Complex regional pain syndrome

Summary

Complex regional pain syndrome (MONDO:0019369) is a disease with 9 GWAS associations across 6 studies and 172 clinical trials. Top therapeutic interventions include diclofenac sodium, dronabinol, and ethosuximide. A subtype of chronic pain syndrome — broader associated-gene and molecular evidence is on the parent page (see Disease family below).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• GWAS associations: 9
• Phenotypes (HPO): 12
• Clinical trials: 172

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-5 / 10 000	26.2	Netherlands	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0009763	Limb pain	Very frequent (80-99%)
HP:0000958	Dry skin	Frequent (30-79%)
HP:0003474	Somatic sensory dysfunction	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0008383	Slow-growing nails	Frequent (30-79%)
HP:0010741	Pedal edema	Frequent (30-79%)
HP:0010742	Edema of the upper limbs	Frequent (30-79%)
HP:0010783	Erythema	Frequent (30-79%)
HP:0010834	Trophic changes related to pain	Frequent (30-79%)
HP:0012533	Allodynia	Frequent (30-79%)
HP:0012534	Dysesthesia	Frequent (30-79%)
HP:0040170	Abnormality of hair growth	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	complex regional pain syndrome
Mondo ID	MONDO:0019369
EFO	EFO:1001998
MeSH	D020918
Orphanet	83452
DOID	DOID:14022, DOID:3223
ICD-10-CM	M89.0
ICD-11	1834504950
SNOMED CT	128200000
UMLS	C0458219
MedGen	96846
GARD	0004647
MedDRA	10064332
NORD	1652
Is cancer (heuristic)	no

Also known as: algoneurodystrophy · CRPS · reflex sympathetic dystrophy

Data availability: 9 GWAS associations (6 studies).

Disease family

This is a subtype of chronic pain syndrome. Genetic, therapeutic, and trial evidence is largely curated at the broader-term level — see the parent page for the associated-gene cohort and molecular evidence.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurological pain disorder › chronic pain syndrome › complex regional pain syndrome

Related subtypes (2): fibromyalgia, loin pain hematuria syndrome

Subtypes (2): complex regional pain syndrome type 1, complex regional pain syndrome type 2

Genetics & variants

GWAS landscape

9 GWAS associations across 6 studies. Top hits map to 3 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs116935049	4e-13	KIF2B - ISCA1P3	G	2.21
rs142714744	7e-13	AEN - ISG20	A	2.24
rs188530633	1e-12	LINC02165 - PPIAP48	C	1.71
rs575463074	1e-11	LINC01968 - XXYLT1	C	2.81
rs528203081	2e-11	SPAG1	A	1.69
rs535285063	4e-11	RPS6KA1 - RN7SL679P	G	1.67
rs532322028	4e-11	GBA3	G	2.85
rs186711928	4e-11	TUBBP9 - TDRG1	C	3.51
rs150746139	3e-08	MOV10L1	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90477601	Verma A	2024	2,258	445,486	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477600	Verma A	2024	555	120,489	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480035	Verma A	2024	555	120,489	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481891	Verma A	2024	309	59,203	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90651579	Liu TY	2025	190	222,707	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST003930	Janicki PK	2016	115	0	Analysis of Common Single Nucleotide Polymorphisms in Complex Regional Pain Syndrome: Genome Wide Association Study Approach and Pooled DNA Strategy.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	9

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	8
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	5
intron_variant	4

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs116935049	17	54049766	G>A	0.001	intron_variant	KIF2B - ISCA1P3	4e-13	Tier 4: intronic/intergenic
rs142714744	15	88633758	A>G	0.004	intergenic_variant	AEN - ISG20	7e-13	Tier 4: intronic/intergenic
rs188530633	16	63790961	C>A,T	0.001	intergenic_variant	LINC02165 - PPIAP48	1e-12	Tier 4: intronic/intergenic
rs575463074	3	194996754	C>T	0.001	intergenic_variant	LINC01968 - XXYLT1	1e-11	Tier 4: intronic/intergenic
rs528203081	8	100170609	A>G,T	0.001	intron_variant	SPAG1	2e-11	Tier 4: intronic/intergenic
rs535285063	1	26585985	G>A	0.001	intergenic_variant	RPS6KA1 - RN7SL679P	4e-11	Tier 4: intronic/intergenic
rs532322028	4	22708793	G>A,T	0	intron_variant	GBA3	4e-11	Tier 4: intronic/intergenic
rs186711928	6	40135707	C>T	0.001	intergenic_variant	TUBBP9 - TDRG1	4e-11	Tier 4: intronic/intergenic
rs150746139	22	50124947	A>G	0.05	intron_variant	MOV10L1	3e-08	Tier 4: intronic/intergenic

Genes & proteins

No associated-gene cohort resolved for this disease. Atlas builds the molecular and therapeutic sections — associated genes, protein families, druggability, pathways, interactions, and drug associations — by aggregating over a disease’s associated genes (resolved via GWAS / GenCC / ClinVar / CIViC), and none resolved here. This is expected for antibody-mediated, autoimmune, or otherwise non-gene-defined conditions; the curated evidence for this disease is its clinical features, GWAS susceptibility, and clinical trials (above).

Function

No pathway enrichment — requires an associated-gene cohort.

Therapeutics

Drugs indicated for this disease

0 approved, 6 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Ascorbic Acid	Phase 3 (in late-stage trials)
Human Immunoglobulin G	Phase 3 (in late-stage trials)
Neridronic Acid	Phase 3 (in late-stage trials)
Nitrous Oxide	Phase 3 (in late-stage trials)
Oxygen	Phase 3 (in late-stage trials)
Zoledronic Acid Anhydrous	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Bupivacaine, Cannabinol, Cetuximab, Ethosuximide, Ketamine, Lenalidomide, Midazolam, Pregabalin, Sodium Chloride, Soticlestat, Triamcinolone Acetonide.

Clinical trials & evidence

Clinical trials

Clinical trials: 172.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	137
PHASE2	13
PHASE4	8
PHASE3	8
EARLY_PHASE1	3
PHASE1	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06306157	PHASE4	ENROLLING_BY_INVITATION	Low Dose Naltrexone Therapy for Complex Regional Pain Syndrome
NCT00296868	PHASE4	COMPLETED	Prophylactic Administration of Vitamin C in Wrist Fractures
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT02265848	PHASE4	COMPLETED	High Frequency Stimulation Trials in Patients With Precision Spinal Cord Stimulator System
NCT02467556	PHASE4	COMPLETED	Psychological Intervention and Physiotherapy With Medication Improves CRPS Patients Outcome
NCT03291197	PHASE4	COMPLETED	Tolerability of Suprascapular and Median Nerve Blocks for the Treatment of Shoulder-hand Syndrome
NCT05970146	PHASE4	UNKNOWN	Cervical Epidural and Stellate Ganglion Block in Upper Limb Complex Regional Pain Syndrome
NCT05997134	PHASE4	UNKNOWN	Three Regimens of Ketamine Infusion in Complex Regional Pain Syndrome
NCT07210515	PHASE3	RECRUITING	Evaluation of IV AMBTX-01 (Neridronate) for Treatment of CRPS Type 1 (CRPS-RISE)
NCT01134289	PHASE3	UNKNOWN	Analysis of Photoplethysmographic Signal in Lumbar Sympathetic Block
NCT01392599	PHASE3	UNKNOWN	Surgical Treatment Of Complex Regional Pain Syndrome Type II (CRPS II)
NCT02504008	PHASE3	UNKNOWN	CREATE-1: A Study to Assess the Efficacy and Safety of AXS-02 in Patients With CRPS-1
NCT02972359	PHASE3	COMPLETED	Safety of Intravenous Neridronic Acid in CRPS
NCT03530345	PHASE3	TERMINATED	Efficacy and Safety of Intravenous Neridronic Acid in CRPS
NCT03560986	PHASE3	TERMINATED	Efficacy and Safety of Intravenous Neridronic Acid in Complex Regional Pain Syndrome (CRPS)
NCT03879538	PHASE3	COMPLETED	Nitrous Oxide for the Treatment of Complex Regional Pain Syndrome
NCT04744675	PHASE2	ACTIVE_NOT_RECRUITING	Peripheral Nerve Injections for CRPS
NCT06419985	PHASE2	NOT_YET_RECRUITING	Ketamine HCl Prolonged Release Oral Tablets for CRPS
NCT00006289	PHASE2	TERMINATED	Neurotropin to Treat Chronic Neuropathic Pain
NCT00067743	PHASE2	COMPLETED	A Study of CC-5013 in the Treatment of Complex Regional Pain Syndrome (CRPS)
NCT00377468	PHASE2	UNKNOWN	Effect of Delta-9-Tetrahydrocannabinol on the Prevention of Chronic Pain in Patients With Acute CRPS (ETIC-Study)
NCT00558753	PHASE2	COMPLETED	Prospective, Randomized Controlled Trial on Perioperative Pregabalin to Reduce Late-onset CRPS After TKA
NCT00579085	PHASE2	COMPLETED	Double Blind Placebo Controlled Study of Outpatient Intravenous Ketamine for the Treatment of CRPS
NCT00689585	PHASE2	TERMINATED	Safety and Efficacy Study of Ethosuximide for the Treatment of Complex Regional Pain Syndrome (CRPS)
NCT01037088	PHASE1/PHASE2	COMPLETED	Effects of Vaporized Marijuana on Neuropathic Pain
NCT01788176	PHASE2	UNKNOWN	The Use of Zoledronic Acid to Complex Regional Pain Syndrome
NCT02094352	PHASE2	TERMINATED	Randomized Controlled Trial of Ketamine Infusion With Continuous Epidural Infusion for Treatment of Complex Regional Pain Syndrome
NCT02490436	PHASE2	COMPLETED	Novel Treatment Option for Neuropathic Pain
NCT03990649	PHASE2	COMPLETED	Study of TAK-935 as an Adjunctive Therapy in Adult Participants With Complex Regional Pain Syndrome (CRPS)
NCT05945147	PHASE2	WITHDRAWN	Ketamine and Midazolam Infusions for CRPS: Feasibility Study
NCT06393101	PHASE1	RECRUITING	The Effects and Mechanisms of a High CBD Cannabis Extract (BRC-002) for the Treatment of Pain and Health in Complex Regional Pain Syndrome
NCT02321566	PHASE1	TERMINATED	Motor Cortex Stimulation for the Treatment of Chronic Facial, Upper Extremity, and Throat Pain.
NCT03686748	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Two Point Discrimination
NCT02753101	EARLY_PHASE1	COMPLETED	[18F]FTC-146 PET/MRI in Healthy Volunteers and in CRPS and Sciatica
NCT03616262	EARLY_PHASE1	UNKNOWN	Efficacy of Botulinum Toxin Injection in Reducing Limb Pain in Patients With Complex Regional Pain Syndrome
NCT02502162	Not specified	RECRUITING	Low-Dose Naltrexone for the Treatment of Complex Regional Pain Syndrome
NCT03137472	Not specified	RECRUITING	TMS for Complex Regional Pain Syndrome
NCT03612193	Not specified	RECRUITING	Role of the Gut Microbiome in Complex Regional Pain Syndrome
NCT03838107	Not specified	RECRUITING	Markers of Trajectory in Pediatric CRPS
NCT04144972	Not specified	RECRUITING	Closed-Loop Deep Brain Stimulation for Refractory Chronic Pain

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DICLOFENAC SODIUM	4	1
DRONABINOL	4	1
ETHOSUXIMIDE	4	1
GABAPENTIN	4	1
MEMANTINE	4	1
NITROUS OXIDE	4	1
OXYGEN	4	1
NERIDRONIC ACID	3	4
SOTICLESTAT	3	1