Complex Regional Pain Syndrome Series: Peripheral Inflammation

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Complex Regional Pain Syndrome (CRPS) is a complex and poorly understood problem. There have been several proposed interacting pathophysiological features of the condition including altered sympathetic nervous system function, central sensitisation, inflammatory factors, immune factors, genetic factors, brain changes and psychological factors (Bruehl, 2015; Marinus et al., 2011). Most diagnostic criteria come from clinical features of the condition and recent advances in understanding the pathophysiological aspects have provided a more comprehensive means to providing an accurate diagnosis (Birklein & Schlereth, 2015; Bruehl, 2015).

This second blog in my musings and understanding of CRPS looks at the peripheral inflammatory stages of CRPS. I apologise now for it may be heavy going.

CRPS is a chronic pain disorder characterised by sensory, autonomic features, motor disturbance and inflammatory changes in the region of the painful body part (Bruehl, 2015). CRPS is more prevalent with the hands or feet and can develop following any insult to tissue. It is sub-divided in two forms CRPS type 1 and CRPS type 2. Both occur because of injury to a body part with type 2 involving an identifiable nerve injury (Smart, Wand, & O’Connell, 2016)

CRPS has several pathophysiological features which may all (or not) be present. This can explain the clinical heterogeneity that is often faced with the condition. Furthermore, the heterogeneity of the condition presents as a complex and challenging problem for both clinician and patient. To discuss the extensive pathophysiological features of the condition is beyond the scope of this paper and the author refers readers to comprehensive texts for further reading (Birklein & Schlereth, 2015; Bruehl, 2015; Harden, Bruehl, Stanton-Hicks, & Wilson, 2007; Marinus et al., 2011; Smart et al., 2016).

As previously mentioned CRPS is more prevalent in the hands or feet and can develop following any insult to associated tissue. More common initiating events are fractures, crush injuries, sprains and surgery (Bruehl, 2010). These types of injuries can cause significant inflammatory responses which with any acute trauma lead to sensitisation of peripheral nociceptors (Marchand, Perretti, & Mcmahon, 2005). CRPS is a complex condition with a complicated pathophysiology and since the diagnostic criteria released in 1994 (Merskey & Bogduk, 1994) confusion for clinicians has resulted in non-CRPS conditions to be diagnosed as CRPS. The International Association­ for the Study of Pain (IASP) updated the 1994 diagnostic criteria to the Budapest criteria in 2007 with research validation in 2010 (Harden et al., 2010, 2007).

IASP Budapest criteria for CRPS

The update was required due to over-diagnosis of non-CRPS conditions including peripheral pain presentations such as peripheral neuropathy or even delayed healing following surgery (Birklein & Schlereth, 2015).

CRPS is associated with a multitude of interacting pathophysiological mechanisms that involve multiple systems from the peripheral tissue to the central nervous system and immune systems. It has been poorly understood due to the lack of animal models to provide measurable biomarkers and most diagnostic criteria come from clinical features of the condition. Recent advances in understanding the pathophysiological aspects have provided a more comprehensive means to providing an accurate diagnosis (Birklein & Schlereth, 2015). The remainder of this blog will briefly investigate the peripheral inflammatory mechanisms of CRPS.

Proposed pathophysiology of CRPS

Inflammatory mechanisms – peripheral

Peripheral sensitisation is activated by inflammatory mechanisms in several ways. As with all initiating injuries a local inflammatory response occurs in the tissues, a component of the tissue healing process. It also activates the process of transduction, the initial precursor to the afferent delivery of electrical activity in the nervous system, in the case of tissue insult, nociception (Dawes, Andersson, Bennett, Bevan, & Mcmahon, 2016). During this process, inflammatory mediators are released including Bradykinin, Prostaglandins, leukotrienes, substance P. This also includes the release of cytokines such as tumour necrosis factor, nerve growth factor, interleukin 1 & 6 (Meyer, Ringkamp, Campbell, & Raja, 2013).

Moreover, inflammatory mechanisms related to CRPS include the amplification of cytokines and nerve growth factor. These two chemical mediators are involved in exciting nociceptors and producing long-term peripheral sensitisation and have also been linked to enhancing the release of pro-inflammatory neuropeptides in primary sensory neurons (Marinus et al., 2011; Sommer & Kress, 2004). Peripheral sensitisation involves the activation of cutaneous nociceptors. The persistent stimulation of cutaneous nociceptors promotes the release of neuropeptides such as substance P and calcitonin gene related peptide (CGRP). These neuropeptides appear to mediate the pro-inflammatory changes that occur in CRPS. This includes inflammatory signs of redness, heat and oedema related to the process of neurogenic inflammation (Dawes et al., 2016; Marinus et al., 2011).

The nociceptor in peripheral sensitisation alters its receptor bioavailability, thus increasing the opportunity for chemical mediator binding. Therefore, due to the increase in receptor numbers there is an increased affinity for binding and nerve depolarisation. Furthermore, studies have shown the impact of prolonged substance P release on keratinocytes (skin cells). An increase in receptor availability on Keratinocytes increases the release of cytokines and neuropeptides and compounds the familiar signs associated with CRPS – limb oedema, redness, heat – a perpetuating cycle (Dallos et al., 2006; Kingery, 2010).

Due to the ongoing inflammatory process, the process of nociception and resultant central sensitisation changes that can occur, a perpetuating cycle of swelling, redness and oedema is maintained.  This is particularly evident in the mechanism of mechanical hyperalgesia, which has been directly related to central sensitisation. Mechanical hyperalgesia refers to an amplified response to some form of deformation of the tissue that normally provokes pain (Woolf, 2011). Maihöfner, Handwerker, Neundörfer, & Birklein, (2005) identified that more than half of CRPS patients presented with pin-prick hyperalgesia. Moreover, sensory neurons involved in the transmission of nociception (A-delta and C-fibers) are responsible for peripheral sensitisation and central sensitisation respectively.

As previously mentioned the pathophysiology of CRPS is a complex one, with the inflammatory component being one part of a multi-factorial aetiology. Inflammation does not primarily involve peripheral tissue it is also postulated to be prevalent in the spinal cord sensitising second order nociceptors. Moreover, additional factors such as glial-neuronal interactions are also likely to occur (Marinus et al., 2011).

People living with CRPS face a turbulent and challenging life due to the multi-factorial pathophysiological features of the condition.  Many personal accounts from patients refer to CRPS as the ‘suicide disease’. Due to the intense levels of pain experienced, patients are prepared to take their own life. The case study in this assignment displayed psychological features of depression, anxiety, stress, severe levels of catastrophic thought and low self-efficacy. Therefore due to the associated psychosocial factors with chronic pain conditions it would seem pertinent that psychological approaches are implemented as part of a management approach for CRPS (Bean, Johnson, Heiss-Dunlop, Lee, & Kydd, 2015). CRPS is not a condition that can be treated via a single interventional approach, with low quality evidence to support several single and combined approach interventions (O’Connell et al., 2013). Complex pathophysiological and psychosocial factors are associated with the condition and so further high quality research is urgently needed for more effective treatment.

If you have gotten this far, thanks so much for reading. In time I aim to release future blogs on the other aspects of CRPS with the aim of looking at interventions more closely.

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