Who is healthy? Aspects to consider when including healthy volunteers in QST-based studies—a consensus statement by the EUROPAIN and NEUROPAIN consortia

Abstract

Clinical and human experimental pain studies often include so-called "healthy" controls in investigations of sensory abnormalities, using quantitative sensory testing (QST) as an outcome measure. However, the criteria for what is considered "healthy" vary among the different studies and between study centers and investigators, partly explaining the high variability of the results. Therefore, several aspects should be considered during inclusion of healthy volunteers in QST-based trials to have homogenous groups of healthy controls with less variability between human experimental studies, so that results are less likely to be false negative or false positive because of subject-related factors. The EUROPAIN and NEUROPAIN consortia aimed to define factors influencing the variability in selection of healthy subjects in QST-based studies before the start of both projects and to give recommendations how to minimize it based on the current literature and expertise of the participants. The present suggestions for inclusion criteria of healthy volunteers into QST-based trials describe a 2-level approach including standardized questionnaires enabling the collection of relevant information on sociodemographic data, medical history, current health status, coping strategies in dealing with pain, and the motivation of the volunteer to participate in the study. These suggestions are believed to help researchers interpret their results in comparison with others and improve the quality of clinical studies including healthy volunteers as controls or in human experimental pain studies. They aim to reduce any confounding factors. Furthermore, the acquired information will allow post hoc analyses of variance for different potential influencing factors.

Reliability of conditioned pain modulation: a systematic review

“…A recently published consensus paper defines the characteristics of healthy subjects in quantitative sensory testing studies. 11 For the reader to ascertain susceptibility to bias, we suggest in future studies the source of the target population, the sampling frame and methods of recruitment, the place or places and dates of recruitment, study inclusion and exclusion criteria, the numbers recruited to the numbers enrolled, and baseline characteristics of the study sample are reported. In addition to facilitating the assessment of risk of bias, more thorough description of a study sample aids the generalization of results to other populations (Table 3).…”

“…42 Recommendations for future reliability studies include due consideration of how the results for a sample of participants may be generalized to a population of interest. Gierthmuhlen et al 11 has described important data collection domains for healthy volunteer quantitative sensory testing studies which may be equally pertinent for dynamic measures such as CPM, including but not limited to sociodemographic data, medical history and current health status, pain coping strategies, psychological factors, history of alcohol and drug abuse, smoking and use of recreational drugs, current medication, depression and anxiety scores, the frequency of any pain episodes during the last 3 to 6 months, and self-reported sleep measurements. Consideration should be given to blinding of both the investigator and the participants of CPM studies, standardization of test instructions, and as to how the test environment and exposure to investigators and other study participants may bias performance or results.…”

“…In healthy volunteer studies, the appreciable variability reported in magnitude and the stability of the CPM effect may be attributable to multiple factors including variation in study characteristics such as study design and testing parameters or variability in sample characteristics as defined by the inclusion and exclusion criteria used to qualify a sample of volunteers as “healthy”. 7,11 …”

Quantitative sensory testing using DFNS protocol in Europe

“…Table 1 Demographic data on healthy subjects and patients suffering from polyneuropathy or peripheral nerve injury for all centers. Details on inclusion and exclusion criteria for entry of the DFNS and IMI Europain and Neuropain database can be found for patients in Maier et al 16 and Demant et al, 4,5 respectively, and for healthy subjects in Gierthmühlen et al 10 …”

Pain Modulation: From Conditioned Pain Modulation to Placebo and Nocebo Effects in Experimental and Clinical Pain

“…Although DNIC seem to be more effective in animals after tissue injury, CPM is often impaired in humans with chronic pain (de Resende et al, 2011; Staud, 2012). Nevertheless, it is important to note that the criteria characterizing normal and deficient CPM using QST vary largely among the different studies (Gierthmühlen et al, 2015). …”