Background: Altered central pain modulation is the predominant pain mechanism in a proportion of
chronic musculoskeletal pain disorders and is associated with poor outcomes. Although existing studies
predict poor outcomes such as persistent pain and disability, to date there is little consensus on what
factors specifically predict altered central pain modulation.
Objectives: To review the existing literature on the predictive factors specifically for altered central
pain modulation in musculoskeletal pain populations.
Study Design: This is a systematic review in accordance with supplemented PRISMA guidelines.
Methods: A systematic search was performed by 2 mutually blinded reviewers. Relevant articles were
screened by title and abstract from Medline, Embase, PubMed, CINAHL, and Web of Science electronic
databases. Alternative sources were also sought to locate missed potential articles. Eligibility included
studies published in English, adults aged 18 to 65, musculoskeletal pain, baseline measurements taken
at the pre-morbid or acute stage, > 3-month follow-up time after pain onset, and primary outcome
measures specific to altered central pain modulation. Studies were excluded where there were
concurrent diseases or they were non-predictive studies. Risk of bias was assessed using the quality
in prognostic studies (QUIPS) tool. Study design, demographics, musculoskeletal region, inclusion/
exclusion criteria, measurement timelines, predictor and primary outcome measures, and results were
extracted. Data were synthesized qualitatively and strength of evidence was scored using the grading of
recommendations, assessment, development, and evaluations (GRADE) scoring system.
Results: Nine eligible articles were located, in various musculoskeletal populations (whiplash, n =
2; widespread pain, n = 5; temporomandibular disorder, n = 2). Moderate evidence was found for 2
predictive factors of altered central pain modulation: 1) high sensory sensitivity (using genetic testing
or quantitative sensory tests), and 2) psychological factors (somatization and poor self-expectation of
recovery), at a pre-morbid or acute stage baseline.
Limitations: At the times of the article publications, the current definitions and clinical guidelines
for identifying altered central pain modulation were not yet available. Careful interpretation of the
information provided using current knowledge and published guidelines was necessary to extract
information specific to altered central pain modulation in some of the studies, avoiding unwarranted
assumptions.
Conclusions: Premorbid and acute stage high sensory sensitivity and/or somatization are the
strongest predictors of altered central pain modulation in chronic musculoskeletal pain to date. This is
the first systematic review specifically targeting altered central pain modulation as the primary outcome
in musculoskeletal pain populations. Early identification of people at risk of developing chronic pain
with altered central pain modulation may guide clinicians in appropriate management, diminishing the
burden of persistent pain on patients and heath care providers alike.
Systematic Review Registration no.: PROSPERO 2015:CRD42015032394
Central Hyperexcitability in Chronic Musculoskeletal Pain: A Conceptual Breakthrough with Multiple Clinical Implications