FRCA Notes

Complex Regional Pain Syndrome

Resources

Complex regional pain syndrome is a chronic, debilitating, pain condition

Incidence 5 - 26/100,000 person-years
4x female preponderance
Tends to occur in the upper limbs more than the lower limbs

Particularly ante-brachial fractures
Has been reported in other areas including face and trunk

CRPS typically arises after trauma to a limb, but arises spontaneously in 10% of cases

The aetiology is largely uncertain; no single theory fully explains the condition
It is likely to be multifactorial, involving aberrant peripheral and central neuroinflammatory mechanisms such as:

Dysregulated inflammatory processes
Vasomotor dysfunction
Changes to peripheral nerves and the cerebral cortex

The extent of these changes will vary between individuals, leading to a clinically heterogenous syndrome

Associations

There are various genetic loci that may be implicated in a genetic predisposition to selective versions of CRPS

HLA-DQ8 may be associated with CRPS (both with and without dystonia)
HLA-B62 may be associated with CRPS with dystonia

There is an association between ACE-I use and CRPS

There is no association between onset of CRPS and psychological factors e.g. depression, anxiety

These features may develop later as a result of CRPS
Other neuropsychological features may develop including neglect, distorted image and asomatognosia (loss of ownership of the limb)

Acutely

In the acute inflammatory phase, the classical signs of an inflammatory response occur
Inflammatory markers (CRP, ESR, WCC) are, however, frequently normal or only mildly elevated

Il-6 and TNFɑ are implicated and may be involved in peripheral nociceptor activation and sensitisation
There are elevated levels of other pro-inflammatory cytokines, including substance P and CGRP

These cause plasma protein extravasation and neurogenic arteriole dilation
This leads to the concept of neurogenically-mediated inflammation

The dysregulated inflammatory process may cause deep-tissue microvascular ischaemia-reperfusion injury
This sensitises the peripheral and central nervous and maintains the inflammation

Chronically

As CRPS becomes chronic, there is cortical reorganisation and altered pain processing
fMRI demonstrates:

Reduced thalamic blood flow
Primary somatosensory cortex (S1) cortical reorganisation
Changes in other areas including motor areas, pre-frontal cortices and insular cortices

Spinal nociceptive neurones become hyper-responsive to peripheral input
This increases nociceptive signalling to the cortex, even in the absence of an input
A shift from inhibition towards facilitating nociception has been found in pain modulation pathways

In the peripheral nervous system, there is:

Decreased epidermal nerve fibres
Reduced sweat gland innervation
Reduced vascular innervation

This small-fibre neuropathy may be causative or consequential

These central, spinal and peripheral aetiologies may be additive/synergistic

Diagnosis is clinical based on the New International Association for the Study of Pain (IASP) clinical diagnostic criteria (i.e. the Budapest Criteria)

Category	Symptom	Sign
Sensory	Hyperalgesia	Allodynia Hyperalgesia
Vasomotor	Changes or asymmetry in skin colour or temperature	Changes or asymmetry in skin colour Temperature asymmetry >1°C
Sudomotor/oedema	Asymmetric sweating Oedema	Asymmetric sweating Oedema
Motor/trophic	Weakness Stiffness Tremor Hair, skin or nail changes	Decreased range of motion Motor dysfunction Hair, skin or nail changes

According to these 2004 Budapest criteria, a diagnosis of CRPS can only be made if all of the following are true:

The patient has continuing pain, disproportionate to the inciting event [pain often severe]
The patient has at least one symptom in ≥3 categories
The patient has at least one sign in ≥2 categories
No other diagnosis can better explain the signs or symptoms

Classification

CRPS Type 1 - not associated with any nerve lesion or damage (i.e. nociplastic)
CRPS Type 2 - associated with nerve lesions/damage (i.e. neuropathic)

NB CRPS subtypes do not differ in presentation, nor does subtype influence subsequent management or prognosis

There's a lack of robust, evidence-based treatment for CRPS
Many of the recommendations are extrapolated from other neuropathic pain conditions
Early treatment may help prevent the development of some of the long-term sequelae of CRPS
Management follows a bio-psycho-social model using an MDT approach

Patient education

Ensure patient understanding of the conditions
Facilitate patient involvement in making informed decisions about treatment options
Examples:

Information leaflets
Sufficient time with patient and relatives explaining diagnosis
Allowing questions

Physical and vocational rehabilitation

Physiotherapy - should be started as soon as diagnosis made
Occupational therapy
Specialised therapy

Mirror therapy: patients describe both limbs, imagine the movements bilaterally and then look at the mirrored limb with/without movement
Graded motor imagery: patients identify limb laterality with imagination, images and mirrors

Psychological interventions

Psychotherapy e.g. CBT to help deal with significant psychological burden of CRPS
Hypnosis
Relaxation therapy
Thermal biofeedback
May be of benefit to patient's family too

Analgesia

Some drugs may be beneficial in the early pro-inflammatory stages

NSAIDs
Bisphosphonates
There is insufficient or conflicting evidence for use of other drugs such as steroids, IVIg, thalidomide, TNFɑ-antagonists

Many patients are referred following a failure of opioid therapy to manage the acute phases

Anti-neuropathic agents

TCAs
Gabapentinoids
Tapentadol

Is useful as it has both μ-agonist and NARI effects
Can be used as part of opioid rotation
It may be helpful when other opioids are providing lower-than-expected benefit due to tolerance

Lidocaine

As 5% plasters
As a low-dose infusion e.g. 2mg/kg IBW for an acute flare

NMDA antagonists

Ketamine as a low-dose infusion can be used to help manage acute flares
Magnesium may provide muscle relaxation and analgesia, but is not evidence-based and need 50mg/kg for analgesic effect

Sympathetic nerve blocks

Paucity of high-quality, high-fidelity clinical trials
May, however, be effective in individual cases

Vitamin C has a minor benefit in preventing CRPS post-surgery e.g. 500 - 1500mg

Vasomotor disturbance

Vasodilators may be useful in the later, 'cold', stages of CRPS to prevent microvascular ischaemia-reperfusion injury

Calcium channel blockers
Alpha antagonists
PDE-V inhibitors

Motor disturbance

(Intrathecal) baclofen may help manage dystonia, although oral medication should be trialled first

Interventional

Interventional options can be used in refractory CRPS
Examples include:

Spinal cord stimulators
Dorsal root ganglion stimulation (which may be superior to spinal cord stimulation)
IV regional nerve blocks

Prognosis and outcomes are difficult to predict
Resolution of CRPS ranges from 74% in the 1^st year to as low as 36% by 6yrs
Return-to-work rates vary in the literature:

Approximately a third (28%) are able to partially return to work
Approximately a third (31%) are left permanently unable to work