Diagnosis, management and impact on patients' lives of cancer-related neuropathic pain (CRNP): A European survey.

OBJECTIVE: This study assessed the impact of cancer-related neuropathic pain (CRNP) on patients and the importance of the patient-healthcare professional (HCP) relationship in diagnosis and management. METHODS: A quantitative online survey was conducted involving adult patients from 13 European countries who had been diagnosed with treatable cancer and experienced symptoms of peripheral neuropathy. RESULTS: Of 24,733 screened respondents, 549 eligible persons met the inclusion criteria and completed the questionnaire. Among individuals still experiencing pain, 75% rated it as 'severe' or 'moderate'. In addition, 61% reported a negative impact on day-to-day activities, and 30% said they had stopped working as a result. A third of respondents had received no diagnosis of CRNP despite reporting painful symptoms to an HCP. HCPs spending enough time discussing pain and understanding the impact on patients' lives were each associated with an increased likelihood of a formal CRNP diagnosis. Compared with individuals currently in active cancer treatment, cancer survivors were less likely to have a diagnosis of CRNP or regular pain conversations with HCPs. CONCLUSION: CRNP remains under-recognised despite its substantial impact on patients' lives. Clinical practice may be improved by strengthening patient-HCP relationships around pain discussions and increasing the focus on pain management among cancer survivors.

Progressive Response to Repeat Application of Capsaicin 179 mg (8% w/w) Cutaneous Patch in Peripheral Neuropathic Pain: Comprehensive New Analysis and Clinical Implications.

OBJECTIVE: To investigate the efficacy of repeated application of capsaicin 179 mg cutaneous patch in nonresponders to the first application. DESIGN: Post hoc, as-treated analysis of two prospective trials (STRIDE and PACE) with 52-week follow-up. BLINDING: Open-label. SETTING: Multicenter clinical trial. SUBJECTS: STRIDE: nondiabetic neuropathic pain; PACE: painful diabetic peripheral neuropathy. METHODS: Patients were divided according to number of applications needed before attainment of a ≥30% reduction in average pain intensity (question 5 of the Brief Pain Inventory [BPI-Q5]). We assessed the change from baseline in average pain intensity (BPI-Q5), mean "interference with sleep" score, Patient Global Impression of Change, quality of life (QOL) via the EuroQol 5-dimension, and Self-Assessment of Treatment. RESULTS: In STRIDE and PACE, respectively, n = 306 and n = 313 received the capsaicin patch; n = 60 and n = 96 had a response after the first application, n = 33 and n = 68 after the second, and n = 11 and n = 43 after the third. Among patients without a ≥30% reduction in pain intensity at 3 months, in STRIDE and PACE, respectively, 23.3% and 28.1% achieved a ≥30% reduction at 6 months, increasing to 33.9% and 45.7% at 12 months. Similar results were obtained when a decrease of ≥50% was used as the responder definition. Progressive improvements in pain intensity in slower responders reached levels similar to those in early responders at month 12 and were accompanied by improvements in sleep, QOL, and patient satisfaction. CONCLUSIONS: Although some patients with peripheral neuropathic pain experience rapid improvements with a single treatment of capsaicin 179 mg patch, some may require two or three treatments before an initial response is observed. Similar benefits for pain, sleep, and QOL can be achieved in early and late responders.

Is the Capsaicin 179 mg (8% w/w) Cutaneous Patch an Appropriate Treatment Option for Older Patients with Peripheral Neuropathic Pain?

Introduction: Capsaicin 179 mg (8% weight per weight) cutaneous patch ("capsaicin patch") is a recommended topical treatment for peripheral neuropathic pain (PNP). In older patients, topical treatments may be preferred over systemic treatments, but data specific to the older population are scarce. Methods: We conducted pooled analyses of multiple clinical trials to evaluate efficacy and safety of capsaicin patch in older patients. The analysis of efficacy included four randomized, double-blind, 12-week studies with similar trial design comparing a single treatment of capsaicin 179 mg cutaneous patch vs low-dose control patch in post-herpetic neuralgia. For the safety evaluation, data were pooled from 18 interventional studies in which capsaicin patch was used in PNP with varying etiologies. Results: Capsaicin patch had similar analgesic efficacy in elderly (n=582) and non-elderly patients (n=545) in terms of change from baseline to 2-12 weeks in the 11-point numeric pain rating scale (NPRS) score for average pain over the previous 24 hours. In both age groups, decrease in NPRS score was significantly greater with capsaicin patch vs control. Older patients treated with capsaicin patch were significantly more likely than those in the control group to achieve responder status (ie mean decrease in NPRS score from baseline to week 2-12 of at least 30% or ≥2 points): 36.1% vs 27.1% (odds ratio [OR] [95% CI] 1.52 [1.06, 2.18]; P=0.0231) and 33.1% vs 20.9% (OR [95% CI] 1.90 [1.30, 2.78]; P=0.0009) for active treatment vs control group, respectively. Similar proportions of non-elderly patients (n=2,311) and elderly patients (n=537) treated with capsaicin patch experienced treatment-emergent adverse events (TEAEs) (81.6% and 78.1%, respectively) and serious TEAEs (8.2% and 7.2%), with application-site reactions the most common TEAEs in both groups. Conclusion: The capsaicin patch was equally efficacious and well tolerated in older patients as in younger patients.

Peripheral neuropathic pain is a common challenge among the elderly, yet effective treatments for this age group remain underexplored. This research focuses on the use of a high-concentration capsaicin patch, a specialized treatment for this type of pain. The patch, which is applied directly to the affected skin area, has been shown to reduce pain significantly for up to 12 weeks. This analysis of multiple clinical trials showed that the high-concentration capsaicin patch significantly reduced pain intensity and was well tolerated in older patients with peripheral neuropathic pain.

Diagnosis, management and impact of painful diabetic peripheral neuropathy: A patient survey in four European countries.

AIMS: The aim of this study was to assess patient perspectives and experiences of the impact of neuropathic pain, painful diabetic neuropathy (pDPN) diagnosis and treatment, and the patient-healthcare professional (HCP) relationship. METHODS: We conducted a quantitative online survey in Germany, the Netherlands, Spain, and the UK among adults with diabetes who responded "yes" to at least four of ten questions of in the Douleur Neuropathique en 4 Questions (DN4) questionnaire. RESULTS: Of 3626 respondents, 576 met the eligibility criteria. Daily pain was rated as moderate or severe by 79 % of respondents. Most participants reported a negative impact of their pain on sleep (74 %), mood (71 %), exercise (69 %), concentration (64 %) and daily activities (62 %), and 75 % of those in employment had missed work because of their pain in the past year. Overall, 22 % of respondents avoided discussing pain with their HCP, 50 % had not received formal pDPN diagnosis, and 56 % had not used prescribed pain medications. Although two-thirds (67 %) of respondents reported feeling satisfied or very satisfied with treatment, 82 % of these patients still experienced daily moderate or severe pain. CONCLUSIONS: Neuropathic pain in people with diabetes affects daily life and remains underdiagnosed and undertreated in clinical practice.

A randomized trial of paliperidone palmitate and risperidone long-acting injectable in schizophrenia.

Paliperidone palmitate (PP) is a recently (USA) approved injectable new-generation antipsychotic. This 53-wk, Phase-III double-blind study was designed to assess the non-inferiority of PP to risperidone long-acting injectable (RIS-LAI) in schizophrenia treatment. Acutely symptomatic patients (n=749), with a Positive and Negative Syndrome Scale (PANSS) total score between 60 and 120 were randomly allocated to gluteal injections of either (a) PP: 50 mg eq. on days 1 and 8, and flexible dosing [25-100 mg eq. (i.e. 39-156 mg USA dosing)] once-monthly; or (b) RIS-LAI: bi-weekly injections of 25 mg on days 8 and 22, and flexible dosing (25-50 mg) starting from day 36, with allowed oral supplementation. Patients (n=747) were 59% men, 92% white, mean (s.d.) age of 41 (11.95) yr and 45% (n=339) completed the study. Mean (s.d.) change from baseline to endpoint in PANSS total score was: -11.6 (21.22) PP; and -14.4 (19.76) RIS-LAI (per-protocol analysis set, primary measure); least-squares means difference was -2.6 (95% CI -5.84 to 0.61), with a prespecified 5-point non-inferiority margin. PP's suboptimal dosing regimen (<150 mg eq. initial dose) resulted in lower median plasma levels of the active moiety in PP-treated vs. RIS-LAI-treated patients. Insomnia was the most common treatment-emergent adverse event, with a similar incidence in both groups (15%). PP did not demonstrate comparable efficacy to RIS-LAI, which may be attributable to the initiation dosing strategy employed. Tolerability of both treatments was comparable to previous studies, with no new safety signals detected.

Localized peripheral neuropathic pain: topical treatment with lidocaine 700 mg medicated plaster in routine clinical practice.

Aim: To provide real-world evidence for the effectiveness and tolerability of lidocaine 700 mg medicated plaster (LMP) in localized peripheral neuropathic pain (l-PNP) treatment compared with first-line oral medications (OM). Patients & methods: This was a noninterventional, retrospective 6-month cohort study in patients refractory to at least one recommended OM, using anonymized medical care data from the German Pain eRegistry. Treatment groups were matched by propensity scoring, considering seven predefined confounding factors. The primary effectiveness end point was the absolute change in average pain intensity index from baseline at weeks 4, 12 and 24 of treatment and over the treatment period. Results: A total of 3081 datasets were retained per treatment group. LMP provided superior pain reductions and significantly greater improvements in pain-related impairments of daily living and quality of life with significantly better tolerability (p < 0.001 for all parameters) than OM. Conclusion: These real-world data confirm the effectiveness and good tolerability of LMP for l-PNP treatment under routine medical care.

Conditions such as shingles, diabetes and surgery may lead to chronic localized neuropathic pain. This pain is often described as burning or stabbing and can limit functioning in daily activities and diminish quality of life. Several oral and topical medications are available for neuropathic pain treatment. The current study compared the effectiveness and tolerability of lidocaine 700 mg medicated plaster applied directly at the painful skin area with oral medications. Anonymized patient data collected in a German pain registry were selected based on predefined criteria (3081 patient data sets per treatment). Lidocaine plaster treatment resulted in superior pain relief, significantly fewer restrictions in daily life activities and better quality of life than the oral medications evaluated and was significantly better tolerated. This study showed that lidocaine 700 mg medicated plaster is effective and well tolerated in the treatment of chronic localized neuropathic pain in routine medical practice.

Painful diabetic peripheral neuropathy: real-world comparison between topical treatment with lidocaine 700 mg medicated plaster and oral treatments.

INTRODUCTION: Painful diabetic peripheral neuropathy (PDPN), a common complication of diabetes mellitus, is challenging to treat. Efficacy and tolerability of the topical lidocaine 700 mg medicated plaster (LMP) and well-established first-line oral medications (OM) were compared in refractory PDPN patients. RESEARCH DESIGN AND METHODS: This is a subgroup analysis of a non-interventional, retrospective 24-week cohort study using anonymized routine medical care data from the German Pain eRegistry. Propensity score matching provided 732 datasets per treatment group. Primary effectiveness endpoint was the absolute change in average 24-hour Pain Intensity Index (0-100 mm) from baseline after 4, 12 and 24 weeks of treatment and over the entire treatment period. RESULTS: The majority of this multimorbid and polymedicated study population of patients with PDPN had suffered pain for more than a year and presented with a high pain burden despite a median of seven previous analgesic medications. LMP treatment resulted in significant reductions in pain intensity and improvements in daily functioning already after 4 treatment weeks. Effectiveness was maintained over the treatment period even when concomitant analgesics were reduced or discontinued and quality of life improved. Mean change in the primary effectiveness parameter over the 24-week treatment period was -30.2 mm (SE 0.38) and -17.0 mm (SE 0.51) in the LMP and OM groups, respectively. Improvements in all effectiveness parameters were significantly greater under LMP than under OM treatment (p<0.001). Significantly fewer patients under LMP than OM experienced drug-related adverse events (DRAEs; 9.6% vs 61.6%, p<0.001) and discontinued treatment due to DRAEs (4.4% vs 35.8%, p<0.001). CONCLUSIONS: LMP was effective and well tolerated in routine clinical care of patients with PDPN. The more favorable benefit/risk profile and greater reduction in intake of concomitant analgesics compared with OM suggest LMP as a useful treatment option for PDPN. TRIAL REGISTRATION NUMBER: EUPAS 32826.

Postsurgical neuropathic pain: lidocaine 700 mg medicated plaster or oral treatments in clinical practice.

Aim: To compare the effectiveness and tolerability of the lidocaine 700 mg medicated plaster (LMP) and oral first-line medications (OM) for the treatment of postsurgical neuropathic pain (PSNP) in routine clinical practice. Patients & methods: Data from a noninterventional, retrospective 24-week cohort study in patients with localized peripheral NP refractory to at least one recommended OM using anonymized German Pain eRegistry data were retrieved. A subgroup analysis was conducted on 531 datasets of PSNP patients. Results: Pain relief, improvements in pain-related impairments of daily living and quality of life, and tolerability were significantly greater under LMP than under OM (p < 0.001 for all parameters). Conclusion: These real-world data show the effectiveness and good tolerability of LMP for PSNP treatment in routine clinical practice.

Surgical procedures may lead to chronic postsurgical neuropathic pain often described as burning or shooting pain. This pain can be treated with medications that are swallowed (oral) or applied to the skin (topical). Our study compared the effectiveness and tolerability of the topical lidocaine 700 mg medicated plaster with oral medications in 531 anonymized patient data sets from a German pain registry. Patients on the lidocaine 700 mg medicated plaster had significantly better pain relief, significantly lower impact of pain on activities of daily life and quality of life and tolerated their treatment significantly better than those on oral medications. The lidocaine 700 mg medicated plaster can be considered as an alternative effective and well-tolerated treatment option for postsurgical neuropathic pain in routine clinical practice.

Lidocaine 700 mg medicated plaster for postherpetic neuralgia: real-world data from the German Pain e-Registry.

Aim: To provide real-world evidence for the effectiveness and tolerability of lidocaine 700 mg medicated plaster (LMP) compared with oral systemic first-line medications (OSM) in postherpetic neuralgia treatment. Patients & methods: Retrospective cohort study in patients refractory to at least one recommended OSM (single drug or a combination of drugs) using anonymized routine medical care data from the German Pain e-Registry. A matched pair approach using propensity score matching was employed. Results: A total of 1711 data sets of postherpetic neuralgia patients were identified per treatment group. The majority (>60%) had experienced pain for more than a year and reported a high burden of pain and reduced quality of life. Six months of LMP treatment provided significantly greater pain reductions, improvements in pain-related impairments and quality of life than OSM treatment (p < 0.001 for all parameters). Drug-related adverse events and treatment discontinuation due to drug-related adverse events also occurred less frequently under LMP treatment (p < 0.001). Conclusion: These real-world data confirm the effectiveness and good tolerability of LMP under routine medical care. The treatment was significantly more effective when compared with first-line oral systemic medications.

Lay abstract Postherpetic neuralgia is the most common complication of shingles. It is a chronic condition causing burning pain that persists long after the shingles rash disappears. There are several oral and topical medications available for pain treatment. Our study compared the effectiveness and tolerability of the topical lidocaine 700 mg medicated plaster with oral medications using anonymized patient data from German clinical practices collected in a pain registry (1711 patient data sets per treatment). Six months of treatment with the lidocaine plaster resulted in better pain relief, fewer restrictions in daily life activities, and better quality of life for the patients than the oral medications investigated. The lidocaine plaster was also significantly better tolerated. The lidocaine 700 mg medicated plaster is effective and well tolerated in routine medical practice.

Comparative Benefit-Risk Assessment for Lidocaine 700 mg Medicated Plaster and Pregabalin in Peripheral Neuropathic Pain Following a Structured Framework Approach.

INTRODUCTION: Peripheral neuropathic pain (PNP) is difficult to treat. Several oral drugs are recommended as first-line treatments. Nevertheless, many patients cannot obtain sufficient pain relief or do not tolerate systemically active treatments. Topical treatments, with a lower risk of systemic side effects such as lidocaine 700 mg medicated plaster, are also recommended in treatment guidelines. This analysis compares the benefit-risk balance of topical 700 mg lidocaine medicated plaster with the benefit-risk balance of oral pregabalin administration for the treatment of PNP following current recommendations on benefit-risk assessment (BRA) methodology. METHODS: The Benefit-Risk Action Team (BRAT) framework was used as structured approach. Selection of key benefits and risks was supported by a patient survey. Published randomized controlled clinical trials were the main source to identify data related to key benefits and risks. The outcome of randomized clinical trials was compared with real-world evidence (RWE) data for consistency. RESULTS: Identified key benefits were pain reduction and improvement in quality of life. Key risks identified were application site reactions, dizziness, confusion, weight gain, peripheral edema, and blurred vision. Overall, there was similarity in key benefits between the comparators; however, a clear advantage regarding key risks in favor of lidocaine 700 mg medicated plaster was observed. This observation was consistent across data from a direct comparison trial, randomized placebo-controlled trials, as well as data from RWE studies. The low number of randomized controlled trials for lidocaine 700 mg medicated plaster was the main limitation. CONCLUSION: Guided by the opinion of patients regarding key benefits and risks deemed important for treatments of peripheral neuropathic pain, our analysis showed that lidocaine 700 mg medicated plaster has a more favorable benefit-risk balance compared to pregabalin (300 and 600 mg daily).

A randomized, double-blind, placebo-controlled study of the efficacy, safety, and tolerability of adjunctive carisbamate treatment in patients with partial-onset seizures.

PURPOSE: To assess the efficacy, safety, and tolerability of adjunctive carisbamate treatment at 800 mg/day and 1,200 mg/day in patients with partial-onset seizures (POS). METHODS: Patients ≥ 16 years of age with an established diagnosis of POS for ≥ 1 year and uncontrolled on one to three antiepileptic drugs were enrolled. Eligible patients remained on stable doses of prescribed antiepileptic drugs for an 8-week pretreatment baseline phase and were then randomized (1:1:1) to receive carisbamate (800 mg/day or 1,200 mg/day), or placebo, for a 14-week double-blind phase. Primary efficacy endpoints were percentage reduction in POS frequency and responder rate (patients with ≥ 50% reduction in POS frequency) during the double-blind versus baseline phase. KEY FINDINGS: Five hundred forty-seven patients were randomized; 540 composed the intent-to-treat (ITT) analysis. Four hundred thirty-four patients (79%) completed the study. The median percent reduction from baseline to treatment phase in POS frequency was: 21% (placebo); 30% (carisbamate 800 mg); 36% (carisbamate 1,200 mg), and 32% (combined carisbamate doses). The combined carisbamate dose group was not significantly different from placebo for the median percent reduction of POS frequency (p = 0.20) or responder rate (p = 0.18). Therefore, the difference from placebo for the individual carisbamate dose groups was also considered nonsignificant, based on a prespecified step-down analysis. Dizziness was the most common treatment-emergent adverse event, with a higher incidence (≥ 5% difference) in the combined carisbamate group (31%) than placebo (9%); the incidence was higher with carisbamate 1,200 mg (32%, n = 58) than with carisbamate 800 mg (30%, n = 53). SIGNIFICANCE: Adjunctive carisbamate therapy in patients with POS did not demonstrate efficacy across the dose range assessed versus placebo. No new safety findings were observed.

Treatment Impact on Patient-Reported Outcomes in Peripheral Neuropathic Pain: Comparing Single Intervention With Topical High-Concentration Capsaicin to Daily Oral Pregabalin.

BACKGROUND: Peripheral neuropathic pain (PNP) is a complex, subjective experience affecting both physical and psychological aspects of functioning. Assessing patient-reported outcomes (PROs) beyond pain relief is important and aligns with the recommendations of IMMPACT (Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials). Moreover, PRO data are key to clinical decision-making when evaluating treatment options. However, direct comparisons between such options are scarce. High-concentration capsaicin 179 mg (8% w/w) cutaneous patch (HCCP) is applied to the skin at minimum intervals of 90 days under physician supervision; alternative recommended treatments for PNP are mostly orally administered on a daily basis. The ELEVATE study directly compared HCCP with pregabalin and found noninferior efficacy of HCCP to pregabalin in relieving pain after 8 weeks, with a significantly faster onset of action and fewer systemic side effects. OBJECTIVES: The objective of this analysis was to compare PRO outcomes defined as secondary objectives of the ELEVATE study after a single intervention with HCCP to daily oral pregabalin for 8 weeks. STUDY DESIGN: ELEVATE was an open-label, randomized (1:1) multicenter study. SETTING: The study included 92 sites in 22 countries in Europe and Asia. METHODS: Five hundred fifty-nine non-diabetic  patients with PNP received a single intervention with HCCP (n = 282; 1-4 patches at baseline) or oral daily pregabalin (n = 277; 150-600 mg, 8 weeks). At baseline (Day 0) and Week 8, patients completed the following PROs in addition to the regular pain assessments: Patient Global Impression of Change (PGIC), Medical Outcomes Study Cognitive Functioning scale (MOS-Cog), Medical Outcomes Study Sleep scale (MOS-Sleep), Treatment Satisfaction Questionnaire for Medication (TSQM), and EuroQol 5-Dimensions 5-levels (EQ-5D-5L) Utility Index (EQ-UI) and Visual Analog Scale (EQ-VAS). RESULTS: At Week 8, 76% and 75.9% of patients on HCCP and pregabalin, respectively, reported to be very much/much/minimally improved on the PGIC. HCCP application was associated with significant improvements from baseline vs. pregabalin in MOS-Cog (mean difference: 4.28 [95% CI: 2.90-5.66]; P < 0.001), EQ-VAS (3.11 [0.30-5.92]; P = 0.030), and TSQM global satisfaction (6.74 [2.29-11.20]; P = 0.029), particularly the side-effects dimension (21.23 [17.55-24.94]; P < 0.0001). No significant differences in improvements were noted for the MOS-Sleep, TSQM convenience, and EQ-UI. LIMITATIONS: The ELEVATE study has an open-label design, with only one comparator (pregabalin); it was limited to 8 weeks. The sample size was determined for the primary endpoint. CONCLUSIONS: A single intervention with HCCP showed benefits vs. daily pregabalin at Week 8 on several PROs. While HCCP has been approved in the United States for PNP treatment in diabetic and PHN patients, these observations provide information on how patients perceive the effects of distinct PNP treatments. They are complementing already existing knowledge on efficacy and safety of different treatment options with data on patient preferences and may help identify the appropriate treatment option in dialogue with the patients and shared decision-making.IRB Approval: At the time of the study, the trial was approved either nationally or at site level. All approvals were granted prior to the initiation of the trial. A list of Ethics Committees that approved the trial is included as a supplemental file. CLINICAL TRIAL REGISTRATION NUMBER: NCT01713426.

Outcomes of the Pediatric Development Plan of Tapentadol.

The opioid analgesic tapentadol was the first pain medication to be developed for the treatment of pain in children under a formal process established by the regulatory authorities. This article summarizes the outcomes of the pediatric development program for tapentadol across the entire age range from birth (including neonates) to adolescents <18 years of age. In addition, the challenges experienced when designing and conducting the pediatric tapentadol clinical trials as well as the interactions with the regulatory authorities are discussed. As a first outcome, the oral solution of tapentadol was authorized in the EU in 2018 as a new treatment option in the hospital setting for moderate to severe acute pain in children from 2 to <18 years of age.

Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study.

We evaluated the efficacy and safety of the investigational long-acting injectable antipsychotic agent paliperidone palmitate (PP) in the treatment of schizophrenia. Patients were randomized to receive gluteal injections of placebo or PP (50 or 100 mg eq., fixed doses), without oral supplementation, on days 1, 8, and 36 (9-wk, double-blind phase) in this phase 2b study. Patients (n=197, intent-to-treat analysis set) were 62% men, mean (s.d.) age 39 (10) yr, with a baseline mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total score of 87.0 (12.5). Mean (s.d.) PANSS total scores showed significant improvement at endpoint (primary measure) for both the PP 50 mg eq. [-5.2 (21.5)] and PP 100 mg eq. [-7.8 (19.4)] groups, vs. placebo [6.2 (18.3)] (p0.001, each dose vs. placebo). This improvement was detected by day 8 and maintained to endpoint (p0.011) for both doses. In the safety analysis set (n=247), fewer PP-treated patients (2%) discontinued for treatment-emergent adverse events vs. placebo-treated (10%). Rates of treatment-emergent extrapyramidal syndrome-related adverse events were comparable between active treatment and placebo, with the exception of parkinsonism-related disorders (50 mg eq. 5%, 100 mg eq. 8%, placebo 1%). Results of other safety measures suggest PP to be generally well-tolerated. Throughout the study, investigators rated injection-site pain as absent (56-71%), mild (24-39%), moderate (2-12%), or severe (0-2%). PP (50 and 100 mg eq. doses) administered as a gluteal intramuscular injection was efficacious and generally tolerated in these patients with acute symptomatic schizophrenia.

Pharmacokinetic-pharmacodynamic assessment of topiramate dosing regimens for children with epilepsy 2 to <10 years of age.

PURPOSE: To identify and validate the efficacious monotherapy dosing regimen for topiramate in children aged 2 to <10 years with newly diagnosed epilepsy using pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation bridging. METHODS: Several models were developed in pediatric and adult populations to relate steady-state trough plasma concentrations (C(min)) of topiramate to the magnitude of clinical effect in monotherapy and adjunctive settings. These models were integrated to derive and support the monotherapy dosing regimen for pediatric patients. KEY FINDINGS: A two-compartmental population PK model with first-order absorption described the time course of topiramate C(min) as a function of dosing regimen. Disposition of topiramate was related to age, body weight, and use of various concomitant antiepileptic drugs. The PK-PD model for monotherapy indicated that the hazard of time to first seizure decreased with increasing C(min) and time since randomization. Higher baseline seizure frequency increased risk for seizures. Age did not significantly influence hazard of time to first seizure after randomization to monotherapy. For adjunctive therapy, the distribution of drug and placebo responses was not significantly different among age groups. Based on the available PK-PD modeling data, the dosing regimen expected to achieve a 65-75% seizure freedom rate after 1 year for pediatric patients age 2-10 years is approximately 6-9 mg/kg per day. SIGNIFICANCE: This analysis indicated no difference in PK-PD of topiramate between adult and pediatric patients. Effects of indication and body weight on PK were adequately integrated into the model, and monotherapy dosing regimens were identified for children 2-10 years of age.

One-year open-label safety and efficacy study of paliperidone extended-release tablets in patients with schizophrenia.

INTRODUCTION: This 52-week open-label extension (OLE) to a double-blind placebo-controlled recurrence prevention study examined the long-term safety and efficacy of flexibly-dosed paliperidone extended-release (ER) tablets in patients with schizophrenia. METHODS: Patients entering the OLE either entered from the double-blind phase (placebo or paliperidone ER treatment) or entered directly from the run-in or stabilization phase (paliperidone ER) of the earlier study. During the OLE, patients were treated with flexibly-dosed paliperidone ER (3-15 mg/day; 9 mg starting dose). Safety and tolerability assessments included incidence of adverse events and extrapyramidal symptoms. Efficacy was also assessed. RESULTS: The study population (n=235) was predominantly men (66%), 18-58 years of age. Twelve patients (5%) experienced an adverse event requiring treatment discontinuation. One or more serious treatment-emergent adverse events were reported in 13 patients (6%). There was one death. The mean Positive and Negative Syndrome Scale total score decreased from open-label baseline to endpoint for all groups, regardless of previous double-blind treatment (placebo or paliperidone ER). CONCLUSION: This year-long OLE provides information on the long-term safety and tolerability of paliperidone ER in patients with schizophrenia. The resulting safety and tolerability profile was similar to that seen in earlier short-term studies.

Tapentadol Prolonged Release for Long-Term Treatment of Pain in Children.

PURPOSE: Investigation of the efficacy and safety of tapentadol prolonged release (PR) compared with morphine PR for long-term treatment of pain in children. PATIENTS AND METHODS: Children aged 6 to <18 years requiring long-term treatment with opioids were studied in a 12-month, 2-part, multi-center trial: Part 1, 14-day open-label, randomized, active-controlled, parallel group non-inferiority trial comparing twice daily tapentadol PR with morphine PR; Part 2, open-label treatment with tapentadol PR for up to 12 months or no treatment "safety observation period". Pain intensity was rated with visual analogue scale or Faces Pain Scale-Revised, and non-inferiority was assessed by comparison of "treatment responders" (those completing the 14-day treatment period and showing pre-defined changes in pain rating) in each group. RESULTS: Twenty-three of 48 centers enrolled 73 patients. In Part 1, 45 and 24 patients received tapentadol or morphine, respectively, of which 40 and 22 completed 14-day treatment. In Part 2, thirty-six and 58 patients entered the tapentadol PR or observation periods, respectively, with 20/36 completing at least 12 weeks of treatment; 10 of the 36 had received morphine in Part 1. Forty-four of the 58 patients in the safety observation period had received tapentadol. Tapentadol PR was non-inferior to morphine PR (lower limit of confidence interval above negative non-inferiority margin of -0.2) in Part 1. Rates of adverse events were as expected with nausea (22.2%) and constipation (15.6%) in the tapentadol PR group, and with vomiting (33.3%), nausea and constipation (each 16.7%) in the morphine PR group. No new safety issues were identified; the safety profile of tapentadol over the 12 months treatment and observation periods was comparable to that established in subjects >18 years old. CONCLUSION: Tapentadol PR was well tolerated and equivalent to morphine PR for both efficacy and safety in children (6 to <18 years old) requiring long-term treatment with opioids.

Population Pharmacokinetics of Tapentadol in Children from Birth to <18 Years Old.

OBJECTIVE: The main aim of this analysis was to characterize the pharmacokinetics (PK) of tapentadol in pediatric patients from birth to <18 years old who experience acute pain, requiring treatment with an opioid analgesic. PATIENTS AND METHODS: Data from four clinical trials and 148 pediatric patients who received a single dose of tapentadol oral or intravenous solution were included. Population PK analysis was performed to determine the contribution of size-related (bodyweight) and function-related (maturation) factors to the changes in oral bioavailability (F), volume of distribution (V), and clearance (CL) with age. Simulations were carried out to compare pediatric exposures to reference adult values. RESULTS: A one-compartment model with allometric scaling on disposition parameters (using theoretical or estimated exponents) and maturation functions on CL and F best described tapentadol PK. The estimated allometric exponents for CL (0.603) and V (0.820) differed slightly from the theoretical values of 0.75 for CL and 1 for V. A maximum in CL/F was observed at about 2-3 years when expressed on a bodyweight basis. Results for younger children as well as the F estimate were sensitive to the scaling approach, but CL/F and V/F as a function of age for the two scaling approaches led to similar curves within the bioequivalence range except below 5 weeks of age. Model-based simulations indicated that the doses used in the included clinical trials lead to exposures within the lower half of the targeted adult exposure. CONCLUSION: The development of tapentadol is one of the first examples following a systematic approach for analgesic drug development for children. Our analysis enabled a full characterization and robust understanding of tapentadol PK in children from birth to <18 years, including preterm infants, and showed the importance of evaluating the sensitivity of the inferences of the PK parameters to the selected scaling approach.

Efficacy, safety and tolerability of two dosing regimens in adolescent schizophrenia: double-blind study.

BACKGROUND: Effective treatments for adolescent schizophrenia are needed. AIMS: To compare efficacy and safety of two dosing regimens of risperidone. METHOD: Double-blind, 8-week study. Patients, 13-17 years, with an acute episode of schizophrenia, randomised 1:1 to risperidone 1.5-6.0 mg/day (regimen A; n=125) or 0.15-0.6 mg/day (regimen B; n=132). TRIAL REGISTRATION NUMBER: NCT00034749. RESULTS: Mean total Positive and Negative Syndrome Scale (PANSS) score improved significantly (P<0.001; effect size=0.49) from baseline to end-point for regimen A (mean=96.4 (s.d.=15.39) to mean=72.8 (s.d.=22.52)) compared with regimen B (mean=93.3 (s.d.=14.14) to mean=80.8 (s.d.=24.33)). Treatment-emergent adverse events occurred in 74% (regimen A) and 65% (regimen B) of patients; 4% of patients overall discontinued for adverse events. Mean change in body weight was 3.2 kg (s.d.=3.49) for regimen A and 1.7 kg (s.d.=3.29) for regimen B. CONCLUSIONS: Adolescent patients in the regimen A group showed greater improvement in total PANSS compared with the regimen B group. Treatment was well tolerated.

No pharmacokinetic interaction between paliperidone extended-release tablets and trimethoprim in healthy subjects.

OBJECTIVE: The effect of trimethoprim, a potent organic cation transport inhibitor, on the pharmacokinetics (PK) of paliperidone extended-release tablets (paliperidone ER), an organic cation mainly eliminated via renal excretion, was assessed. METHODS: Open-label, two-period, randomized, crossover study in 30 healthy males. Single dose of paliperidone ER 6 mg was administered either alone on day 1 or day 5 during an 8-day treatment period of trimethoprim 200 mg twice daily. Serial blood and urine samples were collected for PK and plasma protein binding of paliperidone and its enantiomers. The 90% confidence interval (CI) of ratios with/without trimethoprim for PK parameters of paliperidone and its enantiomers calculated. RESULTS: Creatinine clearance decreased from 119 to 102 mL min(-1) with trimethoprim. Addition of trimethoprim increased unbound fraction of paliperidone by 16%, renal clearance by 13%, AUC(infinity) by 9%, and t((1/2)) by 19%. The 90% CIs for ratios with/without trimethoprim were within the 80-125% range for C(max), AUC(last), and renal clearance. For AUC(infinity), 90% CI was 79.37-101.51, marginally below the lower bound of the acceptance range. Paliperidone did not affect steady-state plasma concentrations of trimethoprim. CONCLUSIONS: No clinically important drug interactions are expected when paliperidone ER is administered with organic cation transport inhibitors.