Protocol for a systematic review and meta-analysis of the relationship between opioid exposure and dopaminergic measures in humans assessed by nuclear medicine imaging

This protocol outlines planned methodology for a systematic review and meta-analysis of dopaminergic neuroimaging findings in individuals with opioid use disorder (OUD). Converging evidence across substance use disorders (SUDs) shows dopaminergic dysregulation, including low dopamine D 2 receptor (D 2 R) availability and dopamine release, correlating to anhedonia, altered reward processing, impulsivity, and drug-seeking. Opioid use indirectly alters dopamine signaling, with preclinical work showing dopamine D 2 receptor and transporter (DAT) changes. However, human Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT) findings are heterogeneous. Therefore, a systematic synthesis is needed to clarify dopaminergic differences related to chronic opioid exposure and their clinical significance. The proposed review will include peer-reviewed studies of adults with diagnosed OUD using PET or SPECT to assess dopaminergic moieties. Databases searched will include PubMed, Scopus, Web of Science, Google Scholar, and Embase. Two independent reviewers will screen records and assess methodological quality. Screening will occur in two stages (title/abstract followed by full-text review) using predefined eligibility criteria. Data will be synthesized descriptively and random-effects meta-analyses will be conducted in Review Manager to estimate pooled dopaminergic measures (e.g., D 2 /D 3 receptor availability, DAT availability). Statistical heterogeneity will be evaluated using the I 2 statistic, and sensitivity analyses will assess the impact of methodological variability (i.e. radiotracer type, abstinence duration). This review protocol was registered to the International Prospective Register for Systematic Reviews (PROSPERO; CRD420251229301). Given the substantial global burden of OUD, systematically investigating its neurobiology will provide important mechanistic insights to support the development of novel pharmacotherapies. Although currently approved medications are available, all act on the μ-opioid receptor (μOR) and are associated with moderate treatment retention and frequent relapse, generating the need for additional, mechanistically informed therapeutic targets. This will be the first systematic review and meta-analysis exploring dopaminergic measures in humans with OUD, aiming to offer a clearer understanding of how key dopaminergic markers differ between affected individuals and healthy controls, and explore their potential clinical relevance. Insights generated may inform the development of alternative, non-μOR pharmacological strategies for OUD, including emerging D 3 -selective therapeutics and κ-opioid receptor modulators with the capacity to indirectly influence dopaminergic system function.