Complex Regional Pain Syndrome Treatment

Complex regional pain syndrome treatment which is the best approach?

Complex regional pain syndrome (CRPS) is a debilitating, painful condition in a limb, associated with sensory, motor, autonomic, skin and bone abnormalities. CRPS commonly arises after injury to that limb, despite there is no relationship to the severity of trauma.1

Limb signs includes swelling/sweating and colour/temperature changes and could reduce with time, even though pain and motor symptoms persist.

Prompt diagnosis and early Complex Regional Pain Syndrome Treatment are assumed to be the best practice in order to avoid both additional physical problems and psychological consequences related to chronic pain.

Moreover, a multimodal and multidisciplinary approach is currently recognized to be the most efficient management strategy for CRPS.

Complex Regional Pain Syndrome Treatment approach

The 4 essential pillars of CRPS management are showed below

All these points have the same relevance and only through an integrated multidisciplinary approach (by expert physicians and healthcare professionals), it is possible to obtain the best result in terms of CRPS relief. As treatment strategy, the first choice is oriented to physiotherapy which must be supported by drug therapy.

The faster the treatment is started, the lower the risk of disability is.

In particular, the objectives of pharmacotherapy are:

  • to reduce pain and fluid retention (oedema)
  • to “protect” the bone tissue and assist the work of the physiotherapist
  • to increase joint mobility and restore the use of the affected limb.

In this article, we are going to focus on drug therapy and on physiotherapy.

Complex Regional Pain Syndrome

pharmacological Treatment

Pharmacological interventions for CRPS seem to be effective when applied early in the disease as they act on peripheral mechanisms.

Different drugs could be used for CRPS treatment. Anyway, the pharmacological class that demonstrated a good efficacy evidence is represented by bisphosphonates, thanks to their ability to act positively on bone marrow oedema and to attenuate the painful symptoms.

Neridronate (administered intravenously) is a bisphosphonate and it is the only treatment with the therapeutic indication for CRPS.

In particular, it has been approved by a national regulatory agency (Italian Medicines Agency, AIFA). So far, international regulatory agencies (i.e. FDA or EMA) have not approved molecules for CRPS treatment.

Neridronate showed to be effective in improving pain, physical function and oedema in patients with CRPS, with short- and long-term benefits.

  • The clinical trial conducted by Professor Varenna M. and colleagues showed that four i.v. infusions of neridronate 100mg are associated with clinically relevant and persistent benefits in CRPS patients.5
  • At the end of the study, 73% of patients treated with neridronate demonstrated a pain level decrease of 50% or greater when compared with patients receiving placebo.
  • A year later none of the patients was referring symptoms linked to


  • 100% of patients who used painkillers at the beginning of the study, discontinued this therapy.

Therefore, the recommended therapeutic strategy includes:

  • CRPS treatment with physiotherapy together with neridronate therapy
  • additional prescription of anti-inflammatories and/or analgesics to reduce inflammation (i.e. non-steroidal anti-inflammatory drugs – NSAIDs – and steroids), contain pain and assist physiotherapy with the aim of improving quality of life.2 

Other possible drug therapy options

  • Tramadol and opioids in CRPS: the use has not been tested in clinical studies.

Although trials conducted in patients with different types of neuropathic pain, showed opioids efficacy, their use is limited due to related side effects. For this reason, the International Association for the Study of Pain (IASP) recommends its administration only as a second line of treatment.

In addition, recent guidelines on the treatment of CRPS advise against the use of strong opioids in these patients, due to a lack of evidence on their effectiveness.

  • Gabapentin is one of the most commonly prescribed drugs for neuropathic pain and for CRPS. It is recommended in patients with CRPS if the pain is not sufficiently controlled by common analgesics. 2
  • Pregabalin has a mechanism of action like Gabapentin and is empirically used during CRPS. However, there are no published studies to this effect. 2
  • Tricyclic antidepressants: there are scientific papers on their use for neuropathic pain, but not specific studies in the treatment of CRPS. Although the literature does not show sufficient data and their use is only anecdotal, tricyclic antidepressants are sporadically used also for CRPS, at low doses, since the analgesic effects are independent of their antidepressant effects.
  • Nutraceuticals are widely used to treat CRPS symptoms, but moderate evidence supports only vitamin C use as a preventive strategy.3

It is important to underline that the appropriate treatment for each CRPS patient must be initiated by clinical experts and, where necessary, in centers specialized in pain management.


CRPS treatment should be started as early as possible, to prevent significant functional limitation, psychological distress, and social and economic fallout3

There is sufficient evidence to support the use of bisphosphonates as preferred agents in the management of CRPS-I in clinical practice4

In vein infusion of the bisphosphonate neridronate is associated with CRPS-I persistent remission.

Physiotherapy in CRPS patients

As CRPS symptoms includes body perception disturbance, sensory incongruities and motor dysfunction, the role of physiotherapy is becoming crucial as much as pharmacological treatment.

There is emerging positive evidence for several techniques including:

  • mirror therapy
  • tactile discrimination training
  • Graded Motor Imagery (GMI)
  • virtual reality.

Mirror therapy

Mirror therapy aims to create an illusion of normality in the affected limb. When used for CRPS, mirror therapy involves concealing the affected limb behind the mirror, while the non-affected limb is positioned so that its reflection is superimposed to where the affected limb should be. The brain gives priority to visual input over proprioceptive input, so when the unaffected limb moves it appears as though the affected limb is functioning normally.

Tactile discrimination

Tactile discrimination is slower in a CRPS-affected limb than in an unaffected limb. This training technique helps patients in concentrating on the delivered stimuli allowing to improve tactile acuity and reduce pain.

Graded Motor imagery

GMI follows a progressive three-stage motor imagery program.

  • Stage 1: participants see a series of photographic flash cards and they are asked to identify (as quickly as possible) whether the depiction is of a left or right limb.
  • Stage 2: participants imagine moving the affected limb into the position demonstrated on the photograph, while the affected hand rests comfortably.
  • Stage 3: involves mirror therapy, whereby both limbs are moved to adopt simple postures as demonstrated on the photograph. 6

Scientific literature reports that Graded Motor Imagery (GMI) produced the greatest benefit in terms of reducing pain when compared to conventional physiotherapy and medical management.

Virtual Reality

Thanks to technology development, the theories regarding mirror therapy have been expanded into the virtual world, with studies looking into the efficacy of virtual reality systems for managing pain.

For example, patients wear digital gloves linked to a specific computer-based program and focus on the motion of the virtual hand, while performing motor tasks such as reaching out, grasping, transferring, and placing. Virtual reality produces analgesic effects through modulation of sensory and emotional aspects of pain processing.

Considering all this positive evidence, physiotherapists are at the forefront of initiating these techniques with CRPS patients. Moreover, the physiotherapy program must be personalized and differentiated according to the type of CRPS (I or II) and the stage of the disease.


CRPS physiotherapy should be started together with pharmacological treatment Physiotherapy and/or occupational therapy, unless contraindicated, should be initiated immediately when CRPS is suspected.

The physiotherapy program must be personalized on patients clinical status CRPS diagnostic, therapeutic and rehabilitative approach To conclude, a multidisciplinary approach is crucial in the CRPS treatment and management. 

A suggested algorithm is showed here below, and it includes both pharmacological treatment and physiotherapy.

CRPS diagnostic, therapeutic and rehabilitative approach

To conclude, a multidisciplinary approach is crucial in the CRPS treatment and management.

A suggested algorithm is showed here below, and it includes both pharmacological treatment and physiotherapy.2 

complex regional pain syndrome treatment

Talk to your doctor

Complex regional pain syndrome can be managed and treatment options are available. In case of chronic pain to a limb with alterations in its sensitivity and mobility, do not hesitate to contact your doctor. Explain your condition in order to plan a proper diagnostic and therapeutic program.


  1. Complex regional pain syndrome in adults UK guidelines for diagnosis, referral and management in primary and secondary care 2018.
  1. Linee Guida CRPS Algodistrofia – (Sindrome Dolorosa Regionale Complessa). Anno di pubblicazione 2017. Anno di primo aggiornamento 2019.
  1. Iolascon G. and Moretti A. Pharmacotherapeutic options for complex regional pain syndrome. Expert Opinion on Pharmacotherapy. Vol. 20, Iss. 11, 2019.
  1. Giusti A. and Bianchi G. Treatment of complex regional pain syndrome type I with bisphosphonates. RMD Open 2015;1:e000056.
  1. Varenna M. et al. Treatment of complex regional pain syndrome type I with neridronate: a randomized, double-blind, placebo-controlled study. Rheumatology 2013;52:534_542.
  1. Pollard C (2013) Physiotherapy management of complex regional pain syndrome New Zealand Journal of Physiotherapy 41(2)