Selective Serotonin Reuptake Inhibitors (SSRIs)


Citalopram, Dapoxetine, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline

 

  Issues for Surgery


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

For depression, panic disorder, anxiety disorders, obsessive-compulsive disorder, bulimia nervosa or hot flushes in women with breast cancer - risk of 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 QT-interval prolongation with citalopram or escitalopram if continued (see Interaction(s) with other Common Medicines used in the Perioperative Period).

Risk of bleeding if continued (see Further Information).


  Advice in the Perioperative period


Elective and Emergency Surgery

Continue1, 2 – check sodium levels pre-operatively (see Further Information).

Dapoxetine is licensed for on-demand treatment before anticipated sexual activity – although not needed in the perioperative period manufacturer advises potential for interactions if dose(s) taken in previous 7 days3 (see Interaction(s) with Common Anaesthetic Agents and Interaction(s) with other Common Medicines used in the Perioperative Period).

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.

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

Patients undergoing Vagotomy or Gastrectomy
Absorption of paroxetine suspension may be reduced post-operatively as in vitro data shows that an acidic environment is required for release of the active drug from the suspension4.


  Interaction(s) with Common Anaesthetic Agents


CNS Excitation (Serotonin Syndrome)

Some opioids act as weak serotonin reuptake inhibitors (SRIs) and can precipitate serotonin syndrome in conjunction with SSRIs. Symptoms of serotonin syndrome have been reported in patients taking SSRIs with the following opioids1, 2, 5, 6, 7: -

  • fentanyl
  • hydromorphone
  • oxycodone
  • pentazocine
  • pethidine
  • tramadol
  • (and possibly) morphine

There is little evidence to suggest the above medications cannot be used safely and effectively with SSRIs, however, patients should be monitored closely and the possibility of serotonin toxicity considered if altered mental state, autonomic dysfunction or neuromuscular adverse effects are observed with concomitant treatment6.

Neuromuscular blocking drugs (NMBDs)

SSRIs reduce the normal activity of plasma cholinesterases; the action of mivacurium and suxamethonium may be prolonged as they are inactivated by hydrolysis by plasma cholinesterases. Other NMBDs with different mechanisms of metabolism or elimination are unlikely to be affected5, 6. There have been no published reports of this interaction in clinical practice, however, bear in mind in the event of an unexpected response to treatment6.

Propofol

Pronounced involuntary upper limb movements immediately after anaesthetic induction were reported in two females taking fluoxetine. It is not clear whether this is an interaction between fluoxetine and propofol or a rare, but previously reported, reaction to propofol6.

Ropivacaine

Fluvoxamine, a potent inhibitor of CYP1A2, significantly reduces plasma clearance of ropivacaine in vivo almost doubling the half-life. Prolonged administration of ropivacaine should be avoided in patients taking fluvoxamine6, 8.


  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.

Methylthioninium chloride (methylene blue)
There have been case reports of serotonin syndrome in patients taking SSRIs who were also given methylthioninium chloride6, 9. The MHRA advise that methylthioninium chloride should be avoided in patients taking drugs that enhance serotonergic transmission, they specifically name SSRIs. 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 administration6, 10. 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 reaction6.

Other medications
There is also an increased risk of developing serotonin syndrome when SSRIs are used concurrently with the following5: -

  • 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 occurs5.

QT-Interval Prolongation

Citalopram and escitalopram are known to cause QT-interval prolongation5, 6, 11, 12. 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 increase.

Medicines that may be used in the perioperative period that are known to prolong the QT-interval include5, 6:-

  • ciprofloxacin*
  • clarithromycin*
  • domperidone - avoid
  • droperidol - avoid
  • erythromycin (especially intravenous)*
  • granisetron - ideally avoid
  • haloperidol - avoid
  • loperamide (increased risk with high doses)*
  • ondansetron - avoid
  • 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)

Increased risk of bleeding (see also Further Information)

Concomitant use of SSRIs with other medications that can increase the risk of bleeding e.g. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) may have an additive effect1, 3, 4, 5, 6, 7, 11, 12, 13, 14, 15. If the combination of SSRI 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 SSRI-associated bleeding) or patients with a history of gastrointestinal bleeding5, 6, 11.

Increased risk of hyponatraemia (see also Further Information)

Concomitant use of SSRIs with NSAIDS may increase the risk of hyponatraemia5, 16.

Codeine

Fluoxetine and paroxetine (but not other SSRIs) are potent CYP2D6 inhibitors so are predicted to decrease the metabolism of codeine to morphine, possibly reducing its analgesic efficacy. With concomitant use monitor patients for a reduced response to codeine and consider using an alternative analgesic if this is observed4, 5, 6.

Tramadol

SSRIs can lower the seizure threshold; concurrent use with tramadol that also lowers the seizure threshold may have an additive effect on the risk of seizure6, 13. In addition tramadol may increase the risk of serotonin syndrome (see Interaction(s) with Common Anaesthetic Agents). Concomitant administration of tramadol with fluoxetine and paroxetine may result in reduced analgesic efficacy due to CYP2D6 inhibition6.


  Further Information


Bleeding

Serotonin released from platelets potentiates platelet aggregation. SSRIs can block platelets reuptake of serotonin from the bloodstream leading to serotonin depletion, impairment of haemostatic function and an increased risk of bleeding1, 16, 17. There are reports of prolonged bleeding time and / or bleeding abnormalities (gastrointestinal bleeding, gynaecological haemorrhages, ecchymoses, cutaneous or mucous bleedings) in patients receiving SSRIs1, 3, 4, 7, 11, 12, 13, 14, 15. 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).

Observational studies suggest a link between SSRIs and an increased risk of perioperative bleeding, with one study indicating SSRIs increase the odds of in-hospital mortality, bleeding and readmission at 30 days; however, patient factors rather than medication factors could not be excluded as the cause1, 17. Other studies have shown increased need for red blood cell transfusions in patients having coronary artery bypass or orthopaedic surgery1, 7, 16, 17. However, a case-control study did not demonstrate an increase in blood loss following hip and knee arthroplasty18. Clinicians should be aware that SSRIs may contribute to perioperative bleeding, further research is needed to determine the significance of this17.

Withdrawal

Abruptly stopping or interrupting treatment with SSRIs is not recommended5, 16. Common withdrawal symptoms include dizziness, numbness, tingling, nausea, vomiting, headache, sweating, anxiety and sleep disorders. In some cases, withdrawal symptoms can be severe and disabling7, 16. Withdrawal reactions usually occur within 3 days of stopping an SSRI, although a delay of up to 2 weeks may be noted with fluoxetine due to its long half-life. Paroxetine and fluvoxamine are associated with a higher risk of withdrawal reactions, possibly due to their short half-lives7. The risk of withdrawal is increased if SSRIs are stopped suddenly after regular administration for more than 8 weeks5.

Hyponatraemia

Hyponatraemia, possibly as a result of inappropriate secretion of antidiuretic hormone has been associated with SSRIs1, 16. Caution is required in patients at increased risk of hyponatraemia, such as elderly, or volume depleted / dehydrated patients or patients treated with diuretics15, 16.


  References


  1. Taylor D, Barnes T, Young A. The Maudsley Prescribing Guidelines in Psychiatry. 13th ed. Chichester: Wiley- Blackwell; 2018.
  2. Peck, T. Wong, A. & Norman, E. Anaesthetic implications of psychoactive drugs. Continuing Education in Anaesthesia Critical Care & Pain. 2010;10(6):177-181
  3. Summary of Product Characteristics – Priligy® (dapoxetine) 30mg film-coated tablets. A. Menarini Farmaceutica Internazionale SRL. Accessed via www.medicines.org.uk 24/07/2019 [date of revision of the text March 2019]
  4. Summary of Product Characteristics – Seroxat ® (paroxetine) 10mg tablets. GlaxoSmithKline Limited. Accessed via www.medicines.org.uk 18/07/2019 [date of revision of the text February 2019]
  5. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 18th July 2019]
  6. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 18th July 2019]
  7. Fluoxetine. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. Electronic version. Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com. [Accessed 18th July 2019]
  8. Summary of Product Characteristics – Naropin ® (ropivacaine) 10mg/ml solution for injection. Aspen. Accessed via www.medicines.org.uk 20/07/2019 [date of revision of the text February 2018]
  9. Bazire S. Psychotropic Drug Directory 2016. The Professionals’ Pocket Handbook and Aide Memoire. Dorsington: Lloyd-Reinhold Publications Limited. 2016.
  10. Summary of Product Characteristics – ProveBlue ® (methylthioninium chloride) 5mg/ml solution for injection. Martindale Pharma. Accessed via www.medicines.org.uk 20/07/2019 [date of revision of the text February 2018]
  11. Summary of Product Characteristics – Cipramil ® (citalopram) Tablets. Lundbeck Limited. Accessed via www.medicines.org.uk 18/07/2019 [date of revision of the text March 2019]
  12. Summary of Product Characteristics – Cipralex ® (escitalopram) 10mg film-coated tablets. Lundbeck Limited. Accessed via www.medicines.org.uk 18/07/2019 [date of revision of the text January 2018]
  13. Summary of Product Characteristics – Prozac ® (fluoxetine) 20mg hard capsules. Eli Lilly and Company Limited. Accessed via www.medicines.org.uk 18/07/2019 [date of revision of the text March 2018]
  14. Summary of Product Characteristics – Faverin ® (fluvoxamine) 50mg film-coated tablets. Mylan. Accessed via www.medicines.org.uk 18/07/2019 [date of revision of the text October 2018]
  15. Summary of Product Characteristics – Lustral ® (sertraline) 100mg film-coated tablets. Pfizer Limited. Accessed via www.medicines.org.uk 18/07/2019 [date of revision of the text November 2018]
  16. Looper KJ. Potential Medical and Surgical Complications of Serotonergic Antidepressant Medications. Psychosomatics 2007; 48(1):1-9
  17. Shepherd SJ, Fiandeiro C & Sander RD. Selective serotonin reuptake inhibitors: depressing perioperative outcomes? British Journal of Anaesthesia. 2015; 115(1):5-7
  18. Tavakoli HR, DeMaio M, Wingert NC et al. Serotonin Reuptake Inhibitors and Bleeding Risks in Major Orthopaedic Procedures. Psychosomatics. 2012; 53(6):559-565