BASIC SCIENCES Tutorial 405

Nonsteroidal Anti-inflammatory
Drugs
Dr J Sylvester, MBChB MRCP1†
1
Speciality Doctor, Barnsley Hospital, UK

Edited by: Dr Alex Konstantatos, Anaesthesia Consultant, The Alfred, Australia

†
Corresponding author email: sylvesterj@doctors.org.uk

Published 18 June 2019

KEY POINTS
 Nonsteroidal anti-inflammatory drugs are simple analgesic compounds with a wide variety of clinical applications and
all anaesthetists should be familiar with their use.
 They act through inhibition of the enzyme cyclooxygenase (COX), to reduce the production of cyclic endoperoxidases.
 They have common side effects involving gastric, renal, cardiovascular, haematological, and respiratory systems that
should be taken into consideration before prescribing.
 Concerns over their cardiovascular safety have led to the withdrawal of many COX-2 inhibitors from the market.

INTRODUCTION
Nonsteroidal anti-inflammatory drugs (NSAIDs) are simple analgesic medications, which along with paracetamol comprise step
1 of the World Health Organisation pain ladder. The World Health Organisation pain ladder is a stepwise approach to analgesia,
starting at step 1 with simple analgesics and working up to weak opioids step 2 and strong opioids at step 3. They are used by
millions of people worldwide to treat a wide variety of acute and chronic pain disorders. In the perioperative period they are
useful medications for treating mild to moderate pain and reducing opioid consumption and side effects. They are also used for
their anti-inflammatory and antipyretic effects.
Indications for NSAIDS include the following:
 Inflammatory conditions
 Chronic joint disease
 Musculoskeletal pain
 Headache
 Menstrual pain
 Dental pain
 Postoperative mild to moderate pain

MECHANISM OF ACTION
NSAIDS work by inhibiting the function of the cyclooxygenase (COX) enzyme and thereby reducing the production of
prostaglandins. Aspirin is an irreversible inhibitor of COX; the remaining NSAIDs work in a reversible manner.
Membrane phospholipids are initially converted to arachidonic acid by phospholipase A2 as a result of inflammation and tissue
damage. Arachidonic acid is then either converted to the prostaglandins via the COX pathway or alternatively converted to

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 Figure 1. Arachidonic acid pathway showing production of prostaglandins from membrane phospholipids. The leukotriene pathway is
responsible to the group of patients with NSAIDs–sensitive asthma.

leukotrienes by the enzyme lipoxygenase (Figure 1). The type of prostaglandin produced depends on the specific tissue.1
Effects of prostaglandins on different tissues are summarised in Table 1.
COX exists in 3 isoforms: COX-1, COX-2, and COX-3. COX-1, the so-called constitutive form, is believed to be present in
normal tissues and is responsible for the production of prostaglandins, which are vital for normal physiological processes such
as the maintenance of renal blood flow, gastric mucosa protection, and platelet adhesiveness.2 COX-2 is absent from most
tissues except in brain, uterus, kidneys, and prostate. It is inducible and levels are up-regulated by tissue damage and injury.
Production of prostaglandin E2 and prostaglandin F2a results in sensitisation of nocioceptic nerve fibres to painful stimuli
following tissue injury.3 NSAIDs cause a reduction in their synthesis and therefore analgesia. COX-3 is found within the central
nervous system and is believed to be the site of action of paracetamol; the exact nature of the isoenzyme is unclear at this time.

A wide variety of NSAIDs are available with different degrees of inhibition of COX-1 and COX-2. Their degree of each
isoenzyme inhibition determines their side-effect profile.

The majority of NSAIDS are administered orally, with the exceptions of ketorolac and parecoxib (intravenous administration)
and diclofenac (oral, intravenous, and per rectum administration). They are weak organic acids and are therefore absorbed
rapidly in the stomach and small intestine. The stomach has a lower pH than the small intestine and therefore, more drug is in
the more absorbable unionised form; however, the main source of absorption is the small intestine due to its larger surface
area. NSAIDs have a high bioavailability due to limited first-pass hepatic metabolism. They are highly protein-bound molecules
and as a result can displace other protein-bound medications leading to increased free drug concentrations and increased risk
of adverse events (eg, displacement of warfarin from albumin leading to an increased risk of bleeding). Bioconversion is mostly
hepatic with metabolites excreted in the urine.

Prostaglandin
Subtype Function
PGE2 Sensitise nerve endings to bradykinin, increase body temperature,
vasodilation, gastroprotection
PGF2a Bronchoconstriction, uterine contractions
PGD2 Bronchoconstriction
PGI2 (prostacyclin) Vasodilatation (vasoconstriction in pulmonary epithelium), decreased
platelet aggregation, gastroprotection
TXA2 Platelet aggregation, vasoconstriction

Table 1. Prostaglandin Subtype and Effect on Tissues. PG - Prostaglandin. TXA2 - Thromboxane A2

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ATOTW 405 — Nonsteroidal Anti-inflammatory Drugs (18 June 2019) Page 2 of 5
 Drug NNT
Ibuprofen 800 mg 1.6
Ketorolac 20 mg 1.8
Diclofenac 100 mg 1.9
Naproxen 440 mg 2.3
Paracetamol 1 g* 3.8
Tramadol 100 mg* 4.8
Table 2. The Number Needed to Treat (NNT) is the Number of People that Needed to be Given
that Medication to Achieve a 50% Reduction in Maximal Pain. *Tramadol and paracetamol have
been added for analgesic efficacy comparison only4

ANALGESIC PROPERTIES
The efficacy of NSAIDs for the treatment of painful conditions is well known. They are often used as part of a multi-modal
approach to analgesia. For best results they should be prescribed regularly along with paracetamol; they should also be
prescribed for the minimum duration to avoid side effects. Direct comparison of NSAIDs can be obtained from the Oxford
league tables of analgesics in acute pain. The league table gives each drug a rating based on its number needed to treat to
reduce pain by 50% when compared to a placebo. (Table 2)

PHARMACODYNAMICS AND SIDE EFFECTS

Gastrointestinal
Gastric side effects can range from mild dyspepsia to massive haemorrhage from perforated gastric ulcer, as a result of
inhibition of prostacyclin production. It is worth noting that gastrointestinal side effects are not solely confined to the stomach.
Prostacyclins have a number of gastric protective effects; they reduce the amount of stomach acid produced and maintain a
protective mucosal layer by increasing mucous production and improving local blood flow. Gastric irritation can also be caused
by direct irritation from the medications themselves.1 Although COX-2 inhibitors are more specific for the COX-2 enzyme, they
still retain some COX-1 inhibition leading to a risk of gastrointestinal bleeding, albeit less than nonspecific NSAIDs.

Renal
Under normal physiological conditions prostacyclin and nitric oxide lead to smooth muscle relaxation in vascular endothelium
and hence vasodilatation. Prostacyclins play a key role in the regulation of afferent and efferent arterial tone in the glomerulus,
known to play a vital role in preservation of renal function in hypovolaemic states. Inhibition of prostacyclin production can lead
to decreased glomerular filtration rate, salt and water retention, and acute kidney injury. These mechanisms are particularly
important in patients with hypovolaemia and chronic cardiac failure who are sensitive to changes in renal perfusion pressure.

Respiratory
Up to 10% of patients with asthma have disease which is exacerbated by NSAIDs.5,6 A proposed mechanism of action is that
inhibition of arachidonic acid metabolism by COX leads to an increase in production of leukotrienes. Leukotrienes have direct
bronchoconstrictor actions.

Cardiovascular
Specific COX-2 inhibitors or ‘coxibs’ were introduced to the market to avoid the common and serious upper gastrointestinal side
effects of COX-1 inhibition by nonspecific NSAIDs. However, concerns over their cardiovascular safety have limited their
widespread use. There is a dose-dependent increase in risk of thrombotic events, both cardiac and cerebral.3 Rofecoxib and
valdecoxib have been withdrawn from the market due to increased cardiovascular events associated specifically with these 2
drugs. The risk is higher in patients with preexisting cardiovascular disease and so the use of COX-2 inhibitors is
contraindicated in patients with heart failure, ischemic heart disease, and peripheral and cerebrovascular disease.

Haematological
In platelets, COX metabolises the arachidonic acid into thromboxane A2, which leads to increased platelet adhesiveness and
vasoconstriction.1 In contrast, in vascular smooth muscle, prostacyclin is formed, which causes vasodilation and reduced
platelet aggregation. Haemostasis is a fine balance between these systems. Thus, NSAIDs lead to reduced platelet function

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ATOTW 405 — Nonsteroidal Anti-inflammatory Drugs (18 June 2019) Page 3 of 5
and adhesiveness and increased bleeding time. Aspirin deserves a special mention as it irreversibly inhibits platelet COX. As a
result, platelets are rendered ineffective for the whole of their 10-day lifespan.

Bone Healing
There is a theoretical risk that NSAIDs, in particular COX-2 inhibitors, reduce bone-healing rates and increase the incidence of
nonunion of fractures. After a fracture there is an increased production of prostaglandins as part of the inflammatory response,
which increases local blood flow.3 It is hypothesised that blocking this mechanism is detrimental to bone healing; however,
there is currently no high-quality scientific evidence to confirm this.

ROLE OF NSAID IN PERIOPERATIVE PRACTICE

NSAIDs can be prescribed as a premedication, administered intraoperatively, and continued postoperatively as part of a multi-
modal analgesic regime. The prescription of NSAIDs should be at the lowest possible effective dose and for the shortest period
of time to avoid any potential side effects. They are safe in most patients in the perioperative period; however, there are certain
conditions which require a special mention.

Pregnancy
NSAIDs provide excellent analgesia for patients post–Caesarean section and can conveniently be administered as a rectal
suppository. However, they are contraindicated during the antenatal period in mothers as there is a risk of premature closure of
the ductus arteriosus and oligohydraminous. They are also contraindicated in patients with preeclampsia as they can worsen
the renal impairment and bleeding risk.

High-risk Surgery
In surgery with a high risk of bleeding such as vascular surgery, or where bleeding can result in catastrophic outcome such as
ophthalmic and neurosurgery, the decision to prescribe NSAIDs should be made on a case-by-case basis and in conjunction
with advice from the surgical team.

Critically Unwell and Elderly Patients

Patients suffering from a critical illness such as severe sepsis or pancreatitis are more reliant on renal arteriolar vasodilatation
from prostaglandins to maintain renal perfusion. If this mechanism is removed by NSAID use it can lead to an increased risk of
acute kidney injury.

Regional Anaesthesia
Although NSAIDs can affect platelet function for up to 7 days and aspirin for the lifetime of the platelet, there is no increased risk
of epidural haematoma and therefore there are no contraindications to patients having either regional anaesthesia or central
neuraxial blockade.7

Angiotensin Converting Enzyme Inhibitor (ACE-I)

As discussed previously, due to the effect on the renal arterioles NSAIDs should be prescribed with caution to patients who take
ACE-I medications due to the risk of acute kidney injury. The mechanism of action of ACE-I medications and their side effects
have previously been covered in ATOTW 28.8

SUMMARY
Nonsteroidal inflammatory drugs are effective simple analgesic medications that all anaesthetists should be familiar
with. Although highly effective, they have a complex mode of action and many potential side effects and drug
interactions. It is vital to know the basic pharmacology when prescribing these medications to avoid any complications.

REFERENCES
1. Lewis KE. Analgesic drugs. In: Pinnock C, Lin T, Smith T. Fundamentals of Anaesthesia. Greenwich MedicalMedia;
1999:628–632.
2. Husband M, Mehta V. Cyclo-oxygenase-2 inhibitors. Cont Educ Anaesth Crit Care Pain. 2013;13(4):131-135.

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ATOTW 405 — Nonsteroidal Anti-inflammatory Drugs (18 June 2019) Page 4 of 5
3. Gupta B. Non-steroidal anti-inflammatory drugs. Update Anaesth. 2008;24(2):115-117.
4. Ong CKS, Lirk P, Tan CH, et al. An evidence based update on nonsteroidal anti-inflammatory drugs. Clin Med Res.
2007;5(1):19-34.
5. Sturtevant J. NSAID induced bronchospasm—a common and serious problem. N Z Dent J. 1999;95(421):84.
6. Lewis SR, Nicholson A, Cardwell ME, Siviter G, Smith AF. Nonsteroidal anti-inflammatory drugs and perioperative bleeding
in paediatric tonsillectomy. Cochrane Database Syst Rev 2013; 7:CD003591 pmid: 23881651
7. Anesthetic Association of Great Britain and Ireland guidelines. Regional anaesthesia and patients with abnormalities of
coagulation. 18/11/2013. https://www.aagbi.org/publications/guidelines/regional-anaesthesia-and-patients-abnormalities-
coagulation-correction-publi. Accessed April 1, 2019.
8. Mayell AC. Hypertension in anaesthesia. Anaesthesia Tutorial of The Week 28. https://www.wfsahq.org/components/com_
virtual_library/media/1f063c489ff87dcbb4dccfcabd851f4b-596e20871496b83e6951765710db38b2-28-Hypertension-in-an
aesthesia.pdf. Accessed May 18, 2019.

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