sending pain signals even though there is nothing left to warn you about.
The sensations are distinct. People with neuropathic pain describe burning that does not correspond to any heat source. Shooting or electric-shock pain that arrives without warning. Tingling, numbness, and pins-and-needles that coexist with sharp pain in the same area. And perhaps the most disorienting symptom: allodynia, where a light touch—clothing brushing against skin, a bedsheet resting on a foot—produces pain that is genuinely excruciating.
These are not exaggerations. They are the predictable result of a nervous system that has lost its ability to distinguish between dangerous and harmless stimuli.
Common conditions that produce neuropathic pain include:
- Diabetic peripheral neuropathy—affecting up to 50% of people with diabetes over their lifetime
- Postherpetic neuralgia—persistent nerve pain after shingles, occurring in roughly 10–18% of shingles patients
- Chemotherapy-induced peripheral neuropathy (CIPN)—affecting 30–70% of patients receiving neurotoxic chemotherapy agents
- Post-surgical nerve damage—occurring in 10–50% of surgeries depending on the procedure
- Phantom limb pain—reported by up to 80% of amputees
- Radiculopathy—compressed or irritated nerve roots in the spine
What these conditions share is a common downstream problem: the nervous system starts amplifying signals it should be filtering out. That amplification has a name, and understanding it explains why ketamine works where other treatments do not.
Central Sensitization: When the Volume Gets Stuck
After nerve injury, something changes in the spinal cord. The dorsal horn neurons—the relay stations where incoming pain signals get processed before heading to the brain—become hyperexcitable. They start responding more strongly to normal inputs and begin firing in response to stimuli that should not register as painful at all.
This process is called central sensitization, and NMDA receptors are at the center of it.
Here is the sequence. Damaged peripheral nerves release excessive glutamate (the brain’s primary excitatory neurotransmitter) at their synapses in the spinal cord. Under normal conditions, NMDA receptors on dorsal horn neurons sit quietly, blocked by a magnesium ion that prevents them from activating. But sustained glutamate bombardment from damaged nerves dislodges that magnesium block. Once NMDA receptors open, they allow calcium to flood into the neuron, triggering a cascade that makes the neuron permanently more excitable.
This is the wind-up phenomenon. Each subsequent pain signal arrives at a neuron that is already primed to over-respond. The volume knob turns up and stays there. Touch becomes painful. Mild discomfort becomes agony. Pain spreads beyond the area of the original nerve damage into adjacent, uninjured tissue.
Standard analgesics do not address this. NSAIDs reduce inflammation at the site of tissue injury, but neuropathic pain is not an inflammatory problem. Opioids dampen pain perception at mu-opioid receptors, but they do not reverse central sensitization—and over time, NMDA receptor activity actually contributes to opioid tolerance, meaning the same dose becomes less effective. Gabapentin and pregabalin modulate calcium channels and help some patients, but response rates hover around 30–40%, leaving the majority without adequate relief.
How Ketamine Targets the Problem
Ketamine is a noncompetitive NMDA receptor antagonist. It binds inside the open ion channel of the NMDA receptor and blocks calcium influx. This is not a peripheral effect or a generalized dampening of brain activity. It is a targeted interruption of the specific receptor type that maintains central sensitization.
The clinical implications are direct. When ketamine blocks NMDA receptors in the dorsal horn of the spinal cord, it:
- Reduces wind-up and temporal summation. The progressive amplification of pain signals slows or stops. Neurons that were firing at five times their normal rate begin returning to baseline activity.
- Reverses allodynia. When NMDA-mediated sensitization decreases, the nervous system begins distinguishing between harmful and harmless stimuli again. Touch stops registering as pain.
- Restores descending inhibitory pathways. The brain has built-in pain-suppression circuits that project down into the spinal cord. Central sensitization disrupts these circuits. Ketamine helps restore their function, reactivating the body’s own ability to regulate incoming pain signals.
- Produces an opioid-sparing effect. Because ketamine addresses NMDA-driven sensitization, patients often find they need lower doses of opioid medications. Research suggests ketamine may also help prevent opioid-induced hyperalgesia—the paradoxical increase in pain sensitivity that can develop with chronic opioid use.
This is fundamentally different from how other pain medications work. Opioids mask the signal. Ketamine addresses the malfunction that is generating the signal in the first place.
What the Clinical Research Shows
A systematic review and meta-analysis of randomized controlled trials published in Pharmaceuticals (2024) examined ketamine as an add-on therapy for patients with multifactorial neuropathic pain. The review found that ketamine produced statistically significant reductions in pain intensity at both one week and 30 days compared to standard treatment alone.
Looking at the individual trials tells a more detailed story. Four of seven double-blind RCTs reported that ketamine infusions produced significantly greater pain reduction than placebo, with differences ranging from 25% to 45% improvement. In one study, 50% of patients achieved meaningful pain relief at the one-month mark.
The American Society of Regional Anesthesia and Pain Medicine (ASRA), the American Academy of Pain Medicine (AAPM), and the American Society of Anesthesiologists (ASA) published joint consensus guidelines recognizing IV ketamine as a treatment option for chronic pain conditions, with particular notation of its applicability to neuropathic pain states. The guidelines recommend that ketamine infusions be administered by clinicians trained in airway management and hemodynamic monitoring—which is standard practice in our clinic, where every session is administered by Marla Peterson, CRNA, a board-certified nurse anesthetist with over 20 years of clinical experience.
Specific findings by condition:
- Phantom limb pain: Multiple studies demonstrate ketamine’s efficacy for phantom limb pain, which is a purely central phenomenon (there is no peripheral nerve left to treat). The fact that ketamine helps here confirms its mechanism of action is central, not peripheral.
- Postherpetic neuralgia: Studies show ketamine reduces both spontaneous pain and touch-evoked allodynia in postherpetic neuralgia, consistent with NMDA receptor blockade reducing central sensitization in the dorsal horn.
- Chemotherapy-induced neuropathy: Early clinical data suggests ketamine infusions may help the subset of CIPN patients whose pain persists after chemotherapy ends, likely by addressing residual central sensitization rather than ongoing nerve damage.
A key finding across studies: patients with evidence of central sensitization—those with allodynia, hyperalgesia, or pain that has spread beyond the original injury site—tend to respond better to ketamine. This makes clinical sense. Ketamine targets the NMDA-driven sensitization process, so patients in whom that process is most active have the most to gain from its interruption.
The Difference Between IV Ketamine and Oral Options
Ketamine can be administered through several routes: intravenous, intramuscular, oral, nasal, and topical. For neuropathic pain, the route matters.
IV administration delivers ketamine directly into the bloodstream with 100% bioavailability. The dose can be precisely titrated during the infusion based on the patient’s response and tolerability. Blood levels rise and fall predictably, and the treating clinician maintains complete control over the concentration reaching the central nervous system.
Oral ketamine has a bioavailability of roughly 20–25% due to extensive first-pass metabolism in the liver. This means the dose reaching the brain is variable and difficult to predict. The liver converts ketamine to norketamine, which has different pharmacological properties and may contribute to side effects without proportional analgesic benefit.
For neuropathic pain specifically, achieving adequate NMDA receptor blockade in the spinal cord requires reliable drug concentrations. The consensus guidelines from ASRA/AAPM/ASA focus on IV infusion protocols precisely because the evidence base is strongest for this route.
What to Expect During Treatment
At Music City Ketamine, IV infusions for neuropathic pain follow a protocol informed by the consensus guidelines and our clinical experience with chronic pain patients. Every session is overseen by Marla with continuous pulse oximetry, blood pressure, and heart rate tracking.
Pain protocols typically involve infusions that may be longer in duration or administered at different intervals compared to mental health protocols. The specific approach depends on the type and severity of neuropathic pain, how long it has been present, and what other treatments you are currently using.
Most patients report that the onset of relief is noticeable during or shortly after the infusion. Some patients describe the experience as a gradual quieting of the background noise—the constant burning or tingling that they had adapted to begins to fade. The duration of relief varies. Some patients maintain improvement for weeks after an infusion series; others benefit from maintenance sessions at individualized intervals.
Two things worth noting. First, ketamine does not require you to stop your current pain medications before starting treatment. It can be used alongside gabapentin, pregabalin, duloxetine, and other neuropathic pain medications. Second, the safety profile of IV ketamine at subanesthetic doses is well-established, with over 50 years of clinical use. Side effects during infusion (dissociation, mild nausea, dizziness) are transient and resolve as the infusion ends.
When Nerve Pain and Depression Coexist
Chronic neuropathic pain and depression are deeply entangled. Roughly 50–60% of chronic pain patients have comorbid depression, and the two conditions share overlapping neurobiology. Sustained pain activates stress pathways that reduce BDNF (brain-derived neurotrophic factor) and weaken synaptic connections in mood-regulating circuits. Chronic depression amplifies pain perception through the same central sensitization pathways that maintain neuropathic pain.
This overlap matters because ketamine addresses both conditions simultaneously through related mechanisms. NMDA receptor blockade triggers BDNF release and synaptogenesis in prefrontal circuits (the antidepressant effect) while also reducing central sensitization in spinal pain circuits (the analgesic effect). For patients who carry both burdens, treating one often improves the other.
We see this regularly in our clinic. A patient comes in for chronic neuropathic pain and, after several sessions, mentions that they are sleeping better, that the hopelessness has lifted, that they feel motivated to do their physical therapy exercises for the first time in months. The pain improvement and the mood improvement are not separate effects. They are the same medication acting on the same receptor system in different parts of the nervous system.
Working with Your Current Treatment Plan
Ketamine is not typically a standalone treatment for neuropathic pain. It works best as part of a comprehensive approach that may include physical therapy, medication management, nerve blocks, and psychological support. The neuroplastic window following each infusion creates a period of enhanced capacity for physical rehabilitation—a time when movement may be less painful and new motor patterns can establish more readily.
If you are currently working with a pain management physician, neurologist, or primary care provider, we coordinate with your existing care team. Ketamine infusion therapy does not replace your other treatments. It adds a mechanism that those treatments cannot provide: direct interruption of NMDA-mediated central sensitization.
For patients in the Nashville metro area—Franklin, Brentwood, Cool Springs, Murfreesboro, Spring Hill—our clinic is located at 480 Duke Dr., Suite #100 in Franklin, just off I-65. Pricing and financing options are available on our website.