Nancy A. Melville

April 10, 2019

This story was revised April 12 with additional comments.

MILWAUKEE — A novel, “non-habit-forming” neurosteroid appears to be effective and well tolerated in the treatment of chronic low back pain, new research suggests.

In a double-blind, randomized controlled trial of almost 100 Iraq/Afghanistan-era veterans, those treated with a pharmaceutical-grade tablet formulation of pregnenolone showed “significant and meaningful reductions” in low back pain intensity ratings at 6 weeks compared with their peers who received matching placebo, investigators report.

The active treatment group also showed greater reductions than the placebo group in two pain-interference domains.

In addition, “those who were randomized to the pregnenolone group had a 2.6-times greater likelihood of obtaining a 20% reduction in their pain,” lead investigator Jennifer Naylor, PhD, Durham Veterans Affairs Health Care System in North Carolina, told Medscape Medical News.

The findings were presented here at the American Pain Society (APS) 2019 meeting.

Anti-inflammatory Properties

The research team at Duke University Medical Center and the Durham VA Medical Center in North Carolina have been exploring biomarkers of post traumatic stress disorder (PTSD) among Iraq and Afghanistan veterans.

They previously showed that serum levels of allopregnanolone, an endogenous progesterone metabolite and downstream metabolite of pregnenolone, were inversely associated with symptoms of depression, anxiety, and low back pain.

Subsequent research has linked allopregnanolone, a positive allosteric modulator of gamma-aminobutyric acid-A (GABAA) receptors, with analgesic and anti-inflammatory and neurotrophic properties.

Amid stepped-up efforts to treat pain with nonpharmacologic methods, the current researchers focused on the effects of pregnenolone in chronic low back pain.

Investigators enrolled 94 Iraq or Afghanistan-era veterans (90% male) in the 6-week study, which included a 4-week treatment period. The participants were randomly assigned to fixed escalation of pregnenolone up to 500 mg per day (n = 45) or to matching placebo (n = 49).

Patients who were currently taking opioids were excluded. While use of other medications were allowed, the regimens were required to have been stable for 4 weeks prior to study entry.

Other exclusions included epidural steroids, facet blocks, nerve blocks, or other invasive procedures to reduce low back pain in the 3 months prior to the start of the study.

New Pain Intervention?

The primary outcome was average pain intensity ratings from a daily pain diary in which 24-hour average pain severity scores were recorded on an 11-point Likert score. Those who received pregnenolone showed significantly greater reductions in low back pain compared with placebo on pain diary scores (P = .024) and pain recall (P = .010).

Significant improvements with pregnenolone vs placebo were also shown in pain interference scores during normal work (P = .040) and general activity (P = .031).

In addition, 51.2% of those in the pregnenolone group reported having at least a 20% improvement in pain symptoms compared with 28.6% of those in the placebo group (odds ratio, 2.62).

There were no serious adverse events in either group.

“Pregnenolone may thus represent a new intervention for pain conditions that is safe, well-tolerated, non-habit-forming, and potentially efficacious for the alleviation of pain symptoms,” the investigators note.

While pregnenolone is available over the counter, the researchers used a pharmaceutical-grade tablet formulation for the study.

“We know from our prior work that when we give patients pregnenolone in tablet form that it increases the levels of allopregnanolone by fivefold,” Naylor said.

“What’s really interesting about this is if we can determine whose blood levels of allopregnanolone are lower, we might be able to use pregnenolone to increase levels that might have been deficient to begin with,” she added.

Postpartum Depression Treatment?

Allopregnanolone has been in the headlines recently, but not for chronic pain. As reported by Medscape Medical News, brexanolone (Zulresso, SageTherapeutics), a proprietary formulation that is chemically identical of allopregnanolone, received approval in March from the US Food and Drug Administration (FDA) for the treatment of postpartum depression when administered as a 60-hour infusion.

However, little is known about a relationship between brexanolone and the pain effects observed with pregnenolone in the new study, noted the current study’s senior author Chris E. Marx, MD, also with Duke University School of Medicine and the Durham Veterans Affairs Health Care System.

“We do not know if there are shared mechanisms of action for improvements in chronic pain and postpartum depression at this time,” Marx told Medscape Medical News.

“Allopregnanolone does many different things in the brain. It is possible that its GABAA receptor activity is an important contributing mechanism of action, as well as its anti-inflammatory effects,” she said. “Allopregnanolone also enhances neurogenesis, and it is neuroprotective in a number of animal models.”

Pregnenolone, meanwhile, currently does not have FDA approval for any indication, and Marx cautions that unregulated over-the-counter formulations are not recommended for the treatment of pain.

“Pregnenolone was custom-synthesized to meet FDA standards for purity for this study. Over-the-counter formulations of pregnenolone are not required to meet this standard,” she said.

“Dietary supplements sold over-the-counter are generally not pharmaceutical-grade, and they are not infrequently contaminated with other products that are not listed on the label,” Marx added. Therefore, “over-the-counter use of pregnenolone is not recommended.”

Concerns and Questions

Commenting on the findings for Medscape Medical News, David Craig, PharmD, clinical pharmacologist with the Moffitt Cancer Center, Tampa, Florida, said he agrees with the cautionary approach regarding pregnenolone, and noted several questions about the neurosteroid and its effects.

“Clearly there was a noticeable difference between pain intensity in the pregnenolone group versus the placebo group, but why was there a difference is the real question,” said Craig, who was not involved with the research.

“It would be interesting to see the researchers conduct another prospective study looking at prednisone versus pregnenolone versus placebo, which could answer the question of whether the pregnenolone is acting as a ‘natural’ anti-inflammatory agent to reduce back pain,” he said.

In addition to efficacy questions, Craig noted that more needs to be learned about longer-term safety effects.

“I think the intervention they used is interesting and potentially innovative, but I have concerns about the acute/chronic use of pregnenolone, as much of what it is and does in the human body is unknown,” he said.

Craig echoed Marx’s warning about use of pregnenolone in a supplementary formulation.

“I have concerns about using OTC products that are potentially unpure, unsafe, and lack studies to support their efficacy,” he said.

Naylor has received a Rehabilitation Research & Development Career Development Award from the Department of Veterans Affairs (VA). Marx receives funding from multiple VA Merit Reviews and is a coapplicant on a pending patent application on neurosteroids and derivatives for CNS disorders. In the past 12 months, Craig has been a consultant to Nektar Therapeutics and SpecGx.

American Pain Society (APS) 2019: Abstract 274. Presented April 5, 2019.