CRPS, rethought: a clinician’s field guide to the neuroimmune storm, early “abort” strategies, and whole-system support

By Dr. Sina Yeganeh D.C., Movability

In collaboration with international colleagues across pain medicine, neurology, rheumatology, rehabilitation, and anesthesiology

Why this guide

Most people with complex regional pain syndrome (CRPS) are told to treat the limb. That is necessary, but it is not sufficient. CRPS is a regional pain syndrome with multi-system features. The peripheral nervous system, immune system, autonomic balance, microvasculature, and cortex all interact to amplify nociception and distort sensorimotor control [1, 2]. In practice, outcomes improve when we treat the limb and the internal environment quickly and in parallel. This guide distills a collaborative protocol that I have developed with international physicians. It is written to be shared with your local clinician, wherever you live.

CRPS in one page: pathophysiology you can use

1) Peripheral neuroinflammation and microcirculatory stress

Early CRPS shows a local inflammatory signal in the affected tissue. Suction-blister studies demonstrate elevated IL-6 and TNF-α in the involved limb compared to the contralateral side, even when plasma is normal [3]. Interstitial lactate is increased, consistent with local tissue hypoxia and anaerobic glycolysis [4, 5]. Endothelin-1 is elevated and nitric oxide metabolites reduced in blister fluid, shifting the NO to ET-1 balance toward vasoconstriction [4]. Clinically, this maps to warm or cold vasomotor phenotypes and swelling. These findings align with a systematic review showing a pro-inflammatory signal across CRPS cohorts [29].

2) Small-fiber and autonomic changes

Skin biopsies and neurophysiology support involvement of small-diameter fibers in a subset of patients. Some meet criteria for small-fiber neuropathy, which helps explain burning pain, allodynia, and sudomotor change [6]. Autonomic testing shows altered heart-rate dynamics and baroreflex function, supporting dysautonomia as part of the syndrome rather than simple overreaction to pain [7].

3) Autoimmunity and autoantibodies, cautiously interpreted

Several groups have identified functionally active autoantibodies against β2-adrenergic and muscarinic M2 receptors in some patients [8], and passive transfer models indicate that patient IgG can provoke CRPS-like features in susceptible animals after minor limb trauma [9]. Translation to therapy is more complex than the mechanism might suggest, as randomized trials of low-dose IVIG in long-standing CRPS have been negative (see Treatment section).

4) Why some people develop CRPS and others do not

Triggering events are typically fractures, sprains, surgery, or immobilization. Host factors add risk. Observational data point to medication and familial contributors, for example the association of ACE inhibitor exposure with incident CRPS [10], and familial clustering implying heritable susceptibility [11]. Vitamin D deficiency has been associated with higher CRPS rates after distal radius fracture in post-menopausal women, although this is not yet a universal finding [26]. Think injury plus vulnerable biology.

Diagnosis, staged correctly

Use the Budapest clinical criteria, and measure severity

The Budapest criteria improve specificity over older IASP rules while maintaining high sensitivity. Apply them as written and exclude better explanations such as infection, compartment syndrome, vascular disease, or neuropathy of a single named nerve [12, 13]. At baseline, score the CRPS Severity Score (CSS). It tracks 17 signs and symptoms and changes with treatment, which makes it useful for monitoring [14]. When feasible, use elements from the COMPACT core outcomes set to standardize follow-up across settings [15].

Pearls clinicians often miss

  • Pain disproportionate to injury with allodynia or hyperalgesia plus at least two of vasomotor, sudomotor or edema, motor or trophic signs is CRPS until proven otherwise [12].

  • Warm and cold phenotypes behave differently. Cold, dystrophic limbs often show microvascular constriction and benefit from vasomotor-savvy care [4].

  • Spreading or mirror symptoms can occur and are not random, which is unsettling to patients but consistent with network-level mechanisms [1].

  • Body-schema disturbance, laterality confusion, and marked movement fear are common and respond to targeted sensorimotor rehabilitation [16, 17].

Why conventional approaches fall short

Late referral, limb-only treatment, single-modality procedures, and immobilization are common pitfalls. They ignore the neuroimmune and autonomic contributors, and they allow cortical re-mapping to consolidate. Evidence-based rehabilitation plus mechanism-targeted medical care started early is consistently associated with better function and pain reduction [1, 2, 15–17, 28].

The Rapid-Start CRPS “abort” concept: what to do in the first 2 to 4 weeks

This is not a sales pitch. It is a practical, aggressive, patient-centered program that any competent team can implement.

Step 1. Confirm the diagnosis quickly, define baseline

  • Apply Budapest criteria, document signs and symptoms, and record CSS [12, 14].

  • Baseline photos, temperature asymmetry, edema, range of motion, and sensory mapping.

  • Rule out red flags that mimic CRPS.

Step 2. Start same-day sensorimotor rehabilitation

  • Graded motor imagery (GMI): left-right limb laterality recognition, imagined movement, and mirror therapy in sequence. Randomized trials show clinically meaningful benefit in long-standing CRPS when properly dosed and progressed [16, 17].

  • Mirror therapy: especially valuable early, delivered under clinician guidance to avoid oversensitization [18].

  • Desensitization and exposure-based movement: structured, frequent, titrated to keep threat low while restoring use.

Step 3. Calm the neuroimmune environment and autonomic tone

  • Sleep restoration, paced breathing, and HRV-guided relaxation: dysautonomia is common in CRPS. HRV-centric strategies are low risk and address sympathetic overdrive [7].

  • Nutrition and correction of deficiencies: prioritize protein adequacy, omega-3 fats from diet, and micronutrient repletion. Correct vitamin D deficiency in fracture cohorts given the observational signal [26]. Avoid overpromising. Evidence for supplements in CRPS per se is limited.

  • Activity dosing: frequent short bouts beat long sessions. Guard against immobilization.

Step 4. Early anti-inflammatory pharmacology for appropriate phenotypes

  • Glucocorticoids in acute or warm-phase CRPS: small trials in post-stroke shoulder-hand syndrome and early CRPS support short courses to blunt inflammatory cascades and restore movement [19]. Randomized data suggest prednisolone can outperform piroxicam in post-stroke CRPS I [19a]. Use carefully and briefly.

  • Bisphosphonates when bone turnover and cold dystrophic features dominate: multiple randomized trials show benefit from pamidronate, clodronate, alendronate, and neridronate in subgroups of CRPS I, with improvements in pain and function and acceptable safety profiles [20–22].

  • Avoid chasing sympathetic blocks as stand-alone cures: evidence is limited. Consider them as part of a broader plan rather than a definitive therapy [30].

Step 5. Rescue options for severe allodynia and hyperalgesia

  • Ketamine infusions: a randomized, double-blind trial demonstrated analgesia with subanesthetic S-ketamine infusions in CRPS I [23]. Open-label series support benefit in some refractory cases [24]. Screen carefully for psychiatric risk and cognitive side effects.

  • Neuromodulation when pain remains disabling after a well-run conservative program: randomized data support dorsal root ganglion stimulation outperforming conventional spinal cord stimulation for focal neuropathic pain including CRPS [25]. Use rigorous patient selection and realistic targets.

Step 6. Where immune-directed therapy stands today

  • IVIG: despite mechanistic promise, a multicenter randomized trial of low-dose IVIG in long-standing CRPS was negative on the primary outcome [31]. Outside of research settings, routine IVIG is not supported.

  • Low-dose naltrexone (LDN): mechanistic rationale via glial modulation exists, but human evidence in CRPS is limited to small studies and case reports. Consider only with informed consent and close monitoring [33, 34].

  • Palmitoylethanolamide (PEA): meta-analysis suggests benefit for chronic pain in general. CRPS-specific randomized trials are lacking, but safety is favorable. It can be considered as an adjunct while acknowledging evidence gaps [32].

The chronic-phase pivot

If symptoms persist beyond 3 months despite good early care, pivot to a long-arc plan that integrates:

  • Continued sensorimotor rehabilitation, progressing GMI to skilled task practice.

  • Treatment of comorbid small-fiber neuropathy when present, and standard neuropathic pain agents as tolerated.

  • Bisphosphonates in appropriate phenotypes, or consideration of neuromodulation in refractory cases [20–22, 25].

  • Ongoing autonomic training and graded exposure to valued activities.

Safety notes and gray zones

  • Vitamin C prophylaxis after wrist fracture has mixed evidence. Some trials and reviews suggest reduced CRPS incidence with 500 mg daily for about 45 to 50 days, while other analyses question consistency. If used, frame as low risk, possibly helpful, not definitive [27].

  • Vitamin D repletion is reasonable for bone health and possibly risk reduction in fracture cohorts, but it is not a specific CRPS treatment [26].

  • Autoantibody findings do not now justify routine immunosuppressive therapy in CRPS without trial enrollment or another clear indication [8, 9, 31].

Dr. Sina’s Action Plan, ideal conditions for speed and efficacy

Purpose

Give any patient and clinician a precise, time-boxed roadmap that restores use, reduces pain, and quiets the neuroimmune storm as quickly and safely as possible.

Core objectives

  • Confirm the diagnosis early and rule out danger.

  • Start sensorimotor rehabilitation on day one.

  • Open a short medical anti-inflammatory window when appropriate.

  • Stabilize autonomic tone and optimize the internal environment.

  • Measure progress weekly and escalate without delay if gains stall.

First 72 hours

  1. Confirm the pattern, exclude emergencies
    Apply the Budapest criteria, document signs and symptoms, photograph the limb, record temperature asymmetry, swelling, range, and sensory findings. Exclude deep vein thrombosis, infection, compartment syndrome, and critical vascular disease when history or exam suggest them. Establish a baseline CRPS Severity Score and select COMPACT-aligned outcomes to track.

  2. Start same-day rehabilitation
    Begin gentle active motion in pain-free arcs several times daily. Launch a brief desensitization ladder with textures and temperature. Start graded motor imagery in sequence, left-right laterality, imagined movement, mirror therapy. Teach pacing, flare management, and task-based exposure that returns the limb to ordinary life quickly.

  3. Create a medical window when the phenotype fits
    If clearly acute and inflamed, consider a short oral corticosteroid taper after screening risks. When bone turnover or cold dystrophic features dominate, consider a bisphosphonate course after renal and dental checks. Use scheduled multimodal analgesia to enable movement. Avoid immobilization beyond what structural healing requires.

  4. Stabilize autonomic tone
    Teach paced breathing about six breaths per minute for ten minutes, one to three times daily. Anchor sleep and wake times. Add brief, frequent aerobic sessions that do not flare pain.

  5. Optimize the internal environment
    Order and act on a focused lab panel, fasting glucose and HbA1c, CBC, ferritin with transferrin saturation, CRP, 25-OH vitamin D, B12 with methylmalonic acid if borderline, magnesium, and thyroid screen when indicated. Correct clear deficiencies. Support nutrition with adequate protein and omega-3 sources. After fractures or limb surgery, a defined vitamin C course may be considered.

Days 4 to 14

  • Progress graded motor imagery and desensitization daily, increase active use in short bouts.

  • Dial in sleep hygiene and autonomic practices, confirm adherence.

  • Begin strength and coordination in protected ranges, then expand to meaningful tasks.

  • Review labs, correct deficits, adjust nutrition.

  • If pain blocks therapy despite the steps above, consider a time-limited bridge, for example a sympathetic block in suspected sympathetically maintained pain, or a sub-anesthetic ketamine infusion in experienced hands, with clear goals tied to rehabilitation.

Weeks 3 to 6

  • Reassess the CRPS Severity Score, range, strength, temperature asymmetry, swelling, and one or two functional goals that matter to the patient.

  • If multiple measures are improving, maintain the course and taper acute medications as function stabilizes.

  • If progress has stalled for two to three weeks despite good adherence, escalate. Options include a bisphosphonate trial if not yet given, a focused interventional window, or a formal neuromodulation evaluation in severe focal distal pain that remains disabling.

Escalation criteria

  • No meaningful drop in CRPS Severity Score by two to three weeks.

  • Persistent inability to participate in rehabilitation because of pain or allodynia.

  • Worsening vasomotor instability or progressive loss of motion despite adherence.

  • Refractory focal distal pain after a complete conservative program, consider dorsal root ganglion stimulation with a formal trial, paired to rehabilitation.

Coordination model

  • Assign a lead clinician responsible for sequencing and outcomes.

  • Hold brief case reviews every 7 to 14 days with rehabilitation, primary care, and procedural stakeholders.

  • Use shared, simple metrics at each review, CRPS Severity Score, range, strength or dynamometry, temperature asymmetry, and patient-defined tasks.

  • Document decisions, next steps, and stop rules for each therapy. Plan de-prescribing as function returns.

Safety and governance

  • Screen carefully before steroids, bisphosphonates, ketamine, or blocks.

  • Mark off-label items and country-specific availability.

  • Separate pediatric, pregnancy, and post-stroke pathways, emphasize intensive rehabilitation and conservative pharmacology in these groups.

  • Educate the patient at each step, explain why each action is chosen, and set clear expectations for timing and milestones.

Key takeaways for patients and clinicians

  • CRPS needs the right trigger plus a susceptible internal environment, which is why early whole-system support matters [1–5, 10, 11, 26].

  • Use the Budapest criteria, measure severity with CSS, and start GMI plus desensitization immediately [12, 14, 16–18].

  • Match drugs to phenotype. Consider short glucocorticoids early in warm-phase disease, bisphosphonates in dystrophic or bone-active phenotypes, and ketamine or neuromodulation for refractory pain after conservative care [19–25].

  • Immune-directed therapies remain mostly investigational. Share decision-making and set expectations clearly [8, 9, 31, 32].

CRPS is a profoundly debilitating condition. I created this guide to support people who are living with it and the clinicians who care for them. I wrote it from the heart and grounded it in science. If it helps even one person turn the condition around or take the first real step toward recovery, it has served its purpose. If you are reading this and struggling, please do not give up. There is a path forward. Small wins count. Keep going.

This guide is educational content, not a substitute for personal medical advice. Some treatments are off-label for CRPS; discuss risks, benefits, and local regulations with your clinician.

References

  1. Marinus J, Moseley GL, Birklein F, et al. Clinical features and pathophysiology of complex regional pain syndrome. Lancet Neurol. 2011;10:637-648.

  2. Duong S, Bravo D, Todd KJ, Finlayson RJ. Treatment of complex regional pain syndrome, an updated review. Can J Anesth. 2018;65:658-672.

  3. Huygen FJPM, et al. Evidence for local inflammation in CRPS type I. Pain. 2002;99:399-407.

  4. Groeneweg JG, et al. Increased endothelin-1 and diminished NOx in blister fluid of CRPS I. BMC Musculoskelet Disord. 2006;7:91.

  5. Birklein F, et al. Increased skin lactate in CRPS. Neurology. 2000;55:1213-1215.

  6. Oaklander AL, Fields HL. Is reflex sympathetic dystrophy or CRPS a small-fiber neuropathy. Ann Neurol. 2009;65:629-638.

  7. Taneyama C, Yokota S, Goto H. Heart rate variability and baroreflex in CRPS I. Clin J Pain. 2013;29:962-966.

  8. Kohr D, et al. Autoantibodies in CRPS. Pain. 2011;152:2690-2700.

  9. Tékus V, et al. CRPS-IgG transfer trauma model. Pain. 2014;155:1402-1411.

  10. de Mos M, et al. ACE inhibitor use associated with CRPS. Pain. 2009;142:218-224.

  11. de Rooij AM, et al. Familial occurrence of CRPS. Eur J Pain. 2009;13:171-177.

  12. Harden RN, Bruehl S, Perez RSGM, et al. Validation of proposed diagnostic criteria, the Budapest criteria. Pain. 2010;150:268-274.

  13. Harden RN. Proposed new diagnostic criteria for CRPS. Pain Med. 2007;8:326-331.

  14. Harden RN, et al. Development of a severity score for CRPS. Pain. 2010;151:870-876.

  15. Grieve S, Perez RSGM, Birklein F, et al. COMPACT core outcomes for CRPS trials. Pain. 2017;158:1083-1090.

  16. Moseley GL. Graded motor imagery is effective for long-standing CRPS I, a randomized controlled trial. Pain. 2004;108:192-198.

  17. Moseley GL. Graded motor imagery for pathologic pain, randomized controlled trial. Neurology. 2006;67:2129-2134.

  18. McCabe CS, et al. Controlled pilot of mirror visual feedback in CRPS I. Rheumatology. 2003;42:97-101.

  19. Braus DF, et al. Shoulder-hand syndrome after stroke, steroid response and prevention insights. Stroke. 1994;25:1182-1187.

    19a. Kalita J, Vajpayee A, Misra UK. Comparison of prednisolone with piroxicam in complex regional pain syndrome following stroke, a randomized controlled trial. QJM. 2006;99:89-95.

  20. Giusti A, et al. Bisphosphonates in CRPS, synthesis of evidence. RMD Open. 2015;1(Suppl 1):e000056.

  21. Robinson JN, et al. Randomized placebo-controlled trial of IV pamidronate in CRPS I. Pain Med. 2004;5:276-283.

  22. Misidou C, Papagoras C. Complex regional pain syndrome, an update, including bisphosphonate data. Rheumatol Int. 2019;39:1261-1270.

  23. Sigtermans MJ, et al. Ketamine for CRPS I, randomized double-blind placebo-controlled. Pain. 2009;145:69-74.

  24. Schwartzman RJ, et al. Outpatient IV ketamine for CRPS, open-label experience. Pain Med. 2009;10:360-369.

  25. Deer TR, et al. ACCURATE trial, dorsal root ganglion versus traditional spinal cord stimulation for focal neuropathic pain including CRPS. Pain. 2017;158:669-681.

  26. Lee SU, et al. Low vitamin D associated with CRPS I after distal radius fracture in post-menopausal women. J Orthop Surg Res. 2020;15:294.

  27. Aïm F, et al. Efficacy of vitamin C in preventing CRPS I after wrist fracture, review of clinical data. Orthop Traumatol Surg Res. 2017;103:381-388.

  28. Harden RN, et al. Practical diagnostic and treatment guidelines for CRPS, 5th ed. Pain Med. 2022;23(Suppl 1):S1-S53.

  29. Parkitny L, et al. Inflammation in complex regional pain syndrome, systematic review and meta-analysis. Pain. 2013;154:2142-2151.

  30. Harden RN, et al. Guideline perspective on interventional procedures in CRPS, see reference 28 for synthesis. Pain Med. 2022;23(Suppl 1):S1-S53.

  31. Goebel A, et al. Low-dose IVIG in long-standing CRPS, randomized trial, negative primary outcome. Ann Intern Med. 2017;167:476-483.

  32. Artukoglu BB, et al. Palmitoylethanolamide for chronic pain, systematic review and meta-analysis. Pain Physician. 2017;20:353-362.

  33. Chopra P, Cooper MS. Treatment of complex regional pain syndrome (CRPS) using low-dose naltrexone (LDN). J Neuroimmune Pharmacol. 2013;8(3):470-476.

  34. Rupp A, Nguyen A, Hill K. Low-dose naltrexone’s utility for non-cancer centralized pain. Pain Manag. 2023;13(6):541-556. (Mechanistic overview of glial modulation in centralized pain)

Sina Yeganeh