NON-OPIOID ANALGESICS

NSAIDs

The non-steroidal anti-inflammatory drugs (NSAIDs) are a structurally diverse group of medications that share the ability to inhibit the enzyme prostaglandin synthetase (cyclo-oxygenase, COX).

There are two isoforms of the COX enzyme, COX-1 and COX-2

COX-1

☛ is constitutively expressed in most normal tissues
☛ produces the prostaglandins necessary for protective and regulatory functions

↳ maintenance of the gastric mucosa
↳ normal renal function
↳ platelet aggregation

☛ inhibition of COX-1 produces the clinically troublesome adverse effects including gastrointestinal toxicity

COX-2

☛   is induced by inflammation
☛   produces the prostaglandins involved in the generation of pain
☛   is also constitutively expressed in the kidney, brain and premenopausal uterus
☛   inhibition of COX-2 is responsible for the analgesic and anti-inflammatory properties of NSAIDs

Non-selective COX inhibitors

☛   are effective analgesics in cancer pain
☛   have analgesic efficacy equivalent to 5-10mg of intramuscular morphine
☛   have a ceiling effect to their analgesic action, but not to their adverse effects
☛   show considerable variation in both efficacy and toxicity between individual patients
☛   the dose needs to be individually titrated and in all cases the lowest effective dose should be used
☛   treatment for several days is required to achieve stable plasma levels and maximal effect

Gastrointestinal toxicity

☛ occurs commonly with non-selective COX inhibitors

↳ particularly in palliative care patients

☛ the risk is increased with

↳ advanced age (linear increase in risk)
↳ history of peptic ulcer
↳ higher doses of NSAID, or long-term use
↳ systemic co-morbidity (e.g. diabetes, cancer, hepatic impairment)
↳ co-prescription of

☑ corticosteroids
☑ anticoagulants
☑ aspirin (including low dose aspirin)

↳ bleeding disorder

☑ thrombocytopenia, abnormal platelet function

↳ H. pylori infection

☛ the risk is reduced by proton pump inhibitors (e.g. omeprazole, lansoprazole)

↳ antacids and sucralfate may reduce symptoms but do not protect against ulceration
↳ H2-receptor antagonists protect the duodenal and oesophageal mucosa but not the stomach
↳ misoprostol is effective but causes diarrheal

☛ palliative care patients requiring continued NSAID therapy should also be treated with a proton pump inhibitor

Selective COX-2 inhibitors (coxibs)

☛   were developed to minimize adverse events mediated by COX-1 inhibition
☛   have analgesic activity equivalent to traditional non-selective NSAIDs, both for acute pain and for the chronic pain associated with osteoarthritis and rheumatoid arthritis
☛   are associated with significantly less gastrointestinal toxicity
☛   have no effect on platelet function
☛   have the same renal effects as non-selective NSAIDs

↳ patients with renal impairment, hypertension, or hypovolaemia are at increased risk

☛   can cause acute neuropsychiatric events including confusion, somnolence, hallucinations
☛   do not induce bronchospasm in patients with aspirin- or NSAID-induced asthma
☛   Note: rofecoxib, valdecoxib and paracoxib have been withdrawn from the market in many countries because of an increased risk of cardiovascular side effects (myocardial infarction and stroke). Lumiracoxib was withdrawn because of hepatic toxicity.

Acetaminophen (Paracetamol)

☛   does not cause gastric irritation or bleeding
☛   does not affect platelet function or cause gastric irritation or bleeding
☛   can cause hepatic toxicity, possibly more likely with

↳ reduced glutathione stores e.g. poor nutritional status, the elderly
↳ regular use of alcohol