Low‑Dose Naltrexone for ADT‑Related Fatigue in Prostate Cancer

A new trial will test whether nightly low‑dose naltrexone (3 mg) reduces fatigue in men with prostate cancer receiving androgen‑deprivation therapy (ADT), while concurrently profiling mitochondrial, inflammatory, and oxidative stress pathways that may drive cancer‑related fatigue in this setting. The single‑arm University of Arkansas study plans to enroll 60 men over 30 months, using FACIT‑F as the primary patient‑reported endpoint and FACT‑P plus safety as key secondary measures, with eligibility spanning men on ADT alone or ADT combined with contemporary AR‑pathway agents such as apalutamide, darolutamide, enzalutamide, or abiraterone.

The trial’s focus addresses a major unmet need, as persistent fatigue is among the most burdensome and prevalent toxicities of ADT, undermining daily function, quality of life, and treatment adherence in a substantial fraction of patients. Mounting evidence links ADT to a pro‑inflammatory state, with elevations in cytokines like interleukin‑6, that correlates with greater fatigue severity, highlighting inflammation as a modifiable biological driver rather than a purely subjective symptom. By explicitly integrating biomarker readouts with patient‑reported outcomes, the study is positioned to clarify which bioenergetic and inflammatory signatures track with clinically meaningful fatigue improvement on therapy.

Mechanistically, the study is anchored in three convergent pathways: mitochondrial bioenergetics, opioidergic signaling, and immune modulation. These pathways plausibly connect ADT to fatigue and provide a rationale for naltrexone’s evaluation at low dose. First, work in cancer‑related fatigue has repeatedly implicated bioenergetic failure, with data showing impaired mitochondrial gene programs and ATP coupling efficiency in fatigued patients, consistent with the trial’s plan to interrogate mitochondrial function longitudinally. Second, therapy‑induced fatigue can engage endogenous opioidergic circuits, (β‑endorphin) mediated signaling has been causally linked to radiation‑related fatigue in preclinical models, suggesting that transient opioid receptor blockade can normalize fatigue‑relevant neuroimmune tone.

Low‑dose naltrexone (LDN) differs biologically from standard‑dose naltrexone by producing only short‑lived antagonism of the opioid growth factor receptor (OGFr), which in turn triggers compensatory up‑regulation of endogenous opioid peptides and OGFr expression, culminating in cell‑cycle restraint and potential antitumor activity in preclinical systems. This exposure‑time–dependent effect is distinct from the continuous blockade seen at conventional 25–50 mg doses, where sustained antagonism can paradoxically favor proliferation in model systems, underscoring why dose and dosing schedule are central to LDN’s proposed benefits. Beyond the OGF–OGFr axis, LDN has demonstrated immunomodulatory properties, including reductions in pro‑inflammatory cytokines such as IL‑6 and TNF‑α, that could counteract the ADT‑associated inflammatory milieu implicated in fatigue pathogenesis.

Clinical trial.