TABLE 6

Factors to consider when planning an experimental human pain study

Topic and Recommendations
Pharmacokinetics
    Design experiment according to pharmacokinetic profile.
    If possible, select drugs with specific and potent analgesic effect especially if models only permit less intense pain intensity.
    Select appropriate (and preferable relative high) dose.
    Use dose-response regimens when possible.
Stimulations
    Select models with optimal control of stimulus intensities.
    Use models with large dynamic range.
    Use models evoking peripheral and central pain mechanisms (e.g., single and repeated electrical stimulation) where appropriate.
    Consider multimodal tests that are advantageous in many experimental conditions.
    In selected cases use multitissue stimulations.
    Design protocol with stimulations at appropriate time according to pharmacokinetics.
    Select deep stimuli whenever possible to mimic the clinical situation.
    Use tonic rather than phasic stimulation to evaluate pain intensity.
    When feasible, add models evoking allodynia and hyperalgesia to mimic clinical pain.
    Use suprathreshold pain stimuli especially in evaluation of weak analgesics.
    Select the stimulus paradigms according to known drug mechanisms (e.g., summated stimuli in evaluation of NMDA antagonists).
    Consider selecting stimulus according to known pain mechanisms (e.g., projection of referred pain in functional diseases).
    Use models with activation predominantly of C fibers.
    Apply “methods of limits” if possible.
    Only models tested for reliability should be selected.
    Prefer models with high internal validity (i.e., most sensitive for analgesics in the painful range of sensations).
    Prefer models with high external validity (i.e., mimics clinical pain and drug mechanisms).
    Consider arousal status of the subjects (avoid prolonged experiments without breaks).
Assessments
    Use both subjective and objective pain assessments if feasible.
    Select reliable psychophysical scales.
    In selected cases, use more qualitative pain assessments (e.g., McGill Pain Questionnaire).
    Select explanatory neurophysiologic or imaging methods if feasible.
    Use predefined and robust output parameters.
    In selected cases, use supplementary assessments (e.g., referred pain areas).
Subjects
    In design, re-evaluate ethical considerations.
    Consider selection of subjects using psychological evaluation.
    Consider enriched enrollment (i.e., evaluate sensitivity to the tests or drugs).
    Select appropriate sample (volunteers/patient groups).
    Consider selection according to gender, age, genotype, etc.
    Reduce anxiety through screening, pretesting and proper instruction.
    Train subjects in pain ratings to increase reliability.
Laboratory
    Use well educated and experienced staff trained in the tests.
    Use same person to perform tests for repeated assessments.
    Pay attention to theoretical and practical education of staff.
    Ensure recommendations for good clinical and laboratory practice are followed.
    Avoid any interruption and disturbing factors during experiments.
    Isolate equipment between experiments to ensure stability (mainly for advanced electronic equipment).
    Reconsider safety issues whenever necessary.
Data analysis
    Evaluate according to predefined primary and secondary endpoints.
    Use statistical adjustment for multiple comparisons.
    Perform baseline corrections in repeated testing.
    Use expert evaluation of neurophysiological/imaging data.