Ibuprofen blood plasma levels and onset of analgesia.

BACKGROUND: Ibuprofen is widely available as an over-the-counter treatment for pain and fever. New formulations are now available, with varying pharmacokinetic profiles. However, few studies have been specifically designed to examine the relationship between ibuprofen plasma levels and onset of analgesia. This study aimed to determine a value, or range of values, for the blood plasma level of ibuprofen at which onset of analgesia could be expected. METHODS: Placebo-controlled clinical trials, investigating the efficacy and pharmacokinetics of ibuprofen 200 mg and 400 mg, were identified. A retrospective posthoc analysis was performed on data from trials that incorporated time to perceived pain relief as an endpoint and the incidence of confirmed/unconfirmed perceptible pain relief was assessed. Mean ibuprofen blood plasma levels were computed at various time points using data from pharmacokinetic trials. RESULTS: Two trials were identified with sufficient data to analyse time to onset of analgesia (Current Controlled Trials ISRCTN73768226, ISRCTN86009231). For 400 mg ibuprofen, the incidence of confirmed perceptible pain relief was significantly greater vs. placebo at 20 min post dosing (both studies). For 200 mg ibuprofen, significance was reached at 20 min (one study). In the 17 trials, with data on plasma concentrations for patients receiving 400 mg ibuprofen, the weighted mean value at 20 min post dosing was 8.4 µg/ml (95% confidence interval, 6.8-10.1). CONCLUSIONS: RESULTS of this study provide useful information for the development of new ibuprofen formulations. Further prospective studies and studies using other endpoints to define efficacy and onset would be of interest.

The analgesic efficacy of intramuscular parecoxib sodium in postoperative dental pain.

BACKGROUND: The parenteral cyclo-oxygenase, or COX, -2 selective inhibitor parecoxib sodium in a 40-milligram dose for intravenous/intramuscular, or i.v./i.m., administration is approved for postoperative pain in Europe, but not yet in the United States. However, previous trials in dental surgical patients have indicated that lower doses may be as effective. METHODS: The authors enrolled 353 patients in a single-center, double-blind, placebo-controlled, dose-ranging study to compare the efficacy and tolerability of single i.m. doses of parecoxib (1-20 mg) with ketorolac tromethamine 30 mg i.m. after dental surgery. Pain assessments occurred at baseline and through 24 hours postdose. RESULTS: A 20-mg dose of parecoxib was significantly more effective than were 1-mg to 10-mg doses and than placebo. The analgesic onset of a 20-mg dose of parecoxib was similar to that of a 30-mg dose of ketorolac. The magnitude of analgesia with a 20-mg dose of parecoxib was significantly lower than that with ketorolac, according to the mean pain intensity difference, or PID, scores from one and one-half to four hours postdose or summed PID, or SPID, -categorical scores at six hours postdose. However, there was no significant difference in mean pain relief; total pain relief, or TOTPAR; and SPID-visual analog scale, or VAS, scores six hours postdose. Mean PID scores for parecoxib 20 mg from 12 to 24 hours postdose were significantly higher than and SPID-VAS mean scores were not statistically significantly different from eight hours onward. CONCLUSIONS: Parecoxib 20 mg i.m. is an effective analgesic dose with an onset and magnitude of analgesic effect approaching that of ketorolac 30 mg i.m. after dental surgery. It also is well-tolerated. CLINICAL IMPLICATIONS: These findings support the use of parecoxib 20 mg i.m. as an initial dosing option for postoperative pain management in countries in which it is approved.

Efficacy and tolerability of the specific cyclooxygenase-2 inhibitor DFP compared with naproxen sodium in patients with postoperative dental pain.

DFP [3-(2-propyloxy)-(4-methyl-sulfonylphenyl)-(5,5-dimethyl)-fu ranone] is a highly specific cyclooxygenase-2 inhibitor (>2500-fold selective in transfected Chinese hamster ovary cell assays) that has demonstrated efficacy in preclinical models of pain and inflammation. The present single-dose, randomized, double-masked, double-dummy, placebo-controlled, parallel-group study was undertaken to compare DFP 5, 25, and 50 mg with naproxen sodium 550 mg and with placebo in 196 patients (mean age, 25.8 years; 187 [95.4%] males) who experienced moderate-to-severe pain after surgical removal of > or =2 third molars. Overall analgesic effect, duration of effect, time to onset of analgesic effect, peak analgesic effect, and tolerability were assessed over a 24-hour postdose period. Both DFP 25 and 50 mg, as well as the active comparator, naproxen sodium 550 mg, were significantly more effective than placebo. The onset of analgesic effect in the DFP 25-mg, DFP 50-mg, and naproxen sodium 550-mg groups did not differ significantly. DFP was generally well tolerated in single doses up to 50 mg. DFP 50 mg was efficacious in the treatment of postoperative dental pain and was indistinguishable from the active comparator, naproxen sodium 550 mg.

Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin (INN, indometacin) inhibit both the constitutive (COX-1) and inducible (COX-2) isoforms of cyclooxygenase. The induction of COX-2 after inflammatory stimuli has led to the hypothesis that COX-2 inhibition primarily accounts for the therapeutic properties of NSAIDs. METHODS: Chinese hamster ovary (CHO) cell lines that express each COX isoform were used to characterize the in vitro selectivity of rofecoxib. Single oral doses of rofecoxib and indomethacin were then assessed in subjects with use of ex vivo COX-isoform specific assays (serum thromboxane B2 [TXB2] and lipopolysaccharide [LPS]-stimulated whole blood prostaglandin E2 and assays of COX-1 and COX-2 activity, respectively). A double-blind, parallel-group study compared the analgesic efficacy of rofecoxib to placebo and ibuprofen in 102 patients with dental pain. RESULTS: Rofecoxib showed a >800-fold COX-2 selectivity with use of CHO cells that express human COX-1 and COX-2. In subjects, dose- and concentration-dependent inhibition of LPS-stimulated prostaglandin E2 was observed with both rofecoxib (IC50 [the concentration estimated to produce 50% inhibition], 0.77 micromol/L) and indomethacin (IC50, 0.33 micromol/L). Whereas indomethacin inhibited TXB2, (IC50, 0.14 micromol/L), no inhibition was observed with rofecoxib even at doses of up to 1000 mg. In the dental pain study, total pain relief (TOTPAR) over the 6 hours after dosing was similar between 50 mg and 500 mg rofecoxib and 400 mg ibuprofen (P > .20). All active treatments showed greater improvement than placebo (P < .001) CONCLUSIONS: Rofecoxib inhibited COX-2 without evidence of COX-1 inhibition, even at oral doses of up to 1000 mg. Nonetheless, rofecoxib showed analgesic activity indistinguishable from that observed with ibuprofen, a nonisoform-selective COX inhibitor. These results support the hypothesis that the analgesic effects of NSAIDs primarily derive from inhibition of COX-2.

Double-blind, single-dose comparison of bromfenac sodium, tramadol, and placebo after oral surgery.

This double-blind, parallel-group study was performed at a single site in patients with moderate or severe pain after oral surgery to remove one or more impacted third molars. Patients recorded their pain intensity at baseline and were then assigned to receive a single dose of bromfenac sodium (25 mg or 50 mg), tramadol (100 mg), or placebo, using a randomized double-blind code. At regular intervals for up to 8 hours after study drug administration, pain intensity and pain relief were recorded and were used to derive the efficacy variables, total pain relief (TOTPAR), pain intensity difference (PID), and summed pain intensity difference (SPID). Both doses of bromfenac were superior to tramadol and placebo in terms of hourly and peak pain relief and PID. The 3-hour and 8-hour TOTPAR and SPID results for both doses of bromfenac also were significantly superior to those for tramadol and placebo, whereas the scores for tramadol did not show superiority to placebo. Similarly, both doses of bromfenac were superior to tramadol and placebo as measured by patient global assessment, time to meaningful pain relief, and duration of pain relief. Bromfenac was well tolerated and was equivalent to placebo with respect to treatment-emergent study events. Overall, significantly more study events (total), digestive events (particularly nausea and vomiting), and nervous system events (particularly dizziness) occurred in patients treated with tramadol than in those in other treatment groups. Single oral doses of bromfenac were more effective, longer-acting, and better tolerated than single doses of tramadol in providing pain relief after oral surgery.

Ketoprofen, acetaminophen, and placebo in the treatment of tension headache.

Seven hundred three subjects completed a randomized, double-blind, parallel-group, single-center study comparing the single-dose efficacy of ketoprofen 12.5 mg, ketoprofen 25 mg, acetaminophen 1000 mg, and placebo in the treatment of tension headache. For the primary efficacy variable, 4-hour sum of pain relief intensity differences, ketoprofen 25 mg was significantly superior to placebo. Ketoprofen 25 mg also demonstrated superior pain relief in the first hour after dosing, and the time to meaningful pain relief was significantly shorter for the ketoprofen 25-mg group. Ketoprofen 12.5 mg proved to be significantly superior to placebo for pain relief intensity difference and pain relief at 3 hours, global assessment of medication at 4 hours, and for time to onset of meaningful pain relief. The data suggest a dose response for ketoprofen 12.5 mg and 25 mg. Acetaminophen 1000 mg proved to be numerically more favorable than placebo in most variables, but could not be separated from placebo with statistical significance. In spite of possible inflation of the placebo response due to sensitivity limits of the study, ketoprofen 25 mg demonstrated a more rapid onset of analgesia compared to acetaminophen 1000 mg, and patients' global assessment rated ketoprofen 25 mg higher than acetaminophen 1000 mg.

A crossover comparison of bromfenac sodium, naproxen sodium, and placebo for relief of pain from primary dysmenorrhea.

Single and multiple oral doses of bromfenac sodium (10 or 50 mg) were compared with naproxen sodium (550 mg loading/275 mg repeat doses) for the relief of pain from primary dysmenorrhea in 54 women using a crossover design. Pain intensity and pain relief were assessed over 6 h after the first dose, and global ratings were made at the end of day 1 and on day 2. A single dose of bromfenac 10 or 50 mg was as effective as the loading dose of naproxen sodium (550 mg) in relieving the pain from dysmenorrhea through a 6-h period. All three active treatments were statistically superior (p < 0.001) to placebo for the primary efficacy variables, 3-h and 6-h total pain relief and 3-h and 6-h summed pain intensity difference. All active treatments were statistically superior (p < 0.05) to placebo for the first dose and day 1 global assessments. One or more adverse study events were reported by 13 patients (25%) who received bromfenac 50 mg, 15 (29%) who received bromfenac 10 mg, 20 (38%) who received naproxen sodium, and 19 (37%) who received placebo. There were no clinically significant differences among the treatments in the types of adverse study events. No serious or unexpected adverse study events were reported, and no women withdrew from the study because of an adverse event. Bromfenac sodium (10 mg or 50 mg) is as effective as naproxen sodium (550 mg loading dose/275 mg repeat doses) for relief of pain from dysmenorrhea.

Comparative study of ibuprofen lysine and acetaminophen in patients with postoperative dental pain.

This single-dose, double-blind, parallel-group, single-site study compared ibuprofen lysine 400 mg with acetaminophen 1000 mg and placebo in 240 patients with moderate-to-severe postoperative dental pain. The relative onset of analgesic response, overall analgesic efficacy, duration of effect, and safety were assessed over a 6-hour postdose period. Analgesic efficacy was assessed by patient self-rating of pain intensity, pain relief, time to meaningful pain relief, need for additional analgesic medication, and patient global evaluation. Both ibuprofen lysine 400 mg and acetaminophen 1000 mg were significantly (P < or = 0.05) more effective than placebo. Ibuprofen lysine had a significantly (P < or = 0.05) faster onset of action with greater peak and overall analgesic effect than did effect than did acetaminophen. All treatments were generally well tolerated.

Histologic evaluation of the bone/graft interface after mandibular augmentation with hydroxylapatite/purified fibrillar collagen composite implants.

Samples of the bone/graft interface were evaluated histologically in five patients 1 year after mandibular ridge augmentation with a composite of hydroxylapatite particles in a matrix of purified fibrillar collagen (HA/PFC). The resulting defects were refilled with HA/PFC after the biopsy specimens were obtained. Histologic examination of the specimens yielded no evidence of purified fibrillar collagen. Hydroxylapatite particles were surrounded by dense fibrous host connective tissue, trabeculae of woven and lamellar bone, or both. HA/PFC was found to be biocompatible with human tissue and receptive to direct bone apposition on the hydroxylapatite particles.

Double-blind crossover comparison of ketoprofen, naproxen, and placebo in patients with primary dysmenorrhea.

Sixty-three women, aged 18 to 39 years, with primary dysmenorrhea received 25 mg, 50 mg, or 75 mg of ketoprofen, 500 mg of naproxen, or placebo as a first dose at the onset of moderate or severe pain. Each patient received three treatments and each treatment was tested in 36 patients. Mean pain relief scores (on a five-point scale) indicated a significant analgesic response for all active treatments; superiority over placebo was shown by ketoprofen 50 mg for six hours, by ketoprofen 75 mg for five hours, by ketoprofen 25 mg for four hours, and by naproxen for four hours. The onset of pain relief and peak relief were reached faster and pain relief lasted longer after 75 mg and 50 mg of ketoprofen than after 25 mg of ketoprofen or 500 mg of naproxen, which in turn were superior to placebo. Treatment was rated good to excellent by 20 patients after 25 mg of ketoprofen, by 26 after 50 mg, and by 28 after 75 mg, and by 22 after naproxen and 11 after placebo. The incidence of side effects was similar in the ketoprofen-treated and naproxen-treated patients.

A single-dose study of the efficacy and safety of FS 205-397 (250 mg or 500 mg) versus aspirin and placebo in the treatment of postsurgery dental pain.

The efficacy and safety of two dose levels of FS 205-397 (either 250 or 500 mg) were compared with the efficacy and safety of aspirin 650 mg and placebo in a 6-hour, single-dose, double-blind study in 161 patients who had undergone extraction of third molars. Each of the doses of FS 205-397, as well as aspirin, produced analgesia. However, the analgesic effects of both the 500 mg dose of FS 205-397 and aspirin were at times significantly better and more prolonged than those produced by the lower dose of FS 205-397. On the other hand, both doses of FS 205-397 had a significantly faster onset of action than aspirin. Side effects, reported by 17% of the 161 patients, did not differ significantly among the four treatment groups with respect to frequency, type, or severity. The most commonly reported side effects were nausea (7%) and drowsiness (6%). The results indicated that FS 205-397, administered in single doses of either 500 or 250 mg, is a safe and effective analgesic for the relief of pain following dental surgery, and may offer particular advantages in terms of onset of effects.

Multicenter clinical trial of ibuprofen and acetaminophen in the treatment of postoperative dental pain.

Pharmacological management of pain for acute and chronic conditions has been guided by a scientific understanding of peripheral and central acting mechanisms for the control of inflammation as well as pain. Oral surgery pain is a reliable model to reference the effectiveness of commonly used analgesics such as ibuprofen and acetaminophen. A total of 706 patients who were experiencing moderate to severe pain received a single dose of ibuprofen, acetaminophen, or placebo. After 6 hours, the degree of pain relief and tolerance was assessed. Ibuprofen has important implications for postoperative pain in clinical practice.

Collagen/hydroxylapatite implant for augmenting deficient alveolar ridges: a 24-month clinical and histologic summary.

A new alveolar ridge augmentation material composed of purified fibrillar collagen (PFC) and particulate hydroxylapatite (HA) (Alveoform Biograft, Collagen Corp., Palo Alto, Calif.) was evaluated in the treatment of 77 edentulous patients in a multicenter study. All patients had mandibular augmentation; 22 also had maxillary implant augmentation. Mean ridge height was 15.4 mm before surgery. Twenty-four-month data showed a mean ridge augmentation of 4.1 mm. Prosthodontists rated the ridge firmness "good" to "excellent" in 96.6% of patients after 2 years. All adverse effects with the exception of some residual paresthesia/dysesthesia resolved spontaneously within 24 months. Bone-graft interface samples were examined histologically in five patients 1 year after mandibular ridge augmentation. No evidence of PFC was found, and the HA particles were surrounded by dense, fibrous, host-connective tissue or trabeculae of woven and lamellar bone. Assessment of PFC/HA-augmented ridges at 24 months showed clinically and histologically significant results.

Comparison of three-day butoconazole treatment with seven-day miconazole treatment for vulvovaginal candidiasis.

In this multicenter, parallel, randomized, investigator-blind trial, we compared the safety and efficacy of a three-day regimen of 2% butoconazole vaginal cream with those of a seven-day regimen of 2% miconazole vaginal cream. Enrolled were 271 nonpregnant women with vulvovaginal candidiasis. Each patient administered her assigned study medication to the posterior vaginal fornix for three or seven consecutive nights. All 271 patients were included in the safety evaluation, and 225 (111 receiving butoconazole and 114 receiving miconazole) were included in the efficacy evaluation. Eight to ten days after treatment completion, 88% of the butoconazole-treated patients and 91% of the miconazole-treated patients were Candida negative; 80% of the butoconazole-treated patients and 82% of the miconazole-treated patients were considered clinically cured. Thirty days after treatment completion, 73% of the butoconazole-treated patients and 69% of the miconazole-treated patients remained Candida negative; 78% of the butoconazole-treated patients and 80% of the miconazole-treated patients remained free of clinical symptoms of vulvovaginitis. None of the differences between the two treatment groups was statistically significant. Six patients (four receiving butoconazole and two receiving miconazole) reported increased symptoms of vulvovaginal irritation, and three of them (two receiving butoconazole and one receiving miconazole) withdrew from the trial. Thus, the efficacy and safety of the three-day butoconazole treatment regimen were equivalent to those of the seven-day miconazole treatment regimen. The advantage of the shorter butoconazole treatment is increased patient compliance with maintenance of high efficacy.

Ketoprofen, ibuprofen, and placebo in the treatment of primary dysmenorrhea: a double-blind crossover comparison.

Under double-blind, crossover conditions, 43 women with primary dysmenorrhea received ketoprofen, ibuprofen, and placebo during three consecutive menstrual cycles. Pain intensity and pain relief were determined before and for 6 hours after the loading dose (ketoprofen 150 mg, ibuprofen 800 mg) and before and 2 hours after the maintenance dose (ketoprofen 75 mg, ibuprofen 400 mg). Mean pain intensity difference and pain relief scores consistently indicated greater pain relief after the loading doses of ketoprofen and ibuprofen than after placebo. Significant (P less than 0.05) mean changes that were measured by 13 indices of analgesia after the loading doses of both ketoprofen and ibuprofen indicated greater efficacy for the active treatments than for placebo. The patients' global evaluations after the loading doses were significantly (P less than 0.05) better for the active treatments than for placebo. The efficacy results were similar after the maintenance doses. The rates of a "good" to "excellent" response were 77% for ketoprofen, 73% for ibuprofen, and 35% for placebo. Ketoprofen and ibuprofen were equally well tolerated, the most frequent adverse experiences being gastrointestinal symptoms for ketoprofen and central nervous system side effects for ibuprofen.

Collagen/hydroxylapatite implant for augmenting deficient alveolar ridges: twelve-month clinical data.

In a multicenter study, 77 edentulous patients had mandibular augmentation with implants of purified fibrillar collagen combined with dense hydroxylapatite (Alveoform Biograft); 22 of these patients also had maxillary augmentation. Most patients had Class III or IV mandibular atrophy, and had outpatient surgery with the subperiosteal tunneling technique. Temporary splints were worn for 24 hours post-surgery. Mean ridge height was 15.3 mm before surgery and 19.5 mm after 12 months, an augmentation of 4.2 mm. Predictable compaction occurred largely in the first few months after denture loading. Most patients, surgeons, and prosthodontists assessed the results of the procedure as good to excellent at 1 year following implantation. Adverse experiences, largely dehiscence and paresthesia, tended to resolve over time. Sera from ten patients demonstrated antibodies to bovine collagen that were not clinically significant. Alveolar augmentation with collagen/hydroxylapatite achieved clinically significant results that compared favorably with those achieved with other types of ceramic implants.

Evaluation of collagen/hydroxylapatite for augmenting deficient alveolar ridges: a preliminary report.

A multicenter study was undertaken to evaluate a new alveolar ridge augmentation material composed of purified fibrillar collagen and particulate hydroxylapatite (PFC/HA). In a study of 77 patients and 99 reconstructed ridges, this material provided superior handling properties over HA alone as evidenced by its ease of surgical placement and manipulation, and the rarity of particle migration or displacement. Moreover, the rapid development of ridge firmness and stability allowed for the loading of dentures within three to six weeks. Prosthodontist evaluations and surveys of patient satisfaction showed great satisfaction with denture fit, comfort, esthetics, speech, and ability to masticate.

A controlled comparative evaluation of acetaminophen and aspirin in the treatment of postoperative pain.

The analgesic effects of acetaminophen (1 gm), aspirin (650 mg), and placebo were evaluated in a double-blind, randomized parallel study. The subjects were 162 outpatients who had experienced moderate or severe pain as a result of dental surgery involving bone removal. Patients evaluated the intensity of their pain and the extent of their relief from pain at 30 minutes, at one hour, and at each subsequent hour for six hours after the administration of the study medication. During the six-hour period, 135 of the 162 patients were remedicated. At the end of the six-hour period each patient assessed overall treatment. Two measures of analgesia were derived from patients' evaluations of the intensity of pain, and three other measures were derived from evaluations of relief from pain. On all six measures used, the groups receiving acetaminophen and aspirin reported analgesic effects significantly superior (P less than 0.05) to those of placebo. Acetaminophen was significantly better than aspirin with respect to the maximum difference in the intensity of pain (P less than 0.05) and the maximum pain relief achieved (P less than 0.03) and according to the global evaluation (P less than 0.02). These differences were most striking in patients with severe initial pain.

Review of the comparative analgesic efficacy of salicylates, acetaminophen, and pyrazolones.

Use of salicylates, acetaminophen, and pyrazolones has become increasingly complex, extending from the treatment of acute, mild pain to chronic, moderately severe pain. The intensity, rather than the nature, of the pain determines the efficacy of aspirin. A clinical dose-response relationship has been established, and time-effect curves indicate that the total threshold-raising effect depends on dosage frequency. Contrary to popular belief, aspirin and acetaminophen appear to be equipotent and equianalgesic for the relief of most pain. The combination of aspirin (650 mg) plus codeine (30 mg) is only slightly more effective than aspirin alone. The same holds true for acetaminophen (600 mg) plus codeine (60 mg); the efficacy of the combination is only slightly better than that of acetaminophen alone.

Zomepirac sodium vs APC with codeine for oral surgery pain.

In this double-blind, repeat-dose study, 323 outpatients with moderate to severe pain after oral surgery assessed zomepirac sodium, a new oral, single-entity, nonnarcotic analgesic, and APC with codeine, 30 mg, a reference standard. Pain relief obtained with 100 mg of zomepirac sodium was significantly superior to that of APC with codeine, 30 mg; 50 mg of zomepirac sodium was as effective as the reference drug. The analgesic acceptability was highest for 100 mg of zomepirac sodium. Both doses of this new drug produced significantly fewer adverse reactions than APC with codeine, 30 mg.