Tramadol/acetaminophen combination tablets for the treatment of chronic lower back pain: a multicenter,randomized, double-blind,placebo-controlled outpatient study

BACKGROUND: Tramadol and acetaminophen (APAP) have both shown efficacy in the treatment of lower back pain. The combination of these 2 agents has demonstrated synergistic analgesic action in animal models at specific ratios. OBJECTIVE: This study assessed the long-term (3-month) efficacy and safety of tramadol 37.5 mg/APAP 325 mg combination tablets in the treatment of chronic lower back pain. METHODS: Patients with at least moderate lower back pain (pain visual analog [PVA] score >/=40 mm on a 100-mm scale) were randomized to receive up to 8 tablets of tramadol/APAP per day or placebo for 91 days. Medication was titrated from 1 to 4 tablets/d by day 10. The primary efficacy measure was PVA score at the final visit. Secondary measures included scores on the Pain Relief Rating Scale (PRRS), Short-Form McGill Pain Questionnaire (SF-MPQ), Roland Disability Questionnaire (RDQ), and 36-Item Short-Form Health Survey (SF-36); the incidence of discontinuation due to insufficient pain relief (Kaplan-Meier analysis); and overall assessments of medication by the patients and investigators. RESULTS: Three hundred eighteen patients (161 tramadol/APAP, 157 placebo) were included in the intent-to-treat population, defined as all patients who took >/=1 dose of study medication and had >/=1 postrandomization efficacy measurement. The mean age of the study population was 53.9 years, 63.2% were female, 90.3% were white, and the mean baseline PVA score was 70.0 mm. There were no significant differences between groups at baseline. Tramadol/APAP significantly improved final PVA scores (P = 0.015) and final PRRS scores (P < 0.001) compared with placebo. Tramadol/APAP also significantly improved RDQ scores (P 相似文献   

A double-blind,single-dose comparison of the analgesic efficacy of tramadol/acetaminophen combination tablets,hydrocodone/acetaminophen combination tablets,and placebo after oral surgery

BACKGROUND: Improved clinical outcomes have been documented with combinations of oral analgesic agents, particularly those with complementary activities. However, because not all combinations or dose ratios lead to enhanced analgesia or reduced adverse events (AEs), each combination and dose ratio must be evaluated individually in carefully designed preclinical and clinical trials. OBJECTIVE: The goal of the study was to compare the efficacy and safety of 37.5 mg tramadol/325 mg acetaminophen tablets (T/APAP), 10 mg hydrocodone bitartrate/650 mg acetaminophen tablets (HC/APAP), and placebo in the treatment of postoperative dental pain. METHODS: This was a single-center, double-blind, parallel-group, placebo- and active-controlled study in adults with at least moderate pain (score > or =50 on a 100-mm pain visual analog scale) after extraction of > or =2 impacted third molars. Patients were randomized to receive 1 or 2 T/APAP tablets, 1 HC/APAP tablet, or placebo. Scores for hourly pain relief (PAR), pain intensity difference (PID), and combined PAR and PID (PRID) were based on reported pain at 30 minutes and each successive hour for 8 hours. Primary efficacy measures were summary pain intensity and pain relief scores (total pain relief [TOTPAR], sum of pain intensity differences [SPID], and sum of pain relief and pain intensity differences [SPRIDI) for 0 to 4 hours, 4 to 8 hours, and 0 to 8 hours. Secondary efficacy measures were hourly PAR, PID, and PRID scores; onset and duration of pain relief; time to remedication with a supplemental analgesic agent; and patients' overall assessment of medication. RESULTS: Two hundred adults took part in the study (50 per treatment group) and were included in the efficacy and safety analyses. T/APAP 75/650 mg and HC/APAP were statistically superior to placebo on the primary efficacy measures of TOTPAR, SPID, and SPRID (P < or = 0.024), as well as on hourly PAR, PID, and PRID over 6 hours (P < or = 0.045). All active treatments were statistically superior to placebo in terms of onset of pain relief (P < or = 0.001), duration of pain relief (P < or = 0.024), time to remedication (P < 0.001), and patients' overall assessment of medication (P < 0.001). A statistically significant dose response with T/APAP (2 tablets > 1 tablet > placebo) was seen for TOTPAR, SPID, and SPRID (all, P < or = 0.018). The median time to onset of pain relief was approximately 34.0 minutes with 2 T/APAP tablets and 25.4 minutes with HC/APAP. Although the median time to onset of pain relief was shorter with HC/APAP, two T/APAP tablets had comparable efficacy to HC/APAP. The median time to remedication with a supplemental analgesic agent was 169.0 minutes in the T/APAP 75/650 mg group and 204.0 minutes in the HC/APAP group. However, the duration of pain relief, as defined by time to remedication, was not significantly different between these 2 groups. The overall incidence of AEs was lower with T/APAP (0% treatment-related AEs) than with HC/APAP (4%) or placebo (10%). The incidence of nausea (18% T/APAP, 36% HC/APAP) and vomiting (12% T/APAP, 30% HC/APAP) was approximately 50% lower with 2 T/APAP tablets than with HC/APAP (P < 0.05). CONCLUSIONS: T/APAP tablets provided effective, rapid (< or = 34 minutes), dose-dependent analgesia for the treatment of postoperative dental pain. Two T/APAP tablets provided analgesia comparable to that provided by HC/APAP with better tolerability.     

Tramadol 37.5-mg/acetaminophen 325-mg combination tablets added to regular therapy for rheumatoid arthritis pain: a 1-week, randomized, double-blind, placebo-controlled trial

OBJECTIVE: This study evaluated the efficacy and tolerability of tramadol 37.5-mg/acetaminophen 325-mg combination tablets (tramadoUAPAP) as add-on therapy in subjects with rheumatoid arthritis (RA) pain that was inadequately controlled by NSAIDs and disease-modifying antirheumatic drugs alone. METHODS: Subjects in this multicenter, double-blind trial were randomized in a 3:1 ratio to receive 1 tramadol/ APAP tablet TID or a matching placebo for 1 week. Stable doses of previous medications were continued during the study. The primary efficacy variable was the mean daily pain relief score over 1 week, measured on a 6-point scale (4 = complete; ' = a lot; 2 = some; 1 = a little; 0 = none; -1 = worse). Secondary outcomes included the mean daily pain intensity score, measured on a 100-mm visual analog scale (VAS) (from 0 mm = no pain to 100 mm = extreme pain); pain intensity and pain relief at day 7; subjects' and investigators' mean overall assessments of study drug, measured on a Likert scale (from 2 = very good to -2 = very poor); and subjects' assessments of 8 aspects of physical function (measured on the Health Assessment Questionnaire). RESULTS: Of 277 subjects randomized to treatment, 267 (201 tramadol/APAP, 66 placebo) were included in the intent-to-treat population. Mean (SD) daily pain relief scores at the end of 1 week were significantly greater in the tramadol/APAP group compared with the placebo group (1.04 [0.89] vs 0.78 [0.80], respectively; P = 0.037), and mean daily pain intensity scores at the end of 1 week were significantly lower (47.23 [19.96] vs 53.81 [16.59]; P = 0.018). Physical function at the end of 1 week did not differ significantly between tramadol/APAP and placebo. Two hundred seventy-two subjects (205 tramadol/APAP, 67 placebo) were evaluable for tolerability. One hundred thirty-three of these subjects had at least 1 adverse event. The incidence of adverse events was significantly higher in the tramadol/APAP group than in the placebo group (57.6% vs 22.4%; P < 0.001). Discontinuations due to adverse events occurred in 19.0% of the tramadol/APAP group and 3.0% of the placebo group (P = 0.001). Of 213 treatment-related adverse events in tramadol/APAP subjects, nausea (34.1%) was the most frequent, followed by dizziness (20.0%) and vomiting (15.6%). One serious adverse event--chest discomfort, nausea, and vomiting after taking study medication-occurred in a subject receiving tramadol/APAP The symptoms resolved 1 day after discontinuing tramadol/APAP. CONCLUSIONS: In this study, tramadol/APAP used as add-on therapy in subjects with symptomatic RA was associated with a significant improvement in pain relief and a significant reduction in pain intensity compared with placebo, with no improvement in physical function. Use of tramadol/APAP may be considered when analgesics are needed in addition to conventional NSAIDs and disease-modifying antirheumatic drugs in subjects with RA.     

Tramadol/acetaminophen combination tablets for the treatment of osteoarthritis flare pain: a multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group, add-on study

BACKGROUND: In a flare of osteoarthritis (OA) pain, increasing the dose of standard anti-inflammatory or routine analgesic drugs may not be practical because of an increased incidence of side effects. In patients achieving inadequate pain relief from traditional non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX)-2-selective inhibitors, it may be appropriate to add an analgesic agent with a different mechanism of action, thereby targeting multiple components of the pain pathway. OBJECTIVE: The addition of tramadol/acetaminophen tablets to existing therapy was compared with the addition of placebo in the treatment of OA flare pain. METHODS: This was a multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group, add-on study. Patients received 1 or 2 tramadol/acetaminophen (37.5 mg/325 mg) tablets QID or matching placebo for 10 days in addition to ongoing NSAID or COX-2-selective inhibitor therapy. The primary outcome measures were average daily pain intensity and average daily pain relief scores from days 1 through 5. RESULTS: Three hundred eight patients were randomized to tramadoUacetaminophen (n = 197) or placebo (n = 111) and were followed for up to 10 days. Patients had a mean (+/-SD) age of 60.1 +/- 9.87 years, and were predominantly female (71.8%) and white (87.7%). Their mean (+/- SD) pain visual analog score at baseline was 73.2 +/- 11.8 mm, and their mean pain intensity score was 2.4 +/- 0.5 (on a scale from 0 = none to 3 = severe). Average daily pain intensity and pain relief scores were significantly improved with tramadol/acetaminophen compared with placebo on the primary assessment of efficacy from days 1 through 5 (both, P < 0.001) and on the assessment of efficacy from days I through 10 (both, P < 0.001) Tramadol/acetaminophen was significantly superior to placebo on the patients' and physicians' overall assessments of medication (both, P < 0.001) and on 3 of 4 subscales (pain [P = 0.004], physical function [P = 0.013], and overall [P = 0.008]) of the Western Ontario and McMaster Universities Osteoarthritis Index Questionnaire. The most common treatment-emergent adverse events with tramadol/acetaminophen were nausea, vomiting, and dizziness. No serious adverse events were reported in the tramadol/acetaminophen group. CONCLUSION: In this study, addition of tramadol/acetaminophen to NSAID or COX-2-selective inhibitor therapy was well tolerated and effective in the treatment of OA flare pain.     

A double-blind placebo-controlled comparison of tramadol/acetaminophen and tramadol in patients with postoperative dental pain

The objective of this study was to compare the analgesic efficacy of tramadol/acetaminophen (APAP) (total dose 75 mg/650 mg) and tramadol (total dose 100 mg) for the control of pain after oral surgery. A total of 456 patients with moderate-to-severe pain within 5 h after extraction of two or more third molars were randomized to receive two identical encapsulated tablets containing tramadol/APAP 37.5 mg/325 mg, tramadol 50 mg, or placebo. Tramadol/APAP was superior to tramadol (P < 0.001) or placebo (P < 0.001) on all efficacy measures: total pain relief (PAR) over 6 h (7.4, 2.5, and 1.5, respectively, on a scale of 0-24); sum of pain intensity differences (PIDs) (3.1, 0.6, and 0.1, respectively, on a scale of -6 to 18); and sum of PAR and PID (10.5, 3.1, and 1.6, respectively, on a scale of -6 to 42). Median times to onset of perceptible and meaningful PAR were 37.6 and 126.5 min, respectively, for the tramadol/APAP group (P < 0.001) for each, compared with tramadol and placebo arms). The most common adverse events with active treatment were nausea, dizziness, and vomiting; these events occurred more frequently in the tramadol group than in the tramadol/APAP group. This study established the superiority of tramadol/APAP 75 mg/650 mg over tramadol 100 mg in the treatment of acute pain following oral surgery.     

Tramadol/acetaminophen for the treatment of acute migraine pain: findings of a randomized, placebo-controlled trial

OBJECTIVE: To compare tramadol/acetaminophen (APAP) and placebo for the management of acute migraine pain. BACKGROUND: Tramadol/APAP tablets reduced moderate-to-moderately severe acute pain in controlled studies of other painful conditions. METHODS: This randomized, double-blind, placebo-controlled, parallel group study enrolled adults with migraine pain as per International Headache Society criteria. Subjects took tramadol/APAP (total dose, 75 mg/650 mg) or placebo for a typical migraine with moderate-to-severe pain. Severity of pain and migraine-related symptoms were recorded before study medication and at 0.5, 1, 2, 3, 4, 6, and 24 hours after study medication. RESULTS: Efficacy analyses included 305 subjects (154 tramadol/APAP and 151 placebo). Treatment response was higher for tramadol/APAP than a placebo at 2 hours after dosing (55.8% vs. 33.8%, P < .001) and at every other assessment from 30 minutes (12.3% vs. 6.6%) through 6 hours (64.9% vs. 37.7%) (all P< or = .022). Subjects in the tramadol/APAP group were more likely than those in the placebo group to be pain-free at 2 hours (22.1% vs. 9.3%), 6 hours (42.9% vs. 25.2%), and 24 hours (52.7% vs. 37.9%) (all P< or = .007). Two hours after dosing, moderate-to-severe symptoms that were less common for tramadol/APAP than placebo included photophobia (34.6% vs. 52.2%, P= .003) and phonophobia (34.3% vs. 44.9%, P = .008), but not migraine-related nausea (38.5% vs. 29.4%, P= .681). Treatment-related adverse events included nausea, dizziness, vomiting, and somnolence. CONCLUSIONS: Tramadol/APAP reduces the severity of pain, photophobia, and phonophobia associated with migraine headache, but does not reduce migraine-associated nausea. Tramadol/APAP might be an appropriate option for the management of moderate-to-severe migraine headache.     

Combination hydrocodone and ibuprofen versus combination oxycodone and acetaminophen in the treatment of moderate or severe acute low back pain

BACKGROUND: Introduced in 1997, the combination of hydrocodone and ibuprofen is the only fixed-dose combination analgesic containing an opioid and ibuprofen that has been approved by the US Food and Drug Administration. OBJECTIVE: This study compared the efficacy and tolerability of combination hydrocodone 7.5 mg and ibuprofen 200 mg (HC/IB) with those of combination oxycodone 5 mg and acetaminophen 325 mg (OX/AC) in the treatment of moderate or severe acute low back pain. METHODS: This was a multicenter, randomized, double-blind, parallel-group, repeat-dose study lasting up to 8 days. The recommended dosing of the study medications was 1 tablet every 4 to 6 hours, not to exceed 5 tablets per day. If adequate pain relief was not obtained, patients were permitted to take up to 4 doses per day of supplemental analgesic medication-the nonopioid component of the assigned study medication (ibuprofen 200 mg or acetaminophen 325 mg). Measures of efficacy included mean daily pain relief scores (0 = no relief, 1 = slight relief, 2 = moderate relief, 3 = good relief, and 4 = complete relief), mean daily number of tablets and doses of study medication, mean daily number of tablets and doses of supplemental analgesic medication, global evaluation (poor, fair, good, very good, or excellent), and results on the modified 36-item Short-Form Health Survey (SF-36). All efficacy measures were analyzed on an intent-to-treat basis. Tolerability was evaluated based on adverse events reported spontaneously or elicited by the in vestigators using nonsuggestive questioning, as well as on the number of patients discontinuing treatment because of adverse events. RESULTS: The study enrolled 147 patients (75 HC/IB, 72 OX/AC). The most common cause of low back pain was muscular/ligamentous injury (97/147; 66.0%), followed by degenerative disk disease (27/147; 18.4%). At baseline, 80 patients (54.4%) reported experiencing moderate pain, and 67 patients (45.6%) reported experiencing severe pain. There were no significant differences between HC/IB and OX/AC with regard to mean ( +/- SD) daily pain relief scores (2.40 +/- 1.06 vs 2.50 +/- 1.01, respectively), mean daily number of tablets of study medication (1.80 +/- 1.70 vs 2.20 +/- 1.60), mean daily number of doses of study medication (1.80 +/- 1.65 vs 2.10 +/- 1.58), mean daily number of tablets of supplemental analgesic medication (0.60 +/- 1.13 vs 0.50 +/- 0.99), mean daily number of doses of supplemental analgesic medication (0.60 +/- 1.07 vs 0.50 +/- 0.90), global evaluations, or mean scores on the modified SF-36. In addition, there were no significant differences in the proportion of patients experiencing adverse events with HC/IB (47; 62.7%) and OX/AC (45; 62.5%). Adverse events were consistent with those generally associated with the component analgesics and predominantly involved the central nervous system and gastrointestinal system. CONCLUSIONS: The results of this study suggest that HC/IB and OX/AC are similarly effective and tolerable in relieving moderate or severe acute low back pain. Additional controlled longitudinal trials are necessary to evaluate the clinical utility of HC/IB in treating acute low back pain.     

Hydrocodone/acetaminophen and tramadol chlorhydrate combination tablets for the management of chronic cancer pain: a double-blind comparative trial

OBJETIVES: The purpose of this study was to compare the analgesic efficacy and tolerability of opioids hydrocodone and tramadol in the relief of cancer pain. METHODS: One hundred and eighteen patients with chronic cancer pain participated in a double-blind, randomized controlled trial. Sixty-two patients received hydrocodone and 56 patients received tramadol. RESULTS: Hydrocodone/acetaminophen was effective in relieving pain in 56.5% of the patients at the starting dose of 25 mg/2500 mg/d. An additional 14.5% of the patients responded to a double dose, and the remaining 29% of patients did not experience any pain relief from hydrocodone administration. One dose of tramadol at 200 mg/d produced pain relief in 62% of the patients and alleviated pain in another 11% of patients at a dose of 400 mg/d, and remaining 27% of patients did not experience pain relief from tramadol. No significant statistical difference in the analgesic efficacy of tramadol clorhydrate and hydrocodone/acetaminophen was found. The groups differed significantly in the incidence of side effects like nausea (P=0.03; relative risk (RR), 1.69; confidence interval (IC) 95%, 1.03-2.77), vomiting (P=0.02; RR, 2.21; IC 95%, 1.14-4.32), dizziness (P=0.03; RR, 2.12; IC 95%, 1.17-3.86), loss of appetite (P=0.02; RR, 3.27; IC 95%, 1.12-9.55) and weakness (P=0.019; RR, 7.75; IC 95%, 0.98-61.05). CONCLUSIONS: There was no superior analgesic efficacy with the administration of hydrocodone/acetaminophen when compared to patients receiving tramadol in the relief of cancer pain. Tramadol produced more mild side effects than hydrocodone.     

Codeine/acetaminophen and hydrocodone/acetaminophen combination tablets for the management of chronic cancer pain in adults: a 23-day, prospective, double-blind, randomized, parallel-group study

BACKGROUND: Analgesics are an essential component of the treatment of cancer-associated pain. Pharmacologic treatment is usually begun with nonopioid analgesics, most frequently acetaminophen. If pain relief is not achieved, the so-called "weak" opioids, such as codeine and hydrocodone, may be used in combination with acetaminophen. Adverse effects (AEs) of the opioids include constipation, somnolence, nausea, and vomiting. Based on the results of a literature search, data comparing the effects of the opioids are lacking. OBJECTIVE: The purpose of this study was to compare the analgesic efficacy and tolerability of codeine phosphate versus hydrocodone bitartrate in combination with acetaminophen in the relief of cancer-related pain. METHODS: This 23-day, prospective, double-blind, randomized, parallel-group study was conducted at 3 Colombian centers: University Libre, Social Security Institute, and General Hospital of Medellín, Cali, Colombia. Outpatients with cancer were eligible for the study if they were aged >-18 years and had chronic (duration, >/= 3 months) moderate to severe cancer-related pain (score on 10-cm visual analog scale [VAS], > 3 cm [moderate]; score on a 4-point verbal pain-intensity scale, > 1 [moderate]). Eligible patients were randomly assigned to receive 1 tablet of codeine/acetaminophen (C/A) 30/500 mg or hydrocodone/acetaminophen (H/A) 5/500 mg PO q4h (total daily doses, 150/2500 and 25/2500 mg, respectively) for 23 days. In both groups, if pain intensity was rated as > 3 on the VAS at week 1 or 2, the dosage was doubled. The primary end point was the proportion of patients who achieved pain relief (defined as a score of > 1 on a 5-point verbal rating scale [VRS] (0 = none; 1 = a little; 2 = some; 3 = a lot; and 4 = complete) on study days 1 and 2 and weeks 1, 2, and 3. The secondary end point was the proportion of patients in whom pain was decreased (VAS score, <- 3 cm). AEs were self-reported on a 4-point VRS (0 = absent; 1 = mild; 2 = moderate; and 3 = severe). RESULTS: Of the 121 patients who participated, 59 received C/A and 62 received H/A. Of the total number of cases, 59% were aged 60 to 89 years, and 55% were men. At baseline, 88% of the patients described their pain intensity as moderate; 12%, severe. Of the patients who received C/A, 58% responded to the initial dosage of 150/2500 mg/d, and 8% of the patients responded to the double dosage; 34% did not experience pain relief. In patients with H/A, pain was reported as absent or mild in 56% of patients at the starting dosage of 25/2500 mg/d; an additional 15% of the patients responded to the double dosage; the remaining 29% of patients did not experience any pain relief. None of the between-group differences in response rates were significant. The most common AEs in the C/A and H/A groups were constipation (36% and 29%, respectively), dizziness (24% and 19%), vomiting (24% and 16%), and dry mouth (15% and 18%), with no significant differences between groups. CONCLUSION: In this study, efficacy and tolerability were comparable between C/A and H/A over 23 days of treatment in these patients with moderate or severe, chronic, cancer-related pain.     

Combination hydrocodone and ibuprofen versus combination codeine and acetaminophen for the treatment of chronic pain

OBJECTIVE: The objective of this study was to compare the effectiveness of combination hydrocodone 7.5 mg and ibuprofen 200 mg with that of combination codeine 30 mg and acetaminophen 300 mg for the treatment of chronic pain. BACKGROUND: Hydrocodone 7.5 mg with ibuprofen 200 mg is the only approved fixed-dose combination analgesic containing an opioid and ibuprofen. METHODS: In this randomized, parallel-group, double-blind, repeated-dose, active-comparator, 4-week, multicenter study, 469 patients were randomly assigned to receive a 1-tablet (n = 156) or 2-tablet (n = 153) dose of combination hydrocodone 7.5 mg and ibuprofen 200 mg (HI1 and HI2, respectively) or a 2-tablet dose of combination codeine 30 mg and acetaminophen 300 mg (CA, n = 160), the active comparator, every 6 to 8 hours as needed for pain. Efficacy was measured through pain relief scores, number of daily doses of study medication, number of daily doses of supplemental analgesics, number of patients who discontinued therapy due to an unsatisfactory analgesic response, and global assessment scores. RESULTS: Of the 469 patients, 255 (54.4%) were female and 214 (45.6%) were male. The mean age was 51.1 years. Types of chronic pain included back (214; 45.6%), arthritic (145; 30.9%), other musculoskeletal (65; 13.9%), cancer (6; 1.3%), diabetic neuropathic (3; 0.6%), postherpetic neuralgic (5; 1.1%), other neurologic (21; 4.5%), and other unclassified chronic pain (10; 2.1%). During the 48 hours prior to the study, 351 (74.8%) patients had been treated with opioid or opioid-nonopioid combination analgesics. The overall mean daily pain relief score was significantly greater in the HI2 group (2.25+/-0.89) than in the HI1 group (1.98+/-0.87) (P = 0.003) or the CA group (1.85+/-0.96) (P < 0.001). The overall mean number of daily doses of study medication was significantly less in the HI2 group (2.94+/-0.99) than in the HI1 group (3.23+/-0.76) (P = 0.036) or the CA group (3.26+/-0.75) (P = 0.014). The overall mean number of daily doses of supplemental analgesics was significantly less in the HI2 group (0.24+/-0.49) than in the HI1 group (0.34+/-0.58) (P = 0.021) or CA group (0.49+/-0.85) (P = 0.010). The number of patients who discontinued treatment due to an unsatisfactory analgesic response was significantly less in the HI2 group (2; 1.3%) than in the CA group (12; 7.5%) (P = 0.008). HI2 was more effective than HI1 and CA as measured by pain relief scores for week 1 (P < 0.001 vs HI1 and CA), week 2 (P < 0.001 vs HI1 and CA), and week 3 (P = 0.008 vs HI1 and P < 0.001 vs CA); daily doses of study medication for week 1 (P = 0.019 vs HI1 and P = 0.011 vs CA); daily doses of supplemental analgesics for week 1 (P = 0.010 vs HI1 and CA); and global assessment scores for week 1 (P = 0.018 vs HI1 and P < 0.001 vs CA), week 2 (P = 0.005 vs HI1 and P < 0.001 vs CA), and week 4 (P = 0.013 vs HI1 and P = 0.023 vs CA). There were no significant differences between HI1 and CA in any efficacy variable. There were no significant differences in the number of patients experiencing adverse events in the HI2 (127; 83%), HI1 (124; 79.5%), and CA (129; 80.6%) groups. However, the mean number of patients who discontinued treatment due to adverse events was significantly greater in the HI2 group (40; 26.1%) than in the HI1 group (23; 14.7%) (P = 0.013). CONCLUSIONS: The results of this study suggest that 2-tablet doses of combination hydrocodone 7.5 mg and ibuprofen 200 mg may be more effective than either 1-tablet doses of this combination or 2-tablet doses of combination codeine 30 mg and acetaminophen 300 mg. Moreover, 1-tablet doses of combination hydrocodone 7.5 mg and ibuprofen 200 mg may be as effective as 2-tablet doses of combination codeine 30 mg and acetaminophen 300 mg.     

Efficacy and safety of low-dose transdermal buprenorphine patches (5, 10, and 20 μg/h) versus prolonged-release tramadol tablets (75, 100, 150, and 200 mg) in patients with chronic osteoarthritis pain: A 12-week,randomized, open-label,controlled, parallel-group noninferiority study

Objective: This study compared the efficacy and safety of low-dose 7-day buprenorphine patches and prolonged-release tramadol tablets in patients with chronic, moderate to severe osteoarthritis (OA) pain of the hip and/or knee.Methods: Eligible patients were adults with a clinical and radiologic diagnosis of OA of the hip and/or knee and moderate to severe pain, as confirmed by a mean Box Scale 11 (BS-11) score ≥4 while using paracetamol 4000 mg/d for pain during the screening week. Patients were randomized in a 1:1 ratio to receive either low-dose 7-day buprenorphine patches (patch strengths of 5, 10, and 20 μg/h, with a maximum dosage of 20 μg/h) or twice-daily prolonged-release tramadol tablets (tablet strengths of 75, 100, 150, and 200 mg, with a maximum dosage of 400 mg/d) over a 12-week open-label treatment period. Supplementary paracetamol was available as rescue medication throughout the study. The primary end point was the difference in BS-11 scores from baseline to the completion of treatment. Noninferiority was assumed if the treatment difference on the BS-11 scale was ?1.5 boxes, indicating a clinically meaningful result. Secondary efficacy variables were rescue medication use, sleep disturbance and quality of sleep, and patients' and investigators' global assessments of pain relief. In addition, patient preference was assessed at the completion visit by asking patients whether, given equal pain relief, they would prefer basic treatment for OA pain with a patch applied once weekly or a tablet taken twice daily. Exploratory variables included investigators' assessments of patients' pain, stiffness, and ability to perform daily activities (Western Ontario and McMaster Universities Osteoarthritis Index); patients' quality of life (EuroQol EQ-5D health states index and EuroQol visual analog scale); and abuse and diversion of study drug.Results: One hundred thirty-four patients (69 receiving 7-day buprenorphine patches and 65 receiving tramadol tablets) were randomized and received ≥1 dose of study medication. A respective 98.6% and 100% of the 2 treatment groups were white, with mean (SD) ages of 64.4 (11.1) and 64.2 (9.3) years. Both treatments were associated with a clinically meaningful reduction in pain from baseline to study completion. The least squares mean change from baseline in BS-11 scores in the 7-day buprenorphine patch and tramadol tablet groups was ?2.26 (95% CI, ?2.76 to ?1.76) and ?2.09 (95% CI, ?2.61 to ?1.58). The efficacy of 7-day buprenorphine patches was noninferior to that of prolonged-release tramadol tablets. The incidence of adverse events (AEs) was comparable in the 2 treatment groups: 226 AEs were reported in 61 patients (88.4%) in the 7-day buprenorphine patch group, and 152 AEs were reported in 51 patients (78.5%) in the tramadol group. Ten patients (14.5%) in the 7-day buprenorphine patch group and 19 (29.2%) in the tramadol tablet group withdrew from the study due to AEs. The most common AEs in the 7-day buprenorphine patch group were nausea (30.4%), constipation (18.8%), and dizziness (15.9%); the most common AEs in the tramadol tablet group were nausea (24.6%), fatigue (18.5%), and pain (12.3%). Most patients (47/67 [70.1%] in the 7-day buprenorphine patch group and 43/61 [70.5%] in the tramadol tablet group) reported that they would prefer a 7-day patch to a twice-daily tablet for future pain treatment.Conclusions: In these patients with chronic, moderate to severe OA pain of the hip and/or knee, 7-day low-dose buprenorphine patches were an effective and well-tolerated analgesic. The buprenorphine patches were noninferior to prolonged-release tramadol tablets. European Union Drug Regulating Authorities Clinical Trials number: 2006-003233-32.     

Efficacy and tolerability of paracetamol/tramadol (325 mg/37.5 mg) combination treatment compared with tramadol (50 mg) monotherapy in patients with subacute low back pain: a multicenter, randomized, double-blind, parallel-group, 10-day treatment study

BACKGROUND: In various pain studies, the single-dose combination of paracetamol/tramadol (PIT) was found to be more effective than either agent alone. PIT could provide benefit in patients with subacute low back pain (LBP). OBJECTIVE: This study compared the efficacy and tolerability of PIT with tramadol alone (T) in patients with subacute LBP and assessed whether, under comparable analgesic conditions, PIT would be better tolerated. METHODS: This was a multicenter, randomized, double-blind, parallel-group study. Patients were enrolled if they suffered from nonspecific LBP lasting 10 to 42 days and experienced at least moderate pain (> or =40 mm on a 100-mm visual analog scale). Patients were randomized and treated for 10 days with PIT (325 mg/37.5 mg) or T (50 mg). The study outcomes were treatment efficacy (pain intensity, pain relief, patient satisfaction, physicians' assessment of pain control) and tolerability (adverse events [AEs], patients' tolerability judgment). RESULTS: A total of 119 patients were enrolled (PIT, n = 59; T, n = 60). Demographic characteristics of patients were comparable between the PIT and T groups in regard to age (mean, 56.5 vs 54.1 years, respectively), sex (women/men, 38121 vs 31129), race (white, 96.1% vs 94.2%), and body mass index (24.9 vs 26.1 kg/m2). Pain intensity (mean [SD] percentage of worst imaginable pain) improved from nearly identical levels at baseline (P/T, 67.5 [13.0] vs T, 65.3 [14.6]; P = NS) to similarly low levels at the final visit (P/T, 27.9 [22.7] vs T, 24.8 [21.6]; P = NS). The reduction in pain intensity was significant in both treatment groups (P < 0.001). Adequate pain relief (ie, "moderate," "important," or "complete") was observed in 81.6% (40149) of PIT patients versus 82.9% (39147) of T patients (P = NS). Comparably high rates of overall patient satisfaction (72.5% [37151] vs 72.9% [35148], respectively; P = NS) were achieved. Both treatment groups took a comparable number of daily units of study medication, which resulted in significantly (P < 0.001) lower daily doses of tramadol in the P/T group (mean [SD], 172.5 [46.6] mg) than in the T group (227.3 [59.7] mg). More P/T patients (84.3%) than T patients (68.8%) judged treatment tolerability as good or very good (P = NS). Significantly fewer AEs (P < 0.001) were observed in PIT patients, and the overall incidence of AEs (mostly opioid-typical AEs [eg, nausea, dizziness/vertigo, sleepiness/drowsiness, constipation, vomiting]) was much lower after P/T compared with T (P = 0.019). The most common AEs in the P/T and T groups were nausea (8159 vs 21160 patients, respectively; P = 0.012) and dizziness (3/59 vs 15/60 patients; P= 0.006). CONCLUSIONS: Tramadol, alone and in combination with paracetamol, provided highly effective analgesia for these patients with subacute LSP However, the combination of PIT, which resulted in 25% less tramadol than equianalgesic daily doses of T alone, considerably reduced the incidence of AEs and improved tolerability.     

The Addition of Tramadol as a Second Opioid May Improve Pain Relief in Severe Osteoarthritis: A Prospective Study

Background: Opioid combination has been shown to reduce the need for escalating doses for the treatment of cancer pain. A prospective study was planned to evaluate the addition of tramadol to a stronger opioid for the treatment of severe pain as a result of osteoarthritis, previously uncontrolled by non‐opioid analgesics or weak opioids. Methods: All subjects received tramadol 200 mg and tizanidine 2 mg. At 2 weeks, tramadol was discontinued for patients still reporting poor pain relief (effectiveness ≤50%), and a stronger opioid was titrated to a morphine equivalent amount (MEA) of 40–60 mg orally. After two additional weeks, patients were then divided into two groups: the Strong Opioid Group (SO) and the Tramadol plus the Strong Opioid Group (TSO). The SO group was allowed to escalate opioid dose for lack of effectiveness; the TSO group received tramadol 150 mg daily, thereafter additional strong opioid titration was allowed. Results: A total of 74 patients were studied: SO (n = 40) and TSOG (n = 34). All patients eventually achieved pain relief quality, with both groups reporting similar Karnofsky Performance Scale effectiveness. The SO group achieved satisfactory pain relief (>50%) at an average daily oral MEA of 120 mg. TSO subjects achieved satisfactory pain relief (>50%) at an average daily oral MEA of 95 mg. Discussion: The addition of tramadol provided a synergistic effect resulting in a 30‐mg decrease in necessary morphine equivalents with fewer opioid‐related adverse effects.     

The combination of ibuprofen and oxycodone/acetaminophen in the management of chronic cancer pain

Thirty subjects with chronic moderate to severe pain who were receiving oxycodone/acetaminophen (oxy/APAP) for analgesia were initially evaluated for at least 7 days for oxy/APAP requirements for pain control. Each subject then received, in a randomized double-blind fashion, either 600 mg ibuprofen or placebo for an additional 7 days while hospitalized. Oxy/APAP usage was recorded daily along with efficacy and toxicity parameters. Overall global evaluations were also recorded on completion of the study. Comparison of mean differences before and after treatment with ibuprofen or placebo indicated a marked decrease in oxy/APAP use with ibuprofen (p less than 0.01) and a slight increase in use in the placebo group. Reduction in oxy/APAP usage occurred within 24 hours and maximized at 5 days. Overall global scores showed a marked preference for the ibuprofen combination over placebo (p less than 0.01). Daily pain intensity (p less than 0.05) and pain relief scores (p less than 0.05) also improved with the addition of ibuprofen. This study indicates that ibuprofen is efficacious in the management of chronic cancer pain, resulting in both enhanced analgesia and a reduction in concomitant narcotic use.     

Combining diclofenac with acetaminophen or acetaminophen-codeine after oral surgery: a randomized, double-blind single-dose study

In a randomized double-blind study, 120 patients with moderate to strong pain after surgical removal of wisdom teeth were given the following in single oral doses: 100-mg enteric-coated diclofenac tablets; 1 g acetaminophen (INN, paracetamol); 1 g acetaminophen plus 60 mg codeine; 100-mg enteric-coated diclofenac tablets plus 1 g acetaminophen; or 100-mg enteric-coated diclofenac tablets plus 1 g acetaminophen plus 60 mg codeine. Patients recorded pain intensity and pain relief for 8 hours. Upside assay sensitivity was confirmed because acetaminophen plus codeine was superior to acetaminophen. Diclofenac plus acetaminophen with and without codeine had superior analgesic effect compared with diclofenac, acetaminophen, or acetaminophen plus codeine. Addition of 60 mg codeine increased the degree of side effects. These results support the clinical practice of combining diclofenac with acetaminophen for acute pain. Of clinical importance are superior and prolonged analgesia and fewer side effects after enteric-coated diclofenac tablets plus acetaminophen compared with acetaminophen plus codeine.     

A randomised, five-parallel-group, placebo-controlled trial comparing the efficacy and tolerability of analgesic combinations including a novel single-tablet combination of ibuprofen/paracetamol for postoperative dental pain

Combination analgesia is often recommended for the relief of severe pain. This was a double-blind, 5-arm, parallel-group, placebo-controlled, randomised, single-dose study designed to compare the efficacy and tolerability of a novel single-tablet combination of ibuprofen and paracetamol with that of an ibuprofen/codeine combination, and a paracetamol/codeine combination, using the dental impaction pain model. Subjects with at least 3 impacted third molars and experiencing moderate to severe postoperative pain were randomised to receive: 1 or 2 tablets of a single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg; 2 tablets of ibuprofen 200 mg/codeine 12.8 mg; 2 tablets of paracetamol 500 mg/codeine 15 mg; or placebo. Results for the primary endpoint, the sum of the mean scores of pain relief combined with pain intensity differences over 12 hours, demonstrated that 1 and 2 tablets of the single-tablet combination of ibuprofen/paracetamol were statistically significantly more efficacious than 2 tablets of placebo (P < 0.0001) and paracetamol/codeine (P ? 0.0001); furthermore, 2 tablets offered significantly superior pain relief to ibuprofen/codeine (P = 0.0001), and 1 tablet was found noninferior to this combination. Adverse events were uncommon during this study and treatment emergent adverse events were statistically significantly less frequent in the groups taking the ibuprofen/paracetamol combination compared with codeine combinations. In conclusion, 1 or 2 tablets of a single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg provided highly effective analgesia that was comparable with, or superior to, other combination analgesics currently indicated for strong pain.     

A comparison of the pharmacokinetics,clinical efficacy,and tolerability of once-daily tramadol tablets with normal release tramadol capsules

This report describes a pharmacokinetic study and a clinical study of three different formulations of oral tramadol: once-daily tramadol tablets 150 and 200 mg, and normal release tramadol capsules 50 mg 8-hourly. The randomized, open-label, crossover pharmacokinetic study included 22 subjects. The three treatments showed equivalent mean systemic availability of tramadol. The mean relative systemic availabilities (90% confidence intervals) for the once-daily tablets 150 mg and the once-daily tablets 200 mg versus the normal release capsules were 89.6 (83.3-95.8)% and 90.5 (84.6-96.8)%, respectively. The values for the once-daily tablet 150 mg versus the once-daily tablet 200 mg were 99.0 (92.6-105.9)%. The randomized, double-blind, double-dummy, crossover clinical study included 134 patients with moderate osteoarthritic pain. The three treatments showed similar efficacy; they all reduced patients' pain scores from baseline and there were no significant treatment differences in pain scores during treatment. The three treatments were also well tolerated.     

A 2-week, multicenter, randomized, double-blind, double-dummy, add-on study of the effects of titration on tolerability of tramadol/acetaminophen combination tablet in Korean adults with knee osteoarthritis pain

BACKGROUND: Combined tramadol/acetaminophen is used to treat pain related to osteoarthritis. However, adverse events (AEs) leading to discontinuation can occur. Dose titration may decrease the risk for AEs. OBJECTIVE: The aim of this study was to assess the effect of tramadol/acetaminophen titration on the development of AEs leading to treatment discontinuation in patients with knee osteoarthritis. METHODS: This 2-week, multicenter, randomized, double-blind, double-dummy, add-on study was conducted at 12 tertiary referral university hospitals in the Republic of Korea. Patients aged 35 to 75 years with knee osteoarthritis receiving a stable dose of NSAIDs and with a daily mean pain-intensity score of > or = 4 on a numeric rating scale (NRS) (0 = no pain to 10 = worst pain) during the 48 hours prior to enrollment were eligible. Patients were randomly assigned to receive 1 tablet of tramadol/acetaminophen 37.5/325 mg QD and 1 placebo BID for 3 days, followed by 1 active tablet BID and 1 placebo QD for 4 days, followed by 1 active tablet TID for 7 days (titration group) or 1 tablet of combined tramadol 37.5 mg/acetaminophen 325 mg TID for 14 days (nontitration group). The primary outcome measure was the rate of treatment discontinuation due to AEs. Secondary outcome measures were time to discontinuation due to AEs, prevalences and characteristics of AEs, decrease from baseline in pain intensity as measured on the NRS, and change in the Korean version of the Western Ontario and McMaster Universities (K-WOMAC) index score (scale: 0 = best to 100 = worst). RESULTS: A total of 250 patients were enrolled (92.0% female; mean [SD] age, 60.2 [7.8] years; mean [SD] weight, 60.0 [9.2] kg [range, 37.5-90.7 kg]; all Korean). The discontinuation rate was significantly lower in the titration group than in the nontitration group (10.5% vs 26.2%; P < 0.001). The Kaplan-Meier survival curve showed that the rates of discontinuation due to AEs were similar in the 2 groups up to day 2, but thereafter the discontinuation rate was significantly lower in the titration group. The most common AEs were nausea (12.1% and 24.6% in the titration and nontitration groups, respectively; P = 0.008), vomiting (4.0% and 17.2%; P < 0.001), and dizziness (9.7% and 22.1%; P = 0.005). No serious AEs were reported in either group. Tramadol/acetaminophen use was associated with a similar decrease from baseline in pain in both the titration and nontitration groups (mean [SD] Delta: NRS, -1.60 [1.62] vs -1.68 [1.58]; total K-WOMAC, -12.86 [13.73] vs -12.52 [16.58]). CONCLUSIONS: In this population of Korean patients with knee osteoarthritis pain managed with a stable dose of NSAIDs, titration of tramadol/acetaminophen over 12 days was associated with improved tolerability and a significantly lower discontinuation rate compared with nontitration. Both regimens significantly reduced from baseline associated with osteoarthritis.     

Rofecoxib versus codeine/acetaminophen in postoperative dental pain: a double-blind, randomized, placebo- and active comparator-controlled clinical trial

BACKGROUND: In recent studies of acute pain and primary dysmenorrhea, rofecoxib, a nonsteroidal anti-inflammatory drug that selectively targets the cyclooxygenase-2 enzyme, was found to be similar in efficacy to ibuprofen and naproxen sodium. OBJECTIVE: The purpose of this study was to determine the analgesic efficacy of a single oral dose of rofecoxib 50 mg compared with the combination of codeine 60 mg/acetaminophen 600 mg in a model of postsurgical dental pain. METHODS: In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate or severe pain after the surgical extraction of > or = 2 third molars, at least 1 of which was a mandibular impaction, were randomized to receive placebo, rofecoxib 50 mg, or codeine 60 mg/acetaminophen 600 mg. Patient evaluations of pain intensity, pain relief, and global assessments were recorded throughout the 24-hour period after dosing. The 2-stopwatch method was used to determine time to confirmed perceptible pain relief. The primary end point assessing overall analgesic effect was total pain relief over 6 hours (TOPAR6). Secondary end points were patient global assessment of response to therapy (PGART) at 6 hours, onset of analgesia, peak analgesic effect, and duration of analgesia. RESULTS: A total of 393 patients were enrolled; 182 received rofecoxib, 180 received codeine/acetaminophen, and 31 received placebo. The overall analgesic effect of rofecoxib 50 mg was greater than that of codeine 60 mg/acetaminophen 600 mg for TOPAR6 (12.4 vs 7.0; P < 0.001) and PGART at 6 hours (P < 0.001). The onset of analgesic effect was similar for rofecoxib and codeine/acetaminophen. Peak analgesic effect as measured by peak pain relief scores during the first 6 hours was significantly greater in the rofecoxib group compared with the codeine/acetaminophen group (P < 0.001), as was the duration of analgesic effect measured by the time to rescue analgesia (9.6 hours vs 2.3 hours, P < 0.001). Adverse events were reported in 33.0%, 46.1%, and 32.3% of patients treated with rofecoxib, codeine/acetaminophen, and placebo, respectively. The most common adverse events were nausea (6.0%, 25.0%, and 9.7%, respectively) and vomiting (3.8%, 18.3%, and 6.5%, respectively). Significantly more patients in the codeine/acetaminophen group than in the rofecoxib group experienced adverse events overall (P < 0.050) and nausea in particular (P < 0.001). CONCLUSION: In this study of moderate to severe postoperative dental pain, the analgesic efficacy of rofecoxib 50 mg was greater than that of codeine/acetaminophen, with a lower incidence of adverse events and nausea.