The personal, social and economic burden of chronic pain is enormous. Tremendous research efforts are being directed toward understanding, preventing, and managing chronic pain. Yet patients with chronic pain, clinicians and the public are sometimes poorly served by an evidence architecture that contains multiple structural weaknesses. These include incomplete research governance, a lack of diversity and inclusivity, inadequate stakeholder engagement, poor methodological rigour and incomplete reporting, a lack of data accessibility and transparency, and a failure to communicate findings with appropriate balance. These issues span pre-clinical research, clinical trials and systematic reviews and impact the development of clinical guidance and practice. Research misconduct and inauthentic data present a further critical risk. Combined, they increase uncertainty in this highly challenging area of study and practice, drive the provision of low value care, increase costs and impede the discovery of more effective solutions. In this focus article, we explore how we can increase trust in pain science, by examining critical challenges using contemporary examples, and describe a novel integrated conceptual framework for enhancing the trustworthiness of pain science. We end with a call for collective action to address this critical issue. PERSPECTIVE: Multiple challenges can adversely impact the trustworthiness of pain research and health research more broadly. We present ENTRUST-PE, a novel, integrated framework for more trustworthy pain research with recommendations for all stakeholders in the research ecosystem, and make a call to action to the pain research community.