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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]

Although the application of CT-guided fluoroscopy techniques for interventional radiology have become more popular, a majority of practitioners in health care remain unfamiliar with their possibilities. Accurate imaging accompanied by guided techniques increase the precision of analgetic procedures, improving results and reducing complications. Main focuses of CT fluoroscopy use in pain management are axial spinal procedures, including zygapophyseal (ZAJ) (facet) joint injection, medial branch rhizolysis, sacroiliac joint injection, transforaminal nerve root block and peri-radicular infiltration, dorsal interlaminar epidural injection, costotransverse and costovertebral joint injections, and blocks of the sympathetic nerve ganglia, splanchnic, and celiac plexus nerve blocks. [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]

Background:: Transdermal buprenorphine is available in Europe for the treatment of moderate to severe chronic pain. It has been evaluated at doses of 35, 52.5, and 70 μg/h for the management of moderate to severe chronic cancer and noncancer pain in 3 randomized, double-blind, placebo-controlled trials, each of limited duration (∼14 days each). Long-term data are essential to determining the performance of an analgesic in the management of chronic pain. Objective:: The purpose of this follow-up study was to obtain data on the efficacy and tolerability of long-term treatment with transdermal buprenorphine in cancer and noncancer patients with chronic persistent pain of moderate to severe intensity. Methods:: This was an open-label, uncontrolled, follow-up study in patients from the 3 previous clinical trials who elected to continue treatment with transdermal buprenorphine 35 μg/h and sublingual buprenorphine tablets (0.2 mg) as needed for breakthrough pain. The patch was to be changed every 72 hours throughout the patient''s course of pain therapy. At visits every 2 weeks for the first 4 weeks and every 4 weeks for the remainder of study participation, patients evaluated their pain relief retrospectively on a 4-point verbal rating scale. They also rated the ease of patch handling using a 3-point verbal rating scale. Patterns of dose escalation and dose stability were monitored over time. Adherence to therapy was determined based on the number of patients who complied with the dosing schedule. Adverse events were documented by type, intensity, location (systemic or local), and relationship to study medication. Results:: Two hundred thirty-nine patients were included in this follow-up study (120 women, 119 men; 100% white; mean [SD] age, 58 [11.3] years; mean weight, 70.8 [14.7] kg). One hundred thirty-four had cancer-related pain and 105 had pain of noncancerous origin. The mean duration of participation was 7.5 months, and 37 (15.5%) patients participated for >12 months. Maximum study participation was 3.4 years in cancer patients and 5.7 years in noncancer patients. One hundred eighty-eight (78.7%) patients were considered adherent to therapy. The majority (65.9%) of patients managed their pain with the patchalone or took no more than 1 additional sublingual tablet daily for breakthrough pain. At least satisfactory pain relief was reported by 215 (90.0%) patients, and the buprenorphine patch was generally well tolerated. The most common systemic adverse drug reactions were nausea (9.2%), dizziness (4.6%), vomiting (4.2%), constipation (3.8%), and tiredness (2.9%), whereas the most common local adverse drug reactions were erythema (12.1%), pruritus (10.5%), and exanthema (8.8%). Conclusion:: Transdermal buprenorphine was generally well tolerated and effective for the long-term treatment of chronic cancer or noncancer pain in these patients who had previously received buprenorphine in 3 short-term clinical trials. [Copyright &y& Elsevier]

Abstract: Background:: The equipotency ratio of transdermal (TD) fentanyl to oral morphine has been established as 1:100; for buprenorphine TD, a ratio of 1:75 has been proposed, although this ratio has not been confirmed in clinical studies. Growing evidence from clinical practice, in which much lower doses of buprenorphine are used, suggests that this conversion ratio may be too high. Objective:: The aim of this study was to comparecalculated equipotent oral morphine doses of fentanyl TD with equipotent oral morphine doses of buprenorphine TD prescribed in clinical practice. Methods:: This retrospective study identified patientswith cancer and noncancer pain who had received ≥1 prescription for fentanyl TD or buprenorphine TD (the all-patients groups) from the German IMS Disease Analyzer-mediplus database, which contains all relevant data concerning drug prescriptions from 400 practices in Germany. Also identified were subgroups of the all-patients groups who had received long-term treatment with fentanyl TD or buprenorphine TD and were considered to have similar pain intensity, as they had previously received similar analgesic medication (the identical-cohort groups). Mean prescribed daily doses for the all-patients and identical-cohort groups were calculated based on the distribution of prescribed patch strengths. Because patients could have applied >1 patch, mean prescribed daily doses were also calculated based on an assumption of double application when appropriate. Equipotent oral morphine doses were estimated using equipotency ratios of 1:100 for fentanyl TD and 1:75 for buprenorphine TD. Results:: The all-patients groups consisted of 2198 patients with noncancer pain and 2544 patients with cancer pain; the identical-cohort groups consisted of 380 patients with noncancer pain and 496 patients with cancer pain (529 women, 347 men; mean age, 74 years [range, 25–101 years]). Equipotent doses of oral morphine were significantly lower in patients receiving buprenorphine TD compared with those receiving fentanyl TD (P &#60; 0.001). In cancer patients, the equipotent oral morphine doses of fentanyl TD and buprenorphine TD were 130.9 to 138.9 mg and 85.2 to 88.8 mg, respectively; in noncancer patients, the corresponding values were 117.0 to 118.3 mg and 80.2 to 80.9 mg. Based on these results, an equipotency ratio of 1:110 to 1:115 for buprenorphine TD would appear to be more appropriate than the proposed ratio of 1:75. Conclusions:: The fact that this retrospective analysis conducted in identical cohorts showed lower calculated equipotent oral morphine doses in the buprenorphine TD groups compared with the fentanyl TD groups calls into question the proposed 1:75 ratio for conversion of buprenorphine TD to equipotent oral morphine doses. Based on the findings of the present study, an equipotency ratio of 1:110 to 1:115 may be more appropriate. However, confirmative data from prospective randomized clinical trials are needed. [Copyright &y& Elsevier]

Background: Buprenorphine is a potent opioid analgesic that is available in sublingual and parenteral formulations. A new formulation, buprenorphine transdermal delivery system (TDS), has been developed.Objective: The aim of this study was to compare the analgesic efficacy and tolerability of the 3 available dosages of buprenorphine TDS (35.0, 52.5, and 70.0 μg/h) with placebo.Methods: This was a randomized, double-blind, placebo-controlled, multicenter study. Patients with chronic, severe pain related to cancer or other diseases and inadequately controlled with weak opioids were randomized to receive buprenorphine TDS 35.0, 52.5, or 70.0 μg/h or placebo patch for up to 15 days. A new patch was applied every 72 hours, for a total of 5 patches. All patients were permitted rescue analgesia with sublingual buprenorphine tablets (0.2 mg) as required for breakthrough pain.Results: A total of 157 patients (86 women, 71 men; mean [SD] age, 58.7 [11.8] years) were initially enrolled in the study. Buprenorphine TDS was associated with significantly higher response rates than was placebo at the 35.0- and 52.5-μg/h dosages (36.6% and 47.5%, respectively, vs 16.2%; P=0.032 and P=0.003, respectively) and a numerically higher response rate at 70.0 μg/h (33.3%), although this difference did not reach statistical significance. Patients treated with buprenorphine TDS experienced a 56.7% reduction in use of sublingual rescue analgesic during the study compared with an 8% reduction with the placebo patch. A total of 43.5% of patients treated with buprenorphine TDS reported good or complete pain relief compared with 32.4% in the placebo group. Pain intensity decreased in a dose-dependent manner with buprenorphine TDS, and the duration of sleep uninterrupted by pain was improved by the end of the study. More than three fourths (78.8%) of patients in the placebo and buprenorphine TDS groups reported at least 1 adverse event (AE) during the study. The most common AEs were central nervous system and gastrointestinal symptoms. The majority of treatment-related AEs were mild or moderate in intensity and were typical of those occurring at the beginning of therapy with a strong opioid.Conclusions: Buprenorphine TDS was shown to be an effective analgesic against chronic, severe pain in this study population. Patients treated with this new formulation of buprenorphine showed improved duration of sleep and reduced need for additional oral analgesics. [Copyright &y& Elsevier]

Abstract: Context: Breakthrough pain is common in patients with cancer and is a significant cause of morbidity in this group of patients. Objectives: The aim of this study was to characterize breakthrough pain in a diverse population of cancer patients. Methods: The study involved 1000 cancer patients from 13 European countries. Patients were screened for breakthrough pain using a recommended diagnostic algorithm and then questioned about the characteristics and management of their pain. Results: Of the 1000 patients, 44% reported incident pain, 41.5% spontaneous pain, and 14.5% a combination. The median number of episodes was three a day. The median time to peak intensity was 10 minutes, with the median for patients with incident pain being five minutes (P < 0.001). The median duration of untreated episodes was 60 minutes, with the median for patients with incident pain being 45 minutes (P = 0.001). Eight hundred six patients stated that pain stopped them doing something, 66 that it sometimes stopped them doing something, and only 107 that it did not interfere with their activities. Patients with incident pain reported more interference with walking ability and normal work, whereas patients with spontaneous pain reported more interference with mood and sleep. As well, 65.5% of patients could identify an intervention that improved their pain (29.5%, pharmacological; 23%, nonpharmacological; 12%, combination). Regarding medications, 980 patients were receiving an opioid to treat their pain, although only 191 patients were receiving a transmucosal fentanyl product licensed for the treatment of breakthrough pain. Conclusion: Breakthrough cancer pain is an extremely heterogeneous condition. [Copyright &y& Elsevier]