title: A review of topical high-concentration L-menthol as a translational model of cold allodynia and hyperalgesia.
abstract: BACKGROUND
  Cold allodynia and cold hyperalgesia are both elusive features of neuropathic pain, particularly in patients with various polyneuropathies. Numerous studies have suggested that topical application of L-menthol causes temporary cold hypersensitivity and thus acts as a proxy for associated symptoms. This review summarizes studies on L-menthol-induced nociception, cold allodynia and cold hyperalgesia in vitro, in animals and in humans.
  
  
  METHODS
  A comprehensive literature search was performed using the PubMed and Google Scholar databases until February 2013. Obtained manuscripts were reviewed for relevancy and reference lists of the retrieved articles were cross-checked for additional important studies. Solely the literature regarding topical application of L-menthol in humans was attained systematically. Of the total identified studies (96), 10 met the inclusion criteria being controlled studies applying L-menthol at a concentration of ≥ 30%.
  
  
  RESULTS
  The extracted data are meticulously compared and presented with emphasis on clarity and transparency. In seven animal studies, cold allodynia or hyperalgesia was successfully established utilizing various methods. Eight studies in healthy volunteers unanimously reported a significant increase in cold pain threshold, representing cold allodynia and increased supra-threshold cold pain sensitivity, thus demonstrating cold hyperalgesia.
  
  
  CONCLUSIONS
  Topical high-concentration L-menthol consistently induces cold hypersensitivity in animals and humans, thus constituting a predictable surrogate model of cold allodynia and hyperalgesia. Understanding translational features of this model and its underlying mechanisms could be valuable in preclinical and human phases of drug development and in improving current treatment of patients with polyneuropathy.
authors: Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Denmark.
authors: H H
authors: HH
authors: Andersen
authors: R V
authors: RV
authors: Olsen
authors: H G
authors: HG
authors: Møller
authors: P W
authors: PW
authors: Eskelund
authors: P
authors: P
authors: Gazerani
authors: L
authors: L
authors: Arendt-Nielsen
mesh_terms: D000818:Animals; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced*; D008610:Menthol; D009437:Neuralgia / Q000139:chemically induced*; D010147:Pain Measurement; D017288:Pain Threshold; D057170:Translational Research, Biomedical
chemical_list: D008610:Menthol