Title of assessment task: Written assignment (3,500 words)

This assessment evaluates your clinical identification and assessment of chronic, complex pain and
knowledge of acute pain management strategies. There are three sections to complete.
Part I: Acute Pain Management Describe two mechanisms of pain relief and provide examples of
treatments that make use of these strategies. For example, you may select the gate control
mechanism, reduced blood flow, or the release of endogenous opioids. Make sure you carefully
explain how each mechanism reduces pain.
Part II: Recognition of Chronic, Complex Pain Choose one of the following chronic pain conditions:
Chronic widespread pain (fibromyalgia) Complex regional pain syndrome Phantom limb pain Chronic
low back pain Arthritis Carpal tunnel syndrome Persistent postsurgical pain Whiplash associated
disorders Page 11 Describe the typical clinical presentation of the pain syndrome, focusing on
symptoms in other body systems that can make the condition complex (e.g., motor, psychological,
cognitive, other sensory, autonomic). Describe the potential structural and functional changes that
have occurred to the nociceptive system to facilitate the development of chronic pain. Outline the
main prognostic indicators for the development and/or progression of the condition. Make sure that
you present information that is specific to your chosen condition.
Part III: Chronic Pain Management For the chronic pain syndrome that you selected above, review the
literature to determine what you would consider the gold-standard management approach for this
condition. Discuss the evidence for the use of this approach and justify why you have determined it is
best practice. You should demonstrate your ability to synthesise and integrate information in this
section rather than discuss studies one-by-one. Make sure that your justification takes into account
the strength of the evidence that you have reviewed. That is, clearly identify if there is low, moderate,
or high quality evidence that the approach is best practice. It is unlikely that you will address this
section using a systematic review. Instead, a narrative-type review is recommended where you can
more easily explain and justify your recommendation. The management approach that you
recommend may not be one that has been specifically evaluated in the literature for your condition,
but rather makes use of a variety of supporting evidence across the literature.
Part I:

Gate control theory

Gate control theory introduced by Melzack and Wall in 1965 is concerned with the balance between
two types of afferents – large and fast conductors (Aβ-fibers) and small and slow nociceptive
afferents (C fibers) (Skevington, 1996). Conductors enter the spinal cord via the dorsal roots,
however synapse in two different regions (laminae) within the dorsal horn. C fibers terminate
predominantly in laminae I and II which contains nociceptive specific neurons. Aβ-fibers terminate in
laminae III, IV and V. Gate control theory suggests that cells of substantia gelatinosa (lamina II) have
an inhibitory influence on the deeper dorsal horn neurons and serves as the ‘gate’ in the spinal cord
(Skevington, 1996). Skevington (1996) explains: “each large and small fiber excites a T-cell and sends
a collateral to a suppressor cell in the substantia gelatinosa (SG), where large fibers excite the
suppressor and small ones inhibit it.” (p. 13). Therefore a T-cell activated by a large fiber produces an
inhibition effect. The supressing SG cell is activated by collateral triggers closing the gate. When
nociceptive input exceeds elicited inhibition, the gate opens and activates pathways that lead to the
perception of pain (Skevington, 1996). While some specifics of the theory have been discounted the
theory still serves as an underpinning principle of several therapeutic interventions including, spinal
cord stimulation, and transcutaneous electrical nerve stimulation (Fishman, Ballantyne, & Rethmell,
2010). The literature detailing the exact mechanisms of the interventions is sparse. Nonetheless, it is
believed that electrical stimulation depolarises Aβ-fibers before it affects C fibers, therefore it should
be possible for stimulation to close the gate (Fishman, Ballantyne, & Rethmell, 2010).

Descending inhibitory pathways

The same gate control theory extends to central control mechanisms in the brainstem as part of the
gating process (Skevington, 1996). The theory suggests that “descending fibers from the
periaqueductal gray (PAG) and nuclei raphes magnus (NRM) inhibit the transmission from afferent
fibers to the T-cells, being mediated by inhibitory neurons in the SG” (Skevington, 1996, p. 13). The
PAG receives signals from cortical and limbic centres involved in the affective component of pain.
Descending signals from the PAG travel via the NRM in the medulla. The serotonergic NRM fibers
descend to inhibit peripheral nociceptors in lamina I and II. It is believed that this descending system
blocks the spinal withdrawal reflex at the dorsal horn level (Fishman, Ballantyne, & Rethmell, 2010).
The theory of the descending inhibitory pathway is used to explain numerous nonpharmacologic
methods of pain relief (Fishman, Ballantyne, & Rethmell, 2010). For instance relaxation with imagery
(R&I), a component of cognitive behavioural treatment for chronic pain. R&I includes meditation,
progressive muscle relaxation, imagery, deep breathing and other related techniques. (Fishman,
Ballantyne, & Rethmell, 2010). However, the pain reduction mechanism facilitated by R&I is
currently under debate. The assumed mechanism is the relief of tension and decreased arousal of
the sympathetic nervous system (Fishman, Ballantyne, & Rethmell, 2010). Other theories suggest
that pain modulation is achieved by the neurochemical changes involving catecholamines and
endorphins or serotonin and norepinephrine at the dorsal horn (Fishman, Ballantyne, & Rethmell,
2010). Further hypothesis explains that noxious signals may be modulated through a descending
inhibitory pathway that involve periaqueductal grey and the rostral anterior cingulate cortex
(Fishman, Ballantyne, & Rethmell, 2010).

Part II:

Complex regional pain syndrome (CRPS) is a biopsychosocial and multifactorial disease. Of all
complex pain conditions CRPS remains the most enigmatic and challenging to treat (Fishman,
Ballantyne, & Rethmell, 2010). The key clinical symptom of CRPS is persistent pain that is
disproportionate to the inciting event (Harden, Baron, & Janig, 2001). Other associated symptoms
include changes of regulation by sympathetic nervous system (SNS) i.e. reduced thermoregulation in
cutaneous vasoconstrictor neurons and changes in sweating modulated by sudomotor neurons
(Harden, Baron, & Janig, 2001). Sensory changes such as mechanical allodynia, hypoesthesia have
been reported in 50% of patients (Harden, Baron, & Janig, 2001). Moreover, a similar proportion of
patients reported somatomotor changes including reduced active range of movement, increased
physiological tremor, and movement disorders (myoclonia, neglect-like symptoms, dystonia)
(Harden, Baron, & Janig, 2001). Research has shown that CRPS patients may experience psychiatric
symptoms such as depression, anxiety and personality disorders. However these symptoms are also
likely across other chronic pain populations and are therefore not seen as a contributing factor to
the development of CRPS. The psychiatric symptoms are thought to be more likely a result of long
and severe persisting pain (Stannard, Kalso, & Ballantyne, 2010). Longstanding presentation of CRPS
may also involve trophic changes, bone demineralization and changes in skin growth (Tajerian &
Clark, 2016). CRPS predominantly affects distal extremities and it has a typical glove or stocking-like
distribution (Villa, Ritting-Rasmussen, Mikkelsen, & Poulsen, 2016). CRPS is classified into type I,
historically known as reflex sympathetic dystrophy, which is characterised by absence of nerve
damage or a minor nerve lesion. In type II formerly known as causalgia, a detectable peripheral
nerve lesion is present and it is essentially a neuropathic pain syndrome (Harden, Baron, & Janig,
2001). The course of the CRPS is dynamic in nature. The symptoms evolve from acute warm phase to
chronic cold phase. In the acute stage the peripheral features are more prominent characterised by
swelling, increased sensitivity and elevated temperatures. As the disease progresses, the
inflammatory symptoms subside, however pain and disability persist with an additional
development of psychologic changes. (Tajerian & Clark, 2016). CRPS typically occurs 4-6 weeks after
a trauma to an extremity, surgery, stroke or even immobilisation of the limb (Villa et al., 2016).
Spontaneous forms of CRPS have been reported in 10-16% of cases. (Villa et al., 2016).

There is little information detailing CRPS pain mechanisms. CRPS is believed to involve multiple
systems including SNS, somatosensory and somatomotor systems, the central endogenous control
system and the neuroendocrine system (Harden, Baron & Jang 2001). Sympathetically maintained
pain (SMP) is often reported in CRPS patients and usually includes spontaneous pain as well as pain
induced by mechanical and cold stimuli. (Harden, Baron & Jang 2001). The hypothesis by Harden,
Baron and Jang (2001) based on three studies involving pharmacological interventions (ganglion
block and local anaesthetic) and physiological intervention (exposure to heat) suggests that
nociceptors are excited and perhaps sensitised by norepinephrine released by the sympathetic
fibers. Harden and colleagues further state: “The nociceptors may have expressed functioning
adrenoreceptors, or the excitatory effect may be indirectly mediated by the vascular bed or by other
components of the microenvironment of the nociceptive terminals. Sympathetically maintained
activity in nociceptive neurons may generate a state of central sensitisation or hyperexcitibility that
can cause spontaneous pain and secondary evoked pain (mechanical or cold allodynia)” (Harden,
Baron, & Janig, 2001). Harden and colleagues further propose a positive feedback circuit model via
the efferent sympathetic outflow. The positive feedback circuit consists of afferent, central and
sympathetic neurons and sympathetic-afferent coupling. According to the authors this circuit would
maintain spontaneous pain, hyperalgesia, allodynia, and the other associated clinical changes
(Harden, Baron, & Janig, 2001). Nevertheless, the direct link between SNS dysfunction and
nociception is still debated. In a study of 24 CRPS patients using microneurography techniques,
Campero, Bostock, Baumann, and Ochoa (2010) found no evidence of activation of nociceptors
related to sympathetic discharge. Despite the current findings of SNS generated pain there is a
mixed evidence of the efficacy of sympatholytic pain relief in CRPS patients. These conflicting
findings may suggest that not all CRPS patients will suffer from sympathetically maintained pain and
thus have to be treated on individual bases (Tajerian & Clark, 2016)

As a result of prolonged increase in excitability of neurons in the spinal cord, peripheral sensitisation
of afferent C fibers may trigger central sensitisation. The underlying mechanism is thought to be due
to the release of excitatory neurotransmitters into the spinal cord. In response, calcium channels
and opioid receptors in the spinal cord, responsible for control over transmitter release and
neuronal activity, trigger release of neurokinin and N-methyl-D-aspartate (NMDA) receptors and
pain processing. The symptoms of central sensitisation include tactile allodynia, secondary
hyperalgesia and enhanced temporal summation (Gierthmuhlen, Binder, & Baron, 2014).

An altered cortical representation of the involved limb has also been linked to central sensitisation
(Tajerian & Clark, 2016). Moreover, 50% of patients in a chronic stage of CRPS I develop hypoalgesia
and hypoesthesia on the entire affected side of the body, which is thought to be a result of CNS
changes. These cause a widespread alteration of the perception of noxious and non-painful
sensations (Harden, Baron, & Janig, 2001). Harden and colleagues suggest that alterations in central
representations in CRPS II population may be due to the peripheral nerve lesion, which causes
chemical, anatomical and physiological changes in the injured afferent neurons. Some not
regenerated dorsal root ganglion cells with unmyelinated afferent fibers die. This loss of root
ganglion cells may lead to changes in the central representations (Harden, Baron, & Janig, 2001).

While psychological co-morbidities are unlikely to predisposing someone to CRPS, psychological

symptoms can still influence the progression of the disease (Gierthmuhlen, Binder, & Baron, 2014).
One theory suggests that the systemic catecholamine release triggered by chronic stress, as seen
in depression and anxiety, may result in increased perception of pain via upregulation of
adrenergic receptors and sympathetic-afferent coupling (Gierthmuhlen, Binder, & Baron, 2014). A
recent New Zealand prospective study by Bean, Johnson, Kydd, Heiss-Dunlop, and Lee (2015) has
found an association between psychological factors and the outcomes of CRPS. Researchers
observed that patients with lower baseline anxiety and disability reported the lowest pain intensity
over 12 months, the duration of the study. Additionally these with lower initial scores on fear and
pain-related fear questionnaires reported the least disability over the period of the study.
Researchers concluded that emotional responses like anxiety, pain-related fear and disability are
linked to more severe presentation of CRPS symptoms (Bean et al., 2015).

Despite increasing knowledge of the mechanisms of CRPS and the available range of therapeutic
interventions, the prognosis of the disease remains poor. In some patients an acute presentation of
CRPS may improve with early intervention. However, if the symptoms persist for a period of one
year or more the prognosis of spontaneous resolution is very low, leaving 80% of patients severely
disabled (Tajerian & Clark, 2016).

CRPS affect females more than males with a ratio ranging from 2:1 to 4:1. There is no bias in age,
however the averge age of diagnosis is 37-50 years. Statistics indicate a higher prevalence of cases
with upper limb involvement by 60% but without side preferences. Although ethnicity and socio-
economic status may be contributing factors the extent of influence is not clear. Nonetheless, the
incidence is higher in European population (26.2 per 100,000) in comparison to USA (21 per
100,000).

The severity of CRPS is determined by the disease course not the etiology. A low skin temperature at
the initial diagnosis is an indicator of an unfavourable progression and outcome (Stannard, Kalso, &
Ballantyne, 2010). It is also curious to mention potential prognostic indicators to the development of
CRPS. In a prospective study by Birklein, Riedl, Sieweke, Weber, and Neundörfer (2009), researchers
have evaluated 145 participants. In the preliminary screening they found that 42% of patients
reported stressful life circumstances in a close relationship to the onset of CRPS. They also found
that 41% of patients had a history of chronic pain before the onset of CRPS. These patients also
reported higher ratings of CRPS related pain (Birklein et al., 2009). Tajerian and Clark (2016) strongly
suggest that research should focus on finding ways of pinpointing the mechanisms behind the early
stages of CRPS. This may open novel approaches to prevention as well as reversing the condition at
its earliest phases.

Part III:
In spite of efforts of different medical and paramedical professions, no gold-standard treatment has
been developed for CRPS management, or its cure. This is mainly due to the evolving nature of the
disease and the heterogeneity of the patients. Partial understanding of the underlying mechanisms
contributes to the limited effectiveness of CRPS management (Tajerian & Clark, 2016). The latest
treatment guidelines by the Reflex Sympathetic Dystrophy Syndrome Association have been
developed in the “humanitarian spirit of making the most of all current thinking in the area” (Harden
et al., 2013). However, the guidelines have been compiled from current literature that lacks strong
research evidence in the area. The authors have compiled evidence emphasising quality data but
have also included less rigorous research that was complemented with the extensive empirical
experience of expert clinicians. Due to the biopsychosocial complexities of CRPS symptoms, the
proposed aim of treatment is a stable, empathetic, multidisciplinary approach of progressive
functional restoration. This approach, although based mainly on traditional, empirical and anecdotal
evidence, has been agreed upon during three expert, consensus-building conferences. The theory of
a similar, interdisciplinary approach, has been proven beneficial for other pain conditions, i.e. low
back pain (Harden et al., 2013).

Multidisciplinary management

To date only one, observational cohort study has addressed the efficacy of a multidisciplinary
approach in CRPS management. The study included 49 participants who completed a comprehensive
pain management programme over four weeks. Patients participated in a structured program for
eight hours each day, five days per week. This programme focused on self-management strategies
and included: pain psychology education, physiotherapy and occupational therapy, nursing
education and regular pain physician appointments. The results of the study showed short-term
significant improvements in physical functioning and perceived disability, greater chronic pain
acceptance and reductions in emotional distress. Although patient reports of pain were not
significantly reduced at discharge, medication usage at one month follow up was significantly
reduced compared to results at the start or the discharge of the program. While randomised
controlled trials would be necessary to confirm the findings of this study, the results were
encouraging and were in line with rehabilitation philosophy of “improving functioning and sense of
well-being as of equal value and relevance to pain reduction” (McCormick et al., 2015). The
limitation of this study included retrospective analysis. The data has been extracted from medical
records from a five year time period. The benefits of this selection was a realistic representation of
CRPS population. Authors included patients with CRPS type I and type II, male and female, from 18
to 89 years of age and with acute or chronic presentation. Another limitation of the study was that
there was no long term follow up, only short-term effects were recorded (McCormick et al., 2015).

Functional restoration

The aim of functional restoration is to guide a patient through a gradual and steady process of
regaining the best possible physiological function (Harden et al., 2013). The therapy usually begins
with non-invasive sensory and motor reactivation modalities. Starting with motor imagery and
progressesing to gentle active movements, weight bearing, gait training, stress loading, and
eventually functional and vocational rehabilitation (Harden et al., 2013). While disciplines like
physiotherapy and occupational therapy have been applied in functional restoration (Harden et al.,
2013; Perez et al., 2010), to date they haven’t been rigorously validated by means of systematic
methodologies. Daly and Bialocerkowski (2012) conducted a systematic review of the application of
physiotherapy to manage CRPS type I. Authors found that physiotherapy aimed to influence a broad
spectrum of CRPS symptoms ranging from pain intensity, to strength, swelling, participation
restriction. This broad spectrum approach posed difficulties to establishing any overall effectiveness
of physiotherapy. Additionally the majority of studies included in this review investigated the effects
of physiotherapy in conjunction with medical management making it difficult to isolate the effects of
physiotherapy. Yet, after a detailed analysis, the authors established that there is a strong (level II)
evidence of using graded motor imagery techniques for CRPS type I treatment in combination with
medical management. Three studies demonstrated that patients who participated in imagery
intervention reported clinically relevant reduction in pain after a six weeks program. The reduction
in pain was maintained for up to six months following treatment. A small number of case-control
series also provided evidence supporting the use of graded exposure techniques, fair evidence on
sensorimotor treatment and mirror visual feedback. These studies, although showing promising
results, require stronger methodological approaches. Additionally, the authors found that there is no
evidence for use of transcutaneous electrical nerve stimulation and stress loading exercises despite
being mentioned in the treatment guidelines by Hayden et al. (2013). However, with the exception
of one study, all RCTs included in this systematic review included participants with only upper limb
CRPS type I. Therefore, there is no evidence that patients with lower limb CRPS type I will benefit in
the same way (Daly & Bialocerkowski, 2012).

Pharmacotherapy

Pharmacological treatment offers symptomatic relief and is necessary to facilitate paramedical

interventions. Pharmacotherapy is a mechanism based treatment and in CRPS is prescribed mainly
for analgesia, but may also improve vascular symptoms, inflammation, dystonia, and psychological
symptoms (Harden et al., 2013). Perez et al. (2010) have proposed evidence based guidelines for the
pharmacological management of CRPS type I. Perez and colleagues researched evidence for the use
of paracetamol, NSAIDs, opioids, anticonvulsants, anaesthetics and local anaesthetics,
antidepressants, free radical scavengers, oral muscle relaxants, botulin toxin, intrathecal baclofen,
corticosteroids, bisphosphonates, and calcium-channel blockers, which are used in the treatment of
CRPS type 1. There is still limited evidence for the effectiveness of the different groups of drugs. The
anticonvulsant gabapentin showed some reduction in pain in the early stages of CRPS type 1 but no
evidence of changes to sensory abnormalities (level II evidence) (Serpell; Van de Vusse et al., as cited
in Perez et al., 2010). There is an indication that the intravenous anaesthetic ketamine reduces pain
(level III evidence) (Correll et al., as cited in Perez et al., 2010). Corticosteroids may have some
beneficial effect, however the dose and the duration of treatment is not established (level III
evidence) (Christensen et al.; Grundberg et al.; Kozin et al., as cited in Perez et al., 2010).
Bisphosphonates showed positive effect on the signs of inflammation (level I evidence) (Forouzanfar
et al.; Manincourt et al., as cited in Perez et al., 2010). Calcium-channel blockers have some effect in
the early stage, however it is also known to cause side effects (level III evidence) (Muizelaar et al.;
Prough et al., as cited in Perez et al., 2010). There is insufficient evidence for any other
pharmacological treatments mentioned above (Perez et al., 2010). Villa et al. (2016) recommend
that for the best results the pharmacological prescriptions should be managed optimally by clinicians
with special knowledge of CRPS.

Psychological treatment

Despite the evidence of a psychological impact on CRPS patients, only one prospective, randomised
study has been conducted in conjunction with physical therapy in 28 children and adolescents. The
participants received six sessions of cognitive behavioural treatment (CBT) including: pain
management strategies, guided imagery, relaxation training, biofeedback, and physiotherapy. A
long-lasting reduction of all symptoms was demonstrated after a six week treatment period
(Stannard, Kalso, & Ballantyne, 2010). Small trials indicate that graded exposure based on CBT and
intensive exposure techniques may reduce pain-related fear especially in patients with low level of
fear avoidance. It is unclear if the same approach is relevant to patients with high levels of
catastrophizing or kinesiophobia (Packham & Holly, 2018).

While there is a sparse evidence of treatment modalities generated for CRPS patients, there are
other untested interventions employed in chronic pain management. Pain neuroscience education
specific to CRPS is being utilised in the clinical setting. However, at present it lacks methodological
evaluation. There is a growing evidence for the benefits of mindfulness in chronic pain conditions,
which could be also utilised in CRPS management. A beneficial effect of virtual reality intervention
has been reported in case studies and small pilot studies research. (Packham & Holly, 2018).

Conclusion

Over decades CRPS has been a challenging disease to manage. It is biomedically multifaceted and
therefore should be treated as such. The presentation often changes over time, and the progression
is variable. Evidence for the efficacy of available treatment modalities is scarce and developing
slowly. The only treatment modality with a realistic chance of bridging the multifaceted presentation
and mechanisms of CRPS is a systematic multidisciplinary approach. Based on current evidence, a
four week multidisciplinary programme is sufficient to improve clinical and subjective results in CRPS
patients. The programme should include a functional restoration component tailored to the need of
the patient. Inclusion of self-management strategies is crucial to long term results. Psychological
factors are important treatment targets in CRPS, psychological assessment and treatment should be
undertaken. Due to the debilitating symptoms, some patients may fail to begin or progress. These
patients may therefore require pharmacotherapy and psychotherapy before they can effectively
engage in functional restoration. The treatments should not exacerbate symptoms of the disease. If
they do, the particular treatment should be discontinued. Pharmacological treatment should
support all other paramedical interventions.

References

Bean, D., Johnson, M., Kydd, R., Heiss-Dunlop, W., & Lee, A. (2015). Do psychological factors
influence recovery from complex regional pain syndrome type 1? A prospective study. Pain, 156(11),
2310-2318. https://doi.org/10.1097/j.pain.0000000000000282

Birklein, F., Riedl, B., Sieweke, N., Weber, M., & Neundörfer, B. (2009). Neurological findings in
complex regional pain syndromes - analysis of 145 cases. Acta Neurologica Scandinavica, 101(4),
262-269. https://doi.org/10.1034/j.1600-0404.2000.09008.x

Campero, M., Bostock, H., Baumann, T., & Ochoa, J. (2010). A search for activation of C nociceptors
by sympathetic fibers in complex regional pain syndrome. Clinical Neurophysiology, 121(7), 1072-
1079. http://doi.org/10.1016/j.clinph.2009.12.038
Daly, A., & Bialocerkowski, A. (2012). Does evidence support physiotherapy management of adult
complex regional pain syndrome type one? A systematic review. European journal of pain, 13(4),
339-353. https://doi.org/10.1016/j.ejpain.2008.05.003

Fishman, S., Ballantyne, J., & Rethmell, J. (2010). Bonica’s management of pain (4th ed.).
Philadelphia, PA: Lippincott Williams & Wilkins.

Gierthmuhlen, J., Bindder, A., & Baron, R. (2014). Mechanism-based treatment in complex
regional pain syndromes. Nature reviews neurology, (10), 518–528.
https://doi:10.1038/nrneurol.2014.140

Harden, N., Oaklander, A., Burton, A., Perez, R., Richardson, K., Swan, M., Barthel, L., Costa, B.,
Graciosa, J., & Bruehl, S. (2013). Complex Regional Pain Syndrome: practical diagnostic and
treatment guidelines, 4th edition. Pain Medicine, 14(2), 180–229, https://doi-
org.ezproxy.aut.ac.nz/10.1111/pme.12033

Harden, R., Baron, R., & Janig, W. (2001). Complex regional pain syndrome. Seattle, WA: IASP Press.

Janig, W., & Baron, R. (2003). Complex regional pain syndrome: mystery explained? Neurology,
2(11), 687-697. https://doi.org/10.1016/S1474-4422(03)00557-X

McCormick, Z., Gagnon. C., Caldwell, M., Patel, J., Kornfeld, S., Atchison, J., Stanos, S., Harden, N., &
Calisoff, R. (2015). Short-term functional, emotional, and pain outcomes of patients with complex
regional pain syndrome treated in a comprehensive interdisciplinary pain management program.
Pain Medicine, 16, 2357–2367. https://doi.org/10.1111/pme.12817

Méndez-Rebolledoa, G., Gatica-Rojasa, V., Torres-Cuecoc, R., Albornoz-Verdugod, M., & Guzmán-
Muñozb, E. (2017). Update on the effects of graded motor imagery and mirror therapy on complex
regional pain syndrome type 1: A systematic review. Journal of back and musculoskeletal
rehabilitation, 30, 441–449. https://doi.org/10.3233/BMR-150500 IOS Press

Packham, T. & Holly, J. (2018). Mechanism-specific rehabilitation management of complex regional

pain syndrome: Proposed recommendations from evidence synthesis. Journal of hand therapy,
31(2), 238-249. https://doi.org/10.1016/j.jht.2018.01.007

Perez, R., Zollinger, P., Dijkstra, P., Thomassen-Hilgersom, I., Zuurmond, W., Rosenbrand, &
Geertzen, J. (2010). Evidence based guidelines for complex regional pain syndrome type 1. BMC
Neurology, 10, 20. https://doi.org/10.1186/1471-2377-10-20
Russo, M., Fiore, N., Vreden, C., Bailey, D., Santarelli, D., McGuire, H., Groth, B., & Austin, P. (2019).
Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain
syndrome. Journal of neuroinflammation, 16(1), 1-17. https://doi.org/10.1186/s12974-019-1449-9

Russo, M., Georgius, P., & Santarelli D. (2018). A new hypothesis for the pathophysiology of complex
regional pain syndrome. Medical hypothesis, 119, 41-53.
https://doi.org/10.1016/j.mehy.2018.07.026

Skevington, S. (1996). Psychology of pain. West Sussex, England: Wiley.

Stannard, C., Kalso, E., & Ballantyne, J. (2010). Evidence-based chronic pain management. West
Sussex, England: Wiley-Blackwell.

Tajerian, M., & Clark, J. (2106). New concepts in complex regional pain syndrome. Hand clinics, 32,
41-49. https://doi.org/10.1016/j.hcl.2015.08.003

Villa, M., Rittig-Rasmussen, B., Moeller, L., Mikkelsen, L., & Poulsen, A. (2016). Complex regional pain
syndrome. Manual therapy, 26, 223-230. https://doi.org/10.1016/j.math.2016.07.001

Packham, T. & Holly, J. (2018). Mechanism-specific rehabilitation management of complex regional

pain syndrome: Proposed recommendations from evidence synthesis. Journal of hand therapy,
31(2), 238-249. https://doi.org/10.1016/j.jht.2018.01.007