People with anxiety can have a variety of symptoms (National Institute of health and Care Excellence (NICE), 2011). These can be divided into two main groups: psychological and physical. Psychological symptoms include fear, irritability, poor concentration, restlessness, sensitivity to noise, disturbed sleep, such as waking during the night or unpleasant dreams, and poor memory, usually because of poor communication. Physical symptoms are mainly the result of increased muscle tension, such as problems with passing wind, loose motions, blurred vision, dizziness or loss of libido; breathing problems, such as tight chest or difficulty breathing; heart changes, such as palpitations, heart pain or missed beats; tension resulting in headache or tremor; and panic attacks leading to sudden episodes of extreme anxiety or apprehension. This is because of overactivity of many parts of the brain, usually caused by some external pressure or reason. The symptoms may be caused by this overactivity. The result is that many systems in the body become overactive, including muscle control, thinking and worrying (Tovote et al, 2015).
The action of anxiolytic medications
Although there are over 80 known different transmitters in the brain, each nerve ending only has one type. These neurotransmitters tend to be grouped together and each seems to have a specific role. In many mental health problems, it is known that some of these transmitters get out of balance, for example if someone has an insufficient amount of a particular transmitter. This can then cause symptoms (Tovote et al, 2015; Blows, 2016).
Epinephrine (E) and norepinephrine (NE) are very similar neurotransmitters and hormones, and both play a role in the body's natural fight- or-flight response to stress. NE, previously called noradrenaline (NA), controls the heart and blood pressure in the body. In the brain, it controls sleep, wakefulness, arousal, mood, emotion and wakefulness/sleep-wake behaviour. Too much NE and someone may feel anxious and jittery. Too little, and they may feel depressed, sedated, dizzy, or have low blood pressure. However, gamma-aminobutyric acid (GABA) is the key transmitter in relation to anxiety, as it is the brain's natural calming agent. It acts as a brake in the brain and keeps its activity in check. When someone is overanxious, it may be that not enough GABA is being released in the brain to help calm it down. A benzodiazepine drug binds to the GABA and acts as an agonist for the inhibitory neurotransmitter to GABA. It that sense it mitigates against the sudden reduction in available GABA, which can trigger panic, restlessness, insomnia, and potentially convulsions or seizures. Drugs, such as benzodiazepines, zopiclone and zolpidem, increase the length of action of GABA. This helps calm the brain and reduces the number of worrying messages being passed. These drugs block GABA at its receptors, so the receptors are activated for longer, and the brain's natural calming messages are passed more strongly (LeDoux, 2000 and 2015; Blows, 2016).
It is important to remember that anxiolytic medication mainly works by strengthening the brain's natural calming agents, but they should not be considered just as tranquillisers, even though they may help someone feel calmer, as they have a much more specific way of working than simple sedation (LeDoux, 2015; Blows, 2016).
Why do people experience side effects?
Anxiolytic medication, bind to gamma-aminobutyric acid (GABA) receptors. GABA is widespread throughout the brain, and so a few adverse side effects are the result of this more generalised sedation, such as confusion. These can be minimised by adjusting the dose. Some benzodiazepines are also used for helping treat epilepsy, as calming drugs before operations, and as muscle relaxants (LeDoux, 2015; Blows, 2016).
Comorbidity
Depressive and anxiety disorders often occur together in patients presenting in the primary care setting. The clinical implications of depression and anxiety comorbidity include increased risk of suicide, psychiatric hospitalisation, disability, decreased compliance/concordance with treatment and increased use of medical and mental health services (Gask et al, 2018). This underscores the need for accurate assessment, as when anxiety and depression present together, they can be harder to treat, as symptoms tend to be more persistent and intense when occurring together (Moscati et al, 2015).
Case study
Sonia, a 37-year-old mortgage broker, has an appointment at her local GP surgery, to see Derek (an advanced nurse practitioner) and arrives with Nathan, her 7-year-old son who has been diagnosed with type 1 diabetes. Sonia lives with her husband in her own three-bedroom house. The woman appears tremulous and becomes tearful while talking about her son's condition. She says that she has been very worried about her son and has not been sleeping very well for the past 5–6 months, though she has been eating reasonably well. She admits that she has felt more tired and demotivated than usual.
Sonia is still going to work but has found it hard to concentrate on her duties as well as before. As a result of this, she constantly worries that she might make a serious mistake at work. She says that she has managed to cope with the support of her husband. However, he also works full-time and there have been days when she has found it difficult to get out of bed. Currently, Sonia feels that she is going through a bad patch and is hopeful that things will get better soon. She does not see a problem with her self-esteem and finds her work enjoyable but exhausting.
When asked, Sonia completely dismisses any idea of self-harm or suicide and says she would never even think about it. She apologises profusely to Derek for becoming emotional and asserts that she is normally very calm and composed but has become overwhelmed by the stress of her son's illness.
In relation to herself, she denies history of any mood episodes, either depression or hypomania. She drinks alcohol socially, never exceeding 8 units per week. She does not smoke or use any illicit drugs. She describes herself as ‘driven’ and ‘ambitious’. She is a keen runner and runs 14–18 miles a week.
She agrees to a brief physical examination. She has tachycardia of 108/min, her pulse is regular, and her blood pressure is 138/88 mmHg. Her palms appear cold and sweaty, but there is no other significant physical finding.
Sonia is pleasant, co-operative and Derek is able to quickly establish a good rapport with her. She is clutching her son protectively but maintains good eye-to-eye contact throughout the interview. Her speech is a normal rate and volume. Her mood is anxious and low. She does not have any psychotic symptoms. Sonia has a good insight into her symptoms.
She does not have any ideas of self-harm, but Sonia reveals that two years ago, she ‘borrowed’ some anxiety and sleeping pills from her mother who kept a stockpile of drugs for emergencies. Sonia remembers the names Ativan and Zolpidem, from the drug boxes, but cannot recall the doses, and how regularly she took the pills.
Sonia asks if she can be prescribed a benzodiazepine drug and some sleeping tablets. She says her husband thinks this would be a good idea.
Discussion
There are many possible explanations as to why women such as Sonia develop anxiety disorders more frequently than men (Carver and Connor-Smith, 2010). Women are more likely to communicate their feelings and it is culturally more acceptable for women to feel anxiety. This makes it easier for them to seek help for the symptoms they might be experiencing. It could also be because men are more likely to self-medicate with substances such as alcohol in an effort to mask anxiety symptoms (Freeman and Freeman, 2013)
Applying the Global Mental Health Assessment Tool (Sharma et al, 2004), Sonia is presenting with a mixture of anxiety and depression and depressive symptoms occurring in the context of her son's illness. She is feeling stressed and increasingly reliant on her husband for support.
Medical/clinical diagnostic possibilities include:
- Mixed anxiety and depression: this is a common presentation in primary care, characterised by a mix of anxiety and depression symptoms without clear prominence of any one type and the presence of one or more physical symptoms, typically tremor, palpitations, and lethargy present for more than 6 months (NICE, 2009; 2019)
- Depression: Sonia does have the core symptoms, namely low/anxious mood, reduced energy and other symptoms such as reduced concentration and poor sleep lasting more than two weeks, suggesting a mild depressive episode
- Bipolar disorder: needs to be excluded by asking about hypomanic/manic episodes (Paris, 2012). Detailed history and mental state examination will be needed to establish the diagnosis and appropriate investigations to rule out any medical disorders will also be required.
NICE guidelines (2009) suggest that when depressive and anxious symptoms coexist, the first priority should usually be to treat the depression. Psychological treatment for depression often reduces anxiety, and many antidepressants also have sedative or anxiolytic effects. The guidelines advocate a stepped care approach (Table 1), which is a system of delivering and monitoring treatments so that the most effective, but least resource-intensive treatment is delivered first. Many patients only have a partial response, while some symptoms are improved, others may persist (especially insomnia, fatigue, and problems concentrating). Consequently, a single daily, morning dose might be preferable to a night-time prescription (Taylor et al, 2018). NICE support the use of cognitive behaviour therapy (CBT), but not other psychodynamic psychotherapies (NICE, 2009).
Table 1. A stepped care model (NICE, 2019)
| Step 1: Mild or suspected depression |
|
| Step 2: Mild to moderate depression |
|
| Step 3: No response or moderate to severe depression |
|
| Step 4: Severe and complex depression, risk to life, severe self-neglect |
|
The advice for mild depression does not help in uncertain decisions, when a particular case may or may not benefit from medication, but this reflects the evidence available (Beck and Alford, 2009). These milder presentations may be subthreshold disorders where health professionals allow the ‘medicalisation of unhappiness’ (Burns, 2013) to legitimise engagement, when all that people may really need in these times of growing social isolation is some or more support (Carver and Connor-Smith, 2010).
Sonia is ambitious, energetic, and committed to supporting her family, and succeeding in her career, but, in the short-term at least, she might benefit from some self-compassion. Kindness and concern for self is a recognised element of healing and mental health recovery (Lazarus, 2006). Therefore, Sonia might be encouraged to attend a local peer-support group, and/or relaxation classes. Social interventions like this should be viewed as ‘protective’ factors that potentially might be helpful in mitigating risk and relieving some of the fear, distress and inertia associated with many presentations of anxiety and depression (Aspinwall and Taylor, 1997). It is possible that Sonia's symptoms might dissipate, once she is assured that her son's condition is manageable. This might require some education about type 1 diabetes, but potentially, it might benefit both Sonia and her child.
A stepped care model approach (NICE, 2019) would be well suited to Sonia's situation, as she has mild mood symptoms and, as per the stepped care model, these are best treated initially in a primary care setting (Tolin et al, 2011). Watchful waiting, ie a follow-up appointment within two weeks with reassurance, is sensible, as symptoms may resolve spontaneously. If Sonia's symptoms persist on subsequent visits, brief psychological interventions may be provided by either a primary care mental health practitioner or a practice counsellor.
Motivational interviewing might also help Sonia change her behaviour (Miller and Rollnick, 2013). Computerised CBT can also be helpful (Arnberg et al, 2014) as well as healthy lifestyle advice about exercise and sleep hygiene. Guided self-help using manuals or self-help books are other options available in primary care (Davidson et al, 2016).
If Sonia's symptoms worsen, treatment can be commenced, taking into account her preferences. Psychological treatments, for example CBT or antidepressant/anxiolytic medication, such as SSRIs, can be effectively administered in primary care (Hofmann and Smits, 2008; Hofmann, 2018). Treatment-resistive cases, psychotic symptoms, atypical symptoms or recurrent episodes should trigger a referral to specialist services. At any stage, if risk profiles change rapidly and risk assessment indicates a risk to self, others or self-neglect, a referral can be made to the crisis team for consideration of inpatient treatment (NICE, 2019).
Given Sonia's revelation about the lorazepam, it is necessary to gently remind her of the importance of only taking medication that has been prescribed, and particularly the risks associated with long-term, unsupervised use of benzodiazepines, such as psychological addiction, dependence and withdrawal (Taylor et al, 2018).
Her self-medication with unprescribed drugs could be interpreted as a form of safety behaviour. In the context of clinical anxiety, safety behaviours are actions performed to prevent, escape, or minimise feared catastrophes and/or associated distress (Rachman et al, 2008). Developing ‘positive’ safety behaviours is something that needs to be discussed with Sonia as part of her treatment/care plan, as these can reduce risks of relapse (Goetz et al, 2016), which for Sonia might be the temptation to take unprescribed medication at some point in the future.
Cases such as this one, where there is comorbidity, are associated with worse health outcomes (Miller et al, 2011). Therefore, Derek should speak to a GP urgently, to discuss an appropriate treatment plan for Sonia, and to confirm the diagnosis. Effective interdisciplinary team working is necessary to manage complex cases safely, and maximise wellbeing for service users and their families (Bailey, 2012). In the circumstances, Derek is right to be cautious about prescribing a benzodiazepine drug.
How should benzodiazepines be used?
Benzodiazepines are used in the treatment and management of pathological and chronic anxiety, agitation and tension (NICE, 2019). They act rapidly and are very useful first aid measures. However, they will only form a small part of overall management of such conditions and may help the person until other anxiety management techniques, such as psychotherapy, can be carried out. NICE recommends that ‘benzodiazepines should not be used to treat panic disorders’ and should only be used ‘with care’ in post-traumatic stress disorder’ (Taylor et al, 2018).
Acute anxiety should not be assumed to be present for more than a month and benzodiazepines should not be lightly prescribed for longer than this, as benzodiazepines are known to enhance GABA transmission and also inhibit microsomal enzymes (Barlow, 2002; Blows, 2016). Some patients, especially those with chronic anxiety, have a tendency to self-treat/medicate and benzodiazepines should be avoided in patients with a history of drug or alcohol abuse. When benzodiazepines are used, those with a slower onset of action, such as GABA partial-agonist Clonazepam, may cause less dependence than Diazepam or Lorazepam (Taylor et al, 2018). Concern has been expressed that some anxiety drugs, such as alprazolam (Xanax) and diazepam (Valium), have been used in many fatal/non-fatal drug overdoses (Cutcliffe and Santos, 2012).
Side effects of benzodiazepines
Headaches, confusion, ataxia, dysarthria, blurred vision, gastrointestinal disturbances, jaundice, amnesia and paradoxical excitement are all possible adverse side effects of benzodiazepines, although drowsiness is the only common side effect (Taylor et al, 2018). Respiratory depression is rare with normal dose oral therapy but may be an added complication with sleep apnoea. It must be looked out for when the intravenous (IV) route is used, especially with midazolam. IV injection can be painful and lead to thrombophlebitis because of the low water solubility of benzodiazepines (Taylor et al, 2018). Diazepam is available in an emulsion form (Diazemuls) to overcome this problem. Benzodiazepines are poorly absorbed from the intramuscular route and the rectal route (such as with diazepam rectal tubules) is an appropriate alternative (Joint Formulary Comimitte, 2020).
Comparative doses
The dose(s) of each drug is approximately equivalent to others (Table 2). Inter-patient variability and different half-lives (a particular problem with the benzodiazepines) make exact calculations difficult.
Table 2. Benzodiazepine comparative doses. Adapted from BNF (2020)
| Benzodiazepine | Dose (mg) |
|---|---|
| Diazepam |
|
| Chlordiazepoxide |
|
| Clobazam |
|
| Flunitrazepam |
|
| Flurazepam |
|
| Loprazolam |
|
| Lorazepam |
|
| Lormetazepam |
|
| Oxazepam |
|
| Nitrazepam |
|
| Temazepam |
|
Benzodiazepine dependence
Dependence is characterised by a strong need to continue taking a drug, a tendency to increase the dose, a psychological dependence on the effects of the drug and a characteristic abstinence syndrome. All of these have been reported to occur with the benzodiazepines (Bandelow et al, 2015). It has been pointed out that withdrawal symptoms are, in the milder states, very similar to acute and chronic anxiety and may in fact be a reappearance of the original symptoms.
Table 3. Dependency/symptoms of withdrawal (from Taylor et al, 2018)
| Dependency | Symptoms |
|---|---|
| Primary | |
| Psychological |
|
| Physical |
|
| Mental |
|
| Secondary | |
| Moderate |
|
| Severe |
|
Management of benzodiazepine withdrawal
Controlled withdrawal may take a long time, with only small reductions in dosage every 7 days or so being tolerated. All symptoms tend to be worse with the shorter-acting or high potency drugs (particularly lorazepam) (Taylor et al, 2018). It is usual to transfer a patient onto a longer-acting drug such as Diazepam, and reduce the dose of that drug at a rate the patient finds acceptable (Taylor et al, 2018; NICE, 2019). Many people find difficulty in completing these withdrawal programmes and long-term support is essential. Withdrawal syndrome has been reported to last for up to a year or longer (Rogers et al, 2007).
Hypnotic drugs for sleep problems
Hypnotic drugs for sleep problems may be useful in the short term, but it is quite difficult to assess the longer-term effectiveness of these drugs, as sleep tends to vary for reasons other than drug treatment, for example external pressures (Klink et al, 1992). If it is decided that someone requires a hypnotic drug for a long time, rather than just when they need it, this should be discussed by the clinical team (NICE, 2004). Crucially, some people do get some withdrawal effects if they stop hypnotics suddenly, for example rebound insomnia (Taylor et al, 2018). When the time comes to stop, it is best to reduce the dose slowly.
Other anxiolytic medication
Buspirone is licensed for the short-term treatment of anxiety. It does not act on benzodiazepine receptors, but is thought to act at specific serotonin (5-HT) receptors (Taylor et al, 2018). Response to treatment is slow, taking 4–6 weeks to reach maximum effect, making it unsuitable for as-required (or pro re nata (PRN)) use. However, the dependence and abuse liability of buspirone is low. Beta-blockers (such as propranolol) do not affect psychological symptoms, such as worry, tension and fear, but they can reduce the physical symptoms of anxiety such as heart palpitations and hand tremor (Joint Formulary Comimitte, 2020). Pregabalin is an anti-convulsant used for the treatment of certain types of epilepsy. It is also licensed for the treatment of generalised anxiety disorder (Joint Formulary Comimitte, 2020).
Box 1.Risk factors for poor withdrawal
- Previous severe withdrawal (including a history of seizures) or post-withdrawal reaction
- Lack of adequate social support
- Elderly or infirm
- History of inappropriate use of alcohol or other drugs of dependence
- Concomitant severe medical biological or psychiatric illness (including personality problems)
Taylor et al, 2018
Conclusion
We all experience symptoms of anxiety during our lifetime, and it is a ‘normal’ physical and psychological response to stress, mediated through adrenaline (epinephrine), noradrenalin (norepinephrine), and GABA (LeDoux et al, 2001; LeDoux, 2015). Anxiolytic medication blocks GABA onto its receptors. GABA is widespread throughout the brain, and so side effects are generally the result of more generalised sedation, for example, a hangover effect the next morning, which is possible with drugs such as nitrazepam.
Anxiety disorders are extreme or pervasive versions of the fight-or-flight response and include a spectrum of different conditions. In the UK, approximately 15–20% of the population experience an anxiety disorder at some stage of their life (Bentall, 2009). However, these can be difficult to diagnose and treat accurately, as they are often comorbid with each other or with other mental illnesses. They also frequently present as physical illnesses, such as heart or gastrointestinal conditions (Barlow, 2002). Depression is graded by severity as mild, moderate, or severe and treatment options are recommended in line with this. Guidelines recommend a stepped care model, where patients are treated according to the severity of the depression and moved up a step if they are unresponsive to treatment or their symptoms worsen (NICE, 2019).
Consequently, not all patients with depression should be given medication. Antidepressants are usually indicated for moderate and severe depressive illnesses, but many mild depressive episodes respond well to psychological and social treatments alone (NICE, 2019).
Key opportunities for Integrated Care Systems and mental health have been identified as preventing ill health, linking physical and mental health and improving mental health services (Centre for Mental Health, 2020). Without changes to prescribing practice, it is difficult to see how these ambitions, can be met. This in term requires effective multidisciplinary and interprofessional working, and person-centred care.
Prescribing medication for anxiety is fraught with difficulty, and prescribers should endeavour to keep an open mind, in relation to useful alternatives or adjuncts to drug therapy (Barker, 2011). It is vital to fully explore the various treatment options, listening to the patient/client, acknowledging their preferences, and responding sensitively to any concerns they might have about drug side effects (Moscarello and Hartley, 2017). When it comes to medicating anxiety, one size does not fit all.
Key Points
- The symptoms of anxiety can be reduced by increasing the strength of the brains natural calming messages
- Anxiolytic medication helps by increasing the strength of the brains natural calming messages
- They are not ‘just tranquilisers’ although they may help someone feel calmer
- They do not directly alter personality
- Anxiolytics are not necessarily addictive, but it is best to stop them slowly if taken for more than about a month.
- They do ‘not’ appear to lose their anxiolytic effect if someone stops taking them.
CPD reflective questions
- What risks are associated with long-term use of benzodiazepine drugs?
- Reflect on the NICE, stepped-care model for mental health. How might you utilise the framework, to inform your own prescribing practice?
- Consider alternatives to drug therapy in relation to anxiety. What are their strengths and limitations?