Barbiturates



Phenobarbital, Primidone 

  Issues for Surgery


For treatment of epilepsy – precipitation of rebound seizures or status epilepticus if omitted.

For treatment of essential tremor (primidone) – return of tremor if omitted.

Risk of withdrawal reaction after prolonged use – if omitted abruptly1, 2.


  Advice in the Perioperative period


Elective and Emergency Surgery

Continue.

Patients should be advised to take their regular medications on the day of surgery3, 4, 5.

Abrupt withdrawal of any anticonvulsant drug should be avoided3.

Ensure that the patient is maintained on a specific manufacturer’s product (see Further Information).

Post-operative Advice

Regular dosing of the patient’s usual oral medication should be re-established as early as possible post-operatively4, 5.

For patients on phenobarbital who are unable to take their regular oral medication post-operatively, consider using the intravenous route. The intravenous dose and frequency should be the same as the established oral dose3.

Primidone is 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.


  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)

Barbiturates are very potent CNS depressants and there may be additive effects with other medicines that also have CNS depressant effects such as1, 2, 3, 6, 7:-

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

(Consult British National Formulary for available drugs in each class)

The degree of CNS depression will depend on the individual patient. Concurrent use need not be avoided, but use with care. Be aware of potential for respiratory depression, especially in patients with restricted respiratory capacity8.

Benzodiazepines
Primidone is predicted to increase the metabolism of midazolam leading to a decrease in exposure; the clinical significance of this is not known however caution is advised3, 8.

Opioids
Primidone is predicted to increase the metabolism of alfentanil and fentanyl leading to a decrease in exposure; increased anaesthetic maintenance requirements may be necessary3, 8.

Primidone is predicted to decrease the exposure to oxycodone – monitor for oxycodone efficacy and adjust the oxycodone dose as necessary3, 8.

Tramadol should be avoided in patients with a history of epilepsy due to an increase in seizure risk3.

Esketamine / Ketamine

The recovery time following administration of esketamine / ketamine with barbiturates may be prolonged8. In addition, primidone is predicted to decrease the exposure to esketamine3, 8. Be aware of this effect and adjust patient management as appropriate8.

Local Anaesthetics

Lidocaine levels following slow intravenous injection might be slightly reduced in patients who are taking phenobarbital. It seems likely that other barbiturates will interact similarly. IV lidocaine is usually titrated to effect so interaction will probably be accommodated with routine use. Bear the possibility of an interaction in mind, particularly in patients given longer infusions of systemic lidocaine or those taking multiple enzyme-inducing antiepileptics8.

Primidone is predicted to increase the risk of methaemoglobinaemia when given with topical prilocaine and the manufacturer advises use with caution or avoid3.


  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)

Barbiturates are very potent CNS depressants and there may be additive effects with antiemetics that also have CNS depressant effects such as cyclizine, droperidol and prochlorperazine*3).

*NB: see Antiepileptics – A General Overview

Corticosteroids

Primidone is predicted to decrease the exposure to dexamethasone and hydrocortisone1, 2, 3. Different corticosteroids appear to be affected to different degrees, monitor the patient and increase the dosage of corticosteroids if necessary, in order to maintain the desired therapeutic response7.

 Antiemetics

For general information regarding the use of antiemetics in patients with epilepsy – see ‘‘Antiepileptics – A General Overview’.

Primidone is predicted to decrease the exposure to ondansetron hence be aware for the potential that ondansetron might be less effective3, 8.

There is potential for an interaction with granisetron but this is unlikely to be clinically significant8.

Antimicrobials

Phenobarbital and primidone increase the rate of metabolism of doxycycline and metronidazole potentially resulting in treatment failure – consider doubling doxycycline dose and increasing metronidazole dose 2-3 fold; monitor for treatment failure 1, 2, 3, 9.

Paracetamol

Primidone decreases exposure to paracetamol due to increased paracetamol metabolism – consider an interaction as a possible cause of any reduction in paracetamol efficacy3, 8.

In addition, primidone inhibits glucuronidation of paracetamol and, hence, may increase the risk of hepatotoxicity although no formal interaction studies have been performed1.


  Further Information


MHRA/CHM Advice: Antiepileptic Drugs: updated advice on switching between different manufacturer’s products (November 2017)3

Phenobarbital and primidone are category 1 antiepileptics and patients should be maintained on a specific manufacturer’s product. (For more information see ‘Antiepileptics – A General Overview).


  References


  1. Summary of Product Characteristics – PRIMIDONE 250mg tablet. SERB. Accessed via www.medicines.org.uk 20/07/2019 [date of revision of the text August 2014]
  2. Summary of Product Characteristics – Phenobarbital Accord Tablets BP 30mg. Accord-UK Ltd. Accessed via www.medicines.org.uk 20/07/2019 [date of revision of the text February 2019]
  3. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com [Accessed 30th June 2019]
  4. Perks A, Cheema S, Mohanraj R. Anaesthesia and epilepsy. BJA: British Journal of Anaesthesia. 2012; 108(4): 562-571
  5. Carter EL, Adapa RM. Adult epilepsy and anaesthesia. BJA Education. 2015;15(3): 111-117
  6. Phenobarbital. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 20th July 2019]
  7. Antiepileptics (Corticosteroids – Interactions of Corticosteroids). In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 20th July 2019]
  8. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 20th July 2019]
  9. Metronidazole. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 20th July 2019]