1. 2017;20;1-13A Systematic Review on the Prevalence, Etiology, and Pathophysiology of Intrinsic Pain in Dermal Scar Tissue
   Systematic Review
   Eveline Bijlard, MD, Lisa Uiterwaal, MD, Casimir A.E. Kouwenberg, MD, Marc A.M. Mureau, MD, PhD, Steven E.R. Hovius, MD, PhD, and Frank J.P.M. Huygen, MD, PhD.

BACKGROUND: Scars can cause pain, even without symptoms of underlying nerve damage. A lack of knowledge on intrinsic scar pain hampers effective treatment of these complaints.

OBJECTIVE: Aggregate current knowledge on the prevalence, etiology, and pathophysiology of intrinsic pain in dermal scars.

STUDY DESIGN: Systematic review.

SETTING: University Medical Center.

METHODS: We searched the Embase, Medline, Cochrane central, CINAHL, Web-of-Science, and Pubmed databases with search terms: scar, skin, pain, and etiology/pathology, adding all synonyms of these terms. Relevant papers were selected and analyzed by 3 reviewers.

RESULTS: Intrinsic pain in scars has a low prevalence. However, pathologic scars and burns regularly cause pain of high intensity. The etiology is multifactorial, the extent of trauma was an important predicting factor. Nerve fiber density did not explain the intrinsic pain when pan-neuronal markers were used, while a correlation with an increased number of C-fiber subtypes seems plausible. Nerve growth factor (that stimulate these C-fibers) plays an important role in wound healing. Thereby, it also sensitizes neurons and promotes inflammation, releasing even more neurotrophic factors. Central sensitization causes a long-lasting effect even after wounds are healed. Furthermore, the opioid-system, that influences inflammation and healing and possible systemic sensory alterations after injury, is discussed.

LIMITATIONS: Liberal selection criteria challenged the systematic selection of papers.

CONCLUSIONS: Burn and pathologic scars often lead to high intensity pain symptoms. This pain has many characteristics of neuropathic pain that could be caused by an imbalance of C-fibers subtypes. The scar tissue itself may alter the nerve fiber distribution; the imbalance results in ongoing neuro-inflammation and pain symptoms.

Key words: Systematic review, scar, pain, epidermal innervation, prevalence, neuro inflammatory response, peptidergic fibers