The role of propranolol for post-exposure chemoprophylaxis of posttraumatic stress disorder and acute stress disorder
Post traumatic stress disorder may be due to excessive adrenergic activation immediately following trauma leading to over-consolidation of traumatic memories. Based on this premise, propranolol has been studied as a means of post-exposure prophylaxis of posttraumatic stress disorder and acute stress disorder. Published trials include a retrospective chart review, a prospective cohort study, and a number of randomized clinical trials. Current data suggest ineffectiveness of propranolol for this indication, but larger, randomized, placebo-controlled trials that include more diverse types of traumas are needed in order to provide more definitive evidence.
INTRODUCTION
Posttraumatic Stress Disorder (PTSD) is defined by an intense fear or helplessness resulting from a stressor (i.e., traumatic event). To be considered PTSD, this reaction must significantly impair the patient's social, occupational, or other important areas of functioning for at least one month.12 Diagnosis of PTSD requires symptoms from at least 3 clusters: re-experiencing symptoms, such as nightmares and flashbacks; hyperarousal symptoms, including hypervigilance and sleep disturbances; and avoidance/numbing symptoms, including restricted affect, anhedonia, and feelings of detachment.2
A known precursor to PTSD is Acute Stress Disorder (ASD). While the symptoms of ASD are very similar to PTSD, the chief difference is the former describes significant symptoms within the first 4 weeks following a traumatic event, the latter relates to symptoms that persist beyond a month.2–5
Research has estimated that approximately 7% of the U.S. population is afflicted with PTSD. The prevalence has been studied mainly in rescue workers, rape victims, military veterans, and burn victims.36–9 The prevalence varies greatly depending on the type of trauma—from 10–20% of rescue workers to 70–80% of rape victims.167
Given the high prevalence of the disorder along with its debilitating nature, prevention of PTSD following exposure to a traumatic event is a desirable clinical strategy.
One theory regarding the pathogenesis of posttraumatic stress disorder is excessive adrenergic activation immediately following trauma leading to over-consolidation of traumatic memories.1011 Much research has been done on ways to decrease this hyperadrenergic state in order to decrease over-consolidation. Although many psychoactive medications have been studied for this purpose, the effects of alcohol, morphine, propranolol, and corticosteroids have shown the most promise.912 Research has shown that noradrenergic blockade reduces memory consolidation.11 Propranolol's lipophilicity permits it to cross the blood brain barrier, thereby blocking norepinephrine receptors in the central nervous system, and, in theory, blocking over-consolidation.9 The purpose of this article is to review the evidence pertaining to the use of propranolol for post-exposure prophylaxis of PTSD and ASD.
DATA SOURCES
PubMed and International Pharmaceutical Abstracts were systematically searched using the key words propranolol; PTSD; stress disorders, post-traumatic; stress disorders, traumatic, acute; and prophylaxis. Free text searches were also conducted. Studies were included if propranolol was used as secondary prophylaxis to prevent PTSD or ASD. Other inclusion criteria were: studies included human subjects who had been exposed to an actual traumatic event; studies included a placebo or control group; and studies were published in English. One retrospective chart review, one prospective cohort, and five controlled clinical trials met these criteria and were reviewed.381113141516 Of note, Table 1, summarizes the randomized clinical trials of PTSD prophylaxis with propranolol.
PUBLISHED STUDIES
Retrospective Chart Review
Only one retrospective chart review has been published regarding the use of propranolol to prevent PTSD.13 McGhee et al. reviewed sixty-five charts of burned service members. Of these, thirty-one received propranolol and thirty-four did not. The investigators found no significant difference in PTSD prevalence between propranolol and placebo (32.3% vs. 26.5%, respectively; p=0.785). Neither the time-lapse prior to administration of propranolol following the traumatic event nor the dose administered was taken into consideration. Also, although the investigators attempted to achieve two groups with similar demographics, patients in the propranolol group had approximately four times more total burned surface area than the patients in the control group. These confounding variables make the results difficult to interpret.
Prospective Cohort
Vaiva et al. published the only prospective cohort regarding propranolol for PTSD prophylaxis. The 19 patients in this study were allowed to self-select whether they wanted to be in the propranolol group or be followed as a control.14 Motor vehicle accident victims and assault victims were recruited from the emergency department. Patients were included in the study if they were 21–30 years old with tachycardia (defined as a resting heart rate of at least 90 beats per minute). Patients were excluded if they had lost consciousness or sustained brain injuries during their trauma, or if they had cardiovascular disease, asthma, or PTSD. Patients in the propranolol group received 40 mg TID for 7 days, followed by an 8–12 day taper period. The first dose was delivered anywhere from 2 to 20 hours after the traumatic event (mean=9.5, SD =6). Medication adherence was measured only via monitoring of resting heart rate one week post-injury. Results revealed a significant reduction in PTSD symptom levels in the propranolol group vs. the control group (p=0.037); however, there was no significant reduction in rates of PTSD in the propranolol group (1 of 11 patients) vs. the control group (3 of 8 patients) (χ2=6.4). The clinical application of this trial is limited by its lack of randomization and the lack of reliable ways to monitor medication adherence.
Randomized Controlled Trials
Hoge et al. examined propranolol versus placebo in the adult population (ages 18–65) when administered within 12 hours of the traumatic event.11 This trial included patients who experienced a significant traumatic stressor as defined by DSM-IV PTSD criteria and who had a heart rate >80 beats per minute upon admission to the emergency department. Patients were excluded if they had a significant physical injury, hospital stay longer than overnight, loss of consciousness, a contraindication to propranolol, blood alcohol level >0.02%, or any known history of psychiatric illness. Patients in the propranolol group received 120 mg BID for 10 days, followed by a 9 day taper period. Adherence was measured via pill counts and a system that logged when bottles were opened. The investigators found no statistically significant difference in physiologic response during script-driven imagery between the propranolol and placebo groups at study endpoint; however, in a post hoc analysis of patients who took their study medication >90% of the time, the propranolol group showed significantly less physiologic response than the placebo group at the 5-week assessment. Regardless, there were no significant differences in the rate of PTSD diagnosis between the propranolol and the placebo groups (14.3% vs. 28.6%, respectively; p=0.66) or when considering the high medication adherence subgroup (14.3% vs. 33.3%, respectively; p=0.62). One limitation of this study is the fact that 6 of the participants were found to be taking confounding substances (as determined by a urine drug screen), but they were included in the final data analysis.
Nugent et al. examined the efficacy of propranolol vs. placebo in the pediatric population.8 The propranolol dosage that was utilized was based on a previous study for the treatment of PTSD in pediatric patients, and a modified pediatric script-driven imagery assessment was administered at 6-weeks post-trauma in the patients' homes.17 Exclusion criteria included hypersensitivity to propranolol, bradycardia, shock, diabetes, preexisting heart condition, or asthma. Patients received a 10-day course of either propranolol or placebo, with the initial dose given within 12 hours of the traumatic event. At the 6-week follow-up assessment, there was no significant treatment group difference in regards to diagnostic status. Medication-adherent girls receiving propranolol experienced more PTSD symptoms relative to girls receiving placebo, whereas medication-adherent boys receiving propranolol showed a nonsignificant trend toward fewer PTSD symptoms relative to boys receiving placebo.
Pitman et al. examined forty-one patients who presented to the emergency department following a traumatic event.15 Approximately 70% of study patients were victims of motor vehicle accidents. To be included in the study, patients had to have a heart rate > 80 beats per minute as well as a significant stressor as defined by DSM-IV criteria. Patients were excluded if they had significant physical injury, a systolic blood pressure <100 mm Hg, were intoxicated, or had a contraindication to propranolol. Patients who were randomized to the propranolol group received 40 mg QID, with the first dose given within 6 hours of initial trauma. Twenty-six patients (63%) returned for the three-month post-trauma assessment, and twenty-two patients (53%) participated in the psychophysiological assessment. There was no significant difference in the rates of chronic PTSD between the propranolol and placebo group (11% vs 13%, respectively; p=0.62). However, none of the patients in the propranolol group had physiological responses during script-driven imagery, whereas six patients in the placebo group had physiologic responses (p=0.04). It is important to note that the timeframe from trauma exposure to first propranolol dose was the shortest in this trial relative to all of the other randomized trials.
Sharp et al. conducted a post-hoc analysis of a previous trial regarding the use of propranolol in the control of hypermetabolic states in pediatric burn victims.31819 The goal of the post-hoc analysis was to determine if propranolol reduces the risk for ASD. Patients in the propranolol group received an average total daily dose of 4 mg/kg/day. On average, the propranolol was started within two days post-injury. The investigators found no significant difference in the rate of ASD in the propranolol group vs. the control group (8% vs. 5%, respectively; p=0.37). Important limitations of this trial included its post-hoc design as well as the fact that six percent of patients had a previous diagnosis of ASD.
Stein et al. studied severely physically injured patients age 18–65 admitted to a level 1 surgical trauma center.16 Patients were excluded if they lived too far for home monitoring, were too medically unstable, or did not speak English. Patients were randomized to receive propranolol, gabapentin, or placebo within 48 hours of the traumatic event. Patients in the propranolol group received 40 mg TID for 10 days with a 4 day taper. Adherence to medication was measured by the study nurse for the first three days and then by phone interview. At the 4 month post-trauma follow-up, there were no significant differences in PTSD rates in the propranolol group vs. the placebo group (25% vs. 25%, respectively; χ2 <1). Gabapentin also failed to show a significant benefit over placebo. Furthermore, propranolol showed no significant benefit over placebo on ASD symptoms at the 1-month follow-up or on PTSD symptoms over time.
DISCUSSION
Overall, there is limited high-quality evidence to judge the effectiveness of propranolol for secondary prophylaxis of PTSD or ASD. Seven published trials include a retrospective chart review, a prospective cohort study, and 5 randomized clinical trials.381113–16 Of the latter, one study3 was a post-hoc analysis that did not include a placebo treatment. The sample sizes of the trials were relatively small, as only two trials included at least 50 patients.313 In terms of generalizability, it is noteworthy that three trials were limited to either pediatric patients or adults within a narrowly defined age range, and two trials were limited to burn victims.381314 Taken together, patients in the trials experienced a variety of traumas, but certain traumas (e.g., sexual) appear to be underrepresented.
The aforementioned limitations of the published literature notwithstanding, the findings of the trials were quite consistently negative (See table 1). Vaiva et al. showed statistically significant results in regards to symptom levels -- but not rates -- of PTSD. 14 Because this study was a prospective cohort that utilized self-selection, the treatment group was not randomized and was subject to bias. Moreover, the sample size was small, and medication adherence was not closely monitored. Thus, results of the study were mixed, and confounding variables limit its usefulness. The studies by Hoge et al. and Pitman et al. provided evidence that propranolol can decrease physiological activity during script-driven imagery.1115 However, in neither case did propranolol treatment result in a reduced rates of PTSD. Thus, while these studies revealed some objective evidence for beneficial effects of propranolol, they do not rise to the level of being considered positive trials.
Because of the limited efficacy displayed in the trials to date, it is impracticable to draw conclusions about the optimal dosage and duration of propranolol therapy by comparing those from positive vs. negative trials. The adult dosages varied between 120 and 240 mg/day, so it is possible that higher dosages may have proven to be more efficacious. Regarding duration of therapy, propranolol was given for a total duration of less than 3 weeks (including tapering) in all trials except the ASD trial. Thus, it is possible that a longer duration may have proven more efficacious.
Allowable time lapses from trauma exposure to first dose of propranolol in the trials ranged from less than 6 hrs. to less than 48 hrs. Whether an even earlier timeframe might lead to improved efficacy of propranolol is merely speculative, but it is interesting that Pitman et al. found encouraging results in regards to physiological responses, and they utilized the shortest time lapse (i.e., < 6 hrs) of the randomized trials.15 Also, Vaiva et al. found encouraging results in regards to PTSD symptom levels, and although the authors did not provide patient-specific information in regards to mean time from trauma exposure to first dose of propranolol, it can be implied from the information supplied concerning range and mean values that some patients received therapy well within 6 hours of the traumatic occurrence.14
SUMMARY
Due to the limited evidence published to date, no firm recommendation can be made at this time as to whether propranolol is an effective agent for secondary prophylaxis of PTSD or ASD. However, current data certainly lean toward the ineffectiveness of propranolol for this indication. Larger, randomized, placebo-controlled trials that include more diverse types of traumas need to be conducted in order to provide more sound evidence. Until more positive data are produced, it is not recommended that propranolol be used routinely as a method to prevent PTSD or ASD in the traumatized population.