Table 2.

Recommendations for Precision Pain Medicine Studies

	Recommendation	Benefit
1.	Test for heterogeneity of treatment effect	Confirms an adequate degree of inter-patient variation in treatment responsiveness to test phenotype-by-treatment interactions.
2.	Select validated phenotyping measures	Maximizes precision in quantifying phenotypes of interest. Facilitates comparison of findings across studies (that use validated measures).
3.	Carefully consider sample size requirements	Testing for phenotype-by-treatment interactions often requires large samples. Adequately powering a trial is essential in minimizing Type II error.
4.	Consider crossover, or N-of-1 trials	Offers much greater power (i.e., greatly reduced sample size requirements) when examining subgroup/phenotype differences in treatment response.
5.	Consider stratified allocation based on phenotypes	Maximizes power to detect phenotype-by-treatment interactions. When possible, implement 50:50 (i.e., equal group sizes) stratified allocation.
6.	When possible, implement back-translation approaches	Facilitates confirmation of hypothesized treatment targets and localization of drug/treatment effects in the nervous system.
7.	Plan for phenotypic clustering	Reduces concerns related to testing multiple, correlated, individual variables. Enhances power by minimizing the need for multiple comparison corrections.
8.	Implement dynamic measurement in trials	Accounts for naturally-occurring phenotypic variability over time, increases reliability of phenotyping measurements.