Pain & Sedation
A 54 year old man presents to the Emergency Department complaining of lower back pain following a day of heavy lifting. You rule out cauda equina syndrome and suspect this is muscular back pain. You recommend non-steroidal anti-inflammatory medication (NSAIDs). Which of the following is NOT a contraindication to use of NSAIDs?
Answer:
Do not prescribe nonsteroidal anti-inflammatory drugs (NSAIDs) to people with:- Active gastrointestinal (GI) bleeding, or active GI ulcer
- A history of GI bleeding related to previous NSAID therapy, or a history of GI perforation related to previous NSAID therapy
- A history of recurrent GI haemorrhage (two or more distinct episodes), or history of recurrent GI ulceration (two or more distinct episodes)
- A history of hypersensitivity/severe allergic reaction to an NSAID (including aspirin) — for example, asthma, rhinitis, angioedema or urticaria
- Severe heart failure
- Severe hepatic impairment (serum albumin less than 25 g/l or Child-Pugh score of 10 or more)
- Severe renal impairment (estimated glomerular filtration rate (eGFR) less than 30 mL/minute/1.73 m2)
NSAID Pharmacology
Pain & Sedation
Last Updated: 12th February 2021
Mechanism of action
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis, which normally potentiates the pain caused by other inflammatory mediators (such as histamine and bradykinin). NSAIDs work by reversibly inhibiting cyclooxygenase (COX) enzymes — the two main types of COX enzyme are COX-1 and COX-2, which have different physiological functions:
- COX-1
- Present in most tissues
- Produces prostaglandins that help to maintain gastric mucosal integrity and platelet-initiated blood clotting
- Inhibition of COX-1 is responsible for gastrointestinal toxicity
- COX-2
- Usually undetected in tissues and produced in response to inflammatory cytokines
- Produces prostaglandins that mediate pain and inflammation
- Inhibition of COX-2 is responsible for the anti-inflammatory effect
The degree of selectivity for COX-1 relative to COX-2 can be used to classify NSAIDs. However, there is no absolute selectivity for one or other COX enzyme — even highly selective COX-2 inhibitors will also inhibit COX-1 at high enough concentrations.
- Standard NSAIDs
- Non-selective NSAIDs e.g. ibuprofen, indometacin, mefenamic acid, and naproxen
- Coxibs
- COX-2 specific NSAIDs e.g. celecoxib and etoricoxib
Therapeutic effects
In single doses NSAIDs have analgesic activity comparable to that of paracetamol, therefore given their side effect profile, paracetamol is preferred, particularly in the elderly.
In regular full dosage NSAIDs have both a lasting analgesic and an anti-inflammatory effect making them useful for the management of continuous or regular pain associated with inflammation e.g. inflammatory arthritides.
Choice of NSAID
Differences in anti-inflammatory activity between NSAIDs are small, but there is considerable variation in individual response and tolerance to these drugs. About 60% of patients will respond to any NSAID; of the others, those who do not respond to one may well respond to another. Pain relief starts soon after taking the first dose and a full analgesic effect should normally be obtained within a week, whereas an anti-inflammatory effect may not be achieved (or may not be clinically assessable) for up to 3 weeks. If appropriate responses are not obtained within these times, another NSAID should be tried.
- Ibuprofen
- Has fewer side effects than other non-selective NSAIDs but its anti-inflammatory properties are weaker, making it unsuitable for conditions where inflammation is prominent e.g. acute gout.
- Naproxen
- Has good efficacy with a relatively low incidence of side effects (but more than ibuprofen); it is recommended first line treatment in acute gout.
- Diclofenac
- Similar in efficacy to naproxen but is associated with a higher incidence of cardiovascular adverse events (and is in fact contraindicated in people with ischaemic heart disease, cerebrovascular disease, peripheral arterial disease and congestive heart failure).
- Mefenamic acid
- Has only minor anti-inflammatory properties and is typically used in the management of painful dysmenorrhoea. It has occasionally been associated with diarrhoea and haemolytic anaemia which require discontinuation of treatment.
Contraindications
Do not prescribe nonsteroidal anti-inflammatory drugs (NSAIDs) to people with:
- Active gastrointestinal (GI) bleeding, or active GI ulcer
- A history of GI bleeding related to previous NSAID therapy, or a history of GI perforation related to previous NSAID therapy
- A history of recurrent GI haemorrhage (two or more distinct episodes), or history of recurrent GI ulceration (two or more distinct episodes)
- A history of hypersensitivity/severe allergic reaction to an NSAID (including aspirin) — for example, asthma, rhinitis, angioedema or urticaria
- Severe heart failure
- Severe hepatic impairment (serum albumin less than 25 g/l or Child-Pugh score of 10 or more)
- Severe renal impairment (estimated glomerular filtration rate (eGFR) less than 30 mL/minute/1.73 m2)
Do not prescribe COX-2 inhibitors, diclofenac, aceclofenac or high dose ibuprofen (more than 2400 mg daily) to people with:
- Ischaemic heart disease
- Peripheral arterial disease
- Cerebrovascular disease.
- Congestive heart failure (New York Heart Association [NYHA] classification II–IV)
- Inflammatory bowel disease (COX-2 inhibitors only)
- Uncontrolled hypertension (persistently above 140/90 mmHg) (etoricoxib or high dose ibuprofen only)
Cautions
Prescribe NSAIDs with caution to people with:
- A history of peptic ulceration (standard NSAIDs are contraindicated), or people at high risk of GI adverse effects
- Allergic disorders and asthma
- Cardiac impairment, or heart failure (NSAIDs may impair renal function)
- Cerebrovascular disease
- Coagulation disorders
- Connective-tissue disorders
- Hypertension (NSAIDs may impair renal function)
- Inflammatory bowel disease (NSAIDs may increase the risk of developing or cause exacerbations of ulcerative colitis or Crohn's disease)
- Ischaemic heart disease
- Peripheral arterial disease
- Risk factors for cardiovascular events for example, hypertension, hyperlipidaemia, diabetes mellitus, smoking
- Hepatic impairment (dose reductions may be necessary)
- Renal impairment (avoid if possible) (sodium and water retention may occur leading to a deterioration in renal function and, possibly renal failure)
- The elderly (increased risk of cardiovascular, renal, and serious GI adverse effects)
- Women trying to conceive (NSAIDs may impair female fertility)
Adverse effects
The risks of adverse effects varies among individual nonsteroidal anti-inflammatory drugs (NSAIDs) and is influenced by the dose and duration of use. The lowest effective dose of NSAID should be prescribed for the shortest period of time to control symptoms and the need for long-term treatment should be reviewed periodically.
Side effects of NSAIDs include:
- Dyspepsia and other upper gastrointestinal (GI) complications are the most common adverse effects of NSAIDs — for example, ulcer, perforation, obstruction or bleeding
- Cardiovascular and renal complications are less common but serious NSAID adverse effects include myocardial infarction, stroke, cardiac failure, hypertension, and renal failure
- Other adverse effects include:
- Prolonged bleeding (for example, after surgery) as a result of inhibition of platelet aggregation
- Bronchospasm (NSAIDs may exacerbate or precipitate asthma)
- Severe skin reactions and angioedema (for example, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis)
- 'Kounis syndrome' (allergic acute coronary syndrome)
- Very rarely, NSAIDs can precipitate severe hepatic reactions (such as hepatitis, liver necrosis, or hepatic failure)
NSAIDs and cardiovascular and renal adverse events
All NSAID use is associated with a small increased risk of thrombotic events independent of baseline cardiovascular risk factors or duration of NSAID use. However, the greatest risk may be in those receiving high doses long-term.
- Cardiovascular (CV) effects
- Inhibition of COX-2 leads to suppression of prostacyclin (which normally protects endothelial cells, produces vasodilation and interacts with platelets to antagonize aggregation)
- Inhibition of COX-1 inhibits conversion of arachidonic acid to thromboxane A2 (a potent platelet aggregator and vasoconstrictor)
- Selective COX-2 inhibition presents a CV risk, as it shifts the prothrombotic/antithrombotic balance and favours thrombosis
- Renal effects
- NSAIDs inhibit prostaglandins PGE2 and PGI2 synthesis which may result in sodium retention, reduced renal blood flow, and renal failure
- The risk for serious cardiac or renal adverse events (including myocardial infarction, heart failure, and hypertension) is increased in people with:
- Cerebrovascular disease
- Heart failure
- Ischaemic heart disease
- Peripheral arterial disease
- Renal impairment
- Risk factors for cardiovascular disease
- Aged > 65 years
NSAIDs and gastrointestinal adverse events
All NSAIDs are associated with serious gastrointestinal toxicity; the risk is higher in the elderly. Evidence on the relative safety of non-selective NSAIDs indicates differences in the risks of serious upper gastrointestinal side-effects:
| Risk of NSAID-induced GI adverse events | NSAIDs |
|---|---|
| Lowest risk | Ibuprofen |
| Intermediate risk | Naproxen, diclofenac, indometacin |
| Highest risk | Piroxicam, ketoprofen, ketorolac |
Recommendations are that NSAIDs associated with a low risk e.g. ibuprofen are generally preferred, to start at the lowest recommended dose and not to use more than one oral NSAID at a time.
Risk factors for NSAID–induced gastrointestinal adverse events
Risk factors for NSAID–induced gastrointestinal (GI) adverse events include:
- Aged over 65 years
- A high dose of an NSAID
- A history of gastroduodenal ulcer, GI bleeding, or gastroduodenal perforation.
- Concomitant use of medications that are known to increase the likelihood of upper GI adverse events (for example, anticoagulants, corticosteroids, selective serotonin reuptake inhibitors [SSRIs])
- A serious comorbidity, such as cardiovascular disease, hepatic or renal impairment (including dehydration), diabetes, or hypertension.
- Heavy smoking
- Excessive alcohol consumption
- Previous adverse reaction to NSAIDs
- Prolonged requirement for NSAIDs
People are considered at:
- High risk if they have a history of previously complicated ulcer, or multiple (more than two) risk factors
- Moderate risk if they have 1–2 risk factors
- Low risk if they have no risk factors
Prevention and management of gastrointestinal adverse effects
To prevent gastrointestinal (GI) adverse effects associated with the use of a nonsteroidal anti-inflammatory drug (NSAID):
- Consider prescribing:
- An alternative analgesic to an oral NSAID if appropriate e.g. paracetamol, topical NSAID
- The lowest dose of NSAID for the shortest period of time
- Only one NSAID at a time (avoid concomitant use with aspirin)
- A short-acting NSAID (e.g. ibuprofen) instead of a long-acting NSAID (e.g. naproxen)
- A COX-2 selective NSAID (but increased cardiovascular risk)
- Co-prescribe a proton pump inhibitor (PPI) for people with osteoarthritis or rheumatoid arthritis, who are elderly, or people with low back pain, axial spondyloarthritis, psoriatic arthritis and other peripheral spondyloarthritides
- For people at:
- High risk of GI adverse events — prescribe a COX-2 selective NSAID (for example, etoricoxib, or celecoxib) instead of a standard NSAID, and co-prescribe a PPI
- Moderate risk of GI adverse events — prescribe a COX-2 inhibitor alone, or an NSAID plus a PPI
- Low risk of GI events — prescribe a non-selective NSAID
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
