Peak Analgesic Effect Research Articles

Magnesium sulfate versus dexmedetomidine as adjuvants to bupivacaine in postoperative epidural analgesia after total knee replacement

Objective The purpose of this study was to evaluate magnesium sulfate (MgSO4) or dexmedetomidine combined with bupivacaine versus bupivacaine for postoperative epidural analgesia in patients undergoing total knee replacement (TKR). Background Epidural analgesia after TKR is an effective widely used technique. Plain bupivacaine is one of the commonly used drugs. Several adjuvants are emerging to enhance its analgesic properties and decrease possible side effects. MgSO4 and dexmedetomidine are promising. Patients and methods This prospective randomized controlled study included 60 patients undergoing TKR who were randomized into three groups for postoperative epidural analgesia: group B bupivacaine, group BM bupivacaine plus MgSO4, and group BD bupivacaine plus dexmedetomidine. Patients received first dose in the postanesthetic care unit and top-up doses were administered if patients had visual analog score greater than 4. The three groups were compared as regards analgesic efficacy, hemodynamic stability, and possible complications. Results No statistically significant difference was found between the three groups as regards patient demographics (age, sex, and the American Society of Anesthesiologists score). Group BD showed superior analgesic criteria with onset at 8.25 ± 1.1 min versus 9.8 ± 1.5 min in group BM and 10.1 ± 1.3 min in group B (P = 0.0002). Earliest peak analgesic effect was noticed in group BD at 14.5 ± 1.2 min versus 16.5 ± 1.6 min in group BM and 16.3 ± 1.5 min in group B (P = 0.0003). Time to top-up dose was longest in group BD (230.4 ± 26.7 min) versus 283.6 ± 32.5 min in group BM and 362 ± 50.1 min in group B (P = 0.0001). Patients in the three groups were hemodynamically stable, apart from four patients in group BM who developed hypotension requiring support (P = 0.01). Conclusion Dexmedetomidine and MgSO4 are safe adjuvants to bupivacaine in post-TKR epidural analgesia. Dexmedetomidine has superior analgesic characters and hemodynamic stability.

Antinociception by fluoro-loxoprofen, a novel non-steroidal anti-inflammatory drug with less ulcerogenic effects, in rat models of inflammatory pain

The use of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammatory pain is limited by gastrointestinal complications. The rapid action of NSAIDs is associated with better pain relief. Previously, we demonstrated that fluoro-loxoprofen, a novel NSAID, has less ulcerogenic potential than other NSAIDs, attributable to its gastroprotective properties. The aim of this study was to investigate and compare the effects of fluoro-loxoprofen on inflammatory pain in rats with those of other NSAIDs. Oral administration of fluoro-loxoprofen, loxoprofen, and celecoxib resulted in equivalent analgesic action against yeast-induced inflammatory pain. The antinociceptive effect of fluoro-loxoprofen was maximized within 1 h after administration, which is less time than that observed for loxoprofen (2 h) and celecoxib (3 h). We confirmed that both fluoro-loxoprofen and loxoprofen suppressed the increases in prostaglandin E2 in inflamed paws. In addition to yeast-induced pain, fluoro-loxoprofen produced a similar effect against adjuvant-induced inflammatory pain, with faster peak analgesic effects than those observed for loxoprofen and celecoxib. Taken together, these results suggest that the analgesic effect of fluoro-loxoprofen is equivalent to that of loxoprofen and celecoxib. Moreover, the analgesic effect of fluoro-loxoprofen against inflammatory pain was more rapid than that of other NSAIDs, and this may be associated with its rapid absorption property.

Pharmacological evaluation of Mallotus philippinensis (Lam.) Muell.-Arg. fruit hair extract for anti-inflammatory, analgesic and hypnotic activity.

Objective:Recently, we observed wound healing activity of 50% ethanol extract of Mallotus philippinensis Muell. Arg (MP) fruit hairs extract (MPE). In several intestinal infections, localized inflammation is of common occurrence and hence we evaluated the anti-inflammatory, analgesic and hypnotic activity of MPE in different rat experimental models.Materials and Methods:Anti-inflammatory activity was evaluated by carrageenan (acute) and turpentine oil induced formalin (subacute) induced paw edema and while granuloma pouch (subacute) in rats. Analgesic and hypnotic activity of MPE was undertaken by tail-flick, hot-plate, and acetic acid-induced writhing tests while pentobarbitone-induced hypnotic potentiation in rats.Results:MPE at a dose of 200 mg/kg at 3 h after their administration showed inhibition of formalin-induced paw edema by 41.60% (P < 0.001) and carrageenan-induced paw edema by 55.30% (P < 0.001). After 7 days of treatments, MPE showed 38.0% (P < 0.001) inhibition against formalin-induced paw edema and reduced weight of turpentine-induced granuloma pouch by 29.6% (P < 0.01) and volume of exudates by 26.1% (P < 0.01), respectively. MPE (200 mg/kg) showed dose-dependent elevation in pain threshold and peak analgesic effect at 120 min as evidenced by increased latency period in tail flick method and increased reaction time in the hot-plate test while the reduction in the number of acetic acid-induced writhes by 45.7% (P < 0.001). The pentobarbitone-induced hypnosis model showed potentiation, as defined by increased duration of sleep in treated group rats as compared to control.Conclusion:Thus, the study revealed MPE is effective in reducing acute and subacute inflammation and showed effective and similar analgesic activity. This seemed to be safe in the treatment of pain and inflammation.

Clinical pharmacology of methadone in neonates and in their mothers. A review

The outstanding properties of methadone are its analgesic activity, its efficacy by oral route, its extended duration of action in suppressing of withdrawal symptoms in physically dependent individuals, and its tendency to show persistent effects with repeated administration. The analgesic activity of methadone, a racemate, is almost entirely the result of its R-methadone content. Respiratory depression is the chief hazard associated with methadone, and its peak respiratory depressant effects typically occur later, and persist for longer than its peak analgesic effect, particularly in the early dosing period. Methadone undergoes extensive metabolism in the liver and the major metabolic pathway is N-demethylation by CYP3A4 and CYP2B6. There is a remarkable interindividual variability in the rate of methadone metabolism. Mothers with opioid addiction are often placed on methadone before delivery in an attempt to reduce illicit opioid usage. Methadone is useful because it can be taken orally, only requires one or two daily doses and has a long-lasting effect. Weaning should not be attempted during pregnancy and, because of increased clearance, the dose of methadone may need to be increased in the last 3 months of pregnancy. Significant positive correlations were found for umbilical cord methadone concentrations, methadone mean daily dose, mean dose during the third trimester, and methadone cumulative daily dose. In conclusion, umbilical cord methadone concentrations were correlated to methadone dose. A total of 55-94% of infants born to opioid-dependent mothers in US show signs of opioid withdrawal. Methadone is useful to avoid use of opioid illicit drugs.

Inhibition of Carbonic Anhydrase Augments GABAA Receptor-Mediated Analgesia via a Spinal Mechanism of Action

Peripheral nerve injury (PNI) negatively influences spinal gamma-aminobutyric acid (GABA)ergic networks via a reduction in the neuron-specific potassium-chloride (K+-Cl–) cotransporter (KCC2). This process has been linked to the emergence of neuropathic allodynia. In vivo pharmacologic and modeling studies show that a loss of KCC2 function results in a decrease in the efficacy of GABAA-mediated spinal inhibition. One potential strategy to mitigate this effect entails inhibition of carbonic anhydrase activity to reduce HCO3–-dependent depolarization via GABAA receptors when KCC2 function is compromised. We have tested this hypothesis here. Our results show that, similarly to when KCC2 is pharmacologically blocked, PNI causes a loss of analgesic effect for neurosteroid GABAA allosteric modulators at maximally effective doses in naïve mice in the tail-flick test. Remarkably, inhibition of carbonic anhydrase activity with intrathecal acetazolamide rapidly restores an analgesic effect for these compounds, suggesting an important role of carbonic anhydrase activity in regulating GABAA-mediated analgesia after PNI. Moreover, spinal acetazolamide administration leads to a profound reduction in the mouse formalin pain test, indicating that spinal carbonic anhydrase inhibition produces analgesia when primary afferent activity is driven by chemical mediators. Finally, we demonstrate that systemic administration of acetazolamide to rats with PNI produces an antiallodynic effect by itself and an enhancement of the peak analgesic effect with a change in the shape of the dose-response curve of the α1-sparing benzodiazepine L-838,417. Thus, carbonic anhydrase inhibition mitigates the negative effects of loss of KCC2 function after nerve injury in multiple species and through multiple administration routes resulting in an enhancement of analgesic effects for several GABAA allosteric modulators. We suggest that carbonic anhydrase inhibitors, many of which are clinically available, might be advantageously employed for the treatment of pathologic pain states. PerspectiveUsing behavioral pharmacology techniques, we show that spinal GABAA-mediated analgesia can be augmented, especially following nerve injury, via inhibition of carbonic anhydrases. Carbonic anhydrase inhibition alone also produces analgesia, suggesting these enzymes might be targeted for the treatment of pain.

Comparison of post operative analgesia with Fentanyl and Sulfentanil via epidural route in thoracic and upper abdominal surgeries

Background: Post-operative analgesia has been considered very important for patient in terms of early mobilization and prevention of complications. Opioid analgesics have long been recognized as among the most effective treatments for pain. Opioids like fentanyl and sufentanil have been successfully used for post-operative analgesia by epidural route. Aims & Objective: To evaluate the efficacy of Sufentanil and Fentanyl for post-operative analgesia following thoracic and upper abdominal surgeries through epidural route. Materials and Methods: This was a prospective randomized parallel group study of 60 patients. They were divided into two groups randomly, F and SF. They were given fentanyl and sufentanil by epidural route for post-operative pain relief following upper abdominal and Thoracic surgery. Pain was assessed through Visual analogue scale. Pain Relief assessment, Pulse rate, BP, Respiratory rate, SPO2, Sedation Score and complication if any were assessed after administration of drug at 0,2,5,10,30,60,,120, 240 and 300 minutes. Result obtained were statistically analysed using students unpaired t test after calculating mean and standard deviation. Results: Patients in both group were comparable in terms of demography with male predominance, ASA grade and type of surgery performed. Onset of pain relief was 7.22 ± 1.82 minutes with fentanyl while 3.40±0.90 with sufentanil. Peak analgesic effect was achieved at 20.36 ± 3.44 minutes with fentanyl while it was quicker with sufentanil (9.3±2.4). Duration of analgesia was higher in sufentanil group (254.1 ± 53.80) in comparison to fentanyl (185.2 ± 43.33). Conclusion: Sufentanil via epidural route provides early onset, peak effect and longer duration of effective analgesia in comparison to Fentanyl. Use of either drug via epidural route provide safety and better stabilization as far as the hemodynamic and respiratory parameters were concerned. But, Patients with sufentanil remained sedated for longer duration than fentanyl.

Analgesic and hypnotic activities of Laghupanchamula: A preclinical study.

Background:In Ayurvedic classics, two types of Laghupanchamula -five plant roots (LP) have been mentioned containing four common plants viz. Kantakari, Brihati, Shalaparni, and Prinshniparni and the fifth plant is either Gokshura (LPG) or Eranda (LPE). LP has been documented to have Shothahara (anti-inflammatory), Shulanashka (analgesic), Jvarahara (antipyretic), and Rasayana (rejuvenator) activities.Aim:To evaluate the acute toxicity (in mice), analgesic and hypnotic activity (in rats) of 50% ethanolic extract of LPG (LPGE) and LPE (LPEE).Materials and Methods:LPEG and LPEE were prepared separately by using 50% ethanol following the standard procedures. A graded dose (250, 500 and 1000 mg/kg) response study for both LPEE and LPGE was carried out for analgesic activity against rat tail flick response which indicated 500 mg/kg as the optimal effective analgesic dose. Hence, 500 mg/kg dose of LPEE and LPGE was used for hot plate test and acetic acid induced writhing model in analgesic activity and for evaluation of hypnotic activity.Results:Both the extracts did not produce any acute toxicity in mice at single oral dose of 2.0 g/kg. Both LPGE and LPEE (250, 500, and 1000 mg/kg) showed dose-dependent elevation in pain threshold and peak analgesic effect at 60 min as evidenced by increased latency period in tail-flick method by 25.1-62.4% and 38.2-79.0% respectively. LPGE and LPEE (500 mg/kg) increased reaction time in hot-plate test at peak 60 min analgesic effect by 63.2 and 85.8% and reduction in the number of acetic acid-induced writhes by 55.9 and 65.8% respectively. Both potentiated pentobarbitone-induced hypnosis as indicated by increased duration of sleep in treated rats.Conclusion:The analgesic and hypnotic effects of LP formulations authenticate their uses in Ayurvedic system of Medicine for painful conditions.

Opioid chronopharmacology: influence of timing of infusion on fentanyl&amp;rsquo;s analgesic efficacy in healthy human volunteers

Chronopharmacology studies the effect of the timing of drug administration on drug effect. Here, we measured the influence of 4 timing moments on fentanyl-induced antinociception in healthy volunteers. Eight subjects received 2.1 μg/kg intravenous fentanyl at 2 pm and 2 am, with at least 2 weeks between occasions, and 8 others at 8 am and 8 pm. Heat pain measurements using a thermode placed on the skin were taken at regular intervals for 3 hours, and verbal analog scores (VAS) were then obtained. The data were modeled with a sinusoid function using the statistical package NONMEM. The study was registered at trialregister.nl under number NTR1254. A significant circadian sinusoidal rhythm in the antinociceptive effect of fentanyl was observed. Variations were observed for peak analgesic effect, duration of effect, and the occurrence of hyperalgesia. A peak in pain relief occurred late in the afternoon (5:30 pm) and a trough in the early morning hours (5:30 am). The difference between the peak and trough in pain relief corresponds to a difference in VAS of 1.3–2 cm. Only when given at 2 am, did fentanyl cause a small but significant period of hyperalgesia following analgesia. No significant changes were observed for baseline pain, sedation, or the increase in end-tidal CO2. The variations in fentanyl’s antinociceptive behavior are well explained by a chronopharmacodynamic effect originating at the circadian clock in the hypothalamus. This may be a direct effect through shared pathways of the circadian and opioid systems or an indirect effect via diurnal variations in hormones or endogenous opioid peptides that rhythmically change the pain response and/or analgesic response to fentanyl.

Hydromorphone efficacy and treatment protocol impact on tolerance and μ-opioid receptor regulation

This study examined the antinociceptive (analgesic) efficacy of hydromorphone and hydromorphone-induced tolerance and regulation of μ-opioid receptor density. Initially s.c. hydromorphone's time of peak analgesic (tail-flick) effect (45 min) and ED 50 using standard and cumulative dosing protocols (0.22 mg/kg, 0.37 mg/kg, respectively) were determined. The apparent analgesic efficacy ( τ) of hydromorphone was then estimated using the operational model of agonism and the irreversible μ-opioid receptor antagonist clocinnamox. Mice were injected with clocinnamox (0.32–25.6 mg/kg, i.p.) and 24 h later, the analgesic potency of hydromorphone was determined. The τ value for hydromorphone was 35, which suggested that hydromorphone is a lower analgesic efficacy opioid agonist. To examine hydromorphone-induced tolerance, mice were continuously infused s.c. with hydromorphone (2.1–31.5 mg/kg/day) for 7 days and then morphine cumulative dose response studies were performed. Other groups of mice were injected with hydromorphone (2.2–22 mg/kg/day) once, or intermittently every 24 h for 7 days. Twenty-four hours after the last injection, mice were tested using morphine cumulative dosing studies. There was more tolerance with infusion treatments compared to intermittent treatment. When compared to higher analgesic efficacy opioids, hydromorphone infusions induced substantially more tolerance. Finally, the effect of chronic infusion (31.5 mg/kg/day) and 7 day intermittent (22 mg/kg/day) hydromorphone treatment on spinal cord μ-opioid receptor density was determined. Hydromorphone did not produce any change in μ-opioid receptor density following either treatment. These results support suggestions that analgesic efficacy is correlated with tolerance magnitude and regulation of μ-opioid receptors when opioid agonists are continuously administered. Taken together, these studies indicate that analgesic efficacy and treatment protocol are important in determining tolerance and regulation of μ-opioid receptors.

Pharmacokinetics and Pharmacodynamics of Intranasal Versus Intravenous Fentanyl in Patients with Pain after Oral Surgery

Fentanyl, a short-acting synthetic opioid, has a pharmacokinetic profile suited to fast relief of brief episodic pain. To characterize the pharmacokinetic-pharmacodynamic correlation of intranasal and intravenous fentanyl in opioid-naïve patients undergoing third molar extraction. A double-blind, double-dummy, crossover design study was conducted, with patients randomized to receive 1 of 4 fentanyl doses (75, 100, 150, or 200 microg) by both the intravenous and intranasal routes. Venous fentanyl concentrations were determined for up to 180 minutes and pain scores were recorded up to 240 minutes postdose. Duration of effect and time to rescue medication were also recorded. The pharmacokinetics of intravenous fentanyl reflected a 2-compartment model with a clearance of approximately 1.5 L/min. There was moderate (<50%) between-subject variability (BSV; %CV [coefficient of variation]) in the systemic kinetics of fentanyl. Bioavailability of intranasal fentanyl was 89%, following first-order absorption, with a lag of approximately 5 minutes and a half-life of approximately 6.5 minutes. Interpatient absorption variability was approximately 30% BSV for all absorption parameters. Intranasal versus intravenous administration led to a delayed mean fentanyl time to maximum concentration (13 vs 6 min) and lower maximum concentration (1.2 vs 2.0 ng/mL). Analgesic effect lagged behind the venous fentanyl concentration, with a half-life of approximately 2.5 minutes as described by a fractional sigmoid maximum drug effect dynamic model. The concentration-analgesia relationship was steep, with a 50% effective concentration of 0.46 ng/mL (Hill coefficient 3.5). Intranasal onset and offset of analgesia were slightly delayed, principally due to the delay and lag in systemic absorption, with slightly lower peak analgesic effect, compared with intravenous fentanyl. Duration of effect was directly related to intranasal fentanyl dose, with pain scores returning to predose values at approximately 120 minutes (75 microg) to approximately 240 minutes (200 microg) after a single dose. Intranasal fentanyl showed kinetic and dynamic properties that are desirable for the management of acute, episodic (breakthrough) pain.

MK-0703 (a Cyclooxygenase-2 inhibitor) in Acute Pain Associated with Dental Surgery: A Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Dose-Ranging Study

MK-0703 is a selective cyclooxygenase-2 inhibitor investigated for the treatment of acute pain and inflammation. The purpose of this single-dose, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study was to compare MK-0703 12.5, 50, and 100 mg with ibuprofen 400 mg or placebo in patients who experienced moderate to severe pain after surgical removal of at least 2 third molars. Overall analgesic effect, duration of analgesic effect, time to onset of analgesic effect, peak analgesic effect, and tolerability were assessed over a 24-hour postdose period. The primary endpoint of this study was total pain relief over 8 hours postdose. The study included 121 patients (mean age, 23 yr); 16, 31, 28, 31, and 15 patients enrolled in the placebo, MK-0703 12.5 mg, MK-0703 50 mg, MK-0703 100 mg, and ibuprofen 400 mg groups, respectively. Both MK-0703 50 and 100 mg were significantly more effective than placebo for all endpoints (P < 0.01) and comparable with ibuprofen 400 mg. The onset of analgesic effect in the MK-0703 50 mg and 100 mg and ibuprofen 400 mg groups did not differ significantly from each other (P > 0.20). MK-0703 was generally well tolerated in single doses up to 100 mg. In summary, MK-0703 50 and 100 mg were efficacious in the treatment of postoperative dental pain and were indistinguishable from the active comparator, ibuprofen 400 mg.

Buprenorphine induces ceiling in respiratory depression but not in analgesia

We measured the effect of two weight adjusted i.v. doses (0.2 mg per 70 kg and 0.4 mg per 70 kg) of the potent opioid buprenorphine on analgesia and respiratory depression in healthy volunteers. The aim of the study was to compare buprenorphine's behaviour with respect to the occurrence of ceiling (or apparent maximum) in these typical micro-opioid protein-(MOP) receptor effects. Ten subjects (5 males) received 0.2 mg per 70 kg, 10 others (5 males) 0.4 mg per 70 kg i.v. buprenorphine. Steady-state inspired minute ventilation at a fixed end-tidal Pco(2) of 7 kPa was measured before drug infusion and at regular intervals after drug infusion. Experimental pain was induced using transcutaneous electrical stimulation and a gradually increasing current. Pain tolerance was measured at regular intervals before and after drug infusion. The studies lasted 8 h. After infusion of the drug ventilation showed a rapid decline and reached peak depression between 150 and 180 min after drug administration. This effect was dose-independent with respect to timing and magnitude. At peak respiratory depression minute ventilation was 13.1 (sd 1.8) litre min(-1) in the 0.2 mg group vs 12.0 (sd 1.3) litre min(-1) in the 0.4 mg group (n.s.). At buprenorphine 0.2 mg a small short-lived analgesic effect was observed with a maximum increase in pain tolerance current of 6.7 (sd 2.8) mA occurring at 75 min after drug administration. Peak analgesic effect was 29% above baseline current. In contrast, buprenorphine 0.4 mg caused a large and long-lived analgesic effect with a maximum increase in pain tolerance current of 23.8 (sd 7.4) mA occurring at 130 min after drug administration. Peak analgesic effect was 160% above baseline current (0.4 vs 0.2 mg, P<0.01). While buprenorphine's analgesic effect increased significantly, respiratory depression was similar in magnitude and timing for the two doses tested. We conclude that over the dose range tested buprenorphine displays ceiling in respiratory effect but none in analgesic effect.

Efficacy and tolerability of the cyclooxygenase-2 inhibitor L-791,515 compared with ibuprofen in patients with postoperative dental pain

Background L-791,515 (L)[(5S)-5-ethyl-3-isopropoxy-5-methyl-4-[4-(methylsulfonyl)phenyl]furan-2(5 H)-one] is a selective cyclooxygenase-2 inhibitor investigated for treatment of acute pain and inflammation. Methods This single-dose, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study compared L 12.5, 50, and 100 mg with ibuprofen 400 mg or placebo in patients who experienced moderate-to-severe pain after surgical removal of≥ 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. Results The study included 121 patients (mean age, 23 years); 16, 31, 28, 31, and 15 patients enrolled in the placebo, L 12.5 mg, L 50 mg, L 100 mg, and ibuprofen 400 mg groups, respectively. Both L 50 and 100 mg were significantly more effective than placebo for all parameters (p <0.01) and comparable to ibuprofen 400 mg. The onset of analgesic effect in the L 50-mg and 100-mg, and ibuprofen 400-mg groups did not differ significantly from each other (p>0.20). L was generally well tolerated in single doses up to 100 mg. Conclusions L 50 and 100 mg were efficacious in the treatment of postoperative dental pain and were indistinguishable from the active comparator, ibuprofen 400 mg. Clinical Pharmacology & Therapeutics (2005) 77, P52–P52; doi: 10.1016/j.clpt.2004.12.091

Analgesic and Hemodynamic Effects of a Single 7.5‐mg Intravenous Dose of Morphine in Patients with Moderate‐to‐Severe Postoperative Pain

To evaluate the analgesic and hemodynamic effects of a single dose of intravenous morphine 7.5 mg in patients experiencing moderate-to-severe postoperative pain, and to determine any gender differences in analgesic response. Randomized, double-blind, parallel-group, multicenter study. Postanesthesia care unit of a university teaching hospital. Eighty-eight patients who underwent total abdominal hysterectomy or prostatectomy. Thirty-seven patients received a single dose of morphine sulfate 7.5 mg and 51 patients received placebo, both administered intravenously for 1 minute. Overall, morphine had no significant effect on systolic or diastolic blood pressure, heart rate, oxygen saturation, or respiratory rate. Compared with baseline, morphine significantly reduced pain intensity at 2, 5, and 10 minutes after administration (p<0.05). The difference in pain intensity between patients who received morphine and those who received placebo, however, was significant only at the 5-minute time point (p<0.02). Patients receiving morphine also reported mild pain relief at 2 and 5 minutes after its administration. Peak analgesic effect was reported 2 minutes after its administration in three quarters of the patients. Significant gender differences also were observed in response to analgesic effect. In women, no significant differences in pain intensity were seen at any time between the morphine and placebo groups, whereas in men receiving morphine, pain intensity was significantly less at 2, 5, and 10 minutes compared with baseline and that seen in the placebo group. Women were generally more satisfied with their pain treatment than were men. A single 7.5-mg intravenous bolus dose of morphine did not appear to provide adequate reduction in perceived pain intensity in patients with moderate-to-severe postoperative pain. In addition, in contrast to the findings of other experimental pain studies, our data suggest that women are more tolerant of postoperative pain than are men.

Comparison of rofecoxib and a multidose oxycodone/acetaminophen regimen for the treatment of acute pain following oral surgery: a randomized controlled trial

SUMMARYObjective: To compare the efficacy of a single dose of rofecoxib 50 mg with a single dose of oxycodone/acetaminophen 10/650 mg over 6 h as well as with a multidose regimen of oxycodone/acetaminophen 10/650 mg followed by oxycodone/acetaminophen 5/325 mg over 24 h.Research design and methods: In this double-blind, randomized, two-phase study, patients with moderate to severe pain after surgical extraction of ≥ 2 third molars, including one mandibular impaction, were treated with rofecoxib 50 mg, oxycodone/acetaminophen 10/650 mg (single-dose phase) followed by 5/325 mg every 6 h as needed (multidose phase), or placebo. Patients rated their pain relief and intensity at 18 time points over 24 h. Efficacy was measured over 6 and 24 h by total pain relief (TOPAR), sum of pain intensity difference (SPID), and patient global assessment of response to therapy (PGART). Primary endpoint for the single dose comparison was TOPAR over 6 h; SPID was the key 24-h endpoint. Onset of analgesic effect, peak analgesic effect, and duration of analgesic effect were also evaluated. Adverse experiences were recorded.Results: 271 patients were randomized to treatment with rofecoxib (n = 121), oxycodone/acetaminophen (n = 120), or placebo (n = 30). For the single dose comparison, rofecoxib-treated patients achieved pain relief at least as effective as oxycodone/acetaminophen-treated patients as assessed by TOPAR6 (12.9 vs 11.3, 95% CI on difference = [–0.1, 3.2], p = 0.059). Patients also rated a single dose of rofecoxib as at least as effective as multidose oxycodone/acetaminophen over 24 h on SPID24 (21.9 vs 18.1, 95% CI on difference = [–1.0, 8.8], p = 0.122). Patients treated with oxycodone/acetaminophen had a shorter time to onset of analgesia than patients treated with rofecoxib (24 vs 35 min, p < 0.05). Patients in the active treatment groups achieved similar peak effects during the single-dose phase. Individuals treated with rofecoxib demonstrated a longer duration of analgesic effect than those treated with a single dose of oxycodone/acetaminophen. Patients on active treatment demonstrated better efficacy than patients on placebo on these prespecified endpoints ( p < 0.001 for both comparisons). Fewer rofecoxib than oxycodone/acetaminophen patients experienced adverse events (47.9 vs 75.8%, p < 0.001), including nausea (19.0 vs 42.5%, p < 0.001), vomiting (9.9 vs 24.2%, p < 0.01), and dizziness (7.4 vs 31.7%, p < 0.001).Conclusion: Patients treated with a single dose of rofecoxib 50 mg achieved an overall analgesic effect at least as effective as patients treated with a single-dose of oxycodone/acetaminophen 10/650 mg over 6 h and multidose oxycodone/acetaminophen over 24 h, with fewer adverse experiences of nausea ( p < 0.001), vomiting ( p < 0.01), and dizziness ( p < 0.001).

NSAIDs and acetaminophen: Comparison of opioid rescue use between Rofecoxib and Oxycodone/Acetaminophen in a double-blind, randomized trial of patients with acute pain

The selective cyclooxygenase (COX)-2 inhibitors, rofecoxib (ROF) and valdecoxib (VAL), have demonstrated efficacy comparable to NSAIDs in various pain models. This study compared the analgesic efficacy of single doses of ROF 50 mg (approved acute pain dose) with VAL 40 mg (twice the maximum approved dose) in postoperative dental pain. This randomized, double-blind study enrolled 125 patients to treatment with single doses of ROF 50 mg (N=51), VAL 40 mg (N=50), or placebo (N=24). Patient pain intensity and pain relief were assessed at 16 prespecified time points over 24 hours using standard scales. The primary endpoint was total pain relief over 12 hours (TOPAR12). Other measurements included patient global assessment at 12 hours, median time to confirmed perceptible pain relief (onset of analgesia), peak pain relief (peak analgesic effect), and median time to rescue medication (duration of effect). Baseline characteristics among the groups were similar. TOPAR12 scores (range 0-48) were similar (p=0.574) between ROF (27.0) and VAL (28.6). ROF and VAL, respectively, provided a similar responder rates on patient global assessment at 12 hours (76% vs 74%) and peak pain relief (3.1 vs. 3.0, range 0-4). Onset of analgesia was similar (<45 minutes) and was achieved by 78% of ROF and 74% of VAL patients. Analgesia duration was also similar (>24hrs). Improvement on all endpoints with active treatments compared to placebo were significant (p<0.001). Incidence of adverse experiences was 35% with ROF compared to 50% for VAL (NS). Adverse experience incidence compared to placebo (71%) was significantly less with ROF (p<0.01), but not with VAL. Placebo events were likely attributable to rescue medication. ROF 50 mg and VAL 40 mg provide similar analgesic effect in postsurgical dental pain setting and were generally well-tolerated.

NSAIDs and acetaminophen: Analgesic effect of rofecoxib 50 mg and valdecoxib 40 mg on postoperative pain: a randomized, placebo-controlled study

The selective cyclooxygenase (COX)-2 inhibitors, rofecoxib (ROF) and valdecoxib (VAL), have demonstrated efficacy comparable to NSAIDs in various pain models. This study compared the analgesic efficacy of single doses of ROF 50 mg (approved acute pain dose) with VAL 40 mg (twice the maximum approved dose) in postoperative dental pain. This randomized, double-blind study enrolled 125 patients to treatment with single doses of ROF 50 mg (N=51), VAL 40 mg (N=50), or placebo (N=24). Patient pain intensity and pain relief were assessed at 16 prespecified time points over 24 hours using standard scales. The primary endpoint was total pain relief over 12 hours (TOPAR12). Other measurements included patient global assessment at 12 hours, median time to confirmed perceptible pain relief (onset of analgesia), peak pain relief (peak analgesic effect), and median time to rescue medication (duration of effect). Baseline characteristics among the groups were similar. TOPAR12 scores (range 0-48) were similar (p=0.574) between ROF (27.0) and VAL (28.6). ROF and VAL, respectively, provided a similar responder rates on patient global assessment at 12 hours (76% vs 74%) and peak pain relief (3.1 vs. 3.0, range 0-4). Onset of analgesia was similar (<45 minutes) and was achieved by 78% of ROF and 74% of VAL patients. Analgesia duration was also similar (>24hrs). Improvement on all endpoints with active treatments compared to placebo were significant (p<0.001). Incidence of adverse experiences was 35% with ROF compared to 50% for VAL (NS). Adverse experience incidence compared to placebo (71%) was significantly less with ROF (p<0.01), but not with VAL. Placebo events were likely attributable to rescue medication. ROF 50 mg and VAL 40 mg provide similar analgesic effect in postsurgical dental pain setting and were generally well-tolerated.

Analgesic and Anti-Inflammatory Activity of Couroupita guianensis Aubl.

Objective: To study analgesic and anti-inflammatory activity of various extracts of flowers and bark of Couroupita guianensis Aubl. Materials and methods: Analgesic activity was evaluated using tail flick method and anti-inflammatory activity was screened by measuring the reduction in carrageenan induced hind paw oedema. The potency of various extracts of flower and bark were compared with (i) paracetamol (200 mg/kg) for analgesic and (ii) indomethacin (10 mg/kg) for anti-inflammatory activities. Results: All the extracts of C. guianensi s showed analgesic and anti-inflammatory activity. The peak analgesic effect of flower was seen after 1 h while bark extracts showed peak effect after 2 h. Maximum reduction in inflammation by the extracts was observed after 3 h. Conclusion: C. guianensis is almost equipotent to paracetamol in its analgesic activity and to indomethacin in its anti-inflammatory activity. So it can be recommended for further studies.

A comparison of rofecoxib versus celecoxib in treating pain after dental surgery: A single-center, randomized, double-blind, placebo- and active-comparator-controlled, parallel-group, single-dose study using the dental impaction pain model

Background: Rofecoxib and celecoxib, selective cyclooxygenase-2 inhibitors, have analgesic efficacy similar to that of nonselective nonsteroidal anti-inflammatory drugs. Objective: This study was designed to confirm earlier findings that the overall analgesic efficacy of rofecoxib 50 mg was superior to that of celecoxib 200 mg and to extend the comparison to include celecoxib 400 mg. Methods: In this single-center, randomized, double-blind, placebo- and active-comparator-controlled, parallel-group, single-dose study, patients who experienced moderate or severe pain after surgical extraction of at least 2 third molars received a single oral dose of either rofecoxib 50 mg, celecoxib 400 mg, celecoxib 200 mg, ibuprofen 400 mg, or placebo. Patients recorded scores of pain intensity, pain relief, and global assessment at prespecified time intervals throughout the 24-hour period after dosing. The end points were total pain relief (TOPAR) score over 8 hours (TOPAR8; primary end point), TOPAR score over 12 hours (TOPAR12), sum of pain intensity difference (SPID) over 8 and 12 hours (SPID8 and SPID12), patient's global assessment of study drug at 8 hours, time to confirmed perceptible pain relief (ie, time to onset of analgesic effect), peak pain intensity difference (PID), peak pain relief, time to first dose of rescue medication (ie, duration of analgesic effect), and percentage of patients using rescue medication. Results: A total of 482 patients (358 females, 124 males; mean age, 22.1 years) were enrolled. Rofecoxib 50 mg ( n = 151 patients) demonstrated significantly greater overall analgesic efficacy compared with celecoxib 400 mg ( n = 151), as measured by TOPAR8 (least squares mean [SE] 17.2 [0.8] vs 15.0 [0.8]; P < 0.05) and TOPAR12 (25.3 [1.2] vs 21.0 [1.2]; P < 0.05), as well as a significantly longer duration of analgesic effect ( P < 0.05). Time to onset of analgesic effect and peak analgesic effect were similar for rofecoxib 50 mg and celecoxib 400 mg. Rofecoxib also showed significantly greater overall analgesic efficacy than did celecoxib 200 mg ( n = 90) including greater TOPAR8 scores (17.2 [0.8] vs 11.5 [1.1]; P < 0.001), faster onset of analgesic effect ( P < 0.001), greater peak analgesic effect ( P < 0.001 for peak pain relief and peak PID), and longer duration of analgesic effect ( P < 0.001). The overall analgesic efficacy of rofecoxib 50 mg was similar to that of ibuprofen 400 mg ( n = 45), except that the duration of analgesic effect of rofecoxib 50 mg was significantly longer ( P < 0.001). All active treatments produced significantly greater overall analgesic efficacy compared with that of placebo ( P < 0.001 for all scores [TOPAR8, TOPAR12, SPID8, SPID12, and patient's global assessment] for all study drugs). The adverse-events (AE) profile was generally similar in all treatment groups. The 3 most common AEs were nausea, postextraction alveolitis, and vomiting. Conclusions: In this study, rofecoxib 50 mg provided generally superior overall analgesic efficacy compared with that of celecoxib 400 and 200 mg, including a significantly longer duration of analgesic effect. The overall analgesic efficacy of rofecoxib 50 mg was generally similar to that of ibuprofen 400 mg, except for a significantly longer duration of analgesic effect.

Comparison of the analgesic efficacy of rofecoxib and enteric-coated diclofenac sodium in the treatment of postoperative dental pain: A randomized, placebo-controlled clinical trial

Background: Rofexocib is a selective cyclooxygenase-2 inhibitor indicated for the treatment of acute pain, with similar analgesic efficacy to ibuprofen and naproxen sodium. Diclofenac sodium is the most commonly prescribed nonsteroidal anti-inflammatory drug worldwide; it is effective for the treatment of pain as well as the signs and symptoms associated with the painful conditions of osteoarthritis and rheumatoid arthritis. Objective: The aim of this study was to compare the analgesic efficacy and tolerability of a single dose of rofexocib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg, and placebo over 8-hour and 24-hour periods in patients with moderate to severe pain after oral surgery. Methods: In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate to severe pain after the surgical extraction of ≥2 third molars were randomized to receive a single dose of rofexocib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given every 8 hours), or placebo. Patients rated pain intensity, pain relief, and global assessments at prespecified times throughout the 24-hour period after initial dosing. Overall analgesic efficacy was determined by total pain relief over 8 hours (TOPAR8) and 24 hours (TOPAR24) and patient global assessments at 8 and 24 hours. Onset of analgesic effect was determined by using the 2-stopwatch method for confirmed perceptible pain relief. Peak analgesic effect was the maximum pain relief attained during the first 8 hours. The duration of analgesic effect was determined by median time to rescue analgesia use. Results: A total of 305 patients were randomized to treatment: 121 received rofexocib, 121 received diclofenac sodium, and 63 received placebo. The baseline demographics were similar among the groups. Overall, 61.3% experienced moderate pain and 38.7% experienced severe pain; 53.1% were female; and the mean age was 23.4 years. The overall analgesic efficacy, as assessed by TOPAR8, of a single dose of rofecoxib 50 mg was significantly greater than a single dose of enteric-coated diclofenac sodium 50 mg (20.5 vs 8.2) and placebo (20.5 vs 5.9). Patient global assessment at 8 hours was also significantly better for rofecoxib compared with enteric-coated diclofenac sodium and placebo. TOPAR24 was significantly greater for a single dose of rofecoxib 50 mg compared with 3 doses of enteric-coated diclofenac sodium 50 mg (64.1 vs 25.1) and placebo (64.1 vs 19.2). At 24 hours, the patient global assessment for rofecoxib was significantly better than that achieved with enteric-coated diclofenac sodium and placebo. The onset of analgesic effect was significantly more rapid for rofecoxib than for enteric-coated diclofenac sodium and placebo (median times: 31 minutes, >4 hours, and >4 hours, respectively). The peak analgesic effect was significantly greater for rofecoxib compared with enteric-coated diclofenac sodium (3.2 vs 1.5) and placebo (3.2 vs 1.1). The duration of analgesia was significantly longer for rofecoxib than enteric-coated diclofenac sodium (median times: >24 hours vs 1 hour and 37 minutes) and placebo (>24 hours vs 1 hour and 37 minutes). Enteric-coated diclofenac sodium was numerically greater than placebo for the key end points measuring overall efficacy (total pain relief and patient global assessment), but diclofenac sodium did not provide as much analgesic effect as expected for a drug effective for pain, osteoarthritis, and rheumatoid arthritis and did not differ significantly from placebo. Overall, both rofecoxib and enteric-coated diclofenac sodium were generally well tolerated, although the rofecoxib group had a significantly lower incidence of clinical and drug-related adverse events than the enteric-coated diclofenac sodium group. Conclusions: A single 50-mg dose of rofecoxib provided greater overall analgesic efficacy over 8 hours, more rapid onset of analgesia, greater maximum analgesic effect, and longer duration of effect than a single 50-mg dose of enteric-coated diclofenac sodium in patients with moderate to severe pain associated with oral surgery. Compared with 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg every 8 hours), a single dose of rofecoxib 50 mg provided greater overall analgesic efficacy over 24 hours.