Complex Regional Pain Syndrome (CRPS)

Original Editors - Katelyn Koeninger and Kristen Storrie from Bellarmine University's Pathophysiology of Complex Patient Problems project and Yves Hubar 

Top Contributors -  Katelyn Koeninger, Kristen Storrie, Laura Ritchie, Laure-Anne Callewaert, Yves Hubar, Angeliki Chorti, Admin, Melissa Coetsee, Evan Thomas, Scott Cornish, Elaine Lonnemann, Kim Jackson, Rachael Lowe, Gayatri Jadav Upadhyay, Gwen Wyns, Matthias Steenwerckx, Vidya Acharya, Lucinda hampton, Habibu Salisu Badamasi, Jo Etherton, Claire Knott, Lauren Lopez, Maria Galve Villa, Michelle Lee, Richmond Stace, WikiSysop, Wendy Walker and Naomi O'Reilly  

Definition

Complex regional pain syndrome (CRPS) is a term for a variety of clinical conditions characterised by chronic persistent pain and are subdivided into Type I and Type II CRPS. It is a condition that can develop after a limb trauma and appears mostly in one or more limbs. CRPS can be considered a regional post-traumatic neuropathic pain problem, and like other neuropathic pain disorders, symptoms are a disproportionate consequence of painful trauma or nerve lesion.

Many names have been used to describe this syndrome such as; Reflex Sympathetic Dystrophy, causalgia, algodystrophy, Sudeck’s atrophy, neurodystrophy and post-traumatic dystrophy. To standardise the nomenclature, the name complex regional pain syndrome was adopted in 1995 by the International Association for the Study of Pain (IASP).

Prevalence

CRPS affects approximately 26 out of every 100,000 people. It is more common in females than males, with a ratio of 3.5:1. CRPS can affect people of all ages, including children as young as three years old and adults as old as 75 years, but typically is most prevalent in the mid-thirties. CRPS Type I occurs in 5% of all traumatic injuries, with 91% of all CRPS cases occurring after surgery.

Clinically Relevant Anatomy

CRPS can affect any part of the body, but occurs most often in the extremities. The wrist is most frequently affected after distal radial fractures.

The central and peripheral nervous systems are connected through neural and chemical pathways, and can have direct control over the autonomic nervous system. It is for this reason that there can be changes in vasomotor and sudomotor responses without any impairment in the peripheral nervous system. Pain, heat, and swelling are usually not located at the site of injury and there may be no clear damage. Central sensitisation is seen as a main cause for developing CRPS.

Figure 1. Nociceptive (painful) information is relayed through the dorsal horn of the spinal cord for processing and modulation before cortical evaluation.

Etiology

Complex regional pain syndrome can develop after different types of injuries, such as

• Sprains and strains
• Surgeries
• Fractures
• Contusions
• Crush injuries
• Nerve lesions
• Stroke

Sometimes the provoking injury can occur spontaneously or can not be determined. One study found that 56% of patients felt their CRPS was due to an ‘on the job’ injury, with the most common type of work-related injury occurring in service employments, such as in restaurants, bakeries, and police offices.

The location of CRPS varies from person to person, often affecting the extremities, occurring slightly more in the lower extremities (+/- 60%) than in the upper extremities (+/- 40%). It can also appear unilaterally or bilaterally  and as mentioned above, occurs regularly in young adults and is more frequent in females than males.

The onset is mostly associated with a trauma, immobilisation, injections, or surgery, but there is no relation between the grade of severity of the initial injury and the following syndrome. A stressful life and other psychological factors may be potential risk factors that impact the severity of symptoms in CRPS.

Clinical Presentation

The differences between Type I and Type II are based on a consensus between clinicians and scientists. The definition of Type II (see below) is open to interpretation. For example, post-traumatic neuralgia has different syndromes with different underlying mechanisms, but it can be included in type II. Hence the definition of both types needs to be improved. In both cases, it can be assumed that long-term central changes have occurred. Changes in the somatosensory, sympathetic, peripheral, somatomotor, and neuroendocrine systems can cause changes in the central nervous system. All symptoms of CRPS II show many similarities to those of CRPS I.

CRPS is clinically characterised by sensory, autonomic, and motor disturbances. The table below shows an overview of the different characteristics of CRPS I and II.

Type	Type I	Type II
Definition	Formerly "Reflex Sympathetic Dystrophy (RSD) " Occurs after a trauma remote from the affected extremity, with or without minor nerve damage	Formerly "Causalgia" Occurs after injury to a major peripheral nerve
Etiology	Minor, soft tissue trauma (sprains, bruises and skin lesions) Bone fracture or surgery Frostbite or burns Stroke Myocardial infarction or lesion of the central nervous system Immobilisation
Sensory disturbances	Allodynia and hyperalgesia Hypoesthesia and hypoalgesia Strange, disfigured, or dislocated feelings in limbs	Allodynia and hyperalgesia Hypersensitivity of the skin to light mechanical stimulation - some patients report intolerance to air moving over skin
Autonomic disorders + inflammatory symptoms	Swelling and edema Changes of sweating (especially hyperhidrosis) Abnormal skin blood flow Colour changes (redness or pale) Temperature changes	Limb is cold and sweaty Distal extremity swelling Changes of sweating Abnormal skin blood flow Temperature changes
Trophic changes	Thick, brittle, or rigid nails Increased or decreased hair growth Fibrosis Thin, glossy, clammy skin Osteoporosis (chronic stage)	Smoothness and mottling of the skin Acute arthritis
Motor dysfunction	Weakness of all muscles Inability to move the extremity Stiffness Tremor Reduced range of motion Severe impairment of complex movements Atrophy	Inability to initiate movement of the extremity Stiffness Tremor Dystonia Reduced range of motion
Pain (sympathetic nervous system)	Burning and spontaneous Disproportionate in the intensity to the inciting event Increase when the extremity is in a dependent position Elicited by movement and pressure at the joints Not in all cases (pain may not be present in 7% of CRPS sufferers) Deep, unpleasant, sensitive, surface, dull	Ongoing Neuropathic Spontaneous Triggered by movement, loud noises, or strong emotions Deep, unpleasant, sensitive, surface, dull

Symptoms can spread beyond the area of the lesioned nerve in Type II. Ongoing neurogenic inflammation, vasomotor dysfunction, central sensitisation and maladaptive neuroplasticity contribute to the clinical phenotype of CRPS. Genetic and psychological factors can influence the vulnerability to CRPS and also affect the mechanisms that maintain CRPS. Peripheral and central changes can be irreversible. The sympathetic nervous system plays a key role in maintaining pain and autonomic dysfunction in the affected extremity.

Patients typically progress through three stages as CRPS develops. CRPS in children does not always follow the same stage patterns and may only slowly improve or, at times, even stagnate.

Stage	Time Period	Classic Signs and Symptoms
Stage I: acute inflammation: denervation and sympathetic hypoactivity	Begins 10 days post injury; Lasts 3-6 months	Pain: more severe than expected; burning or aching; increased with position, physical condition, or emotional disturbances Hyperalgesia, allodynia, hyperpathia: lower pain threshold, increased sensitivity, all stimuli are perceived as painful, increased pain threshold then increased sensation intensity (faster and greater pain) Oedema: soft and localised Vasomotor/Thermal Changes: warmer Skin: hyperthermia, dryness Other: increased hair and nail growth
Stage II: dystrophic: paradoxic sympathetic hyperactivity	Begins 3-6 months after onset of pain; Lasts about 6 months	Pain: worsens, constant, burning, aching Hyperalgesia, allodynia, hyperpathia: present Oedema: hard, causes joint stiffness Vasomotor/Thermal Changes: none Skin: thin, glossy, cool due to vasoconstriction, sweaty Other: thin and rigid nails, osteoporosis and subchondral bone erosion noted on x-rays
Stage III: atrophic	Begins 6-12 months after onset of pain; Lasts for years, or may resolve and reappear	Pain: spreads proximally and occasionally to entire body, may plateau Oedema: hardening Vasomotor/Thermal Changes: decreased SNS regulation, cooler Skin: thin, shiny, cyanotic, dry Other: fingertips and toes are atrophic, thick fascia, possible contractures, demineralisation and ankylosis seen on x-rays

Associated Co-morbidities

CRPS may also be associated with:

• Arterial Insufficiency
• Asthma
• Bone Fractures
• Cellulitis
• Central Pain Syndromes
• Conversion Disorder
• Depression/Anxiety
• Factitious Disorder 
• Lymphedema
• Malignancy
• Migraines
• Nerve Entrapment Syndromes
• Osteomyelitis
• Osteoporosis
• Pain Disorder
• Peripheral Neuropathies
• Rheumatoid Arthritis
• Scleroderma
• Septic arthritis
• Systemic Lupus Erythematosus
• Tenosynovitis
• Thrombophlebitis

Differential Diagnosis

Differential diagnosis includes the direct effects of the following conditions:

• Bony or soft tissue injury
• Peripheral neuropathy, nerve lesions
• Arthritis
• Infection
• Compartment syndrome
• Arterial insufficiency
• Raynaud’s Disease
• Lymphatic or venous obstruction
• Thoracic Outlet Syndrome (TOS)
• Gardner-Diamond Syndrome
• Erythromelalgia
• Self-harm or malingering
• Cellulitis
• Undiagnostic fracture

Diagnostic Procedures

CRPS diagnosis is mainly based on patient history, clinical examination, and supportive investigations.

The Budapest Criteria

The Budapest criteria (also known as the IASP) has been developed for the diagnosis of CRPS, but improvements still need to be made. Clinical diagnostic criteria for complex regional pain syndrome are:

• Constant pain, higher than the normally perceived pain
• Minimum one symptom in three of the following four symptoms. Categories must be reported:
  1. Vasomotor: temperature asymmetry and/or skin colour changes/asymmetry
  2. Sensory: hyperalgesia and/or allodynia
  3. Sudomotor/edema: changes in sweating
  4. Motor/trophic: smaller range of motion, motor dysfunction and/or changes in hair, nails and skin
• Additionally, the patient must also show signs of developing symptoms in at least two symptom categories
• No other illness could explain the set of symptoms the patient is presenting with.

Other Tests

Infrared Thermography

Infrared thermography (IRT) is an effective mechanism to find significant asymmetry in temperature between both limbs by determining if the affected side of the body shows vasomotor differences in comparison to the other side. It is reported having a sensitivity of 93% and a specificity of 89%. This test is hard to obtain so it is not often used for diagnosing of CRPS.

Sweat Testing

Determining if the patient sweats abnormally. Q-sweat is an adequate instrument to measure sweat production. The sweat samples should be taken from both sides of the body at the same time.

Radiographic Testing

Irregularities in the bone structure of the affected side of the body can become visible with the use of X-rays. If the X-ray shows no sign of osteoporosis, CRPS can be excluded if the patient is an adult.

Three Phase Bone Scan

A triple phase bone scan is the best method to rule out Type I CPRS. With the use of technetium Tc 99m-labeled bisophosphonates an increase in bone metabolism can be shown. Higher uptake of the substance means increased bone metabolism and the body part could be affected. The triple-phase bone scan has the best sensitivity, NPV, and PPV compared to MRI and plain film radiographs.

Bone Densitometry

An affected limb often shows less bone mineral density and a change in the content of the bone mineral. During treatment of the CPRS the state of the bone mineral will improve. So this test can also be used to determine if the patient’s treatment is effective.

Magnetic Resonance Imaging (MRI)

MRIs are useful to detect periarticular marrow edema, soft tissue swelling and joint effusions. And in a later stage atrophy and fibrosis of periarticular structures can be detected. But these symptoms are not exclusively signs of CRPS.

Sympathetic Blocks

If the patient shows vasomotor or sudomotor dysfunction and severe pain, blocking the sympathetic nerves proves to be an effective technique to evaluate if the sympathetic nervous system is causing the pain to remain. This technique requires local anesthetic or ablation and is successful if at least 50% of the pain is reduced.

Outcome Measures

There are several methods to evaluate CRPS. Each symptom has another test to evaluate its severity. Below is a list of the different types of instruments with their evaluated symptoms.

Test	Evaluated items	References
Impairment sum score	Pain (VAS and McGill) Skin temperature Volume ROM
Grip Strength	Dynamometry Full fist grip, pinch grip
Foot function (Radboud skills test)	Movements of the foot
Walking stairs	Time, effort, need for assistance
Rising and sitting	Getting in and out of car, bed, toilet
Trend (trauma related neuronal dysfunction) symptom inventory	164 items in 10 subscales (sensory, trophic, autonomic, motor, visceral symptoms)
Neuropathic pain questionnaire	12 items (see figure below)
Brush allodynia	Brush evoked allodynia

There is also the CPRS Severity Score (CSS). It includes signs and symptoms that reflect the sensory, vasomotor, sudomotor/edema and motor/trophic disorders of CPRS.
This scoring list evaluates CRPS symptoms separately in order to develop a self-monitoring tool for patients. It is anticipated that this tool will help to facilitate disease management and improve dialogue between patients and their medical team.
Eight symptoms are evaluated at the baseline visit with self-reported ratings of worst pain in the affected area, disability, depression, and quality of life (SF-36).

Examination

The diagnosis is based on the clinical presentation described above. Procedures start with taking a detailed medical history, taking into account any initiating trauma and any history of sensory, autonomic, and motor disturbances, as well as how the symptoms developed, the time frame, distribution and characteristics of pain.. Assessment for any swelling, sweating, trophic and/or temperature increases, and motor abnormality in the disturbed area is important. Skin temperature differences may be helpful for diagnosis of CRPS. The original International Association for the Study of Pain criteria required only a history and subjective symptoms for a diagnosis of CRPS, but recent consensus guidelines have argued for the inclusion of objective findings.

The examination of the affected limb is from the neck downwards and should be carried out at rest, during activity, and during ambulation. Sensory, motor and autonomic dysfunctions are investigated.

Autonomic Dysfunction

The majority of patients with CRPS have bilateral differences in limb temperature and the skin temperature depends of the chronicity of the disease. In the acute stages, temperature increases are often concomitant with a white or reddish colouration of the skin and swelling. where the syndrome is chronic, the temperature will decrease and is associated with a bluish tint to the skin and atrophy.

Motor Dysfunction

Studies have shown that approximately 70% of the patients with CRPS show muscle weakness in the affected limb, exaggerated tendon reflexes or tremor, irregular myoclonic jerks, and dystonic muscle contractions. Muscle dysfunction often coincides with a loss of range of motion in the distal joints.

Sensory Dysfunction

The distal ends of the extremities require attention when examining a patient with CRPS. However, common findings of regional neuropathic and motor dysfunction have shown us that it is important to broaden the examination both proximally and contralaterally.

Light touch, pinprick, temperature and vibration sensation should be assessed for a complete picture of the CRPS. Most assessments are interlinked, for example, when vibration sensation is highly positive, light touch should also be positive.

To help distinguish the findings of a sensory dysfunction, bilateral comparisons are made. The results should be clear and reliable.

Medical Management

Treatment of complex regional pain syndrome should be immediate, and most importantly directed toward restoration of full function of the extremity. There are several options to treat CRPS.

Medical treatment options include;

• Oral pain-relieving medications including corticosteroids and NSAIDs, as well as acupuncture, provide effective pain relief in approximately 20% of those with CRPS, but this is supported by weak evidence.
• Treatments may be geared to helping patients manage symptoms. Amitriptyline relieves depression and acts as a sleeping aid. Calcium channel blockers can help to improve circulation through SNS effect. Intrathecal baclofen, among other measures, improves motor dystonia.
• Pain intensity and perception of pain is sometimes relieved through use of an implanted transcutaneous electrical nerve stimulation (TENS) unit. Electrical stimulation of the spinal cord can reduce pain intensity and improve health related quality of life. Spinal cord stimulation was more effective than conventional medical management in reducing pain in patients with CRPS type I. and was also shown to be effective in completely eliminating pain in adolescent females 2-6 weeks after stimulation.
• An excessive inflammatory reaction can lead to the overproduction of free radicals, resulting in the destruction of healthy tissue and possibly leading to CRPS. Free radical scavengers have, therefore, been proposed to curtail the disease process. To date, three free radical scavengers, like dimethyl sulfoxide (DMSO), have been investigated for the treatment of CRPS.
  A scorelist (based on pain, daily activities, edema, color, and ROM) showed greater improvement by dimethyl sulfoxide treatment. DMSO seems to provide a mild improvement in range of motion and vasomotor instability in patients with CRPS.
• Due to the inflammatory response seen in CRPS, steroids have been used and resulted in significant improvements in pain, oedema and a better post treatment score.
• Intravenous immunoglobulin can reduce pain in refractory CRPS.
• Hyperbaric oxygen therapy is an effective and well tolerated method for decreasing pain, allodynia, oedema, increasing the range of motion in CRPS and also returning the skin colour to a normal colour.
• There is no significant difference between the effectiveness of Dimethylsulfoxide 50% (DMSO) and N-acetylcysteine (NAC) in treating CRPS type I, but DMSO-treatment was more favourable for warm CRPS whereas NAC is more favourable for cold CRPS
• Low doses of ketamine infusion has been shown to decrease pain in patients with CRPS type I who had been unsuccessful with other conservative methods of management. Ketamine blocks central sensitization by effecting the N-methyl-D-aspartate receptor which has been shown to be effected in CRPS.

• Antidepressants may be utilised to treat associated depression.
• Use of surgical and chemical sympathectomy show moderate improvement in pain scores in patients with CRPS. There were no significant differences found between the surgical and chemical groups when comparing pain scores from day one to four months. More high quality research needs to be done before recommending this as a first line of defence.
• High frequency repetitive transcranial magnetic stimulation on the motor cortex in addition to pharmacological management was effective in reducing pain. This was demonstrated by the scores on the McGill Pain Questionnaire and Short Form-36 which include different aspects of pain such as sensory-discriminative and emotional-affective.
• Surgery, casts, and ice should be avoided when treating CRPS because they further aggravate the nervous system. Surgery leads to further stress, inflammation, and immune system disturbances.
• A stellate ganglion block, or sympathectomy, blocks the nerve pathways causing pain. This may be most beneficial in the early stages of CRPS.

Bone demineralisation is not unusual in CRPS patients, so treatment with calcitonin and biphosphonates is suitable. Calcitonin has received considerable interest in the management of CRPS because of its analgesic properties through release of ß-endorphin as well as its inhibition of bone resorption. Biphosphonates are potent inhibitors of bone resorption;

• Alendronate: less pain and swelling, more range of motion.
• Clodronate: less pain, improved global assessment and higher perceived efficacy (patient self evaluated).
• Palmidronate: less pain, higher overall improvement (patient self reported), and higher functional assessment scores.

Generally biphosphonates have been shown to decrease pain and swelling as well as to increase range of motion for patients with CRPS

Physical Therapy Management

It is difficult to manage CRPS as there is a lack of understanding of the pathophysiologic abnormalities, a lack of specific diagnostic criteria and very low-quality evidence to treat CRPS. The main goals of treatment are a reduction in pain, preservation of limb function and a return to work. Comorbidities such as depression, sleep disturbance, and anxiety also need to be addressed and treated concurrently in a patient-centred, multidisciplinary approach.

A combination of physical and occupational therapy is effective in reducing pain and increasing function in patients who have had CRPS for less than 1 year . Physical therapy focuses on patient education about the condition and functional activities. 

Physical therapy intervention could include any of the following:

• TENS
• Aquatic therapy allows activities to be performed with decreased weight bearing on the lower extremities.
• Mirror therapy
• Desensitisation
• Gradual weight bearing
• Stretching
• Fine motor control

It is important to recognise that CRPS typically follows blood vessel pathways, and therefore symptoms may not always follow neural patterns. As a result of the spread pattern, CRPS treatment should also be provided bilaterally, due to the contralateral connections present between the extremities. Treatment should be based on basic principles of pain management (pain and symptom relief, supportive care, rehabilitation) and due to the lack of evidence in treatment of CRPS treatments are based around that of other neuropathic pain syndromes.

Acute Phase

Immobilisation and contralateral therapy. Intensive active therapy in the acute phase can lead to deterioration.

Chronic Phase

Passive physical therapy including manipulation, manual therapy, massage and mobilisations. Lymphatic drainage can be used to facilitate regression of oedema. Tender areas are recommended to be treated in the following order: more severe before less severe, more proximal and medial before more distally and laterally located points and the area of greatest accumulation of tender areas is treated first. When tender areas are located in a row, the middle is treated first.

Therapeutic exercise includes isometric strengthening therapy followed by active isotonic training in combination with sensory desensitisation programmes. Strength training includes exercises for all four extremities and the trunk. Desensitisation programmes consist of giving stimuli of different fabrics, different pressures (light or deep), vibration, tapping, heat or cold. The exercises can be stress-loading (i.e. walking, carrying weights), endurance training and functional training. When CRPS occurs in the lower extremities, gait re-training is recommended.

Mirror therapy or mirror visual feedback
Mirror therapy is where both hands are placed into a box with a mirror separating the two compartments and, whilst moving both hands, the patient watches the reflection of the unaffected hand in the mirror

There is some evidence to suggest that mirror therapy has the effect of:

• Reducing pain intensity and improving function in post-stroke CRPS
• A significant improvement in pain
• Improving function (low-quality evidence, however)

Graded motor imagery/learning is effective. However, further trials are required GMI plus medical management is more effective than medical management plus physiotherapy GMI may reduce pain and improve function. Other therapies include relaxation, cognitive-behavioral therapy, deep breathing exercises and biofeedback.

Neuromodulation or Invasive Stimulation Techniques

Neuromodulation contains peripheral nerve stimulation with implanted electrodes, epidural spinal cord stimulation, deep brain stimulation and electrotherapy. Electrotherapy includes transcutaneous electric nerve stimulation TENS , spinal cord stimulation (SCS) and non-invasive brain stimulation (repetitive transcranial magnetic stimulation). These techniques help to reduce pain, although further trials are required

Other Treatments

• Whirlpool bath/ contrast baths
• Vocational and recreational rehabilitation
• Psychological therapies: cognitive-behavioural therapy (CBT), operant conditioning (OC), counselling, pain education and relaxation techniques
• Acupuncture, electroacupuncture
• Tactile sensory discrimination training
• Weight bearing
• Ultrasound therapy
• Kinesio taping

Clinical Guidelines

Complex regional pain syndrome in adults UK guidelines for diagnosis, referral and management in primary and secondary care. Royal College of Physicians, May 2012.

Complex regional pain syndrome: practical diagnostic and treatment guidelines, 4th edition. Pain Medicine. 2013, 14: 180-229

Case Reports

• More Than Meets the Eye: Clinical Reflection and Evidence-Based Practice in an Unusual Case of Adolescent Chronic Ankle Sprain
• Thoracic Spine Dysfunction in Upper Extremity Complex Regional Pain Syndrome Type I

Resources

• Reflex Sympathetic Dystrophy Syndrome Association 
• American Chronic Pain Association
• Mayo Clinic
• National Institute of Neurological Disorders and Stroke

Clinical Bottom Line

CRPS is a term for a variety of clinical conditions characterised by chronic persistent pain. There are two types of CRPS and the difference between Types I and II is based on a consensus between clinicians and scientists. All symptoms of CRPS Type II show many similarities to those of CRPS I. It is difficult to manage CRPS as there is a lack of understanding of the pathophysiologic abnormalities and lack of specific diagnostic criteria along with very low-quality evidence to treat CRPS. Clinical studies demonstrate a significant improvement following physical therapy, but there need to be more trials to develop an optimal management programme.