Chronic Pain Guide: Types, Mechanisms, and Regenerative Treatment Options

Chronic pain is pain that persists or recurs for more than three months, according to the International Association for the Study of Pain (IASP), and it comes in three mechanistic types: nociceptive pain from tissue damage, neuropathic pain from nerve damage, and nociplastic pain from altered pain processing in the central nervous system. In the United States, 20.4% of adults had chronic pain in 2019, according to the CDC’s National Health Interview Survey.

The pain type matters because it predicts which treatments are likely to help. Regenerative options such as platelet-rich plasma (PRP), mesenchymal stem cell (MSC) therapy and extracorporeal shockwave therapy (ESWT) target damaged tissue, so their evidence is strongest in localized nociceptive pain. Centrally acting options such as ketamine, low-dose naltrexone (LDN), hyperbaric oxygen therapy (HBOT) and neurofeedback target the nervous system itself and are studied mainly in neuropathic and nociplastic pain.

Table of Contents

• Defining Chronic Pain
• Types of Chronic Pain
• Central Sensitization
• Assessment and Diagnosis
• Conventional Pain Management
• Limits of Conventional Approaches
• Platelet-Rich Plasma (PRP)
• Stem Cell Therapy
• Shockwave Therapy
• Hyperbaric Oxygen Therapy (HBOT)
• Ketamine Infusion Therapy
• Low-Dose Naltrexone (LDN)
• Neurofeedback
• Evidence Summary Table
• Integrating Regenerative Care
• Frequently Asked Questions

Defining Chronic Pain

The International Association for the Study of Pain (IASP) defines chronic pain as pain that persists or recurs for more than three months. This time-based definition is accompanied by functional and psychological dimensions: chronic pain typically disrupts sleep, mood, work capacity, and social function in ways that acute pain does not.

The ICD-11, which took effect in 2022, introduced a new chronic pain classification that distinguishes primary chronic pain (where pain itself is the disease, with no better explanation from another condition) from secondary chronic pain (pain arising as a symptom of an identifiable underlying disease such as cancer, post-surgical damage, or inflammatory arthritis). This distinction has practical implications for treatment targeting.

Chronic pain is not simply prolonged acute pain. The underlying neurobiology shifts substantially over time. What begins as a protective nociceptive signal can become an autonomous, maladaptive process involving structural and functional changes in the peripheral and central nervous system. Understanding this transition is essential for choosing appropriate treatments.

Prevalence and Burden

A 2019 systematic review and meta-analysis in The Lancet estimated chronic pain prevalence at 20-30% in high-income countries, with chronic pain of moderate to severe intensity affecting approximately 10%. In the United States, the CDC’s 2019 National Health Interview Survey, reported by Zelaya and colleagues in NCHS Data Brief 390 (2020), found that 20.4% of adults (about 50 million) had chronic pain, and 7.4% had high-impact chronic pain, defined as pain that frequently limits work or life activities.

The economic burden is substantial. Direct and indirect costs of chronic pain in the US are estimated at $560-635 billion annually, exceeding those of heart disease, cancer, and diabetes combined, according to a 2011 Institute of Medicine report. The majority of these costs come from lost productivity rather than direct medical expenditure.

The same CDC data brief found that chronic pain rises with age and was highest in adults aged 65 and over, and that women reported chronic pain more often than men. For an overview of how the condition is defined and treated across specialties, see our chronic pain condition page.

Types of Chronic Pain

The three types of chronic pain are nociceptive, neuropathic and nociplastic, a classification the IASP uses to describe the mechanism behind a patient’s pain rather than its location. A single person can have more than one type at once, and the mix often shifts over the course of a long illness.

Nociceptive Pain

Nociceptive pain arises from actual or threatened damage to non-neural tissue and is mediated by activation of nociceptors, the specialized sensory neurons that detect potentially harmful stimuli. It is subdivided into somatic pain (arising from skin, muscle, bone, and connective tissue, typically well-localized and aching or throbbing) and visceral pain (arising from internal organs, often poorly localized, cramping, or referred to other areas).

Chronic musculoskeletal pain, including osteoarthritis, tendinopathies, and degenerative disc disease, is primarily nociceptive in origin. Nociceptive pain responds best to treatments that address the underlying tissue pathology: anti-inflammatory medications, physical rehabilitation, and, when appropriate, regenerative interventions targeting the damaged structure directly.

Neuropathic Pain

Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system. It includes conditions such as diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, radiculopathy, chemotherapy-induced peripheral neuropathy, and complex regional pain syndrome (CRPS). Clinically it presents with distinctive features including burning or shooting quality, allodynia (pain from normally non-painful stimuli), hyperalgesia (increased pain from normally painful stimuli), and spontaneous pain.

Neuropathic pain affects 7-10% of the general population, according to a 2014 meta-analysis in PAIN. It is often underdiagnosed and undertreated because standard analgesics (NSAIDs, acetaminophen) provide minimal benefit. The NeuPSIG (Neuropathic Pain Special Interest Group) 2015 guidelines recommend alpha-2-delta ligands (gabapentin, pregabalin), SNRIs (duloxetine, venlafaxine), and tricyclic antidepressants as first-line pharmacologic treatments, with opioids reserved for later lines due to modest efficacy and risk.

Nociplastic Pain

Nociplastic pain was formally defined by the IASP in 2017 to describe pain arising from altered nociception without clear evidence of tissue damage or somatosensory nerve injury that would activate nociceptors or cause neuropathic change. It reflects abnormal central pain processing, and includes fibromyalgia, tension-type headache, irritable bowel syndrome (with pain), and a subset of chronic low back pain and chronic widespread pain.

The distinction matters for treatment selection. Therapies targeting peripheral tissue (PRP, MSC injection) are unlikely to meaningfully impact centrally-mediated nociplastic pain. Treatments targeting central mechanisms, including certain antidepressants, ketamine, LDN, neurofeedback, and cognitive-behavioral therapy, are more appropriate first-line options for this pain subtype.

How do the three pain types compare?

Nociceptive, neuropathic and nociplastic pain differ in where the problem sits, how the pain feels, and which treatments are aimed at it. The table below summarizes the attributes described in the sections above.

What is mixed pain?

Mixed pain is chronic pain in which two or more mechanisms operate at the same time. Chronic low back pain is the classic example: a degenerated disc can drive nociceptive pain, a compressed nerve root can add neuropathic sciatica, and long-standing pain can add a nociplastic layer through central sensitization.

Mixed pain explains why a single treatment rarely resolves long-standing pain. A clinician who identifies each component can pair a tissue-directed treatment with a centrally acting one. The low back pain treatment guide and the neuropathic pain treatment overview cover two of the most common mixed presentations in more depth.

Central Sensitization

Central sensitization is a state of amplified neural signaling in the central nervous system (CNS) that results in pain hypersensitivity. It was first systematically described by Clifford Woolf in 1983 and has become a central concept in pain neuroscience. In sensitization, the pain system becomes hyperresponsive, generating exaggerated responses to stimuli that would not normally be painful, and maintaining pain signals even after the original peripheral trigger has resolved.

Mechanistically, central sensitization involves synaptic strengthening at dorsal horn neurons in the spinal cord, reduced descending inhibitory control from supraspinal centers (including the periaqueductal gray and rostral ventromedial medulla), and microglial activation with release of pro-nociceptive mediators including BDNF, IL-1beta, and TNF-alpha. NMDA receptor activation plays a key role in initiating and maintaining the sensitized state, which is why NMDA antagonists like ketamine are investigated as treatments.

A 2021 position paper from the IASP estimated that central sensitization contributes to pain in 40-60% of patients with chronic musculoskeletal pain conditions, not just in classically nociplastic conditions. Identifying the degree of central sensitization using tools like the Central Sensitization Inventory (CSI) can help guide treatment selection toward centrally-acting therapies.

What are the signs of central sensitization?

Central sensitization shows up as pain that is out of proportion to any tissue injury and that behaves like a turned-up volume dial. Clinical criteria proposed by Jo Nijs and colleagues (2014) lean on three features: pain disproportionate to the injury or pathology, a diffuse or spreading pain distribution, and hypersensitivity to stimuli unrelated to the painful area.

• Pain spreads beyond the original site, sometimes to both sides of the body.
• Light touch, pressure, cold or clothing feel painful (allodynia).
• Bright light, noise, smells or stress make pain or other symptoms worse.
• Pain persists or worsens after the original injury appears healed on imaging.
• Unrefreshing sleep, fatigue and concentration problems travel with the pain.

These signs are common in fibromyalgia, chronic widespread pain and long-standing low back pain. No single blood test or scan confirms central sensitization, so clinicians combine history, examination, questionnaires such as the CSI and, in specialist centers, quantitative sensory testing.

Neuroplastic Changes in Chronic Pain

Neuroimaging studies have documented structural and functional brain changes in chronic pain patients. A 2004 landmark study in The Journal of Neuroscience by Apkarian et al. found that patients with chronic back pain had 5-11% less gray matter density than healthy controls, with losses correlating with pain duration. Subsequent studies have shown similar findings in fibromyalgia, CRPS, and chronic migraine patients.

Importantly, some of these changes appear reversible with effective pain treatment. A 2011 study in Pain found that successful hip joint replacement in OA patients was associated with reversal of previously documented brain gray matter reductions. This bidirectional neuroplasticity supports the value of early and effective pain control, not only for quality of life but for preserving CNS structure.

Assessment and Diagnosis

Effective chronic pain management requires a thorough biopsychosocial assessment. A purely biomedical approach, focusing only on identifying structural lesions, misses the psychological and social amplifiers that are often the primary drivers of disability. The biopsychosocial model, articulated by George Engel and applied to pain by John Loeser, remains the most validated framework for chronic pain assessment.

Key domains to assess include pain location, quality, intensity (NRS 0-10), temporal pattern, and aggravating/relieving factors. Functional impact on activities of daily living, sleep, and work should be documented. Psychological contributors including anxiety, depression, catastrophizing, and fear-avoidance beliefs should be screened using validated instruments such as the PHQ-9, GAD-7, and Pain Catastrophizing Scale (PCS).

The IASP’s grading system for chronic primary pain requires ruling out better explanations before assigning nociplastic categories. Electromyography and nerve conduction studies help classify neuropathic pain. MRI and CT provide structural information relevant to nociceptive sources. Quantitative sensory testing (QST) can objectively measure sensitization, allodynia, and temporal summation, though it is not yet standard clinical practice outside specialized pain centers.

How is the type of chronic pain diagnosed?

Clinicians classify chronic pain by matching the history and examination to a mechanism. Pain that tracks with movement and a specific structure points to a nociceptive source. Pain in a nerve’s territory with burning quality and sensory changes points to neuropathic pain, which screening questionnaires such as the DN4 and painDETECT help flag. Widespread pain with tenderness, fatigue and sleep problems, without a matching injury, points to nociplastic pain.

Most people with long-standing pain benefit from a written summary of this assessment before they spend money on regenerative treatment. It tells the next clinician which mechanism a proposed treatment is meant to address.

Who Treats Chronic Pain?

Chronic pain is treated by a team rather than a single specialty, and the right first stop depends on the dominant pain type. Primary care physicians coordinate care and prescribe first-line medications. Pain medicine specialists, usually anesthesiologists or physiatrists with fellowship training, perform interventional procedures such as nerve blocks and epidural injections.

• Physiatrists (physical medicine and rehabilitation physicians) and sports medicine physicians manage musculoskeletal pain and commonly perform ultrasound-guided PRP and shockwave treatments.
• Orthopedic surgeons evaluate structural joint, tendon and spine problems and decide when surgery is appropriate.
• Neurologists diagnose neuropathic pain, run nerve conduction studies and EMG, and manage migraine and neuralgias.
• Rheumatologists diagnose inflammatory arthritis and commonly manage fibromyalgia.
• Anesthesiologists and psychiatrists run most ketamine infusion programs, with monitoring during each session.
• Hyperbaric medicine physicians supervise HBOT; the Undersea and Hyperbaric Medical Society (UHMS) accredits hyperbaric facilities.
• Pain psychologists deliver CBT and acceptance and commitment therapy, and practitioners certified by the Biofeedback Certification International Alliance (BCIA) deliver biofeedback and neurofeedback.
• Physical therapists lead graded exercise and pain neuroscience education, the core of most rehabilitation plans.

Regenerated.com lists clinics that offer these treatments by city and state. The directory is free for patients, listing order is not paid ranking, Featured slots are labeled and capped, and Verified means a clinic completed our credential checks rather than paid for placement. Being listed is not an endorsement; the guide to Featured, Verified and organic listings explains each label.

Conventional Pain Management

NSAIDs and Acetaminophen

NSAIDs (ibuprofen, naproxen, diclofenac, celecoxib) are first-line pharmacologic treatments for nociceptive musculoskeletal pain. They inhibit cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis and thereby reducing peripheral sensitization and inflammation. Topical formulations deliver effective local concentrations with substantially lower systemic absorption and are preferred for localized pain, particularly in older adults.

Acetaminophen (paracetamol) is widely used but has more modest evidence for musculoskeletal pain than is often assumed. A 2016 Cochrane review found that acetaminophen did not produce clinically meaningful pain reduction in low back pain versus placebo, though it remains appropriate for mild to moderate pain with fewer GI side effects than NSAIDs. Long-term use at doses approaching the 4g/day maximum carries hepatotoxicity risk, particularly with alcohol use.

Antidepressants

SNRIs (duloxetine, venlafaxine) and TCAs (amitriptyline, nortriptyline) have analgesic effects independent of their antidepressant properties, operating through inhibition of norepinephrine and serotonin reuptake in descending pain modulation pathways. Duloxetine is FDA-approved for diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain. A 2014 Cochrane review found duloxetine effective for neuropathic pain with a number needed to treat (NNT) of approximately 6.

TCAs have similar analgesic efficacy to SNRIs but a less favorable side effect profile, particularly anticholinergic effects (dry mouth, constipation, urinary retention), sedation, and cardiac conduction risks in overdose. Amitriptyline at low doses (10-50 mg nightly) is widely used for neuropathic pain and chronic headache, though evidence quality is low to moderate per NeuPSIG guidelines.

Anticonvulsants

Gabapentin and pregabalin bind to the alpha-2-delta subunit of voltage-gated calcium channels, reducing excitatory neurotransmitter release in hyperexcitable pain pathways. Pregabalin is FDA-approved for post-herpetic neuralgia, diabetic peripheral neuropathy, fibromyalgia, and spinal cord injury pain. A 2019 Cochrane review of pregabalin for neuropathic pain (62 studies, n=12,000+) reported NNT of 3.9 for 50% pain reduction in post-herpetic neuralgia and 5.0 for diabetic neuropathy.

Both gabapentinoids carry risks of sedation, dizziness, weight gain, and cognitive dulling. Evidence of misuse and dependency has emerged, particularly with gabapentin co-ingested with opioids. The UK added both gabapentinoids to Schedule 3 controlled drug status in 2019, and similar regulatory discussion is ongoing in the US.

Opioids in Chronic Non-Cancer Pain

Opioids remain controversial for chronic non-cancer pain (CNCP). The CDC’s 2022 Clinical Practice Guideline for Prescribing Opioids for Pain recommends non-opioid therapies as the preferred first-line approach for CNCP, reserving opioids for patients who have failed other treatments and only when expected benefits outweigh risks. This followed evidence that long-term opioid therapy produces, on average, modest improvements in pain intensity (about 2 points on a 10-point scale) with significant risks of tolerance, hyperalgesia, hormonal effects, and diversion.

A 2018 RCT published in JAMA (SPACE trial, n=240) compared opioid versus non-opioid pharmacotherapy for chronic back and hip/knee OA pain over 12 months and found no significant difference in pain-related function between groups, with opioids producing significantly more adverse effects. This trial directly challenged the assumption that opioids are superior analgesics for musculoskeletal chronic pain.

Limits of Conventional Approaches

Conventional pain management is effective for many patients but fails a substantial minority. For chronic low back pain, arguably the most studied pain condition, even the best conventional therapies produce meaningful pain reduction in only 30-50% of patients, with effect sizes that are modest and often not sustained at 12 months. A 2017 systematic review in Annals of Internal Medicine found that most pharmacologic and interventional treatments for chronic low back pain have small or inconsistent effects.

The limitations stem from several realities. First, conventional treatments are symptom-suppressing rather than disease-modifying; they do not repair damaged tissue or reverse the neurobiological changes that sustain central sensitization. Second, many treatments carry dose-limiting side effects that prevent optimal dosing. Third, the heterogeneity of “chronic pain” means that population-level evidence may not predict outcomes for individual patients whose specific mechanisms differ substantially.

These gaps create legitimate motivation for investigating regenerative and neuromodulatory approaches, particularly in patients who have failed first- and second-line conventional therapy.

Most of these newer options are cash pay and many are used off label for pain, so the evidence and the regulatory status deserve the same scrutiny as the mechanism. The sections below rate each treatment, and the chronic pain treatment guide lists the full range of options by condition. For readers focused on avoiding long-term opioids, our article on managing chronic pain without opioids covers the nonopioid plan in more detail.

Platelet-Rich Plasma (PRP)

PRP is produced by centrifuging autologous whole blood to concentrate platelets and their associated growth factors (PDGF, TGF-beta, IGF-1, VEGF, EGF). When injected at a site of tissue pathology, these growth factors promote cellular repair, modulate local inflammation, and may stimulate angiogenesis and matrix remodeling. The analgesic effect of PRP is thought to arise from both reduced inflammation and direct effects on nociceptor sensitization.

What does a PRP injection involve?

A PRP treatment starts with a blood draw from the patient’s arm. The blood is spun in a centrifuge to separate a platelet-rich layer, which is then injected into the painful tendon, joint or disc, usually under ultrasound or fluoroscopic guidance. Preparations differ in platelet concentration and white cell content, described as leukocyte-rich (LR-PRP) or leukocyte-poor (LP-PRP), which is one reason trial results vary.

Sports medicine physicians, physiatrists, orthopedic surgeons and interventional pain physicians perform most PRP injections. Our platelet-rich plasma treatment guide explains preparation and recovery, and you can compare clinics offering PRP injections by state and city.

PRP for Tendinopathy

Tendinopathies (chronic tendon pain with degenerative pathology) are among the best-studied applications of PRP. Lateral epicondylalgia (tennis elbow) and patellar tendinopathy have the largest evidence bases. A 2021 systematic review and meta-analysis in British Journal of Sports Medicine (29 RCTs, n=1,489) found that PRP produced significantly better pain outcomes than corticosteroid injection at 6 and 12 months for lateral epicondylalgia, though corticosteroids were superior at 4-8 weeks. PRP’s benefit appears delayed but more durable. Readers weighing the two injections for tennis elbow can see the trade-offs in PRP versus cortisone injections.

For rotator cuff tendinopathy, a 2020 Cochrane review found insufficient evidence to draw definitive conclusions. Achilles tendinopathy studies have produced mixed results, with some RCTs showing PRP superior to eccentric exercise plus placebo injection, and others showing no significant difference. Patient selection (partial vs. complete tendon degeneration, chronicity) appears to be a major determinant of response.

PRP for Spinal Pain

PRP has been investigated for discogenic low back pain via intradiscal injection and for facet joint pain via intra-articular injection. A 2019 randomized trial published in Pain Medicine (n=47) found that intradiscal PRP injection produced significant improvements in NRS pain scores and Oswestry Disability Index at 8 weeks compared to contrast injection control. A 2022 systematic review confirmed these signals but noted that most trials are small and lack long-term follow-up beyond 1 year.

PRP for Neuropathic Pain

Emerging preclinical data suggest that PRP may promote peripheral nerve repair and reduce neuroinflammation. A 2022 animal study in Frontiers in Pharmacology showed PRP reduced neuropathic pain behaviors and Schwann cell apoptosis in a sciatic nerve crush model. Human studies for neuropathic pain applications are limited to small case series for conditions like carpal tunnel syndrome and diabetic neuropathy. This application remains Preliminary.

Stem Cell Therapy

Mesenchymal stem cells (MSCs) are being investigated for chronic pain through several mechanisms: direct tissue repair at the site of pathology, paracrine anti-inflammatory signaling, and, for neuropathic applications, possible neuroprotective and nerve-regenerating effects via BDNF and NGF secretion. MSC-derived extracellular vesicles (exosomes) are increasingly studied as cell-free analogs that deliver paracrine signals without the logistical and regulatory complexity of live cell preparations.

MSC Therapy for Chronic Low Back Pain

Intradiscal MSC injection is the most studied regenerative approach for discogenic chronic low back pain. A 2017 Phase 2 RCT by Noriega et al. in Transplantation (n=24) compared allogeneic MSC injection to placebo in patients with lumbar disc degeneration and found significant improvement in pain and disability scores at 12 months, with MRI signals suggesting disc height preservation in treated patients. A 2021 systematic review in European Spine Journal covering 6 clinical trials concluded that intradiscal MSC injection is safe and likely beneficial, but larger Phase 3 trials are needed.

MSC Therapy for Neuropathic Pain

Preclinical evidence for MSCs in neuropathic pain is compelling. Multiple rodent models of peripheral nerve injury and spinal cord injury have shown that MSC administration reduces allodynia, hyperalgesia, and neuroinflammation. MSCs appear to modulate microglia and astrocyte activation in the dorsal horn, reducing pro-nociceptive cytokine release. A 2022 review in Progress in Neurobiology summarized 40 preclinical neuropathic pain studies with consistent positive signals, but noted the translation to human trials remains in early stages with few completed RCTs.

Is stem cell therapy for pain approved by the FDA?

No stem cell product has FDA approval for chronic pain, osteoarthritis, back pain or any other orthopedic use. The FDA’s consumer guidance on regenerative medicine therapies states that these therapies have not been approved to treat chronic pain or orthopedic conditions such as osteoarthritis, tendonitis, disc disease and back pain, and it warns about clinics that market unapproved stem cell, cord blood and exosome products. The same caution applies to exosome therapy.

Many US clinics offer same-day procedures using a patient’s own bone marrow aspirate or fat tissue, and whether a given procedure needs FDA approval depends on how the cells are processed and used. These procedures are cash pay. Our stem cell therapy guide covers the cell sources and regulatory categories, and the national list of stem cell therapy clinics shows who offers which approach.

Shockwave Therapy

Extracorporeal shockwave therapy (ESWT) delivers high-energy acoustic waves to target tissues, producing mechanical deformation that stimulates cellular repair processes. Two forms are distinguished: focused ESWT, which concentrates energy at depth, and radial pressure wave therapy (RPWT), which disperses energy more superficially. They are often grouped under the “shockwave” umbrella but have distinct physical properties and evidence bases.

ESWT has the most consistent evidence for calcific shoulder tendinitis, plantar fasciitis, and lateral epicondylalgia. A 2020 systematic review in Physical Therapy (30 RCTs, n=1,882) found that ESWT significantly outperformed sham treatment for plantar fasciitis pain and function at 3 months, with effects maintained at 12 months. The mechanism is thought to involve disruption of calcific deposits, stimulation of tenocyte repair activity, and neovascularization induction.

For broader chronic musculoskeletal pain without clear tendinopathic pathology, evidence is less consistent. A 2018 RCT in Pain found no significant benefit of radial ESWT over sham for chronic non-specific low back pain at 12 weeks. Patient selection based on tissue pathology type, rather than symptom location, appears critical for predicting ESWT response.

Which conditions respond best to shockwave therapy?

Shockwave therapy has its most consistent results in tendon and fascia problems with a clear tissue source: calcific shoulder tendinitis, plantar fasciitis and lateral epicondylalgia. Some focused ESWT devices hold FDA premarket approval for chronic plantar fasciitis, which is narrower than the range of conditions clinics treat with them. Treatment is usually a short series of outpatient sessions without anesthesia, and insurance coverage varies by plan and indication.

The shockwave therapy treatment guide explains focused and radial devices in more depth, and the national directory of shockwave therapy providers lists clinics by location.

Hyperbaric Oxygen Therapy (HBOT)

HBOT (100% oxygen at 1.5-2.4 atmospheres absolute) produces supraphysiologic blood and tissue oxygen levels, triggering a cascade of biological effects including reactive oxygen species (ROS) signaling, angiogenesis, stem cell mobilization from bone marrow, and downregulation of NF-kB inflammatory pathways. For chronic pain, the proposed mechanisms are improved tissue oxygenation in hypoxic or ischemic pain generators and neuroplastic effects on central sensitization.

The most compelling chronic pain evidence for HBOT comes from fibromyalgia and CRPS. A 2015 RCT published in PLOS ONE (n=60, crossover design) found that HBOT (40 sessions at 2.0 ATA) produced significant reductions in tender point counts, pain thresholds (quantitative sensory testing), and VAS pain scores in women with fibromyalgia, with SPECT imaging showing normalization of hyper- and hypoactive brain regions. A 2022 follow-up study at the same Israeli institution confirmed these findings in a larger cohort with persistent effects at 3 months post-treatment.

For CRPS, a 2018 randomized controlled trial published in European Journal of Pain found HBOT reduced allodynia and pain intensity more than sham pressurization in CRPS Type 1, consistent with a central desensitization mechanism. Evidence for HBOT in neuropathic pain from diabetic neuropathy and post-herpetic neuralgia is limited to small observational studies with significant methodological limitations.

Does insurance cover HBOT for chronic pain?

Insurance rarely covers hyperbaric oxygen therapy for chronic pain. Fibromyalgia, CRPS and other pain conditions are not on the Undersea and Hyperbaric Medical Society (UHMS) list of approved indications that most insurers follow, so HBOT for pain is off label and usually paid out of pocket. The research protocols above used a hard-shell chamber at 2.0 ATA, which is a different treatment from the mild hyperbaric (soft-shell) chambers sold for home and spa use.

Our hyperbaric oxygen therapy treatment guide and the summary of FDA-cleared HBOT indications explain where the evidence is strongest. To compare facilities, start with the HBOT clinic directory and ask each one whether it uses a hard-shell chamber and what pressure it treats at.

Ketamine Infusion Therapy

Ketamine is an NMDA receptor antagonist that blocks the glutamatergic signaling pathway central to central sensitization and the “wind-up” phenomenon in chronic pain. At sub-anesthetic doses (typically 0.1-0.5 mg/kg IV over 40-100 minutes in a clinical setting), it produces analgesic and anti-hyperalgesic effects that can persist well beyond its pharmacokinetic half-life, suggesting neuroplastic effects rather than simple receptor occupancy.

Evidence for CRPS and Neuropathic Pain

CRPS is where ketamine has the strongest chronic pain evidence. A 2009 randomized trial by Schwartzman et al. in Pain (n=19) using a 10-day outpatient ketamine infusion protocol found that 83% of the ketamine group achieved significant pain relief at 3 months versus 8% in the placebo group, with effects maintained in some patients at 6 months. Higher-dose “ketamine coma” protocols used in Europe have produced longer remissions but carry greater risk and are not standard of care in the US.

A 2018 Cochrane review of ketamine for chronic neuropathic pain found short-term analgesic benefit in CRPS, phantom limb pain, and spinal cord injury pain, but insufficient evidence for long-term benefit or optimal dosing protocols. The American Society of Regional Anesthesia (ASRA) 2018 consensus guidelines on ketamine for chronic pain found it appropriate as an adjunct for CRPS and cancer pain when other treatments have failed, while noting limitations in evidence quality for other chronic pain conditions.

Safety Considerations

Short-term adverse effects of sub-anesthetic ketamine include dissociation, dizziness, nausea, and hypertension. These are generally manageable with benzodiazepine pre-medication and vital sign monitoring. Long-term concerns include ketamine cystopathy (bladder damage with high-frequency recreational use), psychomimetic effects, and potential for misuse. Clinical protocols using monthly or quarterly infusion series are associated with much lower bladder risk than daily recreational use, but urinary symptoms should be monitored in patients undergoing repeated infusion series.

Is ketamine FDA approved for chronic pain?

Ketamine is FDA approved as an anesthetic, and its use for chronic pain is off label. Esketamine nasal spray (Spravato) is FDA approved for treatment-resistant depression, not for pain. Ketamine infusions for pain are therefore usually cash pay, and protocols differ between clinics in dose, infusion length and number of sessions.

CRPS is the clearest indication, and the CRPS treatment guide covers how ketamine fits alongside physical therapy and nerve blocks. Our ketamine therapy guide describes screening and monitoring, the article on ketamine for chronic pain reviews the pain trials, and the ketamine clinic directory lists providers nationwide.

Low-Dose Naltrexone (LDN)

At standard doses (50 mg), naltrexone blocks opioid receptors to prevent the effects of opioids and alcohol. At doses 10-fold lower (1.5-4.5 mg), it produces a brief opioid receptor blockade followed by rebound upregulation of endogenous opioid systems. It also acts as a TLR4 antagonist on microglia and macrophages, inhibiting microglial activation that contributes to central sensitization and neuroinflammation.

A 2013 double-blind crossover RCT at Stanford (n=31) found that LDN 4.5 mg reduced fibromyalgia symptoms by 30% more than placebo, with improvements in fatigue and pain specific to inflammatory mechanisms. A 2020 RCT published in Pain Medicine (n=40) confirmed LDN’s analgesic effect versus placebo in fibromyalgia. A 2019 open-label trial of LDN in CRPS (n=10) showed meaningful pain reductions in 7 of 10 patients, with one complete responder.

LDN has an excellent safety profile at low doses. The most common side effect is vivid dreams or mild sleep disturbance, typically resolving within 2-4 weeks of starting therapy. Because it is an opioid antagonist, LDN cannot be used in patients on opioid medications. LDN is not FDA-approved for any pain indication and must be compounded; it represents a low-cost, low-risk option worth considering in centralized chronic pain conditions, particularly fibromyalgia and possibly CRPS.

What is the usual LDN dose for chronic pain?

The usual low-dose naltrexone range for chronic pain is 1.5 to 4.5 mg taken once daily, often at night. Prescribers commonly start at 1.5 mg and increase every two weeks toward 3 to 4.5 mg, adjusting for sleep side effects. Because standard naltrexone tablets are 50 mg, LDN is prepared by compounding pharmacies, and naltrexone itself is FDA approved only at standard doses for alcohol and opioid use disorder.

Any licensed prescriber can write for LDN, including primary care physicians, rheumatologists and integrative medicine physicians. The fibromyalgia treatment guide places LDN alongside exercise, sleep care and SNRIs, and our review of LDN for fibromyalgia walks through the trials in detail.

Neurofeedback

Neurofeedback is a form of biofeedback using real-time EEG signal display to train patients to modify their brain activity patterns. In chronic pain, abnormal EEG signatures have been documented, particularly increased theta and alpha power in frontal regions and increased gamma activity correlating with pain intensity. The rationale for neurofeedback is that training patients to shift these patterns could reduce central sensitization and pain perception.

A 2020 systematic review in The Journal of Pain identified 12 RCTs of neurofeedback for chronic pain conditions including fibromyalgia, CRPS, chronic low back pain, and headache. Ten of 12 trials reported significant pain reductions. However, sample sizes were small (median n=21), and blinding is inherently difficult in neurofeedback research. A 2022 RCT in PAIN Reports (n=40) found alpha/theta neurofeedback reduced fibromyalgia pain scores by 38% versus 15% for sham at 8 weeks, with effects maintained at 3 months.

Neurofeedback requires multiple sessions (typically 20-40 sessions of 30-60 minutes each) and has high time and cost burdens. The lack of standardized protocols across studies, with different training targets (alpha, theta, sensorimotor rhythm, and others), makes cross-study comparison difficult. It is best considered as a complement to other pain management approaches in patients with clear evidence of central sensitization who have not responded adequately to pharmacologic treatment.

How is neurofeedback different from biofeedback for pain?

Neurofeedback trains brain activity measured by EEG, while biofeedback trains body signals such as muscle tension (surface EMG), heart rate variability, breathing and skin temperature. Biofeedback has a longer research record in headache and musculoskeletal pain, and neurofeedback targets the central processing that drives nociplastic pain. Both are usually delivered by psychologists or BCIA-certified practitioners and coverage varies by plan.

The neurofeedback therapy guide describes common training protocols, our article on biofeedback for chronic pain covers the body-signal approach, and the neurofeedback provider directory lists practices by state.

Evidence Summary Table

Treatment	Best Indication	Evidence Level	Key Limitation
Topical NSAIDs	Localized nociceptive pain (OA, tendinopathy)	Strong	Systemic conditions not addressed
SNRIs (duloxetine)	Neuropathic pain, fibromyalgia, musculoskeletal pain	Strong	Side effects; not universally effective
Pregabalin/gabapentin	Neuropathic pain, fibromyalgia	Strong	Sedation; dependency risk; modest NNTs
PRP injection	Tendinopathy, OA, discogenic pain	Moderate	No standardized protocol; variable preparation
ESWT	Calcific tendinitis, plantar fasciitis, epicondylalgia	Moderate	Limited to nociceptive/tendon pathology
Ketamine infusion	CRPS, treatment-resistant neuropathic pain	Emerging	Short-term data; limited long-term RCTs
HBOT	Fibromyalgia, CRPS	Emerging	Expensive; accessibility limited; small trials
LDN	Fibromyalgia, centralized pain	Emerging	Off-label; no large Phase 3 trials
MSC therapy	Discogenic pain, osteoarthritis	Emerging	Small trials; no standardized protocols
Neurofeedback	Fibromyalgia, CRPS, nociplastic pain	Preliminary	Time-intensive; protocol heterogeneity
Opioids	Severe acute pain; cancer pain	Strong (with caveats)	Poor long-term efficacy in CNCP; dependency; hyperalgesia

The evidence levels above reflect the strongest indication for each treatment, not chronic pain in general. A treatment rated Moderate for plantar fasciitis can still be unproven for widespread pain, so match the indication column to your own diagnosis before comparing ratings.

How Long Do Chronic Pain Treatments Take to Work?

Chronic pain treatments work on different timescales, and most need weeks to months before a fair judgment is possible. The timings below come from the trials and protocols described in the sections above, not from clinic marketing.

Ask any clinic how and when it will measure progress before starting. A useful plan names a pain and function score at baseline, a date to re-check it, and what happens if the treatment has not helped by then.

Cost, Insurance and Regulatory Status

Insurance coverage for chronic pain treatment follows FDA status and payer policy, which is why conventional care is usually covered and most regenerative care is not. Prices vary widely by metro, clinic type and protocol, so this section describes coverage patterns rather than dollar figures. Ask each clinic for a written, itemized quote that names the number of sessions included.

Health savings accounts and flexible spending accounts can sometimes be used for treatment that a physician documents as medically necessary, but rules vary, so confirm with the plan administrator before booking.

Integrating Regenerative Care into a Chronic Pain Plan

The first step in selecting regenerative or neuromodulatory therapies is identifying the dominant pain mechanism. A patient with chronic knee pain due to OA (nociceptive, structural) is a candidate for PRP or MSC intra-articular injection. A patient with fibromyalgia and widespread hypersensitivity (nociplastic, central) is unlikely to benefit from joint injections but may respond to LDN, HBOT, ketamine, or neurofeedback. Many patients have mixed mechanisms and require layered treatment addressing both peripheral and central contributions.

Psychologically-informed physical therapy and cognitive-behavioral therapy (CBT) should be part of almost every chronic pain treatment plan. A 2017 meta-analysis in JAMA Internal Medicine (38 trials, n=3,800+) found that CBT produced modest but significant reductions in pain intensity, disability, and depression in chronic pain patients, with effects maintained at 12 months. CBT does not eliminate pain, but it reduces pain catastrophizing and improves function in ways that complement biological treatments.

Realistic goal-setting is essential. Complete pain elimination is rarely achievable in established chronic pain. A 30-50% reduction in pain intensity, improved sleep, and return to meaningful activities are realistic treatment targets for most patients with non-cancer chronic pain. Framing treatment goals around function rather than pain scores alone produces better adherence and satisfaction.

A layered plan for knee osteoarthritis might combine weight management, exercise therapy and a PRP or hyaluronic acid injection, while a plan for fibromyalgia might combine graded exercise, sleep treatment, an SNRI or LDN, and CBT. The osteoarthritis treatment guide covers the joint-focused options in more depth.

Questions to Ask Before Starting Regenerative Pain Treatment

Choosing a regenerative pain clinic is easier when you arrive with the same questions for every provider. A well run clinic answers each of these in writing before you pay.

1. What pain mechanism is this treatment meant to address? The answer should match your diagnosis: nociceptive, neuropathic, nociplastic or mixed.
2. Who performs the procedure, and what is their training? Ask for the clinician’s specialty and board certification, and whether imaging guidance is used for injections.
3. What exactly is being injected or delivered? For PRP, ask about the preparation system and leukocyte content. For cell therapies, ask about the cell source and its FDA status.
4. What does the published evidence show for my specific condition? A clinic should be able to name the trials and say plainly where evidence is thin.
5. How many sessions are included, and what is the total cost? Ask for an itemized quote and the refund or rebooking policy.
6. How will progress be measured, and when? Agree on a pain and function score and a date to review it.
7. What are the risks, and who handles complications? Ask how after-hours concerns are managed and whether your primary physician receives a summary.

Our guide to reading a city clinic page explains what each listing shows. Regenerated.com is free for patients, inclusion in the directory is not an endorsement, and the questions above apply equally to every listing.

Frequently Asked Questions

What is the difference between acute and chronic pain?

Chronic pain lasts more than three months, while acute pain is a protective signal of tissue injury that fades as healing occurs. Chronic pain often continues independently of the original injury, driven by central sensitization and neuroplastic changes in the nervous system. The two need different treatment approaches, and treating chronic pain as if it were prolonged acute pain, relying mainly on painkillers, is a common and costly error.

Can PRP help with neuropathic pain?

PRP is not yet an established treatment for neuropathic pain. Animal studies suggest it may support peripheral nerve repair and reduce neuroinflammation, and small human case series in carpal tunnel syndrome and diabetic neuropathy show encouraging early signals. Well-powered controlled trials are still missing, so PRP for nerve pain belongs in research settings for now, and first-line neuropathic drugs such as pregabalin and duloxetine remain the standard starting point.

Is ketamine addictive?

Ketamine can be addictive, and the risk is highest with frequent recreational use. At the sub-anesthetic doses and spaced schedules used in clinical pain protocols, such as monthly or quarterly infusion series, the addiction risk appears low in properly screened patients. People with a history of substance use disorder need careful evaluation first, and a well run clinic uses standardized screening and monitoring at every visit.

How quickly does LDN work for chronic pain?

Most patients who respond to LDN see effects within 4-8 weeks of starting treatment. Some report improvement within 2 weeks. A standard approach is to start at 1.5 mg/day and increase every 2 weeks to a target of 3-4.5 mg/day, which gives time to assess tolerability and response. Patients who see no improvement at 4.5 mg/day after 8-12 weeks are unlikely to be responders.

Can I use LDN if I am taking opioids?

No. LDN is an opioid antagonist and will block opioid receptors, precipitating acute opioid withdrawal in patients on opioid medications. Patients must be fully detoxified from opioids for at least 7-10 days (or longer for methadone) before starting LDN. This is a strict contraindication.

What type of chronic pain is least likely to respond to regenerative injections?

Nociplastic (centralized) pain with no identifiable peripheral pain generator is least likely to respond to peripheral injection therapies like PRP or MSC joint injections. Fibromyalgia, chronic widespread pain syndrome, and central post-stroke pain are driven by CNS dysfunction rather than local tissue pathology. These conditions call for centrally acting treatments such as SNRIs, LDN, CBT and graded exercise, and are poor candidates for local injection therapies.

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Related Reading

• Arthritis Guide: Rheumatoid Arthritis and Osteoarthritis
• Biofeedback Therapy: How It Works, What It Treats, and What the Evidence Shows
• Fibromyalgia: Causes, Diagnosis, and the Complete Treatment Guide
• Hyperbaric Oxygen Therapy (HBOT): How It Works, What It Treats, and What the Evidence Shows
• Joint Pain: Causes, Diagnosis, and the Full Treatment Spectrum
• Ketamine Therapy: Benefits, Risks, Cost, and What to Expect