- To have an extensive understanding of NSAIDS and paracetamol
- To understand their mechanism of action
- To have knowledge of their individual effectiveness
- To be aware of the risks associated with taking NSAIDS and to perform an in-depth risk / benefit analysis prior to prescribing these analgesics
Simple, or non-opioid analgesics, are a wide ranging group of drugs that comprises of non-steroidal anti-inflammatory drugs (NSAIDS) and paracetamol. Both paracetamol and most NSAIDS have antipyretic (fever reducing) properties, however, only NSAIDS have antiplatelet (anti-clotting) and anti-inflammatory effects. Due to its minimal side effects and ability to be tolerated by a large proportion of the population (very young to the very old), paracetamol is the first analgesia of choice for treating mild to moderate pain.
Many NSAIDS and paracetamol are available as over the counter medications and are available as a tablet, capsule, liquid, suppository or topical preparation. Intravenous paracetamol has recently become available in the hospital setting and has been demonstrated to be effective whilst causing minimal side effects. However, this should only be used when the oral route of administration is unavailable. Only one NSAID should be used at one time. Combining different NSAIDS, or different routes of the same NSAID (oral and topical) does not increase the efficacy of the analgesics but does greatly increase the risk of side effects and is therefore not recommended.
Indication for NSAIDS & paracetamol
- mild to moderate pain
- period pain
- migraine and tension headache
- osteoarthritis and rheumatoid arthritis, including juvenile rheumatoid arthritis
- pain caused by cancer, particularly bone cancer
- post-operative pain
- in combination with opioid analgesics for moderate to severe pain
Mechanism of action
Several decades of research have enabled us to understand the mechanisms underpinning the action of NSAIDs and related drugs. The cyclooxygenases (COX) catalyse the conversion of arachidonic acid to biologically active prostaglandins by cyclooxygenase and peroxidase activity. Active prostaglandins have a diverse variety of physiological functions, including protection of the gastrointestinal tract, renal homeostasis, uterine function, embryo implantation and labour, regulation of the sleep-wake cycle and body temperature .
Cyclooxygenase exists in two forms, COX-1 and COX-2. COX-1 is predominantly constitutive and is found in most tissues and particularly in platelets, stomach and kidney. The location and pattern of COX-1 expression illustrates that it is responsible for production of prostaglandins important for responses to circulating hormones and maintenance of gastric mucosal integrity and platelet function. COX-1 levels can be increased two to four fold by inflammatory stimuli.
COX-2 is predominantly inducible though is constitutive in kidney, brain, testicles and tracheal epithelia and is responsible for the biosynthesis of inflammatory prostaglandins. Its levels can increase ten to twenty fold through inflammation, particularly in macrophages, monocytes, synoviocytes, chrondrocytes, fibroblasts and endothelial cells. While the structures of the two enzymes are similar, they differ in a number of ways. COX-2 is rapidly degraded and has a short half life. COX-2 has a larger binding site and compounds binding here may selectively inhibit COX-2. NSAIDS reduce pain and inflammation within the body by reducing the production of prostaglandins (pro-inflammatory chemicals).
Tissue injury leads to nociception by damage to nerve endings, then to inflammation with the release from damaged tissues of chemical substances including prostaglandins, and to hyperalgesia produced by sprouting of damaged nerves and capillaries and invasion of phagocytes and fibroblasts. PGs are involved in the tissue reaction to injury, and PGI2 and PGE2 produced at the site of damage sensitise pain receptors to histamine and bradykinin, leading to hyperalgesia. It is unclear whether prostaglandins produce pain themselves, or if they increase the effect of other painful stimuli on nerve endings, but it is recognised that they are involved in nociceptor activation by painful stimuli.
As they are thought to act by inhibiting cyclooxygenase in damaged tissues, NSAIDs have been described as ‘peripherally acting analgesics’. Although this is the case, there is good evidence that they also have a central nervous system action. Aspirin does have central effects, and NSAIDs do diffuse into the cerebrospinal fluid. For example, indomethacin, ibuprofen and diclofenac depress the evoked response of rat thalamic neurones to peripheral nerve stimulation in a dose-dependent fashion, a central action which contributes to their analgesic effect.
In the 1990s, molecular biology discovered two different gene codes for the enzymes (comprising the so called cyclooxygenases) COX-1 and COX-2. After the enzymes had been characterised (and has become available), new compounds were investigated to determine their ability to selectively inhibit either enzyme . Following studies on the effect of both enzymes on the body, it was concluded that a selective inhibition of COX-2 may be sufficient to achieve analgesic/anti-inflammatory effects but would spare the GI tract and most organ systems.
An international consensus meeting  defined COX-2 specificity and provided a definition of COX-2 specific inhibitors of which rofecoxib and celecoxib fulfil definitions of COX-2 specificity in man. COX-2 inhibitors selectively inhibit the inducible COX-2 enzyme. They are much more selective than preferential inhibitors e.g. meloxicam which has between 3-77 fold selectivity for COX-2 as compared with elecoxib which is 375 fold selective.
However, despite the hype that surrounded the emergence of these drugs COX-2 selectivity does not seem to reduce other adverse effects of NSAIDs (most notably an increased risk of renal failure), and many studies have now demonstrated an increase in the risk for heart attack, thrombosis and stroke by a relative increase in thromboxane . Rofecoxib (commonly known as Vioxx) was removed from the market in 2004 because of these concerns.
Until recently it was unclear the exact mechanism by which paracetamol works, however, recent evidence suggests that paracetamol also works by reducing the synthesis of specific prostaglandins .
Efficacy of simple analgesics
The efficacy of traditional NSAIDs in reducing pain is widely recognised in the management of postoperative pain and persistent pain states such as in arthritis and cancer. McQuay and Moore  reviewed the analgesic efficacy of NSAIDs as compiled from randomised trials with various painful conditions. They considered efficacy in the form of numbers needed to treat (NNT which described the difference between active treatment and control) and noted that at clinical doses of agents such as ibuprofen (400mgs) and diclofenac (25-50mgs), NNT values were about 2-3 in postoperative pain. This means that of every 2 to 3 patients who receive the drug, one patient will report at least 50% relief who would not have done so with placebo. In contrast, the NNTs for codeine (60mgs) or tramadol (100mg) were 16.7 (nearly 17 patients needed to receive the drug for one patient to get 50% pain relief) and 4.8 respectively (nearly 5 patients needed to receive the drug for one patient to get 50% pain relief).
The so-called coal tar analgesics, phenacetin and its active metabolite acetaminophen (Paracetamol) from the para-aminophenol group are effective alternatives to aspirin. Paracetamol is not a NSAID but is commonly discussed in the same arena as aspirin and NSAIDs. Paracetamol is an effective analgesic and antipyretic, but has little anti-inflammatory effect. Paracetamol is an effective analgesic for acute postoperative pain management. A single dose of 1000mgs had an NNT of 4.6 for at least 50% pain relief over 4-6 hours in patients with moderate or severe pain compared with placebo . At therapeutic doses, paracetamol is well tolerated in general, produces no gastrointestinal or platelet effects, and can be taken by patients who react adversely to aspirin.
Paracetamol is rapidly absorbed from the small intestine after oral administration, and the rate of absorption has been used as a marker of gastric emptying. In adults a relatively small paracetamol dose of 10-15g (20-30 tablets) can produce severe hepatic damage. Signs of poisoning are nausea and vomiting, followed by the development of right-sided subcostal pain and tenderness a day later. Liver damage is maximal 3 – 4 days after ingestion and may lead to death. Early signs may therefore be minimal even when toxic doses have been ingested, and every paracetamol overdose should be taken seriously.
Paracetamol has been used peri and postoperatively for many years with the rectal route route commonly being the route used when a patient has been unable to tolerate the oral medication. However, increasing evidence demonstrates that the rectal form has poor bioavailability (30-54% of oral), delayed uptake (103-140 min vs 45-60min for oral) and that sub-therapeutic plasma levels occur frequently . Fortunately a new intravenous preparation has been marketed and has demonstrated a superior efficacy to both oral and rectal forms with greater opioid sparing ability (50%) vs. oral administration (30%) .
While paracetamol is a useful drug in the postoperative period, its perception by patients is that it is only a weak analgesic because it can be purchased over the counter. Therefore patients may need some persuading that it will help their pain after surgery. It has an opioid sparing effect after regular dosing . Often the response in a double blind, randomised trial to placebo is related tot he perceived strength of the active compound. Therefore, the placebo response in a paracetamol trial will be much less than one in which a strong opioid is tested. This may have the effect of apparently decreasing the NNT when looking at a weak analgesic and increasing the NNT when studying a strong opioid.
Side effects of simple analgesics
NSAIDs have undesirable effects and they are a major cause of serious adverse reactions reported to the regulatory authorities. The evidence for harm from classic NSAIDs continues to mount . PGs are local tissue hormones, regulating function, and interference with them can produce problems. Essentially these effects are well recognised in association with long-term aspirin or NSAID therapy: interference with platelet function, renal impairment, peptic ulceration and other gastrointestinal problems, and worsening of asthma. The most significant side effects associated with NSAID usage are:
Platelet cyclooxygenase is essential for the production of cyclic endoperoxides and thromboxane A2, important mediators of aggregation and vasoconstriction, processes which constitute the primary haemostatic response to vessel injury. While it is clear that aspirin and the NSAIDs inhibit aggregation and prolong the skin bleeding time in volunteers, there remains a lack of information on the perioperative situation where the haemostatic response may be altered by the stress of surgery.
Aspirin is well recognised as a factor in increasing blood loss after surgery, a problem also encountered with NSAIDs. The haemostatic effects of aspirin may last up to 14 days because it irreversibly inhibits platelet cyclooxygenase by acetylation of the enzyme and haemostasis only returns to normal when new platelets have been made. In comparison, NSAIDs are reversible inhibitors of cyclooxygenase, and the duration of the platelet effect is much shorter. Low-dose aspirin is now being used prophylactically to reduce the risk of myocardial infarction, cerebral infarction and other arterial occlusions.
The adverse renal effects of NSAIDs are a serious and significant problem and have been well described. The kidney has enzymes for the synthesis of most PGs where they have various physiological roles, including the maintenance of renal blood flow and glomerular filtration rate in the presence of circulating vasoconstrictor hormones, and regulation of tubular handling of electrolytes and water. The clinical significance of this will depend on the age and general medical condition of the patient.
Risk factors for NSAID nephrotoxicity include age (more than 60 years old), atherosclerosis, diuretic therapy, existing renal impairment, and states associated with renal hypoperfusion including cardiac failure, hepatic cirrhosis, and hypovolaemia. ‘Analgesic nephropathy’ with papillary necrosis or interstitial fibrosis is a recognised cause of drug-induced renal failure, and has been reported with most NSAIDs. The ‘renal flank pain’ syndrome, a sudden onset renal failure with haematuria and discomfort, has also been associated with NSAIDs.
It has been known for some time that aspirin can damage the human gastric mucosa and many investigations have indicated that NSAIDs have similar effects . The gastric and duodenal epithelia have various protective mechanisms against acid and enzyme attack. These include the mucus layer, bicarbonate secretion, mucosal hydrophobic properties, rapid cellular regeneration after damage, and an abundant blood supply. PGs are involved with many of these protective factors, which can be disrupted by aspirin and NSAIDs.
If drugs inhibit COX-2 but not COX-1 then the theory would predict that they would be analgesic without the gastrointestinal adverse effects associated with classic NSAIDs. Rofecoxib, for instance failed to inhibit COX-1 at doses up to 1000mgs (20 to 80 fold greater than clinical doses . At present, the evidence for reduced gastrointestinal effects when using COX-2 inhibitors is promising.
COX-2 inhibitors do not produce the endoscopic ulcers found with NSAIDs and the balance of evidence is that serious bleeding is no more frequent than with placebos. The synthetic PG analogue, misoprostol, may prevent NSAID-induced ulcers. NSAIDs inhibit regenerative cell proliferation at the edge of ulcers, and misoprostol also reduces this harmful effect. NSAIDs can also have effects on the lower gut, producing an enteropathy which may account for up to 10% of cases of newly diagnosed colitis.
Aspirin can worsen bronchospasm in patients who have asthma and chronic rhinitis or nasal polyps, and these individuals are also sensitive to other NSAIDs. Around 10% of asthmatics are affected. The importance of this has been emphasised by reports of fatal bronchospasm precipitated in asthmatic patients by ingestion of proprietary preparations containing NSAIDs.
The mechanism of this is unclear, but the ability of a NSAID to produce this syndrome is directly related to its potency as an inhibitor of PG synthesis. It should be noted that, although widely used for postoperative analgesia , very few NSAIDs are specifically licensed for this indication. NSAIDs are used alone in the management of mild-moderate acute pain. Used in combination for severe pain, they have a useful opioid sparing effect .
Reports of side effects with paracetamol when taken at the recommended doses are very rare.
Think about the side effects of this group of drugs. What are you assessing for in terms of complications? How do you manage these complications locally? Does your management reflect evidence based guidelines currently available?
- Brooks, P., Emery, P., Evans, J.F., Fenner, H., Hawkey, C.J., Patrono, C., Smolen, J., Breedveld, F., Day, R., Dougados, M., Ehrich, E.W., -Ba, G.,
- Kvien, T.K., Van Rijswijk, M.H., Warner, T., Zeidler, H., 1999. Interpreting the clinical significance of the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2.. Rheumatology (Oxford), Rheumatology (Oxford) 38, 779-88.
- Patrignani, P., Panara, M.R., Greco, A., Fusco, O., Natoli, C., Iacobelli, S., Cipollone, F., Ganci, A., ,, Maclouf, J., 1994. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases.. J Pharmacol Exp Ther,
- J Pharmacol Exp Ther 271, 1705-12.
- Nussmeier, N.A., Whelton, A.A., Brown, M.T., Langford, R.M., Hoeft, A., Parlow, J.L., Boyce, S.W., Verburg, K.M., 2005. Complications of the
- COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery.. N Engl J Med, N Engl J Med 352, 1081-91.
- Hinz, B., Cheremina, O., Brune, K., 2008. Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man.. FASEB J, FASEB J 22, 383-90.
- McQuay, H.J., Moore, R.A., 1997. Using numerical results from systematic reviews in clinical practice.. Ann Intern Med, Ann Intern Med 126, 712-20.
- Moore, R.A., McQuay, H.J., 1997. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics.. Pain, Pain 69, 287-94.
- Beck, D.H., Schenk, M.R., Hagemann, K., Doepfmer, U.R., Kox, W.J., 2000. The pharmacokinetics and analgesic efficacy of larger dose rectal acetaminophen (40 mg/kg) in adults: a double-blinded, randomized study.. Anesth Analg, Anesth Analg 90, 431-6.
- Pettersson, P.Holmér, Owall, A., Jakobsson, J., 2004. Early bioavailability of paracetamol after oral or intravenous administration.. Acta
- Anaesthesiol Scand, Acta Anaesthesiol Scand 48, 867-70.
Cobby, T.F., Crighton, I.M., Kyriakides, K., Hobbs, G.J., 1999. Rectal paracetamol has a significant morphine-sparing effect after hysterectomy..
- Br J Anaesth, Br J Anaesth 83, 253-6.
- Tramèr, M.R., Schneider, J., Marti, R.A., Rifat, K., 1996. Role of magnesium sulfate in postoperative analgesia.. Anesthesiology, Anesthesiology 84, 340-7.
- Somasundaram, S., Hayllar, H., Rafi, S., Wrigglesworth, J.M., Macpherson, A.J., Bjarnason, I., 1995. The biochemical basis of non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract: a review and a hypothesis.. Scand J Gastroenterol, Scand J Gastroenterol 30, 289-99.
- Ehrich, E.W., Dallob, A., De Lepeleire, I., Van Hecken, A., Riendeau, D., Yuan, W., Porras, A., Wittreich, J., ,, De Schepper, P., Mehlisch, D.R.,
- Gertz, B.J., 1999. Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model.. Clin Pharmacol Ther, Clin Pharmacol Ther 65, 336-47.
- Merry, A.F., Power, I., 1995. Perioperative NSAIDs: towards greater safety.. Pain Reviews, Pain Reviews 2, 268-291.
- Rao, A.S., Cardosa, M., Inbasegaran, K., 2000. Morphine-sparing effect of ketoprofen after abdominal surgery.. Anaesth Intensive Care, Anaesth Intensive Care 28,