Dr. Himmatrao Bawaskar: Transforming Rural Healthcare Through Scientific Inquiry and Advocacy.

Dr. Himmatrao Bawaskar, a distinguished figure in Indian healthcare, has made significant contributions to medical research and public health, particularly in rural areas. Born in 1951 in Maharashtra, his journey from a rural upbringing to receiving one of the highest civilian awards of the Government of India, the Padma Shri, reflects his dedication to the field of medicine and public health. Dr. Bawaskar's groundbreaking research on scorpion stings, notably the use of prazosin, has revolutionized treatment protocols, significantly reducing mortality rates. Beyond scorpion stings, his work spans diverse medical areas, including snake bites and cardiovascular diseases. Moreover, Dr. Bawaskar's advocacy for ethical practices and healthcare reform underscores his commitment to improving healthcare outcomes. His legacy serves as an inspiration for future generations of healthcare professionals and policymakers, emphasizing the transformative power of dedication, compassion, and scientific inquiry in addressing critical healthcare challenges.

Psychotherapeutic and pharmacological agents for post-traumatic stress disorder with sleep disorder: network meta-analysis.

OBJECTIVE: The current guidelines and canonical norms of diagnosis or treatment for Post-traumatic stress disorder (PTSD) with sleep disorder are still conflicting and have not yet reached a consensus. This study aimed to unravel the most effective countermeasures between two categories (psychotherapy and pharmacotherapy) put forward by the National Institute for Health and Clinical Excellence (NICE) and World Federation of Societies of Biological Psychiatry (WFSBP) respectively to treat PTSD individuals co-exist with sleep disorders. METHODS: Four databases, including PubMed, EMBASE, Cochrane Library, and APA PsyNet, were searched from inception to February 02, 2023. RESULTS: Twenty articles with 24 Randomized controlled trials (RCTs) and a total number of 1,647 participants were included. As demonstrated in the network meta-analysis comparison results, CBT-I (standardized mean differences (SMD) = -1.51,95% confidence interval (CI):-2.55 to -0.47), CBT-I plus IRT (SMD = -1.71, 95%CI:-3.39, -0.03), prazosin (SMD = -0.87,95%CI:-1.59 to -0.16) and hydroxyzine (SMD = -1.06, 95%CI: -1.94 to -0.19) significantly reduced PTSD symptoms compared with placebo. In contrast to placebo, CBT-I (SMD = -5.61,95%CI:-8.82 to -2.40) significantly improved sleep quality. For nightmare severity, IRT (SMD =-0.65, 95%CI:-1.00 to -0.31), prazosin (SMD = -1.20,95%CI:-1.72 to -0.67) and hydroxyzine (SMD = -0.98,95%CI:-1.58 to -0.37) significantly reduced nightmare severity in comparison with placebo. CONCLUSIONS: This study suggested that under most circumstances, psychotherapy namely CBT-I had a favorable profile, but pharmacotherapy with prazosin was effective in managing nightmare severity. The sole avail of CBT-I was recommended to improving sleep quality while CBT-I and CBT-I plus IRT showed excellent management of PTSD symptom severity. Exposure to CBT-I isrecommended for depression. The relevant clinical guidelines for the management of individuals with PTSD and sleep disorders may regard this as a reference. PROSPERO: CRD42023415240.

Prazosin Potentiates Mast Cell-Stabilizing Property of Adrenaline.

BACKGROUND/AIMS: Adrenaline quickly inhibits the release of histamine from mast cells. Besides ß2-adrenergic receptors, several in vitro studies also indicate the involvement of α-adrenergic receptors in the process of exocytosis. Since exocytosis in mast cells can be detected electrophysiologically by the changes in the membrane capacitance (Cm), its continuous monitoring in the presence of drugs would determine their mast cell-stabilizing properties. METHODS: Employing the whole-cell patch-clamp technique in rat peritoneal mast cells, we examined the effects of adrenaline on the degranulation of mast cells and the increase in the Cm during exocytosis. We also examined the degranulation of mast cells in the presence or absence of α-adrenergic receptor agonists or antagonists. RESULTS: Adrenaline dose-dependently suppressed the GTP-γ-S-induced increase in the Cm and inhibited the degranulation from mast cells, which was almost completely erased in the presence of butoxamine, a ß2-adrenergic receptor antagonist. Among α-adrenergic receptor agonists or antagonists, high dose prazosin, a selective α1-adrenergic receptor antagonist, significantly reduced the ratio of degranulating mast cells and suppressed the increase in the Cm. Additionally, prazosin augmented the inhibitory effects of adrenaline on the degranulation of mast cells. CONCLUSION: This study provided electrophysiological evidence for the first time that adrenaline dose-dependently inhibited the process of exocytosis, confirming its usefulness as a potent mast cell-stabilizer. The pharmacological blockade of α1-adrenergic receptor by prazosin synergistically potentiated such mast cell-stabilizing property of adrenaline, which is primarily mediated by ß2-adrenergic receptors.

Comparison of alpha-2 agonist versus alpha-1 antagonist for post-traumatic stress disorder-associated nightmares in pediatric patients.

Introduction: Posttraumatic stress disorder (PTSD) in children and adolescents has a high prevalence of accompanying sleep disturbances. Currently, pediatric treatment of PTSD-related nightmares is extrapolated from adult studies. This study aims to determine the effectiveness and safety of clonidine and guanfacine compared with prazosin for the treatment of PTSD-related nightmares. Methods: This was a retrospective, single-center, medical record review of patients 5 to 17 years old admitted to an inpatient psychiatric unit from January 2015 to September 2021. Patients with a new initiation of an alpha-2 agonist (clonidine or guanfacine) or an alpha-1 antagonist (prazosin) with a diagnosis of PTSD, other trauma- or stressor-related disorder or unspecified anxiety disorder were included. The primary endpoint was the percentage of patients with a decrease in the frequency of nightmares. Results: A total of 59 patients were included in the study: 37 in the alpha-2 agonist group and 22 in the alpha-1 antagonist group. There was no statistically significant difference in reduction of nightmares with both groups having a high percentage of patients showing response (alpha-2 agonist: 91.9%, alpha-1 antagonist: 86.4%). Time to decrease in nightmares was comparable between groups with a relatively quick onset. Within the alpha-2 agonist group, clonidine (1.59 ± 1.06 days) compared with guanfacine (3.18 ± 1.74 days) had a statistically significant faster time to reduction in nightmares (p = .005). Discussion: Both pharmacologic classes of medications were effective treatment options for pediatric PTSD-associated nightmares with a low incidence of adverse effects. There was a quick time to onset seen with all agents.

Prazosin and cyproheptadine in combination in the treatment of alcohol use disorder: A randomized, double-blind, placebo-controlled trial.

BACKGROUND AND AIMS: Pre-clinical studies suggest that the simultaneous blockade of the α1b and 5HT2A receptors may be effective in reducing alcohol consumption. This study aimed to assess the efficacy and safety of prazosin (α1b blocker) and cyproheptadine (5HT2A blocker) combination in decreasing total alcohol consumption (TAC) in alcohol use disorder (AUD). DESIGN, SETTING AND PARTICIPANTS: This was a double-blind, parallel group, placebo-controlled, Phase 2, randomized clinical trial conducted in 32 addiction treatment centres in France. A total of 108 men and 46 women with severe AUD took part. INTERVENTION: Participants were randomly assigned to one of the following 3-month treatments: (1) low-dose group (LDG) receiving 8 mg cyproheptadine and 5 mg prazosin extended-release (ER) formulation daily; (2) high-dose group (HDG) receiving 12 mg cyproheptadine and 10 mg prazosin ER daily; and (3) placebo group (PG) receiving placebo of cyproheptadine and prazosin ER. A total of 154 patients were randomized: 54 in the PG, 54 in the LDG and 46 in the HDG. MEASUREMENTS: The primary outcome was TAC change from baseline to month 3. FINDINGS: A significant main treatment effect in the change in TAC was found in the intent-to-treat population (P = 0.039). The HDG and LDG showed a benefit in the change in TAC from baseline to month 3 compared with PG: -23.6 g/day, P = 0.016, Cohen's d = -0.44; -18.4 g/day, P = 0.048 (Bonferroni correction P < 0.025), Cohen's d = -0.36. In a subgroup of very high-risk drinking-level participants (> 100 g/day of pure alcohol for men and > 60 g/day for women), the difference between the HDG and the PG in the primary outcome was -29.8 g/day (P = 0.031, Cohen's d = -0.51). The high and low doses were well-tolerated with a similar safety profile. CONCLUSIONS: A randomized controlled trial of treatment of severe alcohol use disorder with a cyproheptadine-prazosin combination for 3 months reduced drinking by more than 23 g per day compared with placebo. A higher dose combination was associated with a larger magnitude of drinking reduction than a lower dose combination while showing similar safety profile.

Estrogen-receptor status determines differential regulation of α1- and α2-adrenoceptor-mediated cell survival, angiogenesis, and intracellular signaling responses in breast cancer cell lines.

Psychosocial stress promotes cancer pathogenesis involving angiogenesis through alterations in neuroendocrine-immune functions that may involve adrenoceptor (AR)-dependent signaling mechanisms in the brain, lymphoid organs, and cancerous cells. Various concentrations of α1- and α2- AR-specific agonists and antagonists were incubated in vitro with estrogen receptor-positive (ER +) MCF-7, and ER (-) MDA MB-231 cells to examine the secretions of VEGF-A, VEGF-C, and nitric oxide (NO), and expression of signaling molecules- p-ERK, p-CREB, and p-Akt on the proliferation of breast cancer cell lines. Cellular proliferation, VEGF-A and NO secretion, expression of p-ERK, p-CREB, and p-Akt were enhanced in MCF-7 cells treated with α1-AR agonist while VEGF-C secretion alone was enhanced in MDA MB-231 cells. Treatment of MCF-7 and MDA MB-231 cells with α2- AR agonist similarly enhanced proliferation and decreased NO production and p-CREB expression while VEGF-C secretion was decreased in MCF-7 cells and p-Akt expression was decreased in MDA MB-231 cells. α1-AR inhibition reversed cellular proliferation and VEGF-A secretion by MCF-7 cells while α2-AR inhibition reversed the proliferation of MCF-7 and MDA MB-231 cells and VEGF-C secretion by MCF-7 cells. Taken together, breast cancer pathogenesis may be influenced by distinct α-AR-mediated signaling mechanisms on angiogenesis and lymphangiogenesis that are dependent on estrogen receptor status.

The cytotoxic effects of prazosin, chlorpromazine, and haloperidol on hepatocellular carcinoma and immortalized non-tumor liver cells.

Liver cancer annually accounts for over 800,000 cases and 700,000 deaths worldwide. Hepatocellular carcinoma is responsible for over 80% of liver cancer cases. Due to ineffective treatment options and limited surgical interventions, hepatocellular carcinoma is notoriously difficult to treat. Nonetheless, drugs utilized for other medical conditions, such as the antihypertensive medication prazosin, the neuroleptic medication chlorpromazine, and the neuroleptic medication haloperidol, have gained attention for their potential anti-cancer effects. Therefore, this study used these medications for investigating toxicity to hepatocellular carcinoma while testing the adverse effects on a noncancerous liver cell line model THLE-2. After treatment, an XTT cell viability assay, cell apoptosis assay, reactive oxygen species (ROS) assay, apoptotic proteome profile, and western blot were performed. We calculated IC50 values for chlorpromazine and prazosin to have a molar range of 35-65 µM. Our main findings suggest the capability of both of these treatments to reduce cell viability and generate oxidative stress in HepG2 and THLE-2 cells (p value < 0.05). Haloperidol, however, failed to demonstrate any reduction in cell viability revealing no antitumor effect up to 100 µM. Based on our findings, a mechanism of cell death was not able to be established due to lack of cleaved caspase-3 expression. Capable of bypassing many aspects of the lengthy, costly, and difficult cancer drug approval process, chlorpromazine and prazosin deserve further investigation for use in conjunction with traditional chemotherapeutics.

Sleep loss disrupts decision-making ability and neuronal cytomorphology in zebrafish and the effects are mediated by noradrenaline acting on α1-adrenoceptor.

Sleep is an instinct behavior, and its significance and functions are still an enigma. It is expressed throughout one's life and its loss affects psycho-somatic and physiological processes. We had proposed that it might maintain a fundamental property of the neurons and the brain. In that context, it was shown that sleep, rapid eye movement sleep (REMS) in particular, by regulating noradrenaline (NA), maintains the brain excitability. It was also reported that sleep-loss affected memory, reaction time and decision-making ability among others. However, as there was lack of clarity on the cause-and-effect relationship as to how the sleep-loss could affect these basic behaviors, their association was questioned and it was difficult to propose a cure or at least ways and means to ameliorate the symptoms. Also, we wanted to conduct the studies in a simpler model system so that conducting future molecular studies might be easier. Hence, using zebrafish as a model we evaluated if sleep-loss affected the basic decision-making ability, a cognitive process and if the effect was induced by NA. Indeed, our findings confirmed that upon sleep-deprivation, the cognitive decision-making ability of the prey zebrafish was compromised to protect itself by running away from the reach of the exposed predator Tiger Oscar (TO) fish. Also, we observed that upon sleep-loss the axonal arborization of the prey zebrafish brain was reduced. Interestingly, the effects were prevented by prazosin (PRZ), an α1-adrenoceptor (AR) antagonist and when the zebrafish recovered from the lost sleep.

Effects of prazosin treatment on liver enzymes are moderated by alcohol withdrawal symptoms in individuals with alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is associated with significant liver pathology marked by elevated liver enzymes. Prazosin, an alpha1-noradrenergic antagonist significantly improves alcohol drinking outcomes in individuals with alcohol withdrawal symptoms (AW), but effects on liver enzymes are unknown. We assessed the effects of prazosin treatment on the liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), and gamma-glutamyltransferase (GGT) in individuals with AUD. METHODS: Participants (N=100) with AUD were enrolled in a 12-week randomized controlled trial and received either placebo or 16 mg/day of prazosin. Whole blood was drawn from 92 participants to measure liver enzyme levels every 4 weeks, and severity of AW was assessed weekly. Analysis predicting liver function outcomes used linear mixed effects models. RESULTS: Controlling for alcohol consumption, a significant AW × treatment effect was seen for ALT (p < 0.05), AST (p < 0.05) and GGT (p < 0.01). Additionally, AST (b = 0.2, p < 0.01), ALT (b = 0.2, p < 0.05), and GGT (b = 0.3, p < 0.01) were elevated in individuals with higher AW in the placebo but not in the prazosin group (AST: p > 0.66; ALT: p > 0.65). Only in the prazosin group were lower GGT levels associated with higher withdrawal severity (b = -0.16, p < 0.05). CONCLUSIONS: We found an interaction of alcohol withdrawal symptoms and prazosin treatment on liver enzyme levels, which were not influenced by week in the trial or the amount of alcohol consumed. Together, these findings suggest that prazosin treatment reduces liver enzymes over the course of AUD treatment among individuals with significant AW, though replication to establish clinical utility is needed.

A case of prazosin in treatment of rapid eye movement sleep behavior disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dream-enactment behaviors that emerge during a loss of REM sleep atonia. Untreated RBD carries risks for physical injury from falls or other traumatic events during dream enactment as well as risk of injury to the bed partner. Currently, melatonin and clonazepam are the mainstay pharmacological therapies for RBD. However, therapeutic response to these medications is variable. While older adults are most vulnerable to RBD, they are also particularly vulnerable to the adverse effects of benzodiazepines, including increased risk of falls, cognitive impairment, and increased risk of Alzheimer disease. Prazosin is a centrally active alpha-1 adrenergic receptor antagonist often prescribed for trauma nightmares characterized by REM sleep without atonia in patients with posttraumatic stress disorder. We report a case of successful RBD management with prazosin in a patient in whom high-dose melatonin was ineffective. Although there was no observable reduction in dream-enactment behaviors with high-dose melatonin, the possibility of a synergistic effect of prazosin combined with melatonin cannot be ruled out. This case report supports further evaluation of prazosin as a potential therapeutic for RBD. CITATION: Cho Y, Iliff JJ, Lim MM, Raskind M, Peskind E. A case of prazosin in treatment of rapid eye movement sleep behavior disorder. J Clin Sleep Med. 2024;20(2):319-321.

A non-randomized pilot trial of the use of prazosin in the prevention of transition from acute stress disorder to post-traumatic stress disorder.

BACKGROUND: Following a traumatic event, 40-80% of the patients with acute stress disorder (ASD) will develop post-traumatic stress disorder (PTSD), 67% at 6 months. Alpha1-blockers are effective in treating some symptoms of PTSD but their usefulness in acute stress situations remains unclear. We hypothesized that reducing noradrenergic hyperactivity with an alpha1-blocker during the acute phase after a traumatic event could prevent the transition to PTSD in patients with ASD. OBJECTIVE: To investigate the efficacy and safety of a 1-month course of alpha1-blocker (prazosin) to prevent the transition to PTSD in patients with ASD at 6 months. METHOD: In a monocentric open-label prospective pilot study, 15 patients with ASD were included within 3-7 days of exposure to a traumatic event. After enrolment, they received prazosin LP at home at bedtime at 2.5 mg/day for 7 days and then 5 mg/day for 21 days. Incidence of PTSD was assessed at 6 months using the Clinician Administrated PTSD Scale (CAPS). RESULTS: At 6 months, 22% of patients who completed the study (2/9) met the diagnostic criteria for PTSD. This rate was significantly lower than that observed in previous studies (67%; p = .047). The treatment was well tolerated and there were no serious adverse events. CONCLUSIONS: These preliminary findings indicating the safety of prazosin and suggesting its potential to prevent the development of PTSD in ASD require to be replicated in large-scale randomized placebo-controlled studies.Trial registration: The study was pre-registered on a public database (www.clinicalTrials.gov identifier: NCT03045016).

Alpha1-blockers are safe and well tolerated in patients with acute stress disorder.The use of alpha1-blockers 3­7 days after traumatic exposure is worthy of study.Alpha1-blockers could prevent the transition to PTSD in ASD patients at 6 months.

The α1 adrenoceptor antagonist prazosin potentiates morphine induced conditioned place preference in rats.

The norepinephrine (NE) system is involved in pathways that regulate morphine addiction. Here, we investigated the role of α1 adrenoceptor in the ventrolateral orbital cortex (VLO) of rats with repeated morphine treatment and underlying molecular mechanisms. The rewarding properties of morphine were assessed by the conditioned place preference (CPP) paradigm. Prazosin, an α1 adrenoceptor antagonist, was microinjected into the VLO. The expression of α1 adrenoceptor, p-CaMKII/CaMKII, CRTC1, BDNF and PSD95 in the VLO were determined by immunohistochemistry or western blotting. Neurotransmitter NE in the VLO and inflammatory factors in serum were detected separately through high-performance liquid chromatography and enzyme-linked immunosorbent assay. Our experimental results showed that repeated morphine administration induced stable CPP and prazosin promoted the morphine-induced CPP. Microinjection of prazosin in the VLO not only blocked the activity of α1 adrenoceptor, decreased CaMKII phosphorylation and CRTC1, which eventually resulted in a regression of synaptic plasticity-related proteins, but also was accompanied by significantly decreasing of NE in the VLO and increasing of inflammatory cytokines in peripheral blood. These findings suggested that prazosin potentiates the addictive effects of morphine. The effect of increased CPP through reducing α1 adrenoceptor and NE was associated with the CaMKII-CRTC1 pathway and synaptic plasticity-related proteins in the VLO and inflammatory cytokines in the peripheral blood. The NE system may therefore be an underlying therapeutic target in morphine addiction. Additionally, we believe that the clinical use of prazosin in hypertensive patients with morphine abuse may be a potential risk because of its reinforcing effect on addiction.

A Pilot Study on the Effectiveness of Prazosin as a Treatment of Post-Traumatic Stress Disorder-Related Nightmares in Women with Bulimia Nervosa.

Objectives Post-traumatic stress disorder (PTSD) symptoms are reported in over 36% of individuals with bulimia nervosa. To date, none of the clinical trials have examined nightmare reduction in this population. We evaluated the effectiveness of prazosin in bulimic females experiencing PTSD-related nightmares. We hypothesized that prazosin will decrease nightmares, normalize cortisol levels and secretory patterns, and improve sleep. Methods Our seven-week prospective, randomized, double-blind, placebo-controlled crossover pilot trial recruited eight adult women. Each participant received three weeks of prazosin and a placebo, separated by a one-week washout period. The order of treatment was counterbalanced across participants. Self-reports, clinician-administered scales, and salivary cortisol was collected to measure outcomes. Results A significant treatment effect was seen in nightmare intensity on the Clinician-Administered PTSD Scale (CAPS-I) (p=0.026) and a marginally significant effect on nightmare frequency (p=0.069). The only significant main effect of treatment on self-reported sleep parameters was on nightmares. Cortisol secretory patterns did not change, but on average, study participants had significantly higher cortisol levels compared to normative values. ANOVA showed a significant main effect of time for cortisol (F(4, 28) = 6.15, p=.001) but no within or between groups significant effects (ps>.179). Follow-up tests showed the effect of time was linear (F(1, 7) = 10.77, p=.013). Conclusion Prazosin significantly reduced intensity and marginally reduced the frequency of PTSD-related nightmares in bulimia nervosa but did not affect subjective sleep efficiency, quality, cortisol levels, or diurnal cortisol secretory pattern. Larger trials using objective sleep measures are warranted to replicate these findings.

Post-resection Cavity Lavage of High Grade Glioma With a Novel Drug Combination: A Case Report.

BACKGROUND: High grade gliomas are the most common and most lethal primary cancers of the central nervous system. CASE REPORT: We herein present a case report of a long-term surviving 36-year-old female diagnosed with high grade glioma, for which she underwent neurosurgery with a gross total removal of the tumor. Shortly thereafter (<3 months) she was readmitted in a desolate state due to a large recurrence. After Ethical Committee approval, proper explanation, and consent from spouse, she was subjected to a reoperation involving a post-operative infusion into the excised tumor cavity, containing a mixture of a non-physiological amino acid in millimolar concentration and a proapoptotic drug in micromolar concentration. The patient tolerated the treatment well and was discharged in a stable state thereafter. A series of follow ups revealed successive clinical improvements and after 4-6 months, she had recovered with mild left hemiparesis, meaning that she was able to carry out activities of daily living independently. Now, 5.5 years later, after the recurrence and the infusion therapy, she continues to have a mild left hemiparesis and her MRI with contrast shows no evidence of tumor. CONCLUSION: Continuous intratumoral infusion therapy with an artificial amino acid combined with a proapoptotic drug results in complete glioma cell lysis both in vitro and in vivo.

Prospective evaluation of pregnancy outcomes after gestational exposure to prazosin.

AIMS: Prazosin is an antihypertensive medication which can be used to help with post-traumatic stress disorder (PTSD) symptoms. Little data is currently available on its safety in pregnancy. The aim of this study was to assess the fetal and pregnancy safety associated with prazosin exposures in early pregnancy. METHODS: Subjects were 11 patients who took prazosin during pregnancy and were counselled at the FRAME clinic in London Health Sciences Centre (Ontario, Canada) between 1 January 2000 and 31 December 2021. Data on their other exposures and pregnancy outcomes were collected from medical records and through telephone questionnaires. RESULTS: It was found that 6/11 (54.5%) subjects did not report any adverse outcomes and experienced uneventful pregnancies. There were two miscarriages. Birthweights were within the normal range for the remaining nine pregnancies. Adverse events reported were consistent with background population expectation, including: one postpartum haemorrhage, one case of preeclampsia, one preterm birth, two NICU admissions, and two caesarean sections. CONCLUSIONS: For these 11 subjects, pregnancy outcomes after exposure to prazosin were consistent with typical outcomes from unexposed pregnancies. More data are needed to conclude that prazosin is safe for use in pregnant subjects. However, the lack of adverse effects above baseline is reassuring to future patients who may be unintentionally exposed to prazosin while pregnant. Therefore, this study contributes valuable data towards monitoring safety of prazosin in pregnancy.

Randomized controlled pilot trial of prazosin for prophylaxis of posttraumatic headaches in active-duty service members and veterans.

OBJECTIVE: Evaluate the efficacy and tolerability of prazosin for prophylaxis of headaches following mild traumatic brain injury in active-duty service members and military veterans. BACKGROUND: Prazosin is an alpha-1 adrenoreceptor antagonist that reduces noradrenergic signaling. An open-label trial in which prazosin reduced headache frequency in veterans following mild traumatic brain injury provided the rationale for this pilot study. METHODS: A 22-week parallel-group randomized controlled trial  which included 48 military veterans and active-duty service members with mild traumatic brain injury-related headaches was performed. The study design was based on International Headache Society consensus guidelines for randomized controlled trials for chronic migraine. Following a pre-treatment baseline phase, participants with at least eight qualifying headache days per 4 weeks were randomized 2:1 to prazosin or placebo. After a 5-week titration to a maximum possible dose of 5 mg (morning) and 20 mg (evening), participants were maintained on the achieved dose for 12 weeks. Outcome measures were evaluated in 4-week blocks during the maintenance dose phase. The primary outcome measure was change in 4-week frequency of qualifying headache days. Secondary outcome measures were percent participants achieving at least 50% reduction in qualifying headache days and change in Headache Impact Test-6 scores. RESULTS: Intent-to-treat analysis of randomized study participants (prazosin N = 32; placebo N = 16) demonstrated greater benefit over time in the prazosin group for all three outcome measures. In prazosin versus placebo participants, reductions from baseline to the final rating period for 4-week headache frequency were -11.9 ± 1.0 (mean ± standard error) versus -6.7 ± 1.5, a prazosin minus placebo difference of -5.2 (-8.8, -1.6 [95% confidence interval]), p = 0.005 and for Headache Impact Test-6 scores were -6.0 ± 1.3 versus +0.6 ± 1.8, a difference of -6.6 (-11.0, -2.2), p = 0.004. The mean predicted percent of participants at 12 weeks with ≥50% reduction in headache days/4 weeks, baseline to final rating, was 70 ± 8% for prazosin (21/30) versus 29 ± 12% for placebo (4/14), odds ratio 5.8 (1.44, 23.6), p = 0.013. The trial completion rate of 94% in the prazosin group (30/32) and 88% in the placebo group (14/16) indicated that prazosin was generally well tolerated at the administered dose regimen. Morning drowsiness/lethargy was the only adverse effect that differed significantly between groups, affecting 69% of the prazosin group (22/32) versus 19% of the placebo group (3/16), p = 0.002. CONCLUSIONS: This pilot study provides a clinically meaningful efficacy signal for prazosin prophylaxis of posttraumatic headaches. A larger randomized controlled trial is needed to confirm and extend these promising results.

Case series: Continued remission of PTSD symptoms after discontinuation of prazosin.

Post-traumatic stress disorder is a debilitating chronic illness that affects 6 out of 100 adults after a severe trauma. The alpha-adrenergic antagonist prazosin, which is prescribed off-label for flashbacks and nightmares due to trauma, is often continued indefinitely due to reports of symptoms returning upon discontinuation. There is no standard guidance for a trial of discontinuation of prazosin due to intolerance or side effects. In this case series, three patients are started on prazosin leading to remission of trauma-related symptoms, and symptoms continue to remit after treatment for an average of about 2 years followed by discontinuation of the medication. There are many similarities in these case reports which serve to provide guidance as to when a trial of prazosin discontinuation may be warranted.

Prenatal Morphine Exposure Increases Cardiovascular Disease Risk and Programs Neurogenic Hypertension in the Adult Offspring.

BACKGROUND: The opioid overdose and opioid use disorder epidemics are concomitant with increased metabolic and CVD risk. Although opioid use disorder causes adverse pregnancy outcomes, the offspring's cardiovascular health is understudied. We hypothesized that offspring exposed to in utero morphine exposure (IUME) would show increased CVD risk factors and endogenous opioid system dysregulation. METHODS: Sprague Dawley dams were treated with saline (vehicle, n=10) or escalating doses of morphine (5-20 mg/kg per day, SC, n=10) during gestation. Cardiovascular and metabolic parameters were assessed in adult offspring. RESULTS: Litter size and pups' birth weight were not different in response to IUME. Female and male IUME offspring showed reduced body length at birth (P<0.05) and body weight from weeks 1 to 3 of life (P<0.05), followed by a catch-up growth effect. By week 16, female and male IUME rats showed reduced tibia length (P<0.05) and fat mass. IUME increases the mean arterial pressure and the depressor response to mecamylamine (5 mg/kg per day, IP) induced by IUME were abolished by a chronic treatment with an alpha-adrenergic receptor blocker (prazosin; 1 mg/kg per day, IP). Although circulating levels of angiotensin peptides were similar between groups, IUME exacerbated maximal ex vivo Ang (angiotensin) II-induced vasoconstriction (P<0.05) and induced endothelial dysfunction in a sex-specific manner (P<0.05). Proenkephalin, an endogenous opioid peptide that lowers blood pressure and sympathetic-mediated vasoconstriction, showed reduced mRNA expression in the heart, aorta, and kidneys from morphine versus vehicle group (P<0.05). CONCLUSIONS: Among the effects of IUME, neurogenic hypertension, vascular dysfunction, and metabolic dysfunction could be associated with the dysregulation of the endogenous opioid system.