Nonopioid Treatment Option for Chronic Low Back Pain in Veterans

Jennifer Naylor, PhD, clinical & experimental psychologist, Durham VA Health Care System and co-director for the VA Mid-Atlantic MIRECC’s Clinical Core, and Chris Marx, MD, staff psychiatrist, Durham VA Health Care System and codDirector for the VA Mid-Atlantic MIRECC’s Research Core, discuss the impact of a nonopioid solution for the treatment of chronic low back pain among Iraq- and Afghanistan-era US military veterans.  

Please introduce yourselves for our readers.

Jennifer Naylor, PhD: I am a clinical & experimental psychologist within the Durham VA Health Care System and co-director for the VA Mid-Atlantic MIRECC’s Clinical Core. I am also an associate professor in the department of psychiatry & behavioral sciences at Duke University School of Medicine. My research interests include the development of neurosteroid interventions for chronic pain and commonly co-occurring disorders.

Chris Marx, MD: I am a staff psychiatrist within the Durham VA Health Care System and co-director for the VA Mid-Atlantic MIRECC’s Research Core. I am also a professor and vice chair for faculty in the department of psychiatry & Behavioral Sciences at Duke University School of Medicine. My laboratory conducts translational research investigating neurosteroids as biomarker candidates and novel therapeutics for PTSD, TBI, schizophrenia, Gulf War Illness, and pain disorders. 

What existing data led you and your co-investigators to conduct this research? 

Chronic pain conditions are common in the veteran population, and there is an urgent need to develop safe and effective nonopioid treatments for pain. Neurosteroids are promising treatments, as these molecules are enriched in the brain, demonstrate multiple actions in the central nervous system, and have been well-tolerated in our prior research studies. Allopregnanolone is a neurosteroid with analgesic properties. It is a metabolite of pregnenolone, and pregnenolone administration markedly increased downstream allopregnanolone levels in a number of our prior clinical studies. Furthermore, allopregnanolone levels are lower in Veterans who report pain symptoms. We therefore hypothesized that giving pregnenolone as a precursor loading strategy to replenish allopregnanolone, a neurosteroid with analgesic actions, could be clinically therapeutic and result in a reduction of chronic low back pain.

Please briefly describe your study and its findings. Were any of the outcomes particularly surprising?

We conducted a randomized, double-blind, placebo-controlled trial to determine whether pregnenolone reduced chronic low back pain in Iraq/Afghanistan-era veterans. Veterans with chronic low back pain were randomized to receive pregnenolone or placebo for 4 weeks. We found that veterans who received pregnenolone reported significant reductions in low back pain relative to those who received placebo. Participants randomized to pregnenolone also reported that back pain interfered less with their ability to engage in work and activities. Moreover, pregnenolone was very well-tolerated with minimal side effects that were relatively evenly distributed across both pregnenolone and placebo-treated groups. 

What are the possible real-world applications of these findings in clinical practice? 

Although larger studies are needed to replicate these findings, pregnenolone appears to be a safe and efficacious treatment for Veterans with chronic low back pain. If future controlled trials also demonstrate efficacy, pregnenolone could become widely used as a therapeutic to safely manage pain. Additionally, since neurosteroids such as pregnenolone and allopregnanolone have pleiotropic actions in the central nervous system (and reduced neurosteroid levels are also associated with depression and PTSD), they may simultaneously mitigate multiple symptoms that commonly co-occur with chronic pain conditions, including depression and PTSD symptoms. Pregnenolone treatment could thus represent a multi-pronged approach targeting multiple disorders. Our lab is currently conducting a randomized trial to determine if pregenolone reduces symptoms of posttraumatic stress disorder in Iraq/Afghanistan-era Veterans.

Do you and your co-investigators intend to expand upon this research? 

Absolutely. These findings are preliminary and will require replication in a larger cohort of individuals with chronic low back pain.  In addition, it is possible that the analgesic effects of pregnenolone may have been even greater if the dose had been higher and/or if the duration of treatment had been longer. We are also interested in determining if pregnenolone can effectively reduce different types of pain, such as neuropathic pain.  Additionally, we would like to understand the neurobiologic underpinnings of pregnenolone’s therapeutic actions. For example, a number of neurosteroids demonstrate pronounced anti-inflammatory actions that may potentially contribute to their analgesic effects. Investigations are underway to test these hypotheses. We are also examining the relevance of neurosteroids to brain structure, as these molecules appear to be associated with cortical thickness in our recent studies. 

Reference:
Naylor JC, Kilts JD, Shampine LJ, et al. Effect of pregnenolone vs placebo on self-reported chronic low back pain among US military veterans: a randomized clinical trial. JAMA Netw Open. 2020;3(3):e200287. doi:10.1001/jamanetworkopen.2020.0287