The effects of propranolol on fear of tooth removal: A randomized, placebo-controlled, double-blind, parallel design trial

Tooth or moval removal is considered to be the most common distressing surgical
procedure practiced in oral and maxillofacial surgery (Earl, 1994; Oosterink,
de Jongh, Aartman, 2008; Yusa et al., 2004). In a recent study in which
patients were prospectively monitored until 4 weeks after their third molar
removal, postoperative levels of dental anxiety were found to be significantly
associated with the level of emotional distress (i.e., pain, anxiety, or
emotional disturbance) experienced during treatment (De Jongh et al., 2008).
The results further suggest that whether a third molar removal results in a
long-lasting heightened level of anxiety largely depends on the magnitude of
past exposure to aversive dental situations. The combination of frequency of
previous exposure to distressing dental events and preoperative anxiety level
appeared to significantly predict the level of anxiety 4 weeks after treatment,
accounting for 71% of the variance. In 8% of the patients symptoms indicative
of posttraumatic stress disorder (PTSD) developed, which are generally observed
in response to typical life-threatening events, such as witnessing or being the
victim of rape or assault or being exposed to a disaster (American Psychiatric
Association, 2000). PTSD symptom severity assessed 4 weeks after third molar
removal was significantly associated with pain scores during treatment, which
suggests that the experience of pain has the potential to increase such risk.
Thus, distressing or traumatic experiences are likely to make patients
vulnerable, thereby increasing the risk for long-standing dental anxiety and
trauma-related symptoms developing in response to a distressing event.
Evidence for the contention that exposure to distressing experiences increase
the likelihood of developing dental anxiety comes from studies showing that a
high percentage of anxious dental patients indicate 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; De Jongh,
Fransen, Oosterink-Wubbe & Aartman, 2006). 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 may 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 symptoms.
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 orthosympathetic activity such as
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, the subsequent release of
glucocorticoids (the *second wave* of the adrenocortical response)
dose-dependently strengthens the memory enhancing effects of adrenaline, having
an important adaptive function in response to stressful experiences(Tronson, &
Taylor, 2007). 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 trauma 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 these
disabling conditions it would be necessary to be able to transform the way this
experience has initially been 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.

The aim of this study is to determine the effects of propranolol on patients*
crucial fear-related memories and dental trait anxiety in those undergoing
surgical removal of one of their teeth or molars. The hypotheses that are
tested are that individuals who received 80 mg propranolol one hour rpior to
the removal of their teeth, and 40 mg propranolol immediately after removal,
compared to individuals in the placebo-control condition, would report:
1. a significantly lower level of state anxiety during treatment.
2. a significantly lower level of state anxiety in anticipation on a next
appointment.
3. a significantly lower level of dental trait anxiety at four weeks follow up.
4. significantly less brightness, emotional intensity, aversiveness and
intrusiveness of the memory of which patients indicated to be significantly
associated with their fear of dental or oral surgical procedures, both
immediately after the treatment than at four weeks follow-up.
5. significantly less brightness, emotional intensity, aversiveness and
intrusiveness of the memory of their (first) tooth removal, both immediately
after the treatment than at four weeks follow-up.
6. significantly less physiological arousal (i.e. heart rate, blood pressure
and skin conductance) four weeks after the procedure.

In addition, it is hypothesized that the reductions related to these variables
(difference between scores before and at four weeks follow-up) of patients of
the propranolol condition would be significantly greater than those of the
placebo control condition.

Seventy patients with excessive fear for tooth removal will be randomly
allocated to two groups. Both groups of participants will undergo (regular)
tooth or molar removal. One group of receives propranolol pills before and
after treatment, whereas patients in the other group will receive exactly
similar looking placebo pills. An independent researcher who is blind to group
allocation will assess all participants' scores on standardized outcome
measures; before and after completion of the tooth or molar removal, and
finally after completion of treatment (at the second tooth or moral removal: a
follow-up appointment without research intervention).

One hour prior to their treatment during which a tooth will be removed,
patients receive 80 milligrams of propranolol. Propranolol is a beta blocker
which previously has been shown to be effective in terms of reducing state
anxiety in people who were given a dental anesthetic injection. After the
removal of their teeth patients receive a second dose of 40 milligrams with the
intention to reconsolidate the effect of propranolol on the of the wisdom teeth
removal memory.

Propranolol is a relatively safe drug that is commonly prescribed. The main
side-effects include gastroinestinal symptoms (nausea, diarrhea), fatigue,
impotence, decreased concentration, reduced responsiveness and headache; in
addition, there may be pharmacological effects inherent to *-blockers
(bronchospasm, bradycardia, heart block, hypotension and dizziness, heart
failure and cold, cyanotic extremities).

Propranolol should not be used in patients with bronchial asthma, other
obstructive pulmonary disease or a history of bronchospasm. Other
contraindications include hypersensitivity to propranolol, bradycardia,
cardiogenic shock, hypotension, metabolic acidosis, second and third degree AV
block, sick sinus syndrome, untreated phaeochromocytoma, prolonged fasting and
heart failure. Pregnant and lactating women are excluded from this study. This
applies to the entire study.