UK Clinical Pharmacy Association

Diazepam

Issues for surgery

For anxiety and anxiety related issues – 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 depression if continued.

Potential for post-operative delirium 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.

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

Post-operative advice

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 should be advised of the potential of enhanced drowsiness and psychomotor effects and counsel against undertaking skilled tasks (e.g. driving).

Interactions with common anaesthetic agents

Central Nervous System (CNS) depression 

Also see Interactions with other common medicines used in the perioperative period.

Benzodiazepines have CNS depressant effects which may be additive with other medicines that also have CNS depressant effects such as:

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

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 sedation.

Bupivacaine

Diazepam has 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 required.

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 effect.

If benzodiazepines are used concomitantly with opioids, possible euphoria may be enhanced; this may lead to increased psychological dependence.

The current recommendation from manufacturers for the prescribing of benzodiazepines 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 with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

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 reported.

Interactions with other common medicines used in the perioperative period

CNS depression 

Also see Interactions with common anaesthetic agents for information on opioids.

Benzodiazepines have CNS depressant effects which may be additive with antiemetics that also have CNS depressant effects such as:

  • cyclizine
  • droperidol
  • prochlorperazine

Antimicrobials

Macrolide antibiotics

Compounds that inhibit hepatic enzymes may increase the concentration of benzodiazepines and enhance their activity. Hence, caution is recommended when benzodiazepines are co-administered with macrolide antimicrobials (e.g. erythromycin, clarithromycin). 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 diazepam. It is unlikely that any clinically significant increases in benzodiazepine effects will occur.

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 diazepam. 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 necessary. Alternatively, consider changing to a non-interacting PPI (e.g. lansoprazole).

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 gradually.

Post-operative delirium (POD)

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

References

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Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 29th August 2019

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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

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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]

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]

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