A Comparative Assessment of the Inflammatory Markers in Patients with Fibromyalgia under Duloxetine Treatment.

BACKGROUND: This study was carried out to compare the levels of inflammatory markers in the complete blood count before and after they began receiving duloxetine in patients with fibromyalgia syndrome (FMS). METHODS: The patient and control groups were composed of 40 patients diagnosed with FMS in accordance with the 2016 American College of Rheumatology (ACR) criteria and 40 healthy volunteers, respectively. The data collection tools comprised the sociodemographic information form, the fibromyalgia impact questionnaire (FIQ), and the sleep hygiene index (SHI), which were used to assess patients' sociodemographic characteristics, FMS disease activity, and sleep quality, respectively. The inflammatory markers of the patient group were assessed by complete blood count before and after the duloxetine treatment and compared with those of the control group. RESULTS: The white blood cell (WBC), neutrophil, and lymphocyte counts were significantly higher in the patient group than in the control group (p < 0.001, p = 0.036 and p = 0.004, respectively). Moreover, platelet distribution width (PDW) was significantly lower, whereas mean platelet volume (MPV) was significantly higher in the patient group than in the control group (p < 0.001 for both cases). In addition to patients' platelet-to-lymphocyte ratio (PLR) values, C-reactive protein (CRP) levels, and white blood cell (WBC) counts decreasing but not significantly (p = 0.083, p = 0.068, and p = 0.065, respectively), their neutrophil-to-lymphocyte ratio (NLR), hemoglobin (Hgb), and hematocrit (Hct) values declined substantially after commencing duloxetine treatment (p = 0.001, p = 0.008, and p = 0.001, respectively). CONCLUSIONS: The significant reduction in NLR, Hgb, and Hct levels following duloxetine treatment may indicate that these parameters can be utilized as biomarkers in determining the efficacy of treatment and in the follow-up of the treatment in FMS patients.

Duloxetine, Gabapentin, and the Risk for Acute Myocardial Infarction, Stroke, and Out-of-Hospital Death in Medicare Beneficiaries With Non-Cancer Pain.

OBJECTIVE: Duloxetine is a serotonin-norepinephrine reuptake inhibitor prescribed for musculoskeletal and other forms of chronic pain. Its dual pharmacologic properties have the potential to either raise or lower cardiovascular risk: adrenergic activity may increase the risk for acute myocardial infarction (AMI) and stroke, but antiplatelet activity may decrease risk. Gabapentin is another nonopioid medication used to treat pain, which is not thought to have adrenergic/antiplatelet effects. With the current emphasis on the use of nonopioid medications to treat patients with chronic pain, assessing cardiovascular risks associated with these medications among high-risk patients is important. MATERIALS AND METHODS: We conducted a retrospective cohort study among a 20% sample of Medicare enrollees, aged 65 to 89, with chronic pain who were new users between 2015 and 2018 of either duloxetine (n = 34,009) or gabapentin (n = 233,060). We excluded individuals with cancer or other life-threatening conditions at study drug initiation. The primary outcome was a composite of AMI, stroke, and out-of-hospital mortality. We adjusted for comorbidity differences with time-dependent inverse probability of treatment weighting. RESULTS: During 115,668 person-years of follow-up, 2361 patients had the composite primary outcome; the rate among new users of duloxetine was 16.7/1000 person-years compared with new users of gabapentin (21.1/1000 person-years), adjusted hazard ratio = 0.98 (95% CI: 0.83, 1.16). Results were similar for the individual components of the composite outcome as well as in analyses stratified by demographic and clinical characteristics. DISCUSSION: In summary, cohort Medicare patients with non-cancer pain beginning treatment with duloxetine had rates of AMI, stroke, and out-of-hospital mortality comparable to those who initiated gabapentin.

Exploring Clinicians' Perspectives of Barriers to Chemotherapy-Induced Peripheral Neuropathy Assessment and Management in Oncology Practice: A Qualitative Analysis of Semi-structured Interviews.

BACKGROUND: Quantitative reports suggest that the assessment and management of chemotherapy-induced peripheral neuropathy (CIPN) in practice is suboptimal. OBJECTIVE: The purpose of this qualitative analysis was to explore clinician-related perspectives of CIPN assessment, management, and the use of a CIPN decision support tool. METHODS: Clinicians from the breast oncology, gastrointestinal oncology, or multiple myeloma disease centers at Dana-Farber Cancer Institute who interacted with a CIPN clinician decision support algorithm were eligible to participate in the semi-structured interviews. The interview guide included questions about CIPN assessment, management, and clinician-decision support tool use. All interviews were audio-recorded, transcribed, and analyzed using inductive content analysis. RESULTS: Of the 39 eligible clinicians, 15 agreed to be interviewed. Interviewed clinicians were mainly physicians (73.3) and White, non-Hispanic (93.3%). Main themes from the interviews included (1) CIPN management practice patterns (eg, endorsement of non-recommended management strategies or lack of standardization for chemotherapy dose reduction) and barriers (eg, insurance prior authorizations required for duloxetine prescription), (2) CIPN assessment practice patterns (eg, use of subjective instead of objective CIPN assessment approaches) and barriers (eg, difficult to interpret patients' CIPN report between visits), and (3) utilization of the clinician decision support tool (eg, all assessment tasks lead to same management options). CONCLUSIONS: There are several barriers to clinicians' use of evidence-based CIPN assessment and management strategies. IMPLICATIONS FOR PRACTICE: Future work should be focused on addressing barriers to duloxetine prescription, developing evidence-based CIPN assessment and management strategies, improving symptom monitoring, and facilitating referrals to existing supportive care services.

Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT.

BACKGROUND: The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared. OBJECTIVES: To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain. DESIGN: A randomised crossover trial with health economic analysis. SETTING: Twenty-one secondary care centres in the UK. PARTICIPANTS: Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0-10). INTERVENTIONS: Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded. OUTCOMES: The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory - Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0-10), Patient Global Impression of Change score at week 16 and patients' preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost-utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective. RESULTS: A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval -0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6-16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval -0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -0.002 (95% confidence interval -0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline -0.006 (95% confidence interval -0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -£113 (95% confidence interval -£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval -£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval -£13 to £398)]. LIMITATIONS: Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable. FUTURE WORK: Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief. CONCLUSIONS: The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients' preference in terms of side effects. TRIAL REGISTRATION: The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 39. See the NIHR Journals Library website for further project information.

The number of people with diabetes is growing rapidly in the UK and is predicted to rise to over 5 million by 2025. Diabetes causes nerve damage that can lead to severe painful symptoms in the feet, legs and hands. One-quarter of all people with diabetes experience these symptoms, known as 'painful diabetic neuropathy'. Current individual medications provide only partial benefit, and in only around half of patients. The individual drugs, and their combinations, have not been compared directly against each other to see which is best. We conducted a study to see which treatment pathway would be best for patients with painful diabetic neuropathy. The study included three treatment pathways using combinations of amitriptyline, duloxetine and pregabalin. Patients received all three treatment pathways (i.e. amitriptyline treatment for 6 weeks and pregabalin added if needed for a further 10 weeks, duloxetine treatment for 6 weeks and pregabalin added if needed for a further 10 weeks and pregabalin treatment for 6 weeks and amitriptyline added if needed for a further 10 weeks); however, the order of the treatment pathways was decided at random. We compared the level of pain that participants experienced in each treatment pathway to see which worked best. On average, people said that their pain was similar after each of the three treatments and their combinations. However, two treatments in combination helped some patients with additional pain relief if they only partially responded to one. People also reported improved quality of life and sleep with the treatments, but these were similar for all the treatments. In the health economic analysis, the value for money and quality of life were similar for each pathway, and this resulted in uncertainty in the cost-effectiveness conclusions, with no one pathway being more cost-effective than the others. The treatments had different side effects, however; pregabalin appeared to make more people feel dizzy, duloxetine made more people nauseous and amitriptyline resulted in more people having a dry mouth. The pregabalin supplemented by amitriptyline pathway had the smallest number of treatment discontinuations due to side effects and may be the safest for patients.

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Symptom-based pharmacotherapy for neuropathic pain related to spinal disorders: results from a patient-based assessment.

Existing guidelines advocate an updated therapeutic algorithm for chronic neuropathic pain (NeP), but pharmacotherapeutic management should be individualized to pain phenotypes to achieve higher efficacy. This study was aimed to evaluate the efficacy of medications, based on NeP phenotypes, and to propose symptom-based pharmacotherapy. This retrospective study was enrolled 265 outpatients with chronic NeP related to spinal disorders. The patients were classified into three groups: spinal cord-related pain, radicular pain, and cauda equina syndrome. Data were obtained from patient-based questionnaires using Neuropathic Pain Symptom Inventory (NPSI) and the Brief Scale for Psychiatric Problems in Orthopaedic Patients, and from clinical information. The proportions of patients with ≥ 30% and ≥ 50% reduction in NPSI score for each pain subtype (spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia) and drugs were evaluated. The pain reduction rate was significantly lower in patients with spinal cord-related pain, especially for paresthesia/dysesthesia. For spinal cord-related pain, duloxetine and neurotropin had insufficient analgesic effects, whereas mirogabalin was the most effective. Pregabalin or mirogabalin for radicular pain and duloxetine for cauda equina syndrome are recommended in cases of insufficient analgesic effects with neurotropin. The findings could contribute to better strategies for symptom-based pharmacotherapeutic management.

Does Screening for Depressive Symptoms Help Optimize Duloxetine Use in Knee Osteoarthritis Patients With Moderate Pain? A Cost-Effectiveness Analysis.

OBJECTIVE: Duloxetine is a treatment approved by the US Food and Drug Administration for both osteoarthritis (OA) pain and depression, though uptake of duloxetine in knee OA management varies. We examined the cost-effectiveness of adding duloxetine to knee OA care in the absence or presence of depression screening. METHODS: We used the Osteoarthritis Policy Model, a validated computer microsimulation of knee OA, to examine the value of duloxetine for patients with knee OA who have moderate pain by comparing 3 strategies: 1) usual care, 2) usual care plus duloxetine for patients who screen positive for depression on the Patient Health Questionnaire 9 (PHQ-9), and 3) usual care plus universal duloxetine. Outcome measures included quality-adjusted life years (QALYs), lifetime direct medical costs, and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually. Model inputs, drawn from the published literature and national databases, included annual cost of duloxetine ($721-937); average pain reduction for duloxetine (17.5 points on the Western Ontario and McMaster Universities Osteoarthritis Index pain scale [0-100]), and likelihood of depression remission with duloxetine (27.4%). We considered 2 willingness-to-pay (WTP) thresholds of $50,000/QALY and $100,000/QALY. We varied parameters related to the PHQ-9 and the cost of duloxetine, efficacy, and toxicities to address uncertainty in model inputs. RESULTS: The screening strategy led to an additional 17 QALYs per 1,000 subjects and increased costs by $289/subject (ICER = $17,000/QALY). Universal duloxetine led to an additional 31 QALYs per 1,000 subjects and $1,205 per subject (ICER = $39,300/QALY). Under the majority of sensitivity analyses, universal duloxetine was cost-effective at the $100,000/QALY threshold. CONCLUSION: The addition of duloxetine to usual care for knee OA patients with moderate pain, regardless of depressive symptoms, is cost-effective at frequently used WTP thresholds.

Assessment of the Anti-Allodynic and Anti-Hyperalgesic Efficacy of a Glycine Transporter 2 Inhibitor Relative to Pregabalin, Duloxetine and Indomethacin in a Rat Model of Cisplatin-Induced Peripheral Neuropathy.

Cisplatin, which is a chemotherapy drug listed on the World Health Organisation's List of Essential Medicines, commonly induces dose-limiting side effects including chemotherapy-induced peripheral neuropathy (CIPN) that has a major negative impact on quality of life in cancer survivors. Although adjuvant drugs including anticonvulsants and antidepressants are used for the relief of CIPN, analgesia is often unsatisfactory. Herein, we used a rat model of CIPN (cisplatin) to assess the effect of a glycine transporter 2 (GlyT2) inhibitor, relative to pregabalin, duloxetine, indomethacin and vehicle. Male Sprague-Dawley rats with cisplatin-induced mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws received oral bolus doses of the GlyT2 inhibitor (3-30 mg/kg), pregabalin (3-100 mg/kg), duloxetine (3-100 mg/kg), indomethacin (1-10 mg/kg) or vehicle. The GlyT2 inhibitor alleviated both mechanical allodynia and hyperalgesia in the bilateral hindpaws at a dose of 10 mg/kg, but not at higher or lower doses. Pregabalin and indomethacin induced dose-dependent relief of mechanical allodynia but duloxetine lacked efficacy. Pregabalin and duloxetine alleviated mechanical hyperalgesia in the bilateral hindpaws while indomethacin lacked efficacy. The mechanism underpinning pain relief induced by the GlyT2 inhibitor at 10 mg/kg is likely due to increased glycinergic inhibition in the lumbar spinal cord, although the bell-shaped dose-response curve warrants further translational considerations.

Duloxetina para o tratamento da dor neuropática e da fibromialgia / Duloxetine for the treatment of neuropathic pain and of fibromyalgia

INTRODUÇÃO: A dor neuropática é causada por lesões ou doenças que afetam o sistema somatossensorial, caracterizada por dor espontânea ou anormal evocada por estímulo. Por outro lado, a fibromialgia é uma condição crônica caracterizada por dor musculoesquelética generalizada, fadiga, distúrbios do sono, comprometimento cognitivo e ansiedade, sem uma etiologia conhecida. No Brasil, no âmbito do Sistema Único de Saúde (SUS), o tratamento da dor crônica é direcionado, atualmente, pelo Protocolo Clínico e Diretrizes Terapêuticas da Dor Crônica. Dada a complexidade do tratamento da dor crônica neuropática e a ausência de tratamento medicamentoso para tratar a fibromialgia, o presente relatório foi elaborado com o objetivo de compreender a viabilidade do uso de duloxetina no manejo dessas condições clínicas, visando sua possível incorporação no SUS. TECNOLOGIA: Duloxetina (ABRETIA®, CYMBALTA®, CYMBI®, DEPRASIL®, DUAL®, DUATLO®, DULORGRAN®, MYDULO®, NEULOX®, VELIJA®). PERGUNTA: O uso de duloxetina é mais eficaz, seguro e custo-efetivo que os antidepressivos já incorporados ao SUS (amitriptilina, nortriptilina, fluoxetina e clomipramina) para o tratamento de pacientes com dor neuropática e fibromialgia? EVIDÊNCIAS CIENTÍFICAS: A busca pelas evidências retornou um total de 2.279 referências, das quais 19 foram incluídos, sendo 17 revisões sistemáticas e dois ensaios clínicos randomizados (ECR

Cost-effectiveness of duloxetine for knee OA subjects: the role of pain severity.

OBJECTIVE: Establish the impact of pain severity on the cost-effectiveness of generic duloxetine for knee osteoarthritis (OA) in the United States. DESIGN: We used a validated computer simulation of knee OA to compare usual care (UC) - intra-articular injections, opioids, and total knee replacement (TKR) - to UC preceded by duloxetine in those no longer achieving pain relief from non-steroidal anti-inflammatory drugs (NSAIDs). Outcomes included quality-adjusted life years (QALYs), lifetime medical costs, and incremental cost-effectiveness ratios (ICERs). We considered cohorts with mean ages 57-75 years and Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain 25-55 (0-100, 100-worst). We derived inputs from published data. We discounted costs and benefits 3% annually. We conducted sensitivity analyses of duloxetine efficacy, duration of pain relief, toxicity, and costs. RESULTS: Among younger subjects with severe pain (WOMAC pain = 55), duloxetine led to an additional 9.6 QALYs per 1,000 subjects (ICER = $88,500/QALY). The likelihood of duloxetine being cost-effective at willingness-to-pay (WTP) thresholds of $50,000/QALY and $100,000/QALY was 40% and 54%. Offering duloxetine to older patients with severe pain led to ICERs >$150,000/QALY. Offering duloxetine to subjects with moderate pain (pain = 25) led to ICERs <$50,000/QALY, regardless of age. Among knee OA subjects with severe pain (pain = 55) who are unwilling or unable to undergo TKR, ICERs were <$50,600/QALY, regardless of age. CONCLUSIONS: Duloxetine is a cost-effective addition to knee OA UC for subjects with moderate pain or those with severe pain unable or unwilling to undergo TKR. Among younger subjects with severe pain, duloxetine is cost-effective at WTP thresholds >$88,500/QALY.

Assessment of the anti-allodynic efficacy of a glycine transporter 2 inhibitor relative to pregabalin and duloxetine in a rat model of prostate cancer-induced bone pain.

BACKGROUND: The pathobiology of prostate cancer-induced bone pain (PCIBP) is underpinned by both inflammatory and neuropathic components. Here, we used a rat model of PCIBP to assess the analgesic efficacy of a glycine transporter 2 (GlyT2) inhibitor (N-(6-((1,3-dihydroxypropan-2-yl)amino)-2-(dimethylamino)pyridin-3-yl)-3,5-dimethoxy-4-(4-(trifluoromethyl)phenoxy) benzamide) relative to two clinically available adjuvant drugs that are recommended for the relief of neuropathic pain, viz, pregabalin and duloxetine. METHODS: PCIBP was induced in male Wistar Han rats following intra-tibial injection (ITI) of rat prostate cancer (AT3B) cells into the left tibia. Sham-rats received an ITI of heat-killed AT3B cells. PCIBP rats with fully developed mechanical allodynia in the ipsilateral hindpaws as assessed using von Frey filaments, received single oral (p.o.) bolus doses of the GlyT2 inhibitor (3-30 mg/kg), pregabalin (3-100 mg/kg), duloxetine (3-100 mg/kg), or vehicle. Baseline paw withdrawal thresholds (PWTs) were determined in the ipsilateral (injured side) and contralateral hindpaws immediately prior to dosing and at scheduled times for 3 h post dosing in individual animals. RESULTS: Single oral bolus doses of the GlyT2 inhibitor (3-30 mg/kg) evoked partial pain relief at the doses tested in the ipsilateral hindpaws of PCIBP rats without any discernible behavioural side effects. By contrast, single oral bolus doses of pregabalin at 10-100 mg/kg evoked dose-dependent and complete alleviation of mechanical allodynia. By comparison, single oral bolus doses of duloxetine at doses up to 100 mg/kg lacked efficacy. CONCLUSION: Oral administration of this GlyT2 inhibitor evoked partial pain relief in PCIBP rats and did not evoke central nervous system side effects in contrast to GlyT2 inhibitors reported by others.

Duloxetina para el tratamiento de dolor en personas que padecen de fibromialgia / Duloxetine for treating pain in people with fibromyalgia

INTRODUCCIÓN: Este documento técnico se realiza a solicitud del Instituto Nacional de Ciencias Neurológicas; la cual motivó la realización de la pregunta PICO por parte de médicos y especialistas de la siguiente manera, P: pacientes adultos con fibromialgia; I: duloxetina 60 mg; C: pregabalina 150 o 300 mg; O: reducción del dolor, discontinuación por falta de eficacia y eventos adversos. A. Cuadro clínico: La fibromialgia es un síndrome de dolor crónico caracterizado por dolor generalizado, y a menudo asociado con falta de sueño, fatiga, depresión y disfunción cognitiva. La prevalencia a nivel mundial en la población general se estima en un 1,78%, y en la región de las Américas se estima en 2,41%. En Perú, no existen datos estadísticos a nivel nacional. El manejo de la fibromialgia incluye aspectos de educación al paciente, práctica de estilos de vida saludable (incluyendo ejercicios aeróbicos y de fortalecimiento), terapia cognitivo conductual en personas con trastorno del estado de ánimo o estrategias de afrontamiento inadecuadas, y terapias farmacológicas para personas con dolor intenso o trastornos del sueño. Los medicamentos aprobados por la Food and Drug Administration (FDA) para el tratamiento de la fibromialgia son pregabalina, duloxetina y milnacipran. B. Tecnología sanitária: Duloxetina es un inhibidor de la recaptación de serotonina y noradrenalina (IRSN), cuya acción inhibitoria sobre el dolor se produciría por la potenciación de los tractos descendentes inhibitorios del dolor en el sistema nervioso central. La dosis recomendada para fibromialgia consiste en una dosis inicial de 30 mg una vez al día durante una semana, seguida de 60 mg una vez al día. Los eventos adversos más comunes son dolor de cabeza, somnolencia y fatiga. Algunos eventos adversos graves incluyen suicidio, síndrome serotoninérgico, hepatoxicidad, manía, síncope, síndrome de secreción inadecuada de la hormona antidiurética e hiponatremia. Duloxetina cuenta con aprobación de la FDA para el tratamiento de la fibromialgia desde el año 2008. En Perú, cuenta con diecinueve registros sanitarios vigentes y cuatro registros sanitarios con vigencia prorrogada provisional. OBJETIVO: Describir la evidencia científica disponible sobre la eficacia y seguridad de duloxetina para el tratamiento del dolor en personas que padecen de fibromialgia. METODOLOGÍA: Se realizó una búsqueda sistemática en Medline (Pubmed), The Cochrane Library y LILACS utilizando la estrategia de búsqueda descrita en el Anexo 01. Ésta se complementó con la búsqueda de evidencia en páginas institucionales de agencias gubernamentales y buscadores genéricos. Se priorizó la identificación y selección de ensayos clínicos aleatorizados controlados, revisiones sistemáticas (RS) con o sin meta-análisis (MA) de ensayos clínicos aleatorizados controlados, guías de práctica clínica (GPC), evaluaciones de tecnología sanitaria (ETS) y evaluaciones económicas (EE) de América Latina. La calidad de la evidencia se valoró usando las siguientes herramientas: AMSTAR 2 para la valoración de la calidad de RS, la herramienta propuesta por la colaboración Cochrane para ensayos clínicos y AGREE II para valorar el rigor metodológico de las GPC. RESULTADOS: Se identificó dos revisiones sistemáticas (RS) y tres guías de práctica clínica (GPC) que respondieron a la pregunta PICO de interés. CONCLUSIONES: En comparación con placebo, duloxetina produjo un alivio significativo del dolor en forma global y en puntos de corte de al menos 30% y de al menos 50%, incrementó la probabilidad de mejoría clínica percibida y redujo el riesgo de discontinuación por falta de eficacia. En comparación con placebo, duloxetina incrementó el riesgo de eventos adversos, siendo los más comunes náuseas, estreñimiento, hiperhidrosis, diarrea, dolor de cabeza, xerostomía, somnolencia e insomnio. Sin embargo, no se observaron diferencias en el riesgo de eventos adversos serios o discontinuación por eventos adversos. • No se observaron diferencias significativas entre duloxetina y pregabalina en dosis de 150mg o 300 mg sobre la reducción del dolor en al menos 30% o la discontinuación por eventos adversos. Las GPC de EULAR y de Canadá recomiendan duloxetina o pregabalina como opciones de tratamiento para fibromialgia, mientras que CENETEC no recomienda el uso de inhibidores de recaptura de serotonina y noradrenalina. Las revisiones sistemáticas fueron consideradas como nivel de confianza bajo. La calidad de la evidencia fue moderada para las comparaciones entre duloxetina y placebo, y baja para las comparaciones entre duloxetina y pregabalina. Las GPC incluidas obtuvieron un puntaje superior al 80% en la valoración global de calidad.

Effects of vortioxetine on functional capacity across different levels of functional impairment in patients with major depressive disorder: a University of California, San Diego Performance-based Skills Assessment (UPSA) analysis.

Objective: To evaluate the consistency of vortioxetine's effects on functional capacity in adults with major depressive disorder (MDD) and self-reported cognitive symptoms at different levels of functional impairment.Methods: An exploratory analysis of data from a randomized, placebo-controlled, duloxetine-referenced study (NCT01564862) involving 529 patients with moderate to severe MDD treated once-daily with vortioxetine 10/20 mg, duloxetine 60 mg, or placebo for 8 weeks. Analysis of the University of California, San Diego Performance-based Skills Assessment (UPSA) composite scores stratified patients into subgroups by baseline functional impairment and assessed clinically important differences using several cutoffs for change from baseline (CFB) (least-square means) in UPSA composite score. A path analysis was also conducted to determine the proportion of direct versus indirect effects of vortioxetine on functional capacity.Results: Vortioxetine significantly separated from placebo across different baseline levels of functional impairment, particularly at the ≤70 cutoff (mean difference = 5.9, 95% confidence interval, 1.5-10.4). A greater proportion of patients treated with vortioxetine than placebo exhibited UPSA composite score response at each threshold analyzed and were classified as responders based on UPSA CFB of ≥7 (p = 0.006) or ≥9 (p = 0.016). No significant effects were observed for duloxetine versus placebo for any baseline levels of functional impairment or response thresholds. Path analysis demonstrated that 96.9% of the effects on functional capacity can be directly attributed to the treatment effect of vortioxetine and are not mediated by improvements in depressive symptoms as measured by MADRS.Conclusion: The effects of vortioxetine on functional capacity is robust across different level of functional impairment in patients with MDD. The effect on functional capacity was largely independent of the effect on depressive symptoms. Trial Registration: ClinicalTrials.gov identifier: NCT01564862: https://clinicaltrials.gov/ct2/show/NCT01564862; European Clinical Trials Database [EudraCT] Number 2011-005298-22: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-005298-22/DE.

Chemotherapy-induced peripheral neuropathy (CIPN) and its treatment: an NIH Collaboratory study of claims data.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling complication of many chemotherapies. We investigated the feasibility of using health plan claims and administrative data to identify CIPN occurrence by comparing patients who received neurotoxic and non-neurotoxic chemotherapies. METHODS: The sample included over 53,000,000 patients from two regional and one national insurer in the USA (> 400,000 exposed to chemotherapy). Peripheral neuropathy was identified using a broad definition (definition 1) and a specific definition (i.e., drug-induced polyneuropathy code) (definition 2). RESULTS: CIPN incidence as measured by definition 1 within 6 months of chemotherapy initiation was 18.1% and 6.2% for patients who received neurotoxic and non-neurotoxic chemotherapy, respectively (relative risk neurotoxic vs. non-neurotoxic (RR), 2.93 (95% CI, 2.87-2.98)). For definition 2, these incidences were 3.6% and 0.1% (RR, 25.2 (95% CI, 22.8-27.8)). The incidences of new analgesic prescriptions for neurotoxic and non-neurotoxic groups were as follows: gabapentin, 7.1%/1.7%; pregabalin, 0.69%/0.31%; and duloxetine, 0.78%/0.76%. The incidence of CIPN as defined by definitions 1 and 2 was low compared with that of published research studies, but the relative risk of CIPN among patients who received neurotoxic chemotherapies compared with those who received non-neurotoxic chemotherapies was high using definition 2. CONCLUSIONS: These data suggest that as used currently by clinicians, administrative codes likely underestimate CIPN incidence. Thus, studies using administrative data to estimate CIPN incidence are not currently feasible. However, the drug-induced polyneuropathy code is a specific indicator of CIPN in administrative data and may be useful for investigating predictors or potentially preventive therapies of CIPN.

Gabapentin drug misuse signals: A pharmacovigilance assessment using the FDA adverse event reporting system.

BACKGROUND: Although there have been increasing reports of intentional gabapentin misuse, epidemiological evidence for the phenomenon is limited. The purpose of this study was to determine whether there are pharmacovigilance abuse signals for gabapentin. METHODS: Using FDA Adverse Events Reporting System reports from January 1, 2005 to December 31, 2015, we calculated pharmacovigilance signal measures (i.e., reporting odds ratio, proportional reporting ratio, information component, and empirical Bayes geometric mean) for abuse-related adverse event (AR-AE)-gabapentin pairs. Loglinear modeling assessed the frequency of concurrent reporting of abuse-related and abuse-specific AEs (AS-AEs) associated with gabapentin. Findings were compared to a positive (pregabalin) and negative (duloxetine) control. RESULTS: From 2005-2015 there were 5,951,229 unique AE reports submitted to the FDA including 99,977 for gabapentin, 73,977 for duloxetine, and 97,813 for pregabalin. Significant drug-AR-AE pair signals involving gabapentin included: drug abuser, multiple drug overdose, and substance-induced psychotic disorder. Significant drug AR-AE signals involving gabapentin and pregabalin, but not duloxetine, were: ataxia, dependence, drug abuse, increased drug tolerance, and overdose. Compared to duloxetine, gabapentin had significantly greater odds of a co-report for an AS-AE with drug withdrawal syndrome (OR: 6.55), auditory hallucinations (OR: 4.57), delusions (OR: 2.36), euphoric mood (OR: 5.45), ataxia (OR: 2.85), drug abuser (OR: 3.01), aggression (OR: 1.98), psychotic disorder (OR: 1.96), and feeling abnormal (OR: 1.31). CONCLUSIONS: We identified abuse-related signals for gabapentin and highlighted several CNS effects that may be associated with its abuse. Gabapentin prescribers should be aware of the drug's abuse liability and effects that may accompany its use.

In-vitro and in situ assessment of the efflux of five antidepressants by breast cancer resistance protein.

OBJECTIVES: Antidepressants need to penetrate the blood-brain barrier (BBB) to exert their functions in the central nervous system. Breast cancer resistance protein (BCRP), an efflux transporter abundantly expressed in the BBB, prevents the accumulation of many drugs in the brain. This study aimed to identify whether five commonly used antidepressants (sertraline, duloxetine, fluoxetine, amitriptyline and mirtazapine) are BCRP substrates. METHODS: A combination of bidirectional transport and intracellular accumulation experiments was conducted on BCRP-overexpressing MDCKII and wild-type (WT) cells, and in situ brain perfusion was conducted in rats. KEY FINDINGS: The bidirectional transport study revealed that the net efflux ratio (NER) of sertraline reached 2.08 but decreased to 1.06 when co-incubated with Ko143, a selective BCRP inhibitor. Conversely, the other four antidepressants did not appear to be BCRP substrates, due to their low NER values (<1.5). The accumulation of sertraline in MDCKII-BCRP cells was significantly lower than that in MDCKII-WT cells. The presence of Ko143 significantly increased the sertraline accumulation in MDCKII-BCRP cells but not in MDCKII-WT cells. Brain perfusion showed that the permeability of 1 and 5 µm sertraline was significantly higher in the presence of Ko143. CONCLUSIONS: Taken together, BCRP is involved in sertraline efflux.

Risk for Medication Nonadherence Among Medicaid Enrollees With Fibromyalgia: Development of a Validated Risk Prediction Tool.

OBJECTIVE: To develop and validate a risk assessment tool called the Prescription Medication Non-Adherence Prediction Tool (Rx-NAPT) to predict medication nonadherence in patients with fibromyalgia. METHODS: This was a retrospective cohort study using claims data from South Carolina Medicaid. Patients with fibromyalgia who were ≥18 years old and who had filled at least 1 prescription medication for pregabalin, duloxetine, or milnacipran from January 1, 2005, through June 30, 2011 were included. Medication possession ratios (MPRs) were calculated to classify patients as adherent (MPR ≥ 80%) or nonadherent (MPR < 80%). Multivariable logistic models using 100 bootstrap replications (with replacement) were used to identify factors associated with medication nonadherence, including age, gender, race, days' supply, medication type, and fibromyalgia-related comorbidity score. Weighted ß coefficients of the predictors were used to create the Rx-NAPT. Youden's J statistic was used to classify nonadherent patients into different levels of risk. RESULTS: The study sample comprised 6,626 patients with fibromyalgia, where 4,804 (72.50%) were non-adherent and 1,822 (27.50%) were adherent to their prescribed medication(s). Logistic regression models showed that 7 predictors (gender, age, race, fibromyalgia-related comorbidity score, medication type, health maintenance organization coverage, emergency room visit) were statistically significant in ≥50% of the bootstrapped samples. The final model demonstrated reasonable discrimination (area under the curve [AUC] = 0.6224) and calibration (Hosmer-Lemeshow goodness-of-fit; P > 0.05) statistics and was validated internally (AUC = 0.6372). CONCLUSION: Poor adherence with medication remains an important barrier to providing optimal care. Our risk prediction model provides an easy tool to help clinicians better identify patients with fibromyalgia who may not take their medications as prescribed.

Healthcare Costs and Medication Adherence Among Patients with Fibromyalgia: Combination Medication vs. Duloxetine, Milnacipran, Venlafaxine, and Pregabalin Initiators.

OBJECTIVE: To examine medication adherence and healthcare costs for combination prescription initiators (duloxetine/milnacipran/venlafaxine with pregabalin) vs. monotherapy initiators (duloxetine, milnacipran, venlafaxine, and pregabalin) among patients with fibromyalgia syndrome (FMS). METHODS: Our retrospective cohort study used claims data for the South Carolina Blue Cross Blue Shield State Health Plan (SHP). Patients with FMS ≥ 18 years of age, with prescription initiation from July 1, 2007, through June 30, 2010, and SHP enrollment for 12 months pre- and post-index periods were included (combination: n = 100; pregabalin: n = 665; duloxetine: n = 713; milnacipran: n = 131; venlafaxine: n = 272). Medication adherence measures included high adherence (medication possession ratio ≥ 80%) and total supply days. Healthcare costs comprised direct medical expenditures. Propensity score methods of inverse probability of treatment weights were used to control for selection bias due to differing pre-index characteristics. RESULTS: Odds ratios for high adherence were significantly increased (P < 0.05) among the combination cohort vs. the venlafaxine (2.15), duloxetine (1.39), and pregabalin (2.20) cohorts. Rate ratios for total supply days were significantly higher (P < 0.05) for combination vs. venlafaxine (1.23), duloxetine (1.08), and pregabalin (1.32) cohorts. Expenditures for total health care were significantly higher (P < 0.05) for combination vs. duloxetine ($26,291 vs. $17,190), milnacipran ($33,638 vs. $22,886), and venlafaxine ($26,586 vs. $16,857) cohorts. CONCLUSIONS: Medication adherence was considerably better for combination prescription initiators; however, expenditures for total health care were higher. Still, our findings suggest important clinical benefits with the use of combination prescription therapy, and prospective studies of medication adherence are warranted to examine causal relationships with outcomes not captured by healthcare claims databases.

Cost per successfully treated patient for vortioxetine versus duloxetine in adults with major depressive disorder: an analysis of the complete symptoms of depression and functional outcome.

OBJECTIVE: To determine the cost-effectiveness of vortioxetine vs duloxetine in adults with moderate-to-severe major depressive disorder (MDD) in Norway using a definition of a successfully treated patient (STP) that incorporates improvement in both mood symptoms and functional capacity. METHODS: Using the population of patients who completed the 8-week CONNECT study, the cost-effectiveness of vortioxetine (n = 168) (10-20 mg/day) vs duloxetine (n = 176) (60 mg/day) was investigated for the treatment of adults in Norway with moderate-to-severe MDD and self-reported cognitive dysfunction over an 8-week treatment period. Cost-effectiveness was assessed in terms of cost per STP, defined as improvement in mood symptoms (≥50% decrease from baseline in Montgomery-Åsberg Depression Rating Scale total score) and change in UCSD [University of California San Diego] performance-based skills assessment [UPSA] score of ≥7. The base case analysis utilized pharmacy retail price (apotek utsalgspris (AUP)) for branded vortioxetine (Brintellix) and branded duloxetine (Cymbalta). RESULTS: After 8 weeks of antidepressant therapy, there were more STPs with vortioxetine than with duloxetine (27.4% vs 22.5%, respectively). The mean number needed to treat for each STP was 3.6 for vortioxetine and 4.4 for duloxetine, resulting in a lower mean cost per STP for vortioxetine (NOK [Norwegian Kroner] 3264) than for duloxetine (NOK 3310) and an incremental cost per STP of NOK 3051. The use of a more challenging change in the UPSA score from baseline (≥9) resulted in a mean cost per STP of NOK 3822 for vortioxetine compared with NOK 3983 for duloxetine and an incremental cost per STP of NOK 3181. CONCLUSIONS: Vortioxetine may be a cost-effective alternative to duloxetine, owing to its superior ability to improve functional capacity. The dual-response STP concept introduced here represents a more comprehensive analysis of the cost-effectiveness of antidepressants.