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OBJECTIVE: To study the association between benzodiazepine prescribing patterns including dose, type and dosing schedule and the risk of drug overdose death among US veterans receiving opioid analgesics. DESIGN: Case-cohort study SETTING: Veterans Health Administration (VHA), 2004 through 2009. PARTICIPANTS: US veterans, primarily male, who received opioid analgesics between 2004 and 2009. All veterans who died of a drug overdose (n = 2,400) while receiving opioid analgesics and a random sample of veterans (n = 420,386) who received VHA medical services and opioid analgesics were included in the study. Main outcome measure: Drug overdose death, defined as any intentional, unintentional or indeterminate poisoning death caused by any medication or drug, determined by cause of death information from the National Death Index. RESULTS: Twenty seven percent of veterans who received opioid analgesics also received benzodiazepines during the study period. Approximately half of the drug overdose deaths (n=1,185) occurred when veterans were concurrently prescribed benzodiazepines and opioids. Risk of drug overdose death increased based on benzodiazepine prescription history: formerly prescribed vs. not prescribed (adjusted hazard ratio [HR]=2.33, 95% confidence interval [CI]: 2.05-2.64); currently prescribed vs. not prescribed (HR=3.86, CI:3.49-4.26). Risk of drug overdose death increased as daily benzodiazepine dose increased. When compared to clonazepam, temazepam was associated with a decreased drug overdose death risk (HR=0.63, CI: 0.48-0.82). Benzodiazepine dosing schedule was not associated with drug overdose death risk. CONCLUSIONS: Among veterans receiving opioid analgesics, receipt of benzodiazepines was associated with an increased risk of drug overdose death in a dose-response fashion.

Orientador: Guilherme Antonio Moreira de Barros / Resumo: Introdução: A dor é uma experiência pessoal, subjetiva, que envolve aspectos sensitivos e culturais que podem ser alterados pelas variáveis socioculturais e psíquicas do indivíduo, do meio e, apesar de classificações diversas, geralmente relacionada ao sofrimento. No Brasil estudos indicam que, embora cerca de 50% dos pacientes portadores de dor estejam medicados, a maior parte deles está descontente com os resultados do tratamento. Em situação de dor aguda traumática, apenas 7% dos pacientes tem suas dores totalmente aliviadas e, em pacientes em vigência de dor de intensidade moderada a grande, somente 25% receberam opioides como parte de seu tratamento, apesar de recomendação da OMS de uso destes analgésicos, como descrito na escada analgésica. Objetivo: Compreender as razões da baixa prescrição dos opioides no tratamento da dor no Brasil, com ênfase aos entraves sociais, legais e burocráticos existentes. Métodos: Trata-se de um estudo epidemiológico, prospectivo, analítico observacional e transversal, aprovado pela Comissão de Ética em Pesquisa, e realizado a partir de questionário investigativo disponibilizado em plataforma online, com perguntas fechadas e abordagem quantitativa. Foram convidados a participarem do estudo, por meio de mensagens eletrônicas a médicos atuantes em território Nacional. Aqueles que concordaram em participar assinaram, eletronicamente, o Termo de Consentimento Livre e Esclarecido (TCLE) online. Para análise estatística foram realizados os teste... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Pain is a personal, subjective experience, involving sensitive and cultural aspects that can be altered by the socio-cultural and psychological variables of the individual, the environment and, despite different classifications, it is frequently related to suffering. In Brazil studies indicate that, although about 50% of pain patients are medicated, most of them are unhappy with the treatment outcomes. In situations of acute traumatic pain, only 7% of patients have their pain totally relieved and, in patients with moderate to severe pain, only 25% received opioids as part of their treatment, despite of the WHO recommendation to use these analgesics, as described on the analgesic ladder. Objective: To understand the reasons for the low prescription of opioids in the treatment of pain in Brazil, with emphasis on the existing social, legal and bureaucratic barriers. Method: This is a prospective, observational and cross-sectional epidemiological study, approved by the Research Ethics Committee, and carried out using an investigative questionnaire available on an online platform, with closed questions and a quantitative approach. Participants were invited to participate in the study, through electronic messages to medical doctors working in the national territory. Those who agreed to participate signed, electronically, the Free and Informed Consent Term (ICF) online. For statistical analysis, chi-square tests were performed followed by Z tests and Student's t tests.... (Complete abstract click electronic access below) / Doutor

Abstract In four prospective clinical trials, 114 parturients used intravenous patient-controlled remifentanil analgesia during the 1st stage of labour. The median effective dose per bolus was ascertained to be 0.4 μg/kg and the pain scores were reduced with this by a median of 2 on a numerical scale (0–10). Compared with nitrous oxide, 15 parturients included in a cross-over study reported a larger reduction in pain scores during remifentanil analgesia (1.5 vs. 0.5, p =  0.001) and better pain relief scores (2.5 vs. 0.5 on a ranked five point scale 0–4, p  <  0.001). In a parallel study including 45 parturients, epidural analgesia (EDA, 20 ml bupivacaine 0.625 mg/ml and fentanyl 2 μg/ml) was associated with lower pain scores (5.2 vs. 7.3 with remifentanil, p =  0.004) but variables related to satisfaction with analgesia (pain relief score, proportion of mothers with desire to continue with the given medication and termination of the study due to inadequate pain relief) were similar. A comparison of two methods for timing the remifentanil bolus during the uterine contraction cycle suggested that delaying the bolus does not improve analgesia. A period effect was noted in the cross-over trial with higher pain scores and increased drug consumption during the second study period suggesting acute hyperalgesia. Side effects of remifentanil analgesia included respiratory depression warranting oxygen supplementation in 33% of parturients. Sedation was experienced by the parturients using remifentanil and this was scored as stronger than sedation during nitrous oxide and EDA. The number of parturients with nausea did not increase during remifentanil analgesia. Other maternal side effects included dizziness, a difficulty in visual focusing and itching. Foetal heart rate tracing abnormalities were noted. The incidence of abnormal tracings and decreased UapH were not different, however, from that observed during nitrous oxide or EDA. Apgar scores at 1 and 5 minute indicated no neonatal depression.

Submitted by Eunice Novais (enovais@uepg.br) on 2017-08-17T19:02:15Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) FABIANA FERNANDES MADALOZZO COPPLA.pdf: 8129839 bytes, checksum: 555584401fddabd5299b0abdea4be4de (MD5) / Made available in DSpace on 2017-08-17T19:02:15Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) FABIANA FERNANDES MADALOZZO COPPLA.pdf: 8129839 bytes, checksum: 555584401fddabd5299b0abdea4be4de (MD5) Previous issue date: 2017-06-28 / Introdução: A Sensibilidade dental (SD) induzida pelo clareamento é altamente prevalente. A combinação de opioides e analgésicos não opioides pode proporcionar um melhor efeito analgésico. Objetivos: Avaliar o efeito da associação de paracetamol / codeína administrado pré e pós-operatoriamente sobre o risco e a intensidade da SD induzida pelo clareamento dental. Métodos: Realizou-se um ensaio clínico randomizado paralelo, triplo cego, com 105 pacientes saudáveis os quais receberam um placebo ou uma associação de paracetamol / codeína. A primeira dose de (paracetamol 500 mg / codeína 30 mg) ou placebo foi administrada 1 h antes do clareamento em consultório (peróxido de hidrogénio 35%) e doses extras foram administradas a cada 6 h durante 48 h. A SD foi avaliada utilizando duas escalas: 0-10 escala visual analógica VAS e uma escala de classificação numérica NRS 0-4 em diferentes períodos: durante o clareamento, 1 h até 24 h, 24 h até 48 h pós clareamento. A cor foi mensurada antes e um mês após o clareamento dental com uma escala de cores visuais Vita Classical, Vita Bleachedguide 3D-Master e espectrofotômetro Vita Easyshade (Vita Zahnfabrik). O risco absoluto de SD foi avaliado pelo teste exato de Fisher. Os dados da intensidade SD com escala NRS dos dois grupos foram comparados com os testes de Mann- Whitney e Friedman, enquanto que os dados da escala VAS foram avaliados por meio de ANOVA dois fatores de medidas repetidas. As alterações de cor entre os grupos foram comparadas utilizando teste t de Student (α = 0,05). Resultados: Não foram observadas diferenças significativas entre os grupos quanto ao risco e intensidade de SD. O risco absoluto total de SD foi de aproximadamente 96%. Uma alteração de cor de quase 5 unidades da escala de cor visual Vita Classical foi detectada em ambos os grupos, que foram estatisticamente semelhantes (p> 0,05). Conclusão: O uso da associação paracetamol / codeína pré e pós clareamento de consultório não reduz o risco e a intensidade da SD induzida pelo clareamento. Implicações clínicas: O uso de um fármaco analgésico opioide não foi capaz de prevenir SD decorrente de clareamento dental em consultório. / Background: Bleaching-induced TS is highly prevalent. The combination of Opioids and non opioids analgesics may provide a better analgesic effect. Objective: To evaluate the effect of the combination of paracetamol / codeine administered before and postoperatively on the risk and intensity of TS induced by dental whitening. Methods: A triple-blind, parallel, randomized clinical trial was conducted with 105 health patients who received either a placebo or an association of codeine/acetaminophen. The first dose of Tylex® 30 mg (acetaminophen 500 mg/codeine 30 mg) or placebo was administered 1 h before the in-office bleaching (35% hydrogen peroxide), and extra doses were administered every 6 h for 48 h. The TS was recorded using two scales: 0-10 visual analog scale and a 0-4 numeric rating scale in different periods: during bleaching, 1 h up to 24 h, 24 h up to 48 h postbleaching. The color was measured before and one month after dental bleaching with a visual shade guide Vita Classical, Vita Bleachedguide 3D-Master and spectrophotometer Vita Easyshade (Vita Zahnfabrik). The absolute risk of TS was evaluated by Fisher’s exact test. Data of TS intensity with NRS scale of the two groups were compared with Mann-Whitney and Friedman tests, while data from the VAS scale were evaluated by two-way repeated measures ANOVA. The color changes between groups were compared using a Student t-test (α = 0.05). Results: No significant differences between the groups were observed in the risk and intensity of TS. The overall absolute risk of TS was approximate 96%. A color change of nearly 5 shade guide units of the Vita Classical was detected in both groups, which were statistically similar (p > 0.05). Conclusion: The use of acetaminophen/codeine association pre and post in-office bleaching does not reduce the risk and intensity of bleaching-induced TS. Practical Implications: The use of an opioid analgesic drug was not capable to prevent TS arising from in-office dental bleaching.

Increased opioid analgesic (OA) prescribing has been associated with increased risk of prescription opioid diversion, misuse, and abuse. States established prescription drug monitoring programs (PDMPs) to collect and analyze electronic records for dispensed controlled substances to reduce prescription drug abuse and diversion. PDMP data can be used by prescribers for tracking patient’s history of controlled substance prescribing to inform clinical decisions. The studies in this dissertation are focused on the less utilized potential of the PDMP data to enhance public health surveillance to monitor OA prescribing and co-prescribing and association with opioid overdose mortality and morbidity. Longitudinal analysis of OA prescribing and evaluation of the effect of recent policies and opioid prescribing guidelines require consensus measures for OA utilization and computational tools for uniform operationalization by researchers and agencies. Statistical macros and computational tools for OA utilization measures were developed and tested with Kentucky PDMP data. A set of covariate measures using mortality and morbidity surveillance data were also developed as proxy measures for prevalence of painful conditions justifying OA utilization, and availability of heroin and medication treatment for opioid use disorder. A series of epidemiological studies used the developed OA measures as outcomes, and adjusted for time-varying socio-demographic and health care utilization covariates in population-averaged statistical models to assess longitudinal trend and pattern changes in OA utilization in Kentucky in recent years. The first study, “Trends and Patterns of OA Prescribing: Regional and Rural-Urban Variations in Kentucky from 2012 to 2015,” shows significant downward trends in rates of residents with OA prescriptions. Despite the significant decline over time, and after accounting for prevalence of injuries and cancer, the rate of dispensed OA prescriptions among residents in Kentucky Appalachian counties remained significantly higher than the rest of the state. The second study, “Population-Level Measures for High-Risk OA Prescribing: Longitudinal Trends and Relationships with Pain-Associated Conditions,” shows significant reduction in high-risk OA prescribing (e.g., high daily dosage, long-term use, concurrent prescriptions for OA and benzodiazepines) from 2012 to 2016, significantly positive associations between high-risk OA prescribing and cancer mortality rates with no substantial change in the association magnitude over time, and declining strengths of positive associations between high-risk OA prescribing and acute traumatic injuries or chronic non-cancer pain over the study period. The third study, “A Reciprocal Association between Longitudinal Trends of Buprenorphine/Naloxone Prescribing and High-Dose OA Prescribing,” indicates a significant reciprocal relationship between high-dose OA prescribing and buprenorphine/ naloxone prescribing, and a clinically meaningful effect of buprenorphine/naloxone prescribing on reducing OA utilization. The results from the studies advanced the understanding of the epidemiology of opioid use and misuse in Kentucky, and identified actionable risk and protective factors that can inform policy, education, and drug overdose prevention interventions. The developed operational definition inventory and computational tools could stimulate further research in Kentucky and comparative studies in other states.

With an increasing prevalence of osteoarthritis, total knee (TKA) and hip (THA) arthroplasty are the second-and third-most common surgeries in Canada. Although these procedures improve pain and function for a majority of patients, some patients report persistent postoperative pain. Opioids are conventionally used for these patients even though they are associated with addiction, falls, overdose, and death. Recently, many strategies have been proposed to decrease reliance on opioids after TKA and THA, including opioid-free and opioid-reduced multimodal protocols for pain management. Our findings demonstrate that Canadian patients’ receptivity to opioid-free or reduced postoperative protocols is associated with their perception of the efficacy and safety of opioids compared to non-opioid alternatives, and current opioid use. More patients are open to opioid-reduced postoperative care as they perceive that pain will be intolerable without opioids. This overlaps with many Canadian surgeons’ perception that opioids cannot be completely eliminated from postoperative pain management regimens and that patients expect an intolerable level of pain after surgery, warranting opioid use. This highlights a need for enhanced patient education on the safety and efficacy of opioids and alternatives, while managing patients’ expectations of postoperative pain control. Most Canadian and Dutch surgeons reported that they prescribe opioids to nearly all of their patients postoperatively. However, our cross-sectional study indicates that 40% of Canadian patients would be open to receiving no opioids postoperatively. In contrast, Japanese surgeons believed that opioids are unnecessary for managing postoperative pain. Variations observed among orthopaedic surgeons in Canada, the Netherlands, and Japan can be attributed to differences at the surgeon-level (individual practices and beliefs), patient-level (patient characteristics and preferences), and system-level (regulatory frameworks and healthcare systems). Further research is required on surgeon-centered approaches to mitigating opioid use, focusing on education and guidelines/policies for opioid prescribing. / Thesis / Master of Science (MSc) / Opioid analgesics are routinely prescribed to manage pain after total knee and hip replacement surgery. However, opioids are not typically more effective than alternatives and are associated with addiction, overdose, and death. This thesis aims to understand the perceptions of patients and orthopaedic surgeons on opioid use after total knee and hip replacement surgery. The findings demonstrate that more patients are open to receiving opioid-reduced surgery compared to opioid-free surgery, with receptivity being associated with patients’ perceptions of opioid efficacy and safety and current opioid use, highlighting a need for improved patient education. Additionally, orthopaedic surgeons identified challenges and facilitators to postoperative opioid reduction in six key areas: opioid prescribing practices, patient factors, collaborative care, policies/guidelines, surgeon education and training, and personal perceptions/beliefs. Compared to Canadian and Dutch surgeons, Japanese surgeons heavily relied on non-opioid medications as they believed that opioids are unnecessary for managing postoperative pain.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Abstract The purpose of this study was to investigate the clinical implications of a combination of a peripheral opioid, paracetamol (APAP) and ketoprofen (KTP) on the intensity of acute postoperative pain by focusing on tonsillectomy (TE) and third molar extraction. A second focus in the study was to assess the utility of the surgical ultrasonically activated scalpel (HS) technique for TE. In Study I, TE was performed on one side using the HS and on the contralateral side using a “blunt dissection technique”. The first TE study (I) demonstrated that - based on NRS pain scores during the first 10 postoperative hours - intra-operative blood loss and need for haemostasis were greater on the blunt dissection side than on the HS side. Pain scores were higher on the HS side than on the cold dissection side during the second postoperative week. Study III assessed the analgesic effect of a peripheral dose of 4 mg morphine. The peritonsillar infiltration of morphine locally did not significantly decrease pain compared to the control side. Studies (II and IV) included patients who were scheduled for third molar extraction. In Study II, patients received 1000 mg APAP or 100 mg KTP or both or a placebo to evaluate pain relief after third molar extraction. This study demonstrated that the mean sum of pain intensity differences scores up to the 1.5 h mark and the mean time to onset of pain relief at rest and on swallowing were favoured in the combination group more than in the APAP, KTP, and placebo groups. In Study IV, patients were assigned for a submucosal injection of 2 mg morphine or NaCl into either the non-inflamed (Trial I) or the inflamed (Trial II) peridental tissue, while the active control group received the same drugs in reverse order intramuscular (IM). Postoperative pain intensity at rest and on swallowing was assessed in all studies using the numerical rating scale (NRS). Pain scores in the peripheral morphine group at rest (Trials I and II) and on swallowing (Trial I) were not associated with any further pain reduction. Pain scores on swallowing during the 2–6 hours postoperative period (Trial II) were greater in the IM morphine group. HS TE was associated with decreased pain in the early postoperative period, but there was increased pain and otalgia during the second postoperative week. Locally administered peripheral morphine was not associated with any benefit during the postoperative period after TE. The multimodal analgesia combination of a single dose of KTP and APAP demonstrated the same benefit during the early postoperative period without an increase in side effects. Locally administered peripheral morphine produced significant analgesia on swallowing during the early postoperative stage in inflamed tissue after third molar extraction. / Tiivistelmä Hyvä leikkauksen jälkeinen kivunhoito on yksilöllisesti suunniteltua, turvallista, helppokäyttöistä ja taloudellista. Nykyään pyritään kivunlievityksessä hyödyn-tämään eri vaikutuspaikkoihin kohdistuvia hoitoja eli multimodaalista kivun¬hoitoa. Tämän työn tarkoituksena oli selvittää eri kivunlievitysmenetelmien tehoa ja turvallisuutta kahdessa eri toimenpiteessä: nielurisojen poistoleikkauksen (TE) tai viisaudenhampaan poistoleikkauksen jälkeen. Tutkimuskokonaisuus käsittelee leikkaustekniikan (Ultraääniveitsi), lääke-ainekombinaatioiden ja perifeerisesti annostellun morfiinin vaikutusta post-operatiiviseen kipuun. Tutkimusaineisto koostuu neljästä tutkimuksesta. Kaikki työt olivat satunnaistettuja ja kaksoissokkoutettuja. Kipu mitattiin numeerista asteikolla (Numerical Rating Scale, NRS) sekä levossa että nielemisen aikana enintään 2 viikon ajan. Ultraääniveitsen käytön vaikutusta postoperatiiviseen kipuun verrattiin perinteiseen leikkaustekniikkaan. Potilailta toinen nielurisa poistettiin ultraääni¬veistä käyttäen ja toinen tylpästi irrotellen kylmiä instrumentteja käyttäen. Kipu oli perinteisellä tekniikalla leikatulla puolella voimakkaampi kuin ultraääni¬veitsellä leikatulla puolella leikkauspäivänä. Toisen leikkauksen jälkeisen viikon aikana kipu oli kuitenkin voimakkaampaa ultraääniveitsillä leikatulla puolella. Parasetamolin (APAP), ketoprofeenin (KTP) tuottamaa kivunlievitystä ja näiden yhteisvaikutusta verrattiin viisaudenhampaan poistoleikkauksen jälkeen. KTP ja APAP kombinaatio antoi tehokkaamman kivunlievityksen ja nopeamman hoitovasteen kuin kumpikaan lääke yksin annettuna. Perifeerisesti infiltroidun morfiinin vaikutusta kipuun tutkittiin TE sekä viisaudenhampaan poistoleikkauksen jälkeen. TE jälkeen toiselle puolelle infiltroitiin nielurisan taakse 4 mg morfiinia ja toiselle puolelle fysiologista suolaliuosta. Viisaudenhampaan poistoleikkauksessa paikallisesti infiltroitua 2 mg morfiinia verrattiin lihakseen annettuun samaa lääkkeeseen kahdessa eri tilanteessa, joko tulehtuneeseen tai tulehtumattomaan kudokseen annosteltuna. Paikallisesti infiltroidulla morfiinilla ei todettu kipua lievittävää vaikutusta TE jälkeen. Tulehtuneeseen kudokseen infiltroitu morfiini lievensi leikkauksen jälkeistä nielemiskipua 2–6 tuntia leikkauksesta. Tulehtumattomaan kudokseen infiltroidulla morfiinilla ei saatu lisäetua. Yhteenvetona voidaan todeta, että TE ja viisaudenhampaanpoistoleikkauksen jälkeen kivunhoitoa voidaan optimoida multimodaalisin kivunhoidon keinoin. Tutkimustulokset auttavat potilaskohtaisen yksilöllisen kivunhoidon suunnittelussa.

Background Based on the gathered data from the previous pilot study and the results of this study we proceeded to the following study which is being focused on the surveillance of the age group 50 - 64 years in the area of prescribed opioid analgesics. Alongside with this, we explored in what possible combinations the medications can be used by the chronic pain patients in the current moment. Methods The base of the research was the qualitative study which was performed by the half-structured deep interview with the participants from the chronic pain patients. The interviews were carried out during the year 2011. Within the main study were pursued two quantitative substudii during the January and March 2012. The first study was focused on the questionnaire survey about the number of the chronic pain patients in the Czech Republic. The second substudy followed the chronic pain patients and their influence by the environmental conditions with the help of the questionnaire in case of the combinations among the prescribed opioid analgesics with alcohol or non-alcohol addictive drugs. Results Half-structured interviews were carried out with 20 participants and with the help of this tool were gathered data pointing out the increasing trend in non-medical use of opioid analgesics and increasing interest...