Lawrence M. Levin

Ibuprofen Liquigel for Oral Surgery Pain

BACKGROUND Ibuprofen liquigel is a solubilized potassium ibuprofen 200-mg gelatin capsule formulation that was approved for over-the-counter use in 1995. OBJECTIVE This study compared the analgesic efficacy and tolerability of ibuprofen liquigel 200 mg, ibuprofen liquigel 400 mg, acetaminophen caplets 1000 mg, and placebo in patients experiencing moderate or severe pain after surgical removal of impacted third molars. METHODS This randomized, double-blind, parallel-group, 6-hour study was conducted in 210 patients experiencing moderate or severe postoperative pain. Ratings of pain intensity and pain relief were recorded every 15 minutes for the first hour, at 90 and 120 minutes, and then hourly through hour 6. The onsets of first perceptible relief and meaningful relief were recorded using 2 stopwatches. An analysis of variance model was employed to test for significant differences (P < or = 0.05) between treatment groups with respect to pain relief, pain intensity difference, total pain relief (TOTPAR), and summed pain intensity difference (SPID). Stopwatch measures were analyzed using the Cox proportional hazards model. Drug tolerability was assessed by monitoring the occurrence of adverse events. RESULTS During the first 2 hours of the study (TOTPAR 2 and SPID 2), all active treatments were significantly more efficacious than placebo (P < 0.001), with ibuprofen liquigel 200 and 400 mg significantly more efficacious than acetaminophen 1000 mg (P < 0.05 and P < 0.01, respectively). For the entire duration of the study (TOTPAR 6 and SPID 6), only the 2 doses of ibuprofen liquigel were significantly more efficacious than placebo (P < 0.001). Ibuprofen liquigel 200 and 400 mg were also significantly more efficacious than acetaminophen 1000 mg on the summary measures TOTPAR 6 and SPID 6 (P < 0.01 and P < 0.001, respectively). Analysis of the stopwatch data revealed that all active treatments displayed significantly more rapid onsets to confirmed first perceptible relief (P < 0.001 to < 0.05) and meaningful relief (P < 0.001 to < 0.01) than did placebo, with ibuprofen liquigel 400 mg displaying a significantly more rapid onset to meaningful relief than acetaminophen 1000 mg (P < 0.05) and a significantly more rapid onset to confirmed first perceptible relief than acetaminophen 1000 mg (P < 0.001) and ibuprofen liquigel 200 mg (P < 0.01). All adverse events were considered mild or moderate, with an overall incidence of 11.5% in the ibuprofen liquigel 200-mg group, 6.8% in the ibuprofen liquigel 400-mg group, 19.0% in the acetaminophen 1000-mg group, and 25.9% in the placebo group. CONCLUSIONS Ibuprofen liquigel provided greater peak and overall analgesic effects and a more rapid onset to analgesia than did acetaminophen 1000 mg.

Dose-ranging analgesic study of Prosorb diclofenac potassium in postsurgical dental pain.

BACKGROUND ProSorb diclofenac potassium (K) is a novel, liquid-filled rapid-dispersion formulation of the nonsteroidal anti-inflammatory drug diclofenac, placed into soft gelatin capsules. Its time to maximal plasma drug concentration has been shown to be approximately half, and its maximal plasma drug concentration nearly twice, that of immediate-release diclofenac K tablets. OBJECTIVE This study compared the analgesic dose-response relationship and tolerability of 3 doses of ProSorb diclofenac K and placebo in the treatment of pain after dental impaction surgery. METHODS This randomized, double-blind, double-dummy, placebo-controlled parallel-group study was conducted at 6 centers across the United States. Patients aged 18 to 65 years with moderate or severe pain after the removal of > or =1 impacted mandibular third molar were randomly assigned to receive a single dose of ProSorb diclofenac K 25, 50, or 100 mg or placebo. Pain intensity and relief were assessed up to 6 hours after dosing. Rescue treatment was allowed after 1 hour. Efficacy end points included the summed pain intensity difference over 3 and 6 hours (SPID3 and 6); total pain relief at 3 and 6 hours (TOTPAR3 and 6); median times to onset of perceptible and meaningful relief (analgesic onset) and rescue medication use (analgesic duration); and cumulative percentage of patients using rescue medication. Tolerability was assessed using vital sign measurements and spontaneous reporting of adverse events. RESULTS A total of 265 patients (154 women, 111 men; mean age, 23.3 years) were enrolled. All 3 ProSorb diclofenac K groups showed higher SPID6 and TOTPAR6 scores and longer median times to rescue medication use than the placebo group (all, P < 0.001). For these end points, a dose-response relationship was evident between the 100-mg dose and the 25- and 50-mg doses (P < or = 0.05); the 25- and 50-mg doses were similar. In the diclofenac groups, median onset times for first perceptible (< or =22.5 min) and meaningful (< or =53.0 min) relief were significantly more rapid than placebo (P < or = 0.01). Proportions of patients requiring rescue analgesic were < or =50.8% with diclofenac compared with 79.4% with placebo. Proportions of patients assigning a global evaluation of good or better was > or =68% with diclofenac compared with 21% for placebo. Tolerability was similar across all treatment groups. CONCLUSION In this study of patients treated for pain following dental impaction surgery, single doses of ProSorb diclofenac K 25, 50, and 100 mg were more efficacious than placebo with respect to reduction of pain. All 3 doses provided a rapid analgesic onset and were well tolerated.

Comparative osteogenesis of maxilla and iliac crest human bone marrow stromal cells attached to oxidized titanium: a pilot study.

OBJECTIVES Severe alveolar bone loss affects dental implant placement. Bone augmentation by grafting iliac crest bone rich in osteoprogenitor cells such as bone marrow stromal cells (BMSCs) requires a second surgical procedure in non-orofacial bone. Skeletal site-specific osteogenesis indicates maxilla and mandible BMSCs are highly proliferative and exhibit osteogenic properties superior to iliac crest BMSCs. Alveolar bone can be easily obtained during routine dental surgery, but it is unclear if titanium-attached alveolar BMSCs will retain their superior osteogenic properties. This study evaluated and compared in vitro osteogenic properties of titanium-attached maxilla and iliac crest BMSCs in same individuals. MATERIAL AND METHODS Primary culture of maxilla and iliac crest BMSCs from four normal healthy volunteers was expanded in culture. In 24-well plates, first passage BMSCs were seeded directly (1 x 10(4) cells/well) on oxidized titanium disks (1.27 cm diameter and 2 mm thickness) or tissue culture plate. Each cell type was assessed for affinity for titanium, post-attachment survival and osteogenic differentiation based on alkaline phosphatase and osteopontin expressions. RESULTS There was no difference in the affinity of maxilla and iliac crest BMSCs to titanium. However, titanium-attached maxilla BMSCs were apparently more osteogenically responsive than iliac crest cells based on calcium accumulation and gene expression of alkaline phosphatase and osteopontin. But these differences were not statistically significant in this small patient sample. CONCLUSION Maxilla and iliac crest BMSCs have similar attachment affinity for titanium. This pilot study indicates that titanium-attached maxilla BMSCs are more osteogenically responsive and may be a viable and more readily available donor graft material in implant dentistry.

Human bone marrow stromal cells display variable anatomic site-dependent response and recovery from irradiation

OBJECTIVES Orofacial bone is commonly affected by osteoradionecrosis (ORN) during head and neck cancer radiotherapy possibly due to interactions of several factors including radiation damage to resident bone marrow stromal cells (BMSCs). Irradiation causes DNA damage, triggers p53-dependent signalling resulting in either cell-cycle arrest or apoptosis. In same individuals, disproportionately higher rapid growth of orofacial BMSCs relative to those of axial/appendicular bones suggests their response to radiation is skeletally site-specific. We hypothesised that survival and osteogenic recovery capacity of irradiated human BMSCs is site-dependent based on anatomic skeletal site of origin. METHODS Early passage BMSCs from maxilla, mandible and iliac crest of four normal volunteers were exposed to 2.5 to 10 Gy gamma radiation to evaluate clonogenic survival, effects on cell cycle, DNA damage, p53-related response and in vivo osteogenic regenerative capacity. RESULTS Orofacial bone marrow stromal cells (OF-MSCs) survived higher radiation doses and recovered quicker than iliac crest (IC-MSCs) based on clonogenic survival, proliferation and accumulation in G0G1 phase. Post-irradiation p53 level was relatively unchanged but expression of p21, a downstream effector was moderately increased in OF-MSCs. Re-establishment of in vivo bone regeneration was delayed more in irradiated IC-MSCs relative to OF-MSCs. CONCLUSIONS Effect of irradiation on human BMSCs was skeletal site-specific with OF-MSCs displaying higher radio-resistance and quicker recovery than IC-MSCs.

Conventional and extended-release etodolac for postsurgical dental pain

This double-masked, parallel-group, randomized study compared the analgesic efficacy and tolerability of a single investigational 1200-mg dose of extended-release etodolac with those of a single 400-mg dose of extended-release etodolac and twice-daily doses of conventional etodolac 200 and 400 mg and placebo given 8 hours apart in 237 patients with moderate or severe postoperative pain following surgical removal of > or = 2 impacted third molars. Both doses of conventional etodolac and the 1200-mg dose of extended-release etodolac were significantly more effective on all summary analgesic measures than placebo (P < 0.05). Conventional etodolac had an onset of analgesic activity within 45 (400 mg) to 60 (200 mg) minutes and an analgesic duration of 5 to 6 hours. Extended-release etodolac 1200 mg had an onset of action within 60 minutes and an analgesic duration of 12 to 24 hours. At hours 2 and 3, conventional etodolac 400 mg was significantly more effective than the other treatments; from hours 6 through 12, extended-release etodolac 1200 mg was significantly more effective than the other treatments (both, P < 0.05). No serious adverse events were observed in this study, with an incidence of side effects in the active etodolac groups no different than that with placebo. Extended-release etodolac 1200 mg has a prolonged analgesic duration and an acceptable side-effect profile in the oral surgery pain model.

A dose-ranging study of bromfenac sodium in oral surgery pain

OBJECTIVE The purpose of this study was to evaluate the analgesic efficacy and safety of five graded doses of bromfenac sodium in patients experiencing moderate to severe pain after the surgical removal of impacted third molar teeth. STUDY DESIGN The study employed a randomized, double-blind, single-dose, 8-hour, inpatient evaluation period. The treatment groups included placebo (n = 21) and bromfenac (n = 102) at dosage strengths of 5 mg (n = 21), 25 mg (n = 20), 50 mg (n = 20), 100 mg (n = 20), and 200 mg (n = 21). Patients ingested a dose of study medication when their postsurgical pain reached a moderate or severe intensity. Pain intensity and pain relief were rated at 15, 30, 60, 90, and 120 minutes and then hourly for the remaining 6 hours. Efficacy and safety variables were analyzed by means of analysis of variance and chi-squared tests where appropriate. RESULTS At all doses, bromfenac exhibited statistical superiority (p < 0.05) to placebo, with all but the 5-mg dose being significantly more efficacious for every summary analgesic measure (3- and 8-hour sum pain intensity difference and sum pain analog intensity difference, total pain relief, peak effects, sum of pain half gone, and global evaluation). Peak analgesic effects did not increase beyond those provided by the 25-mg dose of bromfenac, although both the 100- and 200-mg bromfenac doses provided a more rapid onset and a longer duration of analgesia than either the 25- or 50-mg dosage strengths. The most common side effects reported were headache, nausea, dizziness, and drowsiness; the incidence in the bromfenac group was no different from that in the placebo group. CONCLUSIONS Bromfenac is a safe and efficacious analgesic, with a threshold dose of 5 mg and a positive dose-response up to 25 mg for peak effects and 100 mg for total analgesic activity.