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Abstract: Background: In 2001, a transdermal matrix patch formulation of buprenorphine was approved for the treatment of moderate to severe cancer pain and severe pain that is unresponsive to nonopioid analgesics. The primary recommendation contained in the prescribing information was that transdermal patches be worn for a 3-day period before application of a new patch. Objective: This study was conducted to evaluate the potential for extending the time the buprenorphine patch is worn from 3 to 4 days. Methods: This single-center, randomized, open-label, crossover Phase III study compared the efficacy and tolerability of the buprenorphine transdermal patch applied for different durations, with patch changes every 3 days versus every 4 days (12 days each), in patients with chronic moderate or severe pain of malignant or nonmalignant origin. Study participants were aged >18 years, had already responded to at least 4 weeks of transdermal buprenorphine, and had achieved steady-state conditions for at least 2 weeks before enrollment. The primary end point was patients’ rating of the quality of treatment (analgesic efficacy and tolerability, rated on a 5-point scale: very good, good, satisfactory, poor, and inadequate) at the completion of each treatment regimen. Also recorded were physicians'' ratings of the quality of treatment; pain intensity, rated on an 11-point numerical rating scale (from 0 = no pain to 10 = worst pain imaginable) and on the McGill Pain Questionnaire (MPQ) (maximum pain = 3.0); health status, assessed using the 36-item Short Form Health Survey (SF-36), expressed as a percentage of the best health condition (100%); and pain relief (5-point scale: complete, good, satisfactory, slight, and none). Local skin tolerability was evaluated for objective and subjective dermatologic symptoms at the patch application sites. Patients recorded daily pain intensities at specified times of day and night, pain relief (5-point verbal rating scale), and sleep duration (<2 hours, >2–3 hours, >3-<6 hours, or >6 hours) in a diary. The safety profile was evaluated based on standard monitoring of adverse events, vital signs, and routine laboratory tests. Results: Forty-nine white patients (25 women, 24 men) were enrolled; their mean (SD) age was 61.6 (11.5) years, and their mean weight was 74.7 (16.7) kg. The most common source of pain was musculoskeletal disorders (40 patients), followed by nervous system disorders (10), neoplasms (9), injuries (5), and other causes (6). Forty-one patients completed the study; 2 patients discontinued because of adverse events, 1 because of lack of efficacy, and 5 for nonmedical reasons. Thirty-three patients provided data per protocol. Patients in the perprotocol population received a mean (SD) transdermal buprenorphine dose of 49.9 (38.9) pg/h. The proportion of patients in the per-protocol population rating the quality of treatment as adequate (combined ratings of very good, good, and satisfactory) was 93.9% (31/33) for both regimens. The physicians'' ratings indicated adequate quality of treatment in 93.8% (30/32) of patients applying 4 patches for 3 days each and 97.0% (32/33) of patients applying 3 patches for 4 days each. Mean (SD) pain intensity scores on the numerical rating scale were similar after completion of the 3− and 4-day regimens (3.73 [1.88] and 3.88 [1.75] points, respectively), as were MPQ scores (0.79 [0.67] and 0.79 [0.78]). The mean (SD) proportion of days with at least satisfactory pain relief was 83.9% (26.1%) and 85.6% (24.4%) for the 3- and 4-day regimens; the corresponding proportions of nights with at least satisfactory pain relief were 85.2% (26.6%) and 88.1% (21.4%). Continuously assessed pain intensities at specified times of day and night (numerical rating scale) did not differ significantly between regimens. Mean SF-36 health status scores did not differ significantly between regimens (total score: 37.7% [17.0%] and 37.7% [17.3%]). Mean rates of nights with good sleep quality were 28.5% (39.9%) for the 3-day regimen and 36.0% (42.6%) for the 4-day regimen. Local skin tolerability was comparable for the 3− and 4-day regimens, with objective findings (mainly erythema) at the patch-application sites in 17 of 32 and 11 of 33 patients, respectively, and subjective symptoms (mainly itching) in 16 of 32 and 13 of 33 patients. The most common adverse events in the safety population were nausea, dizziness/giddiness, and malaise/fatigue (3/49 [6.1%] each). Conclusion: Analgesic efficacy, patients'' satisfaction with the quality of treatment, and skin tolerability did not differ significantly between 3 and 4 days of patch application in these patients with chronic pain who had been previously stabilized on transdermal buprenorphine. [Copyright &y& Elsevier]

Abstract: Background:: Tramadol is widely prescribed, even to the eldest patients. Although age-related differences in pharmacologic responsiveness are to be expected, the pharmacodynamic and pharmacokinetic (PK) properties of tramadol have not been systematically compared between patients of various ages. Objective:: The aim of this study was to explore the effectiveness, PK properties, and safety profile of 2 galenic tramadol formulations in 3 similarly sized age groups with malignant and nonmalignant pain of moderate to severe intensity. Methods:: This prospective, age-group-controlled study was conducted at the ambulatory pain clinic of the Landeskrankenhaus Kärnten, Klagenfurt, Austria. Male and female adults with malignant and nonmalignant pain of moderate to severe intensity were eligible. Patients were stratified into similarly sized age groups, as follows: ≥75, 65-<75, and <65 years. Patients first received the immediate-release galenic formulation of tramadol (tramadol IR) until steady state was achieved, followed by the sustained-release formulation (tramadol SR) until steady state. Serum concentrations of tramadol and its active metabolite (O-desmethyl-tramadol [M1]) were measured using gas chromatography to estimate the age-related PK handling of the analgesic drug. Three validated scales were used to measure pain intensity during the study: a 100-mm visual analog scale (VAS), an 11-point numeric analog scale (NAS), and a 4-point verbal rating scale (VRS). Tolerability was assessed by evaluating daily answers about the potential occurrence of adverse events (and respective details such as type and severity) from baseline until the end of the observation period. Results:: A total of 100 patients were enrolled (58 women, 42 men; mean [SD] age, 65.2 [15.0] years; ≥75, 30 patients; 65-<75, 31 patients; and <65 years, 39 patients). Predominant causes of pain were neoplasms (27.4% of causes) and injury and other external causes (20.8%), and diseases of the musculoskeletal and connective-tissues systems (19.8%). Fifty-five patients completed the study and provided all data as planned. Mean (SEM) steady-state tramadol IR doses were 250 (20.2), 277 (39.8), and 325 (33.1) mg/d in patients aged ≥75, 65-<75, and 65 years, respectively (P = NS); tramadol SR, 278 (27.5), 306 (39.7), and 340 (35.1) mg/d (P = NS). Serum concentrations of tramadol and M1 were statistically similar across all 3 age groups. Overall, mean pain intensity scores, as measured using the VAS and NAS, were decreased from baseline (62.4 [2.0] mm and 6.22 [0.22] points, respectively) to steady state with tramadol IR (23.6 [2.9] mm and 2.65 [0.30] points) and tramadol SR (16.9 [2.5] mm and 1.91 [0.26] points) (all, P < 0.001). Pain intensity before and improvements during both treatment phases were similar across all 3 age groups. Results:: for pain intensity on the VRS also did not find age-related differences. The predominant adverse effects were nausea (27.0% of patients), dizziness and giddiness (18.0%), and malaise and fatigue (15.0%); no significant differences in adverse events were found between age groups. Conclusions:: The fate of tramadol and its active metabolite, and their clinical effects, have been examined here for the first time in a prospective cohort study, which compared patients aged <65 years, 65-<75 years, and ≥75 years. In contrast to expecta tions, it was concluded that tramadol IR and tramadol SR were both generally well tolerated and effective in the treatment of moderate to severe pain in any of the 3 age groups in these patients. Although the eldest group of patients consumed, on average, 20% less tramadol (P = NS) than the youngest group, the PK properties of both drugs were not changed when given to elderly patients. [Copyright &y& Elsevier]