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.     

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.     

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   

Continuous low-level heat wrap therapy is effective for treating wrist pain

OBJECTIVE: To evaluate the efficacy of continuous low-level heat wrap therapy for the treatment of various sources of wrist pain including strain and sprain (SS), tendinosis (T), osteoarthritis (OA), and carpal tunnel syndrome (CTS). DESIGN: Prospective, randomized, parallel, single-blind (investigator), placebo-controlled, multicenter clinical trial. SETTING: Two community-based research facilities. PARTICIPANTS: Ninety-three patients (age range, 18-65 y) with wrist pain. INTERVENTION: Subjects with moderate or greater wrist pain were randomized and stratified to 1 of the following treatments: efficacy evaluation (heat wrap, n=39; oral placebo, n=42) or blinding (oral acetaminophen, n=6; unheated wrap, n=6). Data were recorded over 3 days of treatment and 2 days of follow-up. MAIN OUTCOME MEASURES: The primary comparison was between the heat wrap and the oral placebo group among SS/T/OA subjects for pain relief. Outcome measures included pain relief (0-5 scale), joint stiffness (101-point numeric rating scale), grip strength measured by dynamometry, and perceived pain and disability (Patient Rated Wrist Evaluation [PRWE]); subjects with CTS also completed the Symptom Severity Scale and Functional Status Scale. RESULTS: Heat wrap therapy showed significant benefits in day 1 to 3 mean pain relief (P=.045) and increased day 3 grip strength (P=.02) versus oral placebo for the SS/T/OA group. However, joint stiffness and PRWE results were comparable between the 2 treatments. For the CTS group, heat wraps provided greater day 1 to 3/hour 0 to 8 mean pain relief (P=.001), day 1 to 3 mean joint stiffness reduction (P=.004), increased day 3 grip strength (P=.003), reduced PRWE scores (P=.0015), reduced symptom severity (P=.001), and improved functional status (P=.04). In addition, the heat wrap showed significant extended benefits through follow-up (day 5) in the CTS group. CONCLUSIONS: Continuous low-level heat wrap therapy was efficacious for the treatment of common conditions causing wrist pain and impairment.     

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.     

Tramadol/acetaminophen combination tablets and codeine/acetaminophen combination capsules for the management of chronic pain: a comparative trial

BACKGROUND: Opioid/acetaminophen (APAP) combination analgesics are widely prescribed for the relief of moderate pain. Tramadol is a synthetic analgesic that has been shown to be effective both alone and in combination with APAP. OBJECTIVE: The purpose of this study was to compare the efficacy and tolerability of tramadol/APAP tablets with codeine/APAP capsules. METHODS: This 4-week, randomized, double-blind, parallel-group, active-control, double-dummy, multicenter trial compared tramadol/APAP (37.5 mg/325 mg) with codeine/APAP (30 mg/300 mg) for the management of chronic nonmalignant low back pain, osteoarthritis (OA) pain, or both in adults. Pain relief (scale, 0 = none to 4 = complete) and pain intensity (scale, 0 = none to 3 = severe) were measured 30 minutes and then hourly for 6 hours after the first daily dose each week. Patients and investigators assessed the efficacy (scale, 1 = poor to 5 = excellent) of each medication, and patients recorded daily doses of study and rescue medications. RESULTS: A total of 462 patients (mean age, 57.6 years) were randomly assigned to treatment, with 112 (24%) reporting chronic low back pain, 162 (35%) reporting OA pain, and 188 (41%) reporting both low back and OA pain; 309 patients (67%) received tramadol/APAP and 153 (33%) received codeine/APAP. Pain relief and changes in pain intensity were comparable from day 1, as early as 30 minutes after the first dose, and lasted for at least 6 hours. Total pain relief scores (11.9 for tramadol/APAP; 11.4 for codeine/APAP) and sum of pain intensity differences (3.8 for tramadol/APAP; 3.3 for codeine/APAP) were also comparable throughout. Overall assessments of efficacy by patients (mean score 2.9 in each treatment group) and investigators (mean score 3.0 for tramadol/APAP, 2.9 for codeine/APAP) were similar for the 2 treatment groups. Equivalent mean doses (3.5 tablets or capsules daily) and maximum daily doses (5.5 tablets or 5.7 capsules) were used in the 2 treatment groups. The overall incidence of adverse events was comparable, with a significantly higher proportion of patients in the codeine/APAP group reporting somnolence (24% [37/153] vs 17% [54/309], P = 0.05) or constipation (21% [32/153] vs 11% [35/309], P < 0.01) and a larger proportion of patients in the tramadol/APAP group reporting headache (11% [34/309] vs 7% [11/153], P = 0.08). CONCLUSION: The results of this study suggest that tramadol/APAP tablets (37.5 mg/325 mg) are as effective as codeine/ APAP capsules (30 mg/300 mg) in the treatment of chronic nonmalignant low back pain and OA pain and are better tolerated.     

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.     

Comparison of rofecoxib and oxycodone plus acetaminophen in the treatment of acute pain: a randomized, double-blind, placebo-controlled study in patients with moderate to severe postoperative pain in the third molar extraction model

BACKGROUND: Opiates, acetaminophen, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2-selective inhibitors such as rofecoxib are used in the treatment of acute pain because of their anti-inflammatory and/or analgesic properties. Rofecoxib has demonstrated an improved gastrointestinal safety profile compared with nonselective NSAIDs. OBJECTIVE: The aim of this study was to compare the analgesic efficacy and tolerability profile of rofecoxib 50 mg with those of the centrally acting, nonsalicylate, opiate/nonopiate analgesic combination oxycodone/acetominophen 5/325 in patients with pain after dental surgery. METHODS: In this randomized, double-blind, placebo- and active comparator-controlled study, patients experiencing moderate to severe postoperative pain after extraction of > or =2 third molars (including > or =1 mandibular impaction) received a single oral dose of rofecoxib 50 mg, oxycodone/acetaminophen 5/325 mg, or placebo. End points included total pain relief over 6 hours (TOPAR6, the primary end point) and 4 hours (TOPAR4), patient's global assessment of treatment at 6 hours (GLOBAL6) and 24 hours (GLOBAL24), summed pain intensity difference over 6 hours (SPID6), onset of analgesic effect (time to perceptible/meaningful pain relief, using a 2-stopwatch method), peak pain relief (PEAKPR), peak pain intensity difference (PEAKPID), and duration of analgesic effect (time to use of rescue analgesia). RESULTS: Two hundred twelve patients (63% female, 37% male; 76% white, 24% other; mean [SD] age, 20.9 [4.4] years; age range, 16-41 years) were enrolled in the study and received a single oral dose of rofecoxib 50 mg (n = 90), oxycodone/acetaminophen 5/325 mg (n = 91), or placebo (n = 31). The analgesic effect of rofecoxib was significantly greater than that of oxycodone/acetaminophen at P < 0.001 for TOPAR6, TOPAR4, GLOBAL6, GLOBAL24, and SPID6; at P < 0.010 for PEAKPR and PEAKPID; and at P < 0.001 for median time to use of rescue analgesia. Significantly fewer patients in the rofecoxib group (72.2%) took rescue analgesia within 24 hours postdose compared with the oxycodone/acetaminophen group (94.5%; P < 0.001) and the placebo group (96.8%; P < 0.02). Both active treatments were similar with respect to onset of analgesic effect. Both were generally well tolerated; the overall incidence of adverse experiences in the rofecoxib, oxycodone/acetaminophen, and placebo groups was 51.1%, 64.8%, and 48.4%, respectively. Rofecoxib was associated with a significantly lower incidence of nausea (18.9% vs 39.6%; P < 0.001) and vomiting (6.7% vs 23.1%; P < 0.001) compared with oxycodone/acetaminophen. CONCLUSIONS: In study patients with moderate to severe pain after dental surgery, rofecoxib 50 mg had a greater analgesic effect than oxycodone/acetaminophen 5/325 mg and was associated with less nausea and vomiting.     

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.     

Pain management in osteoarthritis: A focus on onset of efficacy—a comparison of rofecoxib, celecoxib, acetaminophen, and nabumetone across four clinical trials

We compared onset of efficacy (during days 1 to 6) of 2 coxibs (rofecoxib, celecoxib) with acetaminophen and nabumetone by using a prespecified approach to data from 4 similarly designed 6-week randomized osteoarthritis trials. In 2 trials, rofecoxib (12.5 mg and 25 mg once daily) was compared with celecoxib (200 mg once daily) and acetaminophen (4000 mg daily). In the other 2 trials, rofecoxib (12.5 mg) was compared with nabumetone (1000 mg once daily) and placebo. Efficacy end points included Patient Global Response to Therapy and Western Ontario and McMaster Osteoarthritis Index scores. Rofecoxib (12.5- and 25-mg doses) consistently demonstrated a faster onset of osteoarthritis (OA) efficacy than the comparator drugs during the first 6 days of therapy of OA patients experiencing "flare." Acetaminophen resulted in the slowest onset of efficacy. There was a strong correlation (0.7) between efficacy response during days 1 to 6 and that averaged over 6 weeks. Rates of discontinuation as a result of lack of efficacy were significantly lower (P < .02) for each of the coxib-treated groups compared with acetaminophen and for rofecoxib 12.5 mg (P = .01) compared with nabumetone. Rofecoxib treatment, with its faster onset of OA efficacy and lower rates of related discontinuations, might provide efficacy advantages in the treatment of OA pain. PERSPECTIVE: The efficacy of rofecoxib, celecoxib, nabumetone, and acetaminophen is established for the majority of OA patients within the first 6 days of therapy, and this predicts efficacy during the longer term. Rofecoxib provides significantly faster time to onset of efficacy and better improvement on multiple measures versus the comparators.     

Tramadol in post-herpetic neuralgia: a randomized,double-blind,placebo-controlled trial

The efficacy and safety of sustained-release tramadol compared to placebo in the treatment of post-herpetic neuralgia were evaluated in a multicenter, randomized, double-blind, parallel-group study in 127 outpatients. Treatment was administrated for 6 weeks. The dose of tramadol could be increased from 100 mg/day to 400 mg/day (300 mg/day in patients more than 75 years old). Groups were compared on changes in pain intensity on a Visual Analogue Scale (VAS) between inclusion and the 6th week of treatment (covariance analysis as main analysis and repeated measures analysis as complementary analysis) in the per protocol (PP) population. The randomized population comprised 127 patients aged 35-85 years, mostly females (72.4%). Groups were comparable at inclusion both in the intent to treat (ITT) population (63 patients in the tramadol group and 62 patients in the placebo group) and in the PP population (53 patients in the tramadol group and 55 patients in the placebo group). Mean pain intensity on day 43 adjusted on day 1 (covariance analysis) was significantly lower in the tramadol group than in the placebo group in both the PP (P=0.0499), and the ITT (P=0.031) populations. The two groups significantly differed on change in pain intensity over time (repeated measures analysis) in the ITT population (P=0.012). The percentage of pain relief over the 6th week was significantly higher in the tramadol group than in the placebo group (P=0.017). During the 6th week, patients in the tramadol group required less rescue medication than patients in the placebo group (P=0.022). No significant difference was found between groups either in pain intensity on a 5-point Verbal Scale (VRS) or in quality of life measurements. Tramadol was administered at an average dosage of 275.5 (89.7) mg/day after a 1-week dose-adaptation period. Tramadol was well tolerated. No notable difference appeared between groups either in the percentage of patients with treatment-associated adverse events (TAAE) (29.7% in the tramadol group and 31.8% in the placebo group) or in the total number of TAAE (31 in the tramadol group and 28 in the placebo group).     

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.     

Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol

OBJECTIVE: Tramadol hydrochloride (INN, tramadol) exerts its antinociceptive action through a monoaminergic effect mediated by the parent compound and an opioid effect mediated mainly by the O-demethylated metabolite (+)-M1. O-demethylation is catalyzed by cytochrome P450 (CYP) 2D6. Paroxetine is a very potent inhibitor of CYP2D6. The objective of this study was to investigate the influence of paroxetine pretreatment on the biotransformation and the hypoalgesic effect of tramadol. METHODS: With and without paroxetine pretreatment (20 mg daily for 3 consecutive days), the formation of M1 and the analgesic effect of 150 mg of tramadol were studied in 16 healthy extensive metabolizers of sparteine in a randomized, double-blind, placebo-controlled, 4-way crossover study by use of experimental pain models. RESULTS: With paroxetine pretreatment, the area under the plasma concentration-time curve (AUC) of (+)- and (-)-tramadol was increased (37% [P = .001] and 32% [P = .002], respectively), and the corresponding AUCs of(+)- and (-)-M1 were decreased (67% [P = .0004] and 40% [P = .0008], respectively). (+)-M1 and (-)-M1 could be determined in all subjects throughout the study period regardless of paroxetine pretreatment. The sums of differences between postmedication and premedication values of pain measures differed between the placebo/tramadol and the placebo/placebo combination, with median values as follows: pressure pain tolerance threshold, 390 kPa (95% confidence interval [CI], 211 to 637 kPa) versus -84 kPa (95% CI, - 492 to -32 kPa) (P = .001); single sural nerve stimulation pain tolerance threshold, 25.8 mA (95% CI, 15.3 to 29.8 mA) versus 9.0 mA (95% CI, 1.5 to 14.8 mA) (P = .005); pain summation threshold, 10.7 mA (95% CI, 5.2 to 17.6 mA) versus 5.0 mA (95% CI, 2.8 to 11.2 mA) (P = .066); cold pressor pain, -4.2 cm x s (95% CI, -6.8 to -1.9 cm x s) versus -0.4 cm x s (-1.4 to 1.4 cm x s) (P = .002); and discomfort, -4.7 cm (95% CI, -10.6 to -2.8 cm) versus 0.5 cm (-0.1 to 1.4 cm) (P = .002). The sums of differences of the paroxetine/tramadol combination also differed from placebo/tramadol for some of the measures, with median values as follows: cold pressor pain, -2.2 cm x s (95% CI, -3.7 to -0.4 cm x s) (P = .036, compared with placebo/tramadol); and discomfort, -2.0 cm (95% CI, -5.6 to -1.2 cm) (P = .056). For the other measures, the hypoalgesic effect was retained on the paroxetine/tramadol combination, with median values as follows: pressure pain tolerance threshold, 389 kPa (95% CI, 141 to 715 kPa) (P = .278, compared with placebo/tramadol); single sural nerve stimulation pain tolerance threshold, 12.5 mA (95% CI, 6.2 to 28.3 mA) (P = .278); and pain summation threshold, 8.2 mA (95% CI, 4.4 to 14.6 mA) (P = .179). Paroxetine in combination with placebo showed no analgesic effect. CONCLUSIONS: It is concluded that paroxetine at a dosage of 20 mg once daily for 3 consecutive days significantly inhibits the metabolism of tramadol to its active metabolite M1 and reduces but does not abolish the hypoalgesic effect of tramadol in human experimental pain models, particularly in opioid-sensitive tests.     

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.     

Efficacy and safety of extended-release, once-daily tramadol in chronic pain: a randomized 12-week clinical trial in osteoarthritis of the knee

The efficacy and safety of a once-daily extended-release formulation of tramadol hydrochloride (tramadol ER) was evaluated in patients with moderate to severe chronic pain of osteoarthritis (OA). This was a randomized, double-blind, placebo-controlled, parallel-group, 12-week study. Eligible patients with radiographically confirmed OA of the knee meeting the American College of Rheumatology diagnostic criteria, defined by knee pain and presence of osteophytes, plus at least age >50 years, morning stiffness <30 minutes in duration, and/or crepitus, entered a 2-7 day washout period during which all analgesics were discontinued. When pain at the index knee joint reached > or =40 mm (0-100 mm VAS), patients were randomized to tramadol ER or placebo. Tramadol ER was initiated at 100 mg QD and increased to 200 mg QD by the end of 1 week of treatment. After the first week, further increases to tramadol ER 300 mg or 400 mg QD were allowed. Outcome measures included Arthritis Pain Intensity Visual Analogue Scale (VAS), Western Ontario and McMaster Universities Arthritis Scale (WOMAC) Pain, Stiffness, Physical Function VAS subscales, Patient and Physician Global Assessment of Therapy, Sleep, dropouts due to insufficient therapeutic effect, and adverse events. Two hundred forty-six patients were randomized (tramadol ER 124, placebo 122). There were no baseline differences between the two treatments. The mean age was 61 years, mean duration of OA 12.9 years, and the mean tramadol ER dose was 276 mg QD. All efficacy outcome measures favored tramadol ER over placebo. On the primary outcome variable of average change from baseline in Arthritis Pain Intensity VAS over 12 weeks, tramadol ER was superior to placebo (least squares mean change from baseline: 30.4 mm vs. 17.7 mm, P < 0.001). Significant differences from placebo were evident at week 1, the first post-treatment visit. Similarly, outcomes on the WOMAC Pain, Stiffness and Physical Function subscales, the WOMAC Composite Scale, dropouts due to insufficient therapeutic effect, Patient and Physician Global Assessment of Therapy, and Sleep were all significantly better with tramadol ER than placebo (P < 0.001 to < 0.05). Treatment with tramadol ER results in statistically significant and clinically important and sustained improvements in pain, stiffness, physical function, global status, and sleep in patients with chronic pain. A once-a-day formulation of tramadol has the potential to provide patients increased control over the management of their pain, fewer interruptions in sleep and improved compliance.     

Pain during bone marrow aspiration: prevalence and prevention

The prevalence, intensity, determinants and prevention of pain during bone marrow aspiration (BMA) in adults are not well defined. In the first part of this prospective study (observational phase), 132 adult hematological patients undergoing BMA after local anesthesia scored the procedural pain by means of a visual analogue scale (VAS). Moderate to severe pain was defined as a VAS score exceeding 30 mm. Eighty-six percent reported procedural pain. The VAS score (mean+/-SEM) was 27.2+/-2.1 mm. Thirty-six percent of patients graded the pain as moderate to severe. In a linear regression analysis, VAS score correlated positively with the duration of the procedure (P=0.029) and negatively with the age of the patient (P=0.006). In the second part of the study (interventional phase), 100 patients were randomized to 50 mg tramadol or placebo, given orally at least one hour before BMA. VAS scores during aspiration were significantly lower in tramadol recipients versus placebo recipients (16.5+/-3.0 mm and 28.8+/-3.4 mm, respectively, P=0.003). Pretreatment with tramadol reduced the percentage of patients with at least moderate pain from 40% to 20% (P=0.029). Four tramadol and 3 placebo recipients reported side effects (dizziness or sedation). In conclusion, notwithstanding local anesthesia, the great majority of adult hematological patients experience transient pain during BMA that is of at least moderate intensity in over a third. Pretreatment with tramadol lowers pain intensity significantly and is well tolerated.