There is little evidence to guide therapy because of the difficulties in studying specific interventions in complex regional pain syndrome.1-3,11 These difficulties include the need for multidisciplinary treatments, limited numbers of patients, differing diagnostic criteria, the varying nature and duration of the clinical manifestations, and knowing whether recovery is due to treatment or spontaneous remission.
Treatments are often based on expert opinion and what works in other neuropathic pain conditions. It is difficult to prepare guidelines1,11 or advice12 for treatment because of the limited number of trials. One approach is a mixture of several drugs and other interventions according to the symptomatology and comorbidities present. Having an agreed treatment plan can help with management.
Physical therapy
Physiotherapists and occupational therapists have a key role. Standard treatment includes desensitisation, contrast baths (ice-cold vs hot-warm water immersion), hydrotherapy, graded exercise/strengthening, gradual increase in weight loading of the limb (by using weights, or pushing down on a set of bathroom scales), sensory re-education/exposure therapy (placing limb in sand, use of tactile gloves and texture boxes) and oedema control (compressive garments).1 The patient must move, exercise and reintegrate the limb into normal everyday activity.11
Graded motor imagery has evidence supporting its use.6,8 This involves phased ‘brain retraining’ with left–right (laterality) discrimination training (photographs and mobile apps to identify limb side, improving accuracy and speed of response), proceeding to imagined and then mirrored movements.7,13-16 Transcutaneous electrical stimulation has been used but without an evidence base to support it.
Psychological therapy
Psychological sequelae, including depression, anxiety, fear of movement and fear of harm/re-injury, are common due to ongoing pain, physical, emotional and social losses.16-19 Patient education about the pathophysiology, the negative effects of disuse and the reasons for resuming function, and the interplay of psychological and behavioural factors are important as for any chronic pain condition.18 Physical therapists with experience in complex regional pain syndrome routinely use psychological strategies and psychoeducation incorporated with the physical intervention. If the patient fails to make progress (acute phase) or once the condition becomes chronic, a formal psychological assessment should be offered. Then, specific therapies can be considered and tailored for the patient as part of a ‘whole person’ approach.1,20 These include learning, mindfulness and relaxation techniques, the adoption of active rather than passive coping strategies, cognitive behavioural therapy and, recently, acceptance and commitment therapy. Cognitive behavioural therapy (six sessions) in children has been added to outpatient physiotherapy, with positive effect.1
The psychological interventions attempt to address any external factors or incentives that can positively or negatively influence the patient’s problems. For example, claims for compensation may add to the patient’s stress.
Drug therapy
In addition to the lack of evidence for most treatments, few drugs have an indication for complex regional pain syndrome. The lack of subsidy by the Pharmaceutical Benefits Scheme (PBS) can result in significant out-of-pocket expenses for the patients.
The Table includes analgesics typically used in the community as first- to fourth-line therapies. Simple analgesia is used to address pain and stiffness to facilitate movement during exercise and to limit the use of opioids. Paracetamol has no specific evidence in complex regional pain syndrome, but is used.1 NSAIDs, including COX-2 inhibitors, are used, particularly when oedema is present, alone1 or added to paracetamol. Typically, opioids or tramadol have been started for acute pain management after the initial injury. Tramadol’s efficacy is via noradrenaline and serotonin reuptake inhibition (parent compound) and opioid effects (metabolite). The former mechanism results in antineuropathic as well as somatic benefits. Tramadol is used second- to third-line, in some countries, in preference to opioids. The ongoing use of opioids when complex regional pain syndrome is suspected or formally diagnosed is controversial. Generally, if the use of an opioid assists physical gains or compliance with therapy, then continued use is acceptable as third- or fourth-line therapy.

Corticosteroids can be considered in the early inflammatory phase.1,21 The optimal time for starting these and the duration of treatment is uncertain. A prednisolone dose of 30 mg/day can be gradually tapered off, but there is no evidence for any regimen.
As there is some evidence for vitamin C in prevention, it has been used as treatment early in the syndrome. However, there is no evidence to support this practice.
Patients may be prescribed an antidepressant often in combination with an antiepileptic drug, usually one of the gabapentinoids: gabapentin or pregabalin (Table). For sleep disturbance, tricyclic antidepressants are favoured. Giving a higher dose of gabapentin or pregabalin at night can also be tried.
Gabapentin is not subsidised by the PBS for this indication. Although it is more expensive, pregabalin is subsidised if other therapies for neuropathic pain have failed. A head-to-head trial of gabapentin and pregabalin in neuropathic pain has not been done. Their adverse effect profiles are similar (dizziness, altered concentration, sedation). Pregabalin has twice-daily dosing, while gabapentin is given three times a day.
When tricyclic antidepressants or gabapentinoids are poorly tolerated, rotation within the same drug class can be considered (e.g. amitriptyline to nortriptyline, or gabapentin to pregabalin) or to alternative antidepressants or antiepileptics, but there is no reported experience with these strategies (Table). If the patient has severe anxiety or depression and cannot tolerate tricyclics in antidepressant doses, or if their pain or mood is not improving, then alternative antidepressant drugs such as duloxetine can be considered. However, the evidence to support their use for complex regional pain syndrome is lacking. The dose of tricyclics used in complex regional pain syndrome is frequently too low to be effective for treating coexisting depression. Serotonin syndrome is a risk if doses of antidepressants are being escalated and the patient is also taking moderate to maximal doses of tramadol.
Antiepileptic drugs have been used with varying levels of supporting evidence (Table). The off-label use of newer antiepileptic drugs, such as topiramate, for complex regional pain syndrome is expensive.
Specialist interventions
If the patient fails to improve on optimised therapy, then the pain specialist will consider other interventions. Clonidine has low-grade evidence of effectiveness, but is cheap and is often used in Australia. Dimethyl sulfoxide cream has some evidence to support its use, but it is an organic solvent that can irritate the skin. It is available depending on the capacity of local hospital and community pharmacies. Other gels and creams are available but have limited or no supporting evidence. These are often anecdotally effective for patients unable to tolerate oral drugs. They include single or combination drugs such as topical NSAIDs (available over the counter), local anaesthetics, ketamine (e.g. 2.5–5%) or clonidine (e.g. 0.01%) and amitriptyline/nortriptyline (e.g. 2%) gels. Capsaicin may be tried, but it is messy and painful and therefore invariably unpopular with patients. Patches of local anaesthetic, clonidine or capsaicin have also been used but are not always available.
Various regimens of ketamine and lignocaine infusions have become widely used, but patients need to be hospitalised and there is uncertainty regarding the optimal dose, duration and frequency of these treatments.
Calcitonin and bisphosphonates can reduce bone resorption and may have other actions. There is evidence to support their use in complex regional pain syndrome.1
Invasive interventions
Sympathetic blockade (stellate ganglion block and lumbar sympathetic block) has been used extensively despite limited supporting evidence. The blocks are offered generally for the hot florid phase and for the blue cold phase, if there is prominent oedema. It is also unclear whether permanent sympathectomy is better than repeated temporary local anaesthetic blocks. Epidural block (providing sympathetic and somatic block) is sometimes used for inpatient treatment.
Implantable pumps (for lower limb) and stimulators (for lower or upper limb) have been used in severe or resistant complex regional pain syndrome. They require a rigorous selection process, significant expertise to insert, adjustment and ongoing supervision. The evidence to support these interventions is limited and they need further evaluation. The same is true for the experimental use of anti-inflammatories and immunomodulators in complex regional pain syndrome. Infliximab, intravenous immunoglobulin and thalidomide have been tried in very small case series.