Teva-Prazosin mot mardrömmar

Fråga: Har en patient som ställde en läkemedelsfråga. Patienten besväras av oro, sömnsvårigheter och frekventa mardrömmar sedan flera år efter traumatiska upplevelser. Via en bekant fått pröva läkemedlet Teva-Prazosin 1mg 2 tabl till natten med god subjektiv effekt mot mardrömmar, dock endast testat vid ett par tillfällen. Finns som licensläkemedel i Sverige och pat önskar recept. Saknar helt erfarenhet av detta. Vad är evidensen för behandling mot mardrömmar? Hur tänka kring dosering, behandlingslängd, biverkningar och ev kontraindikationer? Ev vid behovs-ordination?

Svar: Sammanfattning
Prazosin has been the preferred first-line pharmacotherapy when medication is deemed necessary for sleep disorders with nightmares in posttraumatic stress disorder (PTSD). Several studies and systematic reviews and meta-analyses demonstrate the efficacy of prazosin in the treatment of PTSD-associated nightmares. However, one large randomized trial showed a lack of benefit with prazosin.

Prazosin treatment is started at 1 mg at bedtime and the dose is gradually increased at intervals ranging from a few days to weekly as tolerated to an effective, tolerated mean dose ranging from 3 to 16 mg, with most studies using final doses in the 10 to 15 mg range. Use of a low starting dose and slow titration minimizes the incidence of side effects such as hypotension and syncope.

Treatment effect takes weeks to occur, with most studies showing efficacy by eight weeks. Improvement can be seen earlier, however. Duration of treatment should be individualized based on course of response and any adverse events. Once the patient has experienced relief of symptoms for a sustained period of time, one can begin a gradual taper of the medication with close clinical follow-up. No study was found that assessed the use of prazosin with doses “as needed”.

For more information on licensläkemedel see the below link, or you are welcome to contact ULIC: https://regionuppsala.se/samverkanswebben/for-vardgivare/kunskapsstod/lakemedel/forskrivarstod/licenser-extempore-och-off-label/licenslakemedel/

SVAR
Sleep disorder in posttraumatic stress disorder (PTSD) is an ”off-label ”use of prazosin (1, 2).

Prazosin, an alpha-1 adrenergic receptor antagonist, is the best studied medication for nightmares in patients with PTSD and has been the preferred first-line pharmacotherapy when medication is deemed necessary according to the clinical guidelines (3) and a position paper (4) from American Academy of Sleep Medicine (AASM). However the AASM task force in their recent position paper (4) downgrade the recommendation for prazosin from ‘recommended’ to ‘may be used for treatment’ of PTSD-associated nightmares and for nightmare disorders, based on a large randomized trial by Raskind and colleagues (7) published 2018 that showed a lack of benefit with prazosin. However, prazosin remains the first choice for pharmacological therapy (4). There may be an interaction with antidepressant medications (4).

An expert opinion from Uptodate regarding nightmares and nightmare disorder in adults (2) concluded that when medication is chosen, treatment with prazosin is suggested (Grade 2C: recommendation is a very weak recommendation; other alternatives may be equally reasonable), however, the experts encourage most patients to engage in psychotherapy prior to or in conjunction with prazosin.

Evidence for use in PTSD

Prazosin has primarily been studied in patients with PTSD-associated nightmares, and trials in this population have had conflicting results (2). However, at least ten studies demonstrate efficacy of prazosin in the treatment of PTSD-associated nightmares (4).

Prazosin compared with placebo or control significantly improved mean overall PTSD symptoms in 2 systematic review and meta-analyses (5, 6).

In a systematic review and metaanalysis (5) of 6 studies in civilian and veteran patients with PTSD, prazosin compared with placebo or control significantly improved mean overall PTSD symptoms (mean difference of 0.77; 5 studies) including an improvement in nightmares (mean difference of 1.01; 5 studies), hyperarousal (mean difference of 1.04; 2 studies), sleep disturbances by reducing trauma nightmares to normal dreams (mean difference of 1.33; 2 studies), increasing total sleep time (by 60.98 minutes; 3 studies), and sleep quality (mean difference of 0.88; 4 studies). Prazosin also significantly improved overall PTSD severity and functional status evaluated by the change in global clinical status (mean difference of 0.94; 4 studies). There was no significant between-group difference in difficulty falling or staying asleep, improving reexperiencing or intrusion symptoms, or avoidance or numbing symptoms.

A 2020 meta-analysis of seven randomized trials in 528 patients with PTSD (6) found that relative to control groups, prazosin had a moderate to large effect on nightmare frequency (Hedges g = 0.61), posttraumatic stress symptoms (g = 0.81), and sleep quality (g = 0.85). Most patients were treated concurrently with psychotherapy and psychiatric medications such as selective serotonin reuptake inhibitors (SSRIs). There was significant between-study heterogeneity. Of note, this meta-analysis included the study of Raskind and colleagues (7). The authors argue that the combined results in this meta-analysis clearly show efficacy of prazosin and concluded that downgrading of the recommendation of prazosin by AASM (4) may be a premature decision.

Lack of benefit of prazosin

In a 26-week randomized trial by Raskind MA et al (7), (N=271; mean age around 52 years; receiving a stable dose of antidepressant, about 78%; alcohol abuse 1%), there was no significant difference in sleep measurements and other assessments of PTSD symptoms between prazosin and placebo in patients with PTSD and frequent nightmares; however, patients with psychosocial instability were excluded from the study. At 10 weeks, both groups improved slightly, and there was no significant difference in Clinician-Administered PTSD scale item B2 (recurrent distressing dreams; score decreased by 1.5 to 2 points in each group), the Pittsburgh Sleep Quality Index (score dropped by 2 to 2.5 points in each group), or the Clinical Global Impression of Change (score indicated no change in both groups). There was no significant difference in total serious adverse events between groups, but new or worsening suicidal ideation was significantly more common in the placebo group compared with prazosin (15% vs 8%). Patients received prazosin in escalating doses to an effective dose that relieved nightmares (maximum dose 5 mg in the morning and 15 mg at bedtime for men, and 2 mg in the morning and 10 mg at bedtime for women) or placebo. Patients in either group did not differ with regard to age, race, coexisting psychiatric disorders, disability status, or experience of war-zone trauma; however, a limitation of this study may be that those with psychotic or cognitive disorders, psychosocial instability, or substance abuse within the prior 3 months were excluded from the study population (7).

The majority of patients in both groups in this study were concurrently receiving an antidepressant. A decreased response to prazosin in patients concurrently taking a selective serotonin reuptake inhibitor was noted by a prior study (4, 8). However further clarification of this possible interaction is needed (8).

Dosage, and duration of Prazosin for PTSD

Prazosin is typically started at 1 mg at bedtime and the dose gradually increased at intervals ranging from a few days to weekly as tolerated (1, 2). The recommended target dose from the Veteran's Administration is 6 to 10 mg; however, efficacy can be seen at lower doses, which may be preferable in low body weight and older individuals. The effective, tolerated mean doses range from 3 to 16 mg, with most studies using final doses in the 10 to 15 mg range (1, 2). Use of a low starting dose and slow titration minimizes the incidence of side effects such as hypotension and syncope.

Treatment effect takes weeks to occur, with most studies showing efficacy by eight weeks (2). Improvement can be seen earlier, however. Duration of treatment should be individualized based on course of response and any adverse events. Once the patient has experienced relief of symptoms for a sustained period of time, one can begin a gradual taper of the medication with close clinical follow-up (2).

No study was found that assessed the use of prazosin with doses “as needed”.

Advese effects and Contraindications

Prazosin was generally well-tolerated in PTSD studies except for several subjects who experienced transient dizziness; mild orthostatic systolic blood pressure reductions and there were no falls or syncopal episodes (4).

The most common adverse reactions with hypertension treatment are; postural dizziness (10,3%), nausea (4,9%), drowsiness (7,6%), headache (7,8%), palpitations (5,3%), weakness (6,5%), and fatigue/malaise (6,9%) (1, 9).

No contraindications, other than hypersensitivity to prazosin, any other component of the product, or other quinazolines, were reported (1, 9).

1. https://www.micromedexsolutions.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch?navitem=topHome&;isToolPage=true#
2. https://www.uptodate.com/contents/nightmares-and-nightmare-disorder-in-adults?search=prazosin%20and%20stress%20disorders%20post%20traumatic&;source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3
3. Aurora RN, Zak RS, Auerbach SH, Casey KR, Chowdhuri S, Karippot A, Maganti RK, Ramar K, Kristo DA, Bista SR, Lamm CI, Morgenthaler TI, Standards of Practice Committee, American Academy of Sleep Medicine. Best practice guide for the treatment of nightmare disorder in adults. J Clin Sleep Med. 2010;6(4):389.
4. Morgenthaler T.I., Auerbach S., Casey K.R., Kristo D., Maganti R., Ramar R., et. al.: Position paper for the treatment of nightmare disorder in adults: an American Academy of Sleep Medicine position paper. J Clin Sleep Med 2018; 14: pp. 1041-1055.
5. Singh B, Hughes AJ, Mehta G, et al: Efficacy of prazosin in posttraumatic stress disorder: a systematic review and meta-analysis. Prim Care Companion CNS Disord 2016; 18(4):16r01943-.
6. Yücel DE, van Emmerik AAP, Souama C, Lancee J. Comparative efficacy of imagery rehearsal therapy and prazosin in the treatment of trauma-related nightmares in adults: A meta-analysis of randomized controlled trials. Sleep Med Rev. 2020;50:101248.
7. Raskind MA , Peskind ER , Chow B , et al: Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med 2018; 378(6):507-517.
8. https://www.uspharmacist.com/article/management-of-nightmare-disorder-in-adults
9. Teva-Prazosin-Canada. SPC (attach file)