Complex regional pain syndrome: advances in epidemiology, pathophysiology, diagnosis, and treatment.

Complex regional pain syndrome (CRPS) is a rare pain disorder that usually occurs in a limb after trauma. The features of this disorder include severe pain and sensory, autonomic, motor, and trophic abnormalities. Research from the past decade has offered new insights into CRPS epidemiology, pathophysiology, diagnosis, and treatment. Early identification of individuals at high risk of CRPS is improving, with several risk factors established and some others identified in prospective studies during the past 5 years. Better understanding of the pathophysiological mechanisms of CRPS has led to its classification as a chronic primary pain disorder, and subtypes of CRPS have been updated. Procedures for diagnosis have also been clarified. Although effective treatment of CRPS remains a challenge, evidence-based integrated management approaches provide new opportunities to improve patient care. Further advances in diagnosis and treatment of CRPS will require coordinated, international multicentre initiatives.

A brief review of complex regional pain syndrome and current management.

Complex regional pain syndrome (CRPS) is a debilitating chronic pain condition that, although exceedingly rare, carries a significant burden for the affected patient population. The complex and ambiguous pathophysiology of this condition further complicates clinical management and therapeutic interventions. Furthermore, being a diagnosis of exclusion requires a diligent workup to ensure an accurate diagnosis and subsequent targeted management. The development of the Budapest diagnostic criteria helped to consolidate existing definitions of CRPS but extensive work remains in identifying the underlying pathways. Currently, two distinct types are identified by the presence (CRPS type 1) or absence (CRPS type 2) of neuronal injury. Current management directed at this disease is broad and growing, ranging from non-invasive modalities such as physical and psychological therapy to more invasive techniques such as dorsal root ganglion stimulation and potentially amputation. Ideal therapeutic interventions are multimodal in nature to address the likely multifactorial pathological development of CRPS. Regardless, a significant need remains for continued studies to elucidate the pathways involved in developing CRPS as well as more robust clinical trials for various treatment modalities.

Complex regional pain syndrome (CRPS) is a debilitating and complex condition that places a significant physical, psychological and emotional burden upon afflicted patients necessitating multi-modal approaches to treatment.The development of the Budapest criteria provided a robust and well-tested set of diagnostic criteria to aid clinicians in the diagnosis of CRPS.The pathophysiology of CRPS has been challenging to elucidate with numerous proposed mechanisms, altogether suggesting a multi-factorial process is involved in the development of this condition.Non-invasive treatments for CRPS are essential in addressing the physical limitations this disease can cause as well as addressing the significant psychological burden that involves increased incidence of depression and suicidal ideation.Invasive treatments offer promising results, especially when considering dorsal root ganglion stimulation; however, the need for more robust clinical trials remains, especially when considering a small portion of patients who have refractory CRPS resort to amputation to control their pain symptoms.

Complex regional pain syndrome: diagnostic challenges and favorable response to prednisolone.

Complex regional pain syndrome (CRPS), characterized by severe and disproportionate pain, is a rare and debilitating condition. Due to its rarity, evidence-based treatment guidelines remain limited, creating a challenge for clinicians. We present the case of a 20-year-old female with CRPS type 1 of the right hand. Her pain, initially triggered by a minor trauma, had persisted for three months. The patient demonstrated severe pain, swelling, hyperesthesia, and restricted range of motion. Despite multiple hospital visits, her symptoms did not improve until she was diagnosed with CRPS and treated with oral prednisolone. A dosage of 40 mg daily led to a dramatic response within 10 days. Our report emphasizes the importance of recognizing CRPS and highlights the potential of prednisolone as a treatment option, particularly in resource-limited settings, where more specialized interventions may be unavailable. Further research is essential to establish a stronger evidence base for the use of steroids in CRPS management.

A decision tree algorithm to identify predictors of post-stroke complex regional pain syndrome.

This prospective cohort study aimed to identify the risk factors for post-stroke complex regional pain syndrome (CRPS) using a decision tree algorithm while comprehensively assessing upper limb and lower limb disuse and physical inactivity. Upper limb disuse (Fugl-Meyer assessment of upper extremity [FMA-UE], Action Research Arm Test, Motor Activity Log), lower limb disuse (Fugl-Meyer Assessment of lower extremity [FMA-LE]), balance performance (Berg balance scale), and physical inactivity time (International Physical Activity Questionnaire-Short Form [IPAQ-SF]) of 195 stroke patients who visited the Kishiwada Rehabilitation Hospital were assessed at admission. The incidence of post-stroke CRPS was 15.4% in all stroke patients 3 months after admission. The IPAQ, FMA-UE, and FMA-LE were extracted as risk factors for post-stroke CRPS. According to the decision tree algorithm, the incidence of post-stroke CRPS was 1.5% in patients with a short physical inactivity time (IPAQ-SF < 635), while it increased to 84.6% in patients with a long inactivity time (IPAQ-SF ≥ 635) and severe disuse of upper and lower limbs (FMA-UE score < 19.5; FMA-LE score < 16.5). The incidence of post-stroke CRPS may increase with lower-limb disuse and physical inactivity, in addition to upper-limb disuse. Increasing physical activity and addressing lower- and upper-limb motor paralysis may reduce post-stroke CRPS.

An update on the pharmacotherapeutic options for complex regional pain syndrome.

INTRODUCTION: Complex regional pain syndrome (CRPS) is a rare and painful condition that has a wide range of triggering factors, often traumatic, and can present various clinical manifestations. The lack of knowledge about the underlying mechanisms has led to numerous treatment approaches, both conservative and surgical, which work through different mechanisms of action. AREAS COVERED: In this review, the authors explore the key aspects of CRPS, including definition, diagnostic criteria, pitfalls, pathogenic hypotheses, and treatment strategies with a focus on pharmacotherapy. The review was based on a comprehensive search of the literature using PubMed, while also considering international guidelines for managing CRPS. EXPERT OPINION: Based on the available evidence, pharmacological interventions appear to be effective in treating CRPS, especially when they target peripheral mechanisms, specifically nociceptive inflammatory pain, and when administered early in the course of the disease. However, there is still a lack of reliable evidence regarding the effects of drugs on central mechanisms of chronic pain in CRPS. In our expert opinion, drug therapy should be initiated as soon as possible, particularly in warm CRPS patient clusters, to prevent significant functional limitations, psychological distress, and negative impacts on individuals' social and economic well-being.

Early versus persistent Complex Regional Pain Syndrome: Is there a difference in patient reported outcomes following rehabilitation?

BACKGROUND: Expert consensus asserts that early treatment of Complex Regional Pain Syndrome (CRPS) leads to better outcomes. Yet no evidence supports this assumption regarding the recognized gold standard of multidisciplinary functional rehabilitation. To address this, we aimed to establish if there is a difference in outcomes between early CRPS (<1 year symptom duration) and persistent CRPS (= >1 year symptom duration) following rehabilitation and whether any gains are maintained at three months. METHOD: Secondary analysis was conducted on previously collected clinical Patient Reported Outcome Measures (PROMS) data from 218 patients attending a residential multidisciplinary rehabilitation programme. Datasets were categorized into early CRPS (n = 40) or persistent CRPS (n = 178) dependent on symptom duration. Function, pain, self-efficacy, kinesiophobia and psychological health domains were compared using repeated measures analysis of covariance for a two group design for group difference post rehabilitation and at three month follow-up. RESULTS: Post-rehabilitation, both groups improved in pain, function, kinesiophobia, psychological health and self-efficacy. At three months, the persistent CRPS group maintained improvements in pain and function. This was not achieved in early CRPS. CONCLUSION: This exploratory study is the first to empirically test the assumption that those with early CRPS have better outcomes following rehabilitation. Our clinical data challenges this, as both early and persistent CRPS groups improved following rehabilitation. Findings indicate that rehabilitation benefits those with CRPS, regardless of symptom duration. However, unlike early CRPS, those with persistent CRPS sustain gains at follow-up. Further prospective exploration is warranted. SIGNIFICANCE: Expert consensus recommends early treatment for Complex Regional Pain Syndrome, yet there is little empirical evidence to support this. Our findings are the first to challenge this assumption by revealing no difference in outcomes between early and persistent CRPS post-rehabilitation. However, those with persistent CRPS maintain gains after three months, unlike people with early CRPS (symptoms < one year). These findings are relevant to clinical practice as they challenge established assumptions, suggesting a focus on improving early CRPS follow-up outcomes.

Impact of different CRPS phenotypes and diagnostic criteria on quantitative sensory testing outcomes: systematic review and meta-analysis.

OBJECTIVES: This review and meta-analysis evaluated the impact of diagnostic criteria and clinical phenotypes on quantitative sensory testing (QST) outcomes in patients with complex regional pain syndrome (CRPS). METHODS: Eight databases were searched based on a previously published protocol. Forty studies comparing QST outcomes between CRPS-I vs II, warm vs cold CRPS, upper vs lower limb CRPS, males vs females, or using Budapest vs older IASP criteria were included. RESULTS: Studies investigating QST differences between CRPS-I vs II (n = 4), between males vs females (n = 2), and between upper and lower limb CRPS (n = 2) showed no significant differences. Four studies compared QST outcomes in warm vs cold CRPS, showing heat hyperalgesia in warm CRPS, with thermal and mechanical sensory loss in cold CRPS. Although CRPS diagnosed using the Budapest criteria (24 studies) vs 1994 IASP criteria (13 studies) showed similar sensory profiles, there was significant heterogeneity and low quality of evidence in the latter. CONCLUSIONS: Based on the findings of this review, classifying CRPS according to presence or absence of nerve lesion into CRPS-I and II, location (upper or lower limb) or according to sex might not be clinically relevant as all appear to have comparable sensory profiles that might suggest similar underlying mechanisms. In contrast, warm vs cold phenotypes exhibited clear differences in their associated QST sensory profiles. To the extent that differences in underlying mechanisms might lead to differential treatment responsiveness, it appears unlikely that CRPS-I vs II, CRPS location, or patient sex would prove useful in guiding clinical management.

Prevalence and predisposing factors of post-stroke complex regional pain syndrome: Retrospective case-control study.

INTRODUCTION: Poststroke complex regional pain syndrome (CRPS) is an important complication in stroke survivors. The identification of factors associated with post-stroke CRPS is important for preventive measures and early diagnosis. METHODS: A total of 141 first-ever stroke survivors in the subacute stage were retrospectively analyzed. Demographic data, diagnosis time, duration of hospitalization, location of brain lesion, etiology, comorbidities, and blood test findings were investigated. Clinical data included Medical Research Council (MRC) grade, Fugl-Meyer assessment (FMA), National Institute for Health Stroke Scale (NIHSS), Berg Balance Scale (BBS). RESULTS: Among 141 patients with subacute stroke, 22 were diagnosed with CRPS, with a prevalence of 15.6 %. The mean time to diagnosis was 38.6 (±16.5) days. The prevalence according to the degree of paralysis was 33.3 % in MRC grades 0 and 1, 8.6 % in grade 2, and 0 % in grade 3 or higher. The incidence rates within 1 month after stroke were 1.42 % and 22.47 % between 1 and 3 months after stroke, respectively. The independent risk factors for CRPS were hospitalization duration and FMA, NIHSS, and BBS scores. The sensitivity and specificity of the NIHSS score for predicting post-stroke CRPS were 86.4 % and 59.7 %, respectively, with an optimal cutoff value of 7.5. CONCLUSIONS: CRPS of the affected upper limb in stroke patients is associated with stroke severity, including paralysis, and the incidence increases over time during the subacute phase. Additionally, having sufficient strength to move through a full range of motion against gravity had a protective effect against CRPS.

Patients With Preexisting Anxiety and Mood Disorders Are More Likely to Develop Complex Regional Pain Syndrome After Fractures.

BACKGROUND: Complex regional pain syndrome (CRPS) is a multifactorial condition that may affect patients who sustain a fracture in the upper and lower extremities. Prior investigations have formed a foundation for exploring a possible association between psychiatric disorders and the development of CRPS; however, current studies are conflicted regarding the existence and temporality of a relationship between psychiatric disorders and the potential development of CRPS. QUESTIONS/PURPOSES: (1) Are patients with preexisting anxiety and mood disorders (AMDs) at increased risk of receiving a diagnosis of CRPS after upper or lower extremity fractures? (2) Are patients with preexisting AMDs at increased risk of being diagnosed with CRPS after surgical fixation of their fracture? METHODS: A large, retrospective cohort study was conducted using the TriNetX electronic medical record platform, which contains data from more than 100 million patients. This platform gathers data from healthcare organizations in the United States and Europe and collects comprehensive data over time that includes temporality rather than simply the binary presence or absence of conditions. The cohort included 760,595 patients older than 18 years with upper or lower extremity fractures between 2003 and 2022. Included patients had a minimum 1-year follow-up. We defined AMDs as any diagnosis of anxiety, depressive episode or disorder, a manic episode, or bipolar disorder. Patients with polytrauma or concurrent upper and lower extremity fractures were excluded to reduce confounders. CRPS I diagnosis was identified via International Classification of Diseases, Tenth Edition codes. Propensity score matching was performed to balance cohorts based on age, gender, and race. Hazard ratios and Aalen-Johansen cumulative incidence curves for the diagnosis of CRPS were calculated for patients with and without AMD diagnoses before sustaining a fracture. A subanalysis was performed in which we examined individuals in the upper and lower extremity fracture cohorts who underwent surgical treatment. RESULTS: Patients with preexisting AMDs were at a higher risk of experiencing CRPS I than patients without AMDs were (upper extremity: HR 1.8 [95% CI 1.7 to 1.9]; p < 0.01, lower extremity: HR 2.2 [95% CI 2.0 to 2.3]; p < 0.01). Similarly, patients with preexisting AMDs were at higher risk of experiencing CRPS I after fracture fixation than patients without AMDs were (upper extremity: HR 1.3 [95% CI 1.2 to 1.5]; p < 0.01, lower extremity: HR 2.3 [95% CI 2.1 to 2.5]; p < 0.01). CONCLUSION: Awareness of the relationship between AMDs and CRPS I will direct future research about the development of this condition and associated neurologic changes. Additionally, surgeons can address AMDs perioperatively and arrange for the treatment of these AMDs with psychiatrists, neurologists, or social work, as appropriate. Accordingly, patients with AMDs should also be made aware of the inherent risk of CRPS I after an upper or lower extremity fracture to comprehensively educate and care for this at-risk patient population. LEVEL OF EVIDENCE: Level III, therapeutic study.

The complex regional pain syndrome: Diagnosis and management strategies.

Complex regional pain syndrome (CRPS) is a chronic disease that affects a limb following an injury or trauma. The CRPS associated with symptoms, including severe pain, swelling, as well as changes in skin color and temperature. Treatment of CRPS requires a multidisciplinary approach, with a focus on personalized treatment plans and addressing psychological factors. This review provides an overview of updates in the diagnosis and treatment of CRPS. There are clinical criteria for diagnosing CRPS, including persistent pain and swelling. The CRPS can also be diagnosed with imaging and laboratory tests. Novel insights into treatment approaches for CRPS have been gained from advances in understanding its pathophysiology. Treatment of CRPS includes both pharmacological and non-pharmacological interventions. The latest guidelines for CRPS treatment emphasize the importance of early diagnosis and intervention, personalized treatment plans, and addressing psychological factors in managing CRPS.

Interpretation and content validity of the items of the Hamilton inventory to evaluate outcomes in Persian-speaking patients with complex regional pain syndrome: A cognitive interview approach.

BACKGROUND: The Hamilton Inventory for complex regional pain syndrome (CRPS) is a multidisciplinary assessment tool to evaluate signs and symptoms in patients with CRPS, developed in the English language. PURPOSE: This study aims to translate and cross-culturally adapt this tool for Persian-speaking patients with CRPS. Furthermore, this study aimed to understand how 1) Persian-speaking experts and patients interpret and calibrate responses to items on the Hamilton Inventory and 2) compensatory strategies that might affect responses. STUDY DESIGN: A cross sectional study with cognitive interview method. METHODS: Ten health care providers and 10 patients with CRPS were interviewed using cognitive interviewing techniques (talk-aloud, semi-structured interview probes). All interviews were recorded and transcribed verbatim. A directed content analysis was done to analyze the interviews using a previously established framework. RESULTS: Overall, the items on the Hamilton Inventory were well received by participants. Areas, where questions were unclear to some participants were recorded and categorized into five themes: Clarity and Comprehension (100%) in item 1 from the health professional tool and (65%) from the eleven items of the patient-reported tool. Perspective modifiers of culture influenced the calibrations of items "I feel my condition has negatively affected my relationships." (12%) and "My symptoms affect my comfort level with intimacy." (20%) from the patient-reported tool. CONCLUSION: The findings of this study demonstrate that there is no need for substantive changes to the items of the Hamilton Inventory, as they tend to be understood by Persian-speaking experts and patients with CRPS.

Chronic Pain Syndromes: Complex Regional Pain Syndrome.

Complex regional pain syndrome (CRPS) is a chronic pain condition characterized by intense pain, usually in a body region that has experienced trauma, and autonomic and inflammatory features. It most commonly develops after an arm or leg injury. Patients typically present with extreme hyperalgesia and/or allodynia. The Budapest Criteria are used to make this clinical diagnosis. Prompt diagnosis and aggressive management are critical because long-term outcomes are improved when treatment is initiated soon after symptom onset. The primary management options are rehabilitation and physical therapy, including such approaches as progressive tactile stimulation, normalization of movement to prevent limited range of motion, and others. No drugs are approved by the Food and Drug Administration (FDA) for CRPS management, but some evidence supports the use of drugs used to manage other types of neuropathic pain (eg, gabapentin, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors). Nonsteroidal anti-inflammatory drugs also are used, and corticosteroids, bisphosphonates, ketamine, and other drugs can be helpful, particularly for early-stage CRPS. When pain severity prevents patients from participating in rehabilitation, referral to a pain specialist is warranted for consideration of procedural interventions, including sympathetic nerve blockade and spinal cord stimulation.

Experiences of diagnosis and treatment for upper limb Complex Regional Pain Syndrome: a qualitative analysis.

INTRODUCTION: Complex Regional Pain Syndrome (CRPS) most frequently affects the upper limb, with high associated disability. Delays to diagnosis and appropriate treatment can adversely impact prognosis and quality of life, but little is known about the healthcare experiences of people with CRPS. This study aimed to explore lived experiences of diagnosis and treatment for people with upper limb CRPS. METHODS: Participants were recruited through online support groups and multiple public and private healthcare settings in the Greater Wellington Region, New Zealand. Semi-structured interviews were conducted with participants who had experienced upper limb CRPS for more than three months and less than three years. Interviews were transcribed verbatim and analysed using reflexive thematic analysis. RESULTS: Thirteen participants (11 female, 2 male) aged between 43 and 68 years were interviewed. Duration of CRPS ranged from 7 months to 2.5 years. Five themes were identified. Participants initially engaged in healthcare out of a desire to return to being the person they were before having CRPS. Three interacting experiences epitomised the overall healthcare experience: (1) not knowing what is going on, (2) not being taken seriously, and (3) healthcare as adding another layer of load. Meanwhile, participants used multiple approaches in an attempt to not let CRPS stop them from continuing to live their lives. CONCLUSIONS: Participants in this study felt that credible information, validation, and simplification from healthcare providers and systems would support their process of navigating towards a meaningful life and self-concept in the presence of CRPS.

Complex regional pain syndrome.

ABSTRACT: Complex regional pain syndrome (CRPS), formerly called reflex sympathetic dystrophy (RSD), is a chronic pain phenomenon associated with an alteration in peripheral and central pain perception in a localized body region. Because of the many risk factors associated with this phenomenon, the true nature of the disease risk and clinical course are a challenge to predict. After the diagnosis is confirmed and treatment is provided promptly, clinicians must consider patient health and function holistically to foster improvement in overall quality of life.

Complex Regional Pain Syndrome: Evidence-Based Advances in Concepts and Treatments.

PURPOSE OF REVIEW: This review presents the most current information about the epidemiology of complex regional pain syndrome (CRPS), classification and diagnostic criteria, childhood CRPS, subtypes, pathophysiology, conventional and less conventional treatments, and preventive strategies. RECENT FINDINGS: CRPS is a painful disorder with multifactorial pathophysiology. The data describe sensitization of the central and peripheral nervous systems, inflammation, possible genetic factors, sympatho-afferent coupling, autoimmunity, and mental health factors as contributors to the syndrome. In addition to conventional subtypes (type I and type II), cluster analyses have uncovered other proposed subtypes. Prevalence of CRPS is approximately 1.2%, female gender is consistently associated with a higher risk of development, and substantial physical, emotional, and financial costs can result from the syndrome. Children with CRPS seem to benefit from multifaceted physical therapy leading to a high percentage of symptom-free patients. The best available evidence along with standard clinical practice supports pharmacological agents, physical and occupational therapy, sympathetic blocks for engaging physical restoration, steroids for acute CRPS, neuromodulation, ketamine, and intrathecal baclofen as therapeutic approaches. There are many emerging treatments that can be considered as a part of individualized, patient-centered care. Vitamin C may be preventive. CRPS can lead to progressively painful sensory and vascular changes, edema, limb weakness, and trophic disturbances, all of which substantially erode healthy living. Despite some progress in research, more comprehensive basic science investigation is needed to clarify the molecular mechanisms of the disease so that targeted treatments can be developed for better outcomes. Incorporating a variety of standard therapies with different modes of action may offer the most effective analgesia. Introducing less conventional approaches may also be helpful when traditional treatments fail to provide sufficient improvement.

Usefulness of thermography in the diagnosis and classification of complex regional pain syndrome.

INTRODUCTION: We propose a protocol for study of complex regional pain syndrome (CRPS) based on a battery of quantitative measures (skin thermography, electrochemical skin conductance and sensory thresholds) and apply such protocol to 5 representative cases of CRPS. PATIENTS AND METHODS: 5 CPRS cases (2 women/3 men) that met the Budapest criteria for the diagnosis of CRPS. RESULTS: All patients showed spontaneous pain and allodynia. Two cases correspond to a stage I, in both the resting basal temperature was increased in the affected limb. Three cases reflect more advanced stages with a decrease in resting temperature and a delay in the recovery of the temperature when compared to contralateral limb. DISCUSSION: These non-invasive quantitative functional tests not only improve the diagnostic accuracy of CRPS but also, they help us to stratify and understand the pathological processes of the disease.

[Complex regional pain syndrome]. / Syndrome douloureux régional complexe.

Complex regional pain syndrome is a clinical entity that usually occurs following trauma, surgery, or other triggering event. Patients complain of pain described as burning, associated with sensory, vasomotor, sudomotor, motor and/or trophic disorders. The pain appears disproportionate to the initial lesion. The diagnosis is purely clinical and based on the Budapest criteria. It is a diagnosis of exclusion. The pathophysiology is still poorly understood and is thought to be multifactorial. Several mechanisms have been described: an inflammatory state, an overactivation of the sympathetic autonomic nervous system and a poor perception of pain at the central level. The management of signs and symptoms is therefore global. It involves physiotherapy and occupational therapy, often combined with analgesic medications. Psychological treatment may be proposed in certain circumstances. The natural evolution is rather favourable.

Le syndrome douloureux régional complexe constitue une entité clinique survenant habituellement suite à un traumatisme, une chirurgie ou un autre événement déclencheur. Les patients se plaignent d'une douleur décrite comme une brûlure, associée à des troubles sensoriels, vasomoteurs, sudomoteurs, moteurs et/ou trophiques. La douleur apparaît disproportionnée par rapport à la lésion initiale. Le diagnostic est purement clinique et repose sur les critères de Budapest. Il s'agit d'un diagnostic d'exclusion. La physiopathologie est encore peu connue, et serait multifactorielle. Plusieurs mécanismes sont décrits : un état inflammatoire, une suractivation du système nerveux autonome sympathique et une mauvaise perception de la douleur au niveau central. La prise en charge des signes et symptômes est donc globale. Elle fait intervenir une rééducation en kinésithérapie et ergothérapie, souvent associée à un traitement antalgique médicamenteux. Une prise en charge en psychologie peut être proposée dans certaines circonstances. L'évolution naturelle est plutôt favorable.

Epidemiology of Upper Limb Complex Regional Pain Syndrome in a Retrospective Cohort of Persons Aged 9-30 Years, 2002-2017.

Introduction This paper describes the epidemiology and clinical presentation of complex regional pain syndrome (CRPS) in a large, integrated health care delivery system; and CRPS incidence rates (IRs) over a time period spanning human papillomavirus (HPV) vaccine licensure and published case reports of CRPS following HPV vaccination. Methods The authors examined CRPS diagnoses in patients aged 9-30 years between January 2002 and December 2017 using electronic medical records, excluding patients with lower limb diagnoses only. Medical record abstraction and adjudication were conducted to verify diagnoses and describe clinical characteristics. CRPS IRs were calculated for 3 periods: Period 1 (2002-2006: before HPV vaccine licensure), Period 2 (2007-2012: after licensure but before published case reports), and Period 3 (2013-2017: after published case reports). Results A total of 231 individuals received an upper limb or unspecified CRPS diagnosis code during the study period; 113 cases were verified through abstraction and adjudication. Most verified cases (73%) were associated with a clear precipitating event (eg, non-vaccine-related injury, surgical procedure). The authors identified only 1 case in which a practitioner attributed CRPS onset to HPV vaccination. Twenty-five incident cases occurred in Period 1 (IR = 4.35/100,000 person-years (PY), 95% confidence interval (CI) = 2.94-6.44), 42 in Period 2 (IR = 5.94/100,000 PY, 95% CI = 4.39-8.04), and 29 in Period 3 (IR = 4.53/100,000 PY, 95% CI = 3.15-6.52); differences between periods were not statistically significant. Conclusion These data provide a comprehensive assessment of the epidemiology and characteristics of CRPS in children and young adults and provide further reassurance about the safety of HPV vaccination.