Abstract
In response to the national opioid public health crisis, there is an urgent need to develop nonopioid solutions for effective pain management. Neurosteroids are endogenous molecules with pleotropic actions that show promise for safe and effective treatment of chronic low back pain. To determine whether adjunctive pregnenolone has therapeutic utility for the treatment of chronic low back pain in Iraq- and Afghanistan-era US military veterans. Randomized, double-blind, placebo-controlled clinical trial that enrolled for 42 months, from September 2013 to April 2017. Participants were Iraq- and Afghanistan-era veterans aged 18 to 65 years with chronic low back pain who received treatment in the Durham VA Health Care System in Durham, North Carolina, over 6 weeks. Data analysis began in 2018 and was finalized in March, 2019. Following a 1-week placebo lead-in, participants were randomized to pregnenolone or placebo for 4 weeks. Pregnenolone and placebo were administered at fixed, escalating doses of 100 mg for 1 week, 300 mg for 1 week, and 500 mg for 2 weeks. The primary outcome measure was the change in mean pain intensity ratings from a daily pain diary (numerical rating scale, 0-10) between visit 3 (baseline) and visit 6. Secondary outcomes included pain interference scores (Brief Pain Inventory, Short Form). Preintervention and postintervention neurosteroid levels were quantified by gas chromatography with tandem mass spectrometry. Hypotheses tested were formulated prior to data collection. A total of 94 participants (84 [89.4%] male; mean [SD] age, 37.5 [9.8] years; 53 [56.4%] of self-reported Caucasian race and 31 [33.0%] of self-reported African American race) were included. Forty-eight participants were randomized to pregnenolone and 52 to placebo, of whom 45 and 49, respectively, were included in baseline demographic characteristics secondary to noncompliance with medications as per protocol. Veterans randomized to pregnenolone reported significant reductions in low back pain relative to those randomized to placebo. Baseline unadjusted mean (SE) pain diary ratings were 4.83 (0.23) and 5.24 (0.22) for the placebo- and pregnenolone-treated groups, respectively (baseline unadjusted mean [SE] ratings for pain recall were 4.78 [0.24] and 5.15 [0.23], respectively). Unadjusted mean (SE) ratings following treatment (visit 6) were 4.74 (0.26) in the placebo group and 4.19 (0.30) in the pregnenolone-treated group. Unadjusted mean (SE) ratings for pain recall following treatment were 4.86 (0.27) for placebo and 4.18 (0.29) for pregnenolone. Least-square mean (LSM) analysis showed that pain scores significantly improved in the pregnenolone-treated group compared with placebo (LSM [SE] change in pain diary rating, -0.56 [0.25]; P = .02; LSM [SE] change in pain recall, -0.70 [0.27]; P = .01). Pain interference scores for work (LSM [SE] change, 0.71 [0.12]; P = .04) and activity (LSM [SE] change, 0.71 [0.11]; P = .03) were also improved in veterans randomized to pregnenolone compared with placebo. Pregnenolone was well tolerated. Participants receiving pregnenolone reported a clinically meaningful reduction in low back pain and 2 pain interference domains compared with those receiving placebo. Pregnenolone may represent a novel, safe, and potentially efficacious treatment for the alleviation of chronic low back pain in Iraq- and Afghanistan-era veterans. ClinicalTrials.gov Identifier: NCT01898013.
Highlights
The development of nonopioid pharmacological interventions that maximize analgesia and function while minimizing adverse outcomes has become a national imperative, as overreliance on prescription opioid medications has played a substantial role in the recent surge of opioid-related addiction and overdose deaths
Forty-eight participants were randomized to pregnenolone and 52 to placebo, of whom 45 and 49, respectively, were included in baseline demographic characteristics secondary to noncompliance with medications as per protocol
Least-square mean (LSM) analysis showed that pain scores significantly improved in
Summary
The development of nonopioid pharmacological interventions that maximize analgesia and function while minimizing adverse outcomes has become a national imperative, as overreliance on prescription opioid medications has played a substantial role in the recent surge of opioid-related addiction and overdose deaths. New treatment modalities for pain are urgently needed, and neurosteroids hold promise in this regard as safe and effective approaches for the treatment of chronic pain. Neurosteroids are endogenous molecules enriched in the brain that exhibit pleiotropic actions in the central nervous system. Allopregnanolone, a positive GABAA (γ-aminobutyric acid) receptor modulator and downstream metabolite of pregnenolone, has known analgesic, neuroprotective, neurotrophic, and anti-inflammatory properties.. Extensive data from preclinical models demonstrate that neurosteroids exhibit pronounced analgesic actions, and data demonstrate that neurosteroids are decreased in the setting of pain symptoms in clinical populations.. Restoration of low or depleted endogenous levels of neurosteroids such as allopregnanolone may have therapeutic utility for chronic low back pain. We hypothesized that adjunctive pregnenolone would reduce pain ratings in Iraq- and Afghanistan-era US military veterans with chronic low back pain
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