PERSPECTIVE
Analgesic safety – myths, mysteries and misconceptions Acute episodes of tension-type headache (TTH) are common and affect people of all ages, races and income levels. Two recommended and commonly used drugs for the treatment of this condition are ibuprofen and paracetamol (1). However, despite – or perhaps because of – their widespread use, many misconceptions persist about their comparative efficacy and safety. Are concerns about the gastrointenstinal (GI) safety of ibuprofen justified in the non-prescription over-the-counter (OTC) setting? Do low doses of ibuprofen – as used for TTH – increase the risk of heart attacks? Is the efficacy of ibuprofen and paracetamol really the same? At OTC doses, ibuprofen is a better analgesic than paracetamol, and any concerns about harm are probably based on a misunderstanding of the evidence
24
Methodological considerations When we look at data, is it important to look in the context of methodology of clinical studies in pain management? Healthcare providers often look to systematic reviews to inform their decision-making. Good meta-analyses are useful because they increase the power and precision of treatment-effect and exposure-risk estimates (2). However, the reliability and accuracy of the conclusions depend on the quality of the primary data, and the measures taken to reduce bias and to control for confounding factors. Gerber et al. (3) identified considerable methodological deficiencies in many meta-analyses published in leading journals; for example, only 52% made any attempt at assessing trial quality, and assessment of randomisation and blinding was carried out in only 31%. As a result, many systematic reviews in the analysis by Gerber et al. probably overstated any treatment effects (3). Observational studies are often considered inferior to randomised controlled trials (RCTs) because of the potential for selection bias and confounding. Yet they have a crucial role to play when it comes to assessing the true incidence of drug-related toxicities, for instance [especially for events that are comparatively rare, as is the case with serious GI or cardiovascular (CV) complications]. The general perception that observational studies lead to an overestimation of treatment effects has been refuted by Concato et al. (4), who showed that well-designed observational studies give the same results as well-designed RCTs, and where there was a sufficiency of evidence to make a judgement.
GI safety
The GI risks associated with the use of prescription-strength NSAIDs are well-documented and range from mild symptoms such as nausea, vomiting and stomach pain to serious events such as GI bleeding. Evidence for such potential complications is consistent across meta-analyses, randomised controlled studies and large observational/real-world studies. Of the various NSAIDs, ibuprofen carries the lowest relative risk, usually because it is only used in practice at doses up to 1200 mg a day. In a meta-analysis published by the safety of non-steroidal anti-inflammatory drugs (SOS) collaborative project, the relative risk of upper GI complications was 1.8 with ibuprofen, compared with 3.3 for diclofenac and 4.1 for naproxen (5). The SOS project investigators looked at analgesic and anti-inflammatory doses combined. This is an important point to consider because the risk of GI complications is dose-dependent and is considerably lower if ibuprofen is used in an OTC setting (6). In fact, the risk might not be increased at all if ibuprofen is used at single OTC doses, as indicated by two Cochrane reviews (7,8). Derry et al. (7) examined all evidence for single doses of ibuprofen in the range of 50–400 mg. The analysis included 72 high-quality clinical studies comparing ibuprofen with placebo in over 9000 individuals. The risk of GI adverse events with ibuprofen was found to be the same as placebo. Rabbie et al. (8) looked at the treatment of migraine headache episodes with a single ibuprofen dose and came to the same conclusion. Studies comparing the incidence of GI side effects with paracetamol and ibuprofen in the OTC setting also found no difference between these two agents (9,10). In the PAIN study, a large RCT involving 8677 people who used ibuprofen, paracetamol or aspirin at maximum or near-maximum OTC doses for the treatment of common painful conditions, the risk of GI events was lower with ibuprofen than with paracetamol (11) (Figure 1).
CV safety Evidence of the CV risks associated with NSAIDs is less clear-cut than that for gastrointestinal complications.
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 24–27 doi: 10.1111/ijcp.12655
25
Perspective
Figure 1 Rate of GI side effects with ibuprofen vs. paracetamol in the PAIN study. Adapted from Moore et al. (11)
Available data mainly come from studies where patients used prescription-strength NSAIDs. However, as with the risk for GI complications, any risk for CV adverse events is probably dose-dependent, and there is no clear evidence of an increased CV risk if NSAIDs are used at or below the maximal approved OTC doses (12). Prescription-strength NSAIDs do increase the risk for heart failure in patients with pre-existing CV risk, according to a large meta-analysis of individual patient data from RCTs of NSAIDs vs. placebo (n = 124,513; 68,342 person years) (13). Most of the investigated NSAIDs also increased the risk of other CV events and vascular death, but with ibuprofen (mostly 2400 mg/day) the increase in vascular death was not statistically significant.
Longitudinal studies where the CV risk of NSAIDs was adjusted for pre-existing CV risk factors indicate that these drugs may in fact reduce the risk of dying from a CV event. Goodson et al. conducted an observational study in 923 patients who used NSAIDs (OTC NSAIDs and prescribed NSAIDs) for the treatment of inflammatory polyarthritis (14). This study had a follow-up period of 15 years, during which 203 deaths occurred. In a multivariate analysis, baseline NSAID use was inversely associated with all-cause mortality [adjusted odds ratio 0.62 (95% CI 0.45–0.84)] and CV disease mortality [adjusted odds ratio 0.54 (95% CI 0.34–0.86)]. Perhaps some of the best evidence comes from a study in the Australian veteran community, which involved a large cohort of elderly people (84,000 cases and 1.7 million controls) (15). The analysis was controlled for multiple potential confounders including comorbidities. In this study, use of prescription NSAIDs had a neutral effect on the risk of a range of CV events (Table 1). Moreover, it reduced the risk of all-cause mortality. A possible explanation for this reduced risk is the long-term impact effective pain relief might have on physical mobility – a factor that has not been considered in any of the studies looking at the CV risk profile of NSAIDs.
Efficacy Multiple studies have examined the analgesic efficacy of ibuprofen and paracetamol in acute and chronic painful conditions at comparable doses, using indirect
Table 1 Odds ratios* (95% CI) for cardiovascular outcomes according to the group of NSAID studied and the frequency of use in the last 2 years (15)
Myocardial infarction
Peripheral arterial disease
Heart failure
Arrhythmias
Cardiac arrest
All-cause mortality
1.00 0.98 1.30 0.89 0.99
(0.81, (1.02, (0.76, (0.86,
1.20) 1.66) 1.05) 1.16)
1.00 1.02 0.92 0.96 0.95
(0.98, (0.87, (0.93, (0.92,
1.06) 0.97) 0.99) 0.98)
1.00 1.00 0.95 0.97 0.95
(0.92, (0.84, (0.90, (0.89,
1.10) 1.08) 1.05) 1.02)
1.00 0.85 0.93 0.90 0.87
(0.73, (0.77, (0.81, (0.78,
0.98) 1.12) 1.01) 0.97)
1.00 0.94 0.85 0.90 0.87
(0.90, (0.80, (0.88, (0.85,
0.97) 0.89) 0.93) 0.90)
1.00 1.02 0.83 1.00 1.16
(0.84, (0.63, (0.78, (0.86,
1.23) 1.11) 1.28) 1.56)
1.00 0.97 0.92 0.95 0.95
(0.94, (0.87, (0.90, (0.89,
1.01) 0.97) 1.00) 1.01)
1.00 0.97 0.93 0.94 0.96
(0.89, (0.82, (0.83, (0.83,
1.06) 1.06) 1.05) 1.11)
1.00 0.87 0.86 0.89 0.83
(0.76, (0.71, (0.75, (0.67,
1.00) 1.06) 1.07) 1.04)
1.00 0.93 0.87 0.82 0.74
(0.90, (0.83, (0.78, (0.69,
0.97) 0.92) 0.86) 0.79)
....................................................................... NSAID type (used in last 2 years) No NSAID 1.00 ns-NSAIDs 1.02 (0.97, 1.07) Ox-Sul-ns-NSAIDs 1.00 (0.93, 1.07) Cox-2 inhibitors 1.02 (0.97, 1.06) Any NSAID 1.00 (0.96, 1.04) NSAID supplies (in last 2 years) None 1.00 1–4 0.95 (0.90, 1.00) 5–10 0.94 (0.87, 1.01) 11–19 1.08 (1.01, 1.15) 20+ 1.10 (1.01, 1.19)
....................................................................... ns-NSAIDs, non-selective NSAIDs; Ox-Sul-ns-NSAIDs, oxicams and sulindac (subset of ns-NSAIDs). *Adjusted for age (to nearest year), residential aged care (RAC) status (in RAC for at least 6 months prior to index date), public or private hospital admissions (for diabetes, obesity, dementia, hypertension, ischaemic heart disease, respiratory disease, liver disease, rheumatoid arthritis or renal disease) at any time prior to the index date, and the use of salicylic acid and derivatives or medications for the following conditions: obesity, diabetes, thrombosis, cardiovascular disease, dementia and obstructive airways diseases within 4 months prior to the index date. ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 24–27
26
Perspective
and direct comparisons. A variety of efficacy measures are used including numbers needed to treat (NNT), percentage of patients who achieved good pain relief and time to remedication. The results are consistent: ibuprofen is a more effective analgesic than paracetamol at the most frequently prescribed doses. Much evidence comes from patients with postoperative pain, typically after third molar extraction. Two rigorously designed Cochrane reviews evaluated all available indirect (16) and direct (17) comparative evidence. Moore et al. (16) conducted a meta-analysis of studies that compared single-dose ibuprofen or paracetamol with placebo in acute postoperative pain models, using at least 50% maximum pain relief over 4–6 h as the outcome measure. The authors reported a NNT of 2.3 (95% CI 2.2–2.4) for 400 mg ibuprofen compared with 3.2 (95% CI 2.9–3.6) for 975/ 1000 mg paracetamol. Similarly, the meta-analysis of studies that directly compared 400 mg ibuprofen with 1000 mg paracetamol in acute postoperative pain models showed a risk ratio of 1.5 (95% CI 1.3–1.7) favouring ibuprofen for at least 50% maximum pain relief over 6 hours, and a risk ratio of 1.5 (95% CI 1.3–1.8) favouring ibuprofen for not using rescue medication (17). Significant differences favouring ibuprofen (or NSAIDs as a class) were also found for other common conditions including musculoskeletal pain (10), period pain (18), migraine headaches (7,8) and TTH (1).
Conclusion Effective treatment of TTH is hampered by myths surrounding the drugs that are recommended for its treatment – in particular with regard to the safety and efficacy of ibuprofen compared with paracetamol. Yet, these generalised assumptions are not supported by the available data.
References 1 Bendtsen L, Evers S, Linde M; EFNS et al. EFNS guideline on the treatment of tension-type headache – report of an EFNS task force. Eur J Neurol 2010; 17: 1318–25. 2 Mulrow CD. Rationale for systematic reviews. BMJ 1994; 309: 597–9. 3 Gerber S, Tallon D, Trelle S et al. Bibliographic study showed improving methodology of metaanalyses published in leading journals 1993-2002. J Clin Epidemiol 2007; 60: 773–80. 4 Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000; 342: 1887–92. 5 Castellsague J, Riera-Guardia N, Calingaert B et al. Safety of Non-Steroidal Anti-Inflammatory Drugs
6
7
8
9
Evidence from a range of large high-quality studies confirms that there are no clear differences in the GI safety profiles of ibuprofen and paracetamol if used at OTC doses and for durations associated with OTC use, and there do not seem to be any CV safety implications with ibuprofen if used as indicated in an OTC setting. Even at prescription doses, ibuprofen use might not carry an increased risk of heart attacks, especially in patients without pre-existing CV risk factors. In addition, where data are available from indirect or direct comparisons of ibuprofen and paracetamol used in a standard way, and comparing standard doses, ibuprofen consistently emerges as the more effective analgesic. Use of the most effective analgesic for the treatment of TTH has additional advantages. It reduces the need for remedication, minimising drug exposure overall with associated safety benefits, and it might steer patients away from taking medication too frequently, thereby reducing their risk of medicationoveruse headache.
Disclosure RAM has received lecture fees from or consulted for a number of pharmaceutical companies (including Reckitt Benckiser) for activities related to analgesics and other healthcare interventions, and received research support from charities, government and industry sources at various times. R. A. Moore Pain Research and Nuffield Division of Anaesthetics, University of Oxford, Oxford, UK Correspondence to: R. Andrew Moore, Pain Research and Nuffield Division of Anaesthetics, University of Oxford, Oxford OX3 7LJ, UK Tel.: + 44 1865 225 674 Fax: + 44 1865 225 402 Email: [email protected]
(SOS) Project. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Saf 2012; 35: 1127–46. Bjarnason I. Ibuprofen and gastrointestinal safety: a dose-duration-dependent phenomenon. J R Soc Med 2007; 100(Suppl. 48): 11–4. Derry C, Derry S, Moore RA et al. Single dose oral ibuprofen for acute postoperative pain in adults. Cochrane Database Syst Rev 2009; 3: CD001548. Rabbie R, Derry S, Moore RA. Ibuprofen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2013; 4: CD008039. Moore N, Le Parc JM, van Ganse E et al. Tolerability of ibuprofen, aspirin and paracetamol for the
treatment of cold and flu symptoms and sore throat pain. Int J Clin Pract 2002; 56: 732–4. 10 Doherty M, Hawkey C, Goulder M et al. A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis 2011; 70: 1534–41. 11 Moore N, van Ganse E, Le Parc J-M et al. The PAIN study: paracetamol, aspirin and ibuprofen new tolerability study. A large-scale, randomised clinical trial comparing the tolerability of aspirin, ibuprofen and paracetamol for short-term analgesia. Clin Drug Invest 1999; 18: 89–98. 12 Moore N, Salvo F, Duong M et al. Cardiovascular risks associated with low-dose ibuprofen and diclofenac as used OTC. Expert Opin Drug Saf 2014; 13: 167–79.
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 24–27
Perspective
13 Coxib and Traditional NSAID Trialists’ (CNT) Collaboration, Bhala N, Emberson J, Merhi A et al. Vascular and upper gastro intestinal effects of nonsteroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382:769–79. 14 Goodson NJ, Brookhart AM, Symmons DP et al. Non-steroidal anti-inflammatory drug use does not appear to be associated with increased cardiovascular mortality in patients with inflammatory polyarthritis: results from a primary care based inception cohort of patients. Ann Rheum Dis 2009; 68: 367–72.
15 Mangoni AA, Woodman RJ, Gaganis P et al. Use of non-steroidal anti-inflammatory drugs and risk of incident myocardial infarction and heart failure, and all-cause mortality in the Australian veteran community. Br J Clin Pharmacol 2010; 69: 689– 700. 16 Moore RA, Derry S, McQuay HJ et al. Single dose oral analgesics for acute postoperative pain in adults. Cochrane Database Syst Rev 2011; 9: CD008659. 17 Bailey E, Worthington HV, van Wijk A et al. Ibuprofen and/or paracetamol (acetaminophen) for
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 24–27
27
pain relief after surgical removal of lower wisdom teeth. Cochrane Database Syst Rev 2013; 12 : CD004624. 18 Marjoribanks J, Proctor M, Farquhar C et al. Nonsteroidal anti-inflammatory drugs for dysmenorrhoea. Cochrane Database Syst Rev 2010; 1: CD001751.
Paper received June 2014, accepted November 2014
Analgesic safety – myths, mysteries and misconceptions Acute episodes of tension-type headache (TTH) are common and affect people of all ages, races and income levels. Two recommended and commonly used drugs for the treatment of this condition are ibuprofen and paracetamol (1). However, despite – or perhaps because of – their widespread use, many misconceptions persist about their comparative efficacy and safety. Are concerns about the gastrointenstinal (GI) safety of ibuprofen justified in the non-prescription over-the-counter (OTC) setting? Do low doses of ibuprofen – as used for TTH – increase the risk of heart attacks? Is the efficacy of ibuprofen and paracetamol really the same? At OTC doses, ibuprofen is a better analgesic than paracetamol, and any concerns about harm are probably based on a misunderstanding of the evidence
24
Methodological considerations When we look at data, is it important to look in the context of methodology of clinical studies in pain management? Healthcare providers often look to systematic reviews to inform their decision-making. Good meta-analyses are useful because they increase the power and precision of treatment-effect and exposure-risk estimates (2). However, the reliability and accuracy of the conclusions depend on the quality of the primary data, and the measures taken to reduce bias and to control for confounding factors. Gerber et al. (3) identified considerable methodological deficiencies in many meta-analyses published in leading journals; for example, only 52% made any attempt at assessing trial quality, and assessment of randomisation and blinding was carried out in only 31%. As a result, many systematic reviews in the analysis by Gerber et al. probably overstated any treatment effects (3). Observational studies are often considered inferior to randomised controlled trials (RCTs) because of the potential for selection bias and confounding. Yet they have a crucial role to play when it comes to assessing the true incidence of drug-related toxicities, for instance [especially for events that are comparatively rare, as is the case with serious GI or cardiovascular (CV) complications]. The general perception that observational studies lead to an overestimation of treatment effects has been refuted by Concato et al. (4), who showed that well-designed observational studies give the same results as well-designed RCTs, and where there was a sufficiency of evidence to make a judgement.
GI safety
The GI risks associated with the use of prescription-strength NSAIDs are well-documented and range from mild symptoms such as nausea, vomiting and stomach pain to serious events such as GI bleeding. Evidence for such potential complications is consistent across meta-analyses, randomised controlled studies and large observational/real-world studies. Of the various NSAIDs, ibuprofen carries the lowest relative risk, usually because it is only used in practice at doses up to 1200 mg a day. In a meta-analysis published by the safety of non-steroidal anti-inflammatory drugs (SOS) collaborative project, the relative risk of upper GI complications was 1.8 with ibuprofen, compared with 3.3 for diclofenac and 4.1 for naproxen (5). The SOS project investigators looked at analgesic and anti-inflammatory doses combined. This is an important point to consider because the risk of GI complications is dose-dependent and is considerably lower if ibuprofen is used in an OTC setting (6). In fact, the risk might not be increased at all if ibuprofen is used at single OTC doses, as indicated by two Cochrane reviews (7,8). Derry et al. (7) examined all evidence for single doses of ibuprofen in the range of 50–400 mg. The analysis included 72 high-quality clinical studies comparing ibuprofen with placebo in over 9000 individuals. The risk of GI adverse events with ibuprofen was found to be the same as placebo. Rabbie et al. (8) looked at the treatment of migraine headache episodes with a single ibuprofen dose and came to the same conclusion. Studies comparing the incidence of GI side effects with paracetamol and ibuprofen in the OTC setting also found no difference between these two agents (9,10). In the PAIN study, a large RCT involving 8677 people who used ibuprofen, paracetamol or aspirin at maximum or near-maximum OTC doses for the treatment of common painful conditions, the risk of GI events was lower with ibuprofen than with paracetamol (11) (Figure 1).
CV safety Evidence of the CV risks associated with NSAIDs is less clear-cut than that for gastrointestinal complications.
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 24–27 doi: 10.1111/ijcp.12655
25
Perspective
Figure 1 Rate of GI side effects with ibuprofen vs. paracetamol in the PAIN study. Adapted from Moore et al. (11)
Available data mainly come from studies where patients used prescription-strength NSAIDs. However, as with the risk for GI complications, any risk for CV adverse events is probably dose-dependent, and there is no clear evidence of an increased CV risk if NSAIDs are used at or below the maximal approved OTC doses (12). Prescription-strength NSAIDs do increase the risk for heart failure in patients with pre-existing CV risk, according to a large meta-analysis of individual patient data from RCTs of NSAIDs vs. placebo (n = 124,513; 68,342 person years) (13). Most of the investigated NSAIDs also increased the risk of other CV events and vascular death, but with ibuprofen (mostly 2400 mg/day) the increase in vascular death was not statistically significant.
Longitudinal studies where the CV risk of NSAIDs was adjusted for pre-existing CV risk factors indicate that these drugs may in fact reduce the risk of dying from a CV event. Goodson et al. conducted an observational study in 923 patients who used NSAIDs (OTC NSAIDs and prescribed NSAIDs) for the treatment of inflammatory polyarthritis (14). This study had a follow-up period of 15 years, during which 203 deaths occurred. In a multivariate analysis, baseline NSAID use was inversely associated with all-cause mortality [adjusted odds ratio 0.62 (95% CI 0.45–0.84)] and CV disease mortality [adjusted odds ratio 0.54 (95% CI 0.34–0.86)]. Perhaps some of the best evidence comes from a study in the Australian veteran community, which involved a large cohort of elderly people (84,000 cases and 1.7 million controls) (15). The analysis was controlled for multiple potential confounders including comorbidities. In this study, use of prescription NSAIDs had a neutral effect on the risk of a range of CV events (Table 1). Moreover, it reduced the risk of all-cause mortality. A possible explanation for this reduced risk is the long-term impact effective pain relief might have on physical mobility – a factor that has not been considered in any of the studies looking at the CV risk profile of NSAIDs.
Efficacy Multiple studies have examined the analgesic efficacy of ibuprofen and paracetamol in acute and chronic painful conditions at comparable doses, using indirect
Table 1 Odds ratios* (95% CI) for cardiovascular outcomes according to the group of NSAID studied and the frequency of use in the last 2 years (15)
Myocardial infarction
Peripheral arterial disease
Heart failure
Arrhythmias
Cardiac arrest
All-cause mortality
1.00 0.98 1.30 0.89 0.99
(0.81, (1.02, (0.76, (0.86,
1.20) 1.66) 1.05) 1.16)
1.00 1.02 0.92 0.96 0.95
(0.98, (0.87, (0.93, (0.92,
1.06) 0.97) 0.99) 0.98)
1.00 1.00 0.95 0.97 0.95
(0.92, (0.84, (0.90, (0.89,
1.10) 1.08) 1.05) 1.02)
1.00 0.85 0.93 0.90 0.87
(0.73, (0.77, (0.81, (0.78,
0.98) 1.12) 1.01) 0.97)
1.00 0.94 0.85 0.90 0.87
(0.90, (0.80, (0.88, (0.85,
0.97) 0.89) 0.93) 0.90)
1.00 1.02 0.83 1.00 1.16
(0.84, (0.63, (0.78, (0.86,
1.23) 1.11) 1.28) 1.56)
1.00 0.97 0.92 0.95 0.95
(0.94, (0.87, (0.90, (0.89,
1.01) 0.97) 1.00) 1.01)
1.00 0.97 0.93 0.94 0.96
(0.89, (0.82, (0.83, (0.83,
1.06) 1.06) 1.05) 1.11)
1.00 0.87 0.86 0.89 0.83
(0.76, (0.71, (0.75, (0.67,
1.00) 1.06) 1.07) 1.04)
1.00 0.93 0.87 0.82 0.74
(0.90, (0.83, (0.78, (0.69,
0.97) 0.92) 0.86) 0.79)
....................................................................... NSAID type (used in last 2 years) No NSAID 1.00 ns-NSAIDs 1.02 (0.97, 1.07) Ox-Sul-ns-NSAIDs 1.00 (0.93, 1.07) Cox-2 inhibitors 1.02 (0.97, 1.06) Any NSAID 1.00 (0.96, 1.04) NSAID supplies (in last 2 years) None 1.00 1–4 0.95 (0.90, 1.00) 5–10 0.94 (0.87, 1.01) 11–19 1.08 (1.01, 1.15) 20+ 1.10 (1.01, 1.19)
....................................................................... ns-NSAIDs, non-selective NSAIDs; Ox-Sul-ns-NSAIDs, oxicams and sulindac (subset of ns-NSAIDs). *Adjusted for age (to nearest year), residential aged care (RAC) status (in RAC for at least 6 months prior to index date), public or private hospital admissions (for diabetes, obesity, dementia, hypertension, ischaemic heart disease, respiratory disease, liver disease, rheumatoid arthritis or renal disease) at any time prior to the index date, and the use of salicylic acid and derivatives or medications for the following conditions: obesity, diabetes, thrombosis, cardiovascular disease, dementia and obstructive airways diseases within 4 months prior to the index date. ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 24–27
26
Perspective
and direct comparisons. A variety of efficacy measures are used including numbers needed to treat (NNT), percentage of patients who achieved good pain relief and time to remedication. The results are consistent: ibuprofen is a more effective analgesic than paracetamol at the most frequently prescribed doses. Much evidence comes from patients with postoperative pain, typically after third molar extraction. Two rigorously designed Cochrane reviews evaluated all available indirect (16) and direct (17) comparative evidence. Moore et al. (16) conducted a meta-analysis of studies that compared single-dose ibuprofen or paracetamol with placebo in acute postoperative pain models, using at least 50% maximum pain relief over 4–6 h as the outcome measure. The authors reported a NNT of 2.3 (95% CI 2.2–2.4) for 400 mg ibuprofen compared with 3.2 (95% CI 2.9–3.6) for 975/ 1000 mg paracetamol. Similarly, the meta-analysis of studies that directly compared 400 mg ibuprofen with 1000 mg paracetamol in acute postoperative pain models showed a risk ratio of 1.5 (95% CI 1.3–1.7) favouring ibuprofen for at least 50% maximum pain relief over 6 hours, and a risk ratio of 1.5 (95% CI 1.3–1.8) favouring ibuprofen for not using rescue medication (17). Significant differences favouring ibuprofen (or NSAIDs as a class) were also found for other common conditions including musculoskeletal pain (10), period pain (18), migraine headaches (7,8) and TTH (1).
Conclusion Effective treatment of TTH is hampered by myths surrounding the drugs that are recommended for its treatment – in particular with regard to the safety and efficacy of ibuprofen compared with paracetamol. Yet, these generalised assumptions are not supported by the available data.
References 1 Bendtsen L, Evers S, Linde M; EFNS et al. EFNS guideline on the treatment of tension-type headache – report of an EFNS task force. Eur J Neurol 2010; 17: 1318–25. 2 Mulrow CD. Rationale for systematic reviews. BMJ 1994; 309: 597–9. 3 Gerber S, Tallon D, Trelle S et al. Bibliographic study showed improving methodology of metaanalyses published in leading journals 1993-2002. J Clin Epidemiol 2007; 60: 773–80. 4 Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000; 342: 1887–92. 5 Castellsague J, Riera-Guardia N, Calingaert B et al. Safety of Non-Steroidal Anti-Inflammatory Drugs
6
7
8
9
Evidence from a range of large high-quality studies confirms that there are no clear differences in the GI safety profiles of ibuprofen and paracetamol if used at OTC doses and for durations associated with OTC use, and there do not seem to be any CV safety implications with ibuprofen if used as indicated in an OTC setting. Even at prescription doses, ibuprofen use might not carry an increased risk of heart attacks, especially in patients without pre-existing CV risk factors. In addition, where data are available from indirect or direct comparisons of ibuprofen and paracetamol used in a standard way, and comparing standard doses, ibuprofen consistently emerges as the more effective analgesic. Use of the most effective analgesic for the treatment of TTH has additional advantages. It reduces the need for remedication, minimising drug exposure overall with associated safety benefits, and it might steer patients away from taking medication too frequently, thereby reducing their risk of medicationoveruse headache.
Disclosure RAM has received lecture fees from or consulted for a number of pharmaceutical companies (including Reckitt Benckiser) for activities related to analgesics and other healthcare interventions, and received research support from charities, government and industry sources at various times. R. A. Moore Pain Research and Nuffield Division of Anaesthetics, University of Oxford, Oxford, UK Correspondence to: R. Andrew Moore, Pain Research and Nuffield Division of Anaesthetics, University of Oxford, Oxford OX3 7LJ, UK Tel.: + 44 1865 225 674 Fax: + 44 1865 225 402 Email: [email protected]
(SOS) Project. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Saf 2012; 35: 1127–46. Bjarnason I. Ibuprofen and gastrointestinal safety: a dose-duration-dependent phenomenon. J R Soc Med 2007; 100(Suppl. 48): 11–4. Derry C, Derry S, Moore RA et al. Single dose oral ibuprofen for acute postoperative pain in adults. Cochrane Database Syst Rev 2009; 3: CD001548. Rabbie R, Derry S, Moore RA. Ibuprofen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2013; 4: CD008039. Moore N, Le Parc JM, van Ganse E et al. Tolerability of ibuprofen, aspirin and paracetamol for the
treatment of cold and flu symptoms and sore throat pain. Int J Clin Pract 2002; 56: 732–4. 10 Doherty M, Hawkey C, Goulder M et al. A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis 2011; 70: 1534–41. 11 Moore N, van Ganse E, Le Parc J-M et al. The PAIN study: paracetamol, aspirin and ibuprofen new tolerability study. A large-scale, randomised clinical trial comparing the tolerability of aspirin, ibuprofen and paracetamol for short-term analgesia. Clin Drug Invest 1999; 18: 89–98. 12 Moore N, Salvo F, Duong M et al. Cardiovascular risks associated with low-dose ibuprofen and diclofenac as used OTC. Expert Opin Drug Saf 2014; 13: 167–79.
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13 Coxib and Traditional NSAID Trialists’ (CNT) Collaboration, Bhala N, Emberson J, Merhi A et al. Vascular and upper gastro intestinal effects of nonsteroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382:769–79. 14 Goodson NJ, Brookhart AM, Symmons DP et al. Non-steroidal anti-inflammatory drug use does not appear to be associated with increased cardiovascular mortality in patients with inflammatory polyarthritis: results from a primary care based inception cohort of patients. Ann Rheum Dis 2009; 68: 367–72.
15 Mangoni AA, Woodman RJ, Gaganis P et al. Use of non-steroidal anti-inflammatory drugs and risk of incident myocardial infarction and heart failure, and all-cause mortality in the Australian veteran community. Br J Clin Pharmacol 2010; 69: 689– 700. 16 Moore RA, Derry S, McQuay HJ et al. Single dose oral analgesics for acute postoperative pain in adults. Cochrane Database Syst Rev 2011; 9: CD008659. 17 Bailey E, Worthington HV, van Wijk A et al. Ibuprofen and/or paracetamol (acetaminophen) for
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pain relief after surgical removal of lower wisdom teeth. Cochrane Database Syst Rev 2013; 12 : CD004624. 18 Marjoribanks J, Proctor M, Farquhar C et al. Nonsteroidal anti-inflammatory drugs for dysmenorrhoea. Cochrane Database Syst Rev 2010; 1: CD001751.
Paper received June 2014, accepted November 2014
