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Background: Clinicians commonly try to use mechanism-based knowledge to make sense of the complexity and uncertainty of chronic pain treatments to create a rationale for their clinical decision-making. Although this seems intuitive, there are some problems with this approach. Discussion: The widespread use of mechanism-based knowledge in clinical practice can be a source of confusion for clinicians, especially when complex interventions with different proposed mechanisms of action are equally effective. Although the available mechanistic evidence is still of very poor quality, in choosing from various treatment options for people with chronic pain, an approach that correctly incorporates mechanistic reasoning might aid clinical thinking and practice. Conclusion: By explaining that not all evidence of mechanism is the same and by making a proposal to start using mechanism-based knowledge in clinical practice properly, we hope to help clinicians to incorporate mechanistic reasoning to prioritize and start choosing what may best work for whom.