# Beyond pain relief: the effects of chronic opioid use on brain structure and function in diabetic neuropathy—a multimodal neuroimaging study

## TL;DR

This study finds that long-term opioid use for diabetic neuropathy pain is linked to changes in brain structure and function, possibly affecting reward systems.

## Contribution

The study is the first to investigate brain changes from chronic opioid use in diabetic neuropathy using multimodal neuroimaging.

## Key findings

- O+ individuals had greater caudate volume compared to O− individuals and those with no DPN.
- Functional connectivity between the caudate and thalamus was lower in O+ individuals compared to those with no DPN.
- Seed-to-voxel analysis showed reduced functional connectivity in O+ individuals in the superior frontal gyri compared to O− individuals.

## Abstract

Despite being commonly prescribed to treat painful diabetic peripheral neuropathy (DPN), the impact on the brain of long-term opioid use as analgesia is unknown. The aim of this study was to determine the structural and functional brain alterations associated with prescription opioid use in a large cohort of people with painful DPN.

A total of 82 patients with diabetes were enrolled: 57 with painful DPN (18 with long-term opioid prescription [O+ individuals] and 39 who were not prescribed opioids [O− individuals]) and a control group of 25 patients with diabetes but without DPN (no DPN) matched for age (± 2 years), sex and type of diabetes. All participants underwent detailed clinical/neurophysiological assessment and brain MRI at 3 T, and a subset (14 in each group, n=42) also underwent resting-state functional MRI.

O+ individuals had greater caudate volume (ANOVA, p=0.03) compared with O− individuals (p=0.03) and those with no DPN (p=0.01). Functional connectivity was lower between the caudate and thalamus (r β = −0.24, seed-level correction −3.9, pFDR ≤0.05) in O+ individuals compared to those with no DPN. Moreover, seed-to-voxel analysis using caudate as the seed showed a significantly lower functional connectivity in O+ individuals compared with O− individuals in a cluster encompassing the superior frontal gyri bilaterally.

We demonstrate that disruption of dopaminergic pathways occurs within the brain when opioids are used for analgesic purposes for painful DPN, which may reflect alterations in reward systems. This study has important clinical implications, as the measures of dopaminergic pathways found in this study may represent neuroimaging biomarkers that could be used to diagnose and monitor the negative consequences of prescription opioid use.

The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-025-06529-w.