Allopregnanolone Levels Are Inversely Associated with Self-Reported Pain Symptoms in U.S. Iraq and Afghanistan-Era Veterans: Implications for Biomarkers and Therapeutics.

BACKGROUND AND OBJECTIVES: Pain symptoms are common among Iraq/Afghanistan-era veterans, many of whom continue to experience persistent pain symptoms despite multiple pharmacological interventions. Preclinical data suggest that neurosteroids such as allopregnanolone demonstrate pronounced analgesic properties, and thus represent logical biomarker candidates and therapeutic targets for pain. Allopregnanolone is also a positive GABAA receptor modulator with anxiolytic, anticonvulsant, and neuroprotective actions in rodent models. We previously reported inverse associations between serum allopregnanolone levels and self-reported pain symptom severity in a pilot study of 82 male veterans. METHODS: The current study investigates allopregnanolone levels in a larger cohort of 485 male Iraq/Afghanistan-era veterans to attempt to replicate these initial findings. Pain symptoms were assessed by items from the Symptom Checklist-90-R (SCL-90-R) querying headache, chest pain, muscle soreness, and low back pain over the past 7 days. Allopregnanolone levels were quantified by gas chromatography/mass spectrometry. RESULTS: Associations between pain ratings and allopregnanolone levels were examined with Poisson regression analyses, controlling for age and smoking. Bivariate nonparametric Mann­Whitney analyses examining allopregnanolone levels across high and low levels of pain were also conducted. Allopregnanolone levels were inversely associated with muscle soreness [P = 0.0028], chest pain [P = 0.032], and aggregate total pain (sum of all four pain items) [P = 0.0001]. In the bivariate analyses, allopregnanolone levels were lower in the group reporting high levels of muscle soreness [P = 0.001]. CONCLUSIONS: These findings are generally consistent with our prior pilot study and suggest that allopregnanolone may function as an endogenous analgesic. Thus, exogenous supplementation with allopregnanolone could have therapeutic potential. The characterization of neurosteroid profiles may also have biomarker utility.

Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans: A Randomized Clinical Trial.

Importance: 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. Objective: To determine whether adjunctive pregnenolone has therapeutic utility for the treatment of chronic low back pain in Iraq- and Afghanistan-era US military veterans. Design, Setting, and Participants: 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. Interventions: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01898013.

The role of screening expectations in modifying short-term psychological responses to low-dose computed tomography lung cancer screening among high-risk individuals.

OBJECTIVE: This study aimed to examine the relationship between pre-screening expectations and psychological responses to low-dose computerised tomography (LDCT) screening among high-risk individuals in the United Kingdom Lung Cancer Screening (UKLS) pilot trial. METHODS: Prior to screening, high-risk individuals randomised into the intervention arm of the UKLS were asked about their expected screening test result. Their actual LDCT scan result was compared with their baseline screening expectation to determine the level of congruence. Levels of concern about and perceived accuracy of the result were assessed in a questionnaire two weeks following receipt of their test result. RESULTS: The sample included 1589 participants. Regardless of their expected results, patients who required follow-up investigations after their initial LDCT scan were the most concerned about their result (p<0.001). Participants who expected to require follow-up, but did not need it, perceived the test to be least accurate (p=0.006). CONCLUSIONS: Lung cancer screening participants who require follow-up or who have unexpected negative results can be identified for supportive interventions. PRACTICAL IMPLICATIONS: These findings can be used to ensure that any future LDCT lung cancer screening programme is tailored to identify and support those high-risk individuals who may benefit from additional help.

An exploratory pilot investigation of neurosteroids and self-reported pain in female Iraq/Afghanistan-era Veterans.

Female Veterans are the most rapidly growing segment of new users of the Veterans Health Administration (VHA), and a significant proportion of female Veterans receiving treatment from VHA primary care providers report persistent pain symptoms. Currently, available data characterizing the neurobiological underpinnings of pain disorders are limited. Preclinical data suggest that neurosteroids may be involved in the modulation of pain symptoms, potentially via actions at gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are neurosteroids that modulate inhibitory GABA receptors and excitatory NMDA receptors, producing complex neuronal effects. Emerging evidence from male Iraq/Afghanistan-era Veterans suggests that reductions in neurosteroid levels are associated with increased pain symptoms and that neurosteroids may be promising biomarker candidates. The current exploratory study thus examined associations between self-reported pain symptoms in 403 female Iraq/Afghanistan-era Veterans and serum DHEAS and DHEA levels. Serum DHEAS levels were inversely correlated with low back pain in female Veterans (Spearman r = -0.103; p = 0.04). Nonparametric analyses indicate that female Veterans reporting moderate/extreme low back pain demonstrated significantly lower DHEAS levels than those reporting no/little low back pain (|Z| = 2.60; p = 0.009). These preliminary findings support a role for DHEAS in pain physiology of low back pain and the rationale for neurosteroid therapeutics in pain analgesia.

A pilot randomized placebo-controlled trial of adjunctive aripiprazole for chronic PTSD in US military Veterans resistant to antidepressant treatment.

Many individuals with post-traumatic stress disorder (PTSD) experience persistent symptoms despite pharmacological treatment with antidepressants. Several open-label monotherapy and adjunctive studies have suggested that aripiprazole (a second-generation antipsychotic) may have clinical utility in PTSD. However, there have been no randomized placebo-controlled trials of aripiprazole use for PTSD. We thus conducted a pilot randomized controlled trial of adjunctive aripiprazole versus placebo among Veterans with chronic PTSD serving in the US military since 11 September 2001 to assess the feasibility, safety, tolerability, and therapeutic potential of aripiprazole. Sixteen Veterans were randomized, and 14 completed at least 4 weeks of the study; 12 completed the entire 8-week trial. Outcome measures included the Clinician-Administered PTSD Scale (CAPS), PTSD Checklist, Beck Depression Inventory, Second Edition, and Positive and Negative Syndrome Scale scores. Aripiprazole was well-tolerated in this cohort, and improvements in CAPS, PTSD Checklist, Beck Depression Inventory, Second Edition, and Positive and Negative Syndrome Scale scores were as hypothesized. Although CAPS change scores did not reach statistical significance, aripiprazole outperformed placebo by 9 points on the CAPS in the last observation carried forward analysis compared with the placebo group (n = 7 per group), and by 20 points in the group randomized to aripiprazole that completed the entire study (n = 5) compared with the placebo group (n = 7). Results suggest promise for aripiprazole as an adjunctive strategy for the treatment of PTSD.