Pharmacology
Musculoskeletal
Regarding NSAIDs, which of the following statements is INCORRECT:
Answer:
All NSAIDs are associated with serious gastrointestinal toxicity. Evidence on the relative safety of non-selective NSAIDs indicates differences in the risks of serious upper gastrointestinal side effects:- piroxicam, ketoprofen, and ketorolac trometamol are associated with the highest risk;
- indometacin, diclofenac, and naproxen are associated with intermediate risk,
- and ibuprofen with the lowest risk (although high doses of ibuprofen have been associated with intermediate risk).
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Pharmacology / Musculoskeletal
Last Updated: 26th March 2019
Mechanism of Action
NSAIDs reduce the production of prostaglandins by inhibiting the cyclooxygenase (COX) enzymes with analgesic, antipyretic and anti-inflammatory effects. The two main types of COX enzyme are COX-1 (which produces prostaglandins that help to maintain gastric mucosal integrity and platelet-initiated blood clotting) and COX-2 (which produces prostaglandins that mediate pain and inflammation). NSAIDs vary in their selectivity for inhibiting different types of COX; specific inhibition of COX-2 (e.g. celecoxib and etoricoxib) is associated with less gastrointestinal intolerance.
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. 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.
Choice of NSAID
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 is 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 mild, moderate, or severe 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.
| Risk of NSAID-induced GI adverse events | NSAIDs |
|---|---|
| Lowest risk | Ibuprofen |
| Intermediate risk | Naproxen, diclofenac, indometacin |
| Highest risk | Piroxicam, ketoprofen, ketorolac |
Contraindications
NSAIDs are contraindicated in people with:
- A history of hypersensitivity or severe allergic reaction to aspirin or any other NSAID
- Severe heart failure (NSAIDs may impair renal function)
- Liver fibrosis, cirrhosis or acute liver failure (risk of variceal bleeding, hepatorenal syndrome and encephalopathy)
- Severe hepatic impairment (e.g. liver enzyme levels more than three times the upper limit of the normal range; serum albumin less than 25 g/L)
- Current treatment for gastrointestinal bleeding, symptomatic peptic ulcer, or gastrointestinal perforation or obstruction
- Coxibs and diclofenac are also contraindicated in people with ischaemic heart disease, cerebrovascular disease, peripheral arterial disease, mild, moderate, or severe heart failure
- Renal failure, with estimated glomerular filtration rate (eGFR) less than 30–15 mL/min/1.73 m2, or creatinine clearance less than 30–20 mL/min, or dehydration (relative)
Cautions
NSAIDs should be used with caution in:
- People with asthma (patients should be offered a trial to assess effect on asthma control)
- The elderly (increased risk of serious adverse effects such as gastrointestinal bleeding and perforation, which may be fatal)
- People with a history of peptic ulceration (standard NSAIDs contraindicated), or those at high risk of gastrointestinal adverse effects
- People with inflammatory bowel disease (NSAIDs may increase the risk of developing or cause exacerbations of ulcerative colitis or Crohn's disease)
- People with hepatitis or cholestasis (increased risk of gastrointestinal bleeding and fluid retention)
- Renal impairment (avoid if possible, sodium and water retention may occur leading to a deterioration in renal function and, possibly renal failure)
- People with heart failure (NSAIDs may impair renal function)
- People with hypertension (NSAIDs may impair renal function)
- In a women trying to conceive (NSAIDs may impair female fertility)
Adverse Effects
Adverse effects may be minimised by selecting an appropriate NSAID and using the lowest effective dose for the shortest duration necessary to control symptoms.
Side effects of NSAIDs include:
- The most common adverse effects of NSAIDs are dyspepsia and other upper gastrointestinal complications such as ulcer, perforation, obstruction or bleeding (especially if risk factors are present - see below)
- Less commonly NSAIDs may cause cardiovascular and renal complications such as myocardial infarction, stroke, cardiac failure, hypertension, and renal failure (the risk is increased in people with IHD, CVD, PAD, CKD, HF or HTN, risk factors for cardiovascular disease and people > 65 years)
- Prolonged bleeding (for example after surgery) because of platelet inhibition
- Asthma (NSAIDs may exacerbate or precipitate asthma. Stop NSAID if it is suspected to have precipitated bronchospasm)
- Severe skin reactions and angioedema (stop NSAID)
- Very rarely, NSAIDs can precipitate severe hepatic reactions such as hepatitis, liver necrosis, or hepatic failure (stop NSAID)
Risk Factors for Increased Risk of Gastrointestinal Adverse Effects
People are at high risk of serious NSAID–induced gastrointestinal adverse events if they have one or more of the following risk factors:
- Using the maximum recommended dose of an NSAID
- Aged 65 years or older
- 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 (e.g. anticoagulants, aspirin, corticosteroids, and antidepressants (selective serotonin reuptake inhibitors, venlafaxine, or duloxetine))
- Serious comorbidity, such as cardiovascular disease, hepatic or renal impairment, diabetes, or hypertension
- Requirement for prolonged NSAID use including people with osteoarthritis or rheumatoid arthritis of any age and people aged 45 years or older with chronic low back pain
- The presence of Helicobacter pylori infection
- Excessive alcohol use
- Heavy smoking
Prevention and Management of Gastrointestinal Adverse Effects
- Preventing gastrointestinal adverse effects
- Consider prescribing:
- An alternative to an NSAID e.g. paracetamol +/- codeine
- The lowest dose of NSAID for the shortest period of time
- Only one NSAID at a time (avoid concomitant use with aspirin)
- A COX-2 selective NSAID (but increased cardiovascular risk)
- If the person is at an increased risk of GI adverse events and requires an NSAID, co-prescribe a proton pump inhibitor (PPI) for gastroprotection (e.g. omeprazole 20 mg od, lansoprazole 15 - 30 mg od)
- Consider prescribing:
- Managing gastrointestinal adverse effects
- Where possible the NSAID should be withdrawn if an ulcer occurs
- The ulcer should be treated with a PPI (a H2-receptor antagonist or misoprostol are alternatives)
- On healing the patient should be tested for H. pylori and treated if required
- If treatment with NSAID needs to continue, options include:
- On healing continue PPI
- Switch to selective COX-2 inhibitor
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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 |
