Serotonin and Noradrenaline Re-uptake Inhibitors (SNRIs)

 Duloxetine, Venlafaxine 

  Issues for Surgery

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

Possible loss of symptom control if omitted.

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 bleeding if continued (see Further Information).

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

  Advice in the Perioperative period

Elective and Emergency Surgery

Continue – check sodium levels pre-operatively (see Further Information).

For patients taking duloxetine who may decide to quit smoking during the perioperative period see Further Information.

Post-operative Advice

Monitor electrolytes, particularly sodium, if risk factors for hyponatraemia (see Further Information).

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 have been reported in patients taking venlafaxine with tramadol or methadone; however, symptoms of serotonin syndrome may occur if SNRIs are given concomitantly with any of the following1, 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, 2.

CNS Depression

The manufacturers of duloxetine and venlafaxine advise caution with concomitant administration of other centrally acting medications (e.g. benzodiazepines, opioids or sedating antihistamines3, 4, 5).

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

CNS Excitation (Serotonin Syndrome)

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

Methylthioninium Chloride (Methylene Blue)
There have been case reports of serotonin syndrome, including a fatality, in patients taking SNRIs who were also given methylthioninium chloride2. The MHRA advise that methylthioninium chloride should be avoided in patients taking drugs that enhance serotonergic transmission, they specifically name venlafaxine but the advice is also applicable to duloxetine. 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 administration2, 6. 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
Symptoms of serotonin syndrome have been reported in patients taking venlafaxine with co-amoxiclav or metoclopramide, however, the general relevance of this is unclear2. There is also an increased risk of developing serotonin syndrome when SSRIs are used concurrently with the following1, 3, 4, 5:- 

  • granisetron
  • ondansetron
  • 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 (see Interaction(s) with Common Anaesthetic Agents)

QT-Interval Prolongation

Venlafaxine, but not duloxetine, is known to cause QT-interval prolongation1, 2, 3, 4, 5. Co-administration of venlafaxine 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 increase 2.

Medicines that may be used in the perioperative period that are known to prolong or predicted to prolong the QT-interval include1, 2: -

  • ciprofloxacin*
  • clarithromycin*
  • domperidone – avoid
  • droperidol*
  • erythromycin (especially intravenous)*
  • granisetron – ideally avoid
  • haloperidol – if concurrent use not avoidable*
  • loperamide (increased risk with high doses)*
  • ondansetron*
  • prochlorperazine – only a theoretical risk

*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)

Increased Risk of Bleeding (see also Further Information)

Concomitant use of SNRIs with other medications that can increase the risk of bleeding e.g. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) or Low Molecular Weight Heparins (LMWHs) may have an additive effect1. 3, 4. 5. If the combination of SNRI and NSAID cannot be avoided, gastroprotection with a H2-receptor antagonist or proton pump inhibitor should be considered for the duration of concomitant use, particularly in elderly patients (who seem at greater risk of SNRI-associated bleeding) or patients with a history of gastrointestinal bleeding)2.

Increased Risk of Hyponatraemia (see also Further Information)

Concomitant use of SNRIs with NSAIDS may increase the risk of hyponatraemia1.

  Further Information


Abruptly stopping or interrupting treatment with SNRIs is not recommended; venlafaxine is associated with a higher risk of withdrawal effects compared with other antidepressants1. Common withdrawal symptoms include nausea, vomiting, headache, anxiety, dizziness, paraesthesia, sleep disturbances, tremor and sweating1, 3, 4, 5. Generally symptoms are mild or moderate and last a few weeks; however, in some cases withdrawal symptoms can be severe and prolonged. Withdrawal reactions usually occur within a few days of stopping an SNRI. The risk of withdrawal is increased if SNRIs are stopped suddenly after regular administration for more than 8 weeks4, 5.


Serotonin released from platelets potentiates platelet aggregation. SNRIs can block platelets reuptake of serotonin from the bloodstream leading to serotonin depletion, impairment of haemostatic function and an increased risk of bleeding. There are reports of bleeding abnormalities (gastrointestinal bleeding, ecchymoses, epistaxis, haematomas and purpura) in patients receiving SNRIs3, 4, 5. This risk is further increased with concomitant use of other medications known to affect platelet function (see Interaction(s) with other Common Medicines used in the Perioperative Period). Venlafaxine may have similar effects on surgical and post-operative bleeding as SSRIs, but duloxetine may not affect bleeding risk7 (see Selective Serotonin Reuptake Inhibitors monograph).


Hyponatraemia, likely due to inappropriate secretion of antidiuretic hormone has been associated with SNRIs3, 4, 5. Caution is required in patients at increased risk of hyponatraemia, such as elderly, or volume depleted/dehydrated patients or patients treated with diuretics or NSAIDs3, 4, 5.

Smoking Cessation

Quitting smoking pre-operatively improves surgical outcomes through reducing risk of post-operative complications8. Tobacco is known to induce CYP1A2 resulting in reduced duloxetine plasma concentrations in smokers2, 4, 5. If a patient taking duloxetine decides to quit smoking during the perioperative period, they should be advised to report any increase in side effects to the prescriber as dosage adjustments may be necessary.


  1. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. [Accessed on 10th August 2019]
  2. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. [Accessed on 10th August 2019]
  3. Summary of Product Characteristics – Efexor® (venlafaxine) XL 75mg hard prolonged release capsules. Pfizer Limited. Accessed via 10/08/2019 [date of revision of the text July 2018] 
  4. Summary of Product Characteristics – Yentreve® (duloxetine) 40mg hard gastro-resistant capsules. Eli Lilly and Company Limited. Accessed via 10/08/2019 [date of revision of the text June 2019]
  5. Summary of Product Characteristics – Cymbalta® (duloxetine) 30mg hard gastro-resistant capsules. Eli Lilly and Company Limited. Accessed via 10/08/2019 [date of revision of the text June 2019]
  6. Summary of Product Characteristics – ProveBlue® (methylthioninium chloride) 5mg/ml solution for injection. Martindale Pharma. Accessed via 10/08/2019 [date of revision of the text February 2018]
  7. Taylor D, Barnes T, Young A. The Maudsley Prescribing Guidelines in Psychiatry. 13th ed. Chichester: Wiley- Blackwell; 2018.
  8. Faculty of Public Health, The Royal College of Surgeons of Edinburgh, The Royal College of Anaesthetists, ash (action on smoking and health). Joint Briefing: Smoking and surgery. April 2016. Available at [Accessed 10th August 2019]