Doi:10.1016/s0006-3223(03)00412-8

Immediate Treatment with Propranolol DecreasesPosttraumatic Stress Disorder Two Months afterTrauma Guillaume Vaiva, Franc¸ois Ducrocq, Karine Jezequel, Benoit Averland,Philippe Lestavel, Alain Brunet, and Charles R. Marmar Background: This study investigated the efficacy of pro-
lated in part to the release of catecholamines (adrenalin pranolol prescribed shortly after trauma exposure in the and noradrenalin), as a consequence of activation of the prevention of posttraumatic stress disorder (PTSD) symp- central nucleus of the amygdala and the locus coeruleus, key components of the neurocircuitry of fear (Goddard Methods: Eleven patients received 40 mg of propranolol
and Charney 1997). A subgroup of trauma victims expe- 3 times daily for 7 days, followed by a taper period of riences a peritraumatic panic-like state that can include 8 –12 days. They were compared with eight patients who hyperventilation, trembling, sweating, and tachycardia, refused propranolol but agreed to participate in the study. which suggest an immediate adrenergic activation at the Though nonrandomized, the two groups did not differ on time of traumatic exposure. Police officers with elevated demographics, exposure characteristics, physical injury peritraumatic arousal and emotional distress during critical severity, or peritraumatic emotional responses. incident exposure, including panic reactions, have greater Results: Posttraumatic stress disorder rates were higher
levels of subsequent posttraumatic stress symptoms (Bru- in the group who refused propranolol (3/8) compared with net et al 2001). Prolonged adrenergic activation, as re- those who received the medication (1/11), as were thelevels of PTSD symptoms (U ϭ 85, p ϭ .037). flected by greater peritraumatic tachycardia, was prospec-tively shown to increase the risk for posttraumatic stress Conclusions: Our results are consistent with earlier
disorder (PTSD) (two positive studies: Bryant et al 2000; findings and suggest that propranolol may be useful formitigating PTSD symptoms or perhaps even preventing Shalev et al 1998; and one negative study: Blanchard et al the development of PTSD. Biol Psychiatry 2003;54: 2002). Prolonged states of adrenergic activation are be- 947–949 2003 Society of Biological Psychiatry lieved to increase the risk for PTSD through increased fearconditioning (Orr et al 2000) and the overconsolidation of Key Words: Posttraumatic stress disorder, immediate
the memories related to the traumatic event (Southwick et treatment, propranolol, peritraumatic distress, short-term Propranolol is a ␤-adrenergic antagonist that is used in the treatment of hypertension and also for the treatment ofanxiety disorders (Laverdure and Boulenger 1991). Basedon pilot data, Pitman et al (2002) have suggested that Introduction
propranolol given within 6 hours of the traumatic event for10 days was superior to a placebo for reducing PTSD Victims of traumatic events display a number of symptoms 1 month posttrauma.
reactions and symptoms during the trauma and in its In France, propranolol can be prescribed for symptoms immediate aftermath. These immediate reactions are re- of tachycardia after temporarily distressing situations. Wetherefore studied the influence of propranolol prescribedshortly after a traumatic event in survivors who presentedwith tachycardia. Based on a model of adrenergic dysregu- From the Clinical School of Psychiatry (GV, FD, KJ, BA, PL), University of Lille II, Lille, France; Department of Psychiatry (AB), McGill University and lation in PTSD proposed by Southwick et al (1999) and Douglas Hospital Research Center, Montreal, Quebec, Canada; and Depart- findings linking hyperarousal to increased fear condition- ment of Psychiatry (CRM), University of California, San Francisco VeteransAffairs Medical Center, San Francisco, California.
ing (Orr et al 2000), we hypothesized that propranolol Address reprint requests to Guillaume Vaiva, M.D. Ph.D., Clinique Michel Fontan, would counter the hyperadrenergic state and decrease CHRU de Lille, 6 rue du Professeur Laguesse, 59037 LILLE cedex, France.
Received February 6, 2003; revised March 19, 2003; accepted April 1, 2003.
PTSD symptoms and diagnosis 2 months posttrauma.
Methods and Materials
Table 1. Between-Group Comparisons of Participants WhoAgreed Versus Refused to Take Propranolol in the Aftermath The trauma victims were recruited at the Emergency Depart- ments of the Douai and Lille hospitals (France) shortly after their admission (2–20 hours posttrauma) after motor vehicle accidents or physical assault. The participants included 21–30-year-old individuals in good physical health with tachycardia of at least 90 beats/min after 20 min of rest in a lying position. Participants were excluded if they had lost consciousness during the trauma, had sustained important physical or traumatic brain injuries, had a cardiovascular or active asthma disease, or in case of past or The subjective severity of the traumatic event was assessed using the Peritraumatic Distress Inventory (Brunet et al 2001). Physical injury severity was assessed with the Trauma Score (Smith 1990). The Treatment Outcome PTSD scale (Davidson and Colket 1997) and the DSM-IV criteria were used to assess PTSD symptoms and diagnosis, respectively. Posttraumatic stress dis- order at baseline and prior trauma history were assessed with the Mini International Neuropsychiatric Interview (Lecrubier et al 1997). After the study protocol was fully explained, the partici- Patients received a monotherapy of 40 mg of propranolol 3 times daily for 7 days. The first pill was prescribed immediately after the 20-min baseline heart rate recording period. Treatment termination included the measure of heart rate at day 7, with an8 –12-day taper period (a drop of 40 mg every 4 days). Two PDI, Peritraumatic Distress Inventory; PTSD, posttraumatic stress disorder.
months after trauma exposure, a psychiatrist, blind to thetreatment status of the participants, assessed them for PTSDsymptoms and diagnosis.
gender, employment, marital status, baseline heart rate, or on the type of event, injury severity score, and peritrau-matic distress.
Analyses were conducted with SPSS 10.0 software (SPSS, Propranolol was delivered 2–20 hours after the trauma Chicago, IL). Because of the small sample size, we used the (mean ϭ 9.5, SD ϭ 6). Compliance was good, as Wilcoxon rank test to compare means and Fisher exact test tocompare rates. The ␣ was set at .05 (two-sided tests). There were evidenced by the resting heart rate obtained 1 week posttrauma (mean ϭ 62, SD ϭ 5). As shown in Table 1,2 months after the traumatic event, PTSD rates werehigher among subjects who refused propranolol (3/8)compared with those who received the medication (1/11), as were the PTSD symptom scores (U ϭ 85, p ϭ .037).
Over a 6-month period, 54 victims presenting to the Treatment tolerance was deemed satisfactory among the Emergency Department met the DSM-IV criteria A1 and participants who, for the most part, had never previously A2 for trauma exposure. Nineteen patients were excluded taken any medication. Despite the prescribed taper period, because of injury severity and four because of age. Of 31 two patients discontinued propranolol abruptly after 1 potential participants, 23 had a resting heart rate greater week. After he discontinued the propranolol without taper than 90 beats/min. Among those 23, 11 agreed to take the period, one of these individuals presented with a marked propranolol, 8 refused but agreed to participate in the anxiety reaction, without any cardiovascular complica- study, and 4 refused to be study participants. As can be tions. Three patients were slightly bothered by a sensation seen in Table 1, the two study groups did not differ on age, Discussion
sample of motor vehicle accident survivors. J Trauma Stress15/3:199 –204.
Recent work on the pathogenic effects of traumatic stress Brunet A, Weiss DS, Metzler TJ, Best SR, Neylan TC, Rogers C, has focused on adrenergic activation, associated with et al (2001): The Peritraumatic Distress Inventory: A pro- states of terror at the time of exposure. Traumatic events posed measure of PTSD criterion A2. Am J Psychiatry are hypothesized to be followed by a critical period of increased brain plasticity, during which long-lasting neu- Bryant RA, Harvey AG, Guthrie RM, Moulds ML (2000): A ronal changes may occur in those who develop traumatic prospective study of psychophysiological arousal, acute stressdisorder and post-traumatic stress disorder. J Abnorm Psychol stress disorders (Shalev 2000). Physiologic arousal during the traumatic event and in the post-immediate phase may Cahill L, Prins B, Weber M, McGaugh JL (1994): Beta- trigger the neurobiological processes that lead to PTSD.
adrenergic activation and memory for emotional events.
Propranolol has been shown to reduce memory for emo- tional events through a central adrenergic blockade (Cahill Davidson JR, Colket JT (1997): The eight-item treatment- et al 1994). Propranolol is a ␤-adrenergic antagonist that outcome post-traumatic stress disorder scale: A brief measure binds to peripheral and central ␤-adrenergic receptors and to assess treatment outcome in post-traumatic stress disorder.
Int Clin Psychopharmacol 12:41–45.
readily crosses the blood– brain barrier. At the clinicallevel, it counters trembling, sweating, and palpitations.
Goddard AW, Charney DS (1997): Toward an integrated neuro- biology of panic disorder. J Clin Psychiatry 58(suppl 2):4 – Central nervous system effects of traumatic exposure are mediated by cognitive appraisals of threat. Greater per- Laverdure B, Boulenger JP (1991): Beta-blocking drugs and ceived threat influences the release of central cat- anxiety. A proven therapeutic value. Encephale 17:481–492.
echolamines by activating the central nucleus of the Lecrubier Y, Sheehan D, Weiller E, Amorin P, Bonora I, amygdala, locus coeruleus, and other structures that con- Sheehan K, et al (1997): The Mini International Neuropsy- chiatric Interview (M.I.N.I.), a short diagnostic interview: This pilot study suggests that administering propranolol Reliability and validity according to the CIDI. Eur Psychiatry12:232–241.
to young healthy individuals with tachycardia is effective Orr SP, Metzger LJ, Lasko NB, Macklin ML, Peri T, Pitman RK in mitigating PTSD symptoms and perhaps in preventing (2000): De novo conditioning in trauma-exposed individuals PTSD. Contrary to other studies, our study controlled for with and without posttraumatic stress disorder. J Abnorm the level of peritraumatic distress, ensuring that both the experimental and control groups were exposed to equally Pitman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, distressing events. The study also has limitations, notably Lasko NB, et al (2002): Pilot study of secondary prevention a small sample size of nonrandomized participants fol- of posttraumatic stress disorder with propranolol. Biol Psy- lowed for a relatively brief period.
Our results are consistent with those of Pitman et al Shalev AY (2000): Biological responses to disasters. Psychiatry (2002), who reported encouraging findings in a pilot, Shalev AY, Sahar T, Freedman S, Peri T, Glick N, Brandes D, et double-blind, controlled trial. Large-scale controlled trials al (1998): A prospective study of heart rate response follow- are warranted with diverse trauma groups and longer ing trauma and the subsequent development of posttraumatic follow-up, to determine the value of propranolol in the stress disorder. Arch Gen Psychiatry 55:553–559.
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