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Acute pain relief by a proprietary, nano-formulated lower-dose oral diclofenac
S74
The Journal of Pain
F14 NSAIDS and Acetaminophen (392) A randomized, double-blind, placebo-controlled, efficacy and safety study of acetaminophen 1000 mg and acetaminophen 650 mg in postoperative dental pain D Qi, L May, B Zimmerman, P Peng, E Atillasoy, S Shelburne, G Simmons, J Brown, and S Cooper; McNeil Consumer Healthcare, Fort Washington, PA At a recent FDA Advisory Committee Meeting related to acetaminophen, the incremental benefit of acetaminophen 1000 mg versus 650 mg was questioned. This topic is very important since acetaminophen 1000 mg is one of the most widely used analgesics. This study uses the Dental Impaction Pain Model to evaluate the dose-response relationship of acetaminophen 1000 mg versus 650 mg. This randomized, double-blind, placebo-controlled study enrolled subjects who required surgical removal of impacted third molars. Subjects received a single dose of acetaminophen 1000 mg, acetaminophen 650 mg, or placebo when they had at least moderate pain and a Visual Analog Scale (VAS) score $50 out of 100 mm post-surgically. Pain intensity and pain relief were measured over 6h (VAS 0-100 mm). All 540 subjects (52%F, age 16-30y, 95% Caucasian) were included in the efficacy analysis. For the primary efficacy endpoint, the Sum of Pain Intensity Difference (SPID) and Total Pain Relief (TOTPAR) scores over 6h (SPRID6), acetaminophen 1000 mg demonstrated a 24% improvement compared to 650 mg (529.4 vs 427.3; p=0.001). Acetaminophen 1000 mg was also significantly superior to 650 mg (p#0.002) for SPID6, TOTPAR6, Time to Rescue analgesic, rescue rates through 4h (20% vs 32%) and 6h (29% vs 46%), and Subject Global Evaluation (49% vs 35% with very good or excellent rating). Both active treatments were significantly superior to placebo (p<0.001) for these efficacy endpoints. The 2 active treatments were similar for stopwatch Times to Confirmed First Perceptible and Meaningful Relief. AEs were reported by 18.5% of subjects, with no clinically important difference among the 3 treatment groups. No serious AEs were reported and no subjects discontinued due to an AE. This study provides definitive evidence of a positive and clinically relevant dose response between acetaminophen 650 mg and acetaminophen 1000 mg.
Abstracts (394) Efficacy of a novel (lozenge) delivery of flurbiprofen over 24 hours B Schachtel, S Aspley, P Berry, N Muir, A Shephard, T Shea, G Smith, and E Schachtel; New York University, New York, NY A lozenge containing 8.75 mg flurbiprofen in a sugar-based flavoured vehicle was developed to provide lasting relief of pharyngeal pain.1 We conducted a multi-center trial in the US to distinguish the analgesic effects of flurbiprofen from the demulcent effect of the sugar-based placebo after multiple doses taken over 24 hours (SPID24). Adult patients with acute sore throat were examined to confirm physical findings of pharyngitis (documented on the TonsilloPharyngitis Assessment, TPA). Three patient-reported outcomes, derived from common symptoms of patients with pharyngitis, were measured on 100-mm visual analog scales: sore throat pain when swallowing (assessed on the sore throat pain intensity scale, STPIS), difficulty swallowing (on the difficulty swallowing scale, DSS), and the sensation of a swollen throat (on the swollen throat scale, SwoTS). After being randomly assigned to flurbiprofen or placebo lozenges under double-blind conditions, patients used these three scales hourly while awake to rate their symptoms, taking additional lozenges as needed (one lozenge every 3-6 hours, up to five lozenges over 24 hours). Among 194 patients, between 18-61 years of age with TPA$4 and STPIS$63mm, there were no baseline differences between the two treatment groups in terms of any demographic or clinical feature, including the TPA, STPIS, SwoTS, or DSS (all p>0.82). Compared to patients taking the placebo lozenges over 24 hours, patients using flurbiprofen had 59% greater STPIS reduction (SPID24), 45% greater DSS reduction, 44% greater SwoTS reduction (all p<0.01). More patients taking flurbiprofen reported clinically meaningful relief of pain ($30%PID) than patients taking placebo (p<0.05). There were no serious or unexpected adverse events. We conclude that flurbiprofen 8.75 mg delivered in a lozenge provides safe, meaningful relief for patients with painful pharyngitis. 1.Schachtel, Clin Pharmacol Ther, 2002.) Supported by a grant from Reckitt Benckiser.
(393) A single centre prospective randomised study to investigate the cerebrospinal fluid (CSF) pharmacokinetics of intravenous acetaminophen in humans
(395) Acute pain relief by a proprietary, nano-formulated lower-dose oral diclofenac
V Mehta, C Sharma, J Long, S Shah, J Rahman, S Ayoub, D Perrett, and R Langford; St. Bartholomew’s Hospital London, London, United Kingdom
New NSAID formulations are being developed to improve tolerability while maintaining efficacy. The purpose of this clinical study was to evaluate time to onset of analgesia in an investigational, proprietary, nano-formulated, lower-dose, oral diclofenac compared with placebo in an acute pain model. This was a Phase 2, multicenter, randomized, double-blind, single-dose, parallel-group, active- and placebo-controlled study. Subjects (N=202) were 18-50 years old, had extraction of $2 third molars ($1 of which was a fully or partially impacted mandibular third molar), and experienced moderate to severe pain intensity #6 hours post-surgery. Subjects assessed baseline pain intensity before receiving a single dose of nano-formulated lower dose diclofenac 18mg or 35mg, celecoxib 400mg, or placebo, and pain intensity and pain relief from 15 minutes through 12 hours. There was a statistically significant (P<0.001) shorter time to onset of analgesia (mean6SE) for nano-formulated lower dose diclofenac 35mg (42min63.6), nano-formulated lower dose diclofenac 18mg (36min63.0), and celecoxib 400mg (54min64.2) compared with placebo (144min69.0). There was also a statistically significant improvement in mean time to first perceptible pain relief, mean time to meaningful pain relief, and mean time to peak pain relief for nano-formulated diclofenac 18mg and 35mg when compared with placebo. Tolerability data were comparable for both nano-formulated diclofenac doses and celecoxib compared with placebo. Nano-formulated lower dose diclofenac demonstrated a faster time to onset of analgesia compared with placebo and was numerically better than celecoxib. Results from this Phase 2 clinical trial suggest that use of this nano-formulated, lower dose formulation may provide clinical benefit in the relief of mild to moderate acute pain. These results are in line with the FDA directive to use the lowest effective NSAID dose. Research funded by Iroko Pharmaceuticals.
Acetaminophen,s (paracetamol) pharmacokinetics in human cerebrospinal fluid (CSF) is poorly understood. Various mechanisms of action are postulated including interaction with cyclooxygenase (COX) enzymes, and with cannabinoid, and/or serotonin receptors. Acetaminophen is metabolized to AM404, the N-arachidonoylphenolamine, conjugate of acetaminophen and arachidonic acid, by fatty acid amide hydrolase (FAAH). AM404 (an inhibitor of COX and agonist of transient receptor potential vanilloid type 1) inhibits the re-uptake of the endocannabinoid, anandamide, into pre-synaptic neurones, preventing its inactivation by FAAH. Acetaminophen is an ineffective analgesic in cannabinoid receptor 1 and FAAH knock-out mice, supporting this proposed mechanism of action. To date, AM404 in CSF following acetaminophen has not been reported. This single centre prospective randomised study was conducted to investigate intravenous acetaminophen,s CSF and plasma pharmacokinetics and metabolites in humans. Following research ethics committee approval and informed consent, CSF and blood was collected from 26 adult male subjects 10211 minutes following intravenous administration of 1G of acetaminophen (ParacetamolRFresenius-Kabi). Acetaminophen and its glucuronide and sulphate metabolites were measured by HPLC with UV detection. AM404 was measured by LC-MS/MS. Acetaminophen was measurable in CSF of all 26 subjects, first detectable at 5nmol. ml 1,10 minutes after administration, and with time, accumulating in CSF from 5 - 99nmol. ml 1. The glucuronide metabolite was detectable (1-15 nmol.ml 1) in 25 subjects and sulphate metabolites (0.1-1.8 nmol.ml 1) in 16 subjects. AM404 was measurable in the CSF (5 pmol.ml 1) from 10 minutes, in 17 subjects (1- 57 pmol.ml 1) with one outlier at 167 pmol.ml 1and in plasma in 7 subjects (2-65 pmol.ml 1). This is the first report of AM404 in human CSF following acetaminophen administration, and may support the hypothesis that AM404 is a mediator of acetaminophen,s action. The accumulation over time is potentially important finding and merits further study.
G Manvelian and B McCarberg; Iroko Pharmaceuticals, LLC, Philadelphia, PA
The Journal of Pain
F14 NSAIDS and Acetaminophen (392) A randomized, double-blind, placebo-controlled, efficacy and safety study of acetaminophen 1000 mg and acetaminophen 650 mg in postoperative dental pain D Qi, L May, B Zimmerman, P Peng, E Atillasoy, S Shelburne, G Simmons, J Brown, and S Cooper; McNeil Consumer Healthcare, Fort Washington, PA At a recent FDA Advisory Committee Meeting related to acetaminophen, the incremental benefit of acetaminophen 1000 mg versus 650 mg was questioned. This topic is very important since acetaminophen 1000 mg is one of the most widely used analgesics. This study uses the Dental Impaction Pain Model to evaluate the dose-response relationship of acetaminophen 1000 mg versus 650 mg. This randomized, double-blind, placebo-controlled study enrolled subjects who required surgical removal of impacted third molars. Subjects received a single dose of acetaminophen 1000 mg, acetaminophen 650 mg, or placebo when they had at least moderate pain and a Visual Analog Scale (VAS) score $50 out of 100 mm post-surgically. Pain intensity and pain relief were measured over 6h (VAS 0-100 mm). All 540 subjects (52%F, age 16-30y, 95% Caucasian) were included in the efficacy analysis. For the primary efficacy endpoint, the Sum of Pain Intensity Difference (SPID) and Total Pain Relief (TOTPAR) scores over 6h (SPRID6), acetaminophen 1000 mg demonstrated a 24% improvement compared to 650 mg (529.4 vs 427.3; p=0.001). Acetaminophen 1000 mg was also significantly superior to 650 mg (p#0.002) for SPID6, TOTPAR6, Time to Rescue analgesic, rescue rates through 4h (20% vs 32%) and 6h (29% vs 46%), and Subject Global Evaluation (49% vs 35% with very good or excellent rating). Both active treatments were significantly superior to placebo (p<0.001) for these efficacy endpoints. The 2 active treatments were similar for stopwatch Times to Confirmed First Perceptible and Meaningful Relief. AEs were reported by 18.5% of subjects, with no clinically important difference among the 3 treatment groups. No serious AEs were reported and no subjects discontinued due to an AE. This study provides definitive evidence of a positive and clinically relevant dose response between acetaminophen 650 mg and acetaminophen 1000 mg.
Abstracts (394) Efficacy of a novel (lozenge) delivery of flurbiprofen over 24 hours B Schachtel, S Aspley, P Berry, N Muir, A Shephard, T Shea, G Smith, and E Schachtel; New York University, New York, NY A lozenge containing 8.75 mg flurbiprofen in a sugar-based flavoured vehicle was developed to provide lasting relief of pharyngeal pain.1 We conducted a multi-center trial in the US to distinguish the analgesic effects of flurbiprofen from the demulcent effect of the sugar-based placebo after multiple doses taken over 24 hours (SPID24). Adult patients with acute sore throat were examined to confirm physical findings of pharyngitis (documented on the TonsilloPharyngitis Assessment, TPA). Three patient-reported outcomes, derived from common symptoms of patients with pharyngitis, were measured on 100-mm visual analog scales: sore throat pain when swallowing (assessed on the sore throat pain intensity scale, STPIS), difficulty swallowing (on the difficulty swallowing scale, DSS), and the sensation of a swollen throat (on the swollen throat scale, SwoTS). After being randomly assigned to flurbiprofen or placebo lozenges under double-blind conditions, patients used these three scales hourly while awake to rate their symptoms, taking additional lozenges as needed (one lozenge every 3-6 hours, up to five lozenges over 24 hours). Among 194 patients, between 18-61 years of age with TPA$4 and STPIS$63mm, there were no baseline differences between the two treatment groups in terms of any demographic or clinical feature, including the TPA, STPIS, SwoTS, or DSS (all p>0.82). Compared to patients taking the placebo lozenges over 24 hours, patients using flurbiprofen had 59% greater STPIS reduction (SPID24), 45% greater DSS reduction, 44% greater SwoTS reduction (all p<0.01). More patients taking flurbiprofen reported clinically meaningful relief of pain ($30%PID) than patients taking placebo (p<0.05). There were no serious or unexpected adverse events. We conclude that flurbiprofen 8.75 mg delivered in a lozenge provides safe, meaningful relief for patients with painful pharyngitis. 1.Schachtel, Clin Pharmacol Ther, 2002.) Supported by a grant from Reckitt Benckiser.
(393) A single centre prospective randomised study to investigate the cerebrospinal fluid (CSF) pharmacokinetics of intravenous acetaminophen in humans
(395) Acute pain relief by a proprietary, nano-formulated lower-dose oral diclofenac
V Mehta, C Sharma, J Long, S Shah, J Rahman, S Ayoub, D Perrett, and R Langford; St. Bartholomew’s Hospital London, London, United Kingdom
New NSAID formulations are being developed to improve tolerability while maintaining efficacy. The purpose of this clinical study was to evaluate time to onset of analgesia in an investigational, proprietary, nano-formulated, lower-dose, oral diclofenac compared with placebo in an acute pain model. This was a Phase 2, multicenter, randomized, double-blind, single-dose, parallel-group, active- and placebo-controlled study. Subjects (N=202) were 18-50 years old, had extraction of $2 third molars ($1 of which was a fully or partially impacted mandibular third molar), and experienced moderate to severe pain intensity #6 hours post-surgery. Subjects assessed baseline pain intensity before receiving a single dose of nano-formulated lower dose diclofenac 18mg or 35mg, celecoxib 400mg, or placebo, and pain intensity and pain relief from 15 minutes through 12 hours. There was a statistically significant (P<0.001) shorter time to onset of analgesia (mean6SE) for nano-formulated lower dose diclofenac 35mg (42min63.6), nano-formulated lower dose diclofenac 18mg (36min63.0), and celecoxib 400mg (54min64.2) compared with placebo (144min69.0). There was also a statistically significant improvement in mean time to first perceptible pain relief, mean time to meaningful pain relief, and mean time to peak pain relief for nano-formulated diclofenac 18mg and 35mg when compared with placebo. Tolerability data were comparable for both nano-formulated diclofenac doses and celecoxib compared with placebo. Nano-formulated lower dose diclofenac demonstrated a faster time to onset of analgesia compared with placebo and was numerically better than celecoxib. Results from this Phase 2 clinical trial suggest that use of this nano-formulated, lower dose formulation may provide clinical benefit in the relief of mild to moderate acute pain. These results are in line with the FDA directive to use the lowest effective NSAID dose. Research funded by Iroko Pharmaceuticals.
Acetaminophen,s (paracetamol) pharmacokinetics in human cerebrospinal fluid (CSF) is poorly understood. Various mechanisms of action are postulated including interaction with cyclooxygenase (COX) enzymes, and with cannabinoid, and/or serotonin receptors. Acetaminophen is metabolized to AM404, the N-arachidonoylphenolamine, conjugate of acetaminophen and arachidonic acid, by fatty acid amide hydrolase (FAAH). AM404 (an inhibitor of COX and agonist of transient receptor potential vanilloid type 1) inhibits the re-uptake of the endocannabinoid, anandamide, into pre-synaptic neurones, preventing its inactivation by FAAH. Acetaminophen is an ineffective analgesic in cannabinoid receptor 1 and FAAH knock-out mice, supporting this proposed mechanism of action. To date, AM404 in CSF following acetaminophen has not been reported. This single centre prospective randomised study was conducted to investigate intravenous acetaminophen,s CSF and plasma pharmacokinetics and metabolites in humans. Following research ethics committee approval and informed consent, CSF and blood was collected from 26 adult male subjects 10211 minutes following intravenous administration of 1G of acetaminophen (ParacetamolRFresenius-Kabi). Acetaminophen and its glucuronide and sulphate metabolites were measured by HPLC with UV detection. AM404 was measured by LC-MS/MS. Acetaminophen was measurable in CSF of all 26 subjects, first detectable at 5nmol. ml 1,10 minutes after administration, and with time, accumulating in CSF from 5 - 99nmol. ml 1. The glucuronide metabolite was detectable (1-15 nmol.ml 1) in 25 subjects and sulphate metabolites (0.1-1.8 nmol.ml 1) in 16 subjects. AM404 was measurable in the CSF (5 pmol.ml 1) from 10 minutes, in 17 subjects (1- 57 pmol.ml 1) with one outlier at 167 pmol.ml 1and in plasma in 7 subjects (2-65 pmol.ml 1). This is the first report of AM404 in human CSF following acetaminophen administration, and may support the hypothesis that AM404 is a mediator of acetaminophen,s action. The accumulation over time is potentially important finding and merits further study.
G Manvelian and B McCarberg; Iroko Pharmaceuticals, LLC, Philadelphia, PA