Prazosin for Military Combat-Related PTSD Nightmares: A Critical Review

Posttraumatic stress disorder (PTSD) is a growing national health issue, characterized by an individual’s immediate response to a putative traumatic event, followed by a persistent triad of clustered neuropsychiatric disturbances that result in life-role impairment and/or clinically significant distress.¹ The psychopathological impact of exposure to traumatic events has long been recognized, especially in the context of war.² Descriptions of combat-related sequelae date back thousands of years.² Although modern conflicts engendered their own unique labels for these difficulties, it was not until after the Vietnam War that PTSD came to be a defined condition in the Diagnostic and Statistical Manual of Mental Disorders, (DSM) III.^2–4

Even though many United States citizens are exposed to at least one lifetime potentially traumatic event,^2,5 relatively few (6%−8%) develop PTSD.^2,4,6,7 Trauma exposure rates and subsequent PTSD rates in service members with combat experiences have been shown to be elevated relative to community rates.^2,4,5,8 Although military combat is one of the most common exposures associated with PTSD in men,⁷ PTSD incidence is greater in women after combat involvement.⁹ A study involving Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) combat veterans revealed rates of exposure to life-threatening events ranging from 84%−95% and self-reported rates of PTSD ranging from 4%−20%.¹⁰ Increased rates of PTSD are associated with greater frequency and intensity of combat exposure.^10–12 Published rates of combat-related PTSD may be an underestimate, considering findings obtained from soldiers via anonymous data collection.¹¹

Trauma-related nightmares are sometimes referred to as the “hallmark” symptom of PTSD,^13,14 with acute prevalence rates as high as 90%.¹⁴ They are a common stress-induced casualty experienced by OIF/OEF military personnel engaged in combat operations¹⁵ and are reported by approximately 50%−70%^13,16 of combat veterans with PTSD. They are among the most common, distressing, and treatment-resistant symptoms of PTSD.^{13,14,17–19} They can also persist beyond resolution of PTSD.¹⁷ Although the temporal relationship between trauma exposure, sleep disruption, and emergent PTSD is an area of ongoing examination,^16,19 the presence of nightmares before¹⁴ or after^14,17 a traumatic experience is predictive of eventual onset of PTSD, as well as a variety of behavioral health conditions and symptoms, including suicidal behavior.¹⁴ Persistent PTSD nightmares can impair quality of life, disrupt sleep, and generate a positive feedback loop of further neuropsychiatric, functional, and quality-of-life impairment.^16–18 Trauma nightmares and sleep disruptions likely interface to promote the emergence, maintenance, and treatment-resistant characteristics of PTSD.^13,14,16,19

PTSD symptomatology is believed to be mediated by excessive noradrenergic tone. Serial ambulatory in-dwelling cerebrospinal fluid noradrenergic monitoring of veterans with combat-related PTSD have revealed persistently elevated levels of norepinephrine, which correlated positively with PTSD symptoms as measured by the total Clinician-Administered PTSD Scale (CAPS; r=0.82, p <0.005).²⁰ Supporting neurobiological evidence underlying the proposed substrates and the mechanistic pathophysiology of PTSD nightmares have been previously reviewed and include functional imaging and polysomnography (PSG), as well as peripheral markers of elevated noradrenergic activity.¹³ The proposed evidentiary model involves final common-pathway imbalanced sleep architecture and fragmented REM sleep, hypothetically related to central adrenergic hyperactivity.¹³ Elevated adrenergic tone is proposed to be consequent of combined amygdalar overactivity and reduced inhibitory medial prefrontal cortical input.¹³

The current 2009 American Psychiatric Association Clinical Practice Guideline Watch commented that traditional first-line psychotropic management of PTSD with FDA-approved selective serotonin reuptake inhibitors (SSRIs) appears to be differentially less efficacious for military veterans with combat-related PTSD.²¹ SSRIs have been characterized as “ineffective” for PTSD nightmares.¹³ In contrast, prazosin therapy has been identified as a promising off-label augmenting agent to traditional antidepressant intervention for the management of combat-PTSD sleep disturbances, including nightmares.^13,21 In a recent Department of Veterans Affairs review,²² prazosin was described as a proven effective treatment for (all-cause) PTSD nightmares.

Prazosin is a generically-available, FDA-approved antihypertensive agent. It is a lipophilic alpha₁ adrenergic antagonist with central activity.^23–25 Prazosin may normalize REM architecture in humans with PTSD²⁵ via attenuation of overly-active central noradrenergic tone, which is hypothesized to be one of the putative key driving pathophysiological processes behind PTSD nightmares.^13,14,16,23

Only one publication²⁶ has specifically reviewed the potential utility of prazosin for all-cause PTSD nightmares since the current APA Guideline Watch. There have been three other interval reviews, including a systematic review and commissioned task force “Best Practice Guide,” examining prazosin for all-cause nightmares,^17,27 as well as an invited review of pharmacologic and non-pharmacological interventions for PTSD sleep disruptions, including nightmares.¹⁹ Although these reviews concluded that evidence supports the use of prazosin to treat nightmares, they all noted limitations with the currently available evidence-base. We are not aware of any critical reviews specifically examining the efficacy of prazosin therapy for combat-related PTSD nightmares. The purpose of this study is to systematically review the off-label use of prazosin for the management of combat-related PTSD nightmares.

Methods

Relevant articles published between 1996 and January 2013 were identified by use of MEDLINE. The following four primary search terms were used: 1) prazosin; 2) Minipress (then adding “or” prazosin from the populated list); 3) posttraumatic stress disorder (then adding “or” stress disorders, posttraumatic, from the populated list); and 4) nightmares (then adding “or” dreams from the populated list). Search terms #3 and #4 were combined, and that combination was then combined separately with search terms 1) prazosin and 2) Minipress. The primary search was augmented with an abstract search of the Military Health Research Forum (http://cdmrp.army.mil/default.shtml) peer-reviewed medical research programs, using “PTSD treatment” as our search term.

Inclusion criteria consisted of military veteran cohort or retrospective trials that examined the effect of prazosin on combat-related PTSD nightmares as a primary outcome measure. We excluded non-English articles, case series with fewer than five subjects, and any article where the majority of subjects did not have combat-related nightmares. For the purposes of this review, "majority" was defined a priori as >50% of subjects. Detected abstracts were reviewed independently by the authors to determine inclusion eligibility. Disagreements were resolved via consensus conference.

Each included study was reviewed by the authors and independently classified according to a modified grading system previously adapted and utilized by Warden et al.’s Neurobehavioral Guidelines Working Group.²⁸ Each study was graded from Class I to Class III, with Class I status reserved for well-designed, double-blind, placebo-controlled trials with comparable validated primary outcome measures and reasonable subject recruitment of a representative population (Table 1). A consensus conference was held to ensure grading agreement among the authors.

Results

Using our search methods, we identified 312 abstracts, which resulted in seven studies that met criteria for review. Six were prospective trials. These included three open-label^15,29,30 and three randomized, placebo-controlled trials (RCTs), of which, two were parallel^18,31 and one was a crossover trial.²⁴ One RCT was a comparison trial.³¹ We identified one Class I,¹⁸ four Class II,^24,30–32) and two Class III^15,29 studies (Table 2). Six of the seven studies showed positive results for prazosin.^{15,18,24,29,30,32}

All seven studies examined the impact of prazosin augmentation on predominately combat-related PTSD nightmares as a primary outcome. Item B2, “recurrent distressing dreams of the event,” from the Clinician-Administered PTSD Scale for DSM-IV (CAPS),³³ was the most common primary outcome measure to evaluate this effect. It was used in six of the seven studies.^{15,18,24,29,30,32} This item measures both the frequency and intensity of nightmares by use of a 5-point dimensional scale, from 0 to 4, for each variable over a specified duration of time³³ (Table 3). The item score is reported as a combination total score of both variables, ranging from 0 to 8, with higher scores indicating greater nightmare pathology. A frequency score of ≥1 combined with an intensity score of ≥2, for a combined score of ≥3 is the typical dichotomous definition of a PTSD “symptom” on the CAPS.³⁴ All seven studies reported a minimum baseline CAPS B2 total score of at least 3.

The Clinical Global Impression of Change Scale (CGI-C) was used in all seven studies. It is a widely-used, brief, clinician-administered continuous measure of global clinical change.³⁵ It is a 7-point scale, ranging from 1 to 7, with lower scores (<4) representative of greater clinical improvement and higher scores (≥4) indicative of increasing clinical difficulties (Table 3).

Across all studies, 185 of 210 enrolled participants (88%) were reported as study completers. Comparison of study methodology revealed that most subjects were evaluated in ambulatory settings; they were predominantly middle-aged men (172 of 181 reported subjects, or 95%) from a variety of armed conflicts dating back from World War II veterans (N=4) through ongoing operations in Iraq/Afghanistan (OIF/OEF; N=24), and most were veterans of the Vietnam War (N>48). The majority of subjects had been exposed to combat (178 of 203, or 88%). Two trials^18,31 quantified combat exposure via the Combat Exposure Scale (CES),³³ with mean entry scores ranging from 9 (“light-to-moderate”) to approximately 18 (“moderate”) combat exposure. Whereas most studies examined “chronic” DSM-IV PTSD,^24,29,30,32 one involved an unreported mixture of PTSD and Acute Stress Disorder related to active (OIF) combat operations.¹⁵ Although two did not specify the PTSD duration, they supplemented the DSM-IV PTSD diagnosis with a supporting continuous CAPS total score.^18,31

Randomized Clinical Trials

Two of the three RCTs were positive, including one Class I study¹⁸ and one Class II study.²⁴ The most recent study³¹ was negative and was graded as Class II evidence.

Two of the RCTs used comparable methods.^18,24 These two studies enrolled a combined total of 50 subjects, of which 40 were analyzed completers. These studies involved a preponderance of middle-aged Vietnam veterans, with mostly (82%) combat-related, chronic DSM-IV PTSD nightmares as defined by a pretreatment mean CAPS B2 score of 5 or 6. Both evaluated the impact of prazosin augmentation relative to continued baseline combined psychotropic and therapy interventions. Active substance misuse was excluded. Eight-to-nine weeks of 9.5 mg²⁴-to-13 mg¹⁸ of nightly prazosin significantly improved nightmares (effect sizes: 1.9–0.94) and global clinical/functional status (effect sizes: 1.4–1.08, respectively). There was no significant outcome difference between those using and those not using concurrent psychotropics.¹⁸ The primary measure of sleep quality (PSQI) was also significantly improved.¹⁸ Statistically significant reduction in nightmares did not occur until Week 8.¹⁸ Specific secondary measures of military combat nightmare frequency and content significantly improved by Week 8.¹⁸ Although dizziness occurred in some subjects, there were no statistically significant changes in blood pressure.¹⁸ Crossover design²⁴ to placebo resulted in rapid return of nightmares in five subjects, which again resolved with requested open-label conversion back to prazosin in four of these subjects.

The third RCT was the most recent and the only negative study detected by the review.³¹ It was a placebo-controlled (N=15), randomized, comparison parallel 8-week trial of prazosin (N=18) versus behavioral sleep intervention (BSI; N=17) for sleep disturbances in a total of 50 enrolled adult (primarily OIF/OEF) veterans. BSI was defined as Masters-level, licensed-therapist delivery of manualized education/behavioral techniques, including image rehearsal therapy, stimulus control, and sleep restriction. Mean prazosin dose was approximately 9 mg per evening. Active substance misuse was excluded. PTSD was determined categorically (DSM-IV) as well as continuously measured via the CAPS total score; 58% of subjects met DSM-IV criteria, and 42% endorsed “subthreshold” PTSD symptoms. The mean sample CAPS total score for current PTSD difficulties was 40, which fell short of available empirically-derived categorical cutoffs for PTSD diagnosis.³⁴ All subjects endorsed baseline clinically-meaningful distressing dreams, as evidenced by a CAPS B2 score of at least 3. Combat exposure was reported in 82% of the analyzed sample and measured via the CES with means ranging from approximately 10 to 18 across the three groups that trended (p=0.09) toward significant difference. Similar to previous RCTs, baseline psychotropics were continued unchanged. However, unlike previous RCTs, this study did not use a comparable primary outcome measure of nightmares. Rather, subject recall of distressing dream frequency upon waking was evaluated as part of a primary-outcome sleep diary. As such, nightmare intensity was not prospectively measured. Although both prazosin and BSI significantly improved insomnia, neither significantly reduced the frequency of nightmares. Multiple potential explanations for this unexpected negative finding were offered, including low baseline frequency of nightmares. Specifically, the mean baseline nightmare frequency across the three groups ranged from 0.09 to 1 nightmare per night. Overall global status as measured by the primary outcome CGI did not significantly improve in either treatment group. No significant differences were noted between active treatment and placebo as measured by the Asberg Side Effect Scale, and there were no significant changes in blood pressure with prazosin.

Open-Label Trials

Three open-label series were found. All were positive, including one Class II³⁰ and two Class III studies.^15,29

The three open-label series^15,29,30 described 44 total subjects. All studies utilized the same primary outcome nightmare (CAPS B2) and global status (CGI-C) measures. They involved both young-adult OIF active combatants¹⁵ and geriatric veterans from a variety of remote conflicts.³⁰ One series did not report comparable demographic data.²⁹ Two studies involved chronic DSM-IV PTSD,^29,30 and one (N=13) included an unspecified mixture of DSM-IV PTSD and Acute Stress Disorder.¹⁵ Collectively and individually, the studies included a preponderance of combat-exposed participants, ranging from 77% to 92% of the samples. Baseline trauma nightmare pathology as measured by the CAPS B2 ranged from 3.6 to 7, which was representative of threshold-symptomatic to severe and frequent nightmares, respectively. All series described the impact of prazosin augmentation relative to continued baseline psychotropics^15,30 or combined psychotropic and non-cognitive therapy intervention.²⁹ Two studies included comorbid medical and mental health conditions^29,30 notable for medically frail geriatric subjects³⁰ whereas the third study¹⁵ did not report comorbidity. Active substance misuse was excluded where reported.^29,30 Mean prazosin dosing ranged from approximately 2 mg-to-10 mg nightly. Statistically significant reduction of nightmares was described across all three studies. Robust improvement was described in both geriatric (N=9) and active combatants (N=13), wherein mean CAPS B2 was significantly reduced, from 6.6 (SD: 1.1) to 0.9 (SD: 1.5); paired t=9.8; p <0.0001) and from 7 (SD: 0.7) to 2.9 (SD: 3; paired t=4.8; p <0.001). Pooled data from these two series^15,30 revealed that nightmare response to prazosin, as defined by a ≥50% reduction in CAPS B2 occurred in 17 of 22 subjects (77%), with 11 of those 17 subjects (65%) attaining total remission (CAPS B2=0). Diminished nightmares correlated significantly with reduced sleep disturbances as measured by the CAPS D1 (r=0.74–0.63; p <0.01 to 0.05) in two series.^15,29 Global clinical status was improved across the studies and was significantly correlated with improved nightmare status (r=0.94; p <0.001) in one series.¹⁵ Similar to the crossover RCT,²⁴ nightmares rapidly re-emerged and again remitted after all-cause prazosin discontinuation and reinitiation, respectively.³⁰ Adverse effects included “non-clinically meaningful” reduction in blood pressure, transient orthostatic lightheadedness (N=1), dizziness (N=1), nocturnal urinary incontinence in a subject with previous prostatectomy (N=1), and nausea with headache (N=1).

Retrospective Chart Review

One retrospective review³² was identified. It was positive, and was graded as Class II evidence.

It described a total of 59 subjects, divided into three groups, including 51 primary analysis participants who were exposed to prazosin and 36 who completed the full 8-week titration. Eight subjects did not take the prazosin and were used as a comparison, non-exposure group. Primary outcome measures included change in PTSD nightmares (CAPS B2 item) and post-treatment global well-being (CGI-C). The review involved an unspecified mixture of male Vietnam and Gulf War veterans. All participants had chronic DSM-IV PTSD with severe, treatment-resistant, combat-related nightmares, as evidenced by a baseline CAPS B2 score ≥5. Active substance misuse was excluded. Baseline psychotropics were continued unchanged. Mean prazosin dosing ranged from approximately 6 mg–10 mg nightly in the prazosin-exposed group (N=51) and titration completers (N=36), respectively. Statistically significant reduction of nightmares was reported in both groups. Specifically, CAPS B2 decreased from 7.1 (0.2) to 4.2 (0.3); (t=9.1; p <0.0001) in the primary analysis group and from 7 (0.2) to 3.5 (0.3); (t=9.6; p <0.0001) in the titration completer group. CAPS B2 did not significantly change in the unexposed group. Post-treatment global status was significantly (t=3.5; p <0.01) improved across the treatment group (CGI–C: 2.9 [0.1]) as compared with the unexposed group (CGI–C: 3.9 [0.1]). The most frequent adverse effects included orthostatic dizziness, (N=3), headache (N=3), and nausea (N=2). Fifteen subjects (29%) discontinued prazosin because of unspecified adverse effects.

Discussion

Our review found a positive evidence-base for the use of prazosin to manage combat-related PTSD nightmares. Seven studies, tracking a total of 210 subjects, were identified. Six of these seven studies used comparable primary outcomes and showed positive results; these included five prospective trials. There were one Class I, four Class II, and two Class III trials.

In light of published limited responsiveness of PTSD nightmares to label PTSD antidepressant interventions^13,19,21 and currently available supportive empirical data,^{15,18,24,29,30,32} off-label prazosin augmentation has been shown to be an evidence-based pharmacological management strategy for military combat-related nightmares. This is consistent with a recent Best Practice Guideline Level A recommendation for prazosin in the management of all-cause nightmares.¹⁷ Benefit has been demonstrated across a continuum of veterans’ ages. Efficacy has been demonstrated in both garrison as well as forward-deployed, active-combat settings. Prazosin augmentation significantly reduced combat-related acute and chronic PTSD nightmares, as well as those occurring as part of an Acute Stress Disorder. Improvement may take weeks. Nightmares rapidly returned and again resolved with prazosin discontinuation and reinitiation, respectively.^24,30 Nightmare improvement correlated with improved sleep^15,29 and global functional status.¹⁵ Benefit may be relatively greater for military combat-trauma nightmares, as opposed to nightmares from other causes.¹⁸ Dosing strategies across available literature were similar. Consistent with FDA label guidance, prazosin was initiated at 1 mg at 30 min–60 min before bedtime to avoid potential first-dose hypotensive complications. Titration decision was typically determined via analysis of clinical response, in a setting of tolerability. The rate of titration varied from 1 mg every few days early in the trials to 2 mg–5 mg per week later in the titrations. Maximum allowable dosing ranged from 4 mg per night in a geriatric cohort to 20 mg (divided) per night. Final effective dosing ranged from approximately 2 mg to 13 mg per night. Prazosin was well-tolerated. The most common adverse effects consisted of orthostatic complications, including transient dizziness and non-statistically significant differences in blood pressure, as compared with placebo.

The only available negative study³¹ is also the most recent trial. It is a Class II prospective study. The impact of this negative trial is limited by the use of a dissimilar and thus difficult-to-compare primary outcome nightmare measure, as well as low frequency of nightmares at study entry, sample dilution with subthreshold PTSD, and recent “high risk for bias” designation.²⁷ The lack of significant improvement with randomized-comparison use of an effective¹⁷ behavioral sleep intervention in this negative trial is evidence that the sample’s entry baseline low-frequency nightmare occurrence may have obscured active-treatment significant improvement.

This review has several limitations. One is the relatively small number of studies and number of subjects. This is compounded by the finding that only two of the reviewed trials^24,32 enrolled only subjects with combat-related PTSD nightmares. Neither of these studies utilized a standardized quantifiable measure of combat exposure (e.g., the Combat Exposure Scale). Another limitation is the heterogeneity of the total reviewed sample in terms of duration of trauma exposure and underlying PTSD, follow-up time, varying exclusion criteria, and entry multi-axial comorbidity and associated allowable concurrent management. Although the review sample were mostly men, this is consistent with gender skewing for outside-the-wire military combat operations.

Nevertheless, given the sobering morbidity and frequency of combat-related PTSD nightmares in conjunction with the available positive evidence-base signal, this review highlights an indication for further randomized, controlled examination of prazosin, specifically in the combat-PTSD cohort. The publication of completed RCTs will ideally better characterize prazosin’s position in the combat-PTSD treatment algorithm. Interested readers are referred to clinicaltrials.gov (search term: “PTSD nightmares” and “prazosin”) to view completed, in-progress, and planned randomized, controlled trials. Indeed, future trials may establish relative prazosin responsiveness in specific combat-exposure profiles, as well as potentially instruct tailored algorithmic management strategies similar to those previously published.¹⁶

Considering the frequency, clinical course, and known bidirectional associations between all-cause nightmares and adverse medical/psychological health outcomes,^7,36,37 increased specialty utilization, along with integration of prazosin into the primary prevention arena, could have a substantial impact on combat veteran well-being and health outcomes.