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Cyclooxygenase Inhibitors: Clinical Use
SUMMARY
Simple analgesics such as paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are highly effective clinically. The introduction of cyclooxgenase-2–inhibitory NSAIDs (coxibs), selective inhibitors of cyclooxygenase-2, has resulted in large quantities of safety and efficacy data. Although there are differences in efficacy between NSAIDs and paracetamol, the efficacy of classic NSAIDs and coxibs is similar, both in single doses used to treat acute postoperative pain and in the chronic situation for treatment of musculoskeletal disorders such as osteoarthritis. For acute pain, the highest doses of NSAIDs produce numbers needed to treat for 50% pain relief approaching 1, which is the theoretically perfect number; for chronic pain such as osteoarthritis, about half of patients will obtain good relief with any particular drug, but half will not. The major differences involve safety with chronic use. NSAIDs and coxibs can cause gastrointestinal bleeding and can precipitate renal failure or congestive heart failure at therapeutic doses. If oral NSAIDs are taken for at least 2 months, the risk for an endoscopic ulcer is 1 in 5; for a symptomatic ulcer, about 1 in 70; for a bleeding ulcer, about 1 in 150; and for death from a bleeding ulcer, about 1 in 1300. Coxibs have a lower risk for gastrointestinal bleeding than NSAIDs do. The odds ratio for acute renal failure is 1.6–2.0 with chronic NSAID therapy. The risk for congestive heart failure is twice as high with chronic NSAID therapy and increases more than 20-fold in patients with a previous history. Coxibs do not reduce the risk for renal or heart failure when compared with NSAIDs. Paracetamol is safe at therapeutic doses but a little less effective. This balance between efficacy and safety is critical for optimal use of the drugs in all therapeutic areas.
The NSAIDs, coxibs, and other non-opioid analgesics are important in pain management, both on and off prescription. People use paracetamol and NSAIDs off prescription to treat pain and fever. NSAIDs and coxibs are prescribed as part of the analgesic ladder.
The phrase “analgesic ladder” is slightly misleading when it comes to optimal use of these drugs. Unlike a real ladder, where the climber goes up or down the rungs, the best pain relief may be obtained if all the rungs on the analgesic ladder are used simultaneously in the sense that non-opioid analgesics work through different mechanisms than opioids do and analgesia from one drug class adds to the analgesia provided by the other class—hence the importance of non-opioid analgesics.
The development of coxibs has given us a clearer picture of the mechanism of NSAID action, but we are still ignorant of precisely where and, in some cases, how the non-opioid analgesics work, even though aspirin was, after all, discovered in 1753 (at Chipping Norton near Oxford) and preparations of willow have been used in herbal and folk medicine for thousands of years.
Beyond understanding where and how the non-opioid analgesics work, the clinical questions about their pharmacology are intriguing. These drugs work as analgesics, but we need to know which is the most and which is the least effective and whether different routes of administration offer any advantage in efficacy. The choice of drug to prescribe has to take into account its relative safety and whether it provides pain relief for the individual patient. Safety issues include adverse effects at therapeutic dosages (gastrointestinal, cardiac, and renal); the impact of the drugs on other diseases, such as asthma, or on processes such as bone healing and bleeding; and drug–drug interactions with warfarin or prophylactic aspirin.
Although the major focus of this chapter is on NSAIDs and coxibs, there is also brief mention of paracetamol, dipyrone, and nefopam.
Introduction
NSAIDs: Cox-1 and Coxibs
The classic explanation of how non-steroidal anti-inflammatory drugs (NSAIDs) work was that they inhibited the constitutive enzyme cyclooxygenase (Cox), thereby decreasing prostaglandin synthesis, which in turn reduced the sensitizing effect of the prostaglandins. Cox was believed to be expressed at constant levels in individual tissues. This was unlikely to be the complete story because of observations such as an increase in Cox activity in inflammation, the ability of corticosteroids to block this increase, and the analgesic efficacy of the drugs for conditions that do not involve inflammation. Similarly, a solely peripheral site of action does not fit easily with the antipyretic effects of aspirin or its ability to produce tinnitus, which seems likely to be occurring centrally.
The research that followed identification of two isoforms of Cox, Cox-1 and Cox-2, has made some of the mechanisms of action clearer ( , ). The two enzymes are very similar. Both are membrane associated. Arachidonic acid released from neighboring damaged membranes is converted by the enzymes into prostaglandins. The differences between the two enzymes lie in their internal configuration, which dictates which drugs bind to each; in their distribution in different body tissues; and in their relative preponderance in normal conditions (constitutive) and in response to inflammation (induced). The broad distinction between the two systemic isoforms Cox-1 and Cox-2 is that Cox-1 is expressed mainly constitutively and gives rise to prostaglandins that mediate normal cellular processes whereas Cox-2 is generally considered to be an inducible enzyme elicited by inflammation and called up to synthesize more prostanoids. Cox-1, as the constitutive isoform, is necessary for normal functions and is found in most cell types. Cox-2, despite being the inducible isoform, is expressed constitutively (i.e., under normal conditions) in a number of tissues, which probably include brain, testis, and kidney.
It is because these prostanoids play a variety of important roles in the normal physiology and functioning of the gastrointestinal tract, the renal system, and the cardiovascular system that NSAID and coxib therapy, by inhibiting prostaglandin and thromboxane production, can interfere with prostaglandin-mediated maintenance of these systems and result in a range of potential adverse effects.
Paracetamol, Dipyrone, and Nefopam
Nobody knows precisely where paracetamol, dipyrone, or nefopam work. The standard explanation for paracetamol is that it acts as a Cox inhibitor in the brain, which explains both its analgesic and its antipyretic actions. The lack of clinical anti-inflammatory activity may be because paracetamol is not active on peripheral Cox. Similar comments are made for dipyrone. Nefopam, though undoubtedly an analgesic, has neither opioid nor NSAID-like activity. It is neither anti-inflammatory nor antipyretic, and like paracetamol and dipyrone, its site of action is presumed to be in the central nervous system.
Clinical Efficacy
How Well Does the Intervention Work?
Clinicians need to know how well the intervention works: the size of the effect and its clinical significance. Knowing only that an intervention works is much, much less helpful, especially when a range of similar interventions is available. The information on relative efficacy given here uses the number needed to treat (NNT) as the measure of clinical significance, with data being derived from quantitative systematic reviews. The NNT describes the difference between active treatment and control, and in Figures 33-1 to 33-4 this is the difference between active drug and placebo in the proportion of patients who achieve at least 50% pain relief over a 6-hour period following a single postoperative dose of the drug.
By deriving the NNT for different analgesics from comparisons with placebo, their relative efficacy can be compared, and such league tables (see Fig. 33-1 ) are easy to understand. As more trials are reported and systematic reviews are compiled to provide similar data on other analgesics, the league table can be extended and refined and thereby allow drug comparison on a credible evidence base. The league table is legitimate only because it uses information on similar patients with valid inclusion criteria (pain of moderate or severe intensity), similar measurement methods, and similar outcomes, with placebo being used as a common comparator, and in circumstances in which we know that the pain model makes no difference ( ). Although it can be argued that head-to-head comparison between analgesics would be better, the problem is that few such comparisons exist and randomized trials to detect small differences in efficacy between two analgesics would need to be massive to be able to detect differences in direction, let alone in the magnitude of the difference.
This approach depends on having outcomes that are clinically useful, and with acute and chronic pain, a reduction in pain intensity of about 50% is often regarded as clinically useful ( , ). Moreover, in chronic pain conditions, a reduction in pain by this amount is associated with major benefits in terms of associated symptoms such as sleep-related problems, depression, and fatigue and in terms of major improvements in quality of life ( ).
Oral Non-opioids
Figure 33-1 shows the NNTs, confidence intervals, and number of patients in the trials at each single oral dose of selected NSAIDs, coxibs, paracetamol, tramadol, and intramuscular morphine. The data are derived from systematic reviews of randomized controlled trials of single doses for postoperative pain. It is clear that the NSAIDs and coxibs do extremely well in this single-dose postoperative comparison. They have NNT values of between 2 and 3, which means that of two or three patients given that drug at that dose, one will achieve at least 50% pain relief, a high hurdle.
The NSAID and coxib NNTs at these doses are lower (i.e., better) than the value achieved by 10 mg of intramuscular morphine, even though the confidence intervals overlap. It has been known for many years from single trials that oral NSAIDs can provide analgesia similar to that achieved with 10 mg of intramuscular morphine, and these data confirm those observations. The limited data that we have on 20 mg of intramuscular morphine give an NNT of less than 2.
Coxibs achieve NNTS that are as good as or better (lower) than NNTs with NSAIDs. The coxibs have been used in postoperative trials at doses several multiples of the dose for chronic pain, whereas the NSAIDs were tested at doses close to the chronic pain dose, so the difference in efficacy between coxibs and NSAIDs in this 6-hour efficacy comparison is largely a function of dose (see Fig. 33-2 ). There is no reason to expect any greater analgesia from the coxibs than from the NSAIDs—which were after all designed specifically to reduce gastrointestinal hemorrhage rather than because they offered greater efficacy—unless the doses are increased relative to the NSAIDs.
Aspirin, 600 or 650 mg, and paracetamol, 1000 mg, are significantly less effective than 10 mg of intramuscular morphine. The point estimates of the NNT are higher, and there is no overlap of the confidence intervals. The original trial results of Houde and Wallenstein suggested milligram-for-milligram equianalgesic equivalence between aspirin and paracetamol for postoperative pain, and this is borne out by our results. Dipyrone, 500 mg orally, has an NNT of 2.4 (1.9–3.2) from data on only 143 patients ( ). It too is an effective drug. We have no NNT for nefopam.
These NNTs were derived from single-dose pain studies. It is not possible from these analyses to comment on the speed of onset of analgesia, but we know from single trials that oral normal-release formulations of the original NSAIDs start to work at roughly half an hour, with the peak effect occurring between 60 and 90 minutes. The duration of analgesia with NSAIDs and coxibs is a function of dose (and kinetics). Bigger doses will provide an analgesic effect longer than the 4–6 hours expected with the standard therapeutic dose. The large coxib doses used in these postoperative trials should therefore result in longer duration of analgesia. Most multiple-dosing studies have been performed in patients with arthritis, and the relative efficacy data shown here from single doses seem to tally well with the multiple-dosing studies.
Another old observation from single trials was that the dose–response relationship for analgesia with NSAIDs was flat, meaning that the increase in analgesia as a result of increasing the dose was less marked than that seen with a similar relative increase in dose for, say, morphine. The results from systematic reviews of single doses (see Fig. 33-2 ) show very similar dose–response relationships for aspirin and paracetamol, a reflection of their milligram-for-milligram equivalence in efficacy, and show the greater potency (more analgesia at a lower milligram dosage) of diclofenac, ibuprofen, and etoricoxib.
The largest doses of etoricoxib, diclofenac, and ibuprofen produce NNTs approaching 1, which is the theoretically perfect NNT (actually, 1.1–1.2 with placebo responses of about 10–15%). Doses are plotted in Figure 33-2 as logarithms. This perhaps emphasizes the clinical perception of the ceiling of non-opioid analgesia. For diclofenac and etoricoxib, the doses shown are on the upper (flatter) part of the sigmoid dose–response curve; further increases in dose may produce little improvement in the NNT. The steeper slopes for aspirin and paracetamol suggest the steep portion of the sigmoid curve; better NNTs could be achieved with larger doses if it were safe to give them.
The analgesic efficacy of the non-opioid analgesics is improved by combining them with weak opioids (see Fig. 33-3 ) ( ). The combination of paracetamol, 600 or 650 mg, with codeine or dextropropoxyphene lowers (improves) the NNT of the combination to levels similar to that of 10 mg of intramuscular morphine. At a practical clinical level, combinations of simple analgesics with opioids are considered effective and are often used as one rung in the ladder of analgesic treatments. The clinical need for combinations is based on the fact that a proportion of patients cannot or should not be given NSAIDs or coxibs, usually because of allergy or gastrointestinal problem. In a young group of study patients this proportion was 17% ( ).
The central argument used against combinations is that a combination of A plus B is no better than A alone. Figure 33-3 illustrates that pooling information from individual trials can provide evidence to deal with this argument in a way that individual trials of conventional size cannot. Clearly, the combinations were better than the individual components alone, and the argument that a combination of A plus B is no better than A alone can be rebutted.
Efficacy with Chronic Use
Efficacy comparisons of NSAIDs and coxibs for arthritis are of high quality, large, and of long duration and have eclipsed previous studies of NSAIDs for arthritis ( ). Coxibs and NSAIDs were more effective than placebo, and coxibs were as effective as the maximum daily doses of most standard NSAIDs (diclofenac, 150 mg, and naproxen, 1000 mg daily). Re-analysis of trial data by using outcomes of at least 30% and at least 50% pain relief over a period of 12 weeks and defining responders as having the response without withdrawal emphasizes the good equivalence between coxibs and most NSAIDs, with the possible exception of ibuprofen ( Fig. 33-5 ; ). Patients achieved either good pain relief or virtually none, and no drug provided good relief of osteoarthritis pain in more than 60% of the patients. No single coxib or NSAID will work in every patient. For coxibs that level of efficacy is achieved with better gastrointestinal safety.
There is limited good-quality evidence from long-duration trials on treatment of chronic low back pain, but the evidence we have is that etoricoxib, 60 or 90 mg, has NNTs of 7 or 8 for at least 50% pain relief over a 12-week period ( ).
Another way of considering efficacy with chronic use is to look at the proportion of patients who discontinue the drug because of lack of efficacy. In the arthritis trials, 20% of patients discontinued by 6 weeks because of the lack of efficacy of placebo, two-thirds of those who discontinue for any reason. For paracetamol, 4 g/day, the discontinuation rate because of lack of efficacy was similar. For the maximum daily dose of NSAIDs or the trial dosages of coxibs, the lack-of-efficacy discontinuation rate at 6 weeks was around 6%. At 6 months, the rate was about 14% for both NSAIDs and coxibs.
Paracetamol was not very different from placebo in trials of patients with osteoarthritis. The NNT of 16 for overall pain was regarded to be of questionable clinical significance ( ), and even that result may be an overestimate because of residual bias in some of the trials. This may be confounded because people with adequate relief from paracetamol do not enter the trials.
Other Routes of Administration
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