Reproducibility of the heat/capsaicin skin sensitization model in healthy volunteers

Abstract

Introduction: Heat/capsaicin skin sensitization is a well-characterized human experimental model to induce hyperalgesia and allodynia. Using this model, gabapentin, among other drugs, was shown to significantly reduce cutaneous hyperalgesia compared to placebo. Since the larger thermal probes used in the original studies to produce heat sensitization are now commercially unavailable, we decided to assess whether previous findings could be replicated with a currently available smaller probe (heated area 9 cm(2) versus 12.5-15.7 cm(2)).

Study design and methods: After Institutional Review Board approval, 15 adult healthy volunteers participated in two study sessions, scheduled 1 week apart (Part A). In both sessions, subjects were exposed to the heat/capsaicin cutaneous sensitization model. Areas of hypersensitivity to brush stroke and von Frey (VF) filament stimulation were measured at baseline and after rekindling of skin sensitization. Another group of 15 volunteers was exposed to an identical schedule and set of sensitization procedures, but, in each session, received either gabapentin or placebo (Part B).

Results: Unlike previous reports, a similar reduction of areas of hyperalgesia was observed in all groups/sessions. Fading of areas of hyperalgesia over time was observed in Part A. In Part B, there was no difference in area reduction after gabapentin compared to placebo.

Conclusion: When using smaller thermal probes than originally proposed, modifications of other parameters of sensitization and/or rekindling process may be needed to allow the heat/capsaicin sensitization protocol to be used as initially intended. Standardization and validation of experimental pain models is critical to the advancement of translational pain research.

Keywords: central sensitization; experimental pain model; hyperalgesia; peripheral sensitization.

Figures

Figure 1

Timeline of training and study sessions. The procedures performed in each session are illustrated. (A) screening/training day and (B) study days. Notes: In the control group there was no drug administration, and additional sets of the same measurements described below (M) were taken after RK2 and RK3. In the gabapentin/placebo group, on session 1 and 2, subjects were randomly assigned to receive gabapentin or placebo. M refers to a set of measurements (mapping of area of hyperalgesia/allodynia, heat pain detection threshold, pain during thermal stimulation). Abbreviations: HC, heat/capsaicin sensitization; RK, rekindling.

Figure 2

Enrollment and allocation of participants in the study. Note: *Reasons for exclusions on screening day: 5= HPDT >47°C; 9= unable to achieve sensitization (area); 1= admitted history of drug abuse; 1= showed lesions on forearm at physical examination; 1= body mass index >33. Abbreviation: HPDT, heat pain detection threshold.

Figure 3

Areas of secondary hyperalgesia and allodynia. Notes: Percentage change of area size after treatment in the placebo/gabapentin group and at the same time-point, after the fourth rekindling, in the control group (M2) compared to baseline (M1); data are presented as medians, 1st, and 3rd quartiles; P-values refer to comparison of percentage changes in VF and brush areas between sessions (control group) and between treatments (placebo/gabapentin group). A P-value less than 0.05 was considered statistically significant. Abbreviations: RK, rekindling; VF, von Frey.

Figure 4

HPDTs in the treatment group. Notes: HPDT changes at the first and second set of measurements (M1 and M2, respectively) are compared to presensitization baseline (M0) in the gabapentin and the placebo sessions; data are presented as medians, 1st, and 3rd quartiles; significantly different couples of measurements are indicated: #P=0.03; *P=0.002. (A P-value less than 0.05 was considered statistically significant). In the placebo group HPDTs remained significantly different than baseline at each time point after induction of heat/capsaicin sensitization. Abbreviations: HPDT, heat pain detection thresholds; RK, rekindling.

Figure 5

Brush and von Frey areas: spontaneous fading despite rekindling procedure in control group. Notes: Spontaneous fading of Brush areas (A and B) and von Frey areas (C and D) despite rekindling procedures is shown in the control group. Data are presented as medians, 1st, and 3rd quartiles. Initial von Frey areas in session 2 are significantly smaller than session 1: *P<0.02 (A P-value less than 0.05 was considered statistically significant). Abbreviation: RK, rekindling.

Figure 6

Mean VAS scores for each minute during the 5-minute RK preceding the sets of measurements M1 (RK1) and M2 (RK4). Notes: Mean VAS scores for each minute during the 5-minute RK preceding the sets of measurements M1 (RK1) and M2 (RK4). Data are presented as means and standard deviations. (A) Session 1 and 2 of the control group are compared; (B) Placebo day and gabapentin day of the treatment group are compared. In both groups and both study sessions, painfulness at each minute of the rekindling procedures decreased significantly between the first and fourth rekindling, despite treatment (or no treatment). Part A: both in session 1 and session 2, VAS scores during RK4 were lower than scores during RK1 (session1: P<0.0025 and session 2 P<0.0009). Part B: both on placebo and gabapentin day RK4 (post-drug), VAS scores were significantly lower than RK1 scores (P<0.00005 and P<0.00001, respectively). A P-value less than 0.05 was considered statistically significant. Abbreviations: RK, rekindling procedure; VAS, visual analog scale.