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Principal Investigator: Christine E. Marx
Organization: DURHAM VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Background: There is currently a severe dearth of safe, non-habit forming pharmacological interventions for
chronic pain disorders, and the clinical need to develop efficacious new therapeutics has never been more
urgent. Fueled by the worsening opioid crisis and further exacerbated by the COVID-19 pandemic, opioid and
other drug overdose deaths have climbed to staggeringly high levels. The rapid development of
pharmacological agents for the management of chronic pain conditions that are safe, well-tolerated, efficacious
and non-addicting is thus of paramount importance. Neurosteroids are naturally occurring molecules that are
enriched in human brain and potentially ideal candidates for the safe and effective treatment of pain. The
proposed project is a randomized, double-blind, placebo-controlled adaptive design study to determine the
safety and efficacy of two promising neurosteroid molecules for the treatment of chronic low back pain in
Veterans. The project logically builds upon the findings from our prior randomized clinical trial (RCT)
demonstrating that the highest dose of pregnenolone (500mg/day) significantly improves chronic low back pain
(Naylor et al., 2020), while also suggesting that higher doses of this molecule a may be even more efficacious.
A second neurosteroid molecule, dehydroepiandrosterone (DHEA) has also been implicated in the
pathophysiology of pain. DHEA levels are inversely associated with pain and our preliminary data demonstrate
that 8-weeks of DHEA treatment is well-tolerated and reduces pain symptoms. Our strong biomarker and
clinical data suggest that both pregnenolone and DHEA appear to have great therapeutic potential for the
treatment of chronic pain conditions. We will thus investigate if these molecules exhibit possible efficacy in low
back pain and determine maximally well-tolerated doses that are safe and optimally efficacious in the proposed
three-arm trial (pregnenolone, DHEA, placebo).
Methods: The proposed project is a Phase II randomized clinical trial utilizing an adaptive design to determine
the safety and efficacy of pregnenolone and DHEA for the treatment of chronic low back pain in Veterans.
Participants will be randomized in a 1:1:1 ratio to 4 weeks of treatment with pregnenolone, DHEA or matching
placebo (N=108, approximately 36 per group). Pregnenolone dosing will begin at 500mg/day and escalate
every week by 500mg as tolerated (to a potential maximum dose 2000mg/day). DHEA dosing will begin at
100mg/day and increase weekly by 100mg/day (to a potential maximum dose 400mg/day). The primary
endpoint will be post-treatment change scores in mean daily pain intensity ratings (numerical rating scale, 0-
10). Secondary endpoint will be changes in pain interference measures (Brief Pain Inventory). Safety will be
thoroughly monitored throughout study participation (SAEs, AEs, clinical laboratory parameters, vital signs,
ECG). Neurosteroid quantifications will be conducted by highly sensitive state-of-the-art and specific mass
spectrometry to investigate baseline and post-treatment neurosteroid levels as biomarker predictors of
therapeutic response, and to determine optimal therapeutic ranges for these neurosteroid interventions.
Conclusion: Chronic pain symptoms profoundly influence quality of life and function in a very large number of
Veterans, and efficacious new treatments that are safe, well-tolerated, and non-habit forming are urgently
needed. Compelling preclinical and clinical data support the possibility that neurosteroids such as
pregnenolone and DHEA may be extremely promising treatments for pain conditions. The proposed RCT
would thus provide pivotal evidence to optimize neurosteroid dosing in pain disorders and could rapidly
translated into Phase 3 clinical trials. Findings from the proposed clinical trial efforts could thus lead to a
potential therapeutic breakthrough for chronic pain conditions.
Terms: <3-arm randomized trial><3-arm trial><Absence of pain sensation><Absence of sensibility to pain><Affect><Afghanistan><After Care><After-Treatment><Aftercare><Allopregnanolone><American><Analgesic Management><Androstenolone><Anxiety><Armed Forces Personnel><Back Ache><Back Pain><Backache><Biological Markers><Blood Serum><Brain><Brain Nervous System><Brief Pain Inventory><CNS Nervous System><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Caring><Central Nervous System><Cessation of life><Chest Pain><Chronic><Chronic low back pain><Clinical><Clinical Data><Clinical Research><Clinical Study><Clinical Trials><Clinical Trials Design><DHEA><Data><Death><Dehydroisoandrosterone><Development><Diagnosis><Dose><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked 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