Marc Kamin

Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study

PURPOSE To evaluate the efficacy and safety of a combination analgesic tablet (37.5 mg tramadol/325 mg acetaminophen) for the treatment of fibromyalgia pain. METHODS This 91-day, multicenter, double-blind, randomized, placebo-controlled study compared tramadol/acetaminophen combination tablets with placebo. The primary outcome variable was cumulative time to discontinuation (Kaplan-Meier analysis). Secondary measures at the end of the study included pain, pain relief, total tender points, myalgia, health status, and Fibromyalgia Impact Questionnaire scores. RESULTS Of the 315 subjects who were enrolled in the study, 313 (294 women [94%], mean [+/- SD] age, 50 +/- 10 years) completed at least one postrandomization efficacy assessment (tramadol/acetaminophen: n = 156; placebo: n = 157). Discontinuation of treatment for any reason was less common in those treated with tramadol/acetaminophen compared with placebo (48% vs. 62%, P = 0.004). Tramadol/acetaminophen-treated subjects also had significantly less pain at the end of the study (53 +/- 32 vs. 65 +/- 29 on a visual analog scale of 0 to 100, P <0.001), and better pain relief (1.7 +/- 1.4 vs. 0.8 +/- 1.3 on a scale of -1 to 4, P <0.001) and Fibromyalgia Impact Questionnaire scores (P = 0.008). Indexes of physical functioning, role-physical, body pain, health transition, and physical component summary all improved significantly in the tramadol/acetaminophen-treated subjects. Discontinuation due to adverse events occurred in 19% (n = 29) of tramadol/acetaminophen-treated subjects and 12% (n = 18) of placebo-treated subjects (P = 0.09). The mean dose of tramadol/acetaminophen was 4.0 +/- 1.8 tablets per day. CONCLUSION A tramadol/acetaminophen combination tablet was effective for the treatment of fibromyalgia pain without any serious adverse effects.

Efficacy of tramadol in treatment of pain in fibromyalgia.

&NA; An outpatient, randomized, double‐blind, placebo‐controlled clinical trial was conducted to evaluate the efficacy and safety of tramadol in the treatment of the pain of fibromyalgia syndrome. One hundred patients with fibromyalgia syndrome, (1990 American College of Rheumatology criteria), were enrolled into an open‐label phase and treated with tramadol 50–400 mg/day. Patients who tolerated tramadol and perceived benefit were randomized to treatment with tramadol or placebo in the double‐blind phase. The primary efficacy outcome measurement was the time (days) to exit from the double‐blind phase because of inadequate pain relief, which was reported as the cumulative probability of discontinuing treatment because of inadequate pain relief. One hundred patients entered the open‐label phase; 69% tolerated and achieved benefit with tramadol. These patients were then randomized to continue tramadol (n = 35) or convert to a placebo (n = 34) during a 6week, double‐blind treatment period. The Kaplan‐Meier estimate of cumulative probability of discontinuing the double blind period because of inadequate pain relief was significantly lower in the tramadol group compared with the placebo group (p = 0.001). Twenty (57.1%) patients in the tramadol group successfully completed the entire double‐blind phase compared with nine (27%) in the placebo group (p = .015). These results support the efficacy of tramadol over a period of 6 weeks in a double blind study for the treatment of the pain of fibromyalgia in a group of patients who had been determined to tolerate it and perceive a benefit.

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 </= 0.027) and scores on many subcategories of the SF-MPQ, including total score (P = 0.021). The tramadol/APAP group had significant improvements on the role-physical (P = 0.005), bodily pain (P = 0.046), role-emotional (P = 0.001), mental health (P = 0.026), reported health transition (P = 0.038), and mental component summary (P = 0.008) subscales of the SF-36. The cumulative incidence of discontinuation due to insufficient pain relief was 22.1% for tramadol/APAP and 41.0% for placebo (P < 0.001). Treatment-emergent adverse events in the tramadol/APAP group included nausea (13.0%), somnolence (12.4%), and constipation (11.2%). CONCLUSIONS In this study, tramadol 37.5 mg/APAP 325 mg combination tablets were effective and had a favorable safety profile in the treatment of chronic lower back pain.

Tramadol allows reduction of naproxen dose among patients with naproxen‐responsive osteoarthritis pain: A randomized, double‐blind, placebo‐controlled study

OBJECTIVE To demonstrate that in patients receiving naproxen for the pain of osteoarthritis (OA), the addition of tramadol will allow a reduction in the naproxen dosage without compromising pain relief. METHODS This trial consisted of a 5-week open-label run-in and an 8-week double-blind phase. Patients with at least moderate pain (> or =40 mm on a 100-mm visual analog scale) of OA of the knee after a 1-week medication washout were treated with naproxen 500 mg/day for 1 week. Patients whose pain scores were reduced to <20 mm were discontinued. The remaining patients received naproxen 1,000 mg/day for 3 weeks. Tramadol 200 mg/day was added during the third week. Patients were then randomized in a double-blind manner to continue tramadol 200 mg/day or to begin placebo in addition to naproxen. Randomization was stratified based on response to naproxen 1,000 mg/day. During the double-blind phase, the naproxen dose was reduced by 250 mg every 2 weeks. The primary efficacy end point was the minimum effective naproxen dose (MEND). The MEND was defined as 250 mg above the naproxen daily dosage at which pain relief was no longer adequate. Patients discontinuing the double-blind phase of the study for reasons other than lack of efficacy were assigned a MEND equal to the last naproxen dose received. If the effect of treatment between the responder and nonresponder groups was statistically different, the difference in the MEND was assessed separately within the groups. RESULTS Of 236 patients randomized (mean age 61 years; 147 females), 90 were stratified as naproxen responders and 146 as naproxen nonresponders. There was a significant difference (P = 0.040) in the treatment effect between the naproxen responders and nonresponders, thus demonstrating a difference in the way responders and nonresponders react to a decrease in naproxen dosage after the addition of tramadol. Among naproxen responders, the MEND was significantly lower in patients receiving tramadol (n = 36) than in patients receiving placebo (n = 54), 221 mg versus 407 mg, respectively (P = 0.021). For the naproxen nonresponders, the mean MEND was 419 mg in the tramadol group and 396 mg in the placebo group (P = 0.706). CONCLUSION In patients with painful OA of the knee responding to naproxen 1,000 mg/day, the addition of tramadol 200 mg/day allows a significant reduction in the dosage of naproxen without compromising pain relief.

Tramadol for the treatment of joint pain associated with osteoarthritis: a randomized, double-blind, placebo-controlled trial☆

Abstract Background: Results from short-term, non—placebo-controlled clinical trials suggest that tramadol is effective as adjunctive therapy for the treatment of joint pain associated with osteoarthritis (OA). Objective: We assessed the efficacy and tolerability of tramadol monotherapy versus placebo in the treatment of joint pain associated with OA. Methods: Patients with symptomatic OA of the knee and at least moderate pain at the end of a 10-day analgesic washout period were randomized to receive tramadol or placebo. After a 7-day titration period (50-mg increments every 2 days to a target dosage of 200 mg/d), patients were permitted to increase their dose up to 400 mg/d as needed for 84 days. Likert scale scores to assess pain intensity (none = 0 to extreme=4) and pain relief (complete relief=3 to severely worse=−3) as well as Western Ontario and McMaster Universities (WOMAC) OA Index scores were obtained at visits on days 14, 28, 56, and 91 of the study. Patient and investigator global assessments of treatment effectiveness were recorded at the final visit (day 91 or at the time of discontinuation). Results: Baseline characteristics were similar for the tramadol (n = 63) and placebo (n = 66) groups; more than half of the patients (mean age 62.5 years) were women (65.1% and 59.1% in the tramadol and placebo groups, respectively). Mean final pain intensity scores were 2.10 in the tramadol group and 2.48 in the placebo group ( P = 0.082, analysis of covariance). Tramadol was significantly more effective than placebo for all secondary outcomes: mean final pain intensity scores ( P = 0.045, t test), pain relief scores ( P = 0.004), patient and investigator global assessments ( P = 0.038 and P = 0.001, respectively), median time to failure of effectiveness ( P = 0.042), and all WOMAC scores ( P ≤ 0.033). Fourteen tramadol and 10 placebo patients discontinued the study because of adverse events (AEs). Other reasons for discontinuation included lack of efficacy (26 tramadol and 43 placebo patients) and patient choice (10 tramadol and 11 placebo patients). The most common AEs during tramadol therapy were nausea, constipation, dizziness, pruritus, and headache; no serious AEs, seizures, or cases of abuse were reported in the tramadol group. Conclusion: Tramadol may be useful as monotherapy in the treatment of joint pain associated with OA.

Tramadol/Acetaminophen Combination Tablets for the Treatment of Pain Associated with Osteoarthritis Flare in an Elderly Patient Population

Objectives: To evaluate the efficacy and safety of adding tramadol 37.5 mg/acetaminophen (APAP) 325 mg combination tablets (tramadol/APAP) to existing therapy for painful osteoarthritis (OA) flare in a subset of elderly patients.

Topiramate Titration to Response: Analysis of Individualized Therapy Study (TRAITS)

OBJECTIVE: To evaluate the relationship between baseline seizure frequency and stabilized topiramate dosage and the effect of individualized treatment on tolerability in adults with partial-onset seizures receiving other antiepileptic drugs (AEDs). METHODS: In this 20-week, open-label trial, dosages of medications were adjusted according to clinical response. Dosage and seizure response data were analyzed for 2 groups defined by baseline seizure frequency: <4 and ≥4 seizures per month. RESULTS: In the outcome evaluable population (n = 471), the mean ± SEM stable topiramate dosage was 303 ± 139 mg/d when baseline seizure frequency was <4 seizures/month and 341 ± 153 mg/d when baseline seizure frequency was ≥4 seizures/month (p = 0.005). The most common adverse events were somnolence (8.5%), fatigue (7.3%), nausea (5.3%), and dizziness (5.0%). Cognitive complaints were reported by <3% of patients. When concomitant AED dosages were reduced, 14% of patients discontinued topiramate due to adverse events compared with 23% if the concomitant AED dosage was unchanged or increased. CONCLUSIONS: When clinicians individualize topiramate dosage according to clinical response, the stabilized topiramate dosage as add-on therapy is influenced by baseline seizure frequency. Topiramate tolerability is improved when dosages of concomitant AEDs are reduced.

Effect of Cotherapy Reduction on Tolerability of Epilepsy Add-On Therapy: A Randomized Controlled Trial

BACKGROUND: Adverse effects are the most common cause for failure of an antiepileptic drug (AED), especially when an AED is added to existing therapy. With the increased drug load, it may not be possible to titrate the newly added AED to effective doses. Reducing the dosage of AED cotherapy as the new drug is introduced may improve tolerability. OBJECTIVE: To evaluate reduction of AED cotherapy as a strategy to improve tolerability and patient retention when a new AED is added to existing therapy. METHODS: In a 20-week, randomized, open-label study, topiramate was initiated as add-on therapy in adults and adolescents (⩾12 y of age) with inadequately controlled partial-onset seizures. Patients were randomized to receive treatment in which adverse events could be managed by adjustments in AED cotherapy (flex-dose group) or treatment in which AED cotherapy dosages remained fixed (fixed-dose group). Topiramate could be adjusted as needed in both groups. In the flex-dose group, patients exited randomized treatment when topiramate was discontinued. In the fixed-dose group, patients exited when AED cotherapy was reduced due to adverse events or when topiramate was discontinued. The primary study outcome was the percentage of patients exiting randomized treatment due to adverse events. RESULTS: The flex-dose group comprised 297 patients; 302 patients were in the fixed-dose group. Significantly fewer patients in the flex-dose group exited the study due to adverse events (16% vs 23% in the fixed-dose group; p = 0.02). In the flex-dose group, 10% (17 of 168) of patients discontinued topiramate due to adverse events after AED cotherapy was reduced versus 22% (29 of 129) when AED cotherapy was not reduced. CONCLUSIONS: Reduction of AED cotherapy is a useful strategy to improve tolerability and retention when topiramate is initiated as adjunctive therapy.

Creutzfeldt-Jakob disease: Possible transmission to humans by consumption of wild animal brains

Although the natural mode of spread of the agent responsible for Creutzfeldt-Jakob disease is unknown, several reports suggest oral transmission through consumption of contaminated food or brain. This report summarizes four cases of Creutzfeldt-Jakob disease in which a history of eating the brains of wild goat or squirrel was obtained. These cases support the hypothesis of possible acquisition of Creutzfeldt-Jakob disease by ingestion of the agent from a presumptive reservoir in the central nervous system of wild animals.

Response letter to Nachamie et al.

To the Editor: We were pleased to see an article by Rosenthal et al. about tramadol/acetaminophen use specifically in older persons. As the authors discuss, there are few studies on osteoarthritis in this age group. We also agree with the study’s endpoints that follow the Osteoarthritis Society’s research guidelines for evaluating pain, function, and the patient’s global assessment, although we have some concerns regarding the methodology of this study as well as the generalizability of the results outlined by the authors. First, a primary eligibility criterion for enrollment was the current use of a nonsteroidal antiinflammatory agent, which several expert consensus panels generally consider to be second-line therapy for osteoarthritis. These consensus panels all agree that acetaminophen alone is considered to be first-line therapy. The study’s intervention was to add tramadol/acetaminophen. By using an intervention that combines tramadol with acetaminophen, it is impossible to differentiate the effect of tramadol from acetaminophen. A multiarm study including acetaminophen only and tramadol only would have been more clinically useful. In addition, we suspect that this study is not generalizable to the typical geriatric osteoarthritis population. The exclusion criteria outlined by the authors essentially limit participants in the study to a functional, physically fit, and mentally intact patient population. These criteria do not come close to representing the often cognitively impaired, frail, and medically complex patient base that geriatricians see. Although the authors need to be commended for studying the elderly, their exclusion criteria make the study group more representative of a typical younger patient population. Additionally, the exclusion criteria are so extensive that we suspect that many people needed to be screened to find the rare older person who met their eligibility criteria, but the authors failed to include this information in the manuscript. We are anxiously awaiting effectiveness and safety studies in a frail geriatric population. Given these concerns, we find that this article provides little insight or guidance for geriatricians in managing pain in a typical population. We urge researchers to continue to study older persons and to perform effectiveness studies more consistently.