Complex regional pain syndrome JG Wilson FCARCSI MG Serpell FRCA

Key points The first description of the painful condition now known as complex regional pain syndrome (CRPS) was published over 140 years ago by Silas Weir Mitchell and colleagues in their paper entitled Gunshot wounds and other injuries of nerves. The description concerned traumatic injuries to major peripheral nerves seen during the American Civil War. The original term ‘reflex sympathetic dystrophy’ described the over activity of the sympathetic nervous system that is sometimes seen in this syndrome; causalgia referred to the ‘burning’ pain often experienced after nerve injury. Following this description, there have been numerous attempts to further describe and define the clinical features.

Definition In 1993, a consensus conference revised and standardized the nomenclature and recommended the use of the term ‘complex regional pain syndrome’. There are two types of the syndrome: CRPS I—symptoms preceded by tissue injury, most commonly limb trauma (absence of nerve injury); and CRPS II—following known major peripheral nerve injury. Both types can be further sub-divided using a diagnostic sympatholytic block into: sympathetically maintained pain (SMP); or sympathetically independent pain (SIP). The syndrome has a wide spectrum of features, and cases can have a large variation in pain severity, ranging from a mild disorder to one which is very disabling. Examples of the causes of CRPS are listed in Table 1.

Pathogenesis The exact pathogenesis of CRPS is unclear. Theories can be divided into peripheral and central mechanisms, with central nervous system abnormality predominating. In CRPS II, the peripheral nervous system is thought to react after a partial nerve injury. The injured and uninjured axons begin to up-regulate functional a2-adrenoceptors which render them sensitive to both systemic catecholamines and

norepinephrine released from postganglionic sympathetic terminals. This occurs in the resting and active C-polymodal nociceptors. Nociceptor activity may be triggered by norepinephrinemediated release of prostaglandins from sympathetic postganglionic neurons. The mechanism involved in the initiation of some of the trophic changes is thought to be denervation hypersensitivity. In the acute phase of CRPS, neurogenic inflammation and inflammatory reactions occur. These may result from the increased levels of cytokines. The peripheral mechanism leads to central hyperexcitability and sensitization, and it is this central mechanism that seems to be predominately responsible for the symptoms of CRPS. Nerve injury induces sprouting of ipsilateral sympathetic axons around the dorsal root ganglia of the central nervous system, and this may constitute a mechanism in which sympathetic activity initiates activity in sensory fibres. Other mechanisms possibly involved include the release of glutamate in the spinal cord and N-methyl-D-aspartate (NMDA) receptormediated hyperexcitability.

Diagnostic criteria for complex regional pain syndrome (CRPS) should use four separate categories for the features of sensory, vasomotor, sudomotor, and motor/trophic changes. CRPS can involve sympathetically mediated pain or sympathetically independent pain. Management should be multidisciplinary and instituted immediately following diagnosis. Early sympathetic blocks and vitamin C may prevent the development of CRPS. Few studies of sufficient quality are available; however, same evidence supports treatment with steroids and bisphosphonates.

Clinical presentation Signs and symptoms may begin at the time of injury or may be delayed for weeks. Sometimes, a traumatic event cannot be identified. CRPS is manifested by a triad of: † Pain (can be excruciating accompanied by hyperalgesia) † Trophic changes (Fig. 1) † Vasomotor disturbances

and

Sensory changes Typically, the pain is described as continuous burning, shooting, aching, or prickly in nature and is localized deep in the somatic tissues. All patients suffer from hyperalgesia to mechanical stimuli or on joint movement. At least one-third suffer from severe allodynia, which implies central nociceptive sensitization. Patients can have

doi:10.1093/bjaceaccp/mkm001 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 7 Number 2 2007 & The Board of Management and Trustees of the British Journal of Anaesthesia [2007]. All rights reserved. For Permissions, please email: [email protected]

JG Wilson FCARCSI Specialist Registrar Fellow in Pain Management Pain Clinic, Gartnavel General Hospital 1053 Great Western Road Glasgow G12 0YN UK MG Serpell FRCA Consultant Anaesthetist and Senior Lecturer Pain Clinic, Gartnavel General Hospital 1053 Great Western Road, Glasgow G12 0YN UK Tel: þ440141 211 3288 Fax: þ440141 211 3466 E-mail: [email protected] (for correspondence)

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Complex regional pain syndrome

Table 1 Examples of causes of CRPS

Motor changes

Trauma Accidental

A variety of factors can contribute to altered motor function in patients with CRPS. The limb can become weak and may also demonstrate coordination deficits. In severe cases, it can become virtually useless, due to misuse and disuse, secondary to bracing and trophic changes. Effects on tendons and muscles lead to contractures. It is also possible for involuntary movements to develop, for example dystonia, tremor.

Surgical Occupational Diseases Visceral Neurological Vascular

Sprains, minor cuts, contusions, dislocations, fractures, crush injuries, traumatic amputation, burns Tight plaster casts Tissue or nerve damage from any procedure Repetitive strain injury, for example pneumatic tools, typing Myocardial infarction Cerebrovascular accident resulting in posthemiplegic dystrophy Nerve damage by tumour invasion General angiopathies, frostbite, thrombosis

Diagnostic criteria a sensory deficit which is often non-dermatomal and can progress proximally. Temperature and proprioception deficits are usually the first to appear. Clinical neurological assessment can be carried out at the bedside (pin prick, cotton wool, joint position, tuning fork, hot and cold roller) or objectively with quantitative sensory testing (mechanical and thermal detection and pain thresholds). Sensory deficits are more common in CRPS II because of the nerve lesion.

Autonomic changes The autonomic system can induce vasomotor and sudomotor changes. Vasomotor effects include changes in colour (vasodilation—red, vasoconstriction—cyanosed or white) and temperature (hot or cold). The sudomotor signs include hyper/hypohydrosis and oedema. All of these changes can be induced or spontaneous.

Trophic changes In the advanced stages of the syndrome, there may be atrophy of the skin, hair, and nails. Demineralization of the bone resulting in osteoporosis may also occur.

The International Association for the Study of Pain proposed formal diagnostic criteria in 1995:1 CRPS I † Follows an initiating noxious event. † Spontaneous pain or allodynia/hyperalgesia occurs beyond the territory of a single peripheral nerve and is disproportionate to the inciting event. † There is or has been evidence of oedema, skin blood flow abnormality, or abnormal sudomotor activity in the region of the pain since the inciting event. † The diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction. CRPS II † Is similar in all respects to CRPS I except there is actual nerve injury. Unfortunately, as only one component has to be present from each of the four criteria, the diagnostic method lacks specificity resulting in over diagnosis. Modified diagnostic criteria were proposed in 1999; these include motor features,2 thus enhancing diagnostic power and therefore distinguishing CRPS from neuropathies that are purely sensory. In addition, a modified diagnostic algorithm has recently been proposed (Table 2). Diagnosis is based on the whole clinical picture. A number of investigations can be used to aid diagnosis by demonstrating altered blood flow or changes in sweating or bone mineralization. These include X-ray, MRI, radionuclide bone studies, vascular studies, and electrodiagnostic techniques. Research tools include microneurography, quantitive sudomotor axon reflex testing, and the resting sweat output.

Prevention and early treatment Fig. 1 The patient has trophic changes of the left arm, which displays oedema of the hand and thin glossy skin. Reproduced from Varma TRK. Neurosurgical techniques in the treatment of chronic pain. Anaesth. Intens. Care Med 2002; 3(1) (with kind permission from The Medicine Publishing Company).

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An overview of treatment options for various treatment objectives is listed in Table 3. Preventing the development of CRPS is the primary objective; this may be achieved by a number of management approaches, including physical therapies and good pain control.

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Complex regional pain syndrome

Table 2 Revised diagnostic criteria of CRPS3

Although there is some evidence for the efficacy of the treatments, their place in routine clinical practice is uncertain.

Clinical signs/symptoms grouped in four domains Positive sensory abnormalities Spontaneous pain Mechanical hyperalgesia Thermal hyperalgesia Deep somatic hyperalgesia Vascular abnormalities Vasodilatation Vasoconstriction Skin temperature abnormalities Skin colour changes Oedema, sweating abnormalities Swelling Hyperhydrosis Hypohydrosis Motor, trophic changes Motor weakness Tremor Dystonia Coordination deficits Hair, nail changes Skin atrophy Joint stiffness Soft tissue

Treatment of established CRPS The mainstay of treatment is a multidisciplinary approach.

Physical therapies A graduated exercise programme is essential. It should be goaldirected and should not aggravate the pain. Physiotherapy should be instituted early, in order to treat secondary complications such as decreased joint and tendon movement and subsequent atrophy. The intensity of treatment should be modified to the severity of the disease. Occupational therapy also plays a role in the functional restoration of the limb.

Pharmacological agents

Interpretation For clinical use 3 symptoms of each category and 2 signs of each category; Sensitivity 0.85; Specificity 0.60 For research use Four symptoms of each category and 2 signs of each category; Sensitivity 0.70; Specificity 0.96

Two controlled studies have shown that stellate ganglion blockade or vitamin C (oxygen-free radical antagonist) may help to prevent the onset of CRPS in some patients.4 Several randomized controlled trials have shown that 100– 400 IU of intranasal calcitonin (inhibits bone resorption by osteoclasts) can be useful in early CRPS (i.e. less than 6–8 weeks).5 I.V. bisphosphonates can also be used in early CRPS, clodronate 300 mg daily and alendronate 7.5 mg daily i.v. has improved function and symptoms.6 The mode of action of calcitonin and bisphosphonates is unknown, as osteoporosis is generally of late onset in CRPS.

Table 3 Treatment objectives of, and therapeutic options for CRPS

Sympathetic nerve blockade

Category

Treatment objective

Therapeutic options

Sensory

Pain

Vasomotor

Sympathetic activity (colour and temperature changes) Inflammation and oedema Motor dysfunction

Neuropathic drugs, WHO analgesic ladder drugs, TENS, acupuncture, psychology Sympathetic blockade

Sudomotor Motor/trophic

Osteoporosis

In 1997, Kingery7 reviewed the controlled clinical trials for CRPS and peripheral neuropathic pain. Until recent improvements, the uncertainty in diagnosis has been a major obstacle in performing clinical trials. In addition, he found the CRPS trials were of small size, and unlikely to be double-blinded, placebo-controlled, and statistically valid. The strongest evidence-base (controlled clinical trials) supports the use of oxygen radical scavengers (dimethylsulphoxide and N-acetylcysteine), gabapentin, corticosteroids, and calcium modulating drugs in established CRPS. Oral prednisolone 10 mg three times daily has been shown to improve the clinical status of some CRPS patients.8 There is logical justification for using non-steroidal antiinflammatory drugs (NSAIDs), as many of the symptoms of CRPS resemble inflammation. It has been suggested that NSAIDs may offer protection against the development of CRPS by reducing the secondary damage resulting from post-trauma inflammation. Substantial anecdotal evidence exists for the effectiveness of several drugs in the treatment of chronic CRPS, including tricyclic antidepressants, anticonvulsants, topical lidoderm, mexiletine, NMDA-receptor blockers, and capsaicin cream. Opioids can also be used in refractory cases. There is evidence for the lack of benefit of droperidol and atropine.

Steroids and anti-inflammatory drugs Physiotherapy and occupational therapy Sodium clodronate

Sympathetic blocks are particularly useful in the early stages of CRPS, to differentiate between SMP and SIP, but also to allow graduated exercise. Local anaesthetic blockade is carried out at the sympathetic paravertebral ganglion, which innervates the site of the CRPS, for example the stellate ganglion or lumbar sympathetic chain for upper and lower limbs, respectively. Pain relief from these blocks generally lasts longer than the duration of action of the local anaesthetic. Intravenous regional analgesia (IVRA) using agents such as lidocaine, clonidine, guanethidine, reserpine, and bretylium have

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all been described. Randomized controlled trials have shown that IVRA is no better than placebo; however, despite this, they continue to be commonly used. SMP can be treated using surgical sympathectomy; radiofrequency techniques have also been described recently. An important problem with permanent sympathectomy techniques is the recurrence of symptoms and neuralgia 6 months to 2 years following the procedure. The techniques work better if performed within 12 months of the original injury.

Transcutaneous electrical nerve stimulation Different studies show varying success rates for the use of transcutaneous electrical nerve stimulation (TENS). This is a non-invasive, simple, and safe technique; therefore, it is always worth considering as an adjunct.

Neuromodulation Neuromodulation can involve spinal cord or peripheral nerve stimulation. Spinal cord stimulation affects sensory dorsal nerve roots as well as the descending inhibitory pain pathways within the spinal cord. It may also induce the endogenous release of opioids. A clinical trial showed that it has a modest effect on pain at 6 months when combined with physical therapy but did not affect quality of life or function.9 However, it may be of use in carefully selected patients and the technique is employed in several centres.

Acupuncture Although used widely, there is little evidence of efficacy in the long term. Two studies comparing acupuncture with placebo have failed to show a significant effect.10

Psychotherapy Psychotherapy is very important in the multidisciplinary approach to this syndrome. Pain affects mood and vice versa; therefore, most patients with CRPS will benefit from psychological evaluation. Psychotherapy educates the patient about chronic pain. Using cognitive behavioural therapy, the emotional and physical aspects are explored and a management plan initiated.

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Amputation Amputation should be considered when there is uncontrolled infection or ischaemia. Amputation for pain relief is often unsuccessful; the majority of patients develop phantom limb pain.

References 1. Stanton-Hicks M, Ja¨nig W, Hassenbusch S, et al. Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain 1995; 63: 127–33 2. Harden RN, Bruehl S, Galer B, et al. Complex regional pain syndrome: are the IASP diagnostic criteria valid and sufficiently comprehensive? Pain 1999; 83: 211 –19 3. Baron R. Classification and diagnostic tools in complex regional pain syndrome. Newsletter of the IASP Special Interest Group on Neuropathic Pain 2006; 7: 3– 7 4. Bogduk N. Complex regional pain syndrome. Curr. Opin. Anaesthesiol. 2001; 14: 541– 46 5. Gobelet C, Waldburger M, Meier JL. The effect of adding calcitonin to physical treatment on reflex sympathetic dystrophy. Pain 1992; 48: 171–75 6. Adami S, Fossaluzza V, Gatti D, Fracassi E, Braga V. Bisphosphonate therapy of reflex sympathetic dystrophy syndrome. Ann Rheum Dis 1997; 56: 201– 04 7. Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndrome. Pain 1997; 73: 123– 39 8. Christensen K, Jensen EM, Noer I. The reflex dystrophy syndrome response to treatment with systemic corticosteroids. Acta Chir Scand 1982; 148: 653–55 9. Kemler MA, Barendse GA, van Kleef M, et al. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med 2000; 343: 618 –24 10. Kho H. The impact of acupuncture on pain in patients with reflex sympathetic dystrophy. Pain Clin 1995; 8: 59– 61

Further reading Sandroni P, Dotson R, Low PA. Complex regional pain syndromes. In: Jensen T, Wilson P, Rice A (eds). Clinical Pain Management—Chronic Pain. Arnold, London, 2003; 383–401 Wilson P, Stanton-Hicks M, Harden RN. CRPS: Current Diagnosis and Therapy. IASP Press, 2005 Baron R, Binder A, Ludwig J, Schattschneider J, Wasner GL. Diagnostic tools and evidence-based treatment of complex regional pain syndrome. Pain. An Updated Review, Refresher Course Syllabus. IASP Press, 2005; 293– 306

Please see multiple choice questions 18 –22

Continuing Education in Anaesthesia, Critical Care & Pain j Volume 7 Number 2 2007