Trazodone

  Issues for Surgery

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

Risk of serotonin syndrome if continued (see Interaction(s) with Common Anaesthetic Agents and Interaction(s) with other Common Medicines used in the Perioperative Period).

Risk of QT-interval prolongation if continued (see Interaction(s) with other Common Medicines used in the Perioperative Period).

  Advice in the Perioperative period

Elective and Emergency Surgery

Continue. 

Post-operative Advice

If a long nil by mouth (NBM) period is anticipated, or if there are concerns with enteral absorption, advice on alternative preparations / routes should be sought from a Psychiatrist.

  Interaction(s) with Common Anaesthetic Agents

Central Nervous System (CNS) Excitation (Serotonin Syndrome)

Some opioids act as weak serotonin reuptake inhibitors (SRIs) and can precipitate serotonin syndrome in conjunction with other serotonergic medication. Symptoms of serotonin syndrome may occur if trazodone is given concomitantly with^{1, 2}:

• fentanyl
• methadone
• pentazocine
• pethidine
• tapentadol
• tramadol

Patients should be monitored closely and the possibility of serotonin toxicity considered if patients experience altered mental state, autonomic dysfunction or neuromuscular adverse effects with concomitant treatment¹.

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

Trazodone has CNS depressant effects which may be additive with other medicines that also have CNS depressant effects such as^{1, 2}:-

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

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

QT-Interval Prolongation (see also Interaction(s) with other Common Medicines used in the Perioperative Period)
Cases of QT-interval prolongation have been reported during post-marketing use of trazodone^{2, 3}.  Co-administration with other medicines known to prolong the QT-interval must be based on careful assessment of the potential risks and benefits for each patient.

Anaesthetic agents that may be used in the perioperative period that are known to, or predicted to, prolong the QT-interval include^{1, 2}: -

• desflurane, isoflurane, sevoflurane*
• thiopental (theoretical)**

*monitor ECG if concurrent use unavoidable; if risk factors for QT-prolongation are also present (increasing age, female sex, cardiac disease, and some metabolic disturbances e.g. hypokalaemia) use greater caution

**monitor ECG with concurrent use if risk factors for QT-prolongation are also present (increasing age, female sex, cardiac disease, and some metabolic disturbances e.g. hypokalaemia).

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

CNS Excitation (Serotonin Syndrome)

Opioids
For a discussion of opioids see under Interaction(s) with Common Anaesthetic Agents above. In addition, trazodone lowers the seizure threshold; concurrent use with tramadol, which also lowers the seizure threshold, may have an additive effect on the risk of seizures².

Methylthioninium chloride (methylene blue)
There has been a case report of serotonin syndrome in a patient taking trazodone who were also given methylthioninium chloride². The MHRA advise that methylthioninium chloride should be avoided in patients taking drugs that enhance serotonergic transmission. If concurrent use is necessary the lowest possible dose of methylthioninium chloride should be given and the patients should be closely monitored for signs of CNS toxicity for 4 hours after administration. However, this advice is contested in one report which suggests even doses as low as 1mg/kg may be sufficient to inhibit monoamine oxidase-A, thus causing a reaction².

Other Medications
There is also an increased risk of developing serotonin syndrome when trazadone is used concurrently with the following¹: -

• granisetron (also see QT-Interval Prolongation below)
• ondansetron (also see QT-Interval Prolongation below)
• linezolid

Monitor patients for symptoms of serotonin syndrome such as fever, tremors, diarrhoea, and agitation. Concurrent treatment should be stopped if serotonin syndrome occurs¹.

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

Trazodone has CNS depressant effects which may be additive with antiemetics that also have CNS depressant effects such as cyclizine, droperidol and prochlorperazine^{1, 2}.

QT-Interval Prolongation

Cases of QT-interval prolongation have been reported during post-marketing use of trazodone^{2, 3}. Co-administration with other medicines known to prolong the QT-interval must be based on a careful assessment of the potential risks and benefits for each patient since the risk of torsade de pointes may increase².

Medicines that may be used in the perioperative period that are known to prolong the QT-interval include²:-

• ciprofloxacin*
• clarithromycin* (also see Macrolide Antibiotics below)
• domperidone – avoid
• droperidol*
• erythromycin (especially intravenous)* (also see Macrolide Antibiotics below)
• granisetron*
• haloperidol – if concurrent use not avoidable*
• loperamide (increased risk with high doses)*
• ondansetron*
• prochlorperazine*

_{*monitor ECG with concurrent use if risk factors for QT-interval prolongation also present (increasing age, female sex, cardiac disease, and some metabolic disturbances e.g. hypokalaemia)}

Macrolide Antibiotics

Clarithromycin and erythromycin are predicted to moderately increase the exposure to trazodone through inhibition of CYP3A4^{1, 2, 3}. Whilst single surgical prophylactic doses should not pose a problem, monitor for side effects and consider reducing trazodone dose if concurrent use cannot be avoided and a prolonged course is required.

  Further Information

Withdrawal

Ideally trazodone should not be withdrawn abruptly as withdrawal effects may occur within 5 days of stopping treatment¹; they are usually mild and self-limiting, e.g. headache, nausea, malaise³, but in some cases may be severe. The risk of withdrawal is increased if trazodone is stopped suddenly after regular administration for more than 8 weeks¹.

  References

1. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 10^th August 2019]
2. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 10^th August 2019]
3. Summary of Product Characteristics – Molipaxin^® (trazodone) 100mg. Zentiva. Accessed via www.medicines.org.uk 10/08/2019 [date of revision of the text August 2018]