The Journal of Pain, Vol 20, No 12 (December), 2019: pp 1394−1415

Available online at www.jpain.org and www.sciencedirect.com

Pain-Related Fear, Pain Intensity and Function in

Individuals With Chronic Musculoskeletal Pain:
A Systematic Review and Meta-Analysis
Javier Martinez-Calderon,* Mar Flores-Cortes,y Jose Miguel Morales-Asencio,z,x and
Alejandro Luque-Suarez*,x
*
Faculty of Health Sciences, Department of Physiotherapy, University of Malaga, Malaga, Spain.
y
Private Clinical Practice, Malaga, Spain.
z
Faculty of Health Sciences, Department of Nursing, University of Malaga, Malaga, Spain.
x
Instituto de Investigacio
n Biome
dica de Ma
laga (IBIMA), Malaga, Spain.

Abstract: Pain-related fear is considered a strong psychological predictor for both chronic pain and
disability. The aims of this study were to systematically review and critically appraise the concurrent
association and the predictive value of pain-related fear affecting both pain intensity and disability in
individuals with chronic musculoskeletal pain (MSK). PubMed, AMED, CINAHL, PsycINFO, PubPsych,
and the grey literature were searched from inception to January 2019. Observational studies reporting
cross-sectional and longitudinal associations between pain-related fear and pain intensity and/or dis-
ability were included. The GRADE criteria judged whether the overall quality and strength of the evi-
dence was high or low in terms of risk of bias, inconsistency, indirectness, imprecision and publication
bias. Seventy observational studies (97% cross-sectional) were included with a total sample of 15,623
individuals (63.56% females) with chronic MSK. Pain-related fear is composed of fear of pain, pain-
related anxiety, and fear-avoidance beliefs. Greater levels of fear of pain, pain-related anxiety, and
fear-avoidance beliefs were significantly associated with greater pain intensity and disability. How-
ever, the quality and strength of the evidence was very low owing to the imprecision of results, risk of
bias, indirectness, and publication bias were common across the included studies. Despite these limita-
tions, these findings highlight the potential role that pain-related fear may play in chronic MSK and
disability. The field would benefit from research using higher quality studies and longitudinal designs.
Perspective: This article presents promising results about the concurrent association between pain-
related fear and both pain intensity and disability in individuals with chronic MSK. Nevertheless, the
overallqualityandstrength of theevidencewasvery lowinterms of riskof bias,indirectness,imprecision,
andpublicationbias.Thus,thefindingsshouldbetakenwithcaution,andfurtherresearchis needed.
PROSPERO: CRD42018082018
© 2019 by the American Pain Society
Key Words: Chronic pain, musculoskeletal pain, fear, psychological factors, systematic review.

C
hronic pain is a global health issue.50 The most
prevalent chronic pain condition is chronic mus-
culoskeletal pain (MSK).21 The global prevalence
of chronic MSK ranges from 11.4 to 60%.27 It is the sec-
ond cause of physical and work disability after mental
and behavioral disorders.28,54,154 The socioeconomic
burden owing to chronic MSK is huge for the individual
and society.114,154 Direct (eg, opioid consumption) and
indirect (eg, loss productivity) annual economic costs
amount to €164.7 billion13 and U.S.$576 billion145 in
Europe and the United States, respectively. The social
and psychological consequences are also critical in terms

Javier Martinez-Calderon, a PhD student at the University of Malaga, is
funded by the University of Malaga through a predoctoral grant. All
authors have made a substantial scientific contribution to the study and
are thoroughly familiar with the primary data. All authors have read the
complete manuscript and take responsibility for its content and
completeness.
Supplementary data accompanying this article are available online at
www.jpain.org and www.sciencedirect.com.
The authors have no conflicts of interest to declare.
Address reprint requests to Javier Martinez-Calderon, Faculty of Health
Sciences, University of Malaga, Arquitecto Francisco Penalosa, 3, 29071
Malaga, Spain. E-mail: calderonjmc@uma.es
1526-5900/$36.00
© 2019 by the American Pain Society
https://doi.org/10.1016/j.jpain.2019.04.009

1394
Martinez-Calderon et al
141 141
of sleep disturbances, depression, social exclu-
sion,19 suicidal ideation,141 and premature mortality.121
Many interventions have been proposed to improve
chronic MSK symptoms.11,25,110,118 However, its recur-
rence and persistence is frequent,27,54 which results in
an enormous challenge for clinicians and researchers.140
The specific mechanisms that impact the development
and course of chronic MSK remain unclear. Biological,
biomechanical, environmental, psychological, and social
factors have been associated with the onset and perpet-
uation of chronic MSK.30,52,77
Psychological factors are probably the most influen-
tial factors in the perception, processing, interpretation,
and coping with chronic pain.94,124 Fear is one of the
psychological factors that has received extra empirical
attention in the last 2 decades.7,40,93,37,164 It is defined
as the emotional reaction to a determined, identifiable,
and immediate threat that causes specific physiological,
cognitive, and behavioral responses to deal with that
threat.1 Fear learning is commonly based on classical
conditioning, where an aversive unconditioned stimulus
is recurrently paired with a neutral conditioned stimulus
and thus provokes fear responses to that conditioned
stimulus.91 In humans, fear can be further acquired
through social observation119 and verbal instructions.109
Verbal processes are invariably involved in the cultural
learning of fear, through conditioning, social learning,
and modeling.109,119 Fear could be verbally transmitted
through cultural learning, which is as important as asso-
ciative experiences in the development, maintenance
and transmission of fear.118 Indeed, individuals may
assign meaning to and interpret the traumatic experien-
ces through their own self-instructions.89 Fear learning is
an adaptive survival mechanism that aims to identify real
or potential signal threats (eg, pain) to initiate appropri-
ate defensive behaviors (eg, escape) that prevent us from
damage.35 However, these behaviors can be counterpro-
ductive in the long term, because they may facilitate the
overgeneralization of fear in response to determined
stimuli that do not entail an objective risk.43
In the context of pain, pain-related fear has been
described as fear of pain, fear-avoidance beliefs, pain-
related anxiety, fear of movement, and kinesiophobia.95
These constructs are often used interchangeably, even
though they are not synonyms. Fear of pain has been
broadly defined, using terms such as fear of injury, fear
of physical activity, and so forth.8 Fear-avoidance beliefs
refer to a fear of physical and work activities that may
elicit pain.88 For example, the avoidance of a deter-
mined social task such as going out with friends owing
to fear of worsening symptoms. Pain-related anxiety is a
future-oriented affective state characterized by the
motivation of individuals to engage in preventive
behaviors such as hypervigilance in the response to
pain.87 The fear of movement is defined as the fear of
executing a particular movement or physical activity
that is wrongfully assumed to cause reinjury.151 Kinesio-
phobia is the extreme form of the fear of movement.117
It is an intense and irrational fear of executing a deter-
mined movement, owing to a feeling of vulnerability to
a painful injury or reinjury.79
The Journal of Pain 1395
Different models of pain propose that pain-related fear
plays a pivotal role in the onset and perpetuation of
chronic pain and disability.5,6,87,152 Consistent with these
models, some evidence has shown how greater baseline
pain-related fear levels predict the transition to chronic
low back pain160 and the maintenance of chronic MSK
and disability.97 In chronic MSK, the overgeneralization
of fear promotes maladaptive hypervigilance and avoid-
ance behaviours,152 which has been associated with more
pain,95 disability,95 attention to pain,125 work absentee-
ism,148 and a lower quality of life.95 Pain-related fear also
mediates the relationship between MSK and disability,86
as well as moderating the effects of physiotherapy,48 cog-
nitive-behavioral therapy,17 and multidisciplinary inter-
ventions47 over pain-related outcomes.
The role of pain-related fear in the development
and perpetuation of chronic pain has been explored
in previous reviews.81,97,144,159,160,163 Nevertheless, the
risk of bias as well as the quality and strength of the
evidence were not evaluated.81,163 The conclusions of
previous systematic reviews were limited to kinesio-
phobia95 and a fear of falling.144 The role of pain-
related fear in the transition to chronic pain160 and
its influence in treatment outcomes159 have also
been explored. In contrast, the concurrent association
and predictive value of pain-related fear on pain
intensity and disability in chronic MSK is unavailable.
Thus, a systematic review may identify key knowl-
edge gaps for future studies and allow stronger con-
clusions than those achieved by any original article.26
Given these considerations, the aim of this study was
to systematically, critically, and objectively synthetize
all the available evidence to i) estimate the concur-
rent association between pain-related fear and both
pain intensity and/or disability and ii) assess the pre-
dictive value of baseline pain-related fear in the
maintenance of pain intensity and disability over
time in samples of patients with chronic MSK based
on an analysis of observational studies.
Methods
The current systematic review followed the PRISMA
statement.90 The review protocol was registered at the
International Prospective Register of Systematic Reviews
(PROSPERO: CRD42018082018) before the identification
of articles and data extraction.
Data Sources and Search Strategy
One reviewer (J.M.C.) conducted an exhaustive
scoping search to ensure that our research objectives
had not been addressed by previous reviews. The fol-
lowing databases were explored in an initial scoping
search: PROSPERO, Cochrane Library, National Insti-
tute for Health and Care Excellence Evidence Search,
and Turning Research into Practice. Afterwards, 2
reviewers (J.M.C. and M.F.C.) independently searched
the following electronic databases from inception of
each database to January 2019 to retrieve all poten-
tial studies which could satisfy our inclusion criteria:
PubMed, The Allied and Complementary Medicine
1396 The Journal of Pain
(AMED), The Cumulative Index to Nursing and Allied
Health Literature (CINAHL), PsycINFO, and PubPsych.
A robust search strategy was design by using search
terms from Medical Subject Headings (MeSH) as well
as keywords generated from subject headings, as fol-
lows: “chronic pain" [MeSH Terms], "shoulder pain"
[MeSH Terms], "neck pain" [MeSH Terms], "low back
pain" [MeSH Terms], "musculoskeletal pain" [MeSH
Terms], "musculoskeletal diseases" [MeSH Terms],
"fibromyalgia" [MeSH Terms], "arthritis" [MeSH
Terms], "osteoarthritis" [MeSH Terms], "rheumatoid
arthritis" [MeSH Terms], "spondylarthritis" [MeSH
Terms], “spondylitis, ankylosing" [MeSH Terms],
"fear" [MeSH Terms], widespread pain, knee pain,
hip pain, ankle pain, epicondylalgia, musculoskeletal
disorders, osteoarthrosis, avoidance, pain-related
fear, fear-avoidance beliefs, fear of movement, and
pain-related anxiety. The full search strategy report is
listed in Appendix A. Additionally, manual searches
were performed, including journals that have pub-
lished articles related to the topic of this review as
well as references lists of the included studies. The
grey literature was also searched to identify any rele-
vant unpublished work. The grey literature included
the NHS Evidence, New York Academy of Medicine
Grey Literature Report, Explore the British Library,
National Guideline Clearinghouse, Open Grey, and
Google Scholar.65 A citation management software in
Mendeley (Mendeley desktop v1.17.4, Elsevier, New
York, New York) and hand checked83 were used to
remove duplicates.
Eligibility Criteria
Based on the PICO framework (P = population;
I = intervention; C = comparator; O = outcome)72 the
PECO framework (P = population; E = exposure; C = com-
parator; O = outcome) was followed by 2 reviewers (J.M.
C. and M.F.C.) independently to determine which stud-
ies satisfied our inclusion criteria. No year of publica-
tion, publication status, ethnicity, gender, or age
restrictions were imposed.
Inclusion criteria were:
1. Adults with chronic MSK (pain duration of >3
months) according to the multidimensional diagnos-
tic criteria for chronic pain.42 Musculoskeletal axial
(neck, back, and/or low back) and peripheral (shoul-
der, elbow, wrist, knee, and/or ankle) pain condi-
tions were included as well as MSK diagnoses such
as chronic myofascial pain, fibromyalgia, chronic
widespread pain, rheumatoid arthritis, spondyloar-
thropathies, and osteoarthritis.
2. Observational studies evaluating either the concur-
rent association or the predictive value of pain-
related fear on both pain intensity and disability.
3. Studies must report ≥1 statistic estimation (eg, corre-
lation) between pain-related fear measures with
pain intensity and/or disability.
4. Only studies written in Spanish and/or English were
considered.
Fear in Chronic Musculoskeletal Pain
Exclusion criteria were:
1. Studies analyzing samples of MSK with a duration of
<3 months or with chronic non-MSK based on the
multidimensional diagnostic criteria for chronic
pain.40
2. Studies reporting mixed MSK samples regarding
pain duration (acute, subacute, and chronic pain)
where statistical analyses were not separately con-
ducted by pain duration.
3. Studies examining pain-related fear in chronic MSK
after surgery.
4. Studies aiming to modify pain-related fear levels in
the context of a clinical trial (eg, exposure in vivo).
5. Studies exploring the influence of pain-related fear
on treatment outcomes (pain intensity and disabil-
ity) after intervention.
6. Studies examining the role that fear plays in human
laboratory models of pain.
7. Studies assessing pain-related fear through the
Tampa Scale for Kinesiophobia.78 Although this
questionnaire has been used to measured fear in
general, a recent review has shown that this tool is
exclusive to assess kinesiophobia.94
8. Case reports, case series, expert opinions, qualitative
studies, reviews, clinical trials, randomized con-
trolled trials, protocols, and abstract.
Study Selection
During the selection process, 2 reviewers (J.M.C. and
M.F.C.) independently followed a short checklist2 based
on the eligibility criteria previously listed (Appendix B).
In the first step, potential articles were screened by title
and abstract. In the second step, the full text of selected
articles were screened. A consensus determined the
study selection. A third reviewer (A.L.S.) solved possible
disagreements (this step was never required).
Data Extraction
Two reviewers (J.M.C. and M.F.C.) independently per-
formed the data extraction process. Study details (first
author and year of publication), sample size, partic-
ipant’s characteristics (mean age, gender, ethnicity,
mean pain duration, mean educational level, and
chronic pain condition), pain-related fear measure(s),
outcome (pain intensity and disability) measure(s), dura-
tion of follow-up (in case of a longitudinal cohort
study), and study design were extracted. A consensus
determined the data extraction. A third reviewer (A.L.
S.) solved any discrepancy between reviewers (this step
was never required). When necessary, the original
authors were contacted by email to obtain further
details.
Risk of Bias Assessment
Two reviewers (J.M.C. and M.F.C.) independently
assessed the risk of bias across the included studies. The
Newcastle-Ottawa Scale is a review tool recommended
Martinez-Calderon et al
to evaluate the presence of risk of bias on non-random-
ized studies.158,165 An adapted version of the Newcastle-
Ottawa Scale was used to analyze the risk of bias in
cross-sectional studies because a specific review tool is
unavailable.16 It has been used in previous systematic
reviews.101 This tool includes 4 risk of bias domains: i)
selection bias (methods for selecting study participants),
ii) performance bias (methods to control for confound-
ing), iii) detection bias (statistical methods), and iv)
information bias (methods of exposure and outcome
assessment). Seven items assess these 4 domains. Each
item is scored from 0 (high risk) to 3 (low risk). There-
fore, studies with a total score from 0 to 6 were rated as
high risk of bias, whereas total score from 7 to 13 and
14 to 21 were rated as moderate and low risk of bias,
respectively.102 The Quality in Prognostic Studies tool is
recommended to assess the risk of bias in longitudinal
cohort studies.68 This tool evaluates the methodologic
quality of studies included in meta-analytic researches.
The Quality in Prognostic Studies tool determines
the presence of low, moderate, or high risk of bias
based on 6 study domains, namely, selection of partici-
pants, study attrition, prognostic factor measurement,
outcome measurement, study confounding, and statisti-
cal analyses.
Inter-Rater Reliability
Inter-rater reliability across reviewers was determined
by percentage of agreement and Cohen’s kappa coeffi-
cient (k).29,106 There was strong agreement between
reviewers for the screening records and full texts (90%
agreement rate and k = 0.8), the data extraction process
(93% agreement rate and k = 0.87), the risk of bias
assessment (90% agreement rate and k = 0.8) and the
quality and strength of the evidence assessment (95%
agreement rate and k = 0.88).106
Data Synthesis and Analysis
Two independent reviewers (J.M.C. and A.L.S.) judged
the quality and strength of the evidence for each pain-
related fear outcome. The Grading of Recommenda-
tions Assessment, Development and Evaluation (GRADE)
criteria are used to detect the presence of risk of bias,
flaws, and errors in data management, as well as to
assess the strength of research evidence and recommen-
dations and allow downgrading the input of studies
with weaker evidence of support.9,64,134 The GRADE cri-
teria classify9,64,134 the evidence as follows: i) high (we
are very confident that the true effect lies close to that
of the estimate of the effect), ii) moderate (we are mod-
erately confident in the effect estimate: the true effect
is likely to be close to the estimate of the effect, but
there is a possibility that it is substantially different), iii)
low (our confidence in the effect estimate is limited and
the true effect may be substantially different from the
estimate of the effect), and iv) very low (our confidence
in the effect estimate is very little; the true effect is likely
to be substantially different from the estimate of
effect).
The Journal of Pain 1397
The quality of the evidence was downgraded 1 (seri-
ous) or 2 (very serious) categories9,64,134 according to
the following considerations:
1. Risk of bias: >50% (serious) or 75% (very serious) of
the information comes from studies with a high or
moderate risk of bias that can sufficiently affect the
interpretation of the results.
2. Inconsistency: >50% (serious) or 75% (very serious)
of the results are inconsistent in terms of effects in
opposite directions or large variations in the degree
to which the outcome is affected (eg, very large and
very small effects or nonsignificant effect). Further-
more, when high heterogeneity was revealed in
meta-analysis (I2 > 50%),70,71 the GRADE criteria
judged inconsistency as serious.
3. Indirectness: >50% (serious) or 75% (very serious) of
the included studies present indirectness in terms of
population (eg, only older people were included
when the review was focused on a larger range of
age) and outcomes (eg, different self-reported tools
to assess the same outcome).
4. Imprecision: >50% (serious) or 75% (very serious) of
the included studies show 95% confidence intervals
(CIs) with wide range (it does not exclude 1.0) and
present small effects in both directions or the 95%
CI is not reported.
5. Publication bias: the GRADE recommendation only
low 1 level at a maximum (not 2) based on suspected
publication bias.
Meta-analyses were conducted by using Stata statisti-
cal software, version 14.0 (Stata Corp, College Station,
Texas).142 The pooled association between pain-related
fear and both pain intensity and disability was com-
puted across the included studies. The following meta-
analyses were carried out: i) pain-related anxiety and
pain intensity, ii) pain-related anxiety and disability, iii)
fear-avoidance beliefs physical activity subscale and
pain intensity, iv) fear-avoidance beliefs physical activity
subscale and disability, v) fear-avoidance beliefs work
subscale and pain intensity, and vi) fear-avoidance
beliefs work subscale and disability. Owing to the scarce
number of studies (k) that evaluated the association
between fear of pain and either pain intensity (k = 1) or
disability (k = 3), meta-analyses for fear of pain were
impossible. Furthermore, studies reporting fear-avoid-
ance beliefs based on the total score of the fear-avoid-
ance beliefs questionnaire were also discarded from
meta-analyses. They were incompatible with those stud-
ies that separately analyzed the 2 subdomains of the
fear-avoidance beliefs questionnaire, namely, the physi-
cal activity and work subscales.
Meta-analyses were performed using standardized b
coefficients and their 95% CIs as association measures,
and random effect models with the inverse of vari-
ance method.69 When no standard errors were
reported, they were calculated from the standardized
b coefficients and P values presented in each study.116
Studies were also excluded from meta-analyses if they
provide insufficient data for computing standard
1398 The Journal of Pain
errors. A positive standardized b coefficient indicated
that greater pain-related fear measures were associ-
ated with more pain intensity and disability. Hetero-
geneity was explored by using the I2 statistic. It
represents the percentage of variation across studies,
which is due to heterogeneity rather than chance.70,71
A value of >25% is considered to reflect low hetero-
geneity, 50% moderate heterogeneity, and 75% high
heterogeneity.70,71 Observed heterogeneity between-
study variance was evaluated by t 2. Additionally, pre-
diction intervals were computed to estimate true
effects. When meta-analyses revealed high heteroge-
neity, sensitivity analyses were conducted by chronic
MSK condition and by reported statistical estimation
(pure correlation versus b coefficient) to estimate pos-
sible sources of heterogeneity. A metaregression anal-
ysis was also computed to estimate the influence of
risk of bias and female gender.12,66 Residual variation
owing to heterogeneity was assessed by residual I2,
and the proportion of between study variance by
adjusted R2. Publication bias was explored by visual
inspection of the funnel plot.44 In the absence of pub-
lication bias, a funnel plot is symmetrical in shape
Fear in Chronic Musculoskeletal Pain
(the points will be scattered in the shape of a funnel
centrally around the total overall estimated effect). In
contrast, publication bias is suspected when the fun-
nel plot is asymmetrical.69 Finally, a narrative synthesis
was conducted to separately analyze cross-sectional
and longitudinal cohort studies.
Results
A total of 15,703 citations were identified through
electronic databases, with 50 additional studies iden-
tified through reference screening and the grey liter-
ature. The authors screened a total of 8,973 titles
and abstracts after removing duplicates. Of these,
authors evaluated 622 full texts. A total of 70 obser-
vational studies (68 cross-sectional and 2 longitudinal
cohort studies) satisfied our eligibility criteria and
were included in the present review. The number of
studies retrieved from each database and the number
of studies excluded in each screening phase are
shown in Fig 1. The full reference list of the excluded
studies in the last screening (n = 552) is reported in
Appendix C.

Records identified through database

searching
(n =15,703)
PubMed n=6,185
Idenficaon

PsycINFO n=3,980
CINAHL n=2,747 Additional records identified
PubPsych n=1,915 through other sources
AMED n=876 (n =50)

Records after duplicates removed

Records excluded by title
(n =8,973)
and abstract
Screening

(n =8,351)

Records screened Full-text articles excluded,

(n =8,973) with reasons
(n =552)
Ineligible if:

1. Not observational design

Full-text articles assessed (104)
for eligibility 2. Not chronic musculoskeletal
Eligibility

pain (138)
(n =622) 3. Not association between pain-
related fear and pain intensity;
disability; or both (97)
4. Pain-related fear tested in the
context of a behavioral task or
treatment (37)
5. Pain-related fear measured in
surgical samples (18)
6. Pain-related fear measure with
the tampa scale for
kinesiophobia (151)
Included

Studies included in 7. Pain-related fear measured in

quantitative synthesis laboratory (3)
8. Pain-related fear after trauma
(n =70) (4)

Figure 1. PRISMA flow diagram of the conducted search.

Martinez-Calderon et al
Characteristics of the Included Studies
A total sample of 15,623 (63.56% females) individuals
with chronic MSK were included in this review (low
back pain: k = 45, N = 6,312; mixed samples of chronic
MSK: k = 11, N = 2,775; neck pain: k = 5, N = 342; rheuma-
toid arthritis: k = 4, N = 5,419; chronic widespread pain:
k = 3, N = 245; osteoarthritis: k = 2, N = 367; and upper
limb pain: k = 1, N = 163). The sample size ranged from
27 to 2,819 participants. The mean age fluctuated from
31.42 years (standard deviation 12.06 years) to 79.74
years (standard deviation 5.77 years). Chronic MSK dura-
tion ranged from 3 months to 14.82 years. Only 18.57%
of the included studies reported the ethnicity of the
sample, with Caucasian and white being the most com-
mon ethnic groups. Pain-related fear was retrieved as
fear-avoidance beliefs (74%), pain-related anxiety
(23%), and fear of pain (6%). Fear-avoidance beliefs
was commonly measured with the fear-avoidance
beliefs questionnaire.155 The Photograph Series of Daily
Activities82 and the Pictorial fear of activity scale-cervi-
cal149 were also used to assess fear-avoidance beliefs.
Pain-related anxiety was evaluated through the Pain
Anxiety Symptoms Scale103 and a short form of the Pain
Anxiety Symptoms Scale.102 Fear of pain was assessed
using the Fear of Pain Questionnaire107 and the Pain
Induced Fear Scale.131 The characteristics of the included
studies are reported in Appendix D.
Risk of Bias Assessment
The risk of bias for cross-sectional studies was evalu-
ated through an adapted version of the Newcastle-
Ottawa Scale. In general terms, 54 studies (79%)
reported a moderate risk of bias whereas 14 studies
(21%) showed a low risk of bias. Selection bias (78%),
performance bias (inadequate sample size and insuffi-
cient power [79%], analyses unadjusted for potential
covariate [79%]), and detection bias (lack of appropri-
ate statistical analysis [46%]) were common across the
included studies. Most of the included studies did not
show attrition and information bias (Table 1).
The Quality in Prognostic Studies tool analyzed the
risk of bias for longitudinal cohort studies. Two longi-
tudinal cohort studies were evaluated.61,128 Grotle et
al.61 reported a low risk of bias for study attrition; a
moderate risk of bias for study confounding, statisti-
cal analysis, study participation, and outcome mea-
surement; and a high risk of bias for prognostic factor
measurement. Pinto et al128 reported a moderate risk
of bias for study participation, outcome measure-
ment, and study cofounding, and a high risk of bias
for study attrition, statistical analysis, and prognostic
factor measurement.
The Overall Quality and Strength of the
Evidence Based on the GRADE Criteria
The application of GRADE criteria attained very low
evidence across the included studies (Table 2 for cross-
sectional studies and Table 3 for longitudinal cohort
studies).
The Journal of Pain 1399
Fear of Pain and Pain Intensity:
Cross-Sectional Analysis
Greater levels of fear of pain were significantly associ-
ated with greater levels of pain intensity in a mixed sam-
ple of chronic MSK (standardized b = 0.34; standard
error = 0.03; P < .0005).32
Fear of Pain and Disability:
Cross-Sectional Analysis
Greater levels of fear of pain were significantly associ-
ated with greater levels of disability in chronic low back
pain (r = .62; P < .001).75 Fear of pain was not related to
disability in mixed samples of chronic MSK.38,105
Pain-Related Anxiety and Pain Intensity:
Cross-Sectional Analysis
Greater levels of pain-related anxiety were signifi-
cantly associated with greater pain intensity in rheuma-
toid arthritis (r = .22; P < .05143), chronic widespread
pain (r = .43; P < .01100,132), and mixed samples of
chronic MSK (r = .22, P < .00121; r = .30, P < .00583; r = .34,
P < .001102). However, the results were ambiguous in
terms of statistical significance regarding the associa-
tion between pain-related anxiety and pain intensity in
chronic low back pain.80,89,126,130,136,137
A meta-analysis was conducted to evaluate the
strength of the association between pain-related anxi-
ety and pain intensity (Fig 2). The pooled results
revealed a weak association between both variables
(standardized b = 0.29; 95% CI = 0.23−0.36; P < .01). The
heterogeneity across the included studies was low
(I2 = 35.9%). Additionally, a metaregression analysis was
performed to detect potential moderators of this associ-
ation. Females gender (standardized b = .39; 95% CI = -
0.15 to 0.93; P = .118) and risk of bias (standardized
b = -0.16; 95% CI = -0.34 to 0.31; P = .900) did not moder-
ate the association between pain-related anxiety and
pain intensity. The funnel plot showed asymmetry,
which means that publication bias could exist
(Appendix E).
Pain-Related Anxiety and Disability:
Cross-Sectional Analysis
Greater levels of pain-related anxiety were signifi-
cantly associated with greater levels of disability in
chronic low back pain (r = .39, P < .001136; r = .40, P <
.05125; r = .41, P < .01137; r = .54, P < .0187; r = .64, P <
.01146) chronic upper limb pain (r = .49, P < .0135) and
mixed samples of chronic MSK (r = .44, P < .001102;
r = .46, P < .00121; r = .61, P < .001103). There was no asso-
ciation between pain-related anxiety and disability in a
sample with rheumatoid arthritis.143 The results were
ambiguous in terms of statistical significance in the asso-
ciation between pain-related anxiety and disability in
chronic widespread pain.99,100
The strength of the association between pain-related
anxiety and disability was evaluated through a meta-
1400 The Journal of Pain Fear in Chronic Musculoskeletal Pain
Risk of Bias Assessment of Cross-Sectional Studies (The Newcastle Ottawa Scale adapted
Table 1.
version)
FIRST AUTHOR SELECTION BIAS PERFORMANCE BIAS DETECTION BIAS INFORMATION BIAS TOTAL SCORE

A B C D E F G

Askary-Ashtiani et al.3 2 2 0 1 3 2 2 12/21

Aslan Telci et al4 1 0 0 1 0 2 3 7/21
Ayre and Tyson et al10 1 0 2 2 3 2 2 12/21
Van Baar et al150 1 0 2 3 3 2 3 14/21
Basler et al15 2 3 1 2 3 3 2 16/21
Brede et al20 2 2 0 1 3 1 2 11/21
Briggs et al22 0 0 0 1 3 3 2 9/21
Camacho-Soto et al23 1 0 3 2 3 2 3 14/21
Crombez et al32 1 0 3 2 3 2 2 13/21
Crombez et al31 1 0 1 2 2 1 1 8/21
Das De et al34 2 2 2 1 3 2 2 14/21
Dehghani et al38 1 0 0 3 2 2 2 10/21
Demmelmaier et al39 1 0 1 2 2 2 2 10/21
Diaz-Cerrillo et al33 1 0 0 1 3 2 2 9/21
Du et al41 2 3 1 3 3 2 2 16/21
Elsig et al45 2 2 1 1 3 1 2 12/21
Esteve et al46 1 0 0 2 2 3 2 10/21
French et al49 1 0 1 2 3 2 2 11/21
Friedrich et al51 1 1 1 1 3 1 2 10/21
Gay et al53 0 0 1 3 3 2 2 11/21
George et al56 1 0 1 1 3 2 2 10/21
George et al58 1 0 1 2 3 3 2 12/21
George et al57 2 2 2 2 3 2 2 15/21
George et al55 2 2 1 2 3 2 2 14/21
Georgoudis et al59 1 0 0 1 3 2 2 9/21
Grotle et al62 1 0 3 3 3 2 2 14/21
Grotle et al60 1 0 0 1 3 2 2 9/21
Guclu et al63 1 0 1 2 3 2 2 11/21
Igwesi-Chidobe et al73 3 2 1 2 3 2 2 15/21
Kaka et al75 1 0 0 1 3 2 2 9/21
Karoly et al76 3 2 2 3 0 3 2 15/21
Kim et al78 1 0 0 1 3 3 2 10/21
Kreddig and Hasenbring80 1 0 1 1 3 3 2 11/21
Larsen et al84 1 0 0 1 3 2 2 9/21
Laufer et al85 1 0 0 1 3 3 2 10/21
Le Borgne et al18 1 0 1 2 3 2 2 11/21
Lewis et al89 1 0 0 1 3 2 2 9/21
€o
Lo € f et al92 1 0 1 2 3 2 2 11/21
Lundgren et al96 1 0 1 2 3 2 2 11/21
Marshall et al98 2 3 2 3 3 2 2 17/21
Martinez et al100 2 2 2 2 3 3 2 16/21
Martinez et al99 2 0 1 1 3 3 2 12/21
McCracken et al105 1 0 1 2 3 2 2 11/21
McCracken and Dhingra104 1 0 0 1 3 2 2 9/21
Melton et al108 1 0 0 2 3 2 2 10/21
Meyer et al111 1 0 0 1 3 2 2 9/21
Meyer et al112 1 0 1 2 3 2 2 11/21
Monticone et al113 1 0 0 1 3 2 2 9/21
Nava-Bringas et al115 2 3 0 1 3 2 2 13/21
Osborn and Jull120 1 0 0 1 3 2 3 10/21
Panhale et al123 1 0 0 1 3 3 2 10/21
Peters et al126 1 0 2 2 3 2 2 12/21
Pfingsten et al127 1 0 1 2 2 2 2 10/21
Ram
ırez-Maestre et al129 1 0 0 1 3 3 2 10/21
Robinson et al 130 1 0 0 1 3 2 2 9/21
Sanchez et al133 1 0 0 1 3 2 2 9/21
Sanchez et al132 1 0 1 2 3 3 2 12/21
Scopaz et al135 1 0 3 2 3 3 2 14/21
(continued on next page)
Martinez-Calderon et al The Journal of Pain 1401
Table 1. Continued
FIRST AUTHOR SELECTION BIAS PERFORMANCE BIAS DETECTION BIAS INFORMATION BIAS TOTAL SCORE

A B C D E F G

Seekatz et al136 1 0 1 1 3 3 2 11/21

Shanbehzadeh et al137 1 0 0 1 3 2 2 9/21
Sions and Hicks 139 1 0 3 2 3 2 2 13/21
Strahl et al143 1 0 3 2 2 3 2 13/21
Thibodeau et al146 1 0 0 1 3 3 2 10/21
Thomas et al147 1 0 0 1 3 2 2 9/21
Waddell et al155 1 0 1 2 3 1 2 10/21
Walker et al156 0 0 1 2 3 2 2 10/21
Wand et al157 2 3 2 2 3 1 1 14/21
Woby et al161 1 0 1 2 3 2 2 11/21

Note: low risk of bias (score from 14/21 to 21/21); moderate risk of bias (score from 7/21 to 13/21); high risk of bias (score from 0/21 to 6/21); A = Is the source popu-
lation appropriate and representative of the population of interest?; B = Is the sample size adequate and is there sufficient power to detect a meaningful difference in
the outcome of interest?; C = Did the study identify and adjust for any variables or confounders that may influence the outcome?; D = Did the study use appropriate
statistical analysis methods relative to the outcome of interest?; E = Is there little missing data and did the study handle it accordingly?; F = Is the methodology of the
outcome measurement explicitly stated and is it appropriate?; G = Is there an objective assessment of the outcome of interest?

analysis. The pooled results showed a moderate associa-
tion between both variables (standardized b = 0.42;
95% CI = 0.35−0.50; P < .01), even though the heteroge-
neity across the included studies was high (I2 = 66.2%;
Fig 3). Thus, sensitivity analyses by chronic MSK condi-
tion were carried out. Only chronic widespread pain
(standardized b = .19; 95% CI = 0.04−0.33; I2 = .0%
P = .688) reduced the heterogeneity. The heterogeneity
remained high in chronic low back pain (standardized
b = .50; 95% CI = .43−0.58; I2 = 59.9%; P = .058), chronic
upper limb pain (standardized b = 0.38; 95% CI = 0.25
−0.51; I2 = 68.1%; P = .043) and mixed samples of chronic
MSK (standardized b = 0.47; 95% CI = 0.42−0.52;
I2 = 66.2%; P = .275). A metaregression analysis was also
conducted to explore the presence of potential
moderators. Females gender moderated the association
between pain-related anxiety and disability (standard-
ized b = -0.57; 95% CI = -0.96 to -0.17; P = .010). However,
the risk of bias was not a moderator of this association
(standardized b = 0.08; 95% CI = -0.08 to 0.25; P = .272).
The funnel plot revealed asymmetry, which indicated
that publication bias could be present (Appendix F).
Fear-Avoidance Beliefs and Pain
Intensity: Cross-Sectional Analysis
Greater levels of fear-avoidance beliefs were signifi-
cantly associated with higher levels of pain intensity in
osteoarthritis150,135 and mixed samples of chronic
MSK.46,49,129,156 However, the results were ambiguous in

Table 2. Summary of Findings and Quality of Evidence Assessment (Cross-Sectional Studies)

SUMMARY OF FINDINGS QUALITY OF EVIDENCE ASSESSMENT (GRADE)

OUTCOME NO. OF NO. OF RISK OF INCONSISTENCYy INDIRECTNESSz IMPRECISIONx PUBLICATION LEVEL OF IMPORTANCE
STUDIES PARTICIPANTS BIAS* BIAS{ EVIDENCE
(K) (N)

Fear of pain
Pain intensity 1 62 Serious (-1) No No Very serious (-2) No Very low Critical
Disability 3 352 Serious (-1) No No Very serious (-2) No Very low Critical
Pain-related anxiety
Pain intensity 12 2,248 Serious (-1) No Serious (-1) Very serious (-2) Serious (-1) Very low Critical
Disability 12 2,112 Serious (-1) Serious (-1) Serious (-1) Very serious (-2) Serious (-1) Very low Critical
Fear-avoidance beliefs
Pain intensity 39 8,398 Serious (-1) Serious (-1) Serious (-1) Very serious (-2) Serious (-1) Very low Critical
Disability 44 9,184 Serious (-1) Serious (-1) Serious (-1) Very serious (-2) Serious (-1) Very low Critical

*Risk of bias: >50% (serious) or 75% (very serious) of the information is from studies with high/moderate risk of bias which sufficiently can affect the interpretation
of results (crucial risk of bias for 1 criterion, or multiple criteria are likely to very seriously alter the results).
yInconsistency: >50% (serious) or 75% (very serious) presence of high degree of inconsistency in the results, such as effects in opposite directions, or large variations
in the degree to which the outcome is affected (eg, very large and very small effects or no significant effect). Furthermore, when high heterogeneity was revealed in
meta-analysis (I2 > 50%), the GRADE criteria judged inconsistency as serious.
zIndirectness: >50% (serious) or 75% (very serious) of included studies present indirectness in terms of population (eg, only older people were included when the
review is focused on all adults ages) and outcomes (eg, different type of outcomes).
xImprecision: >50% (serious) or 75% (very serious) of included studies present 95% CIs with wide range (it does not exclude 1.0) and includes small effects in both
directions or the 95% CI is not reported.
{Publication bias: the GRADE recommendation is to only downgrade 1 level at a maximum (not 2) based on suspected publication bias.
1402 The Journal of Pain Fear in Chronic Musculoskeletal Pain
Table 3. Summary of Findings and Quality of Evidence Assessment (Longitudinal Cohort Studies)
SUMMARY OF FINDINGS QUALITY OF EVIDENCE ASSESSMENT (GRADE)

OUTCOME NO. OF NO. OF RISK OF INCONSISTENCYy INDIRECTNESSz IMPRECISIONx PUBLICATION LEVEL OF IMPORTANCE
STUDIES PARTICIPANTS BIAS* BIAS{ EVIDENCE
(K ) (N)

Fear-avoidance beliefs
Pain intensity 2 843 Serious (-1) Serious (-1) No Serious (-1) Undetected Very low Critical
Disability 2 843 Serious (-1) Serious (-1) No Serious (-1) Undetected Very low Critical

*Risk of bias: >50% (serious) or 75% (very serious) of the information is from studies with a high or moderate risk of bias which sufficiently can affect the interpreta-
tion of results (crucial risk of bias for 1 criterion, or multiple criteria are likely to very seriously alter the results).
yInconsistency: >50% (serious) or 75% (very serious) presence of high degree of inconsistency in the results, such as effects in opposite directions, or large variations
in the degree to which the outcome is affected (eg, very large and very small effects or no-significant effect).
zIndirectness: >50% (serious) or 75% (very serious) of included studies present indirectness in terms of population (eg, only older people were included when the
review is focused on all adults ages) and outcomes (eg, different type of outcomes).
xImprecision: >50% (serious) or 75% (very serious) of included studies present 95% CIs with wide range (it does not exclude 1.0) and includes small effects in both
directions or the 95% CI is not reported.
{Publication bias: the GRADE recommendation is to only downgrade 1 level at a maximum (not 2) based on suspected publication bias.

terms of statistical significance considering the associa-
tion between fear-avoidance beliefs and pain intensity
in chronic low back pain,10,19,32,33,41,53,55,56,57
56,60,62,63,73,78,85,98,108,111,112,113,115,127,136,147,155,157,161
chronic neck pain,3,45,56,75 and rheumatoid arthritis.92,96
A summary of the statistical results is reported in Appen-
dix G.
A meta-analysis was performed to analyze the strength
of the association between fear-avoidance beliefs work
subscale and pain intensity. The pooled results revealed a
weak association between both variables (standardized
b = 0.23; 95% CI = 0.15−0.30; P < .01), with the heteroge-
neity being high among the included studies (I2 = 87.4%;
Fig 4). Sensitivity analyses were conducted by chronic
MSK condition. Chronic neck pain (standardized b = 0.22;
95% CI = 0.05−0.39; P < .01; I2 = 0.0%) and mixed samples
of chronic MSK (standardized b = 0.26; 95% CI =
0.13−0.39; P < .01; I2 = 0.0%) considerably reduced the
heterogeneity. Nevertheless, the heterogeneity was still
high in chronic low back pain (standardized b = 0.24; 95%
CI = 0.15−0.33; P < .01; I2 = 89.3%). Sensitivity analyses
were also performed by statistical estimation (pure

Study n ß (95% CI) Weight

Brede et al. 2011 552 0.22 (0.14, 0.30) 23.85

Kreddig & Hasenbring 2017 133 0.18 (0.01, 0.34) 10.88

Lewis et al. 2012 47 0.37 (0.12, 0.62) 5.71

Martinez et al. 2011 74 0.43 (0.24, 0.62) 9.07

McCracken & Dhingra 2002 282 0.34 (0.24, 0.44) 19.09

Peters et al. 2005 100 0.30 (0.12, 0.48) 9.66

Sanchez et al. 2011 74 0.43 (0.24, 0.62) 9.07

Shanbehzadeh et al. 2017 160 0.22 (0.08, 0.37) 12.68

Overall (I-squared = 35.9%, p = 0.142) 0.29 (0.23, 0.36) 100.00

with estimated predictive interval . (0.14, 0.45)

NOTE: Weights are from random effects analysis

-.619 0 .619

Figure 2. Meta-analysis of the association between pain-related anxiety and pain intensity in individuals with chronic MSK.
Martinez-Calderon et al The Journal of Pain 1403

Study n ß (95% CI) Weight

Brede et al. 2011 552 0.47 (0.40, 0.53) 13.16

Das De et al. 2013 (Trigger finger) 94 0.49 (0.34, 0.64) 9.12

Das De et al. 2013 (Lateral epicondylosis) 41 0.18 (-0.12, 0.48) 4.48

Das De et al. 2013 (Quervain) 28 0.07 (-0.31, 0.45) 3.22

Lewis et al. 2012 47 0.54 (0.34, 0.74) 7.10

Martinez et al. 2011 74 0.22 (0.00, 0.44) 6.64

Martinez et al. 2015 97 0.16 (-0.03, 0.35) 7.46

McCracken et al. 1996 45 0.61 (0.42, 0.80) 7.82

McCracken & Dhingra 2002 282 0.44 (0.35, 0.53) 11.91

Peters et al. 2005 100 0.40 (0.23, 0.57) 8.64

Shanbehzadeh et al. 2017 160 0.42 (0.29, 0.55) 10.31

Thibodeau et al. 2013 78 0.64 (0.51, 0.77) 10.14

Overall (I-squared = 66.2%, p = 0.001) 0.42 (0.35, 0.50) 100.00

with estimated predictive interval . (0.18, 0.67)

NOTE: Weights are from random effects analysis

-.796 0 .796

Figure 3. Meta-analysis of the association between pain-related anxiety and disability in individuals with chronic MSK.

correlation versus b coefficient). Neither pure correlation
(I2 = 87.3%) nor b coefficient (I2 = 71.3%) decreased the
heterogeneity. Other potential moderators were also
considered through a metaregression analysis. Female
gender (standardized b = 0.05; 95% CI = -0.45 to 0.56;
P = .825) and risk of bias (standardized b = -0.04; 95%
CI = -0.22 to 0.14; P = .623) did not moderate the associa-
tion between fear-avoidance beliefs work subscale
and pain intensity. The funnel plot revealed asymmetry,
indicating the possible presence of publication bias
(Appendix H).
A meta-analysis was also carried out to evaluate the
strength of the association between the fear-avoidance
beliefs physical activity subscale and pain intensity. A
weak association was observed between both variables
after pooling the results (standardized b = 0.22; 95%
CI = 0.16−0.28; P < .01). However, the heterogeneity
was high (I2 = 69.9%; Fig 5). In this sense, sensitivity anal-
yses were performed by chronic MSK condition. Chronic
neck pain (standardized b = 0.28; 95% CI = 0.12−0.44; P
< .01; I2 = 41.6%) and osteoarthritis (standardized
(I2 = 2%) in comparison with studies using pure correla-
tions (I2 = 57%). A metaregression analysis showed that
neither female gender (standardized b = 0.04; 95% CI = -
0.53 to 0.62; P = .87) nor risk of bias (standardized
b = -0.001; 95% CI = -0.17 to 0.17; P = .98) moderated the
association between fear-avoidance beliefs physical
activity subscale and pain intensity. Publication bias
were suspected because the presence of asymmetry in
the funnel plot (Appendix I).
Fear-Avoidance Beliefs and Disability:
Cross-Sectional Analysis
Greater levels of fear-avoidance beliefs were signifi-
cantly associated with higher levels of disability in samples
with chronic neck pain,3,45,56,120 osteoarthritis,150,135 and
rheumatoid arthritis.37 Nevertheless, the results were
ambiguous in terms of statistical significance regarding
the association between fear-avoidance beliefs and disabil-
ity in samples with chronic low back pain4,10,15,22,23,32,33,41,
51,53,55,56,58,60,62,63,73,78,85,98,108,111,112,113115,123,133,136,139,155,

b = 0.20; 95% CI = 0.06−0.34; P < .01; I2 = 0.0%) 157,161

decreased the heterogeneity. The heterogeneity
remained high in chronic low back pain (standardized
b = 0.25; 95% CI = 0.21−0.29; P < .01; I2 = 68.3%) and
mixed samples of chronic MSK (standardized b = 0.13;
95% CI = 0.04−0.22; P < .01; I2 = 86.8%). Interestingly,
sensitivity analyses also showed how studies reporting b
coefficient considerably decreased the heterogeneity
and mixed chronic MSK.46,49,51,105,129 A summary of
the statistical results is reported in Appendix J.
The strength of the association between fear-avoid-
ance beliefs work subscale and disability was explored
through a meta-analysis. The pooled results revealed a
weak association between both variables (standardized
b = 0.37; 95% CI = 0.31−0.43; P < .01). However, the
heterogeneity was high (I2 = 72.3%; Fig 6). Sensitivity
1404 The Journal of Pain
Figure 4. Meta-analysis of the association between fear-avoidance beliefs work subscale and pain intensity in individuals with
chronic MSK.
analyses were conducted by chronic MSK condition,
showing how chronic neck pain (standardized b = 0.56;
95% CI = 0.44−0.68; P < .01; I2 = 0.0%) and mixed sam-
ples of chronic MSK (standardized b = 0.30; 95%
CI = 0.20−0.40; P < .01; I2 =37.1%) considerably
decreased the heterogeneity. In contrast, the heteroge-
neity was still high in chronic low back pain (standard-
ized b = 0.37; 95% CI = 0.34−0.41; P < .01; I2 = 73.6%).
Sensitivity analyses also revealed how studies using b
coefficient decreased the heterogeneity more
(I2 = 42.6%) when compared with studies reporting pure
correlations (I2 = 74.5%). Nevertheless, female gender
(standardized b = 0.19; 95% CI = -0.29 to 0.68; P = .416)
and risk of bias (standardized b = 0.12; 95% CI = -0.03 to
0.29; P = .124) were not moderators of this association
after conducting a metaregression analysis. The funnel
plot showed asymmetry, indicating the possible pres-
ence of publication bias (Appendix K).
The strength of the association between fear-
avoidance beliefs physical activity subscale and dis-
ability was explored through a meta-analysis. The
pooled of the results also showed a weak association
between variables (standardized b = 0.33; 95%
Fear in Chronic Musculoskeletal Pain
CI = 0.28−0.39; P < .01), with the heterogeneity being
high (I2 = 80.2%; Fig 7). Sensitivity analyses were per-
formed by chronic MSK condition. Only chronic low
back pain remained with high heterogeneity (stan-
dardized b = 0.33; 95% CI = 0.30−0.36; P < .01;
I2 = 68.4%). Chronic neck pain (standardized b = 0.41;
95% CI = 0.26−0.55; P < .01; I2 = 0.0%), rheumatoid
arthritis (standardized b = 0.13; 95% CI = 0.09−0.16; P
< .01; I2 = 0.0%), osteoarthritis (standardized b = 0.28;
95% CI = 0.15−0.41; P < .01; I2 = 0.0%), and mixed
samples of chronic MSK (standardized b = 0.32; 95%
CI = 0.22−0.41; P < .01; I2 = 1.2%) decreased the het-
erogeneity. Sensitivity analyses also showed that
studies reporting pure correlation had lower hetero-
geneity (I2 =39%) than studies using a b coefficient
(I2 = 82.2%). A metaregression analysis found that
female gender (standardized b = -0.11; 95% CI = -0.58
to 0.35; P = .623) and risk of bias (standardized
b = 0.01; 95% CI = -0.11 to 0.14; P = .858) did not mod-
erate the association between the fear-avoidance
beliefs physical activity subscale and disability. Publi-
cation bias were not considered owing to the symme-
try of the funnel plot (Appendix L).
Martinez-Calderon et al The Journal of Pain 1405

%
Study n ß (95% CI) Weight

Askary-Ashtiani et al. 2014 96 0.33 (0.15, 0.51) 3.88

Ayre and Tyson 2001 121 0.33 (0.17, 0.49) 4.18
Crombez et al. 1999 35 0.03 (-0.31, 0.37) 2.08
Elsig et al. 2014 30 0.06 (-0.30, 0.42) 1.88
French et al. 2007 200 0.30 (0.17, 0.43) 4.70
Gay et al. 2015 67 0.15 (-0.10, 0.40) 2.87
George et al. 2001 (LBP) 104 0.34 (0.17, 0.51) 4.01
George et al. 2001 (NP) 59 -0.17 (-0.42, 0.08) 2.93
George et al. 2011 80 0.37 (0.18, 0.56) 3.72
Georgoudis et al. 2007 70 0.49 (0.31, 0.67) 3.88
Grotle et al. 2004 233 0.22 (0.10, 0.34) 4.76
Grotle et al. 2006 50 0.23 (-0.04, 0.50) 2.75
Guclu et al. 2012 105 -0.02 (-0.22, 0.17) 3.69
Kim et al. 2018 166 0.40 (0.28, 0.53) 4.68
Laufer et al. 2012 63 0.47 (0.28, 0.66) 3.67
Marshall et al. 2017 218 0.29 (0.17, 0.41) 4.77
Meyer et al. 2008 111 0.30 (0.13, 0.47) 4.02
Meyer et al. 2009 78 -0.12 (-0.34, 0.10) 3.31
Monticone et al. 2012 180 0.23 (0.06, 0.41) 3.90
Pfingsten et al. 2000 249 0.35 (0.23, 0.47) 4.84
Scopaz et al. 2009 182 0.20 (0.06, 0.34) 4.49
Seekatz et al. 2016 360 0.21 (0.11, 0.31) 5.11
Waddell et al. 1993 184 0.12 (-0.11, 0.35) 3.21
Walker et al. 2014 183 0.01 (-0.14, 0.16) 4.40
Wand et al. 2016 251 0.04 (-0.08, 0.16) 4.74
Woby et al. 2004 90 0.14 (-0.06, 0.34) 3.53
Overall (I-squared = 69.9%, p = 0.000) 0.22 (0.16, 0.28) 100.00
with estimated predictive interval . (-0.05, 0.49)

NOTE: Weights are from random effects analysis

-.669 0 .669

Figure 5. Meta-analysis of the association between fear-avoidance beliefs physical activity subscale and pain intensity in individu-
als with chronic MSK.

Fear-Avoidance Beliefs and Pain
Intensity: Longitudinal Analysis
Two studies explored the predictive value that base-
line fear-avoidance beliefs have for a subsequent
increase of pain intensity in individuals with chronic low
back pain.61,128 One study reported that baseline fear-
avoidance beliefs weekly predicted more pain intensity
at twelve months (b = 0.17; 95% CI = 0.10−0.23; P <
.001).128 However, another study showed that baseline
fear-avoidance beliefs did not predict changes in pain
intensity at 12 months (fear-avoidance beliefs physical
activity subscale standardized b = .07; P = .716; fear-
avoidance beliefs work subscale standardized b = 0.13;
P = .546).58 Thus, the findings were inconsistent.
Fear-Avoidance Beliefs and Disability:
Longitudinal Analysis
Two studies evaluated whether baseline fear-avoid-
ance beliefs predicted an increase of disability over
time in samples with chronic low back pain.61,128
Baseline fear-avoidance beliefs predicted more dis-
ability at twelve months in 1 study (b = 2.31; 95%
CI = 1.61−3.00; P < .001).128 Nevertheless, another
study revealed that baseline fear-avoidance beliefs
did not predict changes in disability at twelve months
(fear-avoidance beliefs physical activity subscale, stan-
dardized b = 0.17; P = .347; fear-avoidance beliefs
work subscale, standardized b = .06; P = .741).58 Hence,
the findings were also inconsistent.
Discussion
This systematic review and meta-analysis aimed to i)
estimate the concurrent association of pain-related fear
with both pain intensity and/or disability and ii) assess
the predictive value of baseline pain-related fear in the
maintenance of pain intensity and/or disability over
time in samples with chronic MSK, based on the analysis
of observational studies. Our study showed that a large
1406 The Journal of Pain
Figure 6. Meta-analysis of the association between fear-avoidance beliefs work subscale and disability in individuals with chronic
MSK.
body of research supports the concurrent association
between greater fear of pain, pain-related anxiety, and
fear-avoidance beliefs with both greater pain intensity
and disability. However, multiple meta-analyses
revealed that the strength of these associations were
often weak in terms of standardized b coefficient. Fur-
thermore, the heterogeneity was commonly high across
meta-analyses. Many covariates may explain the low
effect size and the high heterogeneity found in meta-
analyses. In this sense, sensitivity analyses, by chronic
MSK condition and by statistical reported estimations,
were conducted. These analyses considerably decreased
the heterogeneity. Metaregression analyses were also
performed to investigate other potential covariates.
Although the risk of bias did not moderate any associa-
tion, female gender moderated the association between
pain-related anxiety and disability, which is in line with
the presence of gender differences in chronic pain.14
Finally, the GRADE criteria judged the concurrent associ-
ation between pain-related fear and both pain intensity
and disability as very low evidence in terms of risk of
Fear in Chronic Musculoskeletal Pain
bias, indirectness, imprecision, and presence of publica-
tion bias. Our review also provided a total of 2 longitu-
dinal cohort studies that reported inconsistent results.
Thus, we cannot draw conclusions about the predictive
role that pain-related fear plays on pain intensity and
disability in chronic MSK. Further longitudinal studies
exploring the role that pain-related fear plays in chronic
MSK outcomes, adjusting by gender as well as by other
potential covariates, are needed.
To our knowledge, this is the first systematic review
and meta-analysis that summarizes the concurrent asso-
ciation and predictive value of pain-related fear on pain
intensity and/or disability in individuals with chronic
MSK. Previous reviews81,163 evaluated the association
between fear and either pain81 or disability163 in hetero-
geneous samples of acute and/or chronic pain such as
irritable bowel syndrome, multiple sclerosis or chronic
headache. Kroska80 showed that greater levels of fear-
avoidance beliefs were significantly associated with
greater pain intensity through an analysis of 118 cross-
sectional studies with a total sample of 25,969
Martinez-Calderon et al The Journal of Pain 1407

%
Study n ß (95% CI) Weight

Askary-Ashtiani et al. 2014 96 0.40 (0.23, 0.57) 3.10

Aslan Telci et al. 2013 56 0.17 (-0.09, 0.42) 2.28
Ayre and Tyson 2001 121 -0.02 (-0.20, 0.16) 3.00
Briggs et al. 2010 56 0.55 (0.36, 0.73) 2.94
Camacho-Soto et al. 2012 200 0.33 (0.21, 0.45) 3.55
Crombez et al. 1999 35 0.40 (0.12, 0.68) 2.07
Demmelmaier et al. 2017 2819 0.13 (0.09, 0.16) 4.20
Elsig et al. 2014 30 0.43 (0.13, 0.73) 1.97
French et al. 2007 200 0.26 (0.13, 0.39) 3.49
Gay et al. 2015 67 0.34 (0.09, 0.59) 2.29
George et al. 2001 (LBP) 104 0.48 (0.33, 0.63) 3.30
George et al. 2001 (NP) 59 0.43 (0.22, 0.64) 2.69
George et al. 2011 80 0.49 (0.32, 0.66) 3.11
Grotle et al. 2004 233 0.30 (0.18, 0.42) 3.61
Grotle et al. 2006 50 0.39 (0.15, 0.63) 2.44
Guclu et al. 2012 105 0.29 (0.11, 0.47) 3.03
Kim et al. 2018 166 0.36 (0.23, 0.49) 3.46
Laufer et al. 2012 63 0.40 (0.19, 0.61) 2.70
Marshall et al. 2017 218 0.45 (0.34, 0.56) 3.72
McCracken et al. 1996 45 0.37 (0.11, 0.63) 2.29
Meyer et al. 2008 111 0.54 (0.41, 0.67) 3.46
Meyer et al. 2009 78 0.13 (-0.09, 0.35) 2.60
Monticone et al. 2012 180 0.28 (0.10, 0.46) 3.00
Nava-Bringas et al. 2016 80 0.31 (0.11, 0.51) 2.79
Panhale et al. 2017 30 0.62 (0.40, 0.84) 2.56
Pfingsten et al. 2000 249 0.35 (0.25, 0.45) 3.74
Sanchez et al. 2009 150 0.27 (0.12, 0.42) 3.30
Scopaz et al. 2009 182 0.28 (0.15, 0.41) 3.45
Seekatz et al. 2016 360 0.23 (0.13, 0.33) 3.79
Sions & Hicks 2011 107 0.20 (0.02, 0.38) 2.96
Waddell et al. 1993 184 0.51 (0.28, 0.74) 2.53
Wand et al. 2016 251 0.09 (-0.03, 0.21) 3.56
Woby et al. 2004 90 0.39 (0.21, 0.57) 3.02
Overall (I-squared = 80.2%, p = 0.000) 0.33 (0.28, 0.39) 100.00
with estimated predictive interval . (0.04, 0.62)
NOTE: Weights are from random effects analysis

-.844 0 .844

Figure 7. Meta-analysis of the association between fear-avoidance beliefs physical activity subscale and disability in individuals
with chronic MSK.

individuals with chronic pain. Zale et al163 revealed that
greater levels of pain-related fear were also associated
with more disability through the analysis of 46 cross-sec-
tional studies with a sample of 9,579 individuals (adults,
adolescents, and children) with acute and/or chronic
pain. However, the GRADE criteria, a robust review tool
to judge the overall quality and strength of the evidence,
was not applied in any of these reviews. Additionally,
pain acceptance was considered a pain-related fear con-
struct, which is not in harmony with the recent distinc-
tion between pain-related fear constructs.94 Specifically
in chronic MSK, a recent systematic review95 showed
strong evidence in the cross-sectional association
between kinesiophobia and both pain intensity and dis-
ability in individuals with chronic MSK. Moreover, this
review reported that greater levels of kinesiophobia at
baseline predict the maintenance of disability over time,
with moderate evidence. The fear-avoidance model of
pain is probably the framework that has received the
most empirical attention in the context of chronic
pain.87,152 This model underlines the importance of
detecting pain-related fear before individuals develop
chronic MSK. In this sense, previous systematic reviews160
showed that greater levels of fear-avoidance beliefs at
baseline predicted poor outcomes (eg, work-related out-
comes) in individuals with subacute low back pain, based
on the analysis of 21 longitudinal studies (N = 9,941). Nev-
ertheless, our review was focused on the role of pain-
related fear in the maintenance of chronic MSK. Only 2
longitudinal cohort studies were retrieved. Therefore,
further longitudinal cohort studies investigating the pre-
dictive value of pain-related fear in both the transition
and perpetuation of chronic MSK are warranted to over-
come the current aforementioned concerns.
The results of this systematic review were generally
consistent in terms of statistical significance. However,
1408 The Journal of Pain
several issues should be considered before drawing firm
conclusions. First, the number of longitudinal cohort
studies retrieved was low. Thus, whether pain-related
fear predicts the perpetuation of chronic MSK cannot
be determined. The determination of the causality is
critical to establishing targeted interventions that may
decrease pain-related fear; thus, a better assessment of
the causal role of fear is needed. Second, meta-analyses
revealed that pain-related fear was more robustly asso-
ciated with disability than with pain intensity. Accord-
ing to previous evidence,95 this finding may reflect that
pain-related fear could be a stronger predictor of dis-
ability in individuals with chronic MSK. This finding
could be explained by the fact that the fear-avoidance
beliefs questionnaire evaluates fear in the context of
physical and occupational setting, which is more in line
with the multidimensional concept of disability than
pain intensity. Nevertheless, further studies are needed
to confirm this statement, because most of the evidence
was based on cross-sectional studies. Third, individuals
with distress endurance responses such a depressive
mood, or eustress endurance responses such an ignoring
or minimizing pain can develop pain-related disability
owing to excessive physical activity.67 However, our
review did not retrieve studies measuring fear-avoid-
ance endurance and, hence, we cannot establish any
conclusion in this sense. Fourth, the term fear-avoidance
suggests that fear and avoidance co-occur simulta-
neously. However, both processes can be certainly inde-
pendent. An individual can experience fear and
confront a stimulus, or an individual can avoid a stimu-
lus but not self-report fear. This misleading conceptuali-
zation of fear and avoidance behaviors could introduce
methodologic errors in the association between fear-
avoidance beliefs with both pain intensity and disabil-
ity. Fifth, meta-analyses revealed the presence of high
heterogeneity across the included studies. In addition to
gender and the type of chronic MSK, previous studies
have suggested that cultural norms and beliefs about
pain could influence the extent to which pain intensity
is associated with fear.80 Furthermore, multiple path-
ways are related to the development and perpetuation
of pain and disability in chronic MSK.30,52 The biopsy-
chosocial profile of every individual with chronic MSK,
including the duration of episodes, fluctuations of pain
intensity, severity of pain, and the presence of social
and contextual factors, may be involved in the mainte-
nance of chronic MSK. Further studies that explore
which factors specifically moderate the association
between pain-related fear and both pain intensity and
disability in chronic MSK are required. This information
may help clinicians to elaborate effective interventions
that reduce the deleterious consequences of fear.
Future Research
This review found some important gaps in the litera-
ture that merit special attention. One of the strengths
of this review is that we were able to identify in which
domains the quality of the evidence was low or very
low. Overall, risk of bias, imprecision, or sparse data and
Fear in Chronic Musculoskeletal Pain
indirectness were identified as problematic domains.
Some of these biases included, first, a failure to ade-
quately control for possible confounding factors; sec-
ond, high heterogeneity with respect to the studied
population, the measures used to assess disability and
the statistical methods; and, third, the fact that in some
studies, the 95% CI around an effect did not exclude 1.0
(ie, there were wide CIs, perhaps owing to the high lev-
els of heterogeneity), or the 95% CI was not reported.
Moreover, most of evidence was derived from cross-sec-
tional studies and, thus, prognosis could not be deter-
mined. The following recommendations should guide
future research: the use of longitudinal cohort studies
that analyses the predictive value of pain-related fear in
the maintenance of chronic MSK: i) in other age ranges
(children, adolescents and adults); ii) after the adjust-
ment for multiples covariates; iii) in acute and subacute
MSK samples; and iv) studies regarding the methodo-
logic flaws found in the present review, specifically the
risk of bias. In this sense, future studies should decrease
selection, performance, and detection biases because
they were the most common biases identified across the
included studies.
Clinical Implications
The current findings indicate that pain-related fear is
associated with chronic MSK and disability. Fear is also
considered a precursor of chronic pain and disabil-
ity,87,97,152 as well as a moderator of treatment effects in
chronic MSK-related outcomes.24,122,138 Importantly,
fear is a modifiable factor36,74,153 and, therefore, a
potential target for prevention strategies. However, the
overall quality of the evidence was very low in the pres-
ent study, thus, we cannot strongly recommend to clini-
cians the assessment and treatment of pain-related fear
in their clinical practice.
In the case of clinicians decide to manage pain-related
fear, the implementation of behavioral experiments and
exposure to feared (but harmless) activities may be a
promising approach to decrease pain-related fear162
even better than pain education.36 Education is based
on instructions and verbal processes that are a strong
source of information for the acquisition of fear, but a
very weak source for the extinction of fear.118
Strengths and Weaknesses of the Study
Our systematic review presents several strengths that
should be mentioned. The use of a robust methodologic
process that adheres to current guidelines and scruti-
nizes the studies for risk of bias and quality of evidence
assessment. Good practices in meta-analysis were also
carried out. Moreover, the inclusion of 70 observational
studies addressing specific pain outcomes (intensity, dis-
ability) that had not been included in prior meta-analy-
ses. This strategy has improved the shortcomings of the
present literature. In contrast, there are some limita-
tions that should be considered. The risk of bias was
common across studies, which limits the results of the
current review. High heterogeneity was detected after
Martinez-Calderon et al
performing meta-analyses. Nevertheless, although we
conducted sensitivity analyses and metaregressions, the
exact sources of this heterogeneity were not identified.
Most of the included studies were cross-sectional in
nature, which means that the predictive value and
impact of pain-related fear on pain intensity and disabil-
ity could not be determined. The findings of this review
should not be generalized to children, or acute, sub-
acute, and nonchronic MSK populations. Finally, disabil-
ity was assessed through a broad set of self-reported
measures. Disability is a wide construct, including activ-
ity limitation, participation restriction, and impair-
ments. This factor may also explain partly the huge
heterogeneity found in this review.
Conclusions
Despite the limitations of this study, the current sys-
tematic review and meta-analysis provided a comprehen-
sive summary of the available evidence regarding the
concurrent association and predictive value of pain-
related fear on pain intensity and disability. Our results
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