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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
SAAD Dig. Author manuscript; available in PMC 2010 June 29.
Published in final edited form as:
SAAD Dig. 2010 January; 26: 27–35.
PMCID: PMC2893885
NIHMSID: NIHMS207720

PROPRANOLOL AND D-CYCLOSERINE AS ADJUNCTIVE MEDICATIONS IN REDUCING DENTAL FEAR IN SEDATION PRACTICE

Lisa J. Heaton, Ph.D., Acting Assistant Professor, Daniel W. McNeil, Ph.D., Professor, and Peter Milgrom, D.D.S., SAAD Visiting Professor

Abstract

Extensive research and clinical experience have demonstrated the usefulness of sedation in helping fearful patients receive dental treatment, particularly when they have urgent treatment needs. In addition, the efficacy of behavioural programmes for managing dental fears is well established. While often these two approaches are seen as oppositional, our work in Seattle, Morgantown and at King’s College London Dental Institute demonstrates the complementarity of the two approaches. Using the example of two compounds, one very familiar, propranolol, and one that has recently become of interest, D-cycloserine, we wish to illustrate the manner in which these medications can be used to enhance behavioural approaches to managing dental anxiety.

Introduction

Pharmacological approaches are an everyday part of dental practice in preventing and alleviating pain, yet many practitioners currently under-utilise them, failing to fully address anxiety, fear and panic. Behaviour therapy alone is very effective1, yet is largely unavailable in dental surgeries or specialist hospitals. The combination of anxiolytic medications and behavioural techniques has great potential but is rarely practised in the UK or elsewhere. Several possibilities are available, including the use of behavioural approaches to enhance compliance with pharmacological approaches (such as sedation). This article focuses on a currently available anti-anxiety medication (propranolol) with demonstrated efficacy, and a medication (D-cycloserine) on the horizon, which has promise in terms of enhancing behavioural exposure (see Table 1 for a glossary of clinical terms) for anxiety disorders, including dental phobia.

Table 1
Glossary of clinical conditioning terms

We have argued in this journal1 that dental sedation patients would be more effectively treated in the long run if they first received preparatory behavioural treatment. Indeed, this approach is being evaluated on a pilot basis at the Department of Sedation and Special Care Dentistry at King’s College London Dental Institute. In this on-going study, patients who are to be sedated because they have difficulty co-operating are able to learn coping skills to manage their own anxiety using a computer-driven self-help program, and therefore have the opportunity to develop more positive associations with dental care. Care then is safer because drug doses can be lower in patients who do not rely on intravenous medications alone to cope with dental treatment.

Propranolol

Propranolol (e.g. Angilol® in the UK) is a beta-adrenergic blocking agent primarily used for hypertension2 and the treatment of migraines.3 It is used in the UK as an anxiolytic. It has been used to treat test anxiety4 and acute stage fright.5 In clinical research, Mealy and colleagues6 randomly assigned 53 patients undergoing day surgery to receive either 10mg propranolol or placebo on the morning of and prior to surgery. Those receiving a low dose of propranolol reported significantly lower scores on the Hospital Anxiety and Depression Scale compared to placebo, but no significant differences were found in blood pressure, heart rate or pain experience between propranolol and placebo. Recommended dosing in the UK is 40mg once daily, increased to 40mg three times daily if necessary.7

Interestingly, the newest version of the British National Formulary8 says that ‘beta blockers… do not affect psychological symptoms of anxiety…’ New evidence, to the contrary, suggests that besides impacting physiological symptoms, propranolol alters the reconsolidation of fearful memories after they are activated. In other words, when a fear memory is recalled (activated), propranolol can block the reconsolidation of the feared memory, such that the memory is less emotionally arousing at that time and in the future.910 Propranolol may work in part to lower noradrenergic activity in the amygdala and subsequent release of cortisol during stressful events,11 thereby disrupting the fear and anxiety conditioning process. Use of propranolol to modify traumatic memories is discussed later in this paper.

Use of propranolol in dentistry

In a study of patients with dental phobia, Liu, Milgrom and Fiset12 found lower self-reported anxiety during dental injections and lower overall pain intensity and perceived aversiveness of treatment with 80 or 120mg of propranolol when compared with placebo. This study built on earlier work by Pichot and colleagues13 comparing oral oxprenolol hydrochloride, diazepam or a placebo as a pre-medication to reduce anxiety and upset before restorative dentistry. In the Liu and colleagues12 study, 23 healthy dental patients meeting DSM-III14 criteria for dental phobia were screened using the Dental Fear Survey (DFS).15 The patients had a mean score of 74 and no subject had a score less than 54, indicating a high level of clinical fear. Only those with high physiological reactivity were included. For reference, a recent study in the Department of Sedation and Special Care Dentistry at Guy’s Hospital found patients referred for sedation at an average DFS score of 68 while restorative patients at St. Thomas’ Hospital had an average score of 35 on the same survey instrument.16

In the Liu and colleagues12 study, the dose of the medication was chosen based on individual response to a physiological challenge and was administered orally by capsule one hour prior to treatment. Patients received either restorative or endodontic care involving an injection of local anaesthetic. The study showed that the group of patients receiving propranolol experienced a clinically significant reduction in anxiety during the procedure as well as less post-treatment pain and evaluation of aversiveness. All were able to co-operate sufficiently to have treatment completed. Nevertheless, there were no differences between groups on observers’ ratings of videos of the appointments, and the observer ratings averaged 4 to 5 on a one-to-seven scale, in which seven indicated maximal upset.

The rationale behind the beta-blocker treatment in the study was that some dental patients primarily are physiological responders17 and their anxiety is manifested by tachycardia, shortness of breath and other symptoms similar to a panic attack, but triggered by a specific stimulus. The patients become afraid of the symptoms of anxiety (i.e. anxiety sensitivity: see Table 1 glossary)18 and often regard their physiological reactivity as potentially life-threatening. Treatment delay and refusal likely is an outcome of such a process, in which patients avoid the dental situation as for them it involves physiological hyper-arousal. Interpreting the results of the study, such patients still may need sedation, as those treated with propranolol behaved no differently from those who received the placebo. Since this article appeared, seven other papers in neuroscience and psychiatry journals have cited it.1925 Interestingly, only one of these papers was in a dental journal and it was not clinical.25

In an earlier longitudinal study of patients undergoing sedation versus behavioural dental fear treatment (formally structured gradual exposure to dental stimuli and subsequent reduction and extinction of fear involving multiple appointments), patients completing behaviour therapy showed better long-term dental attendance at 2-and 10-year follow-up than did patients completing care under general anaesthesia and sedation.2627 Kvale and colleagues28 also published a meta-analysis of dental research papers showing the effectiveness of behaviourally oriented treatment. Ideally, reducing overall dental anxiety prior to sedation can help achieve the goal of patients establishing a pattern of regular dental care after most invasive work has been completed under sedation.29

Propranolol and post-traumatic learning

As previously mentioned, research has shown that propranolol may help change the way in which a traumatic memory is reconsolidated, thereby reducing its fear-inducing properties. It has been argued that some dental fears, elicited by painful dental treatment, are a form of post-traumatic stress disorder (PTSD).30 PTSD is a condition that often develops following a traumatic event and includes recurrent nightmares, flashbacks, feelings of reliving the trauma, intense psychological distress when presented with reminders of the event, emotional numbing or, conversely, hyperarousal.31 Nineteen individuals meeting DSM-IV32 criteria for PTSD for traumatic events such as childhood sexual abuse, physical assault and motor vehicle accidents recounted their personal traumatic experiences and then were administered 40mg of propranolol or placebo by mouth, then 60mg of long-acting propranolol or placebo two hours later.33 One week after receiving propranolol or placebo, participants listened to 30-second scripts describing their personal traumatic experiences, and were asked to imagine the event for 30 seconds. Patients given propranolol after recounting the traumatic scripts showed significantly less physiological responding (i.e. heart rate, galvanic skin conductance, facial muscle EMG) when re-experiencing the event a week later than those given placebo.

Pitman and colleagues34 gave 40mg propranolol by mouth to 41 patients presenting in an emergency room after traumatic accidents (i.e. motor vehicle, motorcycle) and meeting preliminary criteria for PTSD. Patients were given the first dose no later than six hours after the trauma, then four times daily for 10 days. One month after the trauma, one of 10 (10%) patients taking propranolol and six of 20 (30%) of placebo subjects continued to meet the criteria for PTSD. Patients given propranolol also showed significantly less physiological responding (i.e. heart rate, skin conductance, facial muscle EMG) than did those who were administered a placebo.

Assessing the suitability of propranolol for dental fear and anxiety

Patients’ fear of the dental situation should be assessed formally with an instrument such as the Dental Fear Survey (DFS)15 in order to determine the feared aspects of the dental situation for each individual. The DFS questions used to assess symptoms of physiological arousal, addressed in part by propranolol, are presented in Table 2. The DFS is preferable to the MDAS used in research in the UK and elsewhere because it provides the clinician with more information of clinical value.35 While patients with high physiological arousal in the dental situation may find reduction of their physical symptoms of anxiety and fear, propranolol also has the promise of also addressing the fear memory itself, as previously described.

Table 2
Dental Fear Survey:14 questions used to assess physiological reactions When having dental work done:

Guidelines for the use of propranolol are given in the British National Formulary and elsewhere. Use of propranolol with benzodiazepines is not contraindicated, although research has shown that propranolol may prolong elimination of diazepam, but not that of lorazepam or triazolam.36 Also related to dental treatment, animal literature has suggested that propranolol increases the serum levels of lidocaine37 and increases the threshold for lidocaine-induced convulsions.38 Because there are no amnesic effects of propranolol, patients will be fully able to give consent for any subsequent sedation. Administration of propranolol should reduce attendance failures, as fears are often maximal immediately before an appointment.29

One implication of the use of propranolol in dentistry is the use of such a non-selective beta-blocker with some local anaesthetics. There have been reports of an increased likelihood of an elevation in blood pressure when epinephrine-containing local anaesthetics are used.39 Consideration thus needs to be given to the choice of local anaesthetic administered.

Directions for future research in propranolol

Propranolol has been used effectively to manage the physiological symptoms of anxiety and fear in the dental setting.12 Its ability to reduce dental fear and anxiety through longer-term cognitive changes, however, has yet to be studied. Future research in this area may follow prior studies of PTSD-related anxiety symptoms. For example, fearful individuals anticipating dental treatment may be asked to recall a traumatic dental experience a week prior to the scheduled dental treatment. They then are given a dose of propranolol after retrieving this fear memory. A week later, at the dental appointment, they are given another dose of propranolol prior to treatment. If propranolol is able to reduce anxiety related to fearful memories of dental treatment, these individuals should show decreased anxiety in the second appointment, even as they are preparing for imminent dental treatment. Propranolol has promise to reduce fear and anxiety in dental patients both peripherally, by reducing physiological symptoms, as well as centrally, by changing the way the feared experience is re-stored in memory.

A new agent: D-cycloserine

In the past decade, there has been a burgeoning interest in the potential use of D-cycloserine (DCS; Cycloserine, King Pharmaceuticals Ltd., Herts) to facilitate the reduction of fear and avoidance through enhancement of extinction learning (see Table 1, glossary) in exposure-based behavioural treatment. DCS is an antibiotic used in the UK in the treatment of drug resistant tuberculosis40 and currently not listed in the formulary for the treatment of anxiety. At the glycine binding site, DCS is a partial agonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor that affects brain processes involved in fear, specifically in the amygdala.41

Initial animal research testing the use of DCS in expediting extinction learning arose deductively from theories of brain circuitry, as well as empirical data that showed that NMDA antagonists inhibit extinction learning. Existing compounds that were NMDA agonists were identified as potentially impacting extinction, and so were tested with animals. Positive findings from animal work about DCS then led to limited human trials, an excellent example of translational research.42

Use of DCS in the treatment of anxiety

DCS does not act directly as an anxiolytic. Rather, it expedites learning by impacting the neural circuitry that is involved in extinction, which is the basis for behavioural treatments to reduce fears. Ressler and colleagues43 found that 28 individuals with acrophobia (fear of heights) showed greater anxiety reduction, as measured by self-report ratings and skin conductance, after exposure therapy (see Table 1, glossary) with DCS versus participants treated with a placebo. DCS was taken orally by capsule two to four hours prior to exposure therapy. A 500mg dose of DCS was no more effective than a 50mg dose with regard to extinction. Prior research by this group demonstrated through a drug-free extinction trial that DCS has no anxiolytic properties of its own.44 DCS typically is dosed at 50 to 500mg in isolated, rather than chronic, dosing to enhance the effects of exposure treatment for anxiety and fear.41 DCS is generally well tolerated.40

It is important to note that DCS does not appear to make standard behaviour therapy more effective. Rather, it seems to expedite the reduction of fear and anxiety, making behaviour therapy more efficient. This research suggests that administering DCS during a practice session prior to sedation treatment may help the patient decrease his or her fear more quickly than with exposure therapy alone. For example, patients may undergo a brief practice session, during which they ‘rehearse’ the placement of the cannula while practising relaxation strategies. Administration of DCS in conjunction with this rehearsal session would help expedite fear and anxiety reduction, leading to less fear and anxiety during the cannulisation. In this type of learning, reinforcement of fear (e.g. temporary relief of fear by escaping the situation: see Table 1 glossary) is avoided in order to extinguish the fear response through exposure. Systematic practice by the patient of the steps involved in dental treatment (e.g. sitting in the dental chair, relaxing one’s limbs and torso, opening one’s mouth) substitutes for the earlier fear response.

Directions for future research in DCS

To date, clinical studies of DCS’s enhancement of exposure treatment and other cognitive-behavioural treatments have been limited to acrophobia,43 social phobia/social anxiety disorder,41 and obsessive-compulsive disorder.45 Since DCS has been found to enhance exposure treatment, in both animals and humans with regards to several different anxiety conditions, the use of DCS has promise to facilitate extinction learning (see Table 1, glossary) in dental anxiety, fear and phobia as well.

At present, use of DCS in dentistry is theoretically promising, and studies of the enhancement efficacy of DCS in dentistry are at an early stage of development at King’s College London Dental Institute to determine its appropriateness for routine use in clinical care. While it cannot be assumed that DCS will enhance exposure treatment for all phobic or other anxiety disorders, there is considerable promise for using DCS as an aid for dental fear exposure treatment, which ultimately may allow affected patients to utilise dental services more comfortably with improved attendance. In testing its effectiveness, as DCS acts to enhance memory, it is critical that any dental experiences in which DCS is used be positive. Short-term behavioural preparation of patients involves controlled exposure to fearful stimuli, so use during clinical care should be carefully considered and planned to maximise a positive experience throughout. This novel pharmacological adjunct shows promise in its ability to combine with behavioural methods to reduce anxiety and fear in dental patients.

Conclusion

Dental fear is a common problem among adults in the United Kingdom,46 and approximately 25% of adults in the UK avoid dental care due to fear, even when they are experiencing a painful dental condition. These numbers are similar to those found in the United States, and while dental technology has improved considerably over the last 30 years, the prevalence of dental fear has remained remarkably consistent.47 Avoidance of dental treatment due to fear often leads to a significant impairment in oral health.48

Certainly, the field of dentistry has not shied away from utilising pharmacology to help patients be more comfortable and less anxious during dental treatment. Indeed, it has been a leader. The use of pharmacological adjuncts, however, has focused largely on sedative and analgesic medications, which do not allow patients to learn or utilise adequate behavioural strategies to increase their comfort and attendance in the long term. No work has been done to follow up the original study of propranolol by Liu and colleagues and no use of DCS in dentistry has been investigated. Such work is necessary. Propranolol has been used successfully to manage physiological symptoms of anxiety in dentistry12 and other anxiety-provoking situations46, yet it appears from other clinical literature that beta-blockers can be utilised for more long-term anxiety management by changing the way the fear memory is stored in the brain. In this way, administration of beta-blockers not only decreases anxiety in the short term, but also may help alleviate dental anxiety in an enduring way. Such use of propranolol should lead to less need for aggressive treatment and increased patient safety during procedures.

While DCS works via a different mechanism from beta-blockers and is not directly anxiolytic, it shows promise in its ability to also modify individuals’ learned associations with dentistry, allowing more positive associations to be made and anxiety to be decreased over the long term. By enhancing the positive associations made during exposure, individuals’ anxiety about dental treatment may decrease, and dental treatment may be made easier for both patients and providers. Reducing anxiety by using behavioural and pharmacological strategies in combination is an approach appropriate for research into further application in sedation dentistry.

Acknowledgments

Preparation of this paper was supported, in part, by a generous grant to King’s College London Dental Institute from the Society for the Advancement of Anaesthesia in Dentistry (www.saad.org.uk). Dr Heaton is supported by Grant No. 1K23DE019202-01A2, and Dr McNeil is supported in part by Grant No. R01 DE014899-03S1, both from the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.

The authors would like to thank Professor Timothy Newton and Dr David Craig for their valuable editorial contributions to this manuscript.

Contributor Information

Lisa J. Heaton, Dental Fears Research Clinic, Department of Dental Public Health Sciences, Box 357475, University of Washington, Seattle, WA, USA 98195-7475.

Daniel W. McNeil, Department of Psychology and Department of Dental Practice & Rural Health, West Virginia University, Box 6040, Morgantown, WV, USA 26506-6040.

Peter Milgrom, Department of Sedation and Special Care Dentistry, King’s College London Dental Institute.

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