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a r t i c l e in f o abstract
Introduction: Hyperexcitability of the central nervous system has been suggested to play an important
role in pain experienced by patients with unilateral shoulder pain. A systematic literature review
Keywords:
Shoulder pain
following the PRISMA guidelines was performed to evaluate the existing evidence related to the presence
Central nervous system sensitization of central sensitization in patients with unilateral shoulder pain of different etiologies including those
Systematic review with chronic subacromial impingement syndrome. Studies addressing neuropathic pain (e.g., post-stroke
Subacromial impingement syndrome shoulder pain) were not considered.
Methods: Electronic databases PubMed, EBSCO, and Web of Science were searched to identify relevant
articles using predened keywords regarding central sensitization and shoulder pain. Articles were
included till September 2013. Full-text clinical reports addressing studies of central sensitization in
human adults with unilateral shoulder complaints including those diagnosed with subacromial
impingement syndrome were included and screened for methodological quality by two independent
reviewers.
Results: A total of 10 articles were retrieved for quality assessment and data extraction. All studies were
cross-sectional (casecontrol) or longitudinal in nature. Different subjective and objective parameters,
considered manifestations of central sensitization, were established in subjects with unilateral shoulder
pain of different etiologies, including those receiving a diagnosis of subacromial impingement syndrome.
Overall results suggest that, although peripheral mechanisms are involved, hypersensitivity of the central
nervous system plays a role in a subgroup within the shoulder pain population.
Conclusions: Although the majority of the literature reviewed provides emerging evidence for the
presence of central sensitization in unilateral shoulder pain (including those diagnosed with subacromial
impingement syndrome), our understanding of the role central sensitization plays in the shoulder pain
population is still in its infancy. Future studies with high methodical quality are therefore required to
investigate this further.
& 2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.semarthrit.2014.11.002
0049-0172/& 2015 Elsevier Inc. All rights reserved.
M.N. Sanchis et al. / Seminars in Arthritis and Rheumatism 44 (2015) 710716 711
patients with unilateral shoulder pain (including those with SIS) the PRISMA statement guidelines [30] was performed in data-
[8]. CS is dened as an amplication of neural signaling within bases such as PubMed (http://www.ncbi.nlm.nih.gov/sites/
the central nervous system (CNS) that elicits pain hypersensitivity entrez), EBSCO (http://search.ebscohost.com), and Web of Sci-
[9]. CS is a broad term that encompasses distorted sensory ence (http://apps.isiknowledge.com) until September 2013. The
processing in the CNS [10], malfunctioning of descending pain- results for every database and combination of keywords and
inhibitory mechanisms [11], enhanced activity of pain-facilitatory MeSH terms used in the search strategy are represented in
mechanisms [12], and long-term potentiation of the neural syn- Supplementary Table S1. In addition, the reference lists from
apses in the anterior cingulated cortex [13]. Indeed, if the CNS is relevant articles were checked to obtain as complete information
sensitized, minimal tissue damage or sensory input without tissue as possible.
damage could be sufcient to trigger pain perception. This may
explain the mismatch between the pain experienced by patients Study selection
and the extent of injury at the subacromial space commonly found
in patients with SIS [14]. An article had to meet all the following inclusion criteria to be
Different modalities of quantitative sensory testing (QST) have included in this review: (I) it had to be reported in a peer-review
been used to assess central pain dysregulation [15]. QST is based academic journal; (II) it had to study the phenomenon of CS in
on standardized (painful) stimuli applied to cutaneous and mus- human adults (18 years or older) with unilateral shoulder pain,
culoskeletal structures that aim at assessing the sensitivity of these including those with SIS; (III) it had to be a full-text original
structures to specic stimuli modalities. Those stimuli can be research report; and (IV) it had to be written in English. If any of
applied locally (i.e., in the proximity of or at the affected joint or these inclusion criteria were not fullled, the article was excluded
tissue) or at distant sites (i.e., remote from the affected joint or from the literature search. No limitation regarding year of pub-
tissue), providing a better understanding of peripheral and central lication was used, and all clinical study designs were eligible.
nervous system sensitization, respectively. Various QST responses Although review articles were not eligible for inclusion, their
have been associated with CS in patients with unilateral shoulder reference lists were screened to collect relevant articles, which
pain, including alteration of descending pain-inhibitory mecha- were not initially retrieved by the systematic search. Articles
nisms [16] or remote areas of hyperalgesia [8,14]. All these changes related to neuropathic shoulder pain (e.g., pain post-stroke
are considered different pain biomarkers evaluating the same shoulder pain) were excluded.
construct (i.e., CS) [15,17,18].
Currently, it remains unclear whether enough consistent evi-
dence is available regarding CS in unilateral shoulder pain, Study process
including those patients diagnosed with SIS. Recent systematic
literature reviews have demonstrated that CS plays an important After performing the literature search, duplicate articles were
role in other chronic pain conditions such as whiplash [19], removed. Eligibility assessment was performed based on the title
osteoarthritis [20], chronic fatigue syndrome [21], and (to a much and the abstract. Initially, all titles and abstracts of the retrieved
lesser extend) rheumatoid arthritis [22]. In addition, some studies articles were screened to identify relevant articles related to CS in
claim for a role of the CNS in pain experienced by people with unilateral shoulder pain (including those with SIS) using the
unilateral shoulder pain, such as those with rotator cuff tendin- predened inclusion criteria. In case of uncertainty regarding
opathy [23], frozen shoulder [24], and chronic hemiplegic shoulder appropriateness of the article after reading the title and the
pain [25,26]. The latter group of patients addresses neuropathic abstract, the full version of the text was retrieved and checked
pain, as stroke is a typical example of objective evidence of for fulllment of the inclusion criteria. Screening was done
(central) nervous system damage, as required for complying independently by two researchers (M.N.S. and M.K.). A consensus
with the diagnostic criteria for neuropathic pain [27]. As CS has meeting was organized to discuss potential disagreements. When
been well established as the underlying mechanism of neuropathic consensus could not be reached, a third opinion was provided by
pain [17,28,29], neuropathic shoulder pain will not be the focus of another researcher (E.L.L.).
the present systematic review. Here, we focus on non-neuropathic The full-text version of all the articles that met the inclusion
shoulder pain patients, including those with SIS, for examining criteria were retrieved, and methodological quality assessment
whether CS plays a role in these types of shoulder pain. and data extraction were performed.
Although preliminary evidence seems to support the role that CS
plays in subjects with unilateral shoulder pain, there is currently no Quality assessment
systematic literature review available regarding CS in these patients.
Hence, the aim of this study was to systematically review and Methodological quality assessment of the full-text articles
evaluate the existing evidence from the literature, in order to establish was evaluated using the PEDro scale, which is based on the
if there are enough arguments to either support or refute a role for CS Delphi list developed by Verhagen et al. [31]. The inter-rater
in unilateral shoulder pain, including those with SIS. Any type of reliability of the PEDro scale reported a generalized Kappa static
association between CS and unilateral shoulder pain was explored, ranging between 0.40 and 0.75 [32]. This scale is considered
such as the merely presence of CS (i.e., epidemiologic studies), any to provide a measure of internal validity and ability to predict
causeeffect relationship, or the effect of treatments focusing on CS in bias [33,34]. The PEDro scale is composed of 11 items, where the
unilateral shoulder pain patients. Studies related to neuropathic rst relates to external validity (and it is not considered part of
shoulder pain (e.g., post-stroke shoulder pain) were not considered. the total score) and the remaining 10 determine the internal
quality and indicate whether the trial includes enough data to
make it interpretable [35]. The PEDro scale grades articles
Methods getting 6/10 or more points from moderate to high quality,
and it was originally designed to assess the risk of bias in
Search strategy Randomized Control Trials (RCTs) [32]. For non-RCTs, the PEDro
scale was accommodated to the number of items that were
To identify relevant articles regarding central pain processing applicable for each experimental design. For instance, criteria
in patients with SIS, a systematic search of the literature using number 2, 3, 6, 8, and 9 were not scored for cross-sectional and
712 M.N. Sanchis et al. / Seminars in Arthritis and Rheumatism 44 (2015) 710716
Besides evaluating the overall quality, information was Of the 10 selected studies, most were categorized as case
extracted for each included study about (I) study characteristics control (n 7); the other three were cross-sectional studies
(subjects, outcome measures, results regarding CS, and limitations without a control group. Seven articles were classied as etiolog-
of the study), (II) study purpose (etiology, treatment, and diag- ical studies, one as mixed etiologytreatment, and the remaining
nosis), and (III) study design (clinical trial, casecontrol, and cross- two were considered diagnostic studies. Four studies were per-
sectional). If the studies were focused on patients with SIS, the formed specically on subjects with SIS, while the other six
criteria used for diagnosis were retrieved. Finally, the results were included subjects with unilateral shoulder pain of different etiol-
analyzed, and the existing evidence regarding CS in SIS was ogies, in particular with rotator cuff tendinopathy, adhesive
summarized. capsulitis, or labral lesion. Of the four studies that studied CS in
713 hits Pubmed 738 hits Web of Science 449 hits EBSCO 2 hits from
other sources
Total of 1902
Aer screening in- and exclusion criteria 10 studies were eligible for methodological quality assessment
10 studies remain and were included and discussed in this systemac review
patients with SIS [8,14,18,36], two [8,36] specied the criteria used Lozano et al. [8] reported a prevalence of more than 90% of CS in
for reaching a diagnosis of SIS (Supplementary Table S3). their sample of chronic SIS patients. CS was inferred from presence
of widespread hyperalgesia and lower PPTs in subjects with
Risk of bias of individual studies chronic SIS as compared to matched controls.
Initially, there was a 94.5% agreement (104 of 110 items) Quantitative sensory testing (QST)
between the two assessors regarding the risk of bias score of the All the studies included in this review performed QST as a part
selected articles. After a second review, the researchers reached of their outcomes measures. Different modalities of QST were used
consensus in all but three items. A third author was recruited to for assessing sensory and pain perception, with the mechanical
resolve the discrepancy. The results of the risk of bias assessment stimulus being the most common form of external stimulation
are presented in Supplementary Table S2. employed (6/10 studies) [8,18,36,3840]. Most of the studies
Overall, the methodological quality of the studies was good. performed QST at local (i.e., on or in close proximity to the
Only two studies [18,37] did not obtain a score of at least 50% on shoulder) and distant sites (i.e., remote from the affected joint)
quality assessment. There were three studies [8,16,38] that in order to evaluate peripheral and central sensitization,
reached the maximal scoring (5/5) and consequently had the respectively.
lowest risk of bias. All the 10 studies that were retrieved for Four studies [8,14,18,40] demonstrated the presence of not only
methodological assessment were included in this review, and the local but also widespread hyperalgesia in patients with unilateral
characteristics and ndings of these studies are discussed below. shoulder pain [40], including those with SIS [8,14,18], when
compared to controls. Moreover, a higher degree of widespread
Evidence for central sensitization sensitization was associated with higher pain perception in sub-
jects with unilateral shoulder pain including SIS [8,14,16,41] and
The objective of this review was to summarize the current with poor prognosis after surgery intervention in SIS [14].
evidence regarding CS in people with unilateral shoulder pain of Descending modulation of pain has been evaluated through the
different etiologies, including those diagnosed with SIS. In the conditioned pain modulation (CPM) paradigm, which assesses the
following section, the results of this review will be structured activation of the descending endogenous analgesia system [42,43].
according to the different aspects of CS that were identied. If A cohort study studied CPM in subjects with unilateral shoulder
study ndings were restricted to patients diagnosed with SIS pain and healthy controls before and following shoulder surgery
solely, it will be specied. The term unilateral shoulder pain will [16]. At baseline, CPM did not differ between patients and controls,
be used to refer to non-neuropathic shoulder pain of different meaning that both the groups had the same absolute baseline
etiologies including rotator cuff pathology, adhesive capsulitis, or capacity for endogenous pain inhibition. In addition, in the
labral lesion. unilateral shoulder pain group, CPM remained unchanged after
surgery as compared to the pre-surgical assessment. In another
study by the same group [41], CPM stability within and between
Clinical manifestations of CS
sessions was investigated in subjects with unilateral shoulder pain
Gwilym et al. [14] evaluated QST to detect thresholds for
and it was found that uctuation of pain intensity did not
mechanical stimuli (sharp and blunt punctuate stimuli) and heat
signicantly inuence CPM stability.
pain in a sample of 17 patients with chronic SIS waiting for
Suprathreshold heat pain response (SHPR) is a perceptual
arthroscopic subacromial decompression and 17 pain-free con-
manifestation of enhanced central excitability, which it is used as
trols. In addition, referred symptoms were recorded. Patients with
a measure of enhanced descending facilitation of pain [16]. Four
chronic SIS, compared to asymptomatic subjects, experienced
studies [16,38,40,41] used SHPR within experimental pain sensi-
referred pain radiating down the arm and had signicant hyper-
tivity testing. The fth pain rating in a series of suprathreshold
algesia to punctuate stimulus of the skin. These ndings were
heat pain stimuli was the QST measure that best predicted
interpreted as peripheral manifestations of augmented central
shoulder pain intensity in subjects with unilateral shoulder pain,
pain processing (CS). Interestingly, the presence of either hyper-
even after psychological factors were considered [38]. One study
algesia or referred pain before surgery resulted in a signicantly
used SHPR only as the test stimulus for assessing CPM [41].
worse outcome 3 months after surgical decompression.
Coronado et al. [40] found bilateral sensitivity for SHPR in subjects
Hidalgo-Lozano et al. [8] explored the presence of myofascial
with unilateral shoulder pain as compared to pain-free controls,
trigger points (MTrPs) in six different muscles of the shoulder
which was interpreted as suggestive of CS. The severity of central
region in 12 patients with chronic SIS and 10 matched controls.
hyperexcitability measured with SHPR was elevated in patients
Moreover, they determined if the MTrPs were active or latent in
with unilateral shoulder pain and decreased after surgery to values
the affected side of patients with SIS and the dominant side in the
comparable to healthy subjects at baseline [16].
matched control group. Pressure pain thresholds (PPTs) were
assessed at these six locations of the shoulder region and at one
remote site (tibialis anterior). Subjects with SIS showed a greater Psychosocial inuences
number of active and latent MTrPs and signicant lower PPTs in all Elevated levels of psychosocial distress, including depression,
muscles (including the tibialis anterior) when compared to hypervigilance, catastrophizing, and fear avoidance, have been
matched controls. The presence of widespread pressure hyper- associated with many chronic musculoskeletal pain disorders. In
sensitivity, as observed in their sample of chronic SIS patients, was fact, there is evidence suggesting an association between CS and
interpreted as reective of CS [8]. maladaptive behaviors/thoughts [4447], often referred to as
Two studies gave data regarding prevalence of CS in patients cognitive-emotional sensitization [46,48]. Only two studies in this
with chronic SIS. Gwilym et al. [14] found that 65% of their patients review considered psychosocial issues related to unilateral
waiting for subacromial decompression presented features of shoulder pain [37,38].
augmented central pain processing in the form of extended The inuence of pain-related fear and pain catastrophizing on
referred pain areas radiating down the arm, signicant hyper- clinical pain intensity and experimental pain sensitivity using a
algesia to punctuate stimulus of the skin, and lower mechanical cold pressor task was evaluated by George and Hirsh [37]. They
pain threshold in areas distant of the injured tissue. Hidalgo- found that pain-related fear contributed to the variance in
714 M.N. Sanchis et al. / Seminars in Arthritis and Rheumatism 44 (2015) 710716
experimental pain sensitivity, while pain catastrophizing was the they are derived from only two studies that used different
only psychological variable inuencing clinical pain intensity. experimental pain sensitivity protocols. Larger longitudinal studies
Based on those results, the authors recommended consideration are needed to provide compelling evidence of the prevalence of CS
of fear-avoidance models when analyzing the pain experience of in subjects with shoulder pain. Nevertheless, the present review
subjects with unilateral shoulder pain. supports a role of CS in at least some patients with unilateral
The inuence of psychological factors (i.e., pain catastrophizing, shoulder pain, implying that some shoulder pain patients have
anxiety, and depression) on ability of QST (using heat and pressure altered central pain mechanisms contributing (or even dominat-
stimuli) to predict clinical pain intensity was examined [38]. SHPR ing) to the patients clinical picture [53]. Interestingly, some of the
was found to account for a signicant amount of variance in major classication criteria recently proposed for the classication
clinical pain intensity, even after psychological factors were of CS pain (i.e., presence of diffuse pain distribution and hyper-
considered. Subjects with unilateral shoulder pain and elevated algesia) [53] were found in this review to be characteristic of this
pain ratings in QST (suprathreshold heat pain stimuli), pain subgroup of patients.
catastrophizing, and depression had higher levels of clinical pain The severity of central hyperexcitability measured with SHPR did
intensity [38]. change in response to shoulder surgery [16]. This is in line with
Supplementary Table S4 summarizes current evidence regard- ndings from other studies, where surgical removal of the pre-
ing CS in unilateral shoulder pain including SIS. sumed source of nociception (i.e., total knee or hip replacement) did
resolve CS [54,55]. Although not included in this systematic review
Evidence rejecting central sensitization in shoulder pain due to later publication date, a study by Valencia et al [56] found
that changes in QST scores (i.e., difference between pre- and post-
Two studies retrieved in this review did not nd any evidence surgical assessments in SHPR), but not baseline measures of CS,
regarding the presence of CS in subjects with unilateral shoulder were predictive of surgical outcome in their sample of SIS patients.
pain [39] or SIS [36]. Alburquerque et al. [36] bilaterally evaluated Interventions specically addressing descending facilitatory
the presence of MTrPs over several shoulder muscles and PPTs, (e.g., cognitive-behavioral therapy) or descending inhibitory
including a remote site (tibialis anterior). They found data sup- mechanisms (e.g., exercise therapy) in patients with unilateral
porting a role for peripheral sensitization but refuting the presence shoulder pain, including SIS, were not identied in this review.
of central alterations [36]. Coronado et al. [39] found only Future research should examine the effect of treatment modalities
peripheral pain processes implicated in patients with unilateral and their inuence on outcome measures related to CS in this
shoulder pain, as reected by higher experimental pain sensitivity population. Results from this systematic review should increase
to pressure (i.e., lower PPTs) but not thermal stimuli in the clinicians awareness that CS is an important feature of chronic
involved side compared to the uninvolved side. In light of their shoulder pain and thus that treatments aiming at decreasing the
results, the authors concluded that pressure stimuli, such as hyperexcitability of the central nervous system in this population
palpation and mechanical stress testing, can be used to elicit [57] are warranted.
side-to-side differences but not to make determinations about Supraspinal descending facilitatory inuences are able to mod-
the existence of CS. ulate central hypersensibility and inuence the results of QST [58].
Only two studies [37,38] assessed the impact psychosocial factors
could have on psychophysical measures of CS in unilateral
Discussion shoulder pain. Psychosocial factors were found to contribute to
psychophysical measures of CS, suggesting that cognitive-
The aim of this article was to review and evaluate the existing emotional factors contribute to CS in unilateral shoulder pain.
scientic literature regarding the role of CS in unilateral shoulder Still, the small number of studies investigating these factors and
pain of different etiologies, including those with SIS. Different the cross-sectional nature of the studies preclude drawing rm
assessment methodologies were utilized for evaluating the phe- conclusions. Further experimental and prospective studies are
nomenon of CS, aiming to understand the different changes in pain required in order to examine the precise inuence of psychological
sensitivity observed in this population. Eight out of the 10 articles factors on the processing of sensory input in patients with
that were considered in this review seem to support an emerging unilateral shoulder pain, including those diagnosed with SIS.
key role for CS in unilateral shoulder pain, including those with To date there is no gold standard for diagnosis of CS [9].
SIS. This was conrmed through means of different subjective (e.g., Different clinical and laboratory methods are employed for detect-
enlarged radiation of pain) and objective parameters (e.g., wide- ing potential involvement of CS in musculoskeletal pain conditions
spread hyperalgesia). All these ndings are considered clinical (i.e., QST and brain imaging techniques), with no more superior or
manifestations of CS [49]. Furthermore, similar ndings have been reliable method than others. All of them assessed the same basic
previously demonstrated in other chronic pain conditions such as biological concept (CS), but in its different manifestations related
whiplash [50] or chronic low back pain [51], suggesting these to the different aspects of sensitization [15]. For instance, wide-
conditions arise by the same altered mechanism of central pain spread hyperalgesia, which is a manifestation of CS, can be
processing. assessed quantitatively in a standardized way using sensory tests,
CS manifests itself at different degrees over a continuum from such as pressure algometry. This review did not retrieve any study
none at all to severe. Although prevalent in chronic pain, gener- evaluating induced referred muscle pain in the context of shoulder
alized central hypersensitivity is not present in every patient [52]. pain for evaluating generalized hyperalgesia (CS), as previously
For instance, in some populations (e.g., bromyalgia), CS may be done for whiplash [59] or osteoarthritis [60]. The majority of the
the characteristic feature of the disorder. In others, such as in studies of the current review assessed the presence of CS in
shoulder pain, not all patients have CS, but only a subgroup of laboratory conditions, using costly and inaccessible equipment
them have it. Although the presence of peripheral sensitization in for most clinicians. Further investigation regarding the assessment
subjects with unilateral shoulder pain, including those with SIS, is of CS in shoulder pain is required in order to provide new
irrefutable, as was reported by several studies included in this assessment methodologies for CS, which are more accessible and
review [8,18,36,39,40], our review revealed a subgroup of subjects less costly for the clinicians. In this view, the recently proposed
with CS [between 65% and 90% of (SIS) pain] [8,14]. However, these clinical classication criteria for CS pain [53] are worthwhile
prevalence numbers should be interpreted with caution because investigating in patients with chronic shoulder pain.
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