NSAIDs Paracetamol

Aspirin-induced asthma has an onset of 30 minutes to 3 hours after ingestion. Affected individuals are cross-sensitive to all non-steroidal anti-inflammatory drugs (NSAIDs). Paracetamol is seldom associated with cross-sensitivity in patients with aspirin-induced asthma. Aspirin-induced asthma is believed to involve inhibition of COX-1. Patients should be provided with information on which drugs these are. 

The second group of non-opioid analgesics, which are not classified as NSAIDs, consists of substances that lack anti-inflammatory properties, such as phenazones, metamizole (dipyrone) and paracetamol. Their molecules are neutral or weakly basic, have no hydrophilic... 

Cross-reactions with aspirin and NSAIDs are of practical importance. Typically, AIA patients are sensitive to all NSAIDs that preferentially inhibit COX-1 (table 2). Acetaminophen (paracetamol), a weak inhibitor of COX-1, is regarded as a relatively safe therapeutic alternative for almost all patients with AIA. High doses of the drug (>1,000 mg) have been reported to provoke mild, easily reversed bronchos-pasm in some AIA patients [13]. Some rare, well-documented cases of coexistence of aspirin and paracetamol sensitivity have been described. However, according to a recent meta-analysis, less that 2% of asthmatics are sensitive to both aspirin and paracetamol [14]. 

Courtney P, Doherty M. Key questions concerning paracetamol and NSAIDs for osteoarthritis. Ann Rheum Dis 2002 61 767-773. 

The first-line agents in the treatment of rheumatoid arthritis are non-steroidal anti-inflammatory drugs such as diclofenac. Diclofenac and indometacin, another NSAID, tend to have similar activity hov/ever, indometacin has a higher incidence of side-effects and therefore diclofenac is more appropriate for initial treatment. Sodium aurothiomalate is classified as a disease-modifying antirheumatic drug and is used as a second-line treatment in rheumatoid arthritis, but has been superseded by methotrexate, administered v/eekly. Paracetamol is often indicated in the management of osteoarthritis. Local intra-articular injections of dexamethasone may be administered for the relief of soft-tissue inflammatory conditions. 

Alternative products to diclofenac include naproxen and mefenamic acid, both of which are non-steroidal anti-inflammatory drugs. Co-codamol is a mixture of the opioid analgesic codeine and paracetamol and it does not possess the anti-inflammatory component. It may be used in pain management either where NSAIDs are contraindicated or in patients who are intolerant to the effects of NSAIDs. 

There are some additional choices in patients with refractory arthritis despite the use of NSAIDs or paracetamol (acetaminophen), alone or in combination. Narcotics can be used with little risk of addiction, but with the caveat that they can cause cognitive changes, constipation, urine retention and respiratory depression (see section on analgesics). Codeine... 

Paracetamol, synonym acetaminophen, is world wide probably the most popular analgesic and antipyretic. Its mechanism of action is not well understood. It is not really an NSAID as it is only a very weak inhibitor of cyclo-oxygenase and has hardly any anti-inflammatory activity. For the same reason paracetamol gives only negligible gastrointestinal irritation and gives hardly any blockade of platelet aggregation. Paracetamol concentrations in plasma reach a peak in 30-60 minutes, and the half-life in plasma is about 2 hours. Almost 100% of... 

Table 2. Medicines used in nociceptive pain conditions — paracetamol and NSAID ...

Recommended antipyretics are paracetamol, acetylsalicylic acid and short acting NSAIDs to adults. Children under the age of 18 should not be treated with acetylsalicylic acid due to an increased risk of Reye s syndrome in viral infections. 

V.c.1.1. Cyclo-oxygenase inhibition. Inhibition of cyclo-oxygenase reduces the level of circulating prostaglandins and neurogenic inflammation. This is the mechanism of action of nonsteroidal antiinflammatory drugs (NSAID) and aspirin. The mode of action of paracetamol is less clear (inhibition of prostaglandins in the nociceptors of the posterior horn of the spinal cord and action on the supraspinal structures implicated in nociception). 

Type B effects are not related to the pharmacological properties of these drugs. Serious side effects may occur. Allergic skin and liver reactions to aspirin and paracetamol have been reported with risk of fibrosis, particularly in the retroperitoneal region for methysergide and hypersensitivity reactions with NSAID and pure analgesics. 

Some non-steroidal anti-inflammatory drugs (NSAIDs) were found to have the following capacity factors in a particular mobile on a reverse-phase column aspirin 0.4, naproxen 3.6, ibuprofen 14.5, diclofenac 10.4, paracetamol 0.2. Given that the column had a t of 2 min determine the retention times of the NSAIDs. 

Some of the popularly used anti-inflammatory drugs, such as paracetamol, are not an NSAID but have analgesic/antipyretic properties. Paracetamol specifically has relatively weak anti-inflammatory activity. Once excreted, it gets reactivated in the environment through some microbially mediated transformation (Henschel et al., 1997). The exact mechanisms by which paracetamol relieves pain are not very clear. It has a chemical structure that resembles several estronegic compounds. 

In susceptibie individuais, NSAIDs may precipitate acute bronchospasm. It affects 10-20% of adults with asthma but is rare in asthmatic children. The mechanism is related to cyclooxygenase inhibition, with shunting of arachidonic acid metabolism from the prostaglandin pathway to the biosynthesis of ieukotrienes with increased mucosal permeability and bronchospasm. Susceptible patients should avoid NSAIDs since the bronchospasm may be severe and has been fatal. Paracetamol in doses up to 1000 mg daiiy wiii be toierated by most patients. True type I allergic reactions to NSAIDs, with specific IgE, are rare but anaphyloactoid reactions have occasionally been described in patients with a history of aiiergy or bronchiai asthma. 

Clinical use Paracetamol (Ameer and Greenblatt, 1977 Clissold, 1986) has analgesic and antipyretic properties, but no relevant anti-inflammatory action. It is used for the treatment of various mild to moderate pain conditions and to reduce fever. Paracetamol is one of the most popular analgesics as a single drug or in multi-ingredient preparations, often in combination with NSAIDs or weak opioids. 

Analgesic efficacy and clinical use Dextropropoxyphene (Grover, 1988) is a moderately potent opioid analgesic often combined with paracetamol or acetylsalicylic acid or other NSAIDs (Collins et al., 2000). As the hydrochloride or napsylate it is used orally for the treatment of mild, moderate, or severe pain (Beaver, 1984). 

Finally, acetaminophen (paracetamol) products may provide some temporary analgesic effects in people with rheumatoid arthritis, but these products are not optimal because they lack anti-inflammatory effects. As discussed in Chapter 15, acetaminophen can be used to treat mild-to-moderate pain, but the lack of anti-inflammatory effects makes acetaminophen fall short of NSAIDs for conditions such as rheumatoid arthritis. Hence, patients with rheumatoid arthritis usually prefer the effects of NSAIDs to acetaminophen,110 and acetaminophen products are not typically used for the routine treatment of this disease. 

Paracetamol and opioid analgesics are safe to use in porphyria, however diclofenac is one of the drugs known to be unsafe to prescribe in porphyria. There are other NSAIDs such as ibuprofen or naproxen which are not listed as unsafe and the medical team should be advised to amend the prescription accordingly. However if Mrs JC is in severe pain it may be necessary to prescribe a strong opiate. These are safe in porphyria. 

If a patient has ineffective or insufficient pain relief from paracetamol and a topical NSAID, then an oral NSAID or COX-2 inhibitor or weak opioid may be substituted or added in. There may be an element of inflammation as part of the disease and in some patients an NSAID may help. NICE recommend that a proton pump inhibitor is co-prescribed if an NSAID is taken regularly in order to reduce the risk of gastrointestinal events (NICE, 2008). 

This chapter concentrates on some drug choices in acute rather than chronic pain, but the same principles can be used to determine the appropriateness of other types of analgesic. The drugs considered in this section are paracetamol, non-steroidal anti-inflammatories (NSAIDs specifically diclofenac, ibuprofen, indometacin, naproxen, sulindac and tenoxicam) and opioids (codeine, dihydrocodeine, morphine, pethidine and tramadol). Unless otherwise stated, all pharmacokinetic data originate from standard reference sources [1-5] and apply to adults only. 

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