The Drug Titration Paradox Updated and Reinterpreted: With Perfect Titration, Dose and Effect Will Be Uncorrelated

The drug titration paradox is a clinical observation at a population level whereby patients receiving a high dose of medication appear to have a lower-than-average clinical effect, and patients receiving a low dose of medication appear to have a higher-than-average clinical effect. Consequently, there would be a negative correlation between dose and effect. The paradox was previously described as present in all titratable medications, particularly anesthetics. The underlying assumption of the paradox is that titration is gradual, that is, consisting of a sequence of relatively minor adjustments with the intent to avoid target over-shoot. This assumption may not hold true with technological advancements and automated drug delivery. The methodology of the paradox was re-explored without that assumption, both mathematically and with computer simulation of different control schemes that may be used to assist with drug titration. In these cases, achieving a positive correlation between dose and effect and reversing the paradox is possible. Recognizing that a perfectly titrated medication will have zero correlation coefficient at a population level, measuring the correlation coefficient over time can be a useful quality metric in evaluating automation technology in drug delivery.