Two replicate randomized, double-blind, placebo-controlled trials of the time to onset of pain relief in the acute treatment of migraine with a fast-disintegrating/rapid-release formulation of sumatriptan tablets

BACKGROUND: The gastric stasis that commonly accompanies migraine headache may impair absorption of conventional oral tablets in the stomach. A fast-disintegrating/rapid-release formulation of sumatriptan has been developed to enhance tablet disintegration and drug dispersion and potentially improve absorption. OBJECTIVE: Two studies were conducted comparing the time to onset of relief from moderate or severe migraine pain with the fast-disintegrating/rapid-release formulation of sumatriptan tablets 50 and 100 mg and placebo. METHODS: These were 2 identically designed randomized, double-blind, parallel-group studies. Sumatriptan 50 or 100 mg or placebo was taken on an outpatient basis to treat a single moderate or severe migraine attack. Using a personal digital assistant, patients recorded the time of dosing and the time at which pain severity reached none or mild (ie, pain relief) or none (ie, pain free) in real time so that the time to onset of relief could be measured as a continuous variable. Onset of relief was defined as the earliest time point at which a statistically significant difference in pain relief compared with placebo was achieved and maintained through 2 hours after dosing. Before dosing and at pre-determined time points after dosing, patients also provided an assessment of migraine pain as none, mild, moderate, or severe. At a clinic visit within 1 week after treatment of the migraine attack, patients were queried about adverse events. For each adverse event, investigators recorded whether study medication was considered the cause. Data analyses were undertaken for each study individually and, in post hoc analyses of the primary and key secondary end points, on pooled data from both studies. RESULTS: The 2 studies comprised 2696 patients: 902 received sumatriptan 50 mg, 902 received sumatriptan 100 mg, and 892 received placebo. Patients' mean age ranged from 40.2 to 40.8 years across treatment groups, and most patients were female (83%-87%) and white (92%-93%). In the analysis of pooled data, sumatriptan tablets provided significantly more effective pain relief compared with placebo as early as 20 minutes after dosing with the 100-mg dose and as early as 30 minutes after dosing with the 50-mg dose (P < or = 0.05). Similar results were observed for the individual studies: in study 1, sumatriptan tablets were significantly more effective than placebo at 25 minutes with the 100-mg dose and at 50 minutes with the 50-mg dose; in study 2, sumatriptan tablets were significantly more effective than placebo at 17 minutes for the 100-mg dose and at 30 minutes for the 50-mg dose (P < or = 0.05). In the pooled data, the cumulative percentages of patients with pain relief by 2 hours after dosing were 72% for the 100-mg dose and 67% for the 50-mg dose, compared with 42% for placebo (P < or = 0.001, both sumatriptan doses vs placebo). The cumulative percentages of patients with a pain-free response by 2 hours were 47% for the 100-mg dose, 40% for the 50-mg dose, and 15% for placebo (P < or = 0.001, both sumatriptan doses vs placebo). In the individual studies, significantly more patients receiving either sumatriptan dose were migraine free 2 hours after dosing and had sustained pain relief and a sustained pain-free response over 24 hours compared with placebo (P < or = 0.001, both sumatriptan doses vs placebo). The only drug-related adverse events reported in >2% of patients in any treatment group in either study were nausea (both studies: 3% sumatriptan 100 mg, 2% sumatriptan 50 mg, 1% placebo) and paresthesia (study 1: <1% sumatriptan 100 mg, <1% sumatriptan 50 mg, 0% placebo; study 2: 3% sumatriptan 100 mg, 1% sumatriptan 50 mg, <1% placebo). CONCLUSIONS: In these studies, sumatriptan tablets in a fast-disintegrating/rapid-release formulation were effective for the acute treatment of moderate to severe migraine pain, were generally well tolerated, and achieved an onset of pain relief as early as 20 minutes for 100 mg and as early as 30 minutes for 50 mg.     

Multicenter,Double-Blind,Randomized, Placebo-Controlled,Parallel-Group Study of the Efficacy,Safety, and Tolerability of THC:CBD Extract and THC Extract in Patients with Intractable Cancer-Related Pain

This study compared the efficacy of a tetrahydrocannabinol:cannabidiol (THC:CBD) extract, a nonopioid analgesic endocannabinoid system modulator, and a THC extract, with placebo, in relieving pain in patients with advanced cancer. In total, 177 patients with cancer pain, who experienced inadequate analgesia despite chronic opioid dosing, entered a two-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial. Patients were randomized to THC:CBD extract (n = 60), THC extract (n = 58), or placebo (n = 59). The primary analysis of change from baseline in mean pain Numerical Rating Scale (NRS) score was statistically significantly in favor of THC:CBD compared with placebo (improvement of ?1.37 vs. ?0.69), whereas the THC group showed a nonsignificant change (?1.01 vs. ?0.69). Twice as many patients taking THC:CBD showed a reduction of more than 30% from baseline pain NRS score when compared with placebo (23 [43%] vs. 12 [21%]). The associated odds ratio was statistically significant, whereas the number of THC group responders was similar to placebo (12 [23%] vs. 12 [21%]) and did not reach statistical significance. There was no change from baseline in median dose of opioid background medication or mean number of doses of breakthrough medication across treatment groups. No significant group differences were found in the NRS sleep quality or nausea scores or the pain control assessment. However, the results from the European Organisation for Research and Treatment of Cancer Quality of Life Cancer Questionnaire showed a worsening in nausea and vomiting with THC:CBD compared with placebo (P = 0.02), whereas THC had no difference (P = 1.0). Most drug-related adverse events were mild/moderate in severity. This study shows that THC:CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids.     

Efficacy of oxycodone/paracetamol for patients with bone-cancer pain: a multicenter, randomized, double-blinded, placebo-controlled trial

What is known and Objective: Bone‐cancer pain is a common and refractory cancer pain. Opioids, on their own, do not control this type of pain well enough, and co‐analgesics are necessary. Methods: Patients with bone metastasis‐related pain at Numeric Rating Scale ≥4 were enrolled to this randomized placebo‐controlled trial. They had also received morphine or transdermal fentanyl patches for at least 1 week. During the 3‐day efficacy phase, patients received placebo or 1–3 tablets of oxycodone/paracetamol (5/325 mg), four times daily for 3 days. All patients kept a daily pain diary. The primary endpoint was the Pain Intensity Difference (PID). Secondary endpoints were cases of breakthrough pain and rescue morphine consumption. Additional analyses included the Short Form‐6 Dimensions (SF‐6D) quality‐of‐life scale and a general impression (GI) of patient satisfaction with treatment at the end of the phase. Results and Discussion: Of the 246 patients in the intent‐to‐treat set, 89·4% completed the 3‐day efficacy phase. PIDs were 0·9 and 0·3 in the oxycodone/paracetamol and placebo groups respectively, on day 1 (P < 0·001), and 1·5 and 0·3 respectively on day 3 (P < 0·001). Thirty‐eight patients in the treatment group, and 58 in the placebo group, suffered breakthrough pain on day 3 (P < 0·001). The SF‐6D score decreased to 21·2 ± 2·5 in the oxycodone/paracetamol group at the end of the phase (P = 0·001). In the oxycodone/paracetamol group, 67% rated GI as good, very good, or excellent. What is new and Conclusion: Patients with bone‐cancer pain, already on opioids, obtain clinically important, additional pain‐control, with regular oxycodone/paracetamol dosing.     

Pregabalin for Postherpetic Neuralgia: Placebo-Controlled Trial of Fixed and Flexible Dosing Regimens on Allodynia and Time to Onset of Pain Relief

Time to onset of pain relief and improvement in allodynia in 269 patients with postherpetic neuralgia was examined in a 4-week randomized trial comparing flexibly dosed pregabalin (150–600 mg/d), fixed-dose pregabalin (300 mg/d), and placebo. For each patient with clinically meaningful pain reduction (≥30%) at end point, onset of pain relief was defined as the first study day on which a patient reported ≥1-point reduction in pain relative to baseline. Average dose achieved was 396 mg/d in the flexible-dose group compared with 295 mg/d in the fixed-dose group. Median pain relief onset times were 3.5 days (flexible-dose), 1.5 days (fixed-dose), and >4 weeks (placebo). Compared with placebo, significantly more patients in both pregabalin treatment groups achieved ≥30% and ≥50% pain reduction at end point. Almost 95% of patients had brush-evoked allodynia, with 68% having moderate to severe allodynia (≥40/100 mm). At baseline, pain and allodynia were highly correlated. Independent of treatment assignment, improvement in pain and improvement in allodynia were significantly correlated. Allodynia could serve as a useful surrogate outcome measure in future studies. Pregabalin was significantly better than placebo in alleviating allodynia (flexible-dose reduction, 26 mm; fixed-dose, 21 mm; placebo, 12 mm). Discontinuation rates due to adverse events were more frequent in the fixed-dose group.PerspectiveA flexible-dose regimen reduces discontinuations, facilitates higher final doses, and results in a slightly greater pain relief. Allodynia (touch-evoked pain) can be of disabling severity and is present in nearly all patients with postherpetic neuralgia. Allodynia severity is correlated with pain severity and improvement in allodynia is correlated with clinical response.     

Efficacy and tolerability of sumatriptan tablets in a fast-disintegrating, rapid-release formulation for the acute treatment of migraine: results of a multicenter, randomized, placebo-controlled study

BACKGROUND: Sumatriptan tablets have been developed in a fast-disintegrating, rapid-release formulation designed to facilitate tablet disintegration and drug dispersion and to potentially mitigate the effects of gastric stasis that can accompany migraine. OBJECTIVE: This study was conducted to evaluate the efficacy and tolerability of sumatriptan 50- and 100-mg tablets in a fast-disintegrating, rapid-release formulation compared with those of placebo in patients with migraine. METHODS: This clinical trial had a randomized, double-blind, placebo-controlled, parallel-group design. Exclusion criteria included >6 migraines monthly during either of the 2 months before screening; uncontrolled hypertension; suspected or confirmed cardiovascular or cerebrovascular disease; and ophthalmic, basilar, or hemiplegic migraine. Sumatriptan 50 and 100 mg and placebo were taken on an outpatient basis during the mild-pain phase of a single migraine attack. Patients recorded details of the treated migraine on a diary card and rated pain severity immediately before dosing and 30 minutes, 45 minutes, 1 hour, and 2 hours after dosing using a 4-point scale (from 0 = none to 3 = severe). The primary efficacy end point was the proportion of patients who were pain free 2 hours after dosing. Additional efficacy end points were the proportion of patients who were pain free at 30 minutes, 45 minutes, and 1 hour after dosing; the proportion who were migraine free through 2 hours after dosing; and the proportion with a sustained pain-free response. RESULTS: Patients' mean age ranged from 39.7 to 41.5 years across the 3 groups, and the majority were women (79.7%-85.9%) and white (98.7%-100%). One hundred thirty-seven patients received sumatriptan 50 mg, 142 sumatriptan 100 mg, and 153 placebo. In the intent-to-treat population (n = 432), 51.1% of patients who received sumatriptan 50 mg and 66.2% of patients who received sumatriptan 100 mg were pain free 2 hours after dosing, compared with 19.6% of the placebo group (P < 0.001, each sumatriptan dose vs placebo). In an exploratory analysis, the 2-hour pain-free rate with sumatriptan 100 mg was significantly better than that with sumatriptan 50 mg (P = 0.007). Significantly more patients who received sumatriptan 100 mg were pain free compared with placebo at 30 minutes (P < 0.01), 45 minutes (P < 0.001), and 1 hour after dosing (P < 0.001); similar pain-free results were observed in patients who received sumatriptan 50 mg at 45 minutes (P < 0.05) and 1 hour (P = 0.01). In the per-protocol population (n = 313), pain-free efficacy 2 hours after dosing was 52.7% with sumatriptan 50 mg and 74.8% with sumatriptan 100 mg, compared with 21.0% with placebo (P < 0.001, each sumatriptan dose vs placebo). These rates were greater than those in the overall study population, approximately 12.0% of whom treated moderate or severe pain. The only drug-related adverse events reported in >/=3% of patients in any treatment group were nausea and vomiting (<1%, 5%, and 2% in the sumatriptan 50 and 100 mg and placebo groups, respectively), chest symptoms (2%, 3%, and 0%), and malaise and fatigue (1%, 3%, and <1%). No serious adverse events were reported. CONCLUSIONS: In this study, sumatriptan tablets in a fast-disintegrating, rapid-release oral formulation provided pain-free efficacy in the acute treatment of migraine. Efficacy was maximized with the 100-mg dose compared with the 50-mg dose, and by treating early when pain was mild. In the intent-to-treat population, 51.1% of patients who received sumatriptan 50 mg and 66.2% of those who received sumatriptan 100 mg were pain free 2 hours after dosing. In the per-protocol population, 3 of 4 patients taking the 100-mg tablets for mild pain within 1 hour of its onset were pain free at 2 hours. Sumatriptan tablets were generally well tolerated.     

Efficacy of the plantago major L. syrup on radiation induced oral mucositis in head and neck cancer patients: A randomized,double blind,placebo-controlled clinical trial

IntroductionOral mucositis is a complication of radiation therapy in cancer patients. We designed a trial to evaluate efficacy of plantago major on symptoms of radiation induced mucositis in cancer patients.MethodsIn this randomized double blind, placebo-controlled trial 23 patients received plantago major syrup as intervention group and 23 patients received placebo syrup as control group for 7 weeks. Outcome measures were severity of mucositis according to WHO scale and severity of patients' pain assessed by visual analogue scale.ResultsSeverity of mucositis were significantly lower in intervention group compared to placebo group (p value<0.05). Also patients in intervention group experienced significantly less pain compared to placebo group during radiotherapy period (p value<0.05)ConclusionPlantago major L syrup was effective on the reduction of the symptoms of radiation induced mucositis in patients with head and neck cancers.     

Preliminary Observations of a Novel Topical Oil with Analgesic Properties for Treatment of Acute and Chronic Pain Syndromes

Objective: Essential oxygen oil (OxyRub? from CreoMed Inc., Naples, FL, U.S.A.) is a novel topical analgesic currently commercially available in Europe and now available in the U.S.A. It represents an important alternative to other treatments (nonsteroidal anti‐inflammatory drugs, acetaminophen, menthol, camphor) for managing mild to moderate acute and chronic pain. Several clinical trials of this oil will be reviewed. Results: One large (n = 455) open‐label trial found essential oxygen oil to be a safe and effective analgesic for a broad range of patients with acute and chronic pain. In that study, 80% of patients reported that their pain decreased by more than 75%. A double‐blind placebo‐controlled study (n = 50) found significant pain reduction for tendonitis in patients using essential oxygen oil. Another trial of essential oxygen oil vs. placebo (n = 50) with various pain diagnoses found that 98% of patients with various pain diagnoses reported “very good” pain relief in the oil group compared to 48% in the placebo group. Furthermore, a randomized controlled trial in 10 women to measure oxygen microcirculatory effect in the skin showed an increased microcirculatory effect with improved oxygenation (increased partial pressure of oxygen in the skin) after application of essential oxygen oil. In all studies, the oil was well tolerated. None of these studies has been previously published. Conclusions: Based on studies completed, essential oxygen oil has shown itself to be safe, has demonstrated positive analgesic effects for the treatment of acute and chronic pain, and has improved oxygen content in the skin as well as other dermatological parameters.     

Efficacy and tolerability of sustained-release tramadol in the treatment of symptomatic osteoarthritis of the hip or knee: a multicenter, randomized, double-blind, placebo-controlled study

BACKGROUND: Opioid analgesics may be a useful alternative in patients with osteoarthritis who have not responded to first-line treatment with acetaminophen and in whom nonsteroidal anti-inflammatory drugs are contraindicated, ineffective, or poorly tolerated. OBJECTIVE: This study compared the efficacy and tolerability of tramadol LP 200 mg, a new once-daily,sustained-release formulation, with those of placebo in patients with osteoarthritis of the hip or knee. METHODS: In this multicenter, double-blind, placebo-controlled, parallel-group study, patients with osteoarthritis of the hip or knee (European League Against Rheumatism criteria) were randomized to receive either tramadol LP 200 mg once daily or placebo for 14 days. The primary efficacy end point was the change from baseline to the end of the study in scores on the Huskisson visual analog scale for pain. Secondary end points were change in the Lequesne functional discomfort index, global efficacy assessed by the patient and the investigator, time to improvement, and use of acetaminophen as rescue analgesic medication. Global tolerability was assessed by both patients and investigators at the end of the study The number and severity of adverse events occurring during the study and for 2 weeks thereafter were also recorded. RESULTS: Two hundred thirty patients (167 women, 63 men) were evaluable for efficacy and safety Demographic data for the tramadol and placebo groups were as follows: mean (SD) age, 67.1 (7.1) and 66.4 (92) years, respectively; female sex, 72.1% and 73.1%; and mean body weight, 74.7 (13.6) and 74.6 (14.8) kg. All patients were white. The completer analysis included 197 patients (85 tramadol, 112 placebo). Pain was significantly reduced in the tramadol LP group compared with the placebo group on day 7 (P = 0.002) and day 14 (P = 0.010). In the patient's assessment of global efficacy, 77.6% (66) of the tramadol LP group reported improvement by day 14, compared with 59.8% (67) of the placebo group; in the investigator's assessment, the efficacy of tramadol LP was rated very good or good for 612% (52) of patients, compared with 30.4% (34) for placebo. Improvement was reported before day 7 in 882% (75) of patients in the tramadol LP group, compared with 65.2% (73) in the placebo group (P = 0.021); the mean time from the initiation of treatment to reported improvement was 3 days for tramadol LP and 6 days for placebo (P < 0.001). Rates of response (defined as > or =30% pain reduction between days 0 and 14) were 64.7% (55) for tramadol LP and 50.0% (56) for placebo (P = 0.039); no rescue medication was used by 60.0% (51) of the tramadol LP group and 36.6% (41) of the placebo group (P - 0.001). One or more adverse event was reported by 45.0% (50) of the tramadol LP group, compared with 193% (23) of the placebo group (P < 0.001). As would be expected with an opiate agonist such as tramadol, the most common adverse events with this agent involved the gastrointestinal system (nausea, 22.5% [25] of patients; vomiting, 17.1% [19]) and the central nervous system (somnolence, 11.7% [13]). CONCLUSIONS: In this study, tramadol LP 200 mg was significantly more effective than placebo in alleviating pain in patients with osteoarthritis of the hip or knee. It appeared to be relatively well tolerated for an opioid compound.     

Dynamic cancer pain management outcomes: the relationship between pain severity, pain relief, functional interference, satisfaction and global quality of life over time

To examine the relationship between different cancer pain management outcomes over time, 74 patients with the worst cancer related pain rated as four or greater on an 11-point numeric scale were followed weekly with the Brief Pain Inventory (BPI), and the satisfaction questionnaire and global visual analogue scale quality of life (VASQOL) for 3 weeks. Univariate and multivariate regression analyses were performed at weekly time points. The analyses indicated that pain outcomes can be categorized into separate QOL and satisfaction paths linked by the worst pain severity. In the QOL path, the worst pain severity predicted a pain interference score, which consistently predicted VASQOL. For the satisfaction path, independent predictors were pain relief at Week 1, and worst pain severity and changes in worst pain severity at Week 2. No variables predicted satisfaction at Week 3. The data suggest that satisfaction and quality of life may be independent outcomes of pain management. The timing of assessment may itself be important.     

Pain-free results with sumatriptan taken at the first sign of migraine pain: 2 randomized, double-blind, placebo-controlled studies

OBJECTIVE: To evaluate the efficacy and tolerability of sumatriptan, 50-mg and 100-mg tablets, compared with placebo for treatment of migraine at the first sign of pain. PATIENTS AND METHODS: Two identical multicenter randomized, double-blind, placebo-controlled, single-attack studies were conducted from May through November 2000 in adults (aged 18-65 years). Patients treated migraine at the first sign of pain, while pain was mild, but not more than 2 hours after onset with oral sumatriptan, 50 mg or 100 mg, or matching placebo. The primary end point was pain-free relief at 2 hours after treatment with 50 mg of sumatriptan compared with placebo. RESULTS: There were 354 patients in study 1 and 337 patients in study 2. Significantly more patients treated with sumatriptan, 50 mg and 100 mg, were completely free from pain 2 and 4 hours after treatment vs patients treated with placebo (at 2 hours, 50% and 57% vs 29%; at 4 hours, 61% and 68% vs 30%; for both, P < .001). Also, significantly more patients treated with sumatriptan, 50 mg and 100 mg, were migraine-free (no pain or associated symptoms) vs those treated with placebo at 2 and 4 hours after treatment (at 2 hours, 43% and 49% vs 24%; at 4 hours, 54% and 63% vs 28%; for both, P < .001). The incidence of overall adverse events was low with the 50- and 100-mg dose of sumatriptan (placebo, 7%; sumatriptan at 50 mg, 14%; sumatriptan at 100 mg, 16%). CONCLUSIONS: Treatment of migraine at the first sign of pain with sumatriptan, 50-mg and 100-mg tablets, provides superior pain-free relief at 2 and 4 hours after treatment compared with placebo. Results of these studies suggest that sumatriptan at 100 mg may be more efficacious than at 50 mg when used in the early treatment paradigm. Because these studies were not powered to detect statistical differences between active doses, studies to investigate this finding are warranted.     

Single-dose intravenous tramadol for acute migraine pain in adults: a single-blind, prospective, randomized, placebo-controlled clinical trial

BACKGROUND: Tramadol, an atypical opioid, is a narcotic analgesic used for pain management. A search of the current literature found no studies examining the efficacy of intravenous tramadol on migraine pain. OBJECTIVE: The aim of this study was to investigate the efficacy and tolerability of a single dose of intravenous tramadol hydrogen chloride 100 mg in comparison with placebo in patients presenting with migraine. METHODS: Adult migraineurs admitted consecutively to the emergency department of the Kocaeli University Hospital were enrolled in this single-blind (patients), prospective, randomized, placebo-controlled clinical trial. Patients were randomized to receive a 30-minute infusion of either intravenous tramadol (n = 17; 100 mg in 100-mL saline) or placebo (n = 17; 100-mL saline). Pain response was defined as a decrease of visual analogue scale (VAS) (0-100 mm) score to <50% of the pretreatment (baseline) value and a decrease of 4-point verbal scale (FPVS) score (0 = none, 1 = mild, 2 = moderate, 3 = severe) to mild or none. Pain-free response was defined as a decrease of both VAS and FPVS scores to 0. Pain was assessed at baseline and at 30 minutes and 1 hour after treatment completion. Migraine symptoms (eg, photophobia, phonophobia, nausea, vomiting) and adverse events (AEs) were assessed at the same time. A follow-up was also conducted by phone 24 hours after treatment. RESULTS: Forty-four migraineurs were screened and 34 (28 women and 6 men; mean [SD] age, 39.5 [10.4] years; all were white) were enrolled in the study. Each group contained 11 patients with severe pain and 6 patients with moderate pain at baseline FPVS. At the end of 1 hour, pain response was reported by significantly more patients in the tramadol group than in the placebo group (12 [70.6%] vs 6 [35.3%]; P = 0.040). Pain-free response was reported by 5 (29.4%) patients in the tramadol group and 2 (11.8%) patients in the placebo group, although the difference was not statistically significant. Symptoms associated with migraine were also relieved in all patients reporting pain response. No AEs were observed. However, at the 24-hour follow-up, 1 patient in the tramadol group reported transient blurred vision and dizziness within the day of infusion. Headache recurrence was reported by 2 (16.7%) of the 12 patients with pain response in the tramadol group and 1 (16.7%) of 6 patients with pain response in the placebo group. CONCLUSIONS: Intravenous tramadol appeared to be more effective than placebo in pain response rate at the end of the first hour. The slow infusion of tramadol 100 mg in 100-mL saline solution was well tolerated in this group of adult migraineurs.     

Rofecoxib 50 mg and valdecoxib 20 or 40 mg in adults and adolescents with postoperative pain after third molar extraction: results of two randomized, double-blind, placebo-controlled, single-dose studies

OBJECTIVE: These studies assessed the comparative efficacy of rofecoxib and valdecoxib in the treatment of acute postoperative dental pain. METHODS: Two randomized, double-blind, placebo-controlled, single-dose studies were conducted in patients undergoing extraction of > or =2 third molars, with > or =1 mandibular impaction, who experienced moderate or severe pain after extraction. In study 1, patients were randomized in a 4:4:1 ratio to receive rofecoxib 50 mg, valdecoxib 20 mg, or placebo. In study 2, which was an exploratory study, patients were randomized in a 2:2:1 ratio to receive reofecoxib 50 mg, valdecoxib 40 mg, or palcebo. The primary efficacy end point was total pain relief at 12 hours (TOPAR12) for rofecoxib compared with valdecoxib 20 mg (study 1) or valdecoxib 40 mg (study 2). Tolerability was assessed based on clinical adverse experiences (AEs) and vital signs. These studies were performed before both agents were withdrawn from the market. RESULTS: In study 1, 200 patients were randomized to receive rofecoxib 50 mg, 201 to valdecoxib 20 mg, and 49 to placebo. In study 2, 51 patients were randomized to receive rofecoxib 50 mg, 50 to valdecoxib 40 mg, and 24 to placebo. The majority of patients in both studies were female (approximately 54%) and white ( approximately 66%), with a mean age of approximately 22 years and a mean weight of approximately 75 kg. Most (approximately 58%) patients reported experiencing moderate postoperative pain. In study 1, mean TOPAR12 scores were 30.7 for rofecoxib 50 mg, 28.9 for valdecoxib 20 mg, and 5.5 for placebo; in study 2, TOPAR12 scores were 27.0 for rofecoxib 50 mg, 28.6 for valdecoxib 40 mg, and 6.9 for placebo. In both studies, the active treatments were comparable in terms of the primary end point and were statistically superior to placebo (P<0.001). In study 1, rofecoxib was associated with a longer median time to use of rescue medication compared with valdecoxib 20 mg (>24 hours vs 23 hours 58 minutes; P=0.010) and a significantly smaller proportion of patients using rescue medication over 24 hours (35.0% vs 50.2%; P<0.001). In study 2, there were no significant differences in the median time to use of rescue medication or the proportion of patients using rescue medication between active treatments. There were no significant differences in total pain relief at 4 or 8 hours, patients' global assessment, onset of analgesia, or AEs between active treatments in either study. The incidence of clinical AEs in study 1 was similar for rofecoxib 50 mg, valdecoxib 20 mg, and placebo (39.5%, 36.8%, and 49.0%, respectively). In study 2, AEs occurred significantly less frequently with rofecoxib 50 mg compared with placebo (35.3% vs 70.8%, respectively; P<0.01); there was no significant difference between the rate of AEs with valdecoxib 40 mg (50.0%) and placebo. CONCLUSIONS: Rofecoxib 50 mg had comparable analgesic efficacy to valdecoxib 20 and 40 mg in these patients with pain after dental surgery. All active treatments were well tolerated.     

Transdermal buprenorphine in the treatment of chronic pain: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study

BACKGROUND: Buprenorphine, a potent opioid analgesic, has been available in parenteral and oral or sublingual(SL) formulations for >25 years. In 2001, the buprenorphine transdermal delivery system (TES) was introduced at 3 release rates (35, 52.5, and 70 microg/h) for the treatment of chronic cancer and noncancer pain. OBJECTIVE: This study compared the analgesic efficacy and tolerability of buprenorphine TES at a release rate of 35 microg/h with those of buprenorphine SL and placebo in patients with severe or very severe chronic cancer or noncancer pain. METHODS: This multicenter, double-blind, placebo-controlled, parallel-group trial was 1 of 3 Phase III studies involved in the clinical development of buprenorphine TDS. It comprised a 6-day open-label run-in phase in which patients received buprenorphine SL 0.8 to 1.6 mg/d as needed and a double-blind phase in which patients were randomized to receive 3 sequential patches containing buprenorphine TES 35 microg/h or placebo, each lasting 72 hours. Rescue analgesia consisting of buprenorphine SL 02-mg tablets was available as needed throughout the double-blind phase. The main outcome measures were (1) the number of buprenorphine SL tablets required in addition to buprenorphine TES during the double-blind phase compared with the placebo group and compared with the buprenorphine SL requirement during the run-in phase, and (2) patients' assessments of pain intensity, pain relief, and duration of sleep uninterrupted by pain in the double-blind phase compared with the run-in phase. Adverse events were documented throughout the study. RESULTS: One hundred thirty-seven patients were included in the double-blind phase (90 buprenorphine TES, 47 placebo). The buprenorphine TES group included 47 men and 43 women (mean [SD] age, 56.0 [12.1] years), and the placebo group included 23 men and 24 women (mean age, 55.7 [12.9] years). Forty-five patients had cancer-related pain and 92 had noncancer-related pain. The 2 treatment groups were comparable with respect to sex distribution, age, height, and body weight Patients receiving buprenorphine TES significantly reduced their consumption of buprenorphine SL tablets in the double-blind phase compared with patients receiving placebo (reduction of 0.6 [0.4] mg vs 0.4 [0.4] mg; P = 0.03). The relationship between the buprenorphine SL dose in the run-in phase and the number of buprenorphine SL tablets required in the double-blind phase was dose dependent in the active-treatment group only. Patients' assessments of pain intensity and pain relief suggested better analgesia with buprenorphine TES than with placebo, although the differences did not reach statistical significance. The proportion of patients who reported sleeping for >6 hours uninterrupted by pain in the double-blind phase compared with the run-in phase increased by 6.4% in the buprenorphine TDS group (35.6% vs 292%, respectively), compared with a decrease of 5.9% in the placebo group (40.4% vs 463%); no statistical analysis of sleep duration data was performed. Buprenorphine TDS was well tolerated, with adverse events generally similar to those associated with other opioids. The incidence of systemic adverse events in the double-blind phase was similar in the 2 treatment groups (28.9% buprenorphine TDS, 27.6% placebo), with the most common adverse events being nausea, dizziness, and vomiting. After patch removal, skin reactions (mainly mild or moderate pruritus and erythema) were seen in 35.6% of the buprenorphine TDS group and 25.5% of the placebo group. CONCLUSIONS: In the population studied, buprenorphine TDS provided adequate pain relief, as well as improvements in pain intensity and duration of pain-free sleep. It may be considered a therapeutic option for the treatment of moderate to severe chronic pain.     

A randomized controlled trial of oxygen for reducing nausea and vomiting during emergency transport of patients older than 60 years with minor trauma.

OBJECTIVE: To test the hypothesis that oxygen administration reduces nausea and vomiting in patients with minor trauma during ambulance transport. PATIENTS AND METHODS: This study, conducted from January to April 2000, consisted of 100 patients older than 60 years with minor trauma, who were randomly assigned to breathe air or 100% oxygen at 10 L/min through a facemask during ambulance transport. A paramedic, blinded to treatment, recorded vomiting episodes during transport. Patients, also blinded to treatment, rated their levels of pain, nausea, vomiting, anxiety, and overall satisfaction with their care on 100-mm visual analog scales, with greater values indicating more intense sensation. Results from the 2 groups were compared with chi2 or unpaired 2-tailed t tests and presented as means +/- SDs. RESULTS: Before randomization, patients subsequently assigned to receive oxygen had significantly greater pain and nausea. On arrival at the hospital, oxygen saturation was higher in the 50 patients given oxygen (99% +/- 1 % vs 96% +/- 2%; P<.001) than in the 50 patients who breathed air. Reported pain remained greater in the oxygen group. However, those given oxygen had less nausea (22 +/- 29 vs 54 +/- 38 mm; P<.001) and vomiting (4 vs 19 episodes; P<.001), lower heart rates (86 +/- 12 vs 94 +/- 13 beats/min; P<.001), and higher overall satisfaction scores (54 +/- 33 vs 33 +/- 23 mm; P<.001). CONCLUSION: Our results indicate that supplemental oxygen during ambulance transport reduced nausea scores by 50% and decreased vomiting 4-fold. Consequently, patients reported greater satisfaction with their care. Thus, we recommend that patients be given supplemental oxygen during ambulance transport.     

Effects of Ondansetron and Granisetron on Postoperative Nausea and Vomiting in Adult Patients Undergoing Laparoscopic Cholecystectomy: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Background: Postoperative nausea and vomiting (PONV) are common and potentially distressing adverse events (AEs) associated with surgery and anesthesia. In patients undergoing laparoscopic cholecystectomy (LC) without antiemetic prophylaxis, the incidence of PONV can be as high as 72%.Objective: The aim of this study was to investigate the prophylactic antiemetic effects of ondansetron and granisetron in patients undergoing LC when these agents are administered before the end of surgery.Methods: Patients classified by the American Society of Anesthesiologist's physical status as I or II who were scheduled for elective LC were included in this randomized, double-blind, placebo-controlled study. Anesthesia was induced with thiopental 5 mg/kg and fentanyl 2 μg/kg, and was maintained with isoflurane 1% to 3% in 50% oxygen and 50% nitrous oxide and fentanyl as needed. Approximately 20 to 30 minutes before the end of the surgery, the patients randomly received either IV ondansetron 100 μg/kg (group O), IV granisetron 40 μg/kg (group G), or normal saline (group P). Plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined preoperatively and 24 hours postoperatively. The patients were observed for 24 hours for PONV and other possible AEs. Postoperative pain intensity was determined using a 10-cm visual analogue scale. Four-point satisfaction scores were determined at 24 hours.Results: Ninety patients (69 women, 21 men) participated in the study. Demographic characteristics and operative data (duration of surgery and anesthesia and amount of intraoperative fentanyl) were similar in the 3 groups. The only AE reported by patients during the 24-hour observation period was nonsevere headache. The number of patients experiencing headache was similar in group P, group O, and group G (10 [33%] patients, 6 [20%], and 10 [33%], respectively). No significant changes were found in presurgical and postsurgical plasma levels of ALT and AST in any group. The mean (SD) satisfaction scores in group O and group G (3.0 [0.4] and 3.0 [0.6], respectively) were significantly higher than those in group P (2.5 [0.5]; both, P < 0.01). Immediately after surgery (period 0), significantly more patients in the placebo group (21 [70%]) experienced PONV compared with those in the ondansetron group (9 [30%]; P < 0.05) and the granisetron group (7 [23%]; P < 0.01). During the 24-hour observation period, a significantly greater number of patients in group P (18 [60%]) required a single dose of a rescue antiemetic drug compared with those in groups O and G (9 [30%] and 6 [20%], respectively; both, P < 0.01).Conclusions: Patients administered ondansetron 100 μg/kg or granisetron 40 μg/kg 20 to 30 minutes before the end of LC had significantly higher PONV control during the 24-hour postoperative observation period than patients receiving placebo. However, there were no significant differences between the active treatment groups in the incidence of PONV, patient satisfaction, or AEs.     

Comparative Evaluation of Oxygen‐Ozone Therapy and Combined Use of Oxygen‐Ozone Therapy with Percutaneous Intradiscal Radiofrequency Thermocoagulation for the Treatment of Lumbar Disc Herniation

Aim: To compare the efficacy of oxygen‐ozone therapy and the combined use of oxygen‐ozone therapy with percutaneous intradiscal radiofrequency thermocoagulation (PIRFT) for the treatment of contained lumbar disc herniation. Methods: Ninety‐one adult patients with low back pain secondary to contained lumbar disc herniation were randomly assigned into two groups. Ozone group received intradiscal oxygen‐ozone therapy (4 to 7 mL of oxygen ozone mixture); ozone‐PIRFT group received a combination of oxygen‐ozone therapy with PIRFT (radiofrequency lesioning at 80°C for 360 s). Outcome Measures: Primary outcome measures included a visual analog scale (VAS) for pain and the Oswestry disability index (ODI). Secondary outcome measures included pain relief, reduction of analgesic consumption, and patient's satisfaction. Clinical assessment of these outcome measures was performed at 2 weeks, 1 month, 3 months, 6 months, and 1 year after the procedure. Results: VAS scores and ODI were significantly decreased by both ozone and ozone‐PIRFT when compared with the baseline values at all points of follow‐up; however, ozone‐PIRFT produced a significant reduction in the VAS scores and ODI when compared to ozone at 2 weeks, 1 month, 3 months, 6 months, and 1 year follow‐up. Ozone‐PIRFT also resulted in a significant change in all secondary measures at all points of follow‐up, as compared with the ozone group. Conclusion: Ozone‐PIRFT is more efficacious than ozone alone in reducing pain scores, analgesic consumption, improving functional outcome, and satisfaction of patients with contained lumbar disc herniation.     

Evaluation of Aromatherapy in Treating Postoperative Pain: Pilot Study

Abstract:   This study compared the analgesic efficacy of postoperative lavender oil aromatherapy in 50 patients undergoing breast biopsy surgery. Twenty-five patients received supplemental oxygen through a face mask with two drops of 2% lavender oil postoperatively. The remainder of the patients received supplemental oxygen through a face mask with no lavender oil. Outcome variables included pain scores (a numeric rating scale from 0 to 10) at 5, 30, and 60 minutes postoperatively, narcotic requirements in the postanesthesia care unit (PACU), patient satisfaction with pain control, as well as time to discharge from the PACU. There were no significant differences in narcotic requirements and recovery room discharge times between the two groups. Postoperative lavender oil aromatherapy did not significantly affect pain scores. However, patients in the lavender group reported a higher satisfaction rate with pain control than patients in the control group ( P  = 0.0001).     

Efficacy and Safety of a Traditional Herbal Medicine, Hochu-ekki-to in the Long-term Management of Kikyo (Delicate Constitution) Patients with Atopic Dermatitis: A 6-month, Multicenter, Double-blind, Randomized, Placebo-controlled Study

Hochu-ekki-to is a traditional herbal (Kampo) medicine that has been shown to be effective for patients with Kikyo (delicate, easily fatigable, or hypersensitive) constitution. Previous case reports have suggested that this herbal drug was effective for a certain subgroup of patients with atopic dermatitis (AD). We aimed to evaluate the efficacy and safety of Hochu-ekki-to in the long-term management of Kikyo patients with AD. In this multicenter, double blind, randomized, placebo-controlled study, 91 Kikyo patients with AD were enrolled. Kikyo condition was evaluated by a questionnaire scoring system. All patients continued their ordinary treatments (topical steroids, topical tacrolimus, emollients or oral antihistamines) before and after their protocol entry. Hochu-ekki-to or placebo was orally administered twice daily for 24 weeks. The skin severity scores, total equivalent amount (TEA) of topical agents used for AD treatment, prominent efficacy (cases with skin severity score = 0 at the end of the study) rate and aggravated rate (more than 50% increase of TEA of topical agents from the beginning of the study) were monitored and evaluated. Seventy-seven out of 91 enrolled patients completed the 24-week treatment course (Hochu-ekki-to: n = 37, placebo: n = 40). The TEA of topical agents (steroids and/or tacrolimus) was significantly (P < 0.05) lower in the Hochu-ekki-to group than in the placebo group, although the overall skin severity scores were not statistically different. The prominent efficacy rate was 19% (7 of 37) in the Hochu-ekki-to group and 5% (2 of 40) in the placebo group (P = 0.06). The aggravated rate was significantly (P < 0.05) lower in the Hochu-ekki-to group (3%; 1 of 37) than in the placebo group (18%; 7 of 39). Only mild adverse events such as nausea and diarrhea were noted in both groups without statistical difference. This placebo-controlled study demonstrates that Hochu-ekki-to is a useful adjunct to conventional treatments for AD patients with Kikyo constitution. Use of Hochu-ekki-to significantly reduces the dose of topical steroids and/or tacrolimus used for AD treatment without aggravating AD.     

The efficacy and safety of venlafaxine in the prophylaxis of migraine

OBJECTIVE: To evaluate the efficacy and safety of venlafaxine in the prophylaxis of migraine. BACKGROUND: The efficacy of venlafaxine, which is selectively effective on the serotonergic and noradrenergic mechanisms, on various headaches and chronic pain syndromes has been demonstrated. To our knowledge, this is the first placebo-controlled, double-blind, randomized study of two different doses of venlafaxine for migraine treatment. METHODS: In this prospective study, 60 migraine patients without aura were randomly assigned to venlafaxine XR 75 mg, venlafaxine XR 150 mg, or placebo. The frequency of headache attacks, the severity and the duration of attacks, and analgesic use were monitored every 2 weeks for 2 months. Adverse events and patient satisfaction were also evaluated during these visits. At the end of the 2 months, global efficacy and tolerance were investigated. RESULTS: A significant difference was observed between the venlafaxine 150 mg and placebo groups in the number of headache attacks (P= .006). According to patient satisfaction comparisons, the active drug groups were significantly different when compared with placebo (P= .001 at visit 2 and visit 6). When the global efficacy was considered, 80% of patients in the 75-mg group and 88.2% of the patients in the 150-mg group evaluated treatment benefits as either good or very good. CONCLUSIONS: Venlafaxine was more effective than placebo and is safe and well tolerated as migraine prophylaxis.