Cold and L-menthol-induced sensitization in healthy volunteers--a cold hypersensitivity analogue to the heat/capsaicin model

Pain. 2015 May;156(5):880-889. doi: 10.1097/j.pain.0000000000000123.


Topical high-concentration L-menthol is the only established human experimental pain model to study mechanisms underlying cold hyperalgesia. We aimed at investigating the combinatorial effect of cold stimuli and topical L-menthol on cold pain and secondary mechanical hyperalgesia. Analogue to the heat-capsaicin model on skin sensitization, we proposed that cold/menthol enhances or prolong L-menthol-evoked sensitization. Topical 40% L-menthol or vehicle was applied (20 minutes) on the volar forearms of 20 healthy females and males (age, 28.7 ± 0.6 years). Cold stimulation of 5°C for 5 minutes was then applied to the treated area 3 times with 40-minute intervals. Cold detection threshold and pain, mechanical hyperalgesia (pinprick), static and dynamic mechanical allodynia (von Frey and brush), skin blood flow (laser speckle), and temperature (thermocamera) were assessed. Cold detection threshold and cold pain threshold (CPT) increased after L-menthol and remained high after the cold rekindling cycles (P < 0.001). L-menthol evoked secondary hyperalgesia to pinprick (P < 0.001) particularly in females (P < 0.05) and also induced secondary allodynia to von Frey and brush (P < 0.001). Application of cold stimuli kept these areas enlarged with a higher response in females to brush after the third cold cycle (P < 0.05). Skin blood flow increased after L-menthol (P < 0.001) and stayed stable after cold cycles. Repeated application of cold on skin treated by L-menthol facilitated and prolonged L-menthol-induced cold pain and hyperalgesia. This model may prove beneficial for testing analgesic compounds when a sufficient duration of time is needed to see drug effects on CPT or mechanical hypersensitivity.

MeSH terms

  • Administration, Topical
  • Adult
  • Capsaicin / administration & dosage
  • Capsaicin / pharmacology*
  • Cold Temperature / adverse effects*
  • Female
  • Hand / physiopathology
  • Hot Temperature / adverse effects*
  • Humans
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy*
  • Hypersensitivity / drug therapy
  • Male
  • Menthol / administration & dosage
  • Menthol / pharmacology*
  • Pain / chemically induced
  • Pain / drug therapy*
  • Pain / physiopathology
  • Pain / psychology
  • Pain Measurement / methods
  • Pain Threshold / drug effects
  • Skin / blood supply
  • Skin Temperature / drug effects
  • Time Factors


  • Menthol
  • Capsaicin