Multi‐Modal and Tissue‐Differentiated Experimental Pain Assessment: Reproducibility of a New Concept for Assessment of Analgesics

Abstract

Experimental pain models for assessment of analgesic effect needs to be reproducible, valid and responding in a uniform way to changes in pain level. The pain system differs in various tissue types and analgesics may have different effects in different tissues. This study assessed the reproducibility of an experimental model using mechanical, thermal and electrical stimulations. Pain was evoked in three tissues: Skin, muscle and viscera. Pain was evoked and assessed in 24 healthy volunteers. The experiment was repeated three times with 30 min. intervals and twice with a weekly interval. Systematic bias, intra-class correlation (ICC) and coefficient of variation (CV) and valid sample sizes for analgesic testing were assessed. The model proved to be feasible. Most tests were unbiased, showing stable means except for the mechanical and thermal stimulation in viscera, which showed decreasing pain thresholds when the tests were repeated with 30 min. intervals. Generally the pain tests showed relatively high CV (mean 71%, range 8-145%). The pain tests showed high ICC's (Ͼ0.80) when repeated on the same day. When the tests were repeated with an interval of one week, ICC was smaller (mean 0.79 range 0.49-0.96). This means that these tests are useful for analgesic testing recruiting useful sample sizes in a crossover (mean 31 range 2-84) and a parallel study (mean 59 range 3-164) design. Application of this experimental pain model in a cross-over study design with appropriate base-line recordings offers a unique opportunity of revealing analgesic effects on pain arising from different tissues.

Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review

“…Trials with less than 10-12 subjects are hard to test statistically and the findings therefore questionable. However it has been shown that in experimental models with a high reproducibility sample sizes below 10 are powered to show the effect of analgesics [7]. Accordingly we found a well designed study with a sample size of seven, and this was the minimum sample size for the studies included in this review [8].…”

“…Another way of reducing the variance of the outcome is to maintain control with psychophysiological factors, including personality factors and anxiety induced by application of the model [7,128].…”

Assessing efficacy of non‐opioid analgesics in experimental pain models in healthy volunteers: an updated review

“…Trials with fewer than 10-12 subjects are hard to test statistically and the findings therefore questionable. However, it has been shown that experimental models with a high reproducibility sample size <10 are powered to show the effect of analgesics [6]. Accordingly, we found a well-designed study with a sample size of seven, and this was the minimum sample size for the studies included in this review [7].…”

“…This also ensures repeatability, which is crucial for good sensitivity towards analgesic modulation of the pain in the model [6]. In the case of cross-over designed studies it is important that the investigator is the same in all pain assessments, since gender and appearance of the investigator can influence the pain rating of the volunteers [98].…”

Translational pain research: Evaluating analgesic effect in experimental visceral pain models

“…In experimental pain models, it is important to have a robust pain measure to obtain a reliable model and to detect the analgesic effect [8] . In standardized experimental human pain models, the investigator can control the induced pain (including modality, localization, intensity, frequency and duration), and provide quantitative measures of the responses.…”