Onset of Action and Efficacy of Ibuprofen Liquigel as Compared to Solid Tablets: A Systematic Review and Meta-Analysis

. Purpose. Ibuprofen liquigel has been believed to provide faster analgesic effect. However, comparative studies evaluating the efficacy of liquigel versus regular tablets are not available. Hence, we carried out a systematic review and a meta-analysis to compare the onset of action and efficacy of over-the-counter doses of ibuprofen liquigel (IBU LG ) vs ibuprofen tablets (IBU T ). Methods. Published clinical trials of IBU LG and IBU T were identified through a systematic search of various data bases up to October, 2015. Results . In total 18 eligible studies on IBU T and 4 on IBU LG were found. There was no significant difference in the median time to the first perceptible pain relief or the proportion of patients with more than 50% pain relief between the two products. However, IBU LG yielded significantly greater odd ratios in meaningful pain relief at 60, 90 and 120 min, but not at 30 min, as compared with IBU T . Conclusion. The available evidence, although not overwhelming, suggest a faster onset of analgesia for liquigel as compared with tablets. summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.


INTRODUCTION
Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) derivative of the propionic acid that is used throughout the world for relief of pain and inflammation in both acute and chronic conditions [1]. The favorable analgesic effect of ibuprofen, even at low over-the-counter (OTC) oral doses, has made this agent the gold standard against which many new agents are evaluated for efficacy [2].
The management of acute episodes of pain requires the use of analgesic agents that have the ability to get absorbed rapidly and efficiently to yield rapid onset of pain relief.
Ibuprofen is a Biopharmaceutics Classification System (BCS) ( [3]) class II drug with low solubility at pH 1.2 and 4.5 but high solubility at pH 6.8, and is very permeable through physiological membranes [4]. In fact, it is found to be completely absorbed allowing for almost total bioavailability. However, the onset of absorption greatly depends on the dissolution of the dosage form [5].
In recent years, various oral formulations and different salts of ibuprofen have been investigated for their absorption properties and for their speed of onset of action with the hope of providing a rapid rise in plasma concentrations and, hence, a fast analgesic effect. They include S(+) ibuprofen [6], ibuprofen lysine [7,8], ibuprofen sodium [9], ibuprofen arginate [7,10], and ibuprofen liquigel (Advil Liqui-Gels, Pfizer, NY, USA).
Ibuprofen liquigel is a soft gelatin capsule that is hermetically sealed and contains ibuprofen as free acid and potassium salt in a solubilised form [11]. This newer solid dosage form of ibuprofen has been reported to have a rapid rate of absorption in healthy volunteers [12]. While ibuprofen rate of absorption in patients in pain is not reported, it has been shown to be an effective analgesic with minor advantages in onset of action as compared with ketoprofen and acetaminophen 1000 mg [13,14]. However, results of clinical trials, if any, that compare liquigel with solid dosage forms of ibuprofen as an active comparator have not been reported, hence, any advantage of such formulations remains unproven. This is particularly important since, due to the popularity of ibuprofen liquigel, many other analgesics have become available on the market in the form of liquid gel. We, therefore, attempted to compare the onset of analgesia and efficacy of the liquigel with solid dosage forms of ibuprofen by _________________________________________ undertaking a systematic review and meta-analysis of all the studies that report onset of analgesia and efficacy of ibuprofen after administration of these formulations for the treatment of dental pain or migraine or tension-type headache.

METHOD
Published reports of randomized controlled trials on ibuprofen tablets (IBU T ) or liquigels (IBU LG ) at any dose were identified through a systematic search of PubMed, Embase, Google Scholar and the Cochrane library from inception until October, 2015. Key words used in the search included: ibuprofen, onset, human, dental, oral surgery, migraine, and tensiontype headache. Moreover, the reference lists of the retrieved articles were scanned for relevant studies. The screening and eligibility assessment of the reports was carried out independently by the two authors. There was a lack of access to unpublished data, and so the review only included published reports. Moreover, conference abstracts, case reports, or clinical observations were found to lack the details required in the analysis, and thus were not included. No language restriction was imposed.
The review was restricted to clinical studies related to the use of ibuprofen as an analgesic for dental pain, tension-type headache, and migraine. Studies were included if they were randomized, double blind, and placebo controlled studies that evaluated a single dose of ibuprofen administered following a moderate to severe episode of pain associated with one of the above mentioned conditions. Multiple dose studies were included only if the relevant single-dose data were provided. Studies on the use of ibuprofen as a pre-emptive treatment were not included, nor were studies which only used other than the conventional marketed IBU T or IBU LG . Therefore, ibuprofen salt formulations marketed such as ibuprofen sodium or ibuprofen arginate were excluded from the review. The inclusion criteria also required the use of the double stopwatch method, a patient population aged at least 12 years, and monitoring the patients for three hours or more post-dose.
Relevant studies were categorised on the basis of whether the ibuprofen solid tablets or the ibuprofen liquigel were used. In instances where the results from the studies where only reported graphically, the relevant graphs were digitized using digitizeit (http://www.digitizeit.de, Germany) and the "grabit" function in MATLAB (MathWorks Inc., Natick MA, USA), and the data were extracted. In particular, the Kaplan-Meier time to event curves were analysed by the approach suggested by Guyot et al [15].
Two measures of onset of pain relief were considered, namely, the time to the first perceptible pain relief (FPPR) and the meaningful pain relief (MPR), both of which are patient-reported outcome captured as part of the double stopwatch method [16]. Kaplan-Meier survival median times to the above events were averaged with the weights being proportional to both the sample sizes and inverse of the variance. The latter, however, was measurable only for the data reported in the studies that provided a measure of variance. Moreover, the outcome of achieving meaningful pain relief at 30, 60, 90, and 120 min post-dose were calculated. The proportion of patients achieving MPR at the above specific times, and the relevant odd ratios (OR) against placebo were calculated. Setting IBU T as the reference (OR=1), the OR for IBU LG was also calculated by an adjusted indirect comparison [17]. Variation among studies was anticipated, and due to the heterogeneity of the pooled data the OR values for meaningful pain relief were estimated using the DerSimonial-Laird method [18]. Heterogeneity among the studies in reporting an outcome is detected using the Cochran-Q test and the percentage of variation across the different studies that is attributed to heterogeneity is quantified using the I 2 inconsistency test.
As the measure of efficacy, we calculated the total pain relief score (TOTPAR) over 6 h. Pain relief is measured throughout the study at specific time intervals on a 5-point categorical scale (0 (no relief), 1 (slight relief), 2 (moderate relief), 3 (good relief), 4 (complete relief)). TOTPAR, which is an integrated pain score representing a time-weighted measure of the total area under the pain relief curve, has a higher sensitivity than many other outcome measures such as the sum of pain intensity difference score [19]. We used the Student's t-distribution test to compare the calculated TOTPAR scores [20]. Moreover, we used verified linear regression equations to calculate the proportion of patients experiencing more than 50% pain relief as measured by TOTPAR, and calculated the relevant ORs against placebo and against each other [21].

RESULTS
The database search ( Figure 1) resulted in 100 reports that evaluated ibuprofen treatment for dental pain or dental surgery, migraine, or headache, and 3 additional reports were identified from other resources.
Upon our preliminary screening, duplicate reports, only abstracts, case studies, reviews and observational studies were removed. Subsequently, the list was shortened to 64 reports. A further screening revealed that 12 of these reports did not use randomly controlled trials, and 10 did not include ibuprofen as an active comparator in the study; e.g., as a rescue medication. The remaining 42 full text articles were checked for eligibility. Among these, 4 studies were related to the use of ibuprofen as a preemptive treatment, 2 used ibuprofen lysine, 1 used extended-release ibuprofen, 1 used sodium ibuprofen and ibuprofen acid incorporating poloxamer, 8 did not include results of the double stopwatch method, 3 were not placebo-controlled studies, and 1 did not report placebo results. The remaining 22 studies (Table 1) met our inclusion criteria and were included in the review. These consisted of 18 studies that used IBU T and 4 that studied IBU LG . Among the IBU T studies, 4 used Motrin IB (Motrin, McNeil Consumer Healthcare, Fort Washington PA, USA) (IBU Mot ), one used Advil (Pfizer Consumer Healthcare, New York NY, USA), one had an arm for each of these two brands, one used Neurofen (Reckitt Benckiser, Slough, UK), while the rest either used unbranded ibuprofen tablets or did not specify the brand used.

Confirmed first perceptible pain relief
All of the studies included in the review measured pain relief over various times up to 12 h. Moreover, all of the studies claimed to have used the double stopwatch method [16] but some did not report the data.
As a measure of onset of action, FPPR has been presented in 2 studies for IBU LG and in 16 studies for IBU T (Table 2). Moreover, both of the IBU LG studies and five of the IBU T studies provided 95% confidence interval for the median times. FPPR was achieved for 50% of patients significantly faster following both IBU T and IBU LG as compared with placebo. However, the difference between the two formulations was not significant.

Confirmed meaningful pain relief
The MPR values were reported in all 4 of the IBU LG studies and in 13 studies for IBU T (Table 3). Moreover, all of the IBU LG studies and 3 of the IBU T studies provided 95% confidence intervals for the median times. As depicted in Table 3, 50% of the patients who used either IBU T or IBU LG recorded significantly faster MPR than those who took placebo. The median MPR was significantly shorter for IBU LG than for IBU T .
A great deal of variability is observed with the IBU T studies with median MPR ranging from 35 to 161 min. Moreover, when the analysis is restricted to IBU Mot studies, the pooled median time from 5 studies which reported the outcome reduces from 138 to 52 min with sample-size weighing.
Another outcome measure considered, which complements the median times to MPR, is the proportion of patients achieving MPR at 30, 60, 90, and 120 min post-dose (Table 4). Three IBU LG articles provided such data and so did 4 of the IBU T reports. One additional IBU T study provided the data at all times except at 90 min post-dose, and one more provided the data at only 60, and 120 min post-dose. Both treatments provided significantly greater OR than placebo at all measured times.   The differences between the products was not significant at 30 min post-dose, but became significant in favour of IBU LG for all subsequent times. Significant level of heterogeneity is observed in the outcome of time to reach MPR with the IBU T data at all times, with the exception of 30 min post dose. At 2 h post dose, for example, the Cochran-Q test significantly indicates that there is no single value for time to MPR that the different IBU T studies are evaluating, while the I 2 value suggests that over 87% of the total variation across studies is due to heterogeneity rather than chance. No publication bias was detected by the Egger test except for the OR of IBU T against placebo at 2 h post-dose (data not reported).

Total pain relief and proportion of patients achieving at least 50% pain relief
Both IBU T and IBU LG were significantly more effective in relieving pain as measured by TOTPAR (0-6 h) than placebo. The mean pooled TOTPAR score for IBU T was 13.5 (n=661, 8 studies) and 14.9 (95% CI: 14.2, 15.7, n=379, 4 studies) for data that did not report variance and those that did, respectively. This value was 17.0 for IBU LG (95% CI: 16.0, 18.0, n=126, 2 studies) ( Table 5). An independent Student's t-test [20] reveals that IBU LG provided better pain relief as measured by TOTPAR (0-6 h) than that achieved with IBU T , although, with a small effect size (two-tailed t-test, t(503)=2.9, p=0.0042, Cohen's d = 0.29).
The available data allowed calculation of proportion of patients with more than 50% pain relief for 2 IBU LG and 8 IBU T studies (a total of 9 included IBU T groups) ( Table 6). Significantly more patients achieved at least 50% total pain relief over 6 h of dosing with either of IBU T or IBU LG than with placebo, showing an odd ratio of 11.7 (95% CI: 5.20, 26.4) with IBU T and 25.9 (95% CI: 11.4, 58.7) with IBU LG against placebo. No significant difference was observed between the two products when compared to each other. The Cochran-Q test indicates the presence of heterogeneity in the IBU T studies with regards to this outcome and the I 2 inconsistency tests attributes over 80% of the variation in the results to the heterogeneity or other forms of bias rather than chance.

DISCUSSION
The task of developing an analgesic medication with a meaningful onset of action has proven to be difficult if not impossible [22,23]. This has been attributed to the gastric dysfunction that is associated with pain or the trauma of pain [22,24]. Reports [22,25,26], except for one [27] suggest a reasonable correlation between analgesics concentration in the circulation and relief of pain. For an analgesic to act, however, the formulation has to disintegrate and dissolve before the active ingredient become available for absorption through the gastrointestinal (GI) tract. Although, depending on the drug pKa, the process may commence in the stomach, the main site of absorption is the intestine. In the meantime, pain and/or its trauma causes gastric dysfunction; i.e., reduced gastric motility, a slow-down of gastric emptying and reduced fluid excretion that result in slow disintegration and subsequent dissolution in the stomach [22]. Various commercially available formulations, e.g., dissolved drug in soft gelatin capsules are claimed to have rapid GI absorption, hence, quick onset of action [13]. However, clinical evidence suggestive of accelerated onset of action of products containing the same active ingredient is nonexistent or not published. Recently, a more rapid absorption during episodes of pain has been reported for formulations that are not coated and contain some disintegration action, hence, their disintegration and dissolution are less dependent on the gastric function [24]. Similarly, accelerated onset of action has been reported for products with undisclosed formulations that contain various salts of ibuprofen [28,29]. However, such data generated by studying patients in pain are not publicly available for soft gelatin capsules. IBU LG has been compared with various other drugs for the management of pain associated with migraine, headache, or dental procedures including celecoxib [30], acetaminophen [13, 14, 31], and ketoprofen [13], but not with the other more solid formulations of ibuprofen. In the absence of comparative clinical studies, systematic reviews and indirect meta-analysis comparisons remain to be effective means of appraising clinical evidence.
Regarding a desirable onset of action, our analysis of the available data suggests, for the first time, a few advantages of liquigel over other available forms of ibuprofen. While the differences between products in FPPR were not significant ( Table 2), IBU LG yielded a significantly faster MPR (Table 3). Similarly, when IBU LG was compared with IBU T (OR=1), the OR for MPR was greater than unity (9.61 to 19.6) during 60-120 min assessment period. However, at 30 min this value was not significantly elevated for IBU LG (3.1; 95% CI: 0.90, 10.8). It is, therefore, reasonable to suggest that the liquigel exhibits a faster onset of pain relief than the other products. However, a clear difference between the products appears only at 60 min.
In healthy subjects, plasma ibuprofen concentration peaks much faster following oral administration of IBU LG (T max , 30 min, [12]) than other examined products (T max , 2 h, [32]). Ignoring the pathophysiological changes in response to pain [22], such a difference in the rate of absorption is expected to result in a significantly faster onset of analgesia for IBU LG as compared with IBU T . However, our analysis suggests that a significantly greater response is only seen after 60 min rather than 30 min. This delay may be attributed to the paininduced gastric dysfunction. In addition, Jones et al [27] who correlated ibuprofen plasma concentration with its analgesic effect following administration of a soluble form of the drug found no significant link between the two variables despite their T max of 30 min. Therefore, the main reasons for the delay in analgesia following oral doses appear to include i) the pain-induced gastric dysfunction, hence, delayed absorption and ii) a gap between early rise in the drug plasma concentration and its arrival at the site of action. When administered in the form of solution, ibuprofen appears to be absorbed quickly independent of gastric dysfunction as T max values of 25 and 30 min have been reported for both healthy subjects [32] and patients in pain [27], respectively. This is because the drug is available for absorption without the delays caused by disintegration of tablets or opening of capsule shell and subsequent dissolution of the active ingredient. Based on our analysis, it is reasonable to suggest that during episodes of pain, although both IBU LG and IBU T are subject to delayed absorption due to the reported gastric dysfunction, the former provides a faster relief of pain relative to the latter.
In typical clinical trials of analgesics small populations of patients are employed (50-100 patients/study arm, Table 1). Considering the inherent inter-subject variability in such studies, much larger population size is needed for reliable results. By pooling the available clinical trial data that have tested the products of interest, as we have done herein, the data may be analyzed with more statistical power.
While approaches are often adopted to minimize bias in systematic reviews some sources of bias and heterogeneity that are inherent in the studies still exist [33]. In the eligible reports used in this analysis, the brand used is identified in 3 of the 4 IBU LG and only 7 out of 18 IBU T studies. This may ignore the potential between-products variability. For example, in our included reports we had 5 sets of data that identified Motrin IB (Motrin, McNeil Consumer Healthcare, Fort Washington PA, USA) as the brand. We found a shorter time to attain MPR (52.0 min) as compared to the pooled data (104.1 min) but still longer than that for IB LG (35.0 min) (Table 3). Similarly, shorter FPPR values were observed for Motrin than that for the pooled IBU T so that it rendered the difference between Motrin and IBU LG insignificant ( Table 2).
In our analysis we included all data available generated from patients with all acute type of pain (Table 1). However, the majority of the reports had included dental pain. When we analysed the available data on the dental pain only, we noticed very similar results except for FPPR that indicated a significant difference between IBU LG (10.2 min; 95% CI: 9.0, 13.8) and IBU T (26.9 min; 95% CI: 20.4, 40.3). However, this difference was based on only one study for IBU LG that reported FPPR for dental pain.
To measure efficacy, we considered total pain relief score (TOTPAR) over 6 h, which is an outcome measure that is commonly used in clinical trials of analgesia. It is based on summing a categorical pain relief scores (ranging from 0 to 4) for all participants at various time intervals after dosing. The results (Table 5) suggest that IBU LG provides a significantly higher TOTPAR as compared with IBU T , but the size of this effect is small (Cohen's d = 0.29). Another outcome measured that is useful in determining the effectiveness of pain relieving agents is the proportion of patients with more than 50% pain relief (based on TOTPAR). This outcome can be computed according to a linear regression fit that has been developed by Moore et al [21] to dichotomize the data. The pooled odd ratio for this outcome did not indicate a significant difference between IBU LG and IBU T , which suggest that the overall efficacy across the 6 h post-dose was comparable for both products.

CONCLUSION
The meta-analysis of the available clinical data suggests that both solid tablets and liquigel of ibuprofen are effective in controlling moderate to severe episodes of pain. The evidence, although not overwhelming, suggest a faster onset of analgesia for liquigel as compared with tablets. This information is timely in light of the ever increasing number of products in soft gelatin capsules appearing on the market. Well-powered comparative clinical trials are needed in this field.

ACKNOWLEDEGMENTS AND CONFLICTS
This research was supported by a University of Alberta Self-Directed grant. H.A. was a recipient of a scholarship granted by the government of Oman. Authors have no conflict of interest regarding the contents of the paper.    We, therefore, attempted to compare the onset of analgesia and efficacy of the liquigel with solid dosage forms of ibuprofen by undertaking a systematic review and meta-analysis of all the studies that report onset of analgesia and efficacy of ibuprofen after administration of these formulations for the treatment of dental pain or migraine or tension-type headache.
Page 2, paragraph just before Methods

METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
Protocol is with authors. The study is not registered