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Introduction: Results of retrospective studies examining the relationship between prolactin increasing antipsychotics and incident breast cancer have been inconsistent. This study assessed the association between use of high prolactin increasing antipsychotics (HPD) and the incidence of breast cancer using best practices in pharmacoepidemiology. Methods: Using administrative claims data from the MarketScan Medicaid database, schizophrenia patients initiating antipsychotics were identified. Those initiating HPD were compared with new users of non/low prolactin increasing drugs (NPD). Two definitions of breast cancer, two at-risk periods, and two large-scale propensity score (PS) adjustment methods were used in separate analyses. PS models included all previously diagnosed conditions, medication use, demographics, and other available medical history. Negative control outcomes were used for empirical calibration. Results: Five analysis variants passed all diagnostics for sufficient statistical power and balance across all covariates. Four of the five variants used an intent-to-treat (ITT) approach. Between 4,256 and 6,341 patients were included in each group for the ITT analyses, and patients contributed approximately four years of follow-up time on average. There was no statistically significant association between exposure to HPD and risk of incident breast cancer in any analysis, and hazard ratios remained close to 1.0, ranging from 0.96 (95% confidence interval 0.62 - 1.48) to 1.28 (0.40 - 4.07). Discussion: Using multiple PS methods, outcome definitions and at-risk periods provided robust and consistent results which found no evidence of an association between use of HPD and risk of breast cancer. [ABSTRACT FROM AUTHOR]

Background Paliperidone palmitate 6-month (PP6M) demonstrated noninferiority to paliperidone palmitate 3-month in preventing relapse in patients with schizophrenia in a phase 3 double-blind (DB) study (NCT03345342). Here, we report long-term efficacy and safety results from a 2-year single-arm, open-label extension (OLE; NCT04072575) of this DB study. Methods Participants who completed the DB study without relapse were enrolled and followed-up every 3 months up to 2 years. Participants received 4 PP6M gluteal injections (700/1000 mg eq.) at baseline, 6-month, 12-month, and 18-month visits. Efficacy endpoints included assessment of relapse, Positive and Negative Syndrome Scale total score, Personal and Social Performance score, and Clinical Global Impression-Severity scale change from baseline. Safety was assessed by treatment-emergent adverse events (TEAEs), physical examinations, and laboratory tests. Results Of 178 participants enrolled, 154 (86.5%) completed the OLE (mean age: 40.4 years, men: 70.8%; mean duration of PP6M exposure during OLE: 682.1 days). Overall, 7/178 (3.9%) participants relapsed between 20 and 703 days after enrolment. Mean (SD) changes from baseline to endpoint were as follows: Positive and Negative Syndrome Scale total score, 0.7 (8.22); Clinical Global Impression-Severity, 0.0 (0.51); and Personal and Social Performance Scale, 0.5 (7.47). Overall, 111/178 participants (62.4%) reported ≥1 TEAE; most common (>5%) TEAEs were headache (13.5%) and increased blood prolactin/hyperprolactinemia (18.0%); 8/178 (4.5%) participants experienced serious TEAEs, and 6/178 (3.4%) participants withdrew due to TEAEs. No deaths were reported. Conclusions The relapse rate observed with PP6M during the 2-year OLE was low (3.9%). Clinical and functional improvements demonstrated in the DB study were maintained during OLE, and no new safety concerns were identified. Trial registration ClinicalTrials.gov Identifier: NCT04072575; EudraCT number: 2018-004532-30. [ABSTRACT FROM AUTHOR]

Purpose: To examine efficacy and safety of paliperidone palmitate (PP) 6-month (PP6M) vs PP3-month (PP3M) long acting injectable (LAI) in patients with schizophrenia from European sites previously stabilized on PP3M or PP1-month (PP1M). Methods: This post-hoc subgroup analysis used data from a global phase-3 double-blind (DB) randomized non-inferiority study (NCT03345342). Patients were randomized (2:1, respectively) to receive dorsogluteal injections of PP6M (700 mg eq. or 1000 mg eq.) or PP3M (350 mg eq. or 525 mg eq.) in the 12-month DB phase. Primary endpoint was time-to-relapse during the DB phase, using a Kaplan–Meier cumulative survival estimate (non-inferiority margin 95% CI lower bound larger than prespecified as − 10%). Treatment emergent adverse events (TEAEs), physical examinations, and laboratory tests were also evaluated. Results: A total of 384 patients who entered the DB phase were included in European sites (PP6M, n = 260; PP3M, n = 124) with a mean age similar in both groups (mean age [SD] years: PP6M, 40.0 [11.39]; PP3M, 38.8 [10.41]). Baseline characteristics were similar across both groups. The number of patients who experienced a relapse during DB phase were PP6M: 18 (6.9%) vs PP3M: 3 (2.4%) with percentage relapse-free difference of − 4.9% (95% CI: − 9.2%, − 0.5%), thus achieving non-inferiority criteria. Secondary efficacy endpoints indicated comparable improvements. Incidence of TEAEs was similar between PP6M (58.8%) and PP3M (54.8%) groups. Nasopharyngitis, headache, increased weight, and injection-site pain were the most common TEAEs. Conclusion: The efficacy of PP6M was non-inferior to that of PP3M in preventing relapse in the European subgroup previously treated with PP1M or PP3M, which was consistent with the global study. No new safety signals were identified. [ABSTRACT FROM AUTHOR]

Abstract Background Some patients with long-standing low back pain will benefit from treatment with strong opioids. However, it would be helpful to predict which patients will have a good response. A fixed-term opioid trial has been recommended, but there is little evidence to suggest how long this trial should be. We assessed data from a large-scale randomized comparison of transdermal fentanyl (TDF) and sustained-release oral morphine (slow-release morphine; SRM) to determine characteristics of treatment responders. Methods This was a secondary analysis of a previously published 13-month randomized trial involving 680 patients with long-standing low back pain (median age 52 years, 61% women, median duration of back pain 87 months). Pain relief was recorded using visual analogue scales (VAS). Treatment response was defined as pain relief of at least 30% from baseline to any point during the trial. We used a step-wise logistic regression to identify variables that might predict response to treatment. Covariates included treatment group, sex, age, duration of pain, presence of neuropathic pain, baseline pain scores, educational/employment status, use of high doses of opioids, and social functioning (SF)-36 scores. Results Over half the patients in both groups (n = 370; 54% TDF, 55% SRM) were treatment responders. There were no differences between the TDF and SRM responders in terms of age, sex, type or duration of pain between responders and non-responders. The difference in response to treatment between responders and non-responders could be detected at 3 weeks. Lack of response after 1 month had a stronger negative predictive value (i.e., ability to detect non-responders) than the presence of response after 1 month. The most influential factors for predicting a response were employment status (χ2 = 11.06, p = 0.0259) and use of high doses of opioids (χ2 = 3.04, p = 0.0811). Conclusion No clear pattern of baseline pain (type or severity) or patient characteristics emerged that could be used to predict responders before the start of opioid treatment. However, a 1-month trial period appears sufficient to determine response and tolerability in most cases.

Abstract Background This study was designed to evaluate the utility of transdermal fentanyl (TDF, Durogesic®) for the treatment of pain due to osteoarthritis (OA) of the knee or hip, which was not adequately controlled by non-opioid analgesics or weak opioids. The second part of the trial, investigating TDF in patients with rheumatoid arthritis (RA) is reported separately. Methods Current analgesia was optimised during a 1-week run-in. Patients then received 28 days treatment with TDF starting at 25 μg/hr, with the option to increase the dose until adequate pain control was achieved. Metoclopramide was taken during the first week and then as needed. Results Of the 159 patients recruited, 75 with OA knee and 44 with OA hip completed the treatment phase, 30 knee and 18 hip patients entered the one-week taper-off phase. The most frequently used maximum dose of TDF was 25 μg/hr. The number of patients with adequate pain control increased during the run-in period from 4% to 27%, and further increased during TDF treatment to 88% on day 28. From baseline to endpoint, there were significant reductions in pain (p < 0.001) and improvements in functioning (p < 0.001) and physical (p < 0.001) and mental (p < 0.05) health. Scores for 'pain right now' decreased significantly within 24 hours of starting TDF treatment. TDF was assessed favourably and 84% of patients would recommend it for OA-related pain. Nausea and vomiting were the most common adverse events (reported by 32% and 26% of patients respectively), despite prophylaxis with metoclopramide, which showed limited efficacy in this setting. Conclusion TDF significantly increased pain control, and improved functioning and quality of life. Metoclopramide appeared to be of limited value in preventing nausea and vomiting; more effective anti-emetic treatment may enable more people to benefit from strong opioids such as TDF. This study suggests that four weeks is a reasonable period to test the benefit of adding TDF to improve pain control in OA patients and that discontinuing therapy in cases of limited benefit creates no major obstacles.

Once-daily hydromorphone extended-release (OROS® hydromorphone ER) and oxycodone controlled-release (CR) are semisynthetic, ER opioid analgesics with established efficacy. An open-label, randomized, 24-week, parallel group, flexible-dose study demonstrated noninferiority of OROS hydromorphone ER vs. twice-daily oxycodone CR in patients with chronic noncancer pain. In total, 112 patients were enrolled in a 28-week, open-label extension study; 60 patients received OROS hydromorphone ER and 52 received oxycodone CR. The primary efficacy measure was the change from baseline to Weeks 38 and 52 in Brief Pain Inventory item 'pain right now.' Global assessments of efficacy, dosing convenience, and tolerability were secondary endpoints. Mean change in 'pain right now' from baseline to Week 38 was −3.0 (OROS hydromorphone ER) vs. −2.8 (oxycodone CR), and from baseline to Week 52 was −2.9 vs. −2.8; these changes were similar to the changes in the core phase (−2.1 vs. −2.1). Similar improvements were demonstrated for secondary assessments, including pain, pain interference, and quality of life. At Week 52, global assessment of efficacy was rated as 'very good' or 'good' by the majority of patients (OROS hydromorphone ER, 91.7%; oxycodone CR, 86.5%). More patients in the OROS hydromorphone ER group (35.0% vs. 21.2%) assessed mode of drug intake as 'very convenient.' The majority of patients receiving OROS hydromorphone ER (88.3%) and oxycodone CR (88.5%) rated tolerability as 'good' or 'very good' at Week 52; few patients discontinued treatment because of an adverse event (1.6% vs. 0.4%, respectively). The effectiveness of OROS hydromorphone ER and oxycodone CR was maintained through 1 year. [ABSTRACT FROM AUTHOR]

Background: Acetylcholinesterase inhibitors are considered standard of care for Alzheimer's disease in many countries. Galantamine is an acetylcholinesterase inhibitor that may also act via allosteric modulation of nicotinic acetylcholine receptors. Therefore, it may provide benefits compared with other acetylcholinesterase inhibitors. The present study compared galantamine (n = 116) with donepezil (n = 117) in a double-blind trial at nine hospitals in China. Methods: After washout of any previous acetylcholinesterase inhibitors, subjects with mild to moderate Alzheimer's disease received galantamine or donepezil for 16 weeks. Results: Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog/11) scores improved significantly from baseline in both treatment arms, with a significant difference in favor of galantamine on the "language" functional area (P = 0.035). Significantly more galantamine-treated patients responded to treatment (defined as a reduction in ADAS-cog/11 score of .4, .7, or .10 points; all P , 0.05), and had an ADAS-cog/11 score , 20 at end point (P = 0.015). Both treatments were well tolerated, although fewer galantamine-treated patients experienced gastrointestinal adverse events compared with donepezil (30% versus 48%). Conclusion: Cognitive function improved significantly in subjects with mild to moderate Alzheimer's disease treated with galantamine or donepezil, and both treatments were generally well tolerated. Significant benefits for galantamine over donepezil were observed for language and response to treatment. [ABSTRACT FROM AUTHOR]

Objective: To characterize the steady-state pharmacokinetic profile of hydromorphone extended-release (ER) in patients with chronic pain taking concomitant medications. Methods: This open-label repeat-dose study enrolled 22 patients (mean age, 51.4 years; 81.8% female). All patients were receiving at least one concomitant medication; 86.4% were receiving at least two concomitant medications and 81.8% were receiving at least three. Patients receiving a stable dose of an opioid were converted to hydromorphone ER at a 5:1 ratio (morphine equivalent:hydromorphone). The dose was titrated to adequate analgesia over 3-14 days and stabilized between 8-48 mg. Oral morphine immediate-release was permitted for breakthrough pain. Area under the concentration-time curve from 0-24 hours (AUC0-24), maximum plasma concentration (Cmax), trough plasma concentration (Cmin), average plasma concentration (Cavg), and degree of fluctuation (100 × [(Cmax - Cmin) ÷ Cavg]) were calculated based on data from 14 patients. Results: Dose-normalized to 16 mg, mean pharmacokinetic parameter values were: AUC0-24, 41.1 ng . h/mL; Cmax, 2.6 ng/mL; Cmin, 1.1 ng/mL; Cavg, 1.7 ng/mL; and the degree of fluctuation was 99.6%. The pharmacokinetic profile of hydromorphone ER was linear and consistent with dose proportionality. Mean pain intensity difference scores showed statistically significant improvement from 2-21 hours after dosing. Sixteen (72.7%) patients reported at least one adverse event (AE). The most common were constipation (31.8%), headache (22.7%), and vomiting (13.6%). One patient discontinued treatment due to vomiting. No deaths, serious AEs, or unexpected AEs occurred. Conclusion: These findings replicate and extend the steady-state pharmacokinetic profile of hydromorphone ER, previously characterized in healthy volunteers, to a population of chronic pain patients taking numerous concomitant medications. [ABSTRACT FROM AUTHOR]

Galantamine improved symptoms in Alzheimer's disease (AD) patients after 5 to 6 months of treatment. To examine long-term outcomes, this study assessed if continuing of galantamine treatment beyond 12 months delayed further cognitive deterioration. It consisted of two phases: an open label (OL) phase (12 months), followed by a double blind, randomized, placebo controlled withdrawal phase (up to 24 months). Subjects with mild to moderate AD were included in the study and titrated up to 16 mg/day of galantamine. Subjects were eligible to enter the double blind phase if a cognitive decline of <4 points on AD Assessment Scale-cognitive subscale (ADAS-cog)/11 was recorded at the end of the OL phase. The differences between galantamine and placebo in time to dropout were estimated using the Cox proportional hazard model. 47.4% of galantamine and 31.7% of placebo subjects completed the double blind phase. Placebo subjects were more likely to discontinue prematurely than galantamine subjects for any reason (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.10-2.81, p = 0.02), or lack of efficacy (HR 1.80, 95% CI 1.02-3.18, p = 0.04); no statistically significant difference was seen for a change in ADAS-cog ≥4 between treatment groups (HR 1.66, 95% CI 0.78-3.54, p = 0.19). Subjects who responded to 12 months of galantamine treatment benefited from continued drug therapy for up to 36 months. Galantamine was effective in delaying time to cognitive deterioration in subjects with mild to moderate AD. Treatment was generally safe and well tolerated. [ABSTRACT FROM AUTHOR]

This was a randomized, open-label, comparative, parallel group study designed to demonstrate the noninferiority of once-daily OROS® hydromorphone compared with twice-daily sustained-release (SR) oxycodone in subjects with chronic noncancer pain severe enough to require continuous opioid therapy. The core phase (24 weeks) consisted of titration and maintenance periods. This was followed by an optional extension phase (28 weeks), which collected data used to assess long-term safety and efficacy outcomes. Five hundred four subjects were randomized between the 2 treatment groups. The primary efficacy analysis showed that OROS hydromorphone was noninferior to SR oxycodone ( P = 0.011) as measured by change in Brief Pain Inventory (BPI) pain severity subscore “pain right now.” The treatment difference with respect to change in BPI pain severity subscore “pain right now” was 0.29 (95% confidence interval: −0.27 to 0.84). The equianalgesic doses were 16 mg OROS hydromorphone and 40 mg SR oxycodone (median values). Secondary outcomes included other BPI scale items, the Medical Outcomes Study (MOS) Sleep Indices, and quality of life measured by the Short Form 36 (SF-36) questionnaire. Both treatment groups showed improvements in the main secondary efficacy endpoints. No statistically significant differences were shown between the treatment groups, except for the scores for somnolence (MOS sleep subscale) and physical functioning (SF-36), which both had a statistically significant difference between treatments groups in favor of OROS hydromorphone. Both study medications had equivalent and acceptable safety profiles. The results of this open-label study showed that once-daily OROS hydromorphone is a safe and well-tolerated treatment for chronic pain and as efficacious as twice-daily SR oxycodone. [ABSTRACT FROM AUTHOR]

This pooled analysis was designed to determine whether the analgesic response to treatment with OROS® hydromorphone, as measured by the “pain on average” scale of the Brief Pain Inventory (BPI), was different in patients with neuropathic pain compared to those with nociceptive pain, after adjusting for differences in baseline characteristics. Three open-label studies on patients with neuropathic and nociceptive malignant and nonmalignant chronic pain were analyzed. A mixed model for repeated measures linear regression analysis was used to compare the effect of OROS® hydromorphone on patients with neuropathic and nociceptive pain, adjusting for potentially confounding factors. Data from patients with pure neuropathic pain and mixed pain were also compared. Safety and tolerability was assessed by recording the number of adverse events. The primary outcome was “pain on average” (BPI item 5) over time. Secondary outcomes were the effect of OROS® hydromorphone on other BPI items including “pain relief” and “interference with sleep.” Patients with neuropathic pain showed a similar response to treatment with OROS® hydromorphone to those patients with nociceptive pain. There was no statistically significant difference between the pain groups (difference between groups −0.552 at visit 7; P = .060 for overall difference between groups). For some outcome variables, treatment was more effective for patients with neuropathic pain. The treatment was generally well tolerated. This pooled analysis shows that treatment with OROS® hydromorphone had similar efficacy for neuropathic and nociceptive pain. [ABSTRACT FROM AUTHOR]

Background: Some patients with long-standing low back pain will benefit from treatment with strong opioids. However, it would be helpful to predict which patients will have a good response. A fixed-term opioid trial has been recommended, but there is little evidence to suggest how long this trial should be. We assessed data from a large-scale randomized comparison of transdermal fentanyl (TDF) and sustained-release oral morphine (slow-release morphine; SRM) to determine characteristics of treatment responders. Methods: This was a secondary analysis of a previously published 13-month randomized trial involving 680 patients with long-standing low back pain (median age 52 years, 61% women, median duration of back pain 87 months). Pain relief was recorded using visual analogue scales (VAS). Treatment response was defined as pain relief of at least 30% from baseline to any point during the trial. We used a step-wise logistic regression to identify variables that might predict response to treatment. Covariates included treatment group, sex, age, duration of pain, presence of neuropathic pain, baseline pain scores, educational/employment status, use of high doses of opioids, and social functioning (SF)-36 scores. Results: Over half the patients in both groups (n = 370; 54% TDF, 55% SRM) were treatment responders. There were no differences between the TDF and SRM responders in terms of age, sex, type or duration of pain between responders and non-responders. The difference in response to treatment between responders and non-responders could be detected at 3 weeks. Lack of response after 1 month had a stronger negative predictive value (i.e., ability to detect non-responders) than the presence of response after 1 month. The most influential factors for predicting a response were employment status (χ² = 11.06, ρ = 0.0259) and use of high doses of opioids (χ² = 3.04, ρ = 0.0811). Conclusion: No clear pattern of baseline pain (type or severity) or patient characteristics emerged that could be used to predict responders before the start of opioid treatment. However, a 1-month trial period appears sufficient to determine response and tolerability in most cases. [ABSTRACT FROM AUTHOR]

Background: This study was designed to evaluate the utility of transdermal fentanyl (TDF, Durogesic®) for the treatment of pain due to osteoarthritis (OA) of the knee or hip, which was not adequately controlled by non-opioid analgesics or weak opioids. The second part of the trial, investigating TDF in patients with rheumatoid arthritis (RA) is reported separately. Methods: Current analgesia was optimised during a 1-week run-in. Patients then received 28 days treatment with TDF starting at 25 μg/hr, with the option to increase the dose until adequate pain control was achieved. Metoclopramide was taken during the first week and then as needed. Results: Of the 159 patients recruited, 75 with OA knee and 44 with OA hip completed the treatment phase, 30 knee and 18 hip patients entered the one-week taper-off phase. The most frequently used maximum dose of TDF was 25 μg/hr. The number of patients with adequate pain control increased during the run-in period from 4% to 27%, and further increased during TDF treatment to 88% on day 28. From baseline to endpoint, there were significant reductions in pain (p < 0.001) and improvements in functioning (p < 0.001) and physical (p < 0.001) and mental (p < 0.05) health. Scores for 'pain right now' decreased significantly within 24 hours of starting TDF treatment. TDF was assessed favourably and 84% of patients would recommend it for OA-related pain. Nausea and vomiting were the most common adverse events (reported by 32% and 26% of patients respectively), despite prophylaxis with metoclopramide, which showed limited efficacy in this setting. Conclusion: TDF significantly increased pain control, and improved functioning and quality of life. Metoclopramide appeared to be of limited value in preventing nausea and vomiting; more effective anti-emetic treatment may enable more people to benefit from strong opioids such as TDF. This study suggests that four weeks is a reasonable period to test the benefit of adding TDF to improve pain control in OA patients and that discontinuing therapy in cases of limited benefit creates no major obstacles. [ABSTRACT FROM AUTHOR]

A post-hoc analysis of the phase-3 LATITUDE study assessed the impact of abiraterone acetate plus prednisone (AA+P) on overall survival (OS) and radiographic progression-free survival (rPFS) in men with metastatic castration-sensitive prostate cancer (mCSPC) and visceral metastases (VM). Newly diagnosed mCSPC patients were randomized (1:1) to AA+P and androgen deprivation therapy (ADT) or placebo+ADT. Patients with VM in liver or lungs with or without other soft tissue and bone metastases (based on CT/MRI) at baseline were analyzed, after 51.8 months' median follow-up. Co-primary endpoints, OS and rPFS, were analyzed. Among 1199 patients enrolled, 228 (19%) had VM at baseline (114 each in AA+P and placebo groups), of which 53 (23.2%; AA+P = 29, Placebo = 24) had liver metastases and 117 (51.3%; AA+P = 60, Placebo = 57) had lung metastases. In patients with VM, treatment with AA+P versus placebo showed an improvement in OS (median 55.4 vs 33.0 months; HR = 0.582; 95%CI = 0.406–0.835; P = 0.0029) and rPFS (median 30.7 vs 18.3 months; HR = 0.527; 95%CI = 0.366–0.759; P = 0.0005), comparable to that of patients without VM. AA+P versus placebo in lung metastases patients was associated with greater improvement in OS (HR = 0.60; 95%CI = 0.35–1.04; P = 0.0678) than in liver metastases patients (HR = 0.82; 95%CI = 0.41–1.66; P = 0.5814). AA+P versus placebo showed improvement in rPFS in lung metastases patients (HR = 0.50; 95%CI = 0.29–0.89; P = 0.0157), but not in liver metastases patients (HR = 1.05; 95%CI = 0.53–2.09; P = 0.8970). AA+P treatment improved both rPFS and OS in men with mCSPC and visceral disease, especially those with lung metastases. Men with liver metastases had a poorer prognosis and their optimal treatment remains to be defined. ClinicalTrials.gov, number NCT01715285 • AAP+ADT showed survival benefit in mCSPC men regardless of visceral disease status. • Men with liver metastases had a poorer prognosis than those with lung metastases. • A benefit in OS and rPFS was not seen in the small group of men with liver metastases. [ABSTRACT FROM AUTHOR]

Background. Opioid analgesics are included in treatment guidelines for the symptomatic management of osteoarthritis (OA). Starting with a low dose of opioid and slowly titrating to a higher dose may help avoid intolerable side effects. Methods. Subjects aged ≥40 years, with moderate to severe pain induced by OA of the hip or knee not adequately controlled by previous non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol treatment, were enrolled. Subjects received OROS hydromorphone 4 mg or placebo once-daily. The dose was titrated every 3-4 days in case of unsatisfactory pain control during the 4-week titration phase. A 12 week maintenance phase followed. The primary efficacy endpoint was the change in "pain on average" measured on the Brief Pain Inventory (BPI) scale from baseline to the end of the maintenance phase. Results. 139 subjects received OROS hydromorphone and 149 subjects received placebo. All efficacy endpoints showed similar improvements from baseline to end of study in the 2 groups. The safety results were consistent with the safety profile of OROS hydromorphone. Conclusion.The study did not meet the primary endpoint; although many subjects' pain was not adequately controlled at inclusion, their pain may have improved with continued paracetamol or NSAID treatment.

The steady-state pharmacokinetics of an extended-release formulation of hydromorphone, OROS hydromorphone, was investigated in a randomized, open-label, crossover study in healthy volunteers. Participants were randomly assigned to receive 16 mg of OROS hydromorphone once daily and 4 mg of immediate-release hydromorphone four times daily for five consecutive days. The two treatments were separated by a washout period of 7-14 days. Naltrexone was given throughout both treatment periods to block the opioid effects of hydromorphone. Steady-state hydromorphone concentrations were statistically analyzed using Helmert contrasts to determine when steady state was reached. A total of 30 participants were enrolled, of whom 29 completed both treatment periods. The two treatments produced comparable steady-state plasma drug concentrations, but peak-to-trough fluctuations were smaller with OROS hydromorphone (61 percent vs 172 percent) in comparison with immediate release hydromorphone. Overall systemic exposure to hydromorphone was similar between the two formulations. The ratio of the geometric means between the two formulations for the area under the concentration-time curves at steady state was 105.2 percent with a 90% confidence interval (CI) of 99.8-110.8 (geometric mean: 102.7 percent; 90% CI: 97.6-108.2 after correcting for measured drug content), which was within the bioequivalence range (80-125 percent). The analysis of Helmert contrasts showed that steady state conditions were attained by day 4. Both treatments were well tolerated. This study shows that OROS hydromorphone maintains steady-state plasma drug concentrations within the same range as immediate-release hydromorphone at the same total daily dose, with less fluctuation.

Objective: Establishing local tolerability of transdermal opioid systems is important as more systems become available for use in a range of indications. We compared the skin irritation potential of a single application of transdermal fentanyl (Durogesic D-trans; DDTDF) and transdermal buprenorphine (Transtec; TDB) patches in healthy volunteers., Methods: 46 healthy males and females (mean age [range]: 59.6 [50-69] years) with healthy skin received a single dose of both the DDTDF 25 mug/h patch and the TDB 35 mug/h patch in a randomised order under naltrexone cover. The incidence and severity of erythema was assessed at various timepoints after patch removal., Results: There was a non-significant trend towards a higher incidence of erythema 60 min after patch removal with TDB compared with DDTDF. The severity of erythema at 60 min and the incidence of erythema at 72 h after patch removal were significantly higher with TDB than with DDTDF (p = 0.01 and 22% versus 4.9%, p = 0.04, respectively). In general, the results from the chromametric assessment of treated skin were in agreement. The incidence of topical adverse events (AEs) was lower with DDTDF than with TDB (one versus six events) and subjects preferred the DDTDF patch and felt it was less noticeable on the skin. The DDTDF patch was considered less painful to remove, and, consistent with that, the TDB patch was judged to have better adhesion. Twenty-one subjects reported systemic AEs with DDTDF plus naltrexone and 22 with TDB plus naltrexone, most of which were considered treatment-related, 34 and 60 AEs, respectively., Conclusions: Local tolerability of transdermal opioid systems should be considered when making a therapeutic choice. Even after a single application in healthy volunteers, differences in local tolerability, assessed both clinically and by chromametry, and patch comfort were shown between DDTDF and TDB, in favour of DDTDF.

Objectives: To evaluate the effectiveness and safety of transdermal fentanyl (TDF) for the treatment of pain associated with rheumatoid arthritis (RA) or osteoarthritis of the knee or hip (OA), which was not adequately controlled by non-opioid analgesics and/or weak opioids., Methods: The study design incorporated a 1-week run-in period when current analgesic medications were optimised, a 28-day treatment period and a 1-week taper-off period. Patients with RA (n = 104) and OA (n = 159) started treatment with TDF 25 microg/h. Patches were replaced every 72 h, with the option to up-titrate until adequate pain control was achieved. Metoclopramide was taken during the first treatment week and as needed thereafter., Results: 203 patients completed the treatment phase, 90 entered the taper-off phase. 25 microg/h was the most frequently used maximum dose (51%). Pain control was increased from 4% to 29% of patients during run-in. The number of patients reaching adequate pain control in the first treatment week was increased to 75%, and increased further to 88% on day 28 and to 80% at endpoint. From baseline (screening) to endpoint, there were significant reductions in pain (p < 0.001) on the Wisconsin Brief Pain Inventory, and significant improvements in quality of life (Short-Form-36: physical p < 0.001; mental health p < 0.05). Eighty per cent of the patients (n = 134) assessed the treatment favourably; nausea and vomiting were the most common adverse events, mainly occurring at treatment initiation. Efficacy of metoclopramide appeared limited. TDF could be initiated in patients pre-treated with non-opioid analgesics or weak opioids and tapered off without major complications., Conclusions: TDF significantly improved pain control and quality of life, and was well tolerated in patients with RA or knee/hip OA who continued to experience pain on their current analgesic treatment. Treatment could be discontinued without issues. Nausea and vomiting was usually mild during treatment initiation. Patients' well being could be further accommodated by optimising prophylactic treatment.