Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counter dose
Doyle Dr Clinical Research Department, Whitehall-Robins Healthcare, 5 Giralda Farms, Madison, NJ 07940, USA.
: Delineation of non-steroidal anti-inflammatory drug (NSAID) gastrointestinal toxicity has largely depended on retrospective epidemiologic studies which demonstrate that lower doses of NSAIDs pose a lower risk of gastrointestinal toxicity. Ibuprofen, a propionic acid NSAID, has, in most such studies, exhibited a favourable profile in terms of gastrointestinal bleeding. Since 1984, ibuprofen has been available as a non-prescription analgesic/antipyretic with a limit of 1200 mg/day for 10 days of continuous use. Trials and spontaneously reported adverse experiences suggest that gastrointestinal symptoms and bleeding are rare.
: This study prospectively evaluated the gastrointestinal tolerability, as compared to placebo, of the maximum non-prescription dose and duration of ibuprofen use in healthy subjects representative of a non-prescription analgesic user population.
: Gastrointestinal adverse experiences were similar in the placebo and ibuprofen groups (67 out of 413, 16% with placebo vs. 161 out of 833, 19% with ibuprofen). There was no difference between the two groups in the proportion discontinuing due to a gastrointestinal event. Gastrointestinal adverse experiences reported by ≥ 1% of subjects were: dyspepsia, abdominal pain, nausea, diarrhoea, flatulence, and constipation. Seventeen (1.4%) subjects had positive occult blood tests: their frequency was comparable between treatments.
: When used as directed to treat episodic pain, non-prescription ibuprofen at the maximum dose of 1200 mg/day for 10 days, is well-tolerated.
It is a generally-held view among clinicians including gastroenterologists that all NSAIDs pose a risk to the gastrointestinal tract ranging from subjective symptoms of discomfort to frank ulceration and haemorrhage. This viewpoint assumes that the nine heterogeneous classes of NSAIDs are comparable in most respects and fails to consider the pharmacological principles of dose and duration of use. NSAIDs differ widely in their pharmacological profiles. For example, half-lives vary from 2 h for ibuprofen to 50 h for piroxicam or as much as 70 h for tenoxicam. Even within an NSAID class such as the propionic acid derivatives, the potency of cyclooxygenase inhibition varies, exerting a direct impact upon the safety profile of individual NSAIDs. Epidemiologic studies have ranked prescription ibuprofen lowest in provoking gastrointestinal bleeding or peptic ulcer compared to other prescription NSAIDs.1, 2 Other studies have found no significant increase in the relative risk of gastrointestinal bleeding among ibuprofen users at a dose or duration of use beyond the US over-the-counter maximum of 1200 mg/day for 10 days.3–9 Henry noted that the low relative risk for ibuprofen observed in studies may be reflective of the low doses used as well as the short (1–2 h) half-life of ibuprofen.10 Recent meta-analyses of 12 studies in which ibuprofen was included confirmed the observation that the lower over-the-counter analgesic doses of ibuprofen have a distinctly safer gastrointestinal profile as compared to higher, prescription doses.11, 12
Ibuprofen was switched from prescription to non-prescription status in the USA in 1984 based upon its efficacy and safety profile as a prescription drug as well as its safety profile compared with the then-available over-the-counter analgesics, aspirin and acetaminophen. As a result of the prescription heritage of ibuprofen, adverse experience data have been mostly derived from chronic rheumatoid arthritis and osteoarthritis studies using dosage regimens in excess of those recommended on the over-the-counter label. Such studies evaluated special populations that do not represent the typical over-the-counter consumer and do not accurately reflect the true adverse experience profile in the over-the-counter setting. Relevant published safety reports are based upon the extremes of either single-dose tolerability13, 14 or a chronic duration of use exceeding over-the-counter labelling.15 Recently, Strom et al.16 examined the relative risk of gastrointestinal bleeding associated with naproxen sodium and ibuprofen using a prescription Medicaid database to approximate over-the-counter use. This analysis demonstrated, once again, an overall low incidence of upper gastrointestinal bleeding with ibuprofen at lower, over-the-counter analgesic doses.
In contrast to that of the prescription-user population, the demographic profile of the over-the-counter consumer comprises a higher proportion of younger and healthier individuals who use non-prescription analgesics intermittently to treat such self-diagnosable conditions as headache, fever, backache, dental pain, and dysmenorrhea. Because there are no published data on the gastrointestinal effects of ibuprofen when directly tested at the maximum over-the-counter dose in the USA, of 1200 mg for 10 consecutive days, this study was designed to examine this aspect of its safety profile in two formulations—liquigel and tablet. Subjects were enrolled across a wide age range to approximate the typical over-the-counter analgesic user population. The population was ‘all comers’ with a few exceptions related to direct NSAID contraindications. Stool occult blood tests were obtained from subjects twice during dosing to determine whether ibuprofen could induce clinically inapparent gastrointestinal bleeding.
MATERIALS AND METHODS
This multiple-dose, double-blind, randomized, age-stratified, placebo-controlled, parallel group, out-patient study was conducted at six study sites. Eligible participants were randomly assigned according to a computer-generated code in a 2 : 2 : 1 : 1 ratio to: ibuprofen liquigel capsule 200 mg, ibuprofen tablet 200 mg, liquigel capsule placebo, and tablet placebo, respectively. Each study site was randomized independently, and within each site, subjects were stratified into one of three age categories demographically representative of the over-the-counter analgesic user population: 12–34, 35–64, 65 + years.17
Subjects provided a brief medical history, including information regarding their past use of analgesics. Eligible subjects were given study medication and instructed to take two 200 mg capsules (or tablets) every 4–6 h for a total of six capsules or tablets per day for 10 consecutive days. Since the study was double-blind, subjects were provided with acetaminophen in case they required an analgesic. On days 7 (± 1 day) and 10 (± 1 day), subjects collected faecal samples for subsequent occult blood testing (Hemoccult slides; SmithKline Laboratories). Subjects were instructed to follow the directions for stool collection and storage on the envelope containing the slides. Subjects returned the Hemoccult slides to the study site within 1 week of completing the 10-day evaluation. At the return visit, the Hemoccult slides were processed. If one or both of the slides were positive, the subject was referred to a physician (personal or referral).
Eligible subjects were at least 12 years of age and were regular consumers of over-the-counter analgesics (i.e. had a history of over-the-counter analgesic use of at least three but no more than nine times per month for the past 3 months); and all women were using a reliable method of contraception.
The study excluded individuals who had any serious medical condition or used prescription drugs(s) with which NSAID administration was specifically contraindicated; had a known sensitivity to ibuprofen, or any other NSAID; had taken an investigational drug within the past 30 days; were pregnant or nursing. All subjects provided written informed consent on a form approved by a certified Institutional Review Board.
Each day that study medication was taken, the subjects answered the following question in their diary: ‘Have you experienced any medical problems or symptoms today?’ Subjects then recorded a description of the condition, severity, and onset of the problem or symptom. In addition, subjects were contacted on study days 2, 6, and 9 to review study procedures and answer questions. Upon returning to the clinic, additional details about any adverse experiences were obtained from the subject. The investigator then assessed the time of onset, offset, severity, drug relatedness, action taken, outcome, and whether or not the adverse experience was present pre-study. Subjects were provided with an envelope containing two slides for occult blood testing and were directed to collect their stool on days 7 and 10 of dosing.
All subjects who took study medication and returned a diary were included in the analysis. Adverse experiences were classified according to the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) dictionary, third edition. Each term was classified by body system according to the same dictionary, except for the COSTART terms ‘abdominal pain’ and ‘dry mouth’, which were reassigned to the Digestive System.
Differences among and between means and proportions were declared statistically significant if the probability of random occurrence was P ≤ 0.05. All statistical tests were performed using SAS version 6. Continuous demographic variables were analysed using analysis of variance with effects for treatment, site, and their interaction. Categorical demographic variables were analysed using the Cochran–Mantel–Haenszel test, controlling for site.
Fisher’s exact test was used to assess the comparability of the treatment groups with respect to: the frequency of adverse experiences (all reported events regardless of drug relationship were included in the analysis); the proportion of subjects who discontinued from the study due to adverse experiences; and the proportion of subjects with positive faecal occult blood tests on days 7, 10, and both days. The 95% exact confidence bounds for the odds ratio for the incidence of an adverse experience with ibuprofen compared to placebo are also presented. Prospectively, a sample size of ≈ 400 subjects in each of the active treatment groups was selected to provide a 90% statistical power to detect a 9% excess in the incidence of gastrointestinal adverse experiences for ibuprofen liquigel relative to ibuprofen tablets.
There were 1257 subjects randomized to treatment with placebo (liquigel or tablet), ibuprofen liquigel, and ibuprofen tablet. Eleven subjects left the study prior to taking any study medication. The remaining 1246 subjects were included in the primary analysis: 413 placebo; 833 ibuprofen (n = 418 liquigel, n = 415 tablet). Compliance, i.e. ingestion of all 60 tablets/capsules, was 93%. A total of 1206 subjects (96%) completed the entire 10-day treatment period.
Baseline demographics, incidence of gastrointestinal events, and guaiac test results were found to be comparable between both placebo groups as well as between ibuprofen tablet and liquigel groups. Based upon the foregoing results, as well as the proven comparable bioavailability (AUC) of the ibuprofen liquigel and tablet formulations, data for both ibuprofen formulations were pooled for analysis as were data from the two placebo groups. For comparative purposes the results are tabulated for each formulation, however, only the combined ibuprofen treatment groups are discussed. Given the observed placebo rate of gastrointestinal adverse events (16.2%), this study had a 95% power to detect a 9% higher gastrointestinal event rate in the ibuprofen group compared to the placebo group (at 5% significance level).
The treatment groups were comparable for demographic profile (Table 1), medical history, and history of past analgesic use. Approximately half of each treatment group reported using an over-the-counter NSAID, while one-third used acetaminophen exclusively. Fifteen subjects discontinued due to adverse effects: five taking placebo (1.2%) and 10 taking ibuprofen (1.2%). Of these, two in the placebo group (0.5%) and four in the ibuprofen group (0.5%) discontinued due to gastrointestinal adverse effects. Four subjects experienced serious adverse effects (non drug-related) requiring hospitalization: three participants were taking ibuprofen (accidental baclofen overdose, alcohol withdrawal syndrome, acute diverticulitis) and one was taking placebo (acute gangrenous cholecystitis).
Table 1. .
Demographic profile of subjects
Overall, 47% of the subjects reported at least one adverse experience. A significantly greater percentage of placebo subjects (53%) reported an adverse experience, as compared to the ibuprofen subjects (44%) (Table 2.
. Adverse effects classified by organ system
Placebo-treated and ibuprofen-treated subjects had a similar incidence of gastrointestinal adverse effects (67 out of 413, 16% and 161 out of 833, 19%, respectively; P-value = 0.187, odds ratio (OR) = 1.24, 95% CI: 0.90–1.72). Gastrointestinal adverse effects reported by at least 1% of the subjects are shown in Table 2. Gastrointestinal adverse effects reported by both treatment groups were predominantly mild or moderate.
The most frequently reported non-gastrointestinal adverse effects were classified to the Body as a Whole (headache, pain/back pain, and cold) and were significantly lower among those taking ibuprofen, compared to placebo-treated subjects (Table 2).
Subjects with a positive gastrointestinal history were not excluded. Two-placebo treated subjects and four ibuprofen-treated subjects were receiving a concomitant H2 antagonist, proton pump inhibitor, or antacid during the trial. None of these subjects developed gastrointestinal adverse effects. Nineteen placebo-treated and 48 ibuprofen-treated subjects reported a history of ongoing upper gastrointestinal symptoms such as indigestion/dyspepsia, or heartburn at screening. Of this group, details on the five placebo-treated and 14 ibuprofen-treated subjects who reported gastrointestinal symptoms during the trial are shown in Table 3. In all cases, the severity ranged from mild to moderate and resolved either spontaneously or with non-prescription H2 antagonists or antacids. None of the subjects left the study.
. Subjects with positive upper gastrointestinal symptoms at baseline who experienced gastrointestinal symptoms during trial
Analysis of adverse effects by age
The overall adverse effect frequency was comparable between ibuprofen-treated and placebo-treated subjects in the 35–64 and ≥ 65 years age groups. In the 12–34 years age group, a significantly (P = 0.001) higher percentage of placebo subjects (61%) reported an adverse effect than did ibuprofen subjects (43%, OR = 0.48, 95% CI: 0.30–0.75); this was largely due to the higher percentage of Body as a Whole adverse effects among placebo-treated subjects (52%) compared to ibuprofen-treated subjects (32%).
In the 35–64 years age group, the frequency of dyspepsia was greater among ibuprofen-treated subjects (8.9%) compared to placebo (3.3%, P = 0.012, OR = 2.80, 95% CI: 1.20–7.57).
Within each age stratum, the incidence of positive occult blood tests was ≤ 2%, and both treatments within each age group were comparable in the frequency of positive tests.
Analysis of adverse effects by gender
Significantly more placebo-treated men (51%) reported an adverse effect than did ibuprofen-treated men (34%, P < 0.001; OR=0.50, 95% CI: 0.34–0.73). The overall incidence of gastrointestinal adverse effects (placebo= 14%, ibuprofen=13%, P=0.596) and the incidence of specific gastrointestinal adverse effects was not significantly different between the placebo and ibuprofen -treated men (OR=0.86, 95% CI: 0.50–1.5).
The overall incidence of adverse effects reported by placebo and ibuprofen-treated women was similar (54% and 53%, respectively, P=0.807; OR=0.95, 95% CI: 0.68–1.32). Significantly more placebo-treated women reported pain and back pain (9.1% and 6.1%, respectively) compared to ibuprofen-treated women (3.8% and 2.5%, respectively; P=0.008, OR=0.40, 95% CI: 0.19–0.81 and P=0.03, OR=0.39, 95% CI: 0.16–0.96, respectively).
The frequency of gastrointestinal adverse effects was higher in ibuprofen-treated women (25%) than among placebo-treated women (18%; P=0.03; OR=1.57, 95% CI: 1.04–2.4). There were no significant differences between groups for any specific gastrointestinal adverse effect.
For both men and women, the frequency of positive stool occult blood tests was comparable between those receiving ibuprofen and those receiving placebo.
The frequency of dyspepsia among subjects who used acetaminophen as their predominant over-the-counter analgesic (placebo=124 subjects, ibuprofen=231 subjects) was similar between treatment groups (placebo=2.4%, ibuprofen 4.6%, P=0.395, OR=2.017, 95% CI: 0.518–11.45).
Faecal occult blood
Seventeen of 1216 subjects (1.4%) with valid tests had at least one positive faecal occult blood test. The rate was comparable between the treatment groups on day 7, day 10, and overall. Only four of 1196 subjects (0.3%) had positive results on both days 7 and 10.
Of the 17 subjects with positive tests for stool occult blood (Table 4), five had an underlying non-drug-related gastrointestinal condition (e.g. haemorrhoids). Of the remaining 12 subjects, nine agreed to receive medical follow-up care which determined no gastrointestinal pathology or aetiology for the positive test results (three subjects declined to seek follow-up care). The frequency of positive occult blood tests not attributable to an underlying condition (0.8%) was consistent with the known false positive rate (2%) of the faecal occult blood test.18 Since subjects were not required to follow the manufacturer’s instructions for testing, false positives were not unexpected. The comparably low overall incidence of gastrointestinal bleeding associated with the administration of ibuprofen in this trial is consistent with the epidemiological literature for the administration of over-the-counter doses of ibuprofen.2, 3, 6, 19
. Subjects with positive haemoccult tests
This study was the first to examine the gastrointestinal tolerability of the maximum labelled daily dose of over-the-counter ibuprofen (1200 mg) for 10 consecutive days among typical users of over-the-counter analgesics. The results of this placebo-controlled trial are consistent with previously published studies indicating that the potential for ibuprofen to provoke gastrointestinal irritation is low in a typical over-the-counter-user population, including individuals who predominantly use acetaminophen as their over-the-counter analgesic.
Results from within each of the three age groups (12–34 years, 35–64 years, and ≥ 65 years) were generally consistent with those from the entire sample population. The clinical significance of a higher dyspepsia rate among those 35–64 years of age who received ibuprofen is questionable for two reasons: (i) there was no corresponding difference within this strata for other closely related upper gastrointestinal symptoms such as nausea and abdominal pain; and (ii) this finding was not replicated in either of the other two age strata. Additionally, 11 of the 37 cases of dyspepsia in the ibuprofen group were present at baseline compared to zero out of seven in the placebo group. Among subjects 35–64 years of age there was a difference between treatment groups at screening with respect to the presence of upper gastrointestinal symptoms (dyspepsia, heartburn, indigestion). A comparison of treatment-emergent upper gastrointestinal symptoms was conducted to take into account this baseline difference. The incidence of an upper gastrointestinal event in this age group is 3.52% and 6.63% for placebo and ibuprofen, respectively, which is not a significant difference (P=0.133, OR=1.95, 95% CI: 0.80–5.4).
Significantly more women in the ibuprofen group (25%) than in the placebo group (18%) reported gastrointestinal adverse effects; however, there were no significant differences between the treatment groups for any individual gastrointestinal adverse effects and no trend effect in any age strata. Since the frequency of gastrointestinal adverse effects was similar for placebo and ibuprofen in the overall population, this finding was deemed to be clinically unimportant.
The tolerability of ibuprofen at the maximum over-the-counter dosage was further demonstrated by the low percentage of subjects who discontinued due to adverse effects (1.2% in both the ibuprofen and placebo treatment groups). This low percentage compares favourably with other multiple-dose studies that have evaluated chronic ibuprofen therapy at higher prescription dosages of up to 3200 mg/day.20, 21
Additionally, the findings of this study are consistent with the results from previous analyses of single/multiple dose over-the-counter studies.13, 14 Furey reported the side-effects from 15 double-blind randomized controlled trials of over-the-counter doses of ibuprofen, acetaminophen, and placebo.13 A total of 878 subjects received ibuprofen 200 or 400 mg, 849 acetaminophen 650 or 1000 mg, and 852 placebo. The overall frequency of side-effects was comparable; ibuprofen 2.4%, acetaminophen 3.2%, and placebo 2.1%. Upper gastrointestinal upset ranged from 0.8 to 0.9% of subjects in all groups. In DeArmond et al.’s.14 review of 19 studies utilizing single or multiple over-the-counter doses of ibuprofen as the active comparator, a total of 1574 patients received single or multiple doses of ibuprofen 200 or 400 mg and 1061 received placebo. The proportion of subjects who reported adverse effects was similar in the ibuprofen and placebo groups (12.3% and 13.4%, respectively). The most common gastrointestinal adverse effect was nausea reported by 2.1% of placebo-treated subjects and 2.2% of subjects in the ibuprofen group.
The observations in the subset of subjects who reported an ongoing history of upper gastrointestinal symptoms at trial entry are clinically relevant because they dispel the notion that use of even an over-the-counter dose of an NSAID will invariably lead to exacerbated gastrointestinal symptoms.
Overall, adverse effects were reported by a total of 47% of subjects (53% in the placebo group, and 44% in the combined ibuprofen group). In addition to the specific prompting for adverse effects, this high frequency was directly related to the high incidence (33%) of Body as a Whole adverse effects, such as headache, backache, flu, and cold. One could expect that during a 10-day period, ≈ 50% of study subjects would report one or more miscellaneous and probably non-drug related event. Of interest, the proportion of subjects in the ibuprofen group who reported any adverse effects was significantly lower than in placebo-treated subjects. This finding could be attributed to the treatment/prevention of painful symptoms by ibuprofen and all subjects’ avoidance of other analgesic use for a continuous 10-day period. A statistically significantly greater number of placebo-treated subjects (n=139) took at least one dose of supplementary medication than either of the ibuprofen treatment groups (liquigel=92, tablet=81).
Subjects in this trial were required to provide stool samples on study days 7 and 10 for occult blood testing. The reported specificity of the test used in this trial is 98%,18 with the overall frequency of positive results ranging from 1.1% to 7.7% in uncontrolled trials and 1.0% to 3.7% in controlled trials.22 In the present study, the rate of positive tests was 1.4% and there was no significant difference between the treatment groups for the proportion of subjects with a positive result. Of the 17 subjects with positive occult blood tests, five were diagnosed with an underlying pathology unrelated to study medication that reasonably explained the positive result and three refused follow-up care. The remaining nine subjects who had negative follow-up may have had positive stool guaiac tests during the study due to variances in dietary intake, false positives, or drug use. No subjects were rechallenged with drug.
Despite the non-specificity of positive guaiac tests, they are an indirect measure of gastrointestinal bleeding. The high compliance rate of 96% of subjects submitting faecal samples indicates that the procedure can be readily incorporated to large prospective studies. The results demonstrate that the maximum labelled dosage of over-the-counter ibuprofen is not associated with occult gastrointestinal blood loss into the gastrointestinal tract above the background frequency reported for placebo.
In this large prospective study, there was no evidence of increased gastrointestinal bleeding as measured by guaiac test performed on two days, nor was there any evidence in the overall population of a substantial difference in subjective symptoms. In fact, ibuprofen demonstrated a gastrointestinal tolerability profile indistinguishable from placebo even when administered at the maximum over-the-counter dose of 1200 mg/day, for 10 days. These findings confirm the safety profile of over-the-counter ibuprofen for use in painful conditions such as headache, dysmenorrhea, and the minor aches and pains of arthritis.
This study was supported by a grant from Whitehall-Robins Healthcare, Madison, NJ, USA