Benzodiazepines & Benzodiazepine-Like Drugs


 

Alprazolam, Chlordiazepoxide, Clobazam, Clonazepam, Diazepam, Flurazepam, Loprazolam, Lorazepam, Lormetazepam, Nitrazepam, Oxazepam, Temazepam, Zolpidem, Zopiclone 


  Issues for Surgery


For treatment of epilepsy (clobazam, clonazepam) – loss of seizure control if omitted.

For panic disorder in psychiatric patients – exacerbation of symptoms if omitted.

For muscle spasm – loss of symptom control if omitted.

Risk of withdrawal symptoms if omitted (see Further Information).

Increased sedative effect and risk of cumulative central nervous system (CNS) depression if continued.

Potential for post-operative delirium (POD), for elderly patients or those on long-term treatment, if continued (see Further Information).


  Advice in the Perioperative period


Elective and Emergency Surgery

Continue.
Inform Anaesthetist on day of admission of type and dose of benzodiazepine the patient usually takes so anaesthesia can be adjusted accordingly if necessary.

Epilepsy
Patients should be advised to take their regular medications on the day of surgery1, 2, 3.

Abrupt withdrawal of any anticonvulsant drug should be avoided3.

Confirm with the patient if they need to be maintained on a specific manufacturer’s product (see Further Information).

Anxiolysis
Discontinuation of benzodiazepines in psychiatric patients with panic disorders should be avoided. Seek advice from Mental Health Team if necessary.

Post-operative Advice

For Patients with Epilepsy
Clobazam and clonazepam are only available as oral preparations. If patients cannot resume their usual oral medication post-operatively, the advice of a Neurologist should be sought to determine the most appropriate antiepileptic preparation, dose and frequency to be used.

For Patients taking Long-Term Benzodiazepines for other Indications
Restart post-operatively if appropriate.

If patient cannot resume their usual oral medication post-operatively and is at risk of withdrawal, consider using a suitable intravenous preparation. Consult with a Psychiatrist if necessary.

Bear in mind the potential for post-operative confusion and delirium (POD), especially in those patients who are elderly and / or have been taking long-term benzodiazepines (see Further Information).

Patients who are discharged on the day of surgery after having received an anaesthetic and who usually take benzodiazepines / benzodiazepine-like drugs should be advised of the potential of enhanced drowsiness and psychomotor effects and counsel against undertaking skilled tasks (e.g. driving)1.


  Interaction(s) with Common Anaesthetic Agents


For general information regarding the use of anaesthetic agents in patients with epilepsy – see Antiepileptics – A General Overview.

Central Nervous System (CNS) Depression (also see under Interaction(s) with other Common Medicines used in the Perioperative Period).

Benzodiazepines and benzodiazepine-like drugs have CNS depressant effects which may be additive with other medicines that also have CNS depressant effects such as1, 4, 5, 6, 7, 8, 9, 10, 11, 12: -

  • inhalational and intravenous anaesthetics
  • local anaesthetics
  • opioids
  • other benzodiazepines

Thiopental and Propofol
A synergistic interaction has been found for the hypnotic effects of midazolam and thiopental. A similar interaction has been seen between midazolam and propofol5.

Ketamine
Diazepam competitively inhibits ketamine metabolism – pre-medication with diazepam leads to prolonged half-life of ketamine with enhanced effect as a result, leading to increased sedation8, 10.

Bupivacaine
Diazepam and midazolam have been reported to increase plasma levels of bupivacaine (given by caudal injection / spinal anaesthesia). The clinical significance is unclear – reduced doses of bupivacaine may be required4.

Opioids
Giving benzodiazepines with opioids during anaesthesia may reduce the dose required of both drugs. The patient should be monitored and adjustments made according to the effect4. Single-dose intravenous (IV) fentanyl slightly increased single dose IV midazolam exposure4, 13.

If benzodiazepines / benzodiazepine-like drugs are used concomitantly with opioids, possible euphoria may be enhanced; this may lead to increased psychological dependence7, 8, 10, 14, 15, 16, 17, 18, 19, 20, 21.

The current recommendation from manufacturers for the prescribing of benzodiazepines or related drugs with opioids is that concurrent use should be reserved for patients in whom alternative treatment options are not possible or are inadequate. If the decision is made to prescribe benzodiazepines / benzodiazepine-like drugs with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20.

Neuromuscular Blocking Drugs (NMBDs)

There are conflicting reports of the effect of diazepam on NMBDs; potentiation, or antagonism of neuromuscular block, and lack of interaction have all been reported22.


  Interaction(s) with other Common Medicines used in the Perioperative Period


CNS Depression (also see under Interaction(s) with Common Anaesthetic Agents for information on opioids).

Benzodiazepines and benzodiazepine-like drugs have CNS depressant effects which may be additive with antiemetics that also have CNS depressant effects such as cyclizine, droperidol and prochlorperazine1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19.

Antimicrobials

Macrolide Antibiotics
Compounds that inhibit hepatic enzymes may increase the concentration of benzodiazepines and enhance their activity. Hence, caution is recommended when benzodiazepines and benzodiazepine-like drugs are co-administered with macrolide antimicrobials (e.g. erythromycin, clarithromycin)6, 8, 14, 19. Monitor the patient for increased sedative effects and adjust the benzodiazepine dose as necessary.

Ciprofloxacin
Concomitant use of ciprofloxacin may slightly increase blood levels of zolpidem and diazepam4, 18. Concurrent use of ciprofloxacin and zolpidem is not recommended by the manufacturer18; however, evidence for this interaction is limited. It is unlikely that any clinically significant increases in benzodiazepine effects will occur4.

Whilst single surgical prophylactic doses should not pose a problem, continued post-operative treatment may require close monitoring for benzodiazepine adverse effects.

Corticosteroids

Chronic corticosteroid use may increase metabolism of diazepam, due to induction of CYP3A4 or of enzymes responsible for glucuronidation, leading to reduced effects of diazepam8. This is unlikely to be an issue where corticosteroids are used as single doses to reduce post-operative nausea and vomiting or as cover for patients at risk of adrenal insufficiency. However, bear the interaction in mind should continued corticosteroid treatment be necessary.

Proton Pump Inhibitors (PPIs)

Esomeprazole and omeprazole might increase the serum concentrations of benzodiazepines (via CYP2C19 inhibition) leading to increased adverse effects such as drowsiness, although the clinical relevance is low in most patients – monitor the patient for adverse effects (e.g. drowsiness, sedation, ataxia) and adjust the dose of benzodiazepine as necessary4, 5, 7, 8, 10, 11, 21. Alternatively, consider changing to a non-interacting PPI (e.g. lansoprazole)2.


  Further Information


Withdrawal 

Sudden discontinuation of benzodiazepines or benzodiazepine-like drugs is associated with withdrawal symptoms including confusion, toxic psychosis, convulsions, delirium and rebound effects. Doses should be reduced gradually1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 16, 17, 18, 19, 20, 21.

Withdrawal symptoms can occur within a day after stopping short-acting benzodiazepines, such as alprazolam, lorazepam, lormetazepam, oxazepam and temazepam1.

Withdrawal symptoms from zolpidem and zopiclone are unlikely if treatment duration has been less than 4 weeks18, 19.

Post-operative Delirium (POD)

POD has been shown to be a predictor of death, increased mortality, and longer duration of stay especially in ventilated patients23. Benzodiazepines have been found to increase the frequency of POD. The frequency may be higher in elderly patients and those on long-term benzodiazepines23, 24, 25. In addition, if a patient develops POD, consideration should be given to not using benzodiazepines as the first-line agents for treatment23.

MHRA/CHM Advice: Antiepileptic Drugs: updated advice on switching between different manufacturer’s products for a particular drug (November 2017)1

Epilepsy
Clobazam and clonazepam are category 2 antiepileptics, hence the need for continued supply of a particular manufacturer’s product should be based on clinical judgement and consultation with the patient and / or carer taking into account factors such as seizure frequency treatment history, and potential implications to the patient having a breakthrough seizure. Non-clinical factors such as patient anxiety, confusion, potential for dosing errors should also be considered (For more information see Antiepileptics – A General Overview).

Other Indications
There is no specific advice available for maintaining patients on a specific manufacturer’s product for indications other than epilepsy.

 

  References


  1. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 10th July 2019]
  2. Perks A, Cheema S, Mohanraj R. Anaesthesia and epilepsy. BJA: British Journal of Anaesthesia. 2012; 108(4):562-571
  3. Carter EL, Adapa RM. Adult epilepsy and anaesthesia. BJA Education. 2015; 15(3):111-117
  4. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 29th August 2019
  5. Diazepam. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 29th August 2019]
  6. Summary of Product Characteristics – Xanax® (alprazolam) 500 micrograms. Pfizer Limited. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text January 2019]
  7. Summary of Product Characteristics – Frisium® (clobazam) 10mg Tablets. SANOFI. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text July 2018]
  8. Summary of Product Characteristics – Diazemuls Emulsion® (diazepam). Accord-UK Ltd. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text August 2019]
  9. Summary of Product Characteristics – Clonazepam Auden 2mg Tablets. TEVA UK Limited. Accessed via www.mhra.gov.uk 11/09/2019 [date of revision of the text September 2018]
  10. Summary of Product Characteristics – Diazepam Tablets BP 10mg. Accord-UK Ltd. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text December 2018]
  11. Summary of Product Characteristics – Dalmane® (flurazepam) 15mg Capsules. Mylan. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text July 2018]
  12. Summary of Product Characteristics – Loprazolam 1mg Tablets. Zentiva. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text August 2018]
  13. Hase I, Oda Y, Tanaka K. I.v. fentanyl decreases the clearance of midazolam. British Journal of Anaesthesia. 1997; 79:740-743
  14. Summary of Product Characteristics – Lorazepam 2.5mg Tablets. Genus Pharmaceuticals. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text October 2018]
  15. Summary of Product Characteristics – Nitrazepam Tablets 5mg. Accord-UK Ltd. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text December 2018]
  16. Summary of Product Characteristics – Oxazepam Tablets 10mg Tablets. Genus Pharmaceuticals. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text October 2018]
  17. Summary of Product Characteristics – Temazepam 20mg Tablets. Mylan. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text December 2017]
  18. Summary of Product Characteristics – Zolpidem Tartrate 10mg Tablets. Zentiva. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text January 2019]
  19. Summary of Product Characteristics – Zopiclone 7.5mg Tablets. Accord-UK Ltd. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text June 2019]
  20. Summary of Product Characteristics – Dormagen® (lormetazepam) 1mg Tablets. Genus Pharmaceuticals. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text October 2018]
  21. Summary of Product Characteristics – Chlordiazepoxide 10mg Capsules. Kent Pharmaceuticals Ltd. Accessed via www.medicines.org.uk 11/09/2019 [date of revision of the text August 2018]
  22. Atracurium Besilate. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 29th August 2019]
  23. Zhang Y, Tany Y, Yang J et al. Perioperative Use of Benzodiazepines: A Reconsideration of Risks and Benefits. J Anaesth Perioper Med. 2018; 5(1):34-40
  24. Kudoh A, Takase H, Takahira Y. Postoperative confusion increases in elderly long-term benzodiazepine users. Anesthesia & Analgesia. 2004; 99(6):1674
  25. Lepouse C, Lautner CA, Liu A et al. Emergence delirium in adults on the post-anaesthesia care unit. British Journal of Anaesthesia. 2006; 96(6):747-753