The first benzodiazepine was marketed in 1959. It was described as a 'minor tranquilliser' and an alternative to barbiturates. Benzodiazepines act by enhancing the effect of gamma-aminobutyric acid on the GABA-A receptor, thereby resulting in CNS depression. They are anxiolytic, hypnotic, anticonvulsant and muscle relaxants. They also cause psychomotor retardation.

They are useful in the short term. However, long-term use (more than three months, possibly even after a few weeks) is associated with dependence and withdrawal syndrome ¹. One study found that up to 44% of chronic users become dependent.²

Following advice from the Committee on Safety of Medicines (CSM) in 1988,⁴ the overall prescribing of benzodiazepines has markedly reduced.^5,6 A study from Kings College London showed that, within this figure, their use as hypnotics has reduced but their use as anxiolytics has increased.⁷ Recreational use of benzodiazepines is also an increasing problem. In 2010, they represented 1% of drugs used as adjuncts to drugs of primary dependence such as cocaine in the UK.⁵

Aims of management in benzodiazepine dependence⁶

1. Safe withdrawal.
2. Cessation of use.

Practical issues of benzodiazepine usage^8,9

1. Do not prescribe benzodiazepines in someone with a history of drug misuse and dependence.
2. Prescribe the lowest possible doses of benzodiazepines and only prescribe for 2-4 weeks. It is important to remember that patients can get withdrawal symptoms between doses if they are given short-acting benzodiazepines.
3. Use only for severe or disabling anxiety or insomnia.
4. Try alternatives to benzodiazepines, such as relaxation techniques. Low-dose tricyclic antidepressants are used for the short-term treatment of insomnia. However, the data to support this use are lacking and there is the risk of developing dependence.
5. Advise patients of the risk of dependence and impaired reaction times.
6. Elderly patients are particularly prone to adverse effects of benzodiazepines and, therefore, need to be careful.
7. Benzodiazepines also cross the placenta, leading to neonatal side-effects.¹⁰

Possible outcomes on stopping benzodiazepines^9,11

• Recurrence of original disorder.
• Rebound symptoms - last a few days.
• Withdrawal syndrome:¹²
  • Common symptoms: increased anxiety, tremor, irritability, restlessness, depression, dizziness, sweating, insomnia, nightmares, abdominal pain, tachycardia and hypertension (usually mild).
  • Serious symptoms: seizures, delirium, confusion.
  • Other symptoms: anorexia, nausea, tinnitus, excessive sensitivity to light and sound, depersonalisation and derealisation.

Management

Two groups of patients to manage:

• Those using benzodiazepines for a chronic disorder for a long time, e.g. insomnia and who do not abuse their prescription.⁶
• Those who abuse their prescription or buy benzodiazepines illicitly - usually associated with other substance misuse, e.g. opiates.¹³

Management of benzodiazepine dependence in non-abusing patients^6,13

1. Only make a diagnosis of dependence if the patient fits the above criteria.
2. Begin with advisory letters and patient information.
3. Try consultation with GP and practice nurse: provide education on why benzodiazepines are harmful when used chronically. Explain the difficulties that may arise with continued prescribing.
4. Relaxation therapies.
5. Graded discontinuation may be useful:^1,8,11
   • Tailor the regime to the needs of the patient. Some but not all may benefit from switching to a longer-acting benzodiazepine, e.g. diazepam (see dose conversion table, below). Longer-acting forms are less likely to produce rapid onset of withdrawal symptoms. Use the benzodiazepine conversion equivalence table.
   • Gradually reduce the dose. Prodigy gives several examples of regimes that can be used.⁶ One strategy is to reduce by 10% every seven to ten days, e.g. if a patient has been on 40 mg diazepam once daily for a year, then begin by reducing the dose to 35 mg for a week, then 30 mg for a week, then 25 mg for a week, etc. If this patient developed withdrawal symptoms at a reduction to 35 mg then consider going back to 39 mg and then reduce to 38 mg a week later and so on.
   • Another example is withdrawal of temazepam. If a patient is on 20 mg of temazepam at night then reduce dose to 17.5 mg for a week, then 15 mg and then 12.5 mg and so on. Alternatively, the patient can be converted to diazepam (see table below) and then the diazepam dose can be tapered as above.
   • Have regular contact and consider only prescribing for a week at a time.
   • There may be the need for a longer period over which to reduce - one approach is a symptom-guided taper.
6. Other psychological therapies - consider in all patients, e.g. cognitive behavioural therapy and supportive therapies.

Dose conversion table for equivalent doses of benzodiazepines to diazepam 5 mg

Other approaches:¹²

• Antidepressants - only appropriate if depression and/or panic disorder develop during withdrawal.
• Anticonvulsants.
• Beta-blockers - relief of specific symptoms, e.g. palpitations.
• Short-term flumazenil infusions (used in severe cases).¹⁴

These have a variety of effects on withdrawal symptoms and discontinuation rates.

Limiting co-dependence on benzodiazepines and other drugs¹³

• Avoid prescribing benzodiazepines if at all possible - determine exactly what they are needed for and consider alternatives.
• This is a good opportunity for assessing dependence of other substances, e.g. alcohol. Consider a urinary drug screen to detect if other drugs of abuse are being used.
• Benzodiazepines are prescribed in the management of opioid maintenance - this is not always necessary.
• Benzodiazepines are used during alcohol detoxification schedules to prevent occurrence of withdrawal seizures - high doses are not needed. A Cochrane review was unable to reach a definitive conclusion about the effectiveness and safety of benzodiazepines, because of the heterogeneity of the trials.¹⁵ Carbamazepine has been used in patients on high doses.

A summarised approach to managing a patient who is abusing benzodiazepines^6,8,11,12

• Confirm that the patient has a problem - use the DSM-IV list.
• Does the patient abuse other drugs, e.g. alcohol, cannabis? A urine screen may be helpful but ensure you have the patient's consent.
• Educate the patient - cover the problems with abusing benzodiazepines, offer support and assistance, advise them on methods available to stop abusing benzodiazepines - e.g. graded reduction.
• Alternative therapy, such as relaxation therapy or stress reduction, may need to be offered for their insomnia.
• If the patient agrees to reduce benzodiazepines then a signed contract may help them to commit.
• Educate the patient about the withdrawal syndrome and how to counteract it, e.g. relaxation therapy.
• Reduce the dose of benzodiazepine, e.g. 10% reduction in dose every 7-10 days.
• Regular follow-up: this will be based on how each individual patient does. For example, if the patient is developing withdrawal symptoms frequently then they will need to be seen more frequently. Otherwise, review weekly as the dose of benzodiazepine is tapered.

Document references

1. Lingford-Hughes AR, Welch S, Nutt DJ; Evidence-based guidelines for the pharmacological management of substance misuse, J Psychopharmacol. 2004 Sep;18(3):293-335.
2. Minaya O, Fresan A, Cortes-Lopez JL, et al; The Benzodiazepine Dependence Questionnaire (BDEPQ): validity and reliability in Addict Behav. 2011 Aug;36(8):874-7. Epub 2011 Apr 9. [abstract]
3. Substance Dependence, BehaveNet, 2011
4. Benzodiazepines, dependence and withdrawal symptoms. Current Problems - 1988; Number 21: 1-2, Committee on Safety of Medicines
5. The Information Centre for Health and Social Care; Statistics on Drug Misuse: England, 2010
6. Benzodiazepine and z drug withdrawal, Prodigy (March 2009)
7. Reed K et al; The changing use of prescribed benzodiazepines and z-drugs and of over-the-counter codeine-containing products in England: Kings College London, 2011.
8. Davidson B et al; NHS Grampian: Guidance for prescribing and withdrawal of benzodiazepines and hypnotics in general practice, 2006
9. British National Formulary
10. Farst KJ, Valentine JL, Hall RW; Drug testing for newborn exposure to illicit substances in pregnancy: pitfalls Int J Pediatr. 2011;2011:951616. Epub 2011 Jul 17. [abstract]
11. Ashton CH, The Ashton Manual Supplement, 2011
12. Sola CL et al, Sedative, Hypnotic, Anxiolytic Use Disorders, Medscape, Jun 2011
13. Chen KW, Berger CC, Forde DP, et al; Benzodiazepine use and misuse among patients in a methadone program. BMC Psychiatry. 2011 May 19;11:90. [abstract]
14. Hood S, O'Neil G, Hulse G; The role of flumazenil in the treatment of benzodiazepine dependence: physiological and psychological profiles. J Psychopharmacol. 2009 Jun;23(4):401-9. Epub 2009 Jan 22. [abstract]
15. Amato L, Minozzi S, Vecchi S, et al; Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD005063. [abstract]