NSAIDs and COX-2 Inhibitors


 

Standard NSAIDs: Aspirin [analgesic/high-dose > 150mg], Dexibuprofen, Dexketoprofen, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indometacin, Ketoprofen, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Tolfenamic acid

COX-2 Selective Inhibitors: Celecoxib, Etoricoxib

[This monograph does not cover the use of aspirin as an antiplatelet agent – refer to Aspirin monograph]


 Issues for Surgery


Loss of pain control if omitted.

For gout, inflammatory conditions, migraine – loss of symptom control if omitted.

For standard NSAIDs – increased risk of bleeding if continued.


  Advice in the Perioperative period


Elective Surgery

Check blood pressure (BP) and renal function pre-operatively.

Low Bleeding Risk Procedures
Standard NSAIDs and COX-2 inhibitors: Continue1 – including combination products.

EXCEPT:
Aspirin – consider stopping 7 days pre-operatively, and using alternative analgesia, to minimise the risk of bleeding (including combination products).

High Bleeding Risk Procedures
COX-2 inhibitors: Continue, (including meloxicam) – see Further Information

Standard NSAIDs: -

  • Short-acting NSAID – stop 1 day before surgery1, including combination products (see below).
  • Long-acting NSAID – stop five half-lives prior to procedure (see figure 1), including combination products. Consideration should be given to switching to a short-acting NSAID pre-operatively if necessary and following the advice above.
  • Aspirin – stop 7 days pre-operatively (including combination products) and consider using alternative analgesia.
  • If necessary, consideration should be given to prescribing the components of combination products as separate medicines perioperatively (particularly for the combination product dexketoprofen + tramadol).


NSAID Combination Products: -

  • Skudexa® (contains dexketoprofen + tramadol (also see Opioids monograph)
  • Arthrotec® / Misofen® (contains diclofenac + misoprostol)
  • Vimovo® (contains naproxen + esomeprazole) (also see Proton Pump Inhibitors monograph)


Analgesic Aspirin Combination Products:-

(NB: there are many different over-the-counter [OTC] analgesic preparations that contain aspirin together with other medicines)

  • paracetamol + aspirin + caffeine (e.g Anadin® Extra)
  • aspirin + caffeine (e.g. Beechams® Powders)
  • aspirin + codeine (e.g. Codis® 500)
  • Migramax® (contains aspirin + metoclopramide)

Short-acting NSAIDs: Dexibuprofen, Dexketoprofen, Diclofenac (modified and standard release preparations), Flurbiprofen, Ibuprofen (modified and standard release preparations), Indometacin, Mefenamic acid, Tiaprofenic acid, Tolfenamic acid

Figure 1: Recommendations on time prior to surgery NSAID should be stopped for high bleeding risk surgery1, 2, 3, 4, 5, 6, 7, 8

Emergency Surgery

If there is insufficient time to follow the advice above be aware of the potential for increased bleeding risk if patient has taken doses in the days leading up to surgery.

Perioperative Considerations

Neuraxial Anaesthesia (see Further Information)
Although standard NSAIDs can affect platelet function, there is no increased risk of epidural haematoma and therefore there are no contraindications to patients having either regional anaesthesia or neuraxial blockade9.

Post-operative Advice

NSAIDs are a valuable option for post-operative pain relief in those patients in whom their use is not contra-indicated. They may be useful alternatives or adjuncts to opioids10. In surgery with high risk of bleeding or where bleeding can result in catastrophic outcome such as ophthalmic or neurosurgery, the decision to prescribe NSAIDs should be made on a case-by-case basis.

Monitor renal function – there is an increased risk of acute kidney injury (AKI) in patients with use of NSAIDs after surgery (especially in patients undergoing emergency surgery or intraperitoneal surgery)11.

NSAIDs may mask fever and other signs of inflammation – close monitoring for post-operative infection is advised12, 13, 14.

NSAIDs should be prescribed at the lowest effective dose and for the shortest duration possible to minimise adverse effects15. If the surgery has addressed the cause of the pain, NSAID analgesia should be weaned post-operatively with a view to stopping completely.


  Interaction(s) with Common Anaesthetic Agents


Thiopental

The anaesthetic dose of thiopental is reduced and its effects prolonged in patients who have been pre-treated with aspirin (at analgesic dose)14.

Bupivacaine

One study suggests that the failure rate of spinal anaesthesia with bupivacaine is markedly increased in patients receiving indometacin. The clinical significance of this interaction is unclear but should be borne in mind in case of unexpected response to treatment14.

Benzodiazepines

Diazepam might increase diclofenac exposure and have a small effect on the pharmacokinetics of ibuprofen, although the clinical significance of this interaction is unclear14.

Additive dizziness might occur with diazepam and indometacin, bear this in mind should increased dizziness occur14.

Diclofenac moderately reduces both sedative and hypnotic doses of intravenous midazolam; bear the interaction in mind in case of an unexpected response to treatment14.


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


Multiple NSAID Use

Multiple NSAID use should be avoided3, 4, 5, 6, 13, 16, 17, 18, 19, 20, 21, 22, 23.

Ketorolac is an NSAID that is often used as an adjunctive pain relief perioperatively; hence there is an increased risk of NSAID related adverse effects if ketorolac is used concomitantly with another NSAID24.

Bleeding Risk

Low molecular weight heparin (LMWH) / unfractionated heparin (UFH) are predicted to increase the risk of bleeding events when given with NSAIDs10, 18, 19, 22, 25 (see also Hyperkalaemia and Hyponatraemia below).

Gastrointestinal Ulceration and Bleeding

Corticosteroids may increase the incidence and/or severity of ulceration associated with NSAIDs, and increases the possibility of gastrointestinal bleeding3, 4, 5, 6, 7, 10, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 25. Caution with concomitant use and consider the use of gastroprotection such as histamine-2 receptor antagonist or proton pump inhibitor14, 15. This interaction 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.

Nephrotoxicity

There is an increase in the risk of nephrotoxicity if NSAIDs are used concurrently with the following antimicrobials10, 25, 26: -

  • aminoglycosides (e.g. gentamicin) (also see under Antimicrobials below)
  • cephalosporins
  • daptomycin (also see under Antimicrobials below)
  • trimethoprim
  • vancomycin

Hyperkalaemia and Hyponatraemia

Concomitant use of NSAIDs with the following medications can increase the risk of hyperkalaemia10, 27: -

  • co-trimoxazole
  • LMWH / UFH
  • trimethoprim (also see under Nephrotoxicity above)

 NSAIDs and trimethoprim can increase the risk of hyponatraemia10.

Antimicrobials

NSAIDs potentially increase the risk of seizures when given with quinolones (e.g. ciprofloxacin)3, 4, 5, 7, 10, 13, 15, 16, 17, 18, 19, 20, 21, 22, 27. Seizures are rare, so in the majority of patients concurrent use should be without problem. Avoid concurrent use or monitor closely those patients with epilepsy or who are predisposed to seizures14, 15; however, due to the increased risk of seizure associated with quinolones, they are generally avoided in those who are predisposed to seizures.

NSAIDs may reduce excretion of aminoglycosides (e.g. gentamicin)17, 19, 22, which may lead to accumulation and increased risk of adverse effects (also see Nephrotoxicity above).

NSAIDs may reduce excretion of daptomycin – monitor the patient for possible daptomycin adverse effects13.

NSAIDs are highly protein bound, hence concomitant administration with other highly protein-bound drugs such as sulphonamide antibiotics (e.g. co-trimoxazole) should be done with caution and overdose symptoms carefully monitored3, 4 (also see Hyperkalaemia and Hyponatraemia above).

Metoclopramide

Metoclopramide modestly reduces the bioavailability of ketoprofen due to its prokinetic effects. The relatively poor solubility of ketoprofen means that it spends less time in the stomach where it dissolves, and as a result less is available for absorption in the small intestine. The clinical importance of this is unknown, but the recommendation is that ketoprofen (and possibly other NSAIDs that are poorly soluble) should be taken 1 – 2 hours before metoclopramide14.

Conversely, for other NSAIDs (i.e. aspirin, tolfenamic acid), metoclopramide can be used to increase the rate of absorption, and may possibly speed up the onset of analgesic effect14.


  Further Information


COX-1 vs. COX-2 Inhibition and Bleeding Risk

The COX enzymes are responsible for the production of prostaglandins. There are 2 types of COX enzymes – COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain and fever; however, only COX-1 produces prostaglandins that activate platelets and protect stomach and intestinal lining.

Aspirin irreversibly affects COX-1, leading to inhibition of platelet aggregation and vasoconstriction for the entire life cycle of the platelet.

Standard NSAIDs (e.g. ibuprofen) reversibly inhibit the COX enzyme. NSAIDs vary in their selectivity for inhibiting COX-1 and COX-215 and thus their effects on platelet activity and they should not be compared to aspirin1. Due to their reversible action, the bleeding risk is reduced on cessation of therapy (see Evidence Base for Discontinuing NSAIDs Pre-operatively).

COX-2 selective inhibitors (e.g. celecoxib) have less effect on platelet activity due to their selectivity for the COX-2 enzyme. They are not associated with increased bleeding risk in the perioperative period and are safe to continue for both elective and emergency surgery1 although consider possible interactions as detailed in Interaction(s) with Common Anaesthetic Agents and Interaction(s) with other Common Medicines used in the Perioperative Period).

Evidence Base for Discontinuing NSAIDs Pre-operatively

Recommendations on when to stop NSAIDs pre-operatively can sometimes be without the appropriate evidence-base. Discontinuation of NSAIDs should be based on the pharmacokinetics of the drug, COX selectively, patient factors (i.e. renal/hepatic function, pain level and tolerability) and the overall bleeding risk associated with the surgery. In general, levels of active drug reach an acceptably low level within 5 half-lives of stopping therapy1.

Renal Toxicity

Adequate fluid intake should be ensured during treatment with NSAIDs to prevent dehydration and possible associated increased renal toxicity25. Caution should be taken when initiating treatment with NSAIDs in patients with considerable dehydration13, 17.

Hypertension

Due to inhibition of prostaglandin synthesis, NSAIDs can cause fluid retention, oedema and hypertension. BP should be checked prior to initiation of NSAIDs, within 2 weeks of initiation and periodically thereafter12.

Regional Anaesthesia

NSAIDs, when used alone, are not a contraindication to regional anaesthesia9, 28. However, consideration should be given to patients receiving other agents, which may increase the risk of bleeding (e.g. LMWH, aspirin), if regional anaesthesia is planned28.

 

  References


  1. Younan M, Atkinson TJ, Fudin J. A Practical Approach to Discontinuing NSAID Therapy prior to a Procedure. November/December 2013. Available at www.PracticalPainManagement.com [Accessed 7th September 2019]
  2. Summary of Product Characteristics – Eccoxolac® (etodolac). Meda Pharmaceuticals. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text August 2011]
  3. Summary of Product Characteristics – Nabumetone Tablets 500mg. Accord-UK Ltd. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text November 2018]
  4. Summary of Product Characteristics – Naproxen 500mg Tablets. Wockhardt UK Ltd. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text August 2018]
  5. Summary of Product Characteristics – Piroxicam Capsules 20mg. Accord-UK Ltd. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text July 2016]
  6. Summary of Product Characteristics – Indometacin Capsules BP 50mg. Accord-UK Ltd. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text December 2013]
  7. Summary of Product Characteristics – Diclomax Retard® (diclofenac). Galen Limited. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text April 2018]
  8. Summary of Product Characteristics – Etopan® (etodolac) XL 600 mg Film-coated prolonged release tablets. Ranbaxy (UK) Limited a Sun Pharmaceutical Company. Accessed via www.medicines.org.uk 31/08/2019 [date of revision of the text April 2018]
  9. The Association of Anaesthetists of Great Britain & Ireland, The Obstetric Anaesthetists’ Association and Regional Anaesthesia UK. Regional Anaesthesia and Patients with Abnormalities of Coagulation. Anaesthesia. 2013; 68:966 – 72
  10. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 31st August 2019]
  11. National Insitute for Health and Care Excellence. Acute kidney injury: prevention, detection and management. Clinical guideline 169. Accessed via www.nice.org.uk 31/08/2019. Published: 28 August 2013.
  12. Summary of Product Characteristics – Arcoxia® (etoricoxib) 120 mg Film-coated tablets. Merck Sharp & Dohme LImited. Accessed via www.medicines.org.uk 31/08/2019 [date of revision of the text July 2016)
  13. Summary of Product Characteristics – Froben® (Flurbiprofen) 100mg Tablets. Mylan. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text January 2019]
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  15. National Institute for Health and Care Excellence. Clinical Knowledge Summaries. NSAIDs – prescribing issues. Accessed via www.cks.nice.org.uk 31/08/2019. Last revised August 2018
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  17. Summary of Product Characteristics – Brufen® (ibuprofen) 400mg Tablets. Mylan. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text December 2018]
  18. Summary of Product Characteristics – Oruvail® (ketoprofen) 200mg Prolonged-Release Hard Capsules. SANOFI. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text August 2019]
  19. Summary of Product Characteristics – Ponstan Forte® (mefenamic acid) Tablets 500mg. Chemidex Pharma Ltd. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text January 2016]
  20. Summary of Product Characteristics – Sulindac® (sulindac) 200mg Tablets. Mylan. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text December 2017]
  21. Summary of Product Characteristics – Mobiflex® (tenoxicam) 20mg Tablets. Mylan. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text May 2018]
  22. Summary of Product Characteristics – Surgam® (tiaprofenic acid) 300mg Tablets. SANOFI. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text August 2019]
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