Everyone feels anxious or nervous from time to time. Whether it is due to attending an important job interview, sitting exams or moving house, simple nervousness is a common and natural response to significant events that stand out or cause us to change from our normal day-to-day routine.
Clinical anxiety on the other hand is unlike these feelings of temporary nervousness. The anxiety state experienced by individuals suffering from clinical anxiety is often more profound and prolonged and can have a significant impact on their daily lives, with their ability to concentrate, work and carry out routine tasks often severely affected.
Drugs used to treat anxiety are referred to as anti-anxiety or anxiolytic drugs. In practice, the use of the term anti-anxiety drugs may also include sedatives and tranquillizers. An important note of distinction is required here. In the truest sense, “sedatives” are drugs that reduce anxiety while not promoting sleep whereas “hypnotics” are medicines that cause the patient to fall asleep more easily and thus reduce their anxiety state.
The most commonly prescribed group of medicines for the treatment of anxiety is the benzodiazepines. Benzodiazepines are useful for the short term (acute) relief of severe anxiety but are not considered appropriate treatment for acute episodes of mild anxiety (e.g exam stress). They provide their effects by acting at sites in the brain which reduce nerve impulses thought to be involved in causing “agitation” or anxiousness. These drugs not only offer useful anti-anxiety effects but they also have a role in the treatment of epilepsy and can help to relieve painful muscle spasms. Members of this class of drug differ with respect to their anxiolytic actions, producing their calming effects due their ability to act as sedatives or as hypnotic agents:
In addition, they can be categorised in accordance to their duration of time spent in the body:
When taken at the correct dose and for the correct duration, benzodiazepines cause few unwanted side effects. However, common side effects reported include drowsiness, dizziness, nausea/vomiting, forgetfulness and muscle weakness (which may lead to loss of control of movements). These effects are more readily seen with benzodiazepines that have a long duration of action in the body. Long acting benzodiazepines may give rise to a build-up of drug in the body as the previous dose of medication will not have been completely eliminated before the next dose is taken. In addition, prolonged use of benzodiazepines is associated with “dependence” whereby the patient feels that they cannot get through the day without taking their medication. This differs from an addiction in that the patient does not physically crave the drug but instead over-relies (depends) on their medication as an emotional support that enables them to function in their day-to-day activities. Symptoms that may arise from this effect include nausea, depression, sleep problems and anxiety. In an attempt to prevent this, benzodiazepines should always be used at the smallest possible effective dose for the shortest possible duration of time (ideally 2-4 weeks).
Pregnancy and breast-feeding
Benzodiazepines should be used with extreme caution during pregnancy. As benzodiazepines can easily cross into the unborn baby’s bloodstream, high doses and/or prolonged use in the mother may lead to withdrawal symptoms in the unborn child. High doses of benzodiazepine treatment in the last three months of pregnancy have been linked to incidences of low body temperature (hypothermia), shallow breathing and floppy limbs in the newborn child. Therefore, drug treatment should be reserved for instances where the benefits of treatment of the mother outweigh the risks to the unborn child (e.g. control of the mother’s epileptic seizures).
Furthermore, benzodiazepines can also be passed into the mother’s breast milk, causing weight loss and tiredness in the baby and therefore should be avoided where possible while the mother is breast-feeding.
Liver and Kidney disease
All benzodiazepines are processed by the liver and are largely removed from the body in the urine via the kidneys. Therefore any pre-existing liver and/or kidney disease will affect the body’s ability to break down and remove the drug. This will lead to a build-up of the drug and an increased likelihood of unwanted side-effects.
In individuals with liver or kidney disease and in whom benzodiazepine treatment is deemed necessary, the treatment strategy adopted involves the use of drugs with short durations of action (e.g. triazolam or oxazepam) and to use smaller doses than those seen in patients with normal functioning livers and kidneys.
Patients with breathing problems due to disorders of the lung (e.g bronchitis, emphysema, asthma) must be monitored closely when being treated with benzodiazepine medication. All benzodiazepines can cause “respiratory depression” whereby the amount of air taken into the lung in one breath is reduced and/or the amount of breaths taken over a period of time is reduced from that normally seen in the individual. Therefore, careful consideration is required in patients who have a pre-existing breathing problem prior to the initiation of benzodiazepine treatment, as this may impair their breathing further.
As the body ages, the ability of the kidney and liver to carry out its normal functions decreases. This results in slower breakdown and removal of benzodiazepines from the body, leading to a build-up of the drug and the development of side effects.
Moreover, the sleepy (hypnotic) effects of some drugs (especially those with long durations of action) are more pronounced in elderly patients. In these patients movement difficulties - which may appear as unsteadiness leading to falls and/or reduced control of the limbs (e.g. difficulty moving about or increased “clumsiness”) and increased confusion and/or forgetfulness is reported. Again, this problem seems to be more easily seen with the longer acting benzodiazepines.
Finally, co-existing medical problems and their treatment are further important point that need to be addressed when prescribing for elderly patients. Elderly people tend to be taking more prescription medication than any other patients and significant drug interactions between their current medication and the introduction of their new anti-anxiety drug may occur. For example, patients on medication to control high blood pressure (hypertension) may find that combining anxiolytics with their existing medication causes a significant reduction in their blood pressure that may lead to fainting, falls and broken bones (particularly in those with osteoporosis – practically all elderly females to a certain extent).
Therefore three points must be borne in mind when prescribing for the elderly;
Addressing each of these factors will go at least some way toward minimising unwanted side effects in the elderly patient.
Short term use of benzodiazepines is generally a safe and effective treatment strategy used in the management of anxiety. However, long-term use (more than six months duration) can lead to the drug becoming a central part to the daily functioning of the patient. This is understandable when it is considered that these drugs can offer significant benefits in the relief of anxiety and anxiety-related disorders in the patient. Reluctance to stopping treatment and a fear of reverting back to the anxious state that the patient previously experienced are significant factors in affected individuals. Furthermore, long-term use of a drug leads to a phenomenon called “tolerance” whereby the patient requires an increased dose of drug to gain the same benefits seen at the beginning of their treatment. As the dose of benzodiazepine drug is increased so too is the likelihood that side-effects become more evident.
Benzodiazepine Withdrawal Symptoms
Sudden withdrawal of benzodiazepines in patients who have been treated with the drug on a daily basis for more than two to three weeks will cause withdrawal symptoms of varying degrees and intensities in those patients. Typical symptoms seen are largely grouped under the umbrella term “rebound anxiety” and include symptoms normally experienced in anxious individuals such as headaches, nausea, sweating, tremors, dizziness and sleep disturbances. In certain individuals episodes of acute anxiety (panic attacks) may occur whereby physical symptoms such as rapid heart rate (tachycardia), increased breathing rate (hyperventilation), chest pain, trembling and sweating are often experienced. In extreme circumstances these attacks may be so severe that they significantly restrict the daily activities of the sufferer in that they may remain housebound for fear of experiencing an attack once outside.
The onset of these symptoms following sudden withdrawal largely depends on the duration of action of the particular benzodiazepine used in the patient. Withdrawal symptoms may be experienced within a day of stopping treatment with a short acting benzodiazepine (e.g. triazolam) whereas there may be a delay of up to three weeks before symptoms are experienced following withdrawal of longer acting medicines (e.g. diazepam). Unfortunately, the duration of these withdrawal symptoms varies significantly from patient to patient and may be experienced for weeks or months following treatment withdrawal. In some instances, the withdrawal symptoms are so similar to those seen in the original anxious state prior to starting drug treatment that a new course of medication is prescribed in the mistaken belief that the underlying cause for the anxiety has not been resolved with the first course of drug treatment.
It is now considered best practice to gradually reduce the dose of benzodiazepine over a period of several months to a year or more. Current guidelines suggest reducing the daily dose of drug by 10–20% every fourteen days. Unfortunately, even with this gradual reduction, some withdrawal symptoms are likely to occur. In this instance it is best to maintain the current dose until the symptoms improve or are better tolerated before attempting further dose reductions. Alternatively, for patients who are experiencing particular difficulty in their medicine withdrawal another strategy currently used involves switching their current medication to an equivalent dose of diazepam, which should be taken once daily (preferably at bedtime).
Approximate equivalent doses to diazepam 5 mg are:
From here, the diazepam dose can be reduced in steps of approximately 2 mg every 14-21 days. Diazepam is used because it is a long acting benzodiazepine and therefore the withdrawal symptoms will not be seen as quickly or as sharply as those seen with shorter acting medicines. Moreover, because diazepam has longer lasting effects in the body it allows for a more controlled reduction in drug dosing and also gives the body more time to readjust itself back towards a benzodiazepine-free state.
Buspirone (Buspar) is occasionally used for the short-term treatment of anxiety. It is thought to act in the brain via a different mechanism to that shown by the benzodiazepines and does not appear to increase the actions of alcohol on respiratory depression. It is associated with a lower abuse and dependence potential, less sedation compared to benzodiazepines and sudden withdrawal does not give rise to rebound anxiety. However, treatment with buspirone is associated with a 7-14 day delay between starting treatment and providing improvement in symptoms, which gives it a slower onset of action compared to the benzodiazepines and therefore it is not useful when rapid relief from anxiety is required (i.e. in the treatment of panic attacks). In addition, buspirone does not alleviate the withdrawal symptoms seen following suddden stopping of benzodiazepine treatment. Typical side effects seen with buspirone treatment include sleep disturbances, heart palpitations, dizziness and headaches.
Escitalopram (Lexapro), paroxetine (Seroxat, Parox) and venlafaxine (Efexor, Ireven, Venex) can be used in the treatment of generalised anxiety disorder in adults under close supervision. Clomipramine (Anafranil) and moclobemide (Manerix) can be used in the treatment of several anxiety disorders (e.g. panic disorder, phobic states and post-traumatic stress disorder) but this option is generally reserved for patients who do not respond to benzodiazepine or buspirone treatment.
Barbiturates were once commonly used to treat anxiety but are now largely only of historical importance. Like the benzodiazepines, they carry out their anxiolytic actions via a reduction of nerve activity associated with anxiousness, hyperexcitability and agitation. However, these drugs are much more dangerous in use than benzodiazepines as they easily cause respiratory depression and death when used at high doses/overdose or when taken with alcohol. Their poor safety profile, coupled with their wide-ranging drug interactions, tolerance/dependency issues and rebound effects following sudden withdrawal means that they are now not recommended in the treatment of anxiety and anxiety-related disorders.
Meprobamate (Equagesic) was introduced in the mid 1950’s and was commonly used for its sedative properties that were believed to offer a more selective anxiolytic effect than existing treatment options at that time. It was subsequently discovered to have a similar drug profile to that seen in the barbiturates (i.e. high risk of drug dependence and risk of death from high doses) and has been shown to be less effective than the benzodiazepines. Current guidelines do not recommend treatment of anxiety with meprobamate.
Antipsychotic drugs (Neuroleptics)
Certain antipsychotic drugs used in low doses such as fluphenazine (Modecate) are occasionally used for short-term treatment of severe anxiety. Their use is largely reserved for psychologically disturbed patients with associated anxiety disorders.
Hydroxyzine (Ucerax, Aterax) and diphenhydramine (Benylin) offer sedative properties without physical or psychological dependence issues. In practice, their use is considered inappropriate and when they are used to treat anxiety (albeit rarely) they are used in conjunction with other drugs.
Beta-adrenoreceptor blocking drugs (Beta Blockers)
Beta blockers such as propranolol (Inderal) have a limited role to play in the treatment of anxiety. They are ineffective in treating the underlying psychological basis for the anxiety state experienced by the patient but can prove to be effective in treating the physical signs of anxiety by reducing heart palpitations and tremor in the hands. This, in turn, may allow the patient to feel better physically and therefore prevent the development of some behavioural and psychological signs associated with anxiety (e.g. fear).
Zolpidem (Stilnoct, Zolnod), zopiclone (Zimovane, Zopitan, Zorclone) and zaleplon (Sonata) are non-benzodiazepine drugs that work via a mechanism similar to that of the benzodiazepines. They are indicated for the short-term treatment of insomnia that is so debilitating that the patient experiences extreme distress. The effectiveness of these drugs is short lived (ranging from 2-6 weeks) and they are associated with dependency issues (as opposed to addiction as previously differentiated).
Pregabalin (Lyrica) is a medicine that copies the natural chemical in the brain that normally reduces the stimulation of nerves that are involved in anxiety. The way it works does not involve the same process that governs the effectiveness of the benzodiazepines and it appears to have no effect on "feel good" chemicals in the brain such as noradrenaline, serotonin (5-hydroxytryramine; 5-HT) or dopamine. Pregabalin has been shown to offer beneficial effects in reducing both the mental and physical symptoms of anxiety and is licensed for the treatment of generalised anxiety disorder (GAD). However, pregabalin shares the same problem with benzodiazepines in that sudden withdrawal tends to result in the appearance of withdrawal symptoms. As pregabalin appears to provide its anxiolytic effects via a mechanism that is different to that seen with the benzodiazepines, it offers patients an alternative treatment approach to their anxiety management when first line treatment (e.g.benzodiazepines) has failed . The most common side effects reported with pregablin treatment include dry mouth, headache, weight gain, diarrhoea and sleep disturbances, although these effects tend only to be seen with higher doses (>300 mg/ day).
Prof. Peter Weedle is a community pharmacist and adjunct Professor of Clinical Practice at the School of Pharmacy, University College Cork. Peter has a wide range of interests in the area of pharmacy but in particular, medicine use by the elderly, drug interactions, legal and ethical matters. He is co-author of two books: Pharmacy and Medicines Law in Ireland and Medicines: A guide for everybody. This series is based on Medicines: A guide for everybody which was originally published by Penguin, London. Peter can be contacted at: firstname.lastname@example.org
Dr. Mark Ledwidge is a pharmacist with a research and teaching interest in Cardiovascular Disease. In particular, his interests include medication adherence in chronic illness, telemedicine and cardiovascular therapeutics. He is Director of Heart Failure Research in St Vincent’s University Hospital and Adjunct Senior Lecturer in the School of Medicine in University College, Dublin.
Dr. Andrew Fisher is a community pharmacist in Cork City, with an extensive research background in neurological disorder and disease. His particular areas of interest include the pathophysiology and treatment of basal ganglia disorders and epilepsy. Andrew has a wide range of interests within the field of pharmacy including patient compliance, pharmacovigilance and therapeutic drug monitoring.
Mr. Nigel Moloney is a Superintendent Pharmacist in Cork city. Nigel comes from a UK Hospital Pharmacy background and his primary interests are in Acute Medicine, Psychiatry and Risk Management. Nigel has published articles in the scientific press on Risk Management Quantification and Communication between Primary and Secondary Care.
Dr. John McAninly is a community pharmacist in Mallow, Co. Cork who worked in hospital and community pharmacy in the UK, before moving to Ireland. As a former teacher he has a special interest in pharmacy education.
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