# Repurposed Systemic Pharmacologic Agents in Chronic Pain: Emerging Mechanistic and Clinical Insights

## TL;DR

This review explores how drugs originally developed for other conditions may help treat chronic pain by targeting its complex biological mechanisms.

## Contribution

The paper provides a mechanistic and clinical overview of repurposed systemic drugs for chronic pain treatment.

## Key findings

- Systemic drugs like GLP-1 agonists and SGLT2 inhibitors interact with chronic pain pathways.
- These agents may offer treatment options for neuropathic or centralized pain with limited conventional therapy response.
- Mechanisms include glial activation, cytokine signaling, and mitochondrial dysfunction modulation.

## Abstract

Chronic pain is a multisystem disorder involving neuroimmune activation, metabolic dysregulation, mitochondrial dysfunction, and alterations in autonomic and sensory signaling, leading to peripheral and central sensitization, reduced responsiveness to standard analgesics, and persistent symptoms. Growing evidence suggests that several widely used systemic drugs, initially developed for metabolic, cardiovascular, immunological, or neurological conditions, interact with biological mechanisms involved in pain pathophysiology. This narrative review examines the mechanistic and emerging clinical evidence describing how systemically administered pharmacological agents interact with pathways implicated in chronic pain, focusing on glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter-2 inhibitors, metformin, statins, minocycline, ibudilast, low-dose naltrexone, beta-blockers, and cannabinoids. The mechanisms reviewed include glial activation, cytokine signaling, oxidative stress, mitochondrial dysfunction, ion channel sensitization, and autonomic imbalance. The use of these systemic agents may provide additional treatment options for patients with chronic neuropathic, centralized, or mixed pain states who have limited response to conventional therapies, although current clinical evidence remains preliminary.