Posttraumatic stress disorder (PTSD) does not always run an easy course, and the prognosis for some patients may be a chronic disabling illness that lasts for many years. Cukor et al. studied a sample of 727 disaster workers deployed at the site of the World Trade Center after September 11, 2001.1 Four years later, at least 8% of the disaster workers were still suffering from PTSD as a result, and, 6 years later, nearly 6% were still suffering. Given that nearly 50% of these individuals with PTSD had received treatment, it can be concluded that, despite treatment, a sizable proportion of chronic sufferers have treatment-resistant illness. An analysis of recovery rates for 199 PTSD patients over 5 years in a primary care sample suggested that the probability of recovery at 5 years was only 38%.2
The usual treatments for PTSD include antidepressants and trauma-focused cognitive behavioral therapy (tfCBT). Although intuitively popular with patients and government agencies such as the National Institute for Health and Care Excellence (NICE) in the United Kingdom, key studies evaluating tfCBT had drop-out rates of approximately 30%, indicating that a wholly reliable or specific treatment for PTSD is not yet available. For example, in a 2005 study of CBT by Foa et al., the drop-out rate was 34%,3 while it was 21% in a 2007 study of cognitive therapy by Duffy et al.4 Because first-line treatments for PTSD often fail, adjunctive agents such as risperidone are often used, but these agents may also only work in sporadic cases.5 A 6-month trial of adjunctive risperidone for PTSD that was resistant to treatment with SSRIs found no beneficial outcome.5 Other agents such as quetiapine and propranolol have attracted interest, but it is only recent research with prazosin that seems to offer consistently positive findings for key aspects of treatment-resistant PTSD, such as insomnia and recurrent nightmares.6
Prazosin is an alpha-adrenergic blocker that is currently licensed in the United Kingdom for the treatment of hypertension, cardiac failure, Raynaud’s phenomenon, and benign prostatic hypertrophy. In the United States, prazosin is licensed for the treatment of hypertension. Use of prazosin in the treatment of PTSD would be off label, but there is now a research base to support its prescription for PTSD.6
For the purposes of this review, a search of MEDLINE and SUMMON was conducted using key words such as PTSD, prazosin, treatment, and resistance.
Prazosin’s chemical formula is C19H21N5O4 (Figure 1). It is a quinazoline derivative. The systematic name for prazosin is 2-[4-(2-Furoyl)piperazin-1-yl]-6,7-dimethoxyquinazolin-4-amine.
Prazosin is an a1-adrenoceptor blocker that is used as an antihypertensive agent and to treat symptoms of benign prostatic hypertrophy. Prazosin reduces blood pressure by blocking norepinephrine’s action on receptors in vascular smooth muscle. Since a1adrenergic activity is associated with fear and startle responses, a drug such as prazosin that blocks central a1-adrenergic activity is potentially useful in PTSD. Prazosin is metabolized by the liver and its metabolites are excreted in the bile. The metabolites of prazosin also have some hypotensive capability. Prazosin treats urinary hesitancy in prostatic hypertrophy because alpha receptors control constriction of the prostate and ureters. Symptom-linked hypernoradrenergic derangements have been observed in PTSD.7 As an alpha blocker, prazosin may reduce this abnormal hyperadrenergic activity seen in patients with PTSD. Prazosin is a lipophilic molecule and can cross the blood-brain barrier.8
Animal studies have shown that administering prazosin prior to some inescapable stressor can block the development of an exaggerated startle response.9
This finding indicates the role of the noradrenergic system in PTSD, but also hints at a potential preventive role for proazosin.
Cardiovascular medications have a range of neuropsychiatric effects. Adverse psychiatric effects include depression and fatigue with beta blockers, especially lipophilic ones that are more likely to cross the blood-brain barrier, and mania with captopril. Cardiovascular medications that have beneficial neuropsychiatric effects include clonidine used alone or in combination with a stimulant medication for attention-deficit/hyperactivity disorder and as an adjunctive agent in treating adrenergic symptoms in alcohol withdrawal, propranolol for anxiety, and now prazosin for PTSD.10
Efficacy in PTSD
Poor sleep is an intrinsic clinical feature of PTSD, with at least 95% of sufferers reporting insomnia and 83% reporting recurrent dreams of the trauma.11
The finding of insomnia symptoms early on (for instance at 4 months after return from a military campaign) may predict the course of PTSD later on— Wright el al. found insomnia predicted depression and PTSD at 12 months.12 Pharmacological agents that alter the course of insomnia in patients with PTSD thus may have a significant role to play.
Studies that have examined the use of prazosin in the treatment of patients with PTSD are summarized in Table 1.
Raskind et al had observed that when two Vietnam combat veterans with PTSD were prescribed prazosin for symptoms of benign prostatic hypertrophy, they unexpectedly reported elimination of combat trauma nightmares. It was this observation that prompted their first open-label trial of prazosin in chronic combat-induced PTSD, results of which were published in 2000.13
In 2003, Peskind et al. published results of an open-label study of prazosin (2–4 mg 1 hour before bedtime) in nine older males with PTSD (age range 67–83 years) originating from traumas experienced in circumstances such as World War II, the Korean War, and the Holocaust.8 They found significant (p<0.0001) reductions in nightmares as measured by the recurrent distressing dreams item on the Clinician Administered PTSD Scale (CAPS).14 The mean score of 6.6±1.1 fell to 0.9±1.5 over 8 weeks.8 Nightmare suppression persisted as long as the patients took prazosin regularly, with nightmares returning within a few nights of discontinuation.
In another study published in 2003, Raskind et al. studied 10 Vietnam combat veterans with chronic PTSD. These individuals had suffered symptoms since their return from Vietnam at least 25 years earlier.15 This study employed a 20-week, double blind, crossover protocol (i.e., two treatment periods with each participant receiving prazosin in one and placebo in the other in a double-blind fashion). The investigators prescribed a mean dose of 9.5 mg prazosin at bedtime. This study provided significant positive evidence as measured on the CAPS for prazosin’s efficacy in reducing recurrent distressing dreams, initial insomnia, re-experiencing and intrusion, avoidance, and hyperarousal.14
In a subsequent 8-week study published in 2007, Raskind et al. compared treatment with prazosin or placebo in 40 U.S. military veterans with PTSD (evaluable sample=34) in a randomized parallel trial, using primary outcome measures derived from the CAPS (the “recurrent distressing dreams” item), the Pittsburgh Sleep Quality Index (PSQI), and the Clinical Global Impression of Change (CGI-C).16
Thirty-two of the participants were Vietnam veterans, while the others had PTSD related to trauma experienced in the Korean War, World War II, the Gulf War, and the invasion of Panama. Their total CAPS score at study entry averaged 70±20. Secondary outcome measures included total score on the 17-item CAPS, the Nightmare Frequency Questionnaire-Revised (NFQ), the PTSD Dream Rating Scale (PDRS), and the Hamilton Depression Rating Scale (Ham-D). Two patients were lost to follow-up and four discontinued due to adverse effects (3 of whom were on prazosin and 1 on placebo). Prazosin produced significantly greater improvement than placebo on the three primary outcome measures: frequency and intensity of trauma-related nightmares (the CAPS recurrent distressing dreams item), sleep quality (the PSQI), and global clinical status (the CGIC).16 HAM-D scores indicated a reduction in depression, even after sleep rating items were excluded, but this was not significant. Similarly, there was a greater decrease in the total CAPS score with prazosin than placebo, but the result did not attain significance.
In a crossover study of daytime treatment with prazosin/placebo published in 2006, Taylor et al. enrolled 11 civilian outpatients with PTSD who had continued to experience daytime PTSD symptoms despite being on a stable bedtime prazosin dose that had already suppressed trauma-related nightmares.17 The patients who received daytime prazosin showed significantly lower Profile of Mood States (POMS) scores following reminder cues (cues designed to experimentally induce distress using keywords). In those who continued the drug for 10 weeks in an open label phase, global PTSD illness severity was reduced at follow-up.16
In 2008, Taylor et al. published the results of a subsequent 7-week prazosin/placebo crossover study (two blinded treatment periods for prazosin and placebo) in 13 civilian outpatients with PTSD.18 Prazosin significantly increased mean total sleep time by 94 minutes and increased REM sleep time. There were also significantly fewer nightmares and distress awakenings with prazosin treatment.18 The absence of a sedative effect was observed, in that sleep onset latency was unaffected. Among the 13 subjects with PTSD, 10 had comorbid depressive disorders and 3 had comorbid alcohol abuse in remission.
Thompson et al. published a study of the use of prazosin in treating nightmares and distressed awakenings in a series of 22 veterans in 2008.19 No control group was employed in this study. Nightmares were assessed using the “recurrent distressing dreams” item of the CAPS, and this item was modified to rate non-nightmare distressed awakenings (NNDAs) as well. There was significant improvement in trauma nightmares at the p<0.05 level and improvement in sleep difficulty and NNDAs at the p<0.01 level.19
In a retrospective chart review study published in 2009, Boynton et al. evaluated the effect of prazosin on PTSD-related nightmares in 23 refugees with chronic PTSD.20 They found significant improvements from baseline (p<0.0005) on the CAPS nightmare severity rating after 8 weeks and also marked improvement in 6 patients and moderate improvement in 11 others.
In a historical prospective cohort study, Byers et al. compared 237 patients who had been prescribed either prazosin or quetiapine for nocturnal PTSD symptoms using retrospective chart review. They found that the prazosin group was more likely to continue the prescription to the end of the study, and the quetiapine group had more side effects. The authors concluded that prazosin achieved long-term effectiveness.21
In an 8-week study of sleep quality in U.S. military veterans published in 2012, Germain et al. randomized participants to treatment with prazosin (n=18), to a behavioral sleep CBT type intervention (n=17), or to placebo (n=15).22 Sleep quality was measured by self-report (e.g., by measures such as the Insomnia Severity Index and the Pittsburgh Sleep Quality Index) and also by polysomnographic studies. No difference in treatment response was found between the prazosin and behavioral intervention. However, 22 of the 28 subjects in the active treatments groups who completed the study compared to 5 of the 13 participants in the placebo group who completed the study demonstrated a response in terms of sleep specific criteria.22
The American Psychiatric Association published a practice guideline on the treatment of PTSD in 2004. A subsequent “Guideline Watch” published in 2009 recommended prazosin as “among the most promising advances in the pharmacological treatment of PTSD” and recommended a therapeutic dose range, after titration, of 3–15 mg/night.23
Substance misuse is often comorbid with PTSD and has been reported to occur in at least 36% of patients with PTSD.11 Fox et al. investigated the effects of prazosin on stress responses and cravings in people with alcohol dependence in a small, randomized, double-blind, placebo-controlled study.24 The study lasted for 4 weeks and the group treated with prazosin (n=9) demonstrated significantly lower alcohol craving and anxiety, and fewer negative emotions following stress exposure compared with the placebo group (n = 8).
A case study of two adolescents with PTSD was published by Oluwabusi et al.25 They used prazosin to treat a 16-year-old girl who had been violently assaulted and sexually abused by older males and a 15-year-old patient with learning disability and mood disorder with a history of sexual abuse by a family member from 8 years of age who had nightmares and a hyperstartle reaction and hypervigilance. Sleep-related symptoms subsided, in the first case, after 2 weeks of treatment, and in the second case, after 8 weeks of treatment.
In the Boynton et al.20 study described above, the dose range of prazosin was 1–6 mg. In the older patients studied by Peskind et al., the maximum dose was 4 mg, with the modal dose being 2 mg at bedtime.8 In their 2003 study, Raskind et al. used a mean dose of 9.5 mg/day in veterans.15 Raskind et al. described the dosage strategy used in their 2007 study in more detail.16 Prazosin was initiated at 1 mg at bedtime for 3 days and then increased to 2 mg at bedtime until day 7. If trauma nightmares were still present, the dose could be increased to 4 mg at bedtime until day 14. Using the same clinical guidelines, the dose could be increased to 6 mg at bedtime until day 21 and to 10 mg at bedtime until day 28. At the end of the month, the clinician could make a final increase of 5 mg at bedtime for a maximum maintenance dose of 15 mg/day at bedtime. The mean dose used in the 2007 Raskind et al study was 13±3 mg.16 In the 2006 and 2008 studies published by Taylor et al., civilian outpatients were started on 1 mg of prazosin at night, with final doses ranging from 2–6 mg.17,18
In their study of individuals with alcohol dependence, Fox et al. used initial doses of 1 mg/day, which were increased over a 2 week period to 16 mg/day.24
In their 2008 study, Thompson et al. used initial doses of 1 mg at night with an incremental increase every week to a possible maximum dose of 10 mg.19
In the case study of two adolescents, Oluwabusi et al. used doses of 2 and 3 mg/day.25
Side Effects and Tolerability
Clinicians should be aware of several important side effects that can occur with prazosin, including postural hypotension and syncope (especially with the first dose which ideally should be given in surroundings where monitoring is feasible). It is estimated that fatigue affects 5%–15% of patients who are taking alpha-adrenergic agents.10 Other adverse effects include nasal stuffiness, blurred vision, vertigo, gastrointestinal disturbances such as constipation or diarrhea, edema, palpitations, dyspnea, depression, anxiety, and priapism.
In their study of older patients, Peskind et al. found that prazosin was reasonably tolerated with transient dizziness occurring in two of the nine patients and some nocturnal urinary incontinence in one other patient.8
In their study of 10 Vietnam veterans, Raskind et al. found that prazosin was very well tolerated, with only 2 patients (20%) experiencing postural hypotension and dizziness early in treatment.15 These problems resolved with time and as the dose increased.
At the end of the treatment, the difference in mean systolic values, when taken supine and standing, was just 6 mmHg. In their 2007 study, Raskind et al. found that 15 of the 34 subjects (9 of whom were taking prazosin and 6 of whom were on placebo) reported transient dizziness.16 Nasal or sinus congestion was reported by 7 of 34 subjects (6 on prazosin and 1 on placebo), headache was reported by 4 subjects (3 prazosin and 1 placebo), initial insomnia was reported by 2 subjects (1 prazosin and 1 placebo), and dry mouth was reported by 2 subjects taking prazosin.
In 2009, Nuzhat and Osser reported chest pain in a 25-year-old Iraq veteran with PTSD who had been prescribed 1 mg of prazosin as a starter dose.26 The patient had no family or personal history of cardiac problems, but he did have some mild valve regurgitation on echocardiogram. Nuzhat and Osser concluded that the prazosin was the cause of his chest pain.
In terms of tolerability, drop-out rates with prazosin treatment were lower than for psychological treatments such as tfCBT.6
Cautions and Contraindications
Prazosin should not be prescribed to patients with a known sensitivity to prazosin or other quinazolines. Because hypotension can be dangerously exacerbated by administration of prazosin, monitoring of blood pressure prior to and after the administration of the first dose is essential. Caution about hypotension is especially important in older patients. Since prazosin is metabolized by the liver, it should be used with caution in patients with hepatic impairment. The safety of prazosin in pregnancy has not been established. It is excreted in small amounts in breast milk.
Patients with chronic PTSD may already be receiving various psychotropic drugs. If prazosin is being used as an adjunctive agent, clinicians should be alert for a potential exacerbation of prazosin’s hypotensive effects when it is co-administered with antipsychotics such as quetiapine and aripiprazole and/or the benzodiazepines lorazepam and alprazolam. An exacerbation of prazosin’s hypotensive effect can also be seen when it is used in combination with phosphodiesterase-5 (PDE-5) inhibitor drugs such as sildenafil. In an animal study, Takamura et al. found that, if prazosin was co-administered with the selective serotonin reuptake inhibitor citalopram in rats, there was a decrease in the anxiolytic effect of the citalopram.27 Whether this finding would translate into human patients is not yet known but should be kept in mind.
At least 10 research studies (Table 1) support a role for prazosin in the treatment of PTSD. Given that chronic PTSD is often associated with treatment resistance, particularly in terms of sleep disturbance, these studies are of considerable interest and larger scale randomized clinical trials are more than justified.
The studies reviewed in this article support the prescription of prazosin as being effective in PTSD, particularly in reducing nightmares and improving sleep. The studies themselves are somewhat small, so that studies with more subjects and conducted over a longer period would be desirable. Nevertheless, results to date are very promising, particularly given the intractability of chronic treatment-resistant PTSD, such as was the focus of the studies reviewed here. That marked or even moderate symptom reduction was achieved in studies of just a few weeks duration is remarkable and, given that prazosin has been prescribed for many years for other conditions with a reasonable safety record, bodes well for the future of PTSD treatment.
Work with individuals with alcohol dependence has also demonstrated significantly reduced stress response and reduced cravings. As PTSD is often associated with alcohol misuse, the coincident effects of prazosin on alcohol dependence may be an additional benefit for patients with PTSD.
Further clinical studies are required, not only to analyze larger samples, but also to consider questions concerning the optimum duration of treatment, whether prazosin should be used as a first-line therapy, how comorbid depression should be treated, and whether prazosin has a preventive role in early trauma care.
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