Prescribing drugs of dependence in general practice

Part B - Benzodiazepines - Chapter 3

Contraindications and precautions in special groups

Last revised: 06 Nov 2019

Overview

Benzodiazepines should not be prescribed, or prescribed with extreme caution, to:

  • women who are, or may be, pregnant
  • patients with active SUDs, including alcohol (unless it is a part of an alcohol withdrawal program)
  • patients with medical or mental health conditions that may be worsened by benzodiazepines (eg fibromyalgia, chronic fatigue syndrome, depression, bipolar disorder or impulse control disorders)
  • patients being treated with opioids for chronic pain or addiction
  • patients experiencing grief reactions, as benzodiazepines may suppress and prolong the grieving process.

Benzodiazepines are generally not recommended for use in children.

Benzodiazepines may cause aggression, anxiety, nervousness and disinhibition in children and adolescents. Routine use for anxiety disorders cannot be recommended.157

The use of benzodiazepines in the paediatric population is clinically limited.158 Control of acute febrile or epileptic seizures is the primary indication. Seizures commonly occur in the paediatric populations and while most self-terminate within 5 minutes, those lasting longer may warrant medication to control the seizure and avoid status epilepticus (and neurological compromise).159 Buccal or intranasal midazolam and buccal or rectal diazepam are effective for the treatment of acute seizures in children.160

Note that children may have access to benzodiazepines through their parents, their peers or potentially via the internet.

Benzodiazepines should be avoided during pregnancy and breastfeeding. Non-drug approaches for anxiety and insomnia are preferred.

Women who become pregnant and are already taking benzodiazepines should be tapered down to the lowest effective dose, or have it completely withdrawn. With good withdrawal management, there is no evidence that withdrawal is likely to cause problems with the pregnancy.38

As benzodiazepines are highly fat soluble, they rapidly cross the placenta. Benzodiazepines taken early in pregnancy have been linked to congenital abnormalities (eg oral clefts, pyloric stenosis and alimentary tract atresia).161 This association is considered controversial, and data published in the last 10 years do not indicate an absolute contradiction to benzodiazepines in the first trimester.162 However, avoiding benzodiazepines or tapering off (completely or to the lowest possible dose) is recommended.163

Benzodiazepines taken later in pregnancy (late third trimester), during labour or while breastfeeding are associated with risks to the fetus/neonate. They can cause neonatal drowsiness, respiratory depression, poor temperature regulation, poor feeding, hypotonicity (‘floppy baby syndrome’) and neonatal withdrawal syndrome.35,164

Neonates exposed in utero may benefit from breastfeeding to reduce neonatal withdrawal.165,166

Where a hypnotic is necessary, zolpidem has been suggested.163 However, two studies have reported an association between zolpidem and an increased risk of adverse pregnancy outcomes, including small-for-gestational age, low birth weight and preterm deliveries.35

Note that women misusing benzodiazepines during pregnancy may also be using other drugs including alcohol.

Patients over 60 years of age have the most significant risk of harm with benzodiazepine use (particularly if the patient has additional risk factors for cognitive or psychomotor adverse events) relating to falls, fractures and cognitive decline.50,167

Benzodiazepines are used by approximately 15% of people over 65 years of age in Australia.168 Use of benzodiazepines in this age group is often chronic, despite the combination of harms associated with long-term, physiological changes with ageing (eg hepatic metabolism impairment) and the potential for multiple coexisting pathologies and drug interactions.

Older patients are more sensitive to the CNS depressant effects of psychotropic medications including benzodiazepines. This may result in confusion, night wandering, amnesia, pseudo-dementia38 (refer to 1.5.1.1 Cognitive impairment ), ataxia, falls and fractures.

In older patients, all psychotropic medications have been associated with an increased risk of fractures. The risk increase is moderate and similar across all psychotropic medications. One meta-analysis demonstrated that the relative risk of fractures was 1.34 (95% CI=1.24–1.45) for benzodiazepines, 1.60 (95% CI=1.38–1.86) for antidepressants, 1.59 (95% CI=1.27–1.98) for antipsychotics and 1.38 (95% CI=1.15–1.66) for opioids.169

Older people presenting with anxiety symptoms should be treated initially with antidepressants and psychological therapies, rather than benzodiazepines.170

Sedative use for insomnia has shown statistically significant improvements in sleep, but the magnitude of effect is small and the benefits of these drugs may not justify the increased risk.167 Clinical judgement is required.

Zolpidem and other Z drugs have become preferred drugs to manage insomnia. They are widely used among older adults because of perceived improved safety profiles compared with traditional benzodiazepines. However, accumulating data in recent years in patients over 65 years of age suggest possible safety concerns of these medications (zolpidem specifically) including effects on balance and memory and increased fracture risk. Until better studies or pharmacovigilance data become available to guide patient selection for prescribing zolpidem and other Z drugs, judicious use of these hypnotic agents in older adults is warranted.171

Reduction in the use of benzodiazepines in the elderly is a worthwhile goal if this can be achieved without psychotropic substitution. Older patients require planned interventions including CBT and stepped-dose reduction to reduce long-term benzodiazepine prescription.

Patients living in residential aged care facilities

Prescribing for patients living in residential aged care facilities (RACFs) (and other residential facilities) carries all of the risks associated with benzodiazepine use in older patients and presents further special difficulties.

Accreditation of RACFs has resulted in a heightened awareness of the facility’s responsibilities for quality use of medicines.

Medication may occasionally be required to control anxiety, agitation or other disturbed behaviours. Staff should be knowledgeable in the appropriate management of challenging behaviours. Where staff have received education in geriatric care, and where the organisational culture is supportive, there is less use of benzodiazepines.170

In a study of sleep quality in patients using benzodiazepines in RACFs, patients who were long-term users slept more poorly than those who were non-users. The effects were worse in patients taking long-acting benzodiazepines.172 Although patients, doctors, nursing staff and families often fear the consequences of benzodiazepine withdrawal in older patients, there is no evidence that patients experience an ‘unmasking’ of depression or anxiety.173

Successful reduction in the rates of benzodiazepine use in RACF patients results in benefits (eg increased mobility and alertness, reduced incontinence and improved wellbeing).174 Discontinuation of benzodiazepines can often be achieved gradually in RACFs, providing patient, family and nursing staff are cooperative.175

Benzodiazepines have been associated with increased fracture risk in patients living in RACFs. However, a reduction in benzodiazepine use may not lead to a decrease in fracture risk if substitution medications are used.176 Reduction in benzodiazepine use for RACF patients is worthwhile if it can be achieved without psychotropic drug substitution.

Use of multiple psychoactive medications (including benzodiazepines) is common in people who have chronic non-malignant pain (CNMP). Where available, it is advisable that a specialist pain or addiction service becomes involved in the care of these patients.177

The relationship bewteen pain, mental illness, SUD and dependence, and the social environment are complex. A range of addictive drugs has been misused in the context of CNMP including alcohol, benzodiazepines, cannabis, opioids and stimulants. Estimates of dependence (on any drug including alcohol) among people with chronic pain varies. In patients on long-term opioids, prevalence of DSM-5 opioid-use disorder may be as high as 26%.178

Benzodiazepines have little place in the management of chronic musculoskeletal pain. There is sparse evidence that these are clinically effective as muscle relaxants. The decision to use benzodiazepines in the context of multiple sclerosis or muscle disorders should be taken on a case-by-case basis with specialist consultation.

There is a strong association between sleep disturbance and CNMP. Evidence suggests that pain and sleep exist in a complex relationship in which pain causes sleep disturbance and sleep disturbance intensifies pain. This association can impair a patient’s daily function and decrease quality of life.179 Assessment of a patient’s sleep disturbance involves review of the contributing impacts of lifestyle, comorbid anxiety or depression, and uncontrolled pain to focus management on an individualised basis.

Benzodiazepines present additional risk for someone being prescribed opioids in terms of overdose (fatal and non-fatal) and psychomotor impairment. Driving presents a particular risk.

CBT can be useful in addressing emergent anxiety symptoms. Simple reassurance and attention to sleep hygiene can be effective with managing the emergent sleep disturbance. 

For the purposes of this guide, comorbidity will refer to situations where people have problems related both to their use of substances (from hazardous through to harmful use and/or dependence) and to their mental health (from problematic symptoms through to highly prevalent conditions such as depression and anxiety, and to the low-prevalence disorders such as psychosis).177

While it is common to refer to a patient’s psychiatric disorder or SUD as primary or secondary, this may have limited clinical use. It is important to establish whether substance use may be contributing to the patient’s psychiatric problems.177

Symptoms of psychiatric disorders (eg depression, anxiety and psychosis) in patients misusing drugs and/or alcohol are the rule rather than the exception. In addition, these psychiatric disorders increase the risk of harmful substance use and patients may be physically unwell. These patients are often the most challenging to engage and treat, and their prognosis is frequently poor.177

The number of placebo-controlled trials is small, and there remains little evidence to guide treatment.177 Available evidence suggests that a substantial proportion of patients with a comorbid SUD mental illness who are treated with benzodiazepines will develop some form of dependence. Therefore, benzodiazepines should largely be avoided, except in the context of withdrawal.180

Patients with personality disorders have a higher risk of dependence and dose escalation, hence benzodiazepines should be avoided in this group.

Patients who have problematic drug use belong to a complex group at high risk of adverse events. A common drug combination that should be noted is alcohol and benzodiazepines.180 When benzodiazepines are combined with other CNS depressants (eg alcohol, opioids), patients are at risk of respiratory depression, heavy sedation, coma and death. It has been reported that the use of antidepressant drugs in combination with benzodiazepines may also increase the risk of overdose, especially in the case of older TCAs.181 Alcohol and benzodiazepines can produce cross tolerance, and regular use of both can make withdrawal more severe and/or protracted.180

Apart from the risk of overdose, harms associated with polydrug use (particularly among people who inject drugs) include a higher rate of infectious and metabolic complications, as well as psychiatric, social and forensic consequences, with an increasing cost to society.182,183 People who are participating in medication-assisted opioid dependence treatment, and who take benzodiazepines regularly or intermittently, tend to do very poorly, with a higher risk of adverse outcomes.21

There is little evidence to guide practitioners in the management of this often difficult-to-treat population. However, when treating polydrug users, it is recommended not to initiate prescription of benzodiazepines. For polydrug users already taking them, it is recommended to reduce and cease prescription of benzodiazepines in a supervised manner.153

Therapeutic monitoring and prescribing should only occur if GPs have extensive experience in addiction medicine, or in conjunction with specialist supervision. When working with known polydrug users, it is essential to collaborate with local drug and alcohol services, and to provide clear guidelines on the accepted harm-minimisation strategies. Clear boundaries are crucial.

Maintenance benzodiazepine prescribing in illicit drug users cannot be recommended on the basis of existing evidence. Although it may reduce illicit benzodiazepine use in some patients,153 it may not be in the best interests of the patient or the wider community. The very rare exception would be under explicit agreement concerning specified short-term indications (such as outpatient alcohol withdrawal) as advised by a drug and addiction medicine specialist with daily, or at most weekly, dosing at a nominated pharmacy and monitoring with urinary drug test. Drug screens may be useful to monitor other benzodiazepines and drug use, especially in this population. 

Summarising the extensive literature on benzodiazepines and driving, the risk of accident increases proportionally to dose. However, there is no dose without increased risk – including stable, longer term dosing. Risk is highest at initiation, with long-acting benzodiazepines and when benzodiazepines are taken with other sedatives, especially alcohol.

Benzodiazepines have especially been shown to impair vision, attention, information processing, memory, motor coordination and combined-skill tasks. All drivers should be advised of increased crash risk when taking benzodiazepines. Patients who experience any degree of sedation should be cautioned not to drive.

According to Austroads, a person is not fit to hold an unconditional licence if they have an alcohol disorder or other SUD (eg substance dependence, heavy frequent alcohol or other substance use) that is likely to impair safe driving.184

The state or territory driver licensing authority may consider a conditional licence. This is subject to periodic review, taking into account the nature of the driving task and information provided by the treating doctor as to whether the following criteria are met:184

  • the person is involved in a treatment program and has been in remission* for at least 1 month
  • there is an absence of cognitive impairments relevant to driving
  • there is absence of ‘end-organ effects’ that impact on driving.

* Remission is attained when there is abstinence from the use of impairing substance(s) or where substance use has reduced in frequency to the point where it is unlikely to cause impairment. Remission may be confirmed by biological monitoring for the presence of drugs.

Some patients with SUD will continue to drive after being warned not to do so. If GPs are aware that a patient continues to drive in a dangerous way, they should:

  • more strongly recommend the patient stops
  • advise the patient that the GP has an obligation to report behaviours that are dangerous to the patient and others
  • consider reporting dangerous behaviour to state or territory licensing authorities.

This is a difficult situation as it will damage the doctor–patient relationship. However, in some cases the risk of damaging the relationship is outweighed by the risk of the patient (and others) being hurt or killed. If in doubt, contact your medical indemnity provider.

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