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Long-Term Benzodiazepine Use and Withdrawal

Essentials

Withdrawal should be considered when the harmful effects of medication outweigh its benefits.
Only one physician should be in charge of prescribing benzodiazepines to a particular patient.
Withdrawal should be carried out slowly and gradually over several weeks or months.
Any associated psychiatric problems or substance misuse must be addressed at the same time.
If applicable, keep a low threshold in making a special agreement with the patient and an appropriate pharmacy concerning drug delivery.
The risk of developing dependence may be reduced if the stopping time is already planned at the time of prescription.

Diagnostic principles

Benzodiazepine dependence (ICD-10 code F13.2) is characterised by tolerance (gradually reducing efficacy), need to increase the dose, withdrawal symptoms when the dose is reduced T1 and the continuation of use despite the emergence of adverse effects.
There are thee common types of benzodiazepine dependence:
- dependence at usual therapeutic doses (low dose dependence): iatrogenic; in the elderly or in patients in long-term care, after several years of use about half of these patients are affected
- escalating dependence: the use may have started on standard prescribed benzodiazepines which were not stopped. The patient will then gradually need higher doses and will visit different doctors in order to obtain the escalating dose.
- polysubstance misuse: the patient uses benzodiazepines to increase the effect of other drugs or to alleviate withdrawal symptoms.
In harmful use of benzodiazepines (ICD-10 code F13.1) the patient is not dependent, but the drug use may cause physical or mental harm, e.g. behavioural disorders.
Benzodiazepine withdrawal symptoms (ICD-10 code F13.3) include distinctive physical findings T1. Delirium is also possible with a delay of one to two weeks (ICD-10 code F13.4).
The discontinuation of benzodiazepines may theoretically involve the following withdrawal effects: recurrence (relapse, i.e. the original anxiety disorder recurs), rebound (transient exacerbation of the original symptoms) and actual withdrawal symptoms.

Benzodiazepine withdrawal symptoms

Affective and cognitive disorders

Anxiety, fearfulness

Malaise, irritability

Pessimism

Recurring obsessive/compulsive thoughts, mistrustfulness

Sleep disorders

Sleeplessness, disturbed sleep-wake pattern, daytime tiredness

Physical signs and symptoms

Tachycardia (heart rate over 100/min), hypertension

Hyperreflexia, muscle tension, muscle twitching, tremor, ataxia

Agitation, motor restlessness

Myalgia, arthralgia

Nausea, nasal stuffiness

Sweating

Tinnitus

Grand mal seizures

Perception disorders

Feelings of depersonalisation (one's own reality is temporarily lost)

Blurred vision, hyperacusis

Illusions, hallucinations

Initial investigations

The following should be established:
- the true extent and duration of use; data should be obtained from all previous treatment places
- the patient's own attitude towards use and need for withdrawal
- present and past history of substance misuse; what substances, how much, what treatment approaches have been tried.
The benefits and adverse effects should be discussed with the patient. For example, you may consider together with the patient in a systematic manner the aspects listed below.
- Benefits of long-term use
  - In some cases, alternative treatment is inadequate to control anxiety or sleep disturbances, or the medication may also clearly be beneficial in the treatment of a psychiatric or neurological illness.
- Harmful effects of long-term use
  - All benzodiazepines are associated with a risk of dependence.
  - Benzodiazepines have a sedative effect, they predispose the patient to accidents, cause disturbances of the cognitive function and may lead to confusion and agitation, especially in patients with dementia.
  - They occasionally reduce the patient's ability to control impulses, leading to substance misuse and violent behaviour. In substance misusers, they increase the craving for alcohol.
  - Benzodiazepines cross the placenta.
  - Benzodiazepines may cause hazardous situations in traffic or working life.
  - Very large doses are life threatening as also may be polysubstance misuse, however minor.
  - The benefit of sleeping tablets has only been demonstrated in short-term use.
  - There is no evidence that benzodiazepines are beneficial in the treatment of alcohol dependence.
- Benefits associated with withdrawal
  - A realistic picture of the extent of the drug use will become evident.
  - Overall, the patient will rid himself/herself of unnecessary or harmful medication with subsequent improvement of quality of life.
- Problems associated with withdrawal
  - Transient increase in anxiety, and sleep disturbances, may occur (particularly if withdrawal has been too fast).
  - Withdrawal requires motivation, time, patience and collaboration, also on the part of the physician.
Correct diagnosis must be made in accordance with the official classification of diseases and recorded in the patient notes.
It is beneficial to openly explore with the patient the diagnostic criteria (as per the official classification of diseases), the withdrawal symptoms T1 as well as the benefits and harm associated with the medication (see above).
Any existing psychiatric disorders should be identified and treated if indicated. In the presence of mood swings or anxiety disorders, possible SSRIs or other medication should be started even a couple of months before benzodiazepine withdrawal.
Controlled long-term use may be considered where the harmful effects of withdrawal outweigh its anticipated benefits. Its justification should be included in the patient record, and even in such cases the lowest sufficient dose should be aimed for.
Withdrawal is recommended if it is expected to improve the general health of the patient.
The patient should be given written information to read at home, since it improves the prognosis of drug withdrawal.

Staging the treatment and indication for specialist consultation

At a health centre out-of-hours clinic
- the patient should be referred to his/her own doctor
- as a general rule, prescriptions for sedatives are not issued, but medication for acute withdrawal symptoms should be given, see Treatment of Alcohol Withdrawal
- symptoms resulting from withdrawal of intoxicants or medicines are only treated if objective signs are present (threatening behaviour is not a withdrawal symptom, and the patient may be asked to return to the clinic later, or inpatient care may be recommended, see A Patient with Legal Drug Addiction in Primary Care).
Withdrawal may be started right away in primary health care provided that
- the current dose is lower than twice the maximum recommended dose
- the patient is not suffering from a severe psychiatric illness and is not a polysubstance misuser
- the patient is motivated and willing to comply with a treatment plan.
Psychiatric consultation should be considered if
- the patient fails to fully co-operate
- there are signs of a severe personality disorder, or the patient suffers either from uncontrolled severe depression or severe anxiety disorder, or has a history of a psychotic illness, or if he/she has some other significant psychiatric or neuropsychiatric symptom picture.
- medication with benzodiazepine has continued for more than four months without a withdrawal attempt (the consultation should, for example, verify the diagnosis and explore alternative therapies).
A consultation with a physician with expertise in addiction medicine or a psychiatrist, or a referral to a substance abuse clinic, should be considered if
- previous attempts at withdrawal have failed
- the current dose is higher than twice the maximum recommended daily dose
- the patient uses benzodiazepine in doses that exceed the recommended maximum dose without an attempt at withdrawal (during the consultation, among other things the adverse effects should be weighed against the benefits)
- the patient has a current history of polysubstance misuse or heavy alcohol intake.
  - The treatment of a patient with polysubstance misuse problem succeeds best in an addiction psychiatry unit or with consultation support from an addiction psychiatrist.
A consultation with a neurologist should be considered if the patient has
- a past history of convulsions
- a neurological illness the treatment of which would benefit from benzodiazepines.
It is recommended that the patient is admitted to a care facility (general hospital ward, specialist hospital/clinic, psychiatric ward) for the duration of, or at least for the initiation of, the withdrawal therapy if
- the current benzodiazepine dose is more than three times the maximum recommended daily dose (severe high-dose dependency)
- the size of the current dose cannot reliably be ascertained
- the patient is dependent on several substances or has a history of repeated polysubstance misuse
- the patient has other serious comorbidities (such as severe sleep apnoea, coronary artery disease, severe depression)

Treatment plan

The treatment plan, either for long-term use or withdrawal, must be drawn up in writing. The relevant sheets of the patient's medical records may also be copied, and then signed by the patient.
The patient must agree in writing that
- all relevant data may be obtained from previous treatment places
- all relevant prescriptions may be reviewed (particularly relevant if electronic prescriptions are in use)
- a copy of the treatment plan may be sent immediately to all previous treatment places, followed later by information about the treatment progress or cancellation thereof
- in some cases local pharmacies may be asked for information relating to the patient's medicine purchase during the previous year.
The patient should be told that during the withdrawal treatment random drug testing will be carried out, involving either breathalyser testing or urine drug testing (point of care testing for benzodiazepines is, however, fairly unreliable).
The patient should be advised in advance that prescriptions will not be renewed even if claimed to be lost or stolen (however, acute objectively observable withdrawal symptoms must be treated without delay whenever indicated).
In complicated cases (if the dose differs from the official dose recommendations, if the centralisation of treatment is suspected not to succeed or if withdrawal attempts have repeatedly failed in the past) a special agreement can also be made with the appropriate pharmacy. See also A Patient with Legal Drug Addiction in Primary Care.
An electronic prescription system prevents forged prescriptions, but it does not prevent medication abuse.
The patient may be asked to keep a diary of his/her medicine use. The diary will also help the patient to identify risk situations thus allowing him/her to consider alternative coping mechanisms.

Establishing the starting dose

Withdrawal should be started with a dose that is high enough not to cause withdrawal symptoms whilst allowing the patient to sleep (table T1).
- Emergency assessment of withdrawal symptoms: heart rate, blood pressure, tremor, sweating
- Withdrawal symptoms may also be evaluated with the aid of a CIWA-B (Clinical Institute Withdrawal Assessment-Benzodiazepines) questionnaire.
In inpatient care, the diazepam dose may be increased up to 20 mg every 2 hours (up to 200 mg/24 hr) but only if the patient has clinical withdrawal symptoms is not too sedated.
In most cases, it is possible to reduce very high starting doses (in inpatient care) by half even within a couple of days, especially if the drug used is diazepam.
- The dose may be tapered either gradually or in relation to the severity of the withdrawal symptoms; there is no essential difference between these two methods in inpatient care.
- Carbamazepine or sodium valproate may be used as adjuvant drugs during benzodiazepine withdrawal. More details of adjuvant drugs below.
If a previous attempt at withdrawal has failed, or the patient is very vulnerable to withdrawal symptoms, or the drugs used are very short-acting it may be advisable to switch to diazepam over a period of 1-2 weeks in accordance with the equivalent potencies of the drugs (table T2). For slow withdrawal schedules suitable for outpatient care, see website http://www.benzo.org.uk/manual/bzsched.htm.

Withdrawal of low and high dose medication

If the dose the patient is taking is higher than the maximum recommended daily dose, the dose should be reduced by 10-25% every 1-3 weeks.
- The maximum recommended daily dose is about 40 mg for diazepam, 120 mg for oxazepam and 6 mg for alprazolam.
If the dose the patient is taking is less or equivalent to the maximum recommended daily dose, the dose should be reduced by 10-20% every 2-3 weeks. All hypnotics must be tapered off gradually, even after short-term use.
If problems arise in the form of increased symptoms, the dose should not be increased but the rate of withdrawal reduced.
- Withdrawal symptoms develop within 1-2 days after the reduction or discontinuation of short-acting benzodiazepines, but may take 2-14 days to develop after the reduction or discontinuation of long-acting benzodiazepines.
- It is recommended that any p.r.n. (as needed) medication be avoided at this stage, and the aim should be to take medication only at regular intervals.
The patient should be given appointment times at least on a monthly basis, more frequently at the beginning. Withdrawal symptoms should be discussed openly and the patient given encouragement in the withdrawal attempt.
Compromises may be made as regards the rate of withdrawal but not with the target of withdrawal.

Follow-up and prognosis

The patient will benefit from follow-up appointments even after withdrawal has successfully been completed (risk of relapse and other psychiatric symptoms).
Various self-help and discussion groups are available.
In about 70-80% of patients, gradual withdrawal of low dose medication is successful with no major problems. In highly motivated polysubstance misusers, the first withdrawal attempt is successful in one out of four patients. Severe personality disorders undermine the prognosis, particularly in polysubstance misusers.
Cognitive behavioural therapy is not likely to improve the withdrawal result in polysubstance misusers as compared with the conventional care provided by substance abuse clinics Psychosocial Interventions for Benzodiazepine Harmful Use, Abuse or Dependence.
After benzodiazepine withdrawal, many patients will require alternative treatment to manage anxiety or depression.

Unsuccessful withdrawal

Should the withdrawal attempt be unsuccessful, the patient must be encouraged to try again; a judgemental attitude will serve no purpose.
Previous treatment places should be informed of the unsuccessful attempt as per treatment plan.
Specialist consultations as described above.
It may be advisable initially to switch to diazepam or other long-acting benzodiazepines (over 1-2 weeks, overlapping the drugs and making allowance for the difference in potency, see table T2).
Adjuvant drugs may be considered. They are usually of little benefit, but they may be tried, especially if a previous attempt at withdrawal has failed Pharmacological Interventions for Benzodiazepine Discontinuation in Chronic Benzodiazepine Users.
- Propranolol 10-20 (up to 40) mg 2-3 times daily may be beneficial in the control of physical symptoms caused by the overactive autonomic nervous system.
- Valproate and carbamazepine, possibly also oxcarbazepine, gabapentin and topiramate, may alleviate withdrawal symptoms somewhat or at least improve the final outcome and prevent seizures.
- Sedative antidepressants (mirtazapine, mianserin, amitriptyline; for antidepressant drugs see Pharmacological Treatment of Depression) are effective in promoting sleep, as is 25-100 mg of hydroxyzine. Pregabalin may facilitate withdrawal in patients with generalised anxiety disorder, but it should not be used without careful follow-up in anyone with any substance abuse background. Several cases have been reported in which dependency on benzodiazepines has been converted to pregabalin dependency.
- The effect of buspirone is insufficient in patients with drug dependencies. However, some positive results have been achieved in patients with generalised anxiety disorder.
- Melatonin (2-6 mg) has occasionally been somewhat beneficial in sleep disturbances during the withdrawal period.
- Dexmedetomidine, administered under the supervision of an anaesthetist, has helped in averting severe withdrawal symptoms during benzodiazepine and opioid reduction regimes, including children.
- It should always be borne in mind that adjuvant drugs will have their own adverse effects and contraindications.

Characteristics of benzodiazepines

Drug	Equivalent dose, mg¹⁾	Time to peak concentration, min	Half life, h (active metabolites)
Alprazolam	1	40-120	6-12
Diazepam	10	20-90	20-50 (36-200)
Clonazepam	0.5-1	60-240	18-50
Chlordiazepoxide	25	50-120	5-30 (36-200)
Lorazepam	2	60-120	10-20
Midazolam	5-10	20-45	1-3
Nitrazepam	10	30-240	15-38
Oxazepam	30	120-240	4-15
Temazepam	20	30-60	8-22
Triazolam	0.25	50-150	2-5
Zaleplon²⁾	20	30-60	2
Zolpidem²⁾	20	30-180	2-4
Zopiclone²⁾	15	50-240	4-8
¹⁾ The pharmacokinetics of the drugs are not identical, but these approximate doses may be used initially, for example when switching to diazepam from a short-acting agent. ²⁾ Hypnotics similar to benzodiazepines

How to prevent dependency

When prescribing benzodiazepines or other hypnotics, the physician should agree with the patient when the medication is to be stopped.
When treating anxiety disorders Anxiety Disorder or sleep disturbances Insomnia, alternative treatment forms should also always be borne in mind.
The smallest effective dose must always be used. The patient may try to stay off medication from time to time.
Good evidence exists on simple advice by a doctor encouraging the patient to cut down being effective in leading to reduced drug intake.
The way benzodiazepine derivatives cause dependence varies from product to product and, excluding acute care, it is therefore better to favour products such as oxazepam or chlordiazepoxide (onset of action not too fast). Drugs to avoid include diazepam, lorazepam and alprazolam, at least in patients with known drug dependency problems.
Prescriptions should not be written for high amounts; it is better to issue repeat prescriptions.
The grounds for long-term use should be reassessed at least annually. The physician's attitude should not be moralising, but objective.
All except emergency units could consider adopting a principle of not prescribing benzodiazepines at the first appointment; this information can also be openly displayed to the patients.

References

Vicens C, Bejarano F, Sempere E et al. Comparative efficacy of two interventions to discontinue long-term benzodiazepine use: cluster randomised controlled trial in primary care. Br J Psychiatry 2014;204(6):471-9. [PubMed]
Gould RL, Coulson MC, Patel N et al. Interventions for reducing benzodiazepine use in older people: meta-analysis of randomised controlled trials. Br J Psychiatry 2014;204(2):98-107. [PubMed]

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