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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]

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.

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]