Stefan Wilhelm

Background: There are 100 million people with chronic pain in Europe, but despite the large and increasing burden it has not received sufficient policy attention. To date there has been little research to identify critical areas of need in the policy environment, or what actions are required to support treatment and care for patients. Methods: A systematic literature review

Background: To investigate baseline demographics and disease characteristics as predictors of the analgesic effect of duloxetine and pregabalin on diabetic peripheral neuropathic pain (DPNP).Methods: Based on data from the COMBO‐DN study, a multinational clinical trial in DPNP, the potential impact of baseline characteristics on pain relief after 8‐week monotherapy with 60 mg/day duloxetine or 300 mg/day pregabalin was assessed using analyses of covariance. Subgroups of interest were characterized regarding their baseline characteristics and efficacy outcomes.Results: A total of 804 patients were evaluated at baseline. A significant interaction with treatment was observed in the mood symptom subgroups with a larger pain reduction in duloxetine‐treated patients having no mood symptoms [Hospital Anxiety and Depression Scale (HADS) depression or anxiety subscale score p = 0.024]. There were no significant interactions between treatment for subgroups by age (<65 or ≥65 years), gender, baseline pain severity [Brief Pain Inventory Modified Short Form (BPI‐MSF) average pain 2 years), baseline haemoglobin A1c (HbA1c) (<8% or ≥8%), presence of comorbidities and concomitant medication use.Conclusions: Our analyses suggest that the efficacy of duloxetine and pregabalin for initial 8‐week treatment in DPNP was consistent across examined subgroups based on demographics and disease characteristics at baseline except for the presence of mood symptoms. Duloxetine treatment appeared to be particularly beneficial in DPNP patients having no mood symptoms.

Sensory profiles are heterogeneous in neuropathic pain disorders, and subgroups of patients respond differently to treatment. To further explore this, patients in the COMBO-DN study were prospectively assessed by the Neuropathic Pain Symptom Inventory (NPSI) at baseline, after initial 8-week therapy with either duloxetine or pregabalin, and after subsequent 8-week combination/high-dose therapy. Exploratory post hoc cluster analyses were performed to identify and characterize potential subgroups through their scores in the NPSI items. In patients not responding to initial 60 mg/d duloxetine, adding 300 mg/d pregabalin for combination treatment was particularly effective regarding the dimensions pressing pain and evoked pain, whereas maximizing the duloxetine dose to 120 mg/d appeared more beneficial regarding paresthesia/dysesthesia. In contrast, adding 60 mg/d duloxetine to 300 mg/d pregabalin in case of nonresponse to initial pregabalin led to numerically higher decreases in all NPSI dimensions/items compared to maximizing the pregabalin dose to 600 mg/d. Cluster analysis revealed 3 patient clusters (defined by baseline scores for the 10 NPSI sensory items) with different pain profiles, not only in terms of overall pain severity, but also across NPSI items. Mean Brief Pain Inventory average pain improved in all clusters during combination/high-dose therapy. However, in patients with severe pain, the treatment effect showed a trend in favor of high-dose monotherapy, whereas combination therapy appeared to be more beneficial in patients with moderate and mild pain (not significant). These complementary exploratory analyses further endorse the idea that sensory phenotyping might lead to a more stratified treatment and potentially to personalized pain therapy.

Although a range of pharmacotherapeutical options are available for the treatment of bipolar disorder, patient non-adherence to prescribed treatment regimens and early treatment discontinuation remain among the primary obstacles to effective treatment. Therefore, this observational study assessed time on mood stabilizing medication and retention rates in patients with bipolar disorder (BD). In an 18-month, prospective, multicenter, non-interventional study conducted in Germany 761 outpatients (≥18 years) with BD and on maintenance therapy were documented. For analysis, patients were stratified by baseline medication: monotherapy olanzapine (OM, N = 186), lithium (LM, N = 152), anticonvulsants (N = 216), other mood stabilizing medication (OMS, N = 44); combination therapy olanzapine/lithium (N = 47), olanzapine/anticonvulsant (N = 68), other combinations (OC, N = 48). Continuation on medication was assessed as retention rates with 95% confidence intervals. Time to discontinuation and relapse-free time were calculated by Kaplan-Meier analysis. A relapse was defined as increase to CGI-BP >3, worsening of CGI-BP by ≥2 points, hospitalization or death related to BD. A Cox regression was calculated for the discontinuation of mood stabilizing therapy (reference: OM). Logistic regression models with stepwise forward selection were used to explore possible predictors of maintenance of treatment and relapse. After 540 days (18 months), the overall retention rate of baseline medication was 87.7%, without notable differences between the cohorts. The overall mean time on mood stabilizing treatment was 444.7 days, with a range of 377.5 (OMS) to 481 (LM) by cohort. 74.0% of all patients were without relapse, with rates between the cohorts ranging from 58.4% (OC) to 80.2% (LM). Retention rates exceeded controlled trial results in all treatment cohorts, in addition to other explanations possibly reflecting that the physicians were expertly adapting treatment regimens to the individual patient’s disease characteristics and special needs.

Objective: This study questions whether a lower starting dose of duloxetine (DLX) could be beneficial for patients with depression, in terms of tolerability and safety in routine clinical care. Research design and methods: Post-hoc analyses of a multicenter, prospective, non-interventional, 6-month study in adult outpatients with a depressive episode was undertaken. Main outcome measures: Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), discontinuations due to TEAEs and hospitalizations due to depression, were all documented at 2 weeks, 4 weeks, 3 months and 6 months after treatment initiation/switch to DLX. Results: Of 4517 patients enrolled, 4313 were included for TEAE evaluation. TEAEs occurred in 17.2% of patients, and SAEs occurred in 0.79% of patients, including one case of suicidal ideation. 1404 patients discontinued within 6 months (TEAEs: n = 119). Starting treatment with 30 mg/day DLX (72.7%) was favored in females, or after inadequate efficacy of previous antidepressant treatment; 60 mg/day DLX was favored in more severe depression and patients receiving concomitant pain medication. Conclusion: Initiating treatment with 60 mg/day DLX was not associated with poorer tolerability in this study. Physicians may be guided by their clinical experience to carefully consider the individual benefit/risk ratio and TEAE susceptibility when deciding to start treatment with a higher or a lower dose of DLX.

Fragestellung: Offene Studie zur Aufrechterhaltung der Wirkung von 1x täglich (OD) 60mg Duloxetin (DLX) über 26 Wochen bei schmerzhafter diabetischer Polyneuropathie (DPNP) nach 8-wöchiger Akuttherapie. Methoden: Patienten (≥18J) mit täglichen Schmerzen seit ≥6 Mo. aufgrund einer symmetrischen sensomotorischen Neuropathie (Michigan Neuropathy Screening Instrument Score ≥3) und 24h-Durchschnittsschmerz-Score ≥4 auf der Brief Pain Inventory (BPI) Skala erhielten DLX 60mg OD für 8 Wochen. ‘Responder' (≥30% Reduktion des BPI-24h-Durchschnittsschmerzes) wurden 26 Wochen mit DLX 60mg OD weiterbehandelt (Erhaltungstherapie); bei ‘Non-Respondern' die Dosis auf 120mg OD erhöht (Rescue-Therapie). Primäre Zielgröße war die Änderung des BPI 24h-Durchschnittschmerzes von Baseline (Woche 8) bis Endpunkt bei den ‘Responder'-Patienten. Sekundäre Zielgrößen waren ‘BPI Severity (BPI-S)' und ‘Interference (BPI-I)' Scores, ‘Sensory Portion of the Short-Form McGill Pain Questionnaire (SF-MPQ)', ‘Patient's Global Impression of Improvement (PGI-I)' und ‘Clinical Global Impression of Severity (CGI-S)'. Die Änderung der Variablen ab Baseline wurde innerhalb der Gruppen durch t-Test und Konfidenzintervalle (KI) analysiert. Ergebnisse: Von den 216 eingeschlossenen Patienten waren 53% Responder und 32% Non-Responder, 15% beendeten die Studie vorzeitig. Am Ende der Akuttherapie waren der BPI 24h-Durchschnittschmerz (mittlere Änderung -2,49) und alle sekundären Zielgrößen signifikant verbessert (pSchlussfolgerung: Die Wirksamkeit von DLX bei schmerzhafter DPNP blieb nach einer 8-wöchigen Akuttherapie über weitere 26 Wochen erhalten, DLX war gut verträglich.

Purpose: Safety of duloxetine (DLX) in depressed patients (pts) was observed in routine clinical care. Methods: Multicenter, prospective, 6-month observational study in adult outpatients with a depressive episode (ICD-10) starting DLX treatment, with solicited treatment emergent adverse events (TEAEs) reporting by general question. Results: Of 4,517 pts enrolled at 693 centers in Germany (mean age 52.2yrs, 71.8% fe-male), 4,313 could be included for TEAEs evaluation. 45.2% of the pts had concomitant psychiatric and 72.1% concomitant somatic diseases, and moderate to severe overall pain (VAS >30mm) was reported by 80.0% of pts. Concomitant pain medication was taken by 32.3% (permanent at BL) and 60.9% (on demand last 12 mth) pts. 1404 pts discontinued within 6 months (TEAEs: 119; other reasons: 415; no information: 870). 72.9% of pts started DLX with 30mg/d. At 4 wks 83.2% of pts were treated with ≥60mg/d. TEAEs occurred in 741 pts (17.2%). Related TEAEs (≥1%) included nausea, hyperhidrosis, vertigo, restlessness, sleep disorder and dry mouth. Serious TEAEs were reported by 34 pts (0.8%), including one case of suicidal ideation. Hospitalization for depression occurred in 132 (3.1%) pts. No relevant change in mean weight was observed from BL (77.1±15.6kg) to 6 mths (76.9±14.8kg). Conclusions: The TEAEs reported during DLX treatment in routine clinical use in a de-pressed patient population – with concomitant pain in the majority – were similar to previous studies. This study was supported by Lilly Deutschland GmbH, Bad Homburg, and Boehringer Ingelheim, Germany.

Conventional antipsychotics augmented with benzodiazepines have been the standard acute treatment for psychiatric emergencies for more than 50 years. The inability of patients to give informed consent limits randomised, controlled studies. This observational study on immediate therapy for aggression and impulse control in acutely agitated patients (IMPULSE) evaluated the short-term effectiveness and tolerability of atypical and typical antipsychotic medications (AP) in a non-interventional setting. This was a comparative, non-randomised, prospective, open-label, observational study. Treatment over the first 5 days was classified according to whether any olanzapine, risperidone, or haloperidol was included or not. Documentations (PANSS-excited component, CGI-aggression, CGI-suicidality, tranquilisation score) were at baseline (day 1) and days 2–6 after start of AP. During the short treatment-period, PANSS-EC and CGI-aggression scores improved in all cohorts. 68.7% of patients treated with olanzapine, 72.2% of patients treated with risperidone, and 83.3% of patients treated with haloperidol received concomitant benzodiazepines (haloperidol vs. non-haloperidol: p < 0.001). More patients treated with olanzapine (73.8%) were fully alert according to a tranquilisation score and active at day 2 than patients treated with risperidone (57.1%) or haloperidol (58.0%). Current medication practices for immediate aggression control are effective with positive results present within a few days. In this study, concomitant benzodiazepine use was significantly more frequent in patients receiving haloperidol.