"Safety" of Aspirin???

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

Nicholas Moore, Department of Pharmacology, Université Victor Segalen, Hôpital Pellegrin, Bordeaux, France; Eric Van Ganse, Clinical Pharmacology Department, University of Lyon, Lyon, France; Jean-Marie Le Parc, Service de Rhumatologie, Hôpital Ambroise Paré, Boulogne-Billancourt, France; Richard Wall, Boots Healthcare International, Nottingham, England; Hélène Schneid, Boots Healthcare, Courbevoie, France; Mahdi Farhan, Boots Healthcare International, Nottingham, England; François Verrière, François Pelen, Boots Healthcare, Courbevoie, France

Abstract

Objective: This study aimed to compare directly aspirin (acetylsalicylic acid), ibuprofen and paracetamol (acetaminophen), first-line analgesics which are generally well tolerated, from a safety perspective in general practice.
Methods: This was a blinded, multicentre study in general practice of up to 7 days of aspirin, paracetamol (both up to 3g daily) or ibuprofen (up to 1.2g daily), administered for common painful conditions, using patient-generated data with physician assistance. The main outcome was the rate of significant adverse events (serious, severe or moderate events, events resulting in treatment discontinuation or a physician visit). Statistical analysis tested for equivalence between ibuprofen and paracetamol, and for difference with aspirin.
Results: 1108 general practitioners included 8677 adults (2900 aspirin, 2886 ibuprofen, 2888 paracetamol; three patients had no code label number). 8633 (99.5%) were evaluable, of whom 8233 (95%) adhered to the study protocol. The main indications were musculoskeletal or back pain (48%), sore throat, the common cold and flu (31%). Rates of significant adverse events were: aspirin 18.7%, ibuprofen 13.7%, and paracetamol 14.5%. Ibuprofen was statistically equivalent to paracetamol. Both were significantly better tolerated than aspirin (p < 0.001). Total gastrointestinal events (including dyspepsia) and abdominal pain were less frequent with ibuprofen (4 and 2.8%, respectively) than with paracetamol (5.3 and 3.9%) or aspirin (7.1 and 6.8%) [all p < 0.035]. There were six cases of non-serious gastrointestinal bleeding, four with paracetamol and two with aspirin, and one case of peptic ulcer with aspirin.
Conclusion: The overall tolerability of ibuprofen in this large-scale study was equivalent to that of paracetamol and better than that of aspirin. These findings could lead to a reassessment of the use of first-line analgesics for the short-term management of painful conditions in general practice, recommending ibuprofen first, because of the poor tolerability of aspirin and the potential risks of paracetamol overdose.

Introduction

Aspirin (acetylsalicylic acid), ibuprofen and paracetamol (acetaminophen) are first-line analgesics, generally available over the counter (OTC). Paracetamol has a reputation for good tolerability, somewhat offset by severe hepatic toxicity in suicidal or accidental overdose.^[1-4] A common concern with NSAIDs is gastrotoxicity, which is dose- and product-dependent. Case-control studies have shown an increased risk of gastrointestinal (GI) bleeding even with low-dose aspirin as used in cardiovascular prevention,^[5,6] whereas at all doses ibuprofen seems to carry a lower risk of gastrotoxicity than other NSAIDs.^[7] In some studies at OTC doses this risk has been shown to be similar to or less than placebo or paracetamol.^[8,9]

No study has addressed the relative tolerability of aspirin, ibuprofen and paracetamol, as used in daily practice to treat mild to moderate acute pain in adults. Because these drugs are widely used and the disorders treated are not life-threatening, this question is a major public health issue. The present study was therefore designed to compare directly the tolerability of aspirin, ibuprofen and paracetamol in situations mimicking everyday use at OTC doses and durations for various common acute pain indications. This study relied mainly on patient data, which a previous study had shown to be feasible.^[10] Based on existing data on the relative safety of aspirin, ibuprofen and paracetamol,^[8,9,11] the basic premise tested in this study was that paracetamol and ibuprofen would have equivalent tolerability, and that ibuprofen would be better tolerated than aspirin.

Patients and Methods

The PAIN study (Paracetamol, Aspirin, Ibuprofen New tolerability study) was a randomised, multicentre, blinded, parallel-group trial. French general practitioners (GPs) were to include patients aged 18 to 75 years requiring short-term analgesic treatment of mild to moderate pain.

All patients gave written informed consent to participate in the study, which had been previously approved by the Committee for the Protection of Persons participating in Biomedical Research (Hôpital Ambroise Paré, Boulogne-Billancourt, France). The study was conducted according to Good Clinical Practices and the Declaration of Helsinki (as revised in 1989).

Non-inclusion criteria were mainly limited to the contraindications for the drugs from their Summary of Product Characteristics (SPC), or to methodological or legal requirements (details of inclusion and non-inclusion criteria are available from the authors upon request).

Patients were given treatment for at least 1 and at most 7 days, to be started within 24 hours of consultation unless the GP recommended otherwise (e.g. for dysmenorrhoea). They were provided with a diary on which to record adverse events and their severity, medication taken (trial and concomitant medication), and any comments. The diary included specific instructions on the reporting of events and their severity. Patients gave a global opinion of the treatment at the end of the diary, according to a 4-point scale. The diary and unused medication were to be returned to the prescriber at the end of treatment in a sealed envelope.

Patients were not required to see their physician again. Physicians called the patients on the day after the expected start of treatment to ensure that medication had been started, to record or qualify any early adverse event, and to verify that the patients understood and would complete the diary. They called again 7 to 9 days after the start of treatment to make sure the diary would be returned, and/or to record any adverse event. Any second consultation and its reason were also recorded.

Adverse events were identified and graded from the patient diary, from the telephone calls, and from further GP visits. Classification and coding (COSTART) of events were checked by a Study Safety Committee before unblinding. Events that were identical to treatment indication were considered as lack of treatment effect. Those not identifiable were coded as 'unevaluable reaction'. Events were graded as serious, severe, moderate or mild. Serious events were those causing hospitalisation, that were fatal or life-threatening, or that resulted in sequelae. Severe events were those rendering daily activities impossible, moderate events were those interfering with daily activities, and mild events were those without impact on daily activities. Severity grading was considered first from the patient diary, then from the physician consultations or telephone contacts. If severity was not indicated, it was classified by the Safety Committee as missing.

The number of patients with at least one significant adverse event, defined as an event that was serious, severe or moderate, resulted in a second physician consultation, led to cessation of treatment, or was of missing intensity.

The following secondary outcomes measures and additional variables were also determined:

Aspirin 500mg tablets, ibuprofen 200mg tablets and paracetamol 500mg tablets were marketed drugs repackaged identically (Creapharm, Le Haillan, France) and identified only by treatment number. Each patient was issued 42 tablets. The dose prescribed was up to 6 tablets per day, as approved for analgesic use in France.

Patients were allocated randomised treatment numbers through a central telephone service to ensure continuously balanced group distribution.

The study medications were all white round unmarked tablets of approximately the same size. The physicians never saw the tablets, and patients saw only their own treatment. The envelopes containing returned medication were retrieved intact by the study monitors, to ensure physician blinding throughout the study.

The study analysis tested two primary hypotheses, that of equivalence between ibuprofen and paracetamol, and that of difference between ibuprofen and aspirin. The study was not powered to assess the difference between paracetamol and aspirin, since this difference was deemed established from the literature and current practice. The expected incidence rates for significant events, from the literature, were 9% for both paracetamol and ibuprofen, and 12% for aspirin.^[8,11]

Aspirin and ibuprofen were compared using a chi² test to establish whether there was a difference between the groups, using the evaluable or intention-to-treat population (patients who took at least one dose of study medication).

Ibuprofen and paracetamol were compared to establish equivalence, using the perprotocol population (patients who followed the study instructions correctly). Ibuprofen would be considered equivalent to paracetamol if the incidence of significant adverse events was within 30 percentage points of the expected rate for paracetamol, i.e. if the upper limit of the confidence interval (CI) of the difference was less than 2.7% (30% of 9%). Hence this test was constructed as a 1-sided test. The hypothesis that ibuprofen could be better tolerated than paracetamol was not tested.

To account for multiple testing, and achieve an overall 5% level of significance, both comparisons were held to 3.5%, using Dunnett's correction.^[12] For the equivalence comparison, the 1-sided 96.5% upper confidence limit for the difference was constructed.

Considering the expected incidence of significant adverse events for aspirin, ibuprofen and paracetamol (12, 9 and 9%, respectively), 2583 patients per group were sufficient to have 90% power. Assuming a 10% dropout rate, the target recruitment was 8610.

Results

One thousand one hundred and eight GPs included 8677 patients between September 1997 and March 1998: 2900 were randomised to aspirin, 2886 to ibuprofen, and 2888 to paracetamol (three patients had no code label number). 8633 patients (99.5%) were evaluable (intention-to-treat population), of whom 8233 (95%) adhered to the study protocol (per-protocol population). The main protocol deviations were allocation of treatment by the GP without using the central telephone service (177 patients), and the use of prohibited medications (215 patients). These were equally distributed among the treatment groups (fig. 1).

The baseline characteristics of the treatment groups were similar, and factors probably affecting tolerability such as age, indication, concomitant medication or diseases were equally distributed (table I). The most common indications were musculoskeletal and back pain (48.3%) and symptoms associated with sore throat, the common cold and flu (31.5%). The mean treatment duration and the mean number of tablets taken per patient were not different between treatment groups (table I).

The study was completed by 7456 patients, of whom 3771 used the drug to the end of prescription, and 3685 stopped early because of cessation of pain (aspirin 1235, ibuprofen 1246, paracetamol 1204; differences not significant). 1177 patients withdrew early from the study, 541 because of adverse events [aspirin 7.6%, ibuprofen 5.1%, paracetamol 6.1% (table II)], and 576 because of lack of treatment effect (aspirin 7.0%, ibuprofen 6.1%, paracetamol 6.9%). In addition, 55 patients withdrew for other reasons and five were lost to follow-up.

There were six serious adverse events, none considered by the investigator or the Safety Committee as treatment related. These events were: gardening accident, pneumothorax, neck of right humerus fracture, cerebral neoplasm, renal colic, and bronchitis. Three occurred in the aspirin group and three in the ibuprofen group. There was a suicide attempt with study medication by a friend of a patient randomised to paracetamol, with uneventful outcome. There was no difference in serious event frequency between the treatment groups.

Significant adverse events were reported by 18.7% of evaluable patients on aspirin, 13.7% on ibuprofen, and 14.5% on paracetamol (table II). The 1-si ded 96.5% confidence limit for the difference between paracetamol and ibuprofen was below 2.7, thus fulfilling the requirements for equivalence. Significantly fewer patients on ibuprofen or paracetamol had significant adverse events than on aspirin. The relative risk of significant adverse event with aspirin was 1.36 (95% CI: 1.18 to 1.57) compared with ibuprofen and 1.29 (95%CI: 1.12 to 1.48) compared with paracetamol.

Within the per-protocol population, 509 of 2753 patients (18.5%) on aspirin had significant adverse events, significantly more than the 367 of 2743 (13.4%) with ibuprofen or the 378 of 2737 (13.8%) with paracetamol. The 1-sided 96.5% confidence limit for the difference between ibuprofen and paracetamol was 1.24, which fell within the defined equivalence range (table II). The relative risk of significant adverse events with ibuprofen compared with paracetamol was 0.99 (95% CI: 0.85 to 1.16).

Overall for every 100 patients treated with aspirin, five more will have significant adverse events than if they had been treated with ibuprofen, or four more than if they had been treated with paracetamol.

Categories of Significant Adverse Events. In each category, there were significantly more patients in the aspirin than in the ibuprofen or paracetamol groups. Equivalence between ibuprofen and paracetamol was confirmed for all categories of significant adverse event, except for moderate events which significantly fewer patients experienced with ibuprofen than with paracetamol.

Adverse Events by Body System and Term. Adverse events by body system and specific adverse event term are listed in table III. Differences between ibuprofen and aspirin, and ibuprofen and paracetamol were tested at the 3.5% significance level.

More patients reported significant events concerning the body as a whole (which includes abdominal pain) with aspirin (10.1%) than with ibuprofen (7.0%) [p < 0.001] or paracetamol (7.8%). More patients reported significant digestive events with aspirin (7.1%) than with ibuprofen (4.0%) [p < 0.001] or paracetamol (5.3%), and more with paracetamol than ibuprofen (p = 0.025). This was also true for dyspepsia (aspirin 3.1%, ibuprofen 1.4%, paracetamol 2.2%) and for abdominal pain (aspirin 6.8%, ibuprofen 2.8%, paracetamol 3.9%). More patients reported nausea with aspirin (2.5%) than with either paracetamol or ibuprofen (1.5%each). There was no significant difference in the other system organ classes, or individual adverse reaction terms.

There were two rectal haemorrhages and two haematemesis with paracetamol (0.14%), two rectal haemorrhages and one peptic ulcer with aspirin (0.1%), and none with ibuprofen (upper limit of 95% CI: 0.1%).

Including adverse events of mild intensity, 748 patients had adverse events on aspirin (25.9%), 615 on paracetamol (21.4%) and 560 on ibuprofen (19.5%). The difference between aspirin and ibuprofen was significant (p < 0.001). Ibuprofen and paracetamol were equivalent (96.5% confidence limit for difference 0.04).

The analysis including mild adverse events did not change the conclusions concerning all GI events. Abdominal pain (aspirin 11.3%, ibuprofen 6.1%, paracetamol 7.0%) and dyspepsia (aspirin 6.3%, ibuprofen 2.9%, paracetamol 4.1%) were significantly more frequent with aspirin than with ibuprofen. Dyspepsia was more frequent with paracetamol than with ibuprofen (p = 0.012), and the total number of patients with digestive events was also greater (p = 0.014).

Rates of significant events by age, indication or gender were consistently statistically higher with aspirin. There was no evidence for a treatment by subgroup interaction for any of the parameters (data not shown).

On global evaluation, 74.2% of patients on ibuprofen rated the treatment as excellent or good, a significantly higher rating than for paracetamol (69.2%) or aspirin (68.6%) [both p < 0.001].

Discussion

This blinded randomised parallel-group study in general practice showed that the tolerability of low-dose, short-term ibuprofen and paracetamol was equivalent, both being better tolerated than aspirin. Overall, the adverse events were of the same nature for the three drugs, though those observed with aspirin tended to be more severe and more frequent.

Contrary to common belief, non-major GI events were not more frequent with ibuprofen than with paracetamol. This had already been established for serious events in children receiving short-term treatment.^[13]

The study was designed to assess the safety of these drugs as used commonly for analgesia, i.e. short-term use at low doses. The primary source of information for adverse events was the patient diary card. When only the data from the diary cards was considered, the results were the same as when physician data was also included (data not shown). The study format and results were comparable to those of a previous noncomparative study with ketoprofen,^[10] in which the number of unevaluable or lost to follow-up patients was also less than 1%, and the rate of GI events (8.4%) was similar to that observed here with aspirin.

Patients in our study were selected according to the general contraindications of the drugs as described in their SPC. Because at-risk patients were excluded by the protocol (which was consistent with product labelling), there may have been less risk of GI events with the two NSAIDs than in real OTC use. The patient profiles were very much as expected, including the indications for the drugs. The drugs were blinded, marketed formulations to ensure maximum applicability of the results. Choosing an aspirin tablet rather than a buffered or soluble form probably did not increase the rate of adverse events.^[6]

Primary outcome results were those expected when designing the study, i.e. equivalence of significant adverse event rates between ibuprofen and paracetamol, and a lower rate than aspirin, except that the observed rates of significant events were higher than expected (13.7, 14.5 and 18.7% vs 9, 9 and 12% for ibuprofen, paracetamol and aspirin, respectively). This could be related to patient-rather than physician-based recording of data, and/or to the evaluation options, which were designed to maximise event recognition and severity attribution.

The decreasing rates of events from aspirin to paracetamol to ibuprofen were consistent over the entire range of events, whether they were significant or nonsignificant, and for most organ systems or adverse reaction terms. If adverse event intensity is a continuum from mild to severe, attribution of significance only to those rated at least moderate may be arbitrary, but wherever the line is drawn, the same results would be obtained: ibuprofen is at least as well (and possibly better) tolerated than paracetamol, both being better tolerated than aspirin when used on a short-term basis.

These findings are consistent with the general pattern of aspirin, ibuprofen and paracetamol tolerability, whether from single-dose clinical trials, from anti-inflammatory dose trials or from retrospective case-control studies of GI bleeding. In endoscopic studies the mucosal damage observed was similar for low-dose ibuprofen and paracetamol or placebo, and lower than with aspirin.^[14,15] In single-dose comparative studies at doses similar to the unit doses studied here, the overall event rate was 2.4% with ibuprofen, 3.2% for paracetamol, and 2.1% for placebo.^[9] In a review of studies mostly at anti-inflammatory doses, the overall frequency of adverse events was 22.0% with ibuprofen, compared with 16.2% with placebo, 24.9% with paracetamol, and 30.5% with aspirin;^[8] approximately 60% of the adverse reactions were GI-related. These rates are higher than observed here, but the differences between treatments are similar, as is the ratio of GI to non-GI events. The frequency of GI bleeding with ibuprofen was 0.01%^[16] to 0.02%,^[8] compatible with the present study.

Case-control studies of GI bleeding, which consider the upper end of the severity spectrum, generally give ibuprofen as the safest of the NSAIDs, with an odds ratio (OR) for the association with GI bleeding between 1.0 (no difference with non-users of NSAIDs, including paracetamol users) and 2.6.^[7]

In all studies, aspirin had a higher OR for the association with GI bleeds, even at the low doses used for cardiovascular prevention, with ORs ranging from 2 to 4 with NSAID non-users or ibuprofen as reference.^[7] In our study, the relative risk for non-major GI events between aspirin and ibuprofen was 1.8 (95% CI 1.4 to 2.2). It may also be emphasised that the good GI tolerability of ibuprofen did not come at the expense of renal, pulmonary or allergic adverse events.

The digestive tolerability of NSAIDs is dose dependent, so it might be argued that the good tolerability of ibuprofen in our study was related to a low dose, or that the doses may not have been equipotent. The doses were the approved doses for OTC analgesia in France, and there was no indication of lesser activity of ibuprofen: there were no more premature withdrawals because of treatment inefficacy, the proportion of patients stopping treatment because of pain relief was the same, and the overall patient rating was significantly better for ibuprofen. Although efficacy was not the main objective of the study, it appears that at the very least ibuprofen was not used at less effective analgesic doses. Many studies show that the analgesic efficacy of ibuprofen at these doses is in fact greater than that of paracetamol,^[17-20] and also greater than that of the paracetamol-codeine^[21] or paracetamol-dextropropoxyphene combinations,^[22] which are less well tolerated than paracetamol alone. In fact, the doses of aspirin and paracetamol used here are lower than those allowed in many other countries, so that in those countries one could even expect higher event rates for paracetamol and aspirin.

Our findings therefore confirm the general conclusion^[7] that low-dose ibuprofen could be the analgesic of first choice for the short-term management of mild to moderate pain before resorting to higher doses or other NSAIDs, especially aspirin. This is particularly the case considering other problems such as the occurrence of Reye's syndrome in children receiving aspirin and the dangers of voluntary or inadvertent overdose with both paracetamol^[3] and aspirin^[23] in adults and the elderly. There are few if any instances where aspirin could be used but not ibuprofen.

Paracetamol has a reputation for good tolerability and digestive innocuity compared with NSAIDs, offsetting its risk in overdose. Our study shows that, within the constraints of the selected patient population, i.e. a population with no previous GI bleeding or major risk factors for GI bleeding, paracetamol is not better tolerated than ibuprofen, and could in fact be associated with more GI events.

There are few arguments against the use of ibuprofen rather than paracetamol for the short-term management of acute pain; at analgesic doses and durations in this population, the GI risk was not higher than that of paracetamol, and its acute toxicity during intended or accidental overdose is much lower.^[24-26]

This study, as that of Lesko and Mitchell in children,^[13] demonstrates that tolerability and safety aspects of widely used drugs may be assessed with large interventional studies.

Conclusion

In conclusion, this large-scale study in general practice, the first to compare directly the three most commonly used first-line analgesics, aspirin, ibuprofen and paracetamol, at their approved OTC doses, confirms the equivalent tolerability of ibuprofen and paracetamol, which were better tolerated than aspirin. In addition, ibuprofen was associated with fewer GI events than paracetamol. These findings could lead to a reassessment of the use of first-line analgesics for the short-term management of painful conditions in general practice, recommending ibuprofen before aspirin or paracetamol, because of the poor tolerability of aspirin and the potential risks of paracetamol overdose.

The authors would like to thank Dr J.K. Jones for methodological assistance, the investigators and Therapharm for the quality of the trial and of the data, and Andrew Charlesworth of Nottingham Biostatistics Ltd for the statistical analysis. The study was funded by Boots Healthcare International.

Correspondence and reprints: Prof. Nicholas Moore, Department of Pharmacology, Université Victor Segalen, Hôpital Pellegrin, 33076 Bordeaux, France. E-mail: nicholas.moore@pharmaco.u-bordeaux2.fr

Table I. Baseline characteristics (evaluable population)

Table II. Rates of significant adverse event categories (evaluable population)

Table III. Rates of most frequent significant adverse events by COSTART body system and terms (evaluable population)

References

Criteria	Treatment group
aspirin (n = 2890)	ibuprofen (n = 2869)	paracetamol (n = 2874)
Mean (SD) baseline characteristics
Age (y)	43.6 (14.7)	43.3 (14.7)	43.6 (14.8)
Body mass index (kg/m²)	24.4 (4.4)	24.4 (4.4)	24.3 (4.2)
Body temperature (°C)	37.5 (0.7)	37.4 (0.7)	37.4 (0.8)
Gender (no. female, % female)	1672 (57.9)	1673 (58.3)	1664 (57.9)
Indication for treatment [no. (%)]
Musculoskeletal condition	925 (32.0)	954 (33.3)	907 (31.6)
Cold/flu	586 (20.3)	571 (19.9)	548 (19.1)
Backache	461 (16.0)	431 (15.0)	476 (16.6)
Sore throat	317 (11.0)	332 (11.6)	341 (11.9)
Headache	304 (10.5)	297 (10.4)	291 (10.1)
Other	126 (4.4)	105 (3.7)	123 (4.3)
Toothache	112 (3.9)	116 (4.0)	113 (3.9)
Pain of menstrual cramps	55 (1.9)	59 (2.1)	65 (2.3)
Concomitant disease [no. (%)]^a	726 (25.1)	739 (25.8)	713 (24.8)
Concomitant medication [no. (%)]^a	1289 (44.6)	1303 (45.4)	1266 (44.1)
Mean treatment duration (days)	5.4 (1.8)	5.6 (2.2)	5.5 (1.8)
Mean no. of tablets per treatment	20.0 (9.8)	20.5 (9.8)	20.5 (9.8)

Parameter	Aspirin (ASA)	Ibuprofen (IBU)	Paracetamol (PARA)	p-Value (ASA vsIBU)	IBU vs PARA difference 96.5% (upper conf. limit)^a
No. of patients	2890	2869	2874
All significant events (primary analysis, ITT)	539 (18.7%)	392 (13.7%)	416 (14.5%)	<0.001	0.85 Equivalence
All significant events (per-protocol analysis)	509 (18.5%)	367 (13.4%)	378 (13.8%)	<0.001	1.24 Equivalence
Severe AE	138 (4.8%)	100 (3.5%)	92 (3.2%)	0.014	1.15 Equivalence
Moderate AE	353 (12.2%)	245 (8.5%)	294 (10.2%)	<0.001	- 0.31 p < 0.02
AE leading to premature discontinuation	221 (7.6%)	145 (5.1%)	175 (6.1%)	<0.001	0.06 Equivalence
AE leading to extra GP visit	142 (4.9%)	101 (3.5%)	101 (3.5%)	0.009	0.89 Equivalence

	Aspirin (%)	Ibuprofen (%)	Paracetamol (%)	Ibuprofen vs aspirin^a (p-value)	Ibuprofen vs paracetamol^a (p-value)
Systems
Body as a whole	10.1	7.0	7.8	<0.001	0.25
Digestive	7.1	4.0	5.3	<0.001	0.025
Nervous system	2.0	1.9	1.9	0.88	0.99
Respiratory	1.0	0.6	0.6	0.15	0.99
Other special senses	0.9	0.5	0.6	0.09	0.60
Cardiovascular	0.7	0.4	0.6	0.13	0.28
Skin	0.7	0.8	0.6	0.43	0.21
Musculoskeletal	0.4	0.3	0.2	0.67	0.61
Urinary disorders	0.2	0.3	0.2	0.32	0.20
Metabolic-nutritional	0.1	0.1	0.1	0.99	0.42
Terms
Abdominal pain	6.8	2.8	3.9	<0.001	0.024
Dyspepsia	3.1	1.4	2.2	<0.001	0.019
Nausea	2.5	1.5	1.5	0.01	0.91
Unevaluable reaction^b	1.8	1.4	1.3	0.23	0.73
Headache	1.3	1.4	1.6	0.88	0.59
Diarrhoea	0.9	0.8	1.1	NT	NT
Asthenia	0.9	0.8	0.7	NT	NT
Somnolence	0.7	0.6	0.8	NT	NT
Pain	0.9	0.6	0.6	NT	NT
Vomiting	0.7	0.4	0.6	NT	NT
Dizziness	0.6	0.6	0.5	NT	NT
Back pain	0.4	0.5	0.7	NT	NT
Flatulence	0.3	0.4	0.4	NT	NT

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You can reach Vibrant Life in many ways, including by mail to Vibrant Life, 2808 N. Naomi St., Burbank, CA 91504. Within the US and Canada, use the toll free number: (800) 523-4521, the local number: (818) 558-1799, the FAX: (818) 558-7299, eMail to kimberly@oralchelation.com or any one of the hundreds of message forms throughout the 50 web sites. Vibrant Life normally ships the same day we get an order. There are message forms on each of the 100,000+ pages on this and other sites where you can communicate with Vibrant Life. Check out our companion site, at: http://www.oralchelation.net where Karl's 2000 page book is published. Karl Loren is the author and webmaster for this BOOK, as well as for another web site about ORAL CHELATION. His personal philosophical articles are at PHILOSOPHY.

Copyright © May 20, 2008 6:25 AM by Karl Loren on behalf of Vibrant Life, ALL RIGHTS RESERVED. Permission is granted for non-commercial downloading, copying, distribution or redistribution on two conditions: One, that some form of copyright notice is included in every copy distributed or copied, showing the copyright belonging to Vibrant Life, Burbank, CA, at www.oralchelation.com . The second condition is that the material is not to be used for any purpose contrary to the purposes and objectives of this site. This permission does not extend to materials on this site which are copyrighted by others.

^a	Significance level set at 0.035. Formal comparisons assessed only when overall rate >1.0%. p-Values quoted are 2-sidedc 2 tests. No adjustments have been made for multiple comparisons.
^b	Adverse event type not specified.
COSTART = Coding Symbol Thesaurus for Adverse Reaction Terms (3rd ed.); NT = not tested.

All tests for differences between groups were nonsignificant.
^a	Reported as ongoing during the study.

^a	One-sided 96.5% confidence limit for difference between ibuprofen and paracetamol. Equivalence is concluded if upper limit of the confidence interval of the difference in the incidence was <2.7%.
AE = adverse events; conf. = confidence; GP = general practitioner; ITT = intention-to-treat.