Australasian Anaesthesia 2011 - Australian and New Zealand ...

2 Australasian Anaesthesia 2011 Complex regional pain syndrome (CRPS), a brief review 3CLINICAL COURSEThe clinical course is variable and unpredictable. Most patients present with pain which is regional and spreadingto adjacent regions – e.g. pain affecting all of a hand spreading at times proximally to the forearm, or pain affectingthe knee and spreading towards the ankle. With time the pain may spread further. The pain is present bothspontaneously and in response to provocations such as using the limb, changes in temperature, and stress andanger. Often the pain is worse at night; significant disturbance of sleep is common. Swelling may be mild or extreme;commonly it fluctuates, again this can be both spontaneous or in response to the provocations which cause pain.In the early stage of CRPS the affected part may be warm, red and sweaty; later it is likely to be blue and cold;however some patients do not experience the warm phase; and others initially fluctuate between the two with coldmanifestations prevailing later. Swelling is usually more marked in the early stage. Variable motor manifestationsoccur – stiffness, weakness, tremor and impaired co-ordination; their severity tends to mirror the course of thedisease. Increased growth of hair and of the nails may be seen.In some patients – perhaps many patients – spontaneous resolution occurs; in a very small proportion there isan apparently inexorable progression to severe dystrophy with a wasted shiny cold and contractured limb; manypatients endure a persisting fairly stable condition of moderate pain, swelling and stiffness.PATHOPHYSIOLOGYThe pathophysiology of both the onset and the maintenance of CRPS have not been defined; it may be that theclinical entity, with its variable manifestations, is in fact the outcome of more than one pathophysiology. Amongstthe intriguing pieces of evidence are the following. Multiple groups have reported increased amounts of proinflammatorycytokines (tumour necrosis factor alpha (TNF-alpha), interleukin-1beta and interleukin-6 ) and of neuropeptides(substance P, calcitonin gene-related peptide (CGRP)) in tissue fluid from affected regions, or in plasma, or in CSF.Abnormal or excessively sustained release of these agents after tissue damage might lead to CRPS. These cytokinesand neuropeptides can cause pain, swelling, vasodilatation, sweating, increased hair growth and osteoclasticactivity – all phenomena seen in CRPS. Even in CRPS in which there is not injury to a major peripheral nerve, i.e.CRPS-I, reduced density of C-fibres and Adelta-fibres has been reported by more than one research group. In thepast it was considered that excessive activity of the sympathetic nervous system (SNS) was contributory: howeverevidence suggests that, in the affected region at least, there is reduced SNS outflow; however there may besympatho-afferent coupling, i.e. increased expression of adrenergic receptors on nociceptors and their afferentfibres and at their cell bodies in the dorsal root ganglia (as is known to occur after nerve injury) so that the regionis more sensitive to catecholamines despite reduced SNS activity. There appears to be a lack of data, in humansat least, whether central sensitisation occurs at the spinal cord. However there is evidence from multiple groups ofaltered neural processing in the brain (see below – graded motor imagery).PREVENTIONA high quality study of 416 patients in a double-blind prospective multicenter trial by Zollinger et al. 2 found thatvitamin C in a dose of 500 mg or more per day reduced the prevalence of CRPS after wrist fracture from around10% to less than 2%. Treatment was continued for 50 days. It has been speculated that the efficacy of vitamin Cwas due to its anti-oxidant activity.There is no robust evidence to guide, but expert opinion has recommended that patients with a history of CRPSshould avoid surgery on the affected part; if surgery is being undertaken, whether on the affected limb or otherbody extremity, regional blockade might be preventative. The role of perioperative steroids or of ketamine is unclear;in my opinion, their potential benefit would be expected to outweigh potential harm.TREATMENTThere is a dearth of quality evidence regarding treatment of CRPS; where RCTs have been performed the studieshave tended to be small and/ or to be awaiting replication by other researchers. The lack of trials is perhaps dueto the variability of clinical presentations, the need for multiple modalities of treatment, the variability in responseto treatment with some patients seeming to improve spontaneously and others not improving regardless of an arrayof treatments. Thus clinicians must turn to guidelines drawn from a consensus of experts.Allied HealthAs summarised succinctly by the Dutch clinician guidelines in 2006 1 “The key to recovery seems to be in properlyadjusted movement and in learning to reintegrate the affected limb to everyday activity.” Thus physiotherapists andoccupational therapists have the key roles in managing CRPS. In the majority of cases standard treatment, judiciouslymodified and often protracted, suffices. Experience and judgement is required because activity of the affected partcan both mitigate and aggravate CRPS: the challenge is to achieve sufficient use to turn off the CRPS process butnot so much as to cause a flare of CRPS activity. Some patients have moderate or severe CRPS from early on, orfail to respond to lengthy treatment: these patients require additional medical input but always the principle is forthe medical treatment to be facilitating activity of the affected part as this seems to be the key to reversingthe CRPS.In addition to physical and medical measures, psychological support is often appropriate, to assist patients toadjust to live with a significantly painful condition, and to develop strategies and implement behavioural changesto optimise their situation. Many patients will have been let down badly by their medical experience: they will havehad surgery or other treatment which has failed, and often their complaints of pain will have been met with scepticism.Medical treatmentsAmongst medications with RCTs to support their use are: steroids, free-radical scavengers (dimethyl sulfoxidecream, N-acetyl cysteine), biphosphonates. Evidence for calcitonin has been mixed. Agents used for neuropathicpain – opioids, gabapentinoids, and antidepressants blocking re-uptake of noradrenaline (amitriptyline, venlafaxine,duloxetine) - have been used for CRPS. Recently infusions of ketamine have become quite widely used. The infusionis often at doses causing actual or potential sedation; hence patients must be hospitalised; there is uncertaintyregarding optimal dose, duration, and frequency of treatments.SYMPATHETIC BLOCKSympathetic blockade (stellate ganglion block and lumbar sympathetic block) has been used extensively. Therecontinues to be a lack of evidence to support its use: the most recent Cochrane review could find only one RCTof adequate quality and that was for permanent sympathectomy. However sympathetic block continues to berecommended in consensus guidelines. It is unclear whether permanent sympathectomy (i.e. ablation of the relevantganglia) is better than repeated temporary blockade by local anaesthetic; if the latter is undertaken there is uncertaintyregarding the optimal interval between blocks and the optimal duration of treatment. Long-lasting ablation can beachieved surgically or by percutaneous delivery of heat or neurotoxic chemical. Intravenous regional guanethidine(Bier’s block) has been demonstrated not to be effective and it seems to be little used these days. Epidural blockwill provide both sympathetic and somatic block; whether somatic block is advantageous is unclear; generallyepidural treatment will require hospitalisation; duration of the infusion will be limited by apprehension regardinginfection.Due to the severe pain and impaired function of this condition, major interventions are sometimes undertaken.Usually they are reserved for the most severe cases. Their cost, the required expertise, and need for ongoingsupervision have tended to limit their use to compensable patients or well-resourced public clinics. There has beena small RCT supporting the use of spinal cord stimulators (SCS) which showed a modest decrease in pain intensity,a modest improvement in quality of life but no change in function (Kemmler 2000) 3 . The hardware for a spinal cordstimulator plus one one lead costs approximately $25,000; in the past the implanted stimulator had to be replacedwhen the battery was exhausted after several years, a recurring cost of about $18,000. Intrathecal pumps infusingan opioid and sometimes other agents such as clonidine or baclofen are occasionally used; their use tends to belimited to the lower limb because treatment of the upper limb necessitates higher positioning of the intrathecalcatheter or higher infusion rates or both and thus side-effects are more problematic. Such pumps necessitateongoing involvement with the patient to provide refills of the pump and monitor for complications of the intrathecaldevice and intrathecal medications, e.g. granulomas causing neurologic compromise and hormonal suppressionsecondary to chronic opioid use.The past decade has seen the introduction of graded motor imagery (GMI). This technique was originallyinvestigated for use to relieve phantom limb pain. It uses techniques which retrain neural circuits in the brain.Research by an Australian physiotherapist, Lorimer Moseley, has demonstrated that three components of retrainingshould be undertaken and that the order in which patients perform them is important. In the first phase patientspractise ‘lateral recognition’ which requires them to distinguish whether a limb (hand or foot) is left or right whenimages are rapidly presented for a number of minutes, using flash cards or electronic means. Patients with CRPShave impeded recognition of the affected side – manifested by a time lag or higher rate of inaccuracy or both.Improvement requires frequent and sustained practice. Once lateral recognition approaches normality, the patientis encouraged to undertake phase two, ‘imagined movements’ in which movements of the affected part is imagined.When the patient is able do imagined movements without causing aggravation of the CRPS – pain and swellingtheyprogress to phase three ‘mirror movements’ in which the patient observes movements of the contralaterallimb in a mirror so that it is perceived by their brain to be movements of the affected limb. Remarkably this processof neural retraining directed at brain circuitry can reduce or turn off the manifestations of CRPS in the periphery.Further evidence of the role of brain neural processing has been the fascinating observation that CRPS is associatedwith changes in the somatotopic representation of the affected limb: representation shrinks and shifts to a moreproximal part of the cortical somatotopic map. For example if the hand is affected, its representation becomessmaller and is located closer to the shoulder and the face, and thus tactile stimulation of the hand may be perceivedin the shoulder or the face or both. These changes reverse when treatment is successful – a stunning exampleof neuroplasticity.SUMMARYCRPS remains an enigmatic disease. Its pathophysiology is unclear but there is increasing acceptance of the rolesof: firstly an interaction between peripheral nerves, peripheral neuropeptides and cytokines; and secondly reversiblechanges in brain neural patterns. CRPS is particularly likely after injury to the distal upper or lower limb but thereappears to be a high rate of natural resolution. In those with severe or persistent symptoms, CRPS is disabling andoften very distressing. The key to turning off CRPS is believed to be actual or simulated use of the limb; the primaryobjective of medical treatments should be to facilitate function. CRPS has a range of medical treatments includingneuropathic medications and various procedures; the evidence for most treatments of CRPS is weak. Howeverthere is strong evidence for the prophylactic use of vitamin C to prevent CRPS after wrist fractures.There are a number of recent very good reviews available for further reading. 4,5,6