Topical high-concentration menthol: reproducibility of a human surrogate pain model

Human experimental pain models play an important role in studying neuropathic pain mechanisms. The objective of the present study was to test the reproducibility of the topical menthol model over a 1-week period.

We performed an open, two-period study in 10 healthy volunteers with 40 menthol applications. The side of menthol application was randomly assigned. Two trial periods were separated by 1 week. Before and after applying menthol, selected quantitative sensory testing (QST) was performed. The area of mechanical pin-prick hyperalgesia was quantified. Spontaneous pain was recorded.

Application of menthol induced a statistically significant decrease in the cold pain threshold (CPT) (p < 0.001) and mechanical pain threshold and an increase in the mechanical pain sensitivity (MPS) (p < 0.001), indicating cold and mechanical (pin-prick) hyperalgesia. Test-retest reliability was best for CPT (r = 0.959) and MPS (r = 0.930). Intraclass correlation values showed excellent reliability for cold pain and MPS (ICC = 0.96, 0.89). The QST values post-menthol showed high inter-period correlation factors and no significant inter-period differences (paired t-test, t = 1.767-1.361; p = 0.111-0.988). The area size of mechanical hyperalgesia was not reliably reproducible.

For an observation period of 1 week, the signs of cold and mechanical hyperalgesia were reproducible with a highly significant correlation of about r = 0.8 and good agreement except for the area size of mechanical pin-prick hyperalgesia. These results demonstrate that the topical menthol pain model is suitable for pharmacological interventions repeated within an observation period of 1 week.