Propranolol in anxiety: poor evidence for efficacy and toxicity in overdose

Introduction

Anxiety is the most common mental health problem in the UK, with a prevalence of 5.9%.¹ Initial treatments may involve conservative approaches or a combination of antidepressants and psychological therapy, but these may not always be effective or well tolerated. Propranolol is increasingly prescribed by GPs for anxiety, either taken regularly or as-needed,² but many practitioners may not be aware of its toxicity in overdose or the lack of evidence for efficacy.

Discovery and current use

Propranolol, a non-selective beta-adrenergic antagonist, was initially developed in the 1960s by Sir James Black for angina pectoris treatment. Its use in anxiety began in 1965 when Turner and Granville-Grossman noted an anxiolytic effect during trials for its treatment of tachycardia in hyperthyroidism.³ It has a Product Licence in the UK for the treatment of ‘anxiety with symptoms such as palpitations, sweating and tremor’.⁴

Lack of evidence for efficacy

Despite having a UK Product Licence for the treatment of anxiety symptoms, there is little evidence for propranolol’s efficacy in anxiety. It is not recommended by the National Institute for Health and Care Excellence (NICE) or the British Association for Psychopharmacology (BAP) for this condition.^5,6 The most recent systematic review and meta-analysis on the topic concluded there was insufficient evidence to support the routine use of propranolol in the treatment of anxiety.⁷ There are a lack of well-designed clinical studies in this area, with those available being small, underpowered, and at high risk of bias. A significant number of studies are more than 30 years old and focused on panic disorder and social phobia as opposed to generalised anxiety disorder (GAD). Further research is required to either confirm a lack of efficacy for propranolol in anxiety, or provide robust evidence to support its place in treatment. There is some limited evidence to suggest propranolol provides symptomatic relief for the somatic symptoms of anxiety such as palpitations, tremor, and sweating.⁸ The only other area where there may be some evidence for its use is in the prevention of post-traumatic stress disorder (PTSD) symptoms after a traumatic event; however, the NICE guidelines advise against this.⁵

Prescribing trends

Prescriptions for propranolol have been steadily increasing in the UK since 2003.^2,9 Figure 1 shows the increasing rates in propranolol prescriptions between 2019 and 2023 in English GP practices.⁹ These data from Open Prescribing between 2019 and 2023 are limited as they do not give the indication for the prescriptions. However, Archer et al² produced evidence of steadily increasing rates of beta-blocker prescriptions prescribed as anxiolytics from 2003–2018. This suggests the further increases since 2018 are likely at least in part due to prescriptions of propranolol for anxiety, as opposed to other indications such as hypertension, tremor, or migraine. The data published between 2003 and 2018 show that the increase in prescriptions was particularly notable in young adults.²

Figure 1.

Quantity of propranolol prescribed by English GP practices, January 2019-December 2023: Open Prescribing data.

Reasons for increasing propranolol prescriptions for anxiety

There are multiple factors contributing to the trend in increasing propranolol prescriptions for anxiety. There has been a decrease in benzodiazepine prescriptions for anxiety, which is likely due to increasing concerns about dependence and addiction.² GPs are likely to have changed prescribing habits towards propranolol because of its less addictive properties, but similarities to benzodiazepines in terms of onset of action. We further hypothesised the increase could, in part, be caused by national warnings about the abuse potential of pregabalin and its reclassification as a schedule 3 controlled drug. It should be noted however that pregabalin prescriptions have also steadily increased over the same period.⁹

A recent qualitative paper by Archer et al¹⁰ explored GPs’ views in prescribing beta-blockers in anxiety disorders. This study highlighted multiple other potential drivers for prescribing propranolol in anxiety. GPs highlighted that the licensed status for propranolol’s use in anxiety made it a pragmatic option, and that they felt it was ‘low risk’ and specifically a safer alternative than benzodiazapines. GPs also thought patients liked the immediate effect, and expressed views that beta-blockers were not ‘mind altering’ and could be ‘patient managed’. Some GPs mentioned their own anxieties around prescribing selective serotonin reuptake inhibitors (SSRIs) in young adults because of concerns about antidepressants increasing suicidality in this age group.

Toxicity in overdose

As outlined above, propranolol has developed a reputation for being a relatively safe and benign drug, but there is significant evidence to the contrary. Fatalities have been reported with doses as low as 2000 mg.¹¹ The British National Formulary (BNF) recommends doses of up to 120 mg/day for anxiety, so fatal overdose would be possible from a prescription of only 17 days of medication.⁴ Propranolol blocks the action of catecholamines at both beta-1 and beta-2 adrenergic receptors.¹² In overdose this blockade has a number of consequences that can lead to death. The cardiac complications include QRS widening, hypotension, bradycardias, and other arrhythmias including 1st–3rd degree heart block. In severe poisoning it can lead to ventricular fibrillation, ventricular tachycardia, or asystole.¹³ Propranolol also has multiple effects on the central nervous system and can lead to convulsions and coma.¹⁴ Propranolol is more lipophilic than other beta-blockers, and can therefore penetrate the blood–brain barrier to a greater extent. Higher lipophilicity exacerbates systemic toxicity^15,16 and, in cases of overdose, the risk of convulsions is consequently higher in comparison with other beta-blockers.¹⁷ Other complications caused by propranolol that can lead to death include bronchospasm, pulmonary oedema, and hyperkalaemia.¹¹

Given that its limited benefit for somatic symptoms of anxiety stems solely from its action on peripheral receptors, it is conceivable that alternative, less lipophilic beta-blockers may offer a more favourable safety profile with similar therapeutic results. Studies are needed to confirm efficacy before this strategy can be recommended.

National Programme on Substance Use Mortality data on self-poisoning deaths involving propranolol

A recent cross-sectional study looking at the involvement of propranolol in coroner-reported deaths using data from the National Programme on Substance Use Mortality (NPSUM) showed that, of 4473 suicides reported by coroners in England, Wales, and Northern Ireland to NPSUM between 2010 and 2021, 297 (6.6%) involved propranolol.¹⁸ In 184 of these deaths (62.0%) propranolol was implicated as the cause of death. There were between 18 (in 2010) and 33 (in 2021) suicides involving propranolol each year. Although the number of suicides involving propranolol did not change significantly over the time period, the total number of suicides decreased. The proportion of suicides involving propranolol therefore increased from 3.4% in 2010 to 12.3% in 2021. This is likely to be an underestimation of the true number of suicides involving propranolol, as coroners only report deaths to NPSUM related to psychoactive substances. Whether propranolol is a psychoactive substance is open to interpretation, and so some deaths may not have been reported. In total, only 80% of coroners in the UK are thought to report relevant deaths to NPSUM.¹⁸

The NPSUM study¹⁸ also demonstrates that the demographics of those who died by suicide where propranolol was involved differ from suicides as a whole. Most suicides involving propranolol were in women (56.6%). Suicide overall (by any method) is more common in men (62.9%). The median age at death was also younger in suicides when propranolol was involved (44 years versus 46 years). The occupational status was noted to be different in the propranolol cohort — decedents were more likely to be students or in employment.

Given the suicides involving propranolol are proportionally higher among younger patients, caution in this group is particularly advised. It is unlikely that propranolol is a safer option than starting an SSRI in this age group and the combination of prescribing propranolol with a new SSRI given the potential increased risk of suicidality during this period could be particularly dangerous.

Warnings issued after investigations into propranolol-related deaths

On 8 April 2024 a prevention of future deaths report was addressed to the National Medical Director of NHS England¹⁹ after reviewing a death involving a 19-year-old man prescribed propranolol by his GP. The coroner’s inquest stated, ‘I am concerned that doctors in General Practice may not be aware of the risks of fatal overdose from Propranolol, and that in the absence of greater awareness by GPs, the prescription of quantities of Propranolol to those at risk may cause future deaths.’

This is not the first warning issued as a result of investigation of a death caused by propranolol. In February 2020 the Health Services Safety Investigations Body issued a warning²⁰ about the under-recognised risk of toxicity of propranolol in overdose and recommended this should be highlighted in NICE guidelines and the BNF, and that national organisations should support their staff membership to understand the risks when prescribing propranolol. Unfortunately, since this warning propranolol prescriptions in primary care have continued to increase, and deaths from propranolol overdose continue to be reported.

GPs’ awareness of risks

Archer et al interviewed 17 GPs from 10 different GP practices on their views on prescribing propranolol in anxiety. None of those interviewed mentioned concerns relating to overdose.¹⁰ GPs in this study in fact stated that propranolol does not necessitate the stringent follow-up required when prescribing antidepressants. It appears the dangers highlighted by national bodies, as described above, have not been effectively communicated to GPs.

Current guidelines on prescribing in anxiety offer alternative evidence-based options

‘Anxiety’ is an umbrella term for numerous disorders including the phobias, social anxiety disorders, and PTSD. BAP has guidelines for the pharmacolological treatment of most of these diagnoses, but these are beyond the scope of this article. NICE has discrete guidance for the most common: GAD and panic disorder (Figure 2). There are many evidence-based options for both, though not all are available to, or within the remit of, most GPs.

Figure 2.

Summary of NICE guidelines in anxiety disorders.⁵ NICE = National Institute for Health and Care Excellence. SNRI = serotonin norepinephrine reuptake inhibitor. SSRI = selective serotonin reuptake inhibitor.

Generalised anxiety disorder

Both NICE and BAP recommend the use of an SSRI first line.^5,6 As second-line options they recommend an alternative SSRI, serotonin norepinephrine reuptake inhibitor (SNRI), or pregabalin. The BAP guidelines also list all of the medications with an evidence base in GAD (Box 1).

Box 1.

BAP list of evidence-based treatments in GAD

Most SSRIs (citalopram, escitalopram, paroxetine, and sertraline) Duloxetine and venlafaxine Pregabalin Agomelatine Quetiapine Benzodiazepines (alprazolam, diazepam, and lorazepam) Imipramine Buspirone Hydroxyzine Trazodone

BAP = British Association for Psychopharmacology. GAD = generalised anxiety disorder. SSRIs = selective serotonin reuptake inhibitors.

Panic disorder

Both NICE and BAP recommend an SSRI first line.^5,6 BAP highlights the importance of trying higher doses when initially there is no response, and doing this slowly or using benzodiazapines in the short term to minimise or mitigate side effects when the dose is increased. NICE suggests imipramine and clomipramine as second-line options. See Box 2 for a list of all the medications with an evidence base in panic disorder listed within the BAP guidelines.

Box 2.

BAP list of evidence-based treatments in panic disorder

All SSRIs Some TCAs (clomipramine, desipramine, imipramine, and lofepramine) Venlafaxine Reboxetine Some benzodiazepines (alprazolam, clonazepam, diazepam, and lorazepam) Some anticonvulsants (gabapentin and sodium valproate)a

^a Authors would advise against sodium valproate prescription except in very specialist services given more recent evidence of significant complications for babies born to both mothers and fathers taking it. BAP = British Association for Psychopharmacology. SSRIs = selective serotonin reuptake inhibitors. TCAs = tricyclic antidepressants.

Conclusions

Given increasing prescriptions, lack of evidence, and significant rates of fatal overdoses, there needs to be greater awareness of the risks when prescribing propranolol for anxiety disorders. It seems in most cases that the risks are likely to outweigh the benefits. There are many treatment options with a significantly better evidence base for most anxiety disorders that should be considered before propranolol.

Where propranolol is prescribed for any indication, we would suggest that risk of overdose is given serious consideration. Propranolol overdoses appear to disproportionately affect young people and women, which are not groups that are more generally considered at high risk of suicide. The increase in propranolol prescriptions in recent years is higher in young adults so particular caution in this group is advised. Systematic and repeated assessment of suicidality should be carried out when prescribing propranolol for anxiety. GPs should also limit the quantities prescribed (for example, maximum 2 weeks’ prescription) in view of the potential for fatal consequences from a modest amount of medication. Large, unbiased randomised controlled trials are required to conclusively evaluate whether propranolol has any role in the management of anxiety. Further research is needed into whether alternative beta-blockers with a better safety profile could provide relief of somatic symptoms of anxiety.

Overall, an awareness among all clinicians of the dangers of propranolol overdose and the current lack of evidence for its efficacy in treating most types of anxiety is of key importance for safe and effective prescribing.

Provenance

Freely submitted; externally peer reviewed.

Competing interests

The authors have declared no competing interests.