Prazosin is a medication that blocks alpha-1 adrenergic receptors and has an FDA indication for the treatment of hypertension. For us, as mental health clinicians, it is important because it is widely used as an off-label treatment of post-traumatic stress disorder (PTSD).
But, as of November 2020, our field is confused about whether or not to use prazosin for PTSD. This is controversy is important enough that I think we should take look at it and try to clear up the confusion so that we can think about whether or not we should prescribe prazosin for patients with PTSD.
Prazosin is widely prescribed for PTSD-associated nightmares
For example, in a small survey of psychiatrists, off-label prazosin was the most frequently prescribed treatment for PTSD-associated nightmares (Martin et al., 2020).
But, major practice guidelines have downgraded prazosin
The Veterans Administration and Department of Defense jointly issued a practice guideline for the management of posttraumatic stress disorder and acute stress disorder in 2017. For obvious reasons, the views of the VA and DOD with regard to PTSD are important.
This is what their summary recommendations say about the use of prazosin for the treatment of PTSD (emphasis added by us). The recommendations below may come as a surprise to some readers.
1. “For global symptoms of PTSD, we suggest against the use of prazosin as mono- or augmentation therapy.”
2. “For nightmares associated with PTSD, there is insufficient evidence to recommend for or against the use of prazosin as mono- or augmentation therapy.”
The American Academy of Sleep Medicine’s position paper on the treatment of nightmare disorder in adults also downgraded prazosin for PTSD-associated nightmares from “recommended” to “may be used” (Morgenthaler et al., 2018)
What’s going on? Why did these practice guidelines not recommend prazosin for PTSD symptoms overall or for PTSD-associated nightmares? What changed? Should we not prescribe prazosin (off-label) to patients with PTSD?
What did studies of prazosin for PTSD find? And, what changed?
Because two major practice guidelines downgraded their recommendations about using prazosin for PTSD, we have to know at least a little bit about what the research found, what changed, and where we stand now. Let’s look at the evidence chronologically.
Previously published double-blind, randomized, placebo-controlled clinical trials of prazosin for PTSD had been combined by multiple meta-analyses (e.g., Simon and Rousseau, 2017; George et al., 2016; Khachatryan et al., 2016; Singh et al., 2016). They found that prazosin is effective not only for nightmares but also for some other symptoms of PTSD. It was helpful for two broad categories of symptoms:
1. Hyperarousal symptoms
2. Sleep-related symptoms: nightmares, sleep quality, dream content, total sleep time.
What changed is that in 2018, a large, multicenter clinical trial was published that did NOT find prazosin to be more effective than placebo in military veterans with chronic PTSD and frequent nightmares (Raskind et al., 2018). The recommendations of the VA/ DOD practice guideline discussed above were hugely influenced by the negative findings of this one study. (Even though the guideline was published in 2017 and the clinical trial in 2018 the guideline authors had access to the results of this study.)
You may be wondering—why would just one study have such a huge influence on the field? This is because that clinical trial (Raskind et al., 2018) had as many participants as all the previous studies combined. So, it doubled the number of patients for whom data are available.
But, wait. The story is not over yet. There’s more that I have to say on this matter. I’ll try to convince you that both the practice guidelines and the large negative clinical trial are wrong and that prazosin should be used for PTSD-associated nightmares. Or at least in a subgroup of these patients.
What may have gone wrong with the study
We noted above that a large, multicenter clinical trial did NOT find prazosin to be more effective than placebo in military veterans with chronic PTSD and frequent nightmares (Raskind et al., 2018). The recommendations of the 2017 VA/ DOD practice guideline were hugely influenced by the negative findings of this one study.
But, here are some possible reasons why the much-discussed negative prazosin clinical trial (Raskind et al., 2018) does not necessarily overturn everything else we know about prazosin being effective for PTSD-associated nightmares:
1. Speaking generally and not only about prazosin or PTSD, even the best-established treatments sometimes don’t work better than placebo in some individual studies. This is well-known. We can discuss the reasons for this in another article on this website. But, what is important here is that we should not any one study, by itself, make us conclude that a treatment does not work, even if several other studies have found that it does.
2. The authors noted that this study (Raskind et al., 2018) was not the first time that a multicenter, randomized clinical trial involving male military veterans with psychiatric disorders did not find a treatment to be more effective than placebo even though that treatment had been found to be effective in previous studies and was already being used, including in the VA system.
Previous examples of studies from the VA not finding a previously well-established treatment to be more effective than the control group include:
– Sertraline for PTSD, even though sertraline is FDA-approved for PTSD and VA practice guidelines recommend it as a first-line medication for PTSD.
– Trauma-focused psychotherapy for PTSD, even though it is considered to be a first-line psychotherapy for PTSD.
– Naltrexone for alcoholism, even though naltrexone is FDA-approved for this purpose.
– Risperidone for PTSD.
3. The clinical trial (Raskind et al., 2018), unfortunately, included patients who might have been less likely to respond to prazosin and/or more likely to respond to placebo.
– The authors noted that the fact that their study had only included patients with relatively high frequency and intensity of nightmares might have also made it less likely that the participants would benefit from prazosin.
– Due to concern about the increasing incidence of suicide and violent behavior among veterans, the planning committee for the study had decided to exclude patients with psychosocial instability.
It should be noted that the placebo response was quite high in this study (comment by Anghelescu and Moschner, 2018). A high placebo-response rate can be one reason for a treatment not being found to work better than placebo.
Bottom line: Does prazosin work for PTSD-associated nightmares or not?
Again, the reason that clinicians needed to know a bit about the controversy over prazosin for PTSD-associated nightmares is that major practice guidelines seemed to suggest that we don’t know that prazosin is effective for PTSD. My concern was that because of this, clinicians might be less likely to prescribe prazosin to patients with PTSD-associated nightmares, depriving them of a potentially effective treatment.
But now, to summarize what we know, let’s go over the main points:
1. Multiple studies over the years found that prazosin was effective for PTSD-associated nightmares and for hyperarousal symptoms in patients with PTSD.
2. This makes sense biologically because prazosin blocks alpha-1 receptors involved in the noradrenergic response to hyperarousal. We should note in this regard that increased noradrenergic signaling in the brain is believed to be involved in the pathophysiology of PTSD and unduly high noradrenergic activity during REM sleep is believed to be related to trauma-related nightmares (Raskind, 2020).
3. We have already reviewed, in the previous section on this page, many reasons why the clinical trial with negative results about the efficacy of prazosin for PTSD (Raskind et al., 2018) does not, in my opinion, mean that prazosin does not work for PTSD-associated nightmares.
4. Two meta-analyses that were published in 2020 put together both the older studies AND the large clinical trial with negative findings (Raskind et al., 2018) and concluded that combining ALL the research data, prazosin was more effective than placebo for PTSD-associated nightmares (Reist et al., 2020; Zhang et al., 2020). (Optional to read: On the other hand, these meta-analyses disagreed on whether or not prazosin has wider benefits in patients with PTSD—for sleep quality and for overall PTSD symptoms.)
5. Lastly, there is the not-be-neglected fact that prazosin has been widely used in clinical practice for PTSD-associated nightmares and found to work. The American Academy of Sleep Medicine’s position paper on the treatment of nightmare disorder in adults (Morenthaler et al., 2018) says this:
“The Task Force agreed unanimously that it was appropriate to downgrade the recommendation regarding prazosin use because of the above contradictory study. At the same time, it is clearly apparent to clinicians that many patients respond very well to prazosin and this agent remains the first choice for pharmacologic therapy.”
Can you believe it? They don’t “recommend” prazosin for PTSD-associated nightmares anymore but go on to say that “it is clearly apparent to clinicians that many patients respond very well to prazosin and this agent remains the first choice for pharmacologic therapy.”
So, no, it is NOT a psychopharMYTH that prazosin works for PTSD-associated nightmares. What we may need to look into further is—which patients are most likely to respond to it.
Who might respond better to prazosin?
It has been suggested by a top expert on the use of prazosin for PTSD that there appears to be a “noradrenergic” subtype of PTSD that may respond better to prazosin and other anti-adrenergic treatments (Raskind, 2020). Features of this proposed subtype include (Raskind et al., 2020):
1. Higher blood pressure and pulse than expected for the person’s age, level of fitness, etc.
Higher standing blood pressure at baseline (before treatment with prazosin) has been reported to be associated with a better response to prazosin for PTSD symptoms overall, PTSD-associated nightmares, and sleep quality (Raskind et al., 2020; Raskind et al., 2016).
2. Waking up from trauma-related nightmares in a state of distress and along with sweating, tachycardia, and hypervigilance.
3. Making noises and moving large muscles during dreaming.
Note: Normally, when we dream, our muscles lose their tone. If a person is making noises and moving large muscles during dreaming, it means they have REM sleep without atonia.
These factors that may predict a better response to prazosin need confirmation in further research. But, they make sense based on how prazosin works, don’t they? While waiting for further research, I think it is reasonable to look for these features of noradrenergic hyperactivity and consider them as one factor in deciding whether to prescribe off-label prazosin in a patient with PTSD. Other things being equal, we might be more likely to prescribe prazosin or other antiadrenergic medications in patients who have evidence of noradrenergic overactivity.
Optional to read
The VA/DoD practice guideline discussed above said about its own recommendations:
– “We recognize that these recommendations constitute a significant reversal of prazosin’s role in the current management of PTSD.”
– “We are recommending neither for nor against the continuation of prazosin in patients who believe it to be beneficial; the decision to stop or continue prazosin should be individualized and made using [shared decision making].”
Note: For the treatment of PTSD-associated nightmares, specifically, the guideline did not recommend against the use of prazosin. It only noted that there is “insufficient evidence”.
Prazosin for PTSD in children?
TO BE COMPLETED
One limitation of the research on prazosin for PTSD is that the research has been done mainly on males and in veterans.
What about in children? There are no published randomized, controlled clinical trials of prazosin for PTSD in children (as of November 2020), but many case reports have been published of using prazosin in children and adolescents with PTSD who have nightmares (Akinsanya et al., 2017; Racin et al., 2014; Oluwabusi et al., 2012; Strawn et al., 2009).
Morgenthaler TI, Auerbach S, Casey KR, Kristo D, Maganti R, Ramar K, Zak R, Kartje R. Position Paper for the Treatment of Nightmare Disorder in Adults: An American Academy of Sleep Medicine Position Paper. J Clin Sleep Med. 2018 Jun 15;14(6):1041-1055. doi: 10.5664/jcsm.7178. PMID: 29852917; PMCID: PMC5991964.
VA/DOD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder. 2017. Available at this link.
Systematic reviews and meta-analyses
Note: Some meta-analyses were published before the negative results of the Raskind et al. (2018) study were published (Simon and Rousseau, 2017; George et al., 2016; Khachatryan et al., 2016; Singh et al., 2016 ).
Akinsanya A, Marwaha R, Tampi RR. Prazosin in Children and Adolescents With Posttraumatic Stress Disorder Who Have Nightmares: A Systematic Review. J Clin Psychopharmacol. 2017 Feb;37(1):84-88. PubMed PMID: 27930498.
George KC, Kebejian L, Ruth LJ, Miller CW, Himelhoch S. Meta-analysis of the efficacy and safety of prazosin versus placebo for the treatment of nightmares and sleep disturbances in adults with posttraumatic stress disorder. J Trauma Dissociation. 2016 Jul-Sep;17(4):494-510. doi: 10.1080/15299732.2016.1141150. Epub 2016 Feb 2. PMID: 26835889.
Khachatryan D, Groll D, Booij L, Sepehry AA, Schütz CG. Prazosin for treating sleep disturbances in adults with posttraumatic stress disorder: a systematic review and meta-analysis of randomized controlled trials. Gen Hosp Psychiatry. 2016 Mar-Apr;39:46-52. doi: 10.1016/j.genhosppsych.2015.10.007. Epub 2015 Nov 1. PMID: 26644317.
Reist C, Streja E, Tang CC, Shapiro B, Mintz J, Hollifield M. Prazosin for treatment of post-traumatic stress disorder: a systematic review and meta-analysis. CNS Spectr. 2020 May 4:1-7. doi: 10.1017/S1092852920001121. Epub ahead of print. PMID: 32362287.
Simon PY, Rousseau PF. Treatment of Post-Traumatic Stress Disorders with the Alpha-1 Adrenergic Antagonist Prazosin. Can J Psychiatry. 2017 Mar;62(3):186-198. doi: 10.1177/0706743716659275. Epub 2016 Jul 19. PMID: 27432823; PMCID: PMC5317016.
Singh B, Hughes AJ, Mehta G, Erwin PJ, Parsaik AK. Efficacy of Prazosin in Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis. Prim Care Companion CNS Disord. 2016 Jul 28;18(4). doi: 10.4088/PCC.16r01943. PMID: 27828694.
Zhang Y, Ren R, Sanford LD, Yang L, Ni Y, Zhou J, Zhang J, Wing YK, Shi J, Lu L, Tang X. The effects of prazosin on sleep disturbances in post-traumatic stress disorder: a systematic review and meta-analysis. Sleep Med. 2020 Mar;67:225-231. doi: 10.1016/j.sleep.2019.06.010. Epub 2019 Jun 22. PMID: 31972510; PMCID: PMC6986268.
Randomized clinical trials (and commentaries on them)
Anghelescu I, Moschner C. Prazosin for Post-Traumatic Stress Disorder. N Engl J Med. 2018 Apr 26;378(17):1648-9. doi: 10.1056/NEJMc1803171. PMID: 29697913.
McCall WV, Pillai A, Case D, McCloud L, Nolla T, Branch F, Youssef NA, Moraczewski J, Tauhidul L, Pandya CD, Rosenquist PB. A Pilot, Randomized Clinical Trial of Bedtime Doses of Prazosin Versus Placebo in Suicidal Posttraumatic Stress Disorder Patients With Nightmares. J Clin Psychopharmacol. 2018 Dec;38(6):618-621. doi: 10.1097/JCP.0000000000000968. PMID: 30335633.
Raskind MA, Millard SP, Petrie EC, Peterson K, Williams T, Hoff DJ, Hart K, Holmes H, Hill J, Daniels C, Hendrickson R, Peskind ER. Higher Pretreatment Blood Pressure Is Associated With Greater Posttraumatic Stress Disorder Symptom Reduction in Soldiers Treated With Prazosin. Biol Psychiatry. 2016 Nov 15;80(10):736-742. doi: 10.1016/j.biopsych.2016.03.2108. Epub 2016 Apr 11. PMID: 27320368.
Raskind MA, Peskind ER. Prazosin for Post-Traumatic Stress Disorder. N Engl J Med. 2018 Apr 26;378(17):1649-1650. doi: 10.1056/NEJMc1803171. PMID: 29694817.
Raskind MA, Peskind ER, Chow B, Harris C, Davis-Karim A, Holmes HA, Hart KL, McFall M, Mellman TA, Reist C, Romesser J, Rosenheck R, Shih MC, Stein MB, Swift R, Gleason T, Lu Y, Huang GD. Trial of Prazosin for Post-Traumatic Stress Disorder in Military Veterans. N Engl J Med. 2018 Feb 8;378(6):507-517. doi: 10.1056/NEJMoa1507598. PMID: 29414272.
Raskind MA, Peskind ER, Hoff DJ, Hart KL, Holmes HA, Warren D, Shofer J, O’Connell J, Taylor F, Gross C, Rohde K, McFall ME. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol Psychiatry. 2007 Apr 15;61(8):928-34. doi: 10.1016/j.biopsych.2006.06.032. Epub 2006 Oct 25. PMID: 17069768.
Raskind MA, Peskind ER, Kanter ED, Petrie EC, Radant A, Thompson CE, Dobie DJ, Hoff D, Rein RJ, Straits-Tröster K, Thomas RG, McFall MM. Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry. 2003 Feb;160(2):371-3. doi: 10.1176/appi.ajp.160.2.371. PMID: 12562588.
Ressler KJ. Alpha-Adrenergic Receptors in PTSD – Failure or Time for Precision Medicine? N Engl J Med. 2018 Feb 8;378(6):575-576. doi: 10.1056/NEJMe1716724. PMID: 29414268.
Oluwabusi OO, Sedky K, Bennett DS. Prazosin treatment of nightmares and sleep disturbances associated with posttraumatic stress disorder: two adolescent cases. J Child Adolesc Psychopharmacol. 2012 Oct;22(5):399-402. PubMed PMID: 23083029.
Racin PR, Bellonci C, Coffey DB. Expanded usage of prazosin in pre-pubertal children with nightmares resulting from posttraumatic stress disorder. J Child Adolesc Psychopharmacol. 2014 Oct;24(8):458-61. PubMed PMID: 25299588.
Strawn JR, Delbello MP, Geracioti TD. Prazosin treatment of an adolescent with posttraumatic stress disorder. J Child Adolesc Psychopharmacol. 2009 Oct;19(5):599-600. doi: 10.1089/cap.2009.0043. PubMed PMID: 19877989.
Loeffler G, Coller R, Tracy L, Derderian BR. Prescribing Trends in US Active Duty Service Members With Posttraumatic Stress Disorder: A Population-Based Study From 2007-2013. J Clin Psychiatry. 2018 Jun 26;79(4):17m11667. doi: 10.4088/JCP.17m11667. PMID: 29985565.
Raskind MA. Toward a personalized medicine approach to trauma-related nightmares. Sleep Med Rev. 2020 Apr;50:101272. doi: 10.1016/j.smrv.2020.101272. Epub 2020 Jan 25. PMID: 32088375.
Copyright © 2017 to 2020, Simple and Practical Medical Education, LLC. All rights reserved. May not be reproduced in any form without express written permission.
Disclaimer: The content on this website is provided as general education for medical professionals. It is not intended or recommended for patients or other laypersons or as a substitute for medical advice, diagnosis, or treatment. Patients must always consult a qualified health care professional regarding their diagnosis and treatment. Healthcare professionals should always check this website for the most recently updated information.