Benzodiazepines: Dependence and addiction in general practice

Abstract

Benzodiazepines are only recommended for short periods (2–4 weeks), yet there is evidence of substantial long-term use across the UK. Poor availability of services is one major challenge in supporting withdrawal. Confusion about terminology can lead to inaccurate or inadequate diagnosis of benzodiazepine dependence and addiction, and sub-optimal management of these patients. This article provides an overview of benzodiazepines, diagnostic criteria and available management strategies.

How do benzodiazepines work?

Gamma-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter of the central nervous system (CNS). Benzodiazepines exert their effect through allosteric modulation, increasing affinity for GABA, promoting hyperpolarisation and inhibition of neurones (Baldwin et al., 2013). The pharmacodynamic profile of these agents is explained by the various locations of these receptors throughout the CNS (Table 1).

Table 1.

Pharmacodynamic effects of benzodiazepines and clinical uses

Main action	Mainly found	Clinical use
Sleep	Thalamus, cortex and cerebellum	Insomnia
Anxiolysis and Myorelaxant	Limbic system, motor neurones and dorsal horn of the spinal cord	Anxiety Alcohol withdrawal Muscular spasm
Anticonvulsant	Limbic system and cortex	Seizures
Amnesia	Hippocampus	—

Source: Vinkers and Olivier (2012).

What are they used for?

Broadly, benzodiazepines can be grouped into hypnotic and anxiolytic agents based on their effect; however, all have degrees of hypnotic, anxiolytic, myorelaxant, anticonvulsant and amnesic properties (Soyka, 2017). Within general practice, the main uses are outlined in Table 1; with all indications playing a role in palliative care.

Sharing a similar mode of action, pharmacokinetically they can be categorised into short- and long-acting agents. Typically, short-acting benzodiazepines are utilised as hypnotics, whereas longer-acting formulas are used for their other properties. However, the latter carry an associated risk of accumulation (Soyka, 2017).

Legal status of benzodiazepines

Due to the potential for abuse, benzodiazepines are controlled drugs (Class C) under the Misuse of Drugs Act (1971). The majority are listed as Schedule 4, although midazolam and temazepam, are Schedule 3 (Misuse of Drug Regulations, 2001). These determine the legal status surrounding supply and possession, establishing that without an authorised prescription both are illegal, carrying penalties (Box 1).

Box 1.

Penalties associated with illegal benzodiazepine activity.

Supply

• Up to 14 years in prison and/or unlimited fine

Possession

• Up to 5 years in prison and/or unlimited fine

Travelling abroad

There are implications for those who are in possession of benzodiazepines and travelling. For patients with a supply covering 3 months or greater, a personal import/export license is required. Further information can be obtained from either the Home Office/UK Government website (Home Office, 2019). Applications require support via letter from the prescriber, including details as outlined in Box 2. Even when not required, it is still recommended this evidence is carried. Of note, this only facilitates process through UK customs, hence it is also necessary to advise that requirements of the destination, be understood and met prior to travel (Home Office, 2019).

Box 2.

Roles of the prescriber in supporting export/import license.

• Patient’s name and address

• Quantities of drug to be carried

• Strength and form of drug to be carried

• Country/countries of destination

• Departure and arrival dates to UK

• Details of professional registration

Source: Home Office (2019).

Driving

The Driver and Vehicle Licensing Agency (DVLA) do not impose restrictions for patients who are taking benzodiazepines as prescribed and within therapeutic range as outlined by the British National Formulary (BNF). However, if addiction is diagnosed or if dosages exceed recommendations, there are clear restrictions as set out in Box 3. It is the patient’s responsibility to inform the DVLA, and the clinician’s responsibility to make the patient aware of this point.

Box 3.

DVLA restrictions in benzodiazepine substance abuse.

Group 1 (Car and motorcycle)

• Must not drive and must notify DVLA if persistent misuse/dependence

• License will be refused or revoked for a minimum of 1 year, which must be free of dependence

• Independent assessment or urine screen may be required prior to relicense

Group 2 (Bus and lorry)

• Must not drive and must notify DVLA if persistent misuse/dependence

• License will be refused or revoked for a minimum of 3 years, which must be free of dependence

• Independent assessment or urine screen is usually required prior to relicense

Source: DVLA (2019).

Tolerance, dependence and addiction

Tolerance

Tolerance occurs when the response to a drug becomes less than the initial response. An increased tolerance means larger quantities are required to establish the effects of previous, lower doses. Tolerance to benzodiazepines is poorly understood; it develops quickly to hypnotic and anticonvulsant effects, but not with their anxiolytic and amnesic effects, particularly when used intermittently and over long periods (Baldwin et al., 2013; Cheng et al., 2018; Vinkers and Olivier, 2012). Tolerance is often explained as a homeostatic process through receptor downregulation in the presence of a constant stimulus. However, this does not appear to be the mechanism with benzodiazepines, which appears multifactorial (Cheng et al., 2018).

Dependence

Dependence, used interchangeably with physical dependence, is a phenomenon in which exposure to a drug creates a state where removal manifests in withdrawal, alleviated through re-introduction of the drug. This is predictable and occurs with many different drug classes (e.g. beta-blockers), hence dependence in isolation is not evidence of addiction (Baldwin et al., 2013; Saunders, 2017).

Addiction

The development of an addiction (also known as substance use disorder or substance dependence), is an unpredictable and adverse reaction (American Psychiatric Association, 2013). Although tolerance and dependence can be indicators of addiction, they are in their own right independent phenomena (Vinkers and Olivier, 2012), which are physiological and predictable. The differentiating feature for addiction is the presence of psychological dependence or impaired control. As such, if patients only exhibit physiological signs, they should not be diagnosed with addiction (American Psychiatric Association, 2013).

So, what is the problem with benzodiazepines?

If tolerance and dependence do not imply addiction, are they concerning? Withdrawal effects can potentiate prolonged use, increasing the risk of addiction. Addiction can occur in as little as 1 month (De las Cuevas et al., 2003), and therefore, use beyond a month is not recommended.

The estimates of 250 000 long-term users (Davies et al., 2017) are probably a gross underestimation given the availability of benzodiazepines for online purchase. With the exception of palliative care, they are not a first line treatment for any symptom or disease, and should only be prescribed in a small minority of resistant presentations. We must, therefore, reflect as a profession on the role we play in this problem, especially as there is a lack of specialist services to assist people with stopping the use of benzodiazepines (Kennedy and O’Riordan, 2019). It may be of use to undertake local clinical audits of benzodiazepine use, not only to identify patients that could stop, but also to reflect on local prescribing practices.

Abuse and diversion

The potential for abuse is high, with around 30% of patients misusing prescription benzodiazepines (Kapil et al., 2014). They are commonly diverted, with prescriptions a common means of illicit supply. Diazepam 10 mg has a particularly high street value, thus this preparation should be avoided in practice (Ford and Law, 2014).

Additional harms associated with benzodiazepines

Benzodiazepines are associated with negative cognitive and psychomotor effects, increasing the risk of road traffic accidents, and in the elderly potentiating falls and associated injuries. These are enhanced with alcohol or opiates, and improved through benzodiazepine withdrawal. This is particularly the case in the elderly, although the adverse effects may persist for a long period after use, and can even cause permanent effects (Baldwin et al., 2013; Dell'Osso et al., 2015).

Identifying inappropriate benzodiazepine use

Short-term use of benzodiazepines aims to reduce the development of tolerance, dependence and addiction. However, many patients end up taking them well beyond the intended period of short-term use. Patients can be broadly divided into three main groups, requiring different consideration:

Those taking long-term benzodiazepines, prescribed by a specialist in neurology, psychiatry or palliative care: medication should not be altered without specific advice

The inadvertently dependent patient: those taking long-term benzodiazepines, potentially inadvertently, within the terms of the prescription

The addicted patient: those taking long-term benzodiazepines with a maladaptive/abusive pattern

Diagnosis of those with addiction

Addiction requires identification, as this will have a significant impact on management, and has different consequences in respect of driving regulations (DVLA, 2019). The diagnosis of addiction can be made in practice through the internal classification of diseases (ICD-10) criteria (Table 2). The ICD-10 contains six criteria, with at least three required to diagnose addiction. For this diagnosis the criteria surrounding impaired control or social dysfunction must be met, as the presence of tolerance and dependence without the former features is not indicative of addiction (American Psychiatric Association, 2013).

Table 2.

ICD-10 substance addiction diagnostic criteria.

Criterion	Observed behaviour
• Diagnostic criteria for addiction (benzodiazepine substance dependence F13.24): Presence of three or more criteria concurrently within the last 12 months
Criterion 1 (Impaired Control)	A strong desire or compulsion to use the substance
Criterion 2 (Impaired Control)	Impaired capacity to control substance use, in terms of onset, termination and levels of use, evidenced by taking the substance in larger amounts over a longer period than intended or by a persistent desire or unsuccessful attempts to reduce or stop use
Criterion 3 (Dependence)	A physical withdrawal state, when substance use is reduced or stopped, evidenced by withdrawal symptoms or by use of the same or similar substance to avoid or relieve these symptoms
Criterion 4 (Tolerance)	Evidence of tolerance to the effects of the substance, such that there is a need for significantly increasing amounts to achieve intoxication or desired effect, or a markedly diminished effect with continued use of the same amount of substance
Criterion 5 (Social Impact)	Preoccupation with substance use as manifested by important alternative pleasures or activities being given up or reduced due to substance use or a great deal of time spent in activities to obtain take or recover from the effects of substance abuse
Criterion 6 (Impaired Control)	Persistent use despite clear evidence of harmful consequences, as evidenced by continued use when the individual is actually aware or may be expected to be aware of the nature and extent of the harm
Reprinted from The ICD-10 Classification of Mental and Behavioural Disorders. Diagnostic criteria for research. World Health Organization, Copyright (1993).

Management of dependence, addiction and benzodiazepine withdrawal

Dependence and subsequent withdrawal make de-prescribing challenging, even for those without addiction. Every effort should be made to engage all patients, gaining their consent and cooperation when reducing or removing benzodiazepine prescriptions. This enables patient control, which can increase success (Kennedy and O’Riordan, 2019). Mental health should be assessed prior to reduction, as any underlying conditions should be addressed as part of the treatment regime. It is also important to assess and document alcohol use at baseline, as this may be substituted to overcome withdrawal effects (Ford and Law, 2014).

The inadvertently dependent patient

These patients pose a challenge, as they are not aware of their dependence or perceive the benefits to be greater than the risk. Simple strategies such as prompting review, through a letter and information on benzodiazepine dependence, can be enough in some cases to lead to abstinence, with greater effects seen when this is personalised (Darker et al., 2015). Templates for such letters can be found from the All Wales Medicines Strategy Group (2011). A lack of guidelines for management is now being addressed by the National Institute for Heath and Care Excellence, and is expected in October 2021. Available evidence-based recommendations are summarised in Box 4.

Box 4.

Recommendations for the management of the inadvertently dependent patient.

• Identify and make diagnosis

• Send advisory letter and information

• Offer and provide appointment

° Discuss benefits of stopping and harms of continuing

° Assess and establish readiness to change

° Assess and treat any concomitant mental health conditions

• Consider switching to diazepam

• Create reducing regime

• Discuss withdrawal symptoms to be expected

• Regularly offer pathways into psychological support and provide ongoing assessment

• Offer regular and as required follow-up

Source: Ford and Law, (2014) and Lingford-Hughes et al., (2012).

The inadvertently dependent patient who is not ready to stop

Here it is important to discuss reasons for continued use in a non-judgmental manner. A discussion should confirm that the patient is aware of the benefits and risks, and also address misconceptions and provide information about different interventions. However, when this does not lead to them agreeing to taper down and stop, benzodiazepines should not be refused as this can potentiate addictive behaviour. Encourage small reductions, which can lead to health benefits and further dose decreases through positive reinforcement. There should be ongoing opportunities to reduce use (Dell’Osso et al., 2015). Creating a system to prompt an annual benzodiazepine review may be helpful to ensure this is done routinely and not left to opportunistic encounters.

Switching to diazepam

Switching to diazepam is recommended, but based on little evidence. Although it is longer-acting and may be used to cease short-acting benzodiazepines, it brings the risk of accumulation. Diazepam’s variety of formulations and concentrations provide the greatest benefit in a reducing regime (Lader and Kyriacou, 2016).

If prescribing diazepam, hepatic function should be assessed. In cases of liver impairment, oxazepam or temazepam may be preferred. A conversion table is presented in Table 3 to assist switching as outlined in the BNF, however, these conversions are approximations, and variations may be required in practice.

Table 3.

Benzodiazepine equivalents to diazepam 5 mg.

Benzodiazepine	Approximate equivalent dose to diazepam 5 mg
Alprazolam	250 micrograms
Chlordiazepoxide	12.5 mg
Lorazepam	500 micrograms
Nitrazepam	5 mg
Oxazepam	10 mg
Temazepam	10 mg

Source: Joint Formulary Committee (2018).

Reducing regime

Benzodiazepines should always be withdrawn gradually if used for longer than 2–4 weeks, and especially in high doses, as rapid withdrawal can induce convulsions, delirium and psychosis. Reducing regimes are based on clinical experience and expert consensus; thus, they may require adaptation within practice. The BNF provides a step-down schedule for diazepam in the sleep disorder section, outlining a reduction by 5–10% every 1–4 weeks. Tapering regimes for common benzodiazepines have been created by the All Wales Medicines Strategy Group (2011), some of which are outline in Table 4.

Table 4.

Reducing regimes for common benzodiazepines.

	Diazepam	Chlordiazepoxide	Nitrazepam	Temazepam
Stage 1 (1–2 weeks)	20 mg	90 mg	30 mg	20 mg
Stage 2 (1–2 weeks)	18 mg	75 mg	25 mg	15 mg
Stage 3 (1–2 weeks)	16 mg	60 mg	20 mg	12.5 mg
Stage 4 (1–2 weeks)	14 mg	50 mg	15 mg	10 mg
Stage 5 (1–2 weeks)	12 mg	45 mg	10 mg	7.5 mg
Stage 6 (1–2 weeks)	10 mg	40 mg	5 mg	5 mg
Stage 7 (1–2 weeks)	8 mg	35 mg	5 mg alternate nights	2.5 mg
Stage 8 (1–2 weeks)	6 mg	30 mg	Stop	2.5 mg alternate nights
Stage 9 (1–2 weeks)	4 mg	25 mg		Stop
Stage 10 (1–2 weeks)	3 mg	20 mg
Stage 11 (1–2 weeks)	2 mg	15 mg
Stage 12 (1–2 weeks)	1 mg	10 mg
Stage 13 (1–2 weeks)	Stop	5mg
Stage 14 (1–2 weeks)		Stop

Source: All Wales Medicines Strategy Group (2011).

Overall, this process may take from several months to over a year depending on the effects of reduction in individual patients. At each step-down, the patient should be reviewed and not progressed until withdrawal effects have ceased, remembering that the next reduction may need to be more gradual. Every effort should be made to support patients to persist with withdrawal symptoms, with increasing doses not recommended. The final stages of reduction and removal may be the most protracted (Ford and Law, 2014; Joint Formulary Committee, 2018).

Benzodiazepine withdrawal syndrome

Withdrawal symptoms can occur following a reduction or cessation of benzodiazepines. They tend to manifest quicker (2–3 days) in shorter-acting than longer-acting agents (5–10 days), and this can be as long as 3 weeks. Many arise from increasing excitability with the brain and can be physical, psychological or sensory in nature (Box 5). They are greatest in those taking higher doses for extended periods or taking shorter-acting agents (Ford and Law, 2014) and may be most troublesome in the final stages and removal of benzodiazepines (Lader and Kyriacou, 2016).

Box 5.

Common symptoms in benzodiazepine withdrawal.

Physiological

• Muscle spasm/weakness

• Flu-like symptoms

• Tremor

• Appetite loss

• Palpitations

Psychological

• Anxiety

• Insomnia

• Nightmares

• Agitation

• Depression

Sensory

• Hyperacusis

• Photophobia

• Dysesthesia

• Paraesthesia

• Derealisation

Source: Ford and Law, (2014) and Soyka (2017).

Patients should be informed that withdrawal is a normal physiological response, yet encouraged to report symptoms to allow support. Occasionally, most often in those taking benzodiazepines for 20 years or more, withdrawal symptoms may be very protracted, lasting 6–18 months after the final dose (Ford and Law, 2014).

Medications to assist withdrawal

Pharmacological treatments for withdrawal symptoms exist, however, evidence remains scarce. They are symptom orientated and include beta-blockers, carbamazepine and antidepressants (Soyka, 2017). Due to scarcity of evidence, they should be avoided where possible, and notably they are not licensed for benzodiazepine withdrawal (Joint Formulary Committee, 2018).

Psychological interventions

Non-pharmacological interventions can improve success rates in benzodiazepine withdrawal, through better management of dependence and underlying mental health conditions. Evidence is emerging that cognitive behavioural therapy, when utilised with a reducing programme, improves success rates over the first 3 months. There may also be roles for individualised information and relaxation therapies. Effectiveness has yet to be shown for motivational interviewing or other forms of psychological therapy (Darker et al., 2015).

Onward referrals

A lack of specialist services nationally, to assist in the management of complex patients, means referral to general substance abuse or mental health service will be required. Indications for referral are outlined in Box 6. However, the long waiting lists inherent in these services should not be forgotten, and in practice a referral does not always equate to the provision of support.

Box 6.

Criteria to consider referral to specialist services.

• Unable to manage patient sufficiently

• Failure to withdraw or treatment failure

• Presence of coexisting mental health conditions

• Severe addiction/abuse of benzodiazepines

• Coexisting and problematic alcohol use

• Coadministration with other opioids, hypnotic or anxiolytic medications

Source: Royal Australian College of General Practitioners (2015).

The addicted patient

For those with true addiction, there are little in the way of evidence-based guidelines to assist in managing this challenge. However, ongoing prescriptions cannot be justified in terms of a benefit-to-harm ratio. As many patients obtain illicit benzodiazepines via prescriptions (Kapil et al., 2014), there are legal implications for the prescriber. Red flags for addiction include frequently demanding benzodiazepines, attempting to renew prescriptions early or frequent reports of lost or stolen prescriptions. The responsibility lies with the prescriber, hence, if they are unable to rationalise the benefits of a prescription to the patient, benzodiazepines should not be issued.

If addiction is reported or suspected, a face-to-face assessment should explore the reasons for use with an aim to help the patient address underlying factors. Prescribing as maintenance therapy in addiction cannot be recommended, thus when prescribing benzodiazepines it should be done with clear goals and timeframes alongside a management plan for reduction. Reported use does not need to be met, with doses greater that 30 mg of diazepam (or equivalent) rarely needed. If patients complain of effects such as insomnia, they should be advised when dividing doses to save at least 1/3 for night time (Ford and Law, 2014). Initial aims to reduce use to ‘therapeutic’ doses are realistic, but should not be prolonged (Lingford-Hughes et al., 2012). Previous recommendations apply in the management of addiction (e.g. switching to diazepam); however, there should be a clear time-frame rather than reductions according to patient symptoms and preferences. Key recommendations for management specific to this group are summarised in Box 7.

Box 7.

Recommendations for the management of addicted patients.

• Face-to-face assessment discussing findings honestly and inform patient of plan to withdraw

• Set out clear timeframes document and jointly agree withdrawal plan

• Consideration of diazepam switch: Maximum dose equivalent 30 mg diazepam at initiation

• Do not prescribe diazepam in 10 mg preparations (high street value/diversion)

• Consider safeguards such as daily/weekly dispensing or instalment prescriptions

• Challenge inappropriate requests for prescriptions

• Do not provide repeats for lost or stolen scripts

• Only provide small quantities for temporary patients

• Provide onward referrals where unmanageable (e.g. drugs and alcohol service)

Source: Ford and Law, (2014) and Lingford-Hughes et al. (2012).

These patients can be challenging. Locally agreed protocols and patient contracts are invaluable, empowering standardisation and best practice. If these are not available locally, this would be a constructive service improvement and personal development project. Templates and useful recourses, such as communication strategies to deal with inappropriate requests, can be found from the All Wales Medicines Strategy Group (2011) and Royal Australian College of General Practitioners (2015).

A holistic approach

Addiction can encroach on every aspect of a patient’s life. The multiple reviews needed to help someone wean off benzodiazepines provide an opportunity to assess and target health promotion strategies within such individuals, along with identifying and addressing triggers that may have potentiated substance use initially. Consideration should thus be given to the physical, psychological, social and spiritual implications of benzodiazepine use within the patient’s life, with appropriate multi-disciplinary involvement as indicated.

Safeguarding is everybody’s responsibility

Finally, it is important to consider safeguarding issues for children or vulnerable adults in the care of those with addiction. Alhough the abuse of agents may be a risk factor and prompt safeguarding concerns, they are not synonymous. A non-judgemental and sensitive assessment should prevail when considering social circumstances. In the case of any identified risks or disclosures, safeguarding concerns should be raised in line with local protocols.

KEY POINTS

Tolerance and dependence develop rapidly to benzodiazepines; when initiating these medications, prescribe short courses only (max 2–4 weeks)

There are distinct differences between those with inadvertent dependence and true addiction, which require different assessment and management

A diagnosis of substance dependence should be made and classified using the ICD-10 criteria

Those with tolerance and/or withdrawal symptoms alone should not be diagnosed with addiction

Non-pharmacological interventions may assist withdrawal of benzodiazepines alongside tapering

Patients should be assessed holistically and treated with a non-judgemental attitude with consideration of social circumstances and any potential safeguarding concerns

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