Prescribing drugs of dependence in general practice

Part B - Benzodiazepines - Chapter 1

Introduction

Last revised: 06 Nov 2019

Summary

The arrival of benzodiazepines into clinical practice in the 1960s was met with enthusiasm.

It allowed doctors to offer patients a class of medication with a range of properties (eg sedative/hypnotic, anxiolytic, anticonvulsant, muscle relaxation) at a time when there were few effective therapeutic alternatives. Benzodiazepines were effective and appeared safe in comparison to barbiturates, chloral hydrate and other drugs, which were problematic due to toxicity and overdose.1

Due to the seeming paucity of side effects, rapid onset of effect and a pressing mental health need, benzodiazepines were quickly used and prescribed short- and long-term for anxiety, depression, insomnia, mental illness and neuromuscular conditions. By the 1970s, they were the most commonly prescribed drugs in the world.2 In 1978, more than 2.3 billion doses of diazepam were sold in the US alone.3

In the 1980s, evidence of the addictive nature of benzodiazepines grew and it became generally accepted that benzodiazepines brought their own problems. In 1988, the Committee on Safety of Medicines (UK) published the first guideline for benzodiazepine use and recommended limiting the length of treatment to 2–4 weeks.4 Since then, many international guidelines have advocated for the reduction in prescribing benzodiazepines, particularly short-acting benzodiazepines for long-term disorders such as anxiety.

However, there has been – and still is – a wide divergence between recommendations and clinical practice.

In Australia, nearly 7 million benzodiazepine prescriptions are currently recorded through the Pharmaceutical Benefits Scheme (PBS), Repatriation PBS and private scripts each year.5 Benzodiazepines have remained a major anxiolytic therapy, and given the trend towards larger quantity scripts, not just for short-term use.5

There is growing apprehension in Australia regarding the harms associated with the sanctioned and unsanctioned use of benzodiazepines.6 The misuse of alprazolam is particularly problematic. It appears to be disproportionately associated with misuse, fatal and non-fatal overdoses, paradoxical excitation, and withdrawal and rage responses, as well as traffic accidents and crime-related harms.7

The conditions where benzodiazepines are most commonly prescribed (ie anxiety and insomnia) remain sources of debate in medical circles. General practitioners (GPs) must consider multiple factors when prescribing benzodiazepines, including potential prescription abuse. Good clinical governance and an evidence-based approach remain key to safe and appropriate prescribing (refer to RACGP’s Prescribing drugs of dependence in general practice, Part A – Clinical governance framework).

This guide aims to provide assistance to GPs in the appropriate prescribing of benzodiazepines in the context of general practice.

It is designed to discourage inappropriate use and reduce harms by providing GPs with:

  • evidence of the advantages and disadvantages associated with the use of benzodiazepines
  • support for appropriate prescribing of benzodiazepines within regulatory frameworks
  • support for safer prescribing within their practices
  • alternatives to benzodiazepines, including non-drug options
  • tools for managing patients who are prescribed benzodiazepines such as objective goals and time limited prescribing
  • tools for recognising and managing higher risk situations.

Implementing principles from this guide should reduce the risk that GPs will be involved in an adverse event associated with prescribing benzodiazepines.

This guide is a reference to assist the management of benzodiazepine prescribing. It is part of a reference series on drugs of dependence. It is not a set of mandatory rules. Recommendations should be considered and implemented as required, and where appropriate to the individual practice and patient.

The appendices contain examples of some practice policies. These examples are not individually approved or endorsed by the RACGP Council, or by the RACGP Standards for general practices (4th edition) (the Standards). They are based on policies and practices from national and international sources. If practices wish to adopt any of these policies, they should be modified for relevance and applicability to the local context. 

Drugs of dependence have important therapeutic uses and are highly beneficial to many individuals. The clinically appropriate supply of these medicines needs to be maintained.8

This guide is a resource to assist with the appropriate and accountable prescribing of benzodiazepines to prevent and reduce harms to patients, and to prevent medico-legal issues for GPs.

GPs need to be aware of the broad issues around benzodiazepine use in society, as well as specific problems at a patient level, and how to address these issues with practice-based interventions.

Issues surrounding benzodiazepines

Variations in prescribing

Benzodiazepine prescribing rates vary between clinicians and practices. GPs vary in the extent to which they are willing to prescribe benzodiazepines. Some consider benzodiazepines to be extremely useful drugs for multiple situations, while others feel they have no place in general practice. Richard Balon wrote, ‘… benzodiazepines have been hesitantly lauded and frequently enthusiastically vilified ... ’9

The range of approaches to prescribing benzodiazepines may be explained by the variation in attitudes to the drugs, the changing context of prescribing, differing perceptions of the role and responsibility of the GP (and the personal responsibility of the patient), issues around alternative treatment options, perceptions of patient expectations, non-clinical considerations (eg race, gender) and the doctor–patient relationship.8

Questions about over prescribing

Comparing the prevalence of conditions for which benzodiazepines are indicated and the number of prescriptions dispensed, the evidence suggests that they may be over-prescribed and/or prescribed outside published guidelines.10

In 1991, there were an estimated 9.2 million benzodiazepine prescriptions dispensed from Australian retail pharmacies – enough to provide a daily dose for 3% of the adult population.Since then there has been a modest declining trend in prescription numbers, although there are still approximately 7 million prescriptions for benzodiazepines written each year. Nearly 5 million prescriptions are subsidised through the PBS, and the rest are private or under co-payment prescriptions.11 Since 2000, there has been a shift away from the PBS to private scripts.5

The modest decline can be partly explained by the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). The use of SSRIs doubled between 2000–11, and have become the primary pharmacological treatments for anxiety disorders.5

Figure 1A.  Defined daily dose (DDD)/1000 people/day

Figure 1A.

Defined daily dose (DDD)/1000 people/day

Figure 1B. Number of prescriptions

Figure 1B.

Number of prescriptions

Reproduced with permission from Islam MM, Conigrave KM, Day CA, Nguyen Y, Haber PS. Twenty-year trends in benzodiazepine dispensing in the Australian population. Intern Med J 2013;44:57–64.​

Despite a decrease in the prevalence of benzodiazepine prescriptions overall, diazepam and alprazolam prescribing increased.5

Figure 2B.  Number of prescriptions.

Figure 2B.

Number of prescriptions.

Reproduced with permission by Islam MM, Conigrave KM, Day CA, Nguyen Y, Haber PS. Twenty-year trends in benzodiazepine dispensing in the Australian population. Intern Med J 2013;55:57–64.​

Questions about safety of prescribing

Coronial data reported in the Australian media have raised public concern about the safety of prescription medications. Based on Victorian drug-related death data,12 prescription drugs are associated with 77% of all drug-related deaths.

Approximately half (48.8%) of all drug-related deaths are associated with benzodiazepines, which were identified as causal or contributory.

The number of deaths associated with benzodiazepines as a single drug is uncommon, and less than that from alcohol.

The most serious adverse events with benzodiazepines occur in the context of polydrug use (the use of more than one psychoactive substance in combination). The Coroner’s Court of Victoria’s figures suggest benzodiazepines, when used in conjunction with prescription or illicit opioids, are associated with a significant number of drug-related deaths.12 Similar findings occur when used in conjunction with antidepressants and antipsychotic drugs.

In many of the benzodiazepine-related deaths (57%), there was a positive history of substance abuse.12

State coroners have called on the RACGP to address benzodiazepine prescribing by GPs following these benzodiazepine-related deaths.

Regulatory bodies are also reviewing benzodiazepines and how they are prescribed. As of February 2014, alprazolam has been rescheduled by the Therapeutic Goods Administration (TGA) to a Schedule 8 (S8) drug, due to concerns about misuse and harms. This followed a dramatic increase in the prescriptions for alprazolam (especially private prescriptions) – rising from 4.1% of the population in 1998 to 27.9% in 2010 – and a trend towards higher dose formulations.13–15

Table 1.Drug related deaths in Victoria 2010

Table 1.

Drug related deaths in Victoria 201012

Increasing awareness of problematic use, including misuse

Problematic use has been identified in men and women of all ages. According to the National Drug Strategy Household Survey, in 2010:16

  • tranquillisers/sleeping pills (including benzodiazepines) were used for non-medical purposes by 3.2% of the Australian population aged 14 years and older at some stage in their lifetime
  • benzodiazepines were used for non-medical purposes by 1.4% of Australians in the 12 months before the survey
  • non-medical use of benzodiazepines is highest in people aged 20–29 (2.9%).

Awareness of diversion is relatively high, with benzodiazepines acknowledged as being among the most commonly diverted prescription medications (along with opioids) for illicit use.17 However, unintentional misuse is less known. Australia is likely to have a large, but relatively hidden, population who unintentionally misuse benzodiazepines and who have developed an iatrogenic dependence.18 Patients may also intentionally take medications outside of recommended use (eg larger doses) for what they consider to be a legitimate medical purpose (eg chronic insomnia).

Deliberate misuse of benzodiazepines for non-medical purposes occurs for a variety of reasons. People use benzodiazepines to:6,7

  • enjoy the effects (especially taking large intermittent doses in a binge pattern)
  • enhance an opiate effect
  • help come down from stimulants
  • combat opiate withdrawal symptoms
  • substitute for their drug of choice.

The benzodiazepine, flunitrazepam, has been used to facilitate sexual assault.

The true prevalence of benzodiazepine misuse is unknown. However, the harms associated with non-medical prescription drug use, notably dependence and overdose, are well documented.17

The factors involved

Source of benzodiazepine misuse

In contrast to other drugs used for non-medical reasons, medical practitioners are the main source for benzodiazepine misuse.19

Individuals may obtain prescription medicines for non-medical purpose through a variety of means including:

  • multiple doctors (doctor shopping or prescription shopping)
  • drug theft (including from pharmacies)
  • forgery of prescriptions
  • inappropriate prescribing
  • illicit market purchases
  • procuring medicines from family, friends or acquaintances20
  • bartering for sex or other services
  • the internet.

In a survey of recent users of tranquilisers and sleeping pills for non-medical purposes, 71% thought these drugs were easy to obtain.16 Patients are often highly skilled at obtaining prescriptions. They may present with a range of plausible and compelling reasons for why they should receive benzodiazepines. The most common is that they are benzodiazepine dependent and at risk of seizures if not prescribed the drug.21 Patients often describe medical reasons for needing to take the medicine (eg epilepsy and anxiety).

Benzodiazepines are often combined with other drugs

Benzodiazepines are often used in combination with other drugs, including alcohol (polydrug use). This can dramatically increase the risk of harm (eg road traffic accidents and overdose). This also presents a medico-legal risk for prescribers (eg if the patient was not warned, concurrent drug or alcohol use was not assessed, or the risk or presence of substance use disorder [SUD] was not assessed).

A Melbourne study of adolescents who died of a drug overdose found a pattern of escalating attendance at general practices in the 6 months before death. The main reason for attendance was to obtain prescriptions for benzodiazepines.21 Another study found 55% of heroin-related deaths and 88% of methadone deaths in Victoria involved benzodiazepines.22 More than 90% of a cohort of heroin users in Sydney reported using benzodiazepines; 35% of the sample had injected benzodiazepines and 26% of those who had ever used benzodiazepines were diagnosed as dependent.23 The 2011 Victorian Illicit Drug Reporting System (IDRS) – a sentinel survey of people who inject drugs – reported 92% of lifetime and 71% recent benzodiazepine use.24

Numerous benzodiazepines are available. They can be classified according to their main use, speed of onset, duration of action and drug half-life.

While benzodiazepines differ in their pharmacokinetics (absorption, distribution, metabolism, excretion), they all have similar pharmacodynamic properties and clinical actions.

Properties

Benzodiazepines have four basic properties that give rise to their clinical use:

  • anxiolytic
  • sedative/hypnotic
  • anticonvulsant
  • muscle relaxant.

Benzodiazepines can also produce anterograde and retrograde amnesia. This effect is used peri-procedurally.

These properties are the result of enhancement of activity of the major inhibitory neurotransmitter in the central nervous system (CNS), gamma-aminobutyric acid (GABA). Benzodiazepines bind to receptors on the GABA-A receptor complex causing inhibitory effects throughout the brain, including drowsiness and cognitive impairment (cerebral cortex), dampening of emotions such as fear and anxiety (mesolimbic dopamine system), memory impairment and anticonvulsant actions (hippocampus), and impairment of balance, motor control, muscle tone and coordination (cerebellum and other motor areas). These effects are non-selective.

Newer Z drugs (eg zolpidem and zopiclone) enhance the activity of GABA by binding at the same location as benzodiazepines. While these drugs have similar actions to benzodiazepines, they are marketed for insomnia due to their kinetic profile. High doses are required to produce the other actions such as decreased anxiety.25 There is evidence Z drugs, which are now the most commonly prescribed hypnotic agents, share similar risks to benzodiazepines.26–29

Speed of onset

Benzodiazepines are rapidly absorbed orally. After ingestion, peak effects will occur within 30 minutes to 2 hours (refer to Table 2). The more fat-soluble drugs (eg diazepam) enter the CNS more rapidly.

Table 2. Summary of the speed of onset, half-life and equivalent dose

Table 2.

Summary of the speed of onset, half-life and equivalent dose

Adapted with permission from Drug and Alcohol Withdrawal Clinical Practice Guidelines – NSW. Sydney: Ministry of Health, 2008.30

Metabolism and duration of activity

Benzodiazepines vary greatly in the speed at which they are metabolised and several different mechanisms are involved. Depending on their metabolic structure, benzodiazepines are short, medium or long acting (refer to Table 2).

For the majority of benzodiazepines, the elimination half-life is significantly longer than the duration of clinical action. As they are rapidly redistributed into fatty tissue after absorption, the noticeable clinical effects wear off after a few hours. However, the drugs may continue to exert subtle effects and, with repeated dosing, accumulation within the fatty tissue occurs and a steady state of blood concentration can be reached in approximately five half-lives. Due to slow leaching from fatty tissue, benzodiazepines may be detected in urine tests weeks to months after cessation of benzodiazepine use.

Benzodiazepines are metabolised by the liver and excreted renally. Metabolism may be impaired in patients with liver and/or kidney disease. Lorazepam, oxazepam and temazepam are metabolised by glucuronidation and therefore do not produce active metabolites. These are rarely susceptible to medication interactions, although their sedative effects remain synergistic. Some other benzodiazepines undergo metabolism by the cytochrome P450 (CYP450) 3A4 hepatic enzyme system and many are weak inhibitors of the CYP enzymes. Therefore, these benzodiazepines may have significant interactions with other drugs that are metabolised by these enzyme pathways.

Refer to Resource B for common drug–drug interactions.

Tolerance

Tolerance to all drugs of dependence develops with repeated use.31 Steady state plasma concentrations of benzodiazepines and their metabolites are reached after about five elimination half-lives, usually a few days to 2 weeks after starting therapy. Within a few days of reaching a steady state of plasma concentration, patients may start to experience a loss of effect from benzodiazepines,32 due to a range of neuroadaptive and physiological mechanisms.

Tolerance to the different benzodiazepine effects develops at different speeds and to different degrees, and may never be complete.2,32–34 The degree of tolerance differs between patients:35

  • A high proportion of patients with epilepsy develop tolerance to the anticonvulsant effects within a few weeks. This is similar to patients with spasticity disorders and the muscular relaxant effects.2
  • Tolerance to the hypnotic effects is less clear. Some of the literature claims it develops rapidly,2 while other authors claim it is slower.25 The evidence is limited by the length of trials.32 Sleep studies have shown that tolerance develops to the hypnotic effects of some rapidly eliminated benzodiazepines (eg triazolam) by 2 weeks, whereas for others (eg midazolam) tolerance emerges slowly and minimally.32,36 Tolerance also appears to develop with the Z drugs, however to a low degree.3,32,36
  • Tolerance to the anxiolytic and amnesic effects of benzodiazepines probably does not occur at all.32 Although, there is some evidence that a slow (years) tolerance may develop.2,37

Long-term use of benzodiazepines may produce chronic changes in benzodiazepine-receptor functioning, which are thought not to fully return to their pre-addicted state after withdrawal and abstinence.38

There is a high degree of cross-tolerance between benzodiazepines and other sedative/hypnotic medications and alcohol.39

The development of tolerance is associated with escalation in dose, binge dosing and is one of the criteria for dependence31 and SUD40 (refer to Table 3). However, it is unusual for patients to steadily increase their dosage, even with long-term use, as might be expected with the development of tolerance.25,41 Patients who are prescribed benzodiazepines for anxiety or sleep problems usually do not escalate their doses even over a lengthy period of use. However, high-dose benzodiazepine mono-dependence has been reported.3

Equivalent dosages

Equivalent doses are primarily used when making a transfer between drugs. Comparative oral doses of benzodiazepines are described in various sources, such as the Therapeutic Guidelines.35 However, the clinical potency of different drugs varies among individuals and it is difficult to demonstrate equivalence with drugs having very different half-lives (refer to Table 2). Due to this and variations in metabolism among people, these equivalence tables should be used with caution. 

Tolerance also makes it difficult to calculate equivalence.

Adverse effects on mental health and functioning

While used commonly for mental illness, benzodiazepines are associated with a range of adverse effects on mental health and function.

Cognitive impairment

Cognitive impairment is a broad term that encompasses several symptoms of benzodiazepine-induced CNS effects.42

Acute administration may induce dose-related sedation, drowsiness, learning impairment, psychomotor slowing and anterograde amnesia.33,43–48

Chronic cognitive effects are modified by tolerance to some, but not all of the acute effects.3 A range of cognitive and psychomotor effects may persist after withdrawal.49

Long-term use of benzodiazepines has been associated with significant long-term cognitive impairment and increased risk of dementia in various studies.50–52 The difficulty with these studies is symptoms that may naturally precede dementia for 10 years or more (eg anxiety, sleep disorders) are the very indications for which benzodiazepines are commonly prescribed.53

Other prospective trials show no association between benzodiazepines and accelerated cognitive decline.54

One aspect of psychomotor functioning that has received a lot of attention is driving ability. Benzodiazepines are associated with a 60–80% increase in the risk of traffic accidents, and taking alcohol and benzodiazepines together increases accident risk more than seven times.55

Anxiety

Patients may experience new or worsened anxiety while taking benzodiazepines long term or after stopping long-term use (rebound anxiety).37,56

Depression

Patients taking benzodiazepines may experience aggravated depression or depression that first appears during benzodiazepine use.37,57 Benzodiazepines may cause and aggravate depression, possibly by reducing the output of neurotransmitters such as serotonin and noradrenaline.

Paradoxical stimulation and disinhibition

Benzodiazepines may have a disinhibitory effect (especially at high doses), leading patients to behave out of character and potentially placing themselves in dangerous situations because of an impaired perception of inherent risk. Common scenarios involve high-risk sexual behaviour and reckless driving.42 So called ‘benzo binges’ have been associated with shoplifting and other crimes.30

Patients may also experience paradoxical excitement with increased anxiety, insomnia, talkativeness, restlessness, mania, and occasionally rage and violent behaviour (known as the ‘Rambo effect’).7

Refer to Precautions in special groups interventions for further precautions and adverse effects.

Dependence, withdrawal syndrome and problematic use

Dependence – A contemporary understanding

Despite its familiarity and ubiquitous use, the concept of dependence is complex.

Historically, dependence has been defined in pharmacological terms. That is a state that develops during chronic drug treatment in which cessation elicits an abstinence reaction (withdrawal). This is time limited and reversible by renewed administration of the drug.

As awareness of problematic use grew, the definition of benzodiazepine dependence changed to include benzodiazepine addiction and abuse. Various definitions evolved with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), International Classification of Disorders, 10th edition (ICD-10), World Health Organization (WHO) and leading authors describing it as a cluster of behavioural, cognitive and physiological phenomena that may develop after repeated substance use. This definition acknowledged that dependence is a complex condition that involves variable combinations of interacting patient and drug factors (eg reinforcement, tolerance, withdrawal).

This has created difficulties in determining incidence and prevalence of benzodiazepine dependence, caused inadvertent changes in reporting levels of adverse drug events58 and difficulties in comparing dependence and withdrawal reactions in benzodiazepine alternative (eg SSRIs).

The DSM-5 criteria combine the former DSM-IV categories of substance abuse and substance dependence into a single condition of SUD, measured on a continuum from mild to severe. The essential feature of SUD is a cluster of cognitive, behavioral and physiological symptoms indicating the individual continues using the substance despite significant substance-related problems.

Withdrawal syndrome

Benzodiazepine withdrawal syndrome is highly variable. It remains unclear why some long-term users can withdraw without difficulty, even after years of continuous use, while others undergo protracted agonies.59

The symptoms of withdrawal usually appear within 2–3 half-lives of the benzodiazepines being withdrawn.60 They usually lessen and then disappear within a few weeks.60 Sudden withdrawal of benzodiazepines can be associated with seizures.

The mildest form of withdrawal is rebound.3 Rebound comprises of the original symptoms recurring transiently at a greater intensity.3 Discontinuation of benzodiazepines is frequently associated with rebound anxiety and insomnia.36,61–66 Withdrawal symptoms include irritability, paraesthesia, tinnitus, headaches, dizziness, poor memory, poor concentration, perceptual distortions, menstrual disturbances and sensory hypersensitivity.38,59,65,67 Withdrawal symptoms can usually be minimised by gradual reduction.68,69 There is evidence that some patients suffer protracted withdrawal symptoms that can continue for months to years after cessation.59 There is debate about whether these persistent symptoms are withdrawal reactions, or simply features of an underlying disorder or worsening of that condition, which is triggered by treatment withdrawal.25

Short- and intermediate-acting benzodiazepines carry a greater risk of rebound and withdrawal than long-acting benzodiazepines. Withdrawal syndrome can appear while the patient is still taking medication. This may be because the patient avoids increasing the dose to cover increased tolerance,59 or the patient is taking short-acting formulations and experiencing withdrawal as blood levels drop.

Incidence of withdrawal symptoms

The occurrence of withdrawal syndrome is related to high dosage and long-term use.3

Authors argue that based on the incidence of withdrawal symptoms, evidence of benzodiazepine dependence can be quite high. Withdrawal symptoms from benzodiazepines prescribed for insomnia can ensue after 4–6 weeks of use in approximately 15–30% of patients.70 Others suggest much higher incidences of withdrawal: in the order of 30–45% of patients who have used regular therapeutic doses of benzodiazepines for more than a few months.71

It has been debated whether this is a clinical problem.72 For example, it has been suggested that in the absence of SUDs, the risk of addiction to benzodiazepines during long-term treatment of anxiety and related disorders has been exaggerated. In addition, the pharmacological dependence that develops when benzodiazepines are used long-term does not denote an all-encompassing preoccupation with and craving for benzodiazepines, nor does it create compulsive or uncontrollable benzodiazepine-seeking behaviour and adverse health and/or social consequences.73

Cravings and reinforcement

The reinforcement potential of a drug is its ability to maintain or increase the frequency of drug-taking or drug-seeking behaviour. Drugs may have positive reinforcement potential by creating a reward (or ‘high’) or negative reinforcement potential by alleviating some form of distress (eg anxiety or withdrawal symptoms).57

Benzodiazepines predominantly demonstrate negative reinforcement effects.71 By alleviating anxiety and withdrawal symptoms, it can encourage continued use. Used alone, and at therapeutic doses, they have not been associated with significant positive reinforcement for most patients (ie the drug itself does not encourage further use or dose escalation). Patients with a history of alcohol abuse, or even those with moderate alcohol consumption, appear to experience greater reinforcement effects with benzodiazepines. High doses may have positive reinforcing effects in some patients, particularly polydrug users.71

The spectrum of problematic use

Problematic use rarely develops in patients taking a normal, therapeutic dose for short periods. However, particular patient populations may be more vulnerable to developing problematic use.

An original US report focusing specifically on the development of physiological dependence, especially at therapeutic doses, notes that benzodiazepines do not strongly reinforce their own use and are not widely abused drugs. When abuse does occur, it is almost always among individuals who are also actively abusing alcohol, opiates or other sedative hypnotics.74

Low-dose or therapeutic-dose dependence

In cases of low-dose dependence, benzodiazepines were usually initiated for their anxiolytic or hypnotic effects. Doses may escalate slightly over years, however, prescriptions usually remain within therapeutically recommended limits.57

While high-dose dependence may be easier to recognise through drug-seeking behaviours, GPs should be aware of the more subtle behaviours of patients with low-dose dependence.

Patients with low-dose dependence tend to return at regular intervals to obtain repeat prescriptions, often before the previous supply has run out. They often carry their tablets around, and it is not uncommon for them take an extra dose before an anticipated stressful event or a night in a strange bed. They have difficulty stopping the medication or reducing the dosage due to withdrawal symptoms.57

In contrast with patients with high-dose dependence (prescribed or recreational), patients with low-dose dependence tend not to abuse other drugs or alcohol.57

Problematic benzodiazepine use

Based on the available epidemiological data, the prevalence of benzodiazepine abuse is generally low in the therapeutic setting (ie where the drug is correctly medically prescribed). The American Psychiatric Publishing Textbook of Psychopharmacology quotes prevalence of 0.6% for abuse and 0.5% for dependence among therapeutic users.75 However, the incidences are much higher in people who abuse alcohol and other drugs.75

Supporting this, a 2013 study found most patients used benzodiazepines according to guidelines, and only 0.9% ended up as excessive users after 3 years.76 Again, problematic use occurred mostly in individuals with alcohol and drug histories.

If benzodiazepine use disorder has become moderate or severe, it can become a long-term and distressing problem. There are several behaviours that indicate a patient may have problematic benzodiazepine use (eg escalating use patterns, drug-seeking behaviour and doctor or prescription shopping).77

GPs need to maintain vigilance in identifying SUDs, assist patients in recognising disordered use where it exists, set goals for recovery and assist patients to seek appropriate treatment.

Morbidity and mortality

Epidemiological studies have demonstrated an excess of consultations for accidents among persons taking benzodiazepines.78

In Victoria alone, benzodiazepines were involved in 3135 ambulance attendances in 2010–11 and 3440 in 2011–12. In terms of all alcohol and drug related attendances, they were the second most common only to alcohol. There was a disproportionate increase in the involvement of alprazolam compared to all benzodiazepines in ambulance attendances.79,80

In older patients, benzodiazepines are associated with higher risk of falls and subsequent injuries.81–83

The harmful effects of benzodiazepines, other than the risk of dependence with long-term use, have been associated (ie not proven cause and effect) with a 4–6-fold increased risk of death from all causes.84

Research has found patients prescribed hypnotic drugs (including benzodiazepines, Z drugs, barbiturates and sedative antihistamines) have an elevated risk of dying compared to those prescribed with no hypnotics.84 There is a dose-dependent relationship, but even patients prescribed fewer than 18 hypnotic doses per year experienced increased mortality.84 Note that this research did not find that hypnotic drugs were the cause of premature death – at best, it found a potential association.

Large cohort studies refute the relationship between benzodiazepine therapy and premature death. Emerging evidence suggests underlying psychiatric disorders are the principal determinant driving the association between hypnotics and mortality risk.85

Please refer to RACGP’s Prescribing drugs of dependence in general practice, Part A – Clinical governance framework for further information on clinical governance and its role in improving safety and quality for the use of drugs of dependence in general practice.

Laws and regulations

Most benzodiazepines are Schedule 4 (S4) ‘prescription only’ medicines. The exceptions are flunitrazepam and alprazolam, which are classed as S8 drugs.

Each state and territory has laws regulating the prescription of these medicines. Generally, there are tighter controls around the prescribing of S8 drugs and for prescribing to patients with known addiction. For example, GPs must seek a permit or an authority from the relevant state or territory health department when prescribing an S8 drug to persons who are drug dependent.

Some states have subsets of S4 drugs that involve prescribing restrictions or additional requirements; benzodiazepines often fall into this category.

GPs must be familiar with the relevant legislative requirements associated with writing prescriptions for S4 and S8 drugs.

State and territory departments and government-funded drugs of dependence units (or equivalent) can provide information regarding prescribing. Refer to Resource C.

General practice systems of care

The quality and safety of patient care is no longer confined to the individual practitioner. General practices have responsibilities to work collaboratively with practitioners to address the safety and quality of health services provided in their facilities.

Practice systems of care around benzodiazepines can be put in place to maximise health outcomes and social functioning for patients while minimising drug and alcohol misuse, abuse, diversion and crime. Systems of care also provide the necessary infrastructure and support for GPs to perform their job efficiently and effectively.

Staff education and competency

Practices should ensure they have the level of knowledge among team members and practice capacity to address the issues associated with benzodiazepine prescribing (eg identification of patients with more complex needs and those at higher risk). Prescriber education is particularly important. The risk of benzodiazepine misuse and dependence is lower when the first-time prescriber is a specialist in general practice compared to a prescriber without specialty training.76 GPs who are regularly involved in managing patients with problematic use of benzodiazepine or other drugs and alcohol should consider further training and developing good working relationships with addiction specialists.

Practices should promote the development of competency in prescribing benzodiazepines. Where potentially inappropriate and suboptimal prescribing is identified, practices and GPs have an opportunity to engage in education and support, and improve patient outcomes.

Dependence programs

Access to relevant programs is limited in some areas of Australia. Practices may wish to consider supporting GP-based benzodiazepine detoxification programs in-house. Benzodiazepine detoxification typically requires significant and frequent communication with patients, more regular visits with the GP and other clinical staff, on-call mechanisms and management of patients who are often highly anxious.86 Suitably qualified staff, organised support and ongoing quality assurance arrangements may be required. GPs involved in this type of program should feel comfortable prescribing adjunct medications.86

Balancing patients’ needs with practice capacity (risk stratification)

Patients should be appropriately evaluated to determine the complexity of services required.

One of the goals in the initial assessment of a patient is to obtain a reasonable assessment of clinical complexity/risk in the context of concurrent SUD or psychopathology. In this context, patients can be stratified into three basic groups. The following will offer a practical framework to help determine which patients may be safely managed in the primary care setting, should be co-managed with specialist support and should be referred on for management in a specialist setting.

GPs with advanced training in addiction medicine and/or mental health management are suited to taking on higher responsibilities under this model.

  • Group I – Managed in primary care: Patients with no evidence of past or current history of SUD or mental illness, apart from the presenting problem.
  • Group II – Managed in primary care with specialist support: Patients may have a past history of a treated SUD or a significant family history of problematic drug use. They may also have a past or concurrent psychiatric or chronic pain disorder. While not actively addicted, patients are at increased risk, which may be managed in consultation with appropriate specialist support.
  • Group III – Managed by specialist services: This group of patients represents the most complex cases to manage because of an active SUD or major, untreated psychopathology. These patients are either actively misusing prescription drugs or pose significant risk to both themselves and to the practitioners, who may lack the resources or experience to manage them.

It is important to remember that all groups can be dynamic. Group II can become Group III with relapse to active addiction, while Group III patients can move to Group II with appropriate treatment. In some cases, as more information becomes available to the practitioner, the patient who was originally thought to be low risk (Group I) may be reclassified as Group II or even Group III. It is important to continually reassess risk over time.87

Care coordination

A key message from inter-professional dialogue is that all health professionals (eg psychiatrists, pharmacists, GPs, nurses) have difficulties when dealing with high-risk patients and prescribing benzodiazepines.88 There should be an agreed set of professional standards regarding communication and transfer of care. In particular, the responsibility of ongoing prescribing duties should be explicit.

Prescribing may be initiated and recommended by other specialists, or during hospital in-patient care. When prescribing is transferred from secondary to primary care, the following information should be relayed to the GP:

  • indication for use
  • expected length of treatment
  • when the treatment will be reviewed and by whom
  • advice about withdrawal if indicated
  • clear indications of the GP’s role
  • clear agreement on roles of all clinicians between GP and secondary care
  • clear indications of support and referral pathways to the secondary service.

GPs should take care when patients on high doses of benzodiazepines are transferred from secondary care without a therapeutic rationale for clinical benefits or planned withdrawal schedule. GPs are not required to continue prescriptions commenced elsewhere if they are not comfortable doing so. However, GPs should not undermine the professional advice of colleagues, and should attempt immediate contact by telephone to clarify the management plan when there are concerns.

With continued monitoring of care, issues may arise which should prompt specialist review or immediate transfer to hospital (refer to RACGP’s Prescribing drugs of dependence in general practice, Part A – Clinical governance framework). The following should prompt consideration for referral to specialist mental health services:89

  • insufficient experience to manage the patient’s condition requiring benzodiazepine therapy, or insufficient practice infrastructure to provide ongoing recall and review
  • multiple attempts at treatment have not resulted in sustained improvement
  • severe coexisting depressive symptoms or a risk of suicide
  • evidence of problematic drug use
  • comorbid physical illness and concomitantly prescribed treatments which could interact with prescribed psychotropic medication
  • proposed interventions are not available within primary care services.

Practice policies and standards

General practices should have agreed clinical policies regarding prescribing benzodiazepines to improve the quality and consistency of prescribing, and improve safety for patients and practice staff.

Practices should consider having policies regarding:

Simple, practice-based interventions can be quite effective. Practice-based letters sent to a general practice population have repeated proven effectiveness in reducing benzodiazepine use in older patients.90 A 10-year follow-up in the Netherlands after such an intervention revealed 60% of these patients remained abstinent of benzodiazepine use.91 Those who returned to benzodiazepine therapy often did so at lower doses. Simple educational interventions may also reduce inappropriate benzodiazepine use.90,92

Benzodiazepine misuse might not be a highly visible problem in every practice, however all practices should be involved in supporting steps to reduce inappropriate benzodiazepine use in their practice and community. Each general practice should assess their own needs and develop policies that suit their circumstances.

Using and managing information

To help GPs manage prescribing risks, practices should have infrastructure (computer based or other) that provides:

  • standardised patient information on benzodiazepines, including the effects on driving and operating machinery (refer to Resource D.1 in the PDF version)
  • a treatment plan when there is a clinical decision to continue benzodiazepines. The plan should clearly outline the responsibilities of the patient and the practice, and include an agreement to review and monitor clinical progress against therapeutic goals
  • access to high-quality information systems and/or prescription shopping hotlines to assist in curtailing prescription abuse
  • mechanisms/processes within the practice to share information regarding benzodiazepine abuse/misuse
  • formalised benzodiazepine withdrawal guidelines within the practice (refer to Resource D.2B in the PDF version)
  • standardised patient information on sleep hygiene methods (refer to Resource D.4 in the PDF version).

Quality improvement

Quality improvement measures around benzodiazepine prescribing include developing policies or an audit, communicating with patients and managing risks.

Further information about quality improvement can be found in the RACGP’s Prescribing drugs of dependence in general practice, Part A – Clinical governance framework.

Accountable prescribing of benzodiazepines

Key points

  • Prescribing benzodiazepines, as with any treatment, should be based on a comprehensive medical assessment, a diagnosis, thoughtful consideration of the likely risks and benefits of any medication as well as alternative interventions, and a management plan derived through shared decision making and continual clinical monitoring.
  • GPs should be aware of the concerns associated with benzodiazepines such as potential dependence, withdrawal, problematic drug use (including diversion and misuse), and known harmful effects, including falls, potential cognitive decline and motor vehicle accidents. These risks should be discussed with patients.
  • GPs may wish to use the diagnosis of SUD rather than dependence, addiction or abuse. This is based on the DSM-5 sedative, hypnotic or anxiolytic use disorder criteria. This is a more neutral term that may reduce stigmatisation of patients with problematic use of benzodiazepines and other drugs/alcohol.
  • Treatment seeks to maximise outcomes for the health and social functioning of the patient while minimising risks. To minimise risks, benzodiazepines should be prescribed at the lowest effective dose, for the shortest clinical time frame.
  • Once started, some patients find it hard to stop benzodiazepines. Therefore, prescription should be accompanied with a plan to reduce and cease benzodiazepines.
  • Patients who use two or more psychoactive drugs in combination (polydrug use), and those with a history of substance misuse may be more vulnerable to major harms. Significant caution should be taken if prescribing benzodiazepines to patients with comorbid alcohol/substance abuse or polydrug use. GPs should consider seeking specialist opinion in management of these patients.
  • Benzodiazepines are generally regarded by clinical practice guidelines as a short-term therapeutic option. Long-term use, beyond 4 weeks, should be uncommon, made with caution and based on thoughtful consideration of the likely risks and benefits of benzodiazepines.
    • If alternatives to benzodiazepine treatment fail, have limited benefit or are inappropriate (either psychologically or pharmacologically), supervised benzodiazepine treatment may remain an acceptable long-term therapeutic option.
    • Long-term benzodiazepine prescriptions should be at the lowest effective dose, preferably given intermittently, and regular attempts at reduction should be scheduled. Continued professional monitoring of health outcomes is required.
    • Benzodiazepines should be prescribed from one practice and preferably one GP, with prescriptions dispensed from one pharmacy.
  • GPs should develop strategies to manage inappropriate requests for benzodiazepines by patients.

Evidence-based prescribing of benzodiazepines

The evidence base for benzodiazepine use continues to evolve, but despite the length of time they have been used in clinical practice, the evidence remains incomplete in many areas.93 The clinical recommendations and practice points presented in this guide are based on the best available evidence.

With respect to benzodiazepine therapy, recommendations based on these randomised controlled studies do not always reflect clinical reality. It is recognised that randomised controlled trials are generally a maximum of 12 weeks and performed in restricted patient groups with little comorbidity or other features resembling conventional clinical samples.94

Practical prescribing decisions

Good prescribing practice involves careful and considered diagnosis; clear therapeutic goals; the use of non-drug therapies where suitable; prescribing appropriate types, formulations and amounts of medication; explaining the effects of medications and any risk of dependence; and implementing regular medication reviews.

The risks of problematic use and diversion make prescribing benzodiazepines more challenging.

The short-term use of benzodiazepines can be helpful for symptomatic relief across a wide range of clinical conditions. Given the potential for harm with benzodiazepine use, clinical discipline is required. The immediate relief with benzodiazepines is tempting, yet the best outcomes are often achieved with non-drug treatment. However, these interventions take time, may not be available in a timely fashion, and involve engagement and effort from patients.

While the thrust of this guide is that benzodiazepines should generally be prescribed less, care should be exercised when changing from one psychoactive substance to another or when using combination therapies. All psychoactive drugs have risks and benefits. Some non-benzodiazepine drugs also have problems with dependence and problematic use (eg quetiapine). There is consensus that although benzodiazepines have been problematic, when prescribing is placed in the broader historical context and the types of patients prescribed benzodiazepines are considered, it is apparent that other psychotropic drugs have raised similar problems.58,95–99

Assessing risk

Patients who previously misused drugs (eg opioids, anti-alcohol or smoke cessation treatments) have a higher risk of becoming excessive users compared to patients who have not previously misused drugs.76 Greater challenges exist for patients already prescribed benzodiazepines for some time. Once a benzodiazepine prescription has been started, it may be harder to stop.

To minimise harms associated with prescription drug misuse, GPs need to maintain vigilance in identifying SUDs, assist patients in recognising disordered use where it exists, set goals for recovery and assist patients to seek appropriate treatment.

Recognising patients with problematic benzodiazepine use

There are several behaviours that indicate a patient may have problematic benzodiazepine use, such as escalating use patterns, drug-seeking behaviour and doctor or prescription shopping.77

Drug-seeking behaviours that indicate risk, but are less predictive of problematic use include:

  • attending early for prescription renewal
  • complaining aggressively about the need for higher doses
  • hoarding drugs during periods of reduced symptoms
  • requesting specific drugs
  • acquiring similar drugs from other medical sources
  • escalating unsanctioned doses 1–2 times
  • using the drug to treat other symptoms
  • selling prescription drugs.

Drug-seeking behaviours that are highly predicative of problematic use include:

  • forging prescriptions
  • stealing or borrowing another patient’s drugs
  • injecting oral formulations
  • obtaining prescription drugs from non-medical sources
  • abusing illicit drugs concurrently
  • escalating unsanctioned doses multiple times
  • losing prescriptions repeatedly.

Patients may be extremely convincing, using plausible stories and even manipulating a GP’s discomfort with confrontation to obtain medication.77

For ways to manage patient who may be drug seeking, refer to patient scripts in Resource A in the PDF version.

Patients with previous substance use problems, or those who use antipsychotic medication, are at increased risk of disordered benzodiazepine use.76 However, any patient can develop problematic use, and so universal precautions are important when considering prescribing.

Assessment of substance use disorder

The DSM-5 criteria combine the old DSM-IV categories of substance abuse and substance dependence into a single condition of SUD, measured on a continuum from mild to severe.40

The essential feature of SUD is a cluster of cognitive, behavioral and physiological symptoms indicating the individual continues using the substance despite significant substance-related problems.40

Using the term SUD should:

  • reduce confusion associated with the terms dependence, addiction and abuse (which have been inconsistently and often incorrectly used to describe points on a spectrum of disordered use)
  • be more acceptable to patients and their carers – a diagnosis of being ‘drug dependent’ may be confronting and create stigma.

Diagnosis of SUD requires the presence of at least two of 11 criteria, across four categories: impaired control, social impairment, risky use and pharmacology. Based on the total number of criteria the patient has, the substance use disorder can be classified as mild (2–3 symptoms), moderate (4–5 symptoms) or severe (6 or more symptoms). It is hoped these severity classifiers may help to clarify treatment options (refer to Table 3).

Although the term SUD is a helpful addition, the term dependence will necessarily be used when discussing any ‘drug of dependence’.

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (Copyright 2013). American Psychiatric Association. All Rights Reserved.

Patient focus

Key points

  • All patients, including those who use benzodiazepines and other drugs and alcohol problematically, have the right to respectful care that promotes their dignity, privacy and safety.

Sharing prescribing decisions

Treatment and care of patients should take into consideration their needs and preferences. Clinical options and patient information should be culturally appropriate. It should be accessible to people with individual needs including those with physical, sensory or learning disabilities, and those who do not speak or read English.

Fully informing patients about the benefits and drawbacks of benzodiazepines may improve shared decision making between the patient and doctor. While there are time constraints in a consultation, this approach may reduce GPs’ workload with fewer patients returning for repeat prescriptions.8

Non face-to-face methods of communication can also be useful. For example, a study involving direct delivery of an educational tool on benzodiazepines to older patients increased their risk perception of inappropriate prescriptions.100

Exploring patient preferences, ideas and expectations during a consultation may lead to fewer benzodiazepine prescriptions. Evidence suggests doctors sometimes assume patients want drug treatment and/or would be resistant to withdrawal, whereas some patients prefer not to use medication or wish to discontinue drugs.8

Patients need good information and access to alternative treatments including CBT for insomnia and anxiety. These interventions may be made available in the practice or through local services. There are many resources available on the internet (eg computer-based anxiety therapies).

Clinical responsibility in shared decision making

While most patients’ involvement with drugs of dependence is clinically driven, there can be elements of manipulation (and rarely criminal intent) behind patients’ requests for benzodiazepines.

The important caveat when prescribing drugs of dependence relates to healthcare benefits. Some patients with drug dependency may request higher doses on the basis that they are making a choice as an informed patient, or as harm minimisation.

Patients have a right to good healthcare, but not a right to drugs of dependence. Patients need to be informed of this at the beginning of any trial using drugs of dependence. If the clinician feels further therapy is detrimental to a patient’s health, then clinical withdrawal of medication should begin.

Doctors typically have a strong desire to alleviate a patient’s distress and suffering. The psychological phenomenon of transference in addiction, pain and mental illness can result in doctors having difficulty in these clinical areas. Some GPs may find it difficult to set boundaries for patients, and are therefore at risk of being pressured to prescribe inappropriately. Other GPs may have difficulty saying ‘no’ or believe they are ‘helping’ or taking a harm minimisation approach by giving in to a patient’s requests for drugs.

All practitioners express difficulty responding to patients who use manipulative behaviour (eg threatening to self-harm if they do not receive medication). GPs should educate themselves about appropriate responses to common manipulative behaviours used to access drugs of dependence. To aid GPs’ negotiation skills, scripted replies have been developed to help with appropriate responses in difficult situations (refer to Resource A in the PDF version).

Aboriginal and Torres Strait Islander peoples

There is very little literature on benzodiazepine use in Aboriginal and Torres Strait Islander peoples. While the clinical recommendations in this guide are the same for all patients, there is a need to understand the complex cultural context of Aboriginal and Torres Strait Islander peoples to build an effective therapeutic alliance. Working with local, respected Aboriginal Health Workers and/or drug and alcohol workers is crucial for comprehensive bio-psychosocial care.

Resources

The Working Together book is relevant in understanding and providing mental health care to Aboriginal and Torres Strait Islander peoples. 

The Handbook for Aboriginal Alcohol and Drug Work includes useful information on benzodiazepines. 

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