A pill against fear and phobia? The effects of propranolol on memories of individuals suffering from dental phobia. A prospective double blind randomized controlled trial.

If someone suffers from a marked fear that is excessive or unreasonable, cued
by the presence or anticipation of a specific object or situation it is likely
that this person has a specific phobia (American Psychiatric Association,
2000). Specific phobia is the most prevalent anxiety disorder with a prevalence
rate of 10-12% (Bijl, van Zessen & Ravelli, 1997; Oosterink, De Jongh &
Hoogstraten, in press). It is also a debilitating condition. A large
epidemiological study of over 20,000 people in 6 different countries
(ESEMeD-project), showed that having a specific phobia is associated with more
sick leave (11% over the past 30 days) than other mental disorders including
alcohol addiction (3%), depression (9%) or purely somatic conditions, such as
cardiac disease (7%) and diabetes (2%; Alonso et al., 2004).
While some phobias appear to be acquired following a specific traumatic
experience with the phobic stimulus, such events are rarely found in the
etiology of others. For example, it has been found that the most common
category of phobic fears, phobias of harmless animals (e.g. spiders, mice, bats
etc.) are not the result of an experience associated with terror or pain
(Davey, 1992). Likewise, a study among water-phobic children showed that only
2% of the phobias could be attributed to a direct conditioning event after
which water was subsequently feared (Menzies & Clark, 1995). Conversely, there
are particular types of fears which are almost exclusively related to
confrontations with a traumatic stressor.
A typical example of a traumatically induced type of specific phobia (i.e.,
*traumatic phobia*, McNally & Saigh, 1993) is dental phobia. In some studies,
96% of a group of anxious dental patients indicated having experienced one or
more terrifying dental treatment events that could explain the onset of their
dental fear or phobia (Locker, Liddell, Dempster, & Shapiro, 1999). To this
end, the experience of helplessness appears to have the greatest potential risk
of precipitating pathological forms of dental anxiety (Oosterink, De Jongh &
Aartman, 2009). As individuals tend to construct highly negative images and
dysfunctional cognitions of such events (De Jongh & Ter Horst, 1993; De Jongh
et al., 1994), phobic individuals, like those suffering from posttraumatic
stress disorder (PTSD), are likely to experience excessive retrieval of fearful
memories of past horrific events (De Jongh, Aartman & Brand, 2003). Research
indicates that such memories are difficult to suppress (De Jongh et al., 1996;
Muris et al., 1998), and as phobias are characterized by fear networks of high
associative strength, confrontation with a phobic stimulus is likely to provoke
retrieval of stimulus-associated fear memories with a strong physiological
response (Cuthbert et al., 2003; Foa & Kozak, 1986; Lang, 1985). Research
supports this notion showing that images of previous distressing events, and
associated negative beliefs, are not only triggered by a direct confrontation
with a phobic object or situation, but also in anticipation of such an event,
and can even occur spontaneously (De Jongh, Fransen, Oosterink-Wubbe & Aartman,
2006). There are indications that every reactivation of such aversive
experiences further strengthens the aversive memory trace (De Quervain &
Margraf, 2008). This means that activation of aversive memories not only plays
an important role in the symptomatology of fears and phobias, but also in the
process contributing to the maintenance, and aggravation of these conditions.
Last century much progress has been made in understanding the process of
consolidation and re-consolidation of memories (Cahill & McGaugh, 1998;
Lechner et al., 1999). In this process a brain structure termed the amygdala is
crucial since it is involved with the formation of enhanced declarative memory
for emotionally arousing events (Cahill & McGaugh, 1998; McGaugh, 2000; Phelps,
2004). In a threatening situation adrenaline and noradrenaline (or epinephrine
and norepinephrine) are released by the adrenal medulla which mediates the
body's short term stress response, leading to vasoconstriction, increased heart
rate, a higher blood pressure and sweat production. Adrenaline is also released
as a neurotransmitter in the brain. This stress hormone leads to a state of
alertness and has been found to modulate the processing of emotional
information via the amygdala (van Stegeren, 2008). What is less known is that
the endogenous stress hormones feed back directly to the amygdala to strengthen
the long term memory of the same events that initially induced their release
(Cahill, 2003). As adrenaline seems to enhance memory in a dose-dependent way
glucocorticoids have an important adaptive function in response to stressful
experiences. That is, in addition to give rise to an immediate response to an
emotional event, these hormones aid future responses by enhancing declarative
memory of this event.
A large proportion of people suffer from conditions that result from the
personal experience of something terrible and the disturbing effects of how it
is remembered. Both PTSD and dental phobia are excellent examples of such
conditions. In order to effectively treat the symptomatology it would be
necessary to be able to transform the way this experience is encoded. This
would require some type of intervention that blocks or diminishes the human
stress response as this would help reconsolidating the memory of an emotionally
powerful experience into a less emotionally charged form, resulting in less
re-experiencing and thus in a reduced fear response. There is evidence to
suggest that the ß-adrenergic blocker propranolol is physiologically capable of
doing this.

Brunet and his colleagues investigated the effect of the ß-adrenergic receptor
antagonist propranolol on the alleviation of PTSD symptoms (Brunet et al.,
2008). In this study, 19 individuals with chronic PTSD were asked to describe
the event that caused their PTSD, in order to reactivate their traumatic
memories. Immediately following this intervention, subjects received either 40
mg of short-acting propranolol and two hours later 60 mg of long-acting
propranolol or twice a placebo. A script of this traumatic event was created
and after a week subjects had to listen to their personal script again. It was
found that when propranolol was provided within hours after their mental
imaginary, physiologic responses (i.e. heart rate and skin conductance) two
weeks later were significantly smaller in the propranolol than in the placebo
group, suggesting a long-lasting effect of propranolol on memory.
Thus, elevated levels of propranolol seem to interrupt the vicious cycle of
spontaneous retrieving, re-experiencing and the reconsolidation of negative or
traumatic memories and, thereby, promote forgetting (De Quervain & Margraf,
2008). A recent study on the acquisition and alleviation of spider fear
supports the notion that a fear response can be weakened by disrupting the
reconsolidation process, and that this disruption may prevent the return of
fear (Kindt, Soeter & Vervliet, 2009). In their study, 60 undergraduate
students aged 18 to 28 viewed fear-related images on a computer and learned to
link pictures of spiders with a mild shock to the hand, which created a fearful
memory. After a 24-hour break, the researchers randomly gave each participant
either 40 milligrams of propranolol or a placebo. An hour and a half later,
they asked the students to view the spider pictures again and to remember what
they had learned the day before. The students who received propranolol showed
no eye blink startle reflex when viewing the spider pictures, a finding that
suggests the entire fear memory was removed. The results of this study suggest
that propranolol exerts effects on the memory system by disrupting the
reconsolidation process. According to the authors the results may be explained
by the fact that the beta-adrenergic blockade during reconsolidation
selectively disrupts the protein synthesis of the amygdalar fear memory, which
may result in *deconsolidation of the fear memory trace while leaving the
declarative memory in the hippocampus untouched* (Kindt, Soeter & Vervliet,
2009. Limitations of this study are that the subjects did not suffer from a
relevant clinical (i.e. phobic) condition and that only a behavioral expression
of the fear response (i.e., startle reflex) was measured. Furthermore, it is
not clear whether the memory effects resulted in a long-term reduction of
spider fear.
If memories of spiders are indeed amendable to the effects of propranolol then
it could be assumed that people with dental fear could also profit from this
intervention. Indications that propranolol potentially has the possibility of
inducing positive effects on peoples* phobic fear response come from a study
conducted by Liu et al. which showed that administering propranolol at least
temporarily reduces dental patients* level of state anxiety during dental
treatment (Liu, Milgrom & Fiset, 1991). In this study 23 subjects who met the
DSM-III-R criteria for simple phobia received an individual dosage of either
propranolol or placebo prior a dental treatment, and performed a behavioural
avoidance test consisting of actual dental treatment. Results showed a
reduction in self-reported anxiety, pain intensity and aversiveness during the
injection phase of dental treatment following propranolol. Although these
results are promising, since no follow-up was included, it remains uncertain
whether the reduced physiologic responding is permanent and to what extent
propranolol has the ability to cause long standing changes in anxiety and
related conditions.

The aim of the study is to examine the effect of propranolol on intrusive
memories of people suffering from a specific phobia (i.e. dental phobia). It is
hypothesized that the administration of propranolol prior to dental treatment:
1. would be associated with alleviation of patients* level of emotional arousal
(i.e., heart rate) and reduction of self-reported anxiety during treatment.
2. would be associated with a reduction of the emotional intensity,
aversiveness and intrusiveness of: a.) the key memory associated with person*s
dental phobia immediately following treatment, and at four weeks follow-up, and
b.) the memory of the dental treatment four weeks following the treatment.
3. would be associated with a reduction of dental trait anxiety at four weeks
follow-up.
4. Further, is hypothesized that the administration of propranolol perse (i.e.,
without memory activation) would not have effect on any of the outcome
variables.

Sixty patients with specific phobia according to the structured interview for
DSM-IV (First et al., 2002) will be randomly assigned to one of two groups.
Patients in both groups will receive their regular dental treatment (i.e.
fillings, root canal treatments and/or extractions) to expose them to the
dental situation and reactivate earlier dental memories.
One group will receive propranolol prior to treatment, while the subjects of
the other groupwill get a placebo administered.
An independent dentist blinded to group allocation will assess all participants
using the scores on a series of standardized outcome measures on entry to the
study (at baseline), on completion of dental treatment (post-treatment), and
finally at a four weeks follow-up assessment.

After a standardized period of 14 days after initial assessment all patients we
be re-assessed using the same self-report measures as administered at the
initial assessment. Patients return for routine dental treatment in the morning
of the day of their appointment. Two hours before treatment subjects take
either a propranolol or a placebo capsule (40 mg), which will specifically be
prepared by the pharmacology department of the Vrije Universiteit.
After a 30 seconds baseline period patients will be requested to listen to the
script of the most crucial memory, composed two weeks before, and imagine the
event for a 30s-period. Next, patients will be asked to rate the extent to
which various emotions accompanies the memory, to rate the vividness of the
memory, sense of *nowness* and re-experiencing of physical sensations and
emotions which were present in the original event, impact in terms of
interference with daily activities, uncontrollability, and distress caused by
the intrusion of the memory over the past week. Also heart rate and blood
pressure will be recorded. After this, regular dental treatment starts.
Immediately following treatment, data regarding operative psychological
distress (i.e., pain, anxiety and emotional disturbance during treatment) will
be obtained using three separate visual analogue scales (VASs), ranging from 0
(*not at all painful/anxious/disturbing*) to 100 (*extremely
painful/anxious/disturbing*). Also other operative variables that will be
examined as potential predictors of increased levels of anxiety and occurrence
of trauma-related symptoms.
All patients will be asked to repeat their medication (propranolol 40 mg or
placebo pill) two times, with four hours in between.

Follow up assessment
After four weeks when all participants return back for the follow-up
appointment no propranolol will be administered. They will be asked to bring up
two memories: the initial, most crucial memory related to the dental phobia and
the memory of the treatment four week earlier. First, patients are asked to
rate the extent to which various emotions accompanied the initial memory, to
rate the vividness of this memory, sense of *nowness* and re-experiencing of
physical sensations and emotions that were present in the original event,
impact in terms of interference with daily activities, uncontrollability, and
distress caused by the intrusion over the past week. Next, after a 30 seconds
baseline period subjects listen to the script, and imagine the event for a
30s-period during which heart rate and blood pressure are recorded. The same is
repeated but now for the memory of the dental treatment four weeks previously.
Next, the dental treatment starts. Immediately following treatment, data
regarding operative psychological distress (i.e., VASs on pain, anxiety and
emotional disturbance during treatment) as well as data on other operative
variables will be obtained.

Many patients request some type of drug for their symptoms of state anxiety, as
they find it hard to deal with the dental traetment situation, but until now
these have not been found to be safe or have negative effects in term of
re-learning. Thus, the participants may profit from this intervention.
Propranolol is a widely used and relatively safe product with limited side
effectsof which the most important are: fatigue, slow pulse, cold extremities,
sleep disturbances and nightmares.