Reduced intraepidermal nerve fiber density in patients with chronic ischemic pain in peripheral arterial disease

Pain. 2014 Sep;155(9):1784-1792. doi: 10.1016/j.pain.2014.06.003. Epub 2014 Jun 12.


Chronic ischemic pain in peripheral arterial disease (PAD) is a leading cause of pain in the lower extremities. A neuropathic component of chronic ischemic pain has been shown independent of coexisting diabetes. We aimed to identify a morphological correlate potentially associated with pain and sensory deficits in PAD. Forty patients with symptomatic PAD (Fontaine stages II-IV), 20 with intermittent claudication (CI), and 20 with critical limb ischemia (CLI) were enrolled; 12 volunteers served as healthy controls. All patients were examined using pain scales and questionnaires. All study participants underwent quantitative sensory testing (QST) at the distal calf and skin punch biopsy at the distal leg for determination of intraepidermal nerve fiber density (IENFD). Additionally, S100 beta serum levels were measured as a potential marker for ischemic nerve damage. Neuropathic pain questionnaires revealed slightly higher scores and more pronounced pain-induced disability in CLI patients compared to CI patients. QST showed elevated thermal and mechanical detection pain thresholds as well as dynamic mechanical allodynia, particularly in patients with advanced disease. IENFD was reduced in PAD compared to controls (P<0.05), more pronounced in the CLI subgroup (CLI: 1.3 ± 0.5 fibers/mm, CI: 2.9 ± 0.5 fibers/mm, controls: 5.3 ± 0.6 fibers/mm). In particular, increased mechanical and heat pain thresholds negatively correlated with lower IENFD. Mean S100 beta levels were in the normal range but were higher in advanced disease. Patients with chronic ischemic pain had a reduced IENFD associated with impaired sensory functions. These findings support the concept of a neuropathic component in ischemic pain.

Keywords: Chronic ischemic pain; Intraepidermal nerve fiber density; Pain questionnaires; Peripheral arterial disease; Quantitative sensory testing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Chronic Pain / etiology
  • Chronic Pain / pathology*
  • Chronic Pain / physiopathology
  • Epidermis / innervation*
  • Female
  • Humans
  • Ischemia / etiology
  • Ischemia / pathology*
  • Ischemia / physiopathology
  • Lower Extremity / pathology
  • Lower Extremity / physiopathology
  • Male
  • Middle Aged
  • Nerve Fibers / pathology*
  • Neuralgia / etiology
  • Neuralgia / pathology*
  • Neuralgia / physiopathology
  • Pain Measurement
  • Peripheral Arterial Disease / complications
  • Peripheral Arterial Disease / pathology*
  • Peripheral Arterial Disease / physiopathology