Background: In many countries, buprenorphine and methadone are licensed for the maintenance treatment (MT) of opioid dependence. Despite many short-term studies, little is known about the long-term (12-month) effects of these treatments in different settings, i.e. primary care-based (PMC) and specialized substitution centers (SSCs). Objectives: To describe over a period of 12 months: (1) mortality, retention and abstinence rates; (2) changes in concomitant drug use, somatic and mental health; and (3) to explore differences between different types of provider settings. Methods: 12-Month prospective-longitudinal naturalistic study with four waves of assessment in a prevalence sample of N= 2694 maintenance patients, recruited from a nationally representative sample of N= 223 substitution physicians. Results: The 12-month retention rate was 75%; the mortality rate 1.1%. 4.1% of patients became “abstinent” during follow-up. 7% were referred to drug-free addiction treatment. Concomitant drug use decreased and somatic health status improved. No significant improvements were observed for mental health and quality of life. When controlling for initial severity, small PMC settings revealed better retention, abstinence and concomitant drug use rates. Conclusion: The study underlines the overall 12-month effectiveness of various forms of agonist MT. Findings reveal relatively high retention rates, low mortality rates, and improvements in most 12-month outcome domains, except for mental health and quality of life. PMC settings appear to be a good additional option to improve access to MTs.

This study reports the investigation of hyperbaric opioids and 10% glucose studied in a experimental in vitro model of a subarachnoid space and the in vivo subarachnoid administration of hyperbaric opioids and 10% glucose in horses. The first in vitro phase was done with a translucid poly vinil chloride (PVC) model filled with horse cerebral spinal fluid and injected with hyperbaric opioids and 10% glucose tinted with methylene blue. The objective was to evaluate the physic behavior of the substances within the model. In the second in vivo phase, the hyperbaric opioids (morphine, methadone and buprenorphine) were subarachnoidally administered in six adult horses through a subarachnoid catheter. Cardiopulmonary effects, behavior and pain threshold to noxious electrical stimulation on the perineal, lumbar, sacral and thoracic dermatomes was evaluated. Theresults demonstrated that the model was able to indicate the more appropriate opioids to be used subarachnoidally, and that segmental analgesia was considered intense with hyperbaric morphine and hyperbaric methadone, and moderate with hyperbaric buprenorphine, with minimal effects on cardiorespiratory function, without ataxia or CNS excitation. / Este trabalho apresenta a investigação da utilização de soluções hiperbáricas de opióides e glicose a 10% em um modelo experimental in vitro do espaço subaracnóide, bem como o estudo in vivo da administração de opióides hiperbáricos e glicose a 10% pela via subaracnóide em cavalos. A primeira fase in vitro , constou da utilização de um modelo confeccionado em PVC (policloreto de vinila) transparente, preenchido com líquido cérebro espinhal eqüino, onde foram injetados os agentes opióides hiperbáricos e glicose a 10% marcados com azul de metileno, com o objetivo de avaliar o comportamento físico de distribuição das substâncias no modelo. Na segunda fase in vivo , os opióides hiperbáricos (morfina, buprenorfina e metadona) e glicose a 10% (grupo controle) foram administrados pela via subaracnóide em seis cavalos adultos por meio de um cateter. Avaliaram-se efeitos cardiorrespiratórios, comportamentais e limiar doloroso por estimulação elétrica dos dermátomos perineal, sacral, lombar e torácico. Os resultados mostraram que o modelo proposto serviu como base para a escolha dos agentes utilizados pela via subaracnóide. Houve produção de analgesia segmentar considerada intensa com a morfina hiperbárica e a metadona hiperbárica, e analgesia moderada com a buprenorfina hiperbárica, com mínimos efeitos sobre as funções cardiorrespiratórias, sem ocorrência de ataxia ou excitação do SNC.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Pain control of synovitis is important in the reduction of stress responses, suffering and occurrence of laminitis on the contralateral limb. The use of epidural opioids stands out for its analgesic quality, reduction of doses of the drugs used, reduction of their side effects and prolonged period of action. The study aimed to evaluate the physiological and the analgesic effects of epidural administration of 0.1 mg/kg of morphine or 5 μg/kg of buprenorphine in ponies submitted to synovitis induced with E. coli lipopolysacharide (LPS) in the radiocarpal articulation. Six healthy ponies weighing 131.3 kg and age between 3.5 to 9 years were used and divided randomly in 3 groups and arranged in a Latin Square. The control group (GC) received 0.15 mL/kg of 0.9% NaCl solution, morphine group (GM) received 0.1 mg/kg of morphine and buprenorphine group (GB) 5 μg/kg of buprenorphine via epidural and dilluted in 0.9% NaCl solution, using a stardard total volume of 0.15 mL/kg and time of administration of 10 seconds/mL. After general and specific clinical examination, they were sedated and the carpal synovitis was induced with 0.5 ng of LPS administered to the radiocarpal articulation. Subsequently, an epidural catheter was introduced in the epidural space, so that the treatments would be placed in the thoracolumbar region. 6 hours after LPS, the animals were submitted to a new general and specific clinical exam (time 0) and assigned to one of the treatments. The general physical examination (HR, RR, SAP, CRT, color of mucous membranes, TºC and intestinal motility) and specific (pain on palpation, maximum angle of carpal flexion, pain on maximum flexion, grade of articulation movement, stride lenght and lameness degree) were carried out 30 minutes and 1, 2, 4, 6, 8, 10, 12, 16, 20 and 24 hours after epidural administration of the assigned treatment by a blind examinator. Parametric variables were analyzed with ANOVA, followed by Dunnett test for intra group and Tukey test between groups. For the non-parametric variable Wilcoxon test was used. Differences was considered significant when P<0.05. The synovitis induction model produced changes in the lameness degree, pain on palpation and angle of flexion, maintaining present pain on maximum flexion and reduced grade of articulation movement, but it did not cause changes in the physiological parameters. The control group showed changes in lameness in relation to physiological parameters up to 12 hours. Lameness degree was reduced in GM and GB for 30 minutes up to 12 hours and 6 up to 12 hours, respectively. Regarding physiological parameters, alterations were observed in the intestinal motility, where hypomotility occurred at 1 hour in GM and for 30 minutes up to 1 hour in GB; and body temperature, which was maintained higher in GM and GB up to 10 hours. The intra-articular synovitis induction model with the use of LPS was efficient for 12 hours. Morphine provided analgesia starting at 30 minutes and lasting for 12 hours after its administration, whereas buprenorphine was effective only after 6 hours, lasting for another 6 hours. / O controle da dor da sinovite é importante na diminuição das respostas ao estresse, do sofrimento e da ocorrência de laminite no membro contralateral. O uso de opióides pela via epidural destaca-se pela qualidade analgésica, redução da dose dos fármacos empregados e redução de efeitos colaterais e prolongado período de ação. O estudo objetivou avaliar os efeitos fisiológicos e analgésicos da administração epidural de 0,1 mg/kg de morfina ou 5 μg/kg de buprenorfina em pôneis submetidos à sinovite induzida com lipopolissacarídeo (LPS) de E. coli na articulação radiocarpiana. Foram utilizados 6 pôneis hígidos, divididos em 3 grupos autocontrole e dispostos em um Quadrado Latino. O controle (GC) recebeu 0,15 mL/kg de solução de NaCl 0,9%, o grupo morfina (GM) recebeu 0,1 mg/kg de morfina e o grupo buprenorfina (GB) 5 μg/kg de buprenorfina, ambos pela via epidural e diluídos em solução de NaCl 0,9%, padronizando-se um volume final de 0,15 mL/kg e tempo de administração de 10 segundos/mL. Após avaliação dos parâmetros fisiológicos basais, os animais foram sedados e submetidos ao modelo de indução da sinovite, administrando-se 0,5 ng de LPS na articulação radiocarpiana. Ato contínuo foi introduzido um cateter epidural no referido espaço, até a região tóraco-lombar. 6 horas após a administração do LPS, os animais foram submetidos a um novo exame clínico geral e específico (tempo 0) e administrados um dos tratamentos. Os exames clínicos geral (FC, f, PAS, TPC, coloração das mucosas, TºC e motilidade intestinal) e específico (dor à palpação, ângulo de flexão máxima do carpo, dor à flexão máxima, grau de movimentação da articulação, comprimento do passo e grau de claudicação) foram realizados aos 30 minutos e 1, 2, 4, 6, 8, 10, 12, 16, 20 e 24 horas após a administração epidural, por um observador cego aos tratamentos. Para as variáveis paramétricas utilizou-se análise de variância para amostras pareadas, com posterior teste de Dunnett. Para comparações entre os grupos, realizou-se análise de variância, seguido de teste de Tukey. Para as variáveis não-paramétricas utilizou-se o teste de Wilcoxon para amostras pareadas. As diferenças foram consideradas significantes quando P<0,05. O modelo de indução da sinovite produziu alterações no grau de claudicação, dor à palpação e ângulo de flexão, mantendo presentes dor à flexão máxima e reduzido grau de movimentação da articulação, mas não causou alterações nos parâmetros fisiológicos. O GC apresentou diferença na análise da claudicação em relação aos parâmetros basais até 12 horas. GM e GB apresentaram redução de claudicação entre 30 minutos e 12 horas, e 6 e 12 horas, respectivamente. Dentre os parâmetros fisiológicos, observaram-se alterações na motilidade intestinal, ocorrendo hipomotilidade aos 30 minutos no GM e entre 30 minutos e 1 hora no GB; e na temperatura corporal, que se manteve elevada até 10 horas em GM e GB. O modelo de indução da sinovite foi eficiente por 12 horas. A morfina proporcionou analgesia entre 30 minutos e 12 horas após a sua administração, enquanto que a buprenorfina apresentou esse efeito somente após 6 horas, permanecendo por mais 6 horas.

La buprénorphine (BUP) peut être responsable d’une dépression respiratoire à l’origine d’intoxications graves parfois mortels. Cependant, les mécanismes exacts de ces effets respiratoires délétères ne sont pas encore clairement établis. Les objectifs de cette thèse étaient d’analyser la variabilité des effets respiratoires de la BUP en y intégrant : 1) le rôle exact de la P-glycoprotéine (P-gp) 2) le rôle de l’acquisition d’une tolérance aux opioïdes, tout en précisant les différences potentielles entre tolérance aux effets analgésiques et respiratoires et les mécanismes moléculaires mis en jeu. Pour cela, nous avons étudié en pléthysmographie les effets respiratoires de la BUP et de son métabolite actif la norbuprénorphine (NBUP) chez la souris Fvb femelle. Nous avons mesuré leur transport par la P-gp à la barrière hémato-encéphalique (BHE) en perfusion cérébrale in situ, après inhibition pharmacologique ou suppression du gène codant pour la P-gp. Nous avons étudié la part de variabilité dans ces effets, attribuable au sexe et à la souche de souris. Nous avons ainsi démontré que la P-gp exprimée à la BHE joue un rôle-clé dans la protection contre les effets respiratoires délétères induits par la BUP, en empêchant l’entrée dans le compartiment encéphalique de son métabolite, la NBUP. Nous avons observé que les souris Fvb femelles sont plus sensibles à la toxicité respiratoire de la BUP que les souris Fvb mâles qui sont, eux-mêmes plus sensibles à ces effets que les souris Swiss mâles, sans que la P-gp ne soit à aucun moment impliquée dans cette variabilité. Enfin, nous avons montré qu’une tolérance aux effets analgésiques et respiratoires de la BUP se développe de façon significativement plus réduite chez les souris Fvb déficientes en P-gp, suggérant un rôle crucial pour ce transporteur dans l’acquisition et l’expression de la tolérance à la BUP. Par ailleurs, nous avons montré qu’après administration répétée de morphine, apparait une tolérance plus faible à ses effets respiratoires qu’à ses effets analgésiques. La mise en évidence d’une superactivation de l’adénylate cyclase dans la région périaqueducale impliquée dans les effets antinociceptifs des opioïdes, et non dans le tronc cérébral qui contient les centres de régulation de la ventilation, pourrait au moins en partie, expliquer cette différence d’intensité de tolérance observée. Enfin, pour compléter nos travaux expérimentaux, nous avons réalisé deux mini-revues bibliographiques pour, d’une part faire la synthèse des mécanismes de la tolérance aux opioïdes et de leur rôle dans la dépression respiratoire et d’autre part, analyser les situations déjà rapportées d’effets cliniques nés d’interactions médicamenteuses médiées par la P-gp. / Buprenorphine (BUP) may be responsible for respiratory depression resulting in serious andsometimes fatal poisonings. However, the exact mechanisms leading to these deleterious respiratoryeffects still remain unclear. The objectives of this thesis were to study the variability of BUP-inducedrespiratory effects by focusing on: 1) the involvement of P-glycoprotein 2) the role of tolerance to opioids in addition to investigating possible differences among tolerance to opioid-related antinociceptive and respiratory effects as well as the involved molecular mechanisms. We studied the respiratory effects of BUP and its active metabolite, norbuprenorphine (NBUP) using plethysmography in female Fvb mice. We measured P-gp-related transport of BUP and NBUP at the blood-brain barrier (BBB) using in situ brain perfusion after pharmacological P-gp inhibition as well as in P-gp knock-out mice. We also studied the role of gender and mice strain in the variability of BUP-related respiratory effects. We showed that P-gp at the BBB plays a key-protective role against BUP-related respiratory effects by limiting NBUP distribution into the brain. We observed that female Fvb mice are more sensitive to BUP-induced deleterious respiratory effects than male Fvb mice thatare more sensitive than male Swiss mice. Furthermore, we assessed that gender- and strain-attributedvariability is not related to P-gp. Finally, we demonstrated that tolerance to BUP-induced antinociceptive and respiratory effects is significantly reduced in P-gp knockout mice in comparison to controls, suggesting a critical role for P-gp in tolerance to BUP. In parallel, we showed that repeated administration of morphine results in reduced tolerance to its respiratory effects in comparison to its antinociceptive effects. Adenylate cyclase super-activation that we evidenced in the periaqueductal grey matter, the area involved in opioid-related analgesia control, but not in the brainstem, the area that contains centres of ventilation regulation, may at least in part be responsible for these observed differences in tolerance. Finally, to complete our experimental researches, we performed two mini-reviews, aiming at summarizing the various mechanisms of tolerance and their involvement in respiratory depression in addition to highlighting the importance of drug-drug interactions leading to P-glycoprotein inhibition in the occurrence of deleterious clinical effects.

Background: The buprenorphine transdermal system (BTDS) is approved in the US for the management of chronic pain. Due to its high affinity for mu-opioid receptors with a slow dissociation profile, buprenorphine may potentially displace or prevent the binding of competing mu-opioid-receptor agonists, including immediate-release (IR) opioids, in a dose-dependent manner. Health care professionals may assume that the use of IR opioids for supplemental analgesia during BTDS therapy is not acceptable. Materials and methods: This post hoc analysis evaluated the use of IR opioids as supplemental analgesia during the management of moderate-severe chronic pain with BTDS at 52 US sites (BUP3015S, NCT01125917). Patients were categorized into IR-opioid and no-IR-opioid groups. At each visit of the extension phase, adverse events, concomitant medications, and information from the Brief Pain Inventory (BPI) were recorded. Results: The most common supplemental IR opioids prescribed during BTDS treatment (n=354) were hydrocodone-acetaminophen and oxycodone-acetaminophen. The mean daily dose of IR opioids (morphine equivalents) for supplemental analgesia was 22 mg. At baseline, BPI pain intensity and BPI - interference scores were higher for patients in the IR-opioid group. In both treatment groups, scores improved by week 4, and then were maintained throughout 6 months of the open-label extension trial. The incidence of treatment-emergent adverse events was similar in both groups. Conclusion: Patients who were prescribed IR opioids reported lower scores for BPI pain intensity and pain interference to levels similar to patients receiving BTDS without IR opioids, without increasing the rate or severity of treatment-emergent adverse events. Patients prescribed concomitant use of IR opioids with BTDS had greater treatment persistence. The results of this post hoc analysis provide support for the concomitant use of IR opioids for supplemental analgesia during the management of moderate-severe chronic pain with BTDS.

Ergebnisse einer breit angelegten Repräsentativerhebung zur Substitutionstherapie in Deutschland an 2694 Patienten zeigen, dass trotz hoher und komplexer Ko- und Multimorbidität mit psychischen Erkrankungen nur selten Psychiater an der Therapie beteiligt sind. Nur 16% der Substitutionsärzte (n=223) sind Psychiater oder Psychotherapeuten und nur 21% der substituierten Drogenabhängigen werden von Psychiatern behandelt. Die meisten substituierenden Psychiater sind in Institutsambulanzen psychiatrischer Kliniken tätig (51,3%), kaum in eigener Praxis (7,2%). Der Großteil der Substitutionsversorgung wird von Allgemein- und Hausärzten geleistet. Die relative Abstinenz psychiatrischer Kollegen bei der Substitution drogenabhängiger Patienten wird kritisch diskutiert. / Results of a nationally representative study in 2,694 patients reveal that most physicians (n=223) involved in substitution treatment of opioid-dependent patients are general practitioners, while only 16% have a psychiatric/psychotherapeutic background and only 21% of the addictive patients are treated by psychiatrists. This contrasts with the remarkably complex pattern of co- and multimorbidity with other mental disorders in such patients. Most psychiatrists engaged in substitution treatment work in specialized outpatient wards (51.3%), and few were operative in their own or private practice (7.2%). Implications of these critical findings are discussed.

The purpose of this study is to describe and analyze how health care providers, working at care facilities providing maintenance treatment programs for opiate dependence, perceive and manage the legal framework governing the treatment. The study is limited to a few particular rules within this framework which over the recent decade have been the subject matter of debate regarding i.a. their alleged lack of relation to scientific research and their frequently disastrous implications for program participants. The empirical material consists of interviews with five respondents working at four different care facilities and has been analyzed by using Lipskys theory on street-level bureaucrats as policymaking agents. The results of the study show that the rules are looked upon and dealt with in a liberal fashion and that the primary loyalty of the maintenance treatment staff is clearly directed towards promoting the well-being of their patients and helping them reach their treatment goals rather than strictly following the rules.

Studiens syfte är att undersöka individens subjektiva upplevelse av att genomgå läkemedelsassisterad behandling för opioidberoende (LARO). För att besvara studiens syfte och frågeställningar har vi använt oss av kvalitativ metod i form av både fokusgruppintervju och individuella intervjuer. I fokusgruppintervjun intervjuade vi tre yrkesverksamma för att bredda våra kunskaper inom ämnet och även för hjälp till utformningen av intervjuguiden för de individuella intervjuerna. De individuella intervjuerna bestod av sex intervjupersoner, tre som har LARO-behandling i dagsläget och tre som tidigare har haft det. Materialet från fokusgrupp- och de individuella intervjuerna presenteras i empirin med hjälp av en tematisk analys. Empirin har sedan analyserats med hjälp av tidigare forskning och Goffmans teori om stigma. Studien visar att det finns flera olika aspekter som framkommer som viktiga i individens upplevelse av att ha LARO-behandling. I studien har särskilt fysiska biverkningar och känslomässig avstängdhet lyfts som en viktig aspekt. Även sidomissbruk verkar vara något studiens deltagare anser vara ett viktigt problem. Hämtningen av medicin och kontroll är också en aspekt som verkar vara en stor del av att ha LARO-behandling. En viktig aspekt är även behandlingens livräddande förmåga, men trots denna verkar dessutom en bundenhet till behandlingen upplevas som ett problem av deltagarna. Studien visar en variation i hur individen med LARO-behandling påverkas av sociala sammanhang. Å ena sidan verkar relationerna till närstående och familj i vissa fall ha fortsatt varit fungerande, eller till och med bättre. Å andra sidan beskrivs relationerna ha försämrats. Vi kan även se hos samtliga deltagare att de varit varsamma med vilka de var öppna för om sin behandling. Studien visar att i vissa fall kunde omgivningen vara förstående, i andra fall kunde omgivningen se ner på individen. Hos våra intervjudeltagare är upplevelsen av personalens bemötande i stort positiv. Studien diskuterar skillnader i åsikter gällande frågan kring huruvida man kan vara drogfri under pågående LARO-behandling. Vissa respondenter anser att man kan vara drogfri, men lyfter sidomissbruk som ett hinder. Andra respondenter anser att man inte riktigt kan klassas som drogfri ifall man erhåller substitutionsbehandling. / The purpose of the study is to examine individuals’ subjective experiences of undergoing medication-assisted treatment for opioid dependency (LARO). To address the study’s purpose and research questions we used a qualitative method, utilizing both focus group interviews and individual interviews. In the focus group interview we interviewed three professionals to broaden our knowledge of the subject and to assist in the development of the interview guide for the individual interviews. The individual interviews included six participants: three currently undergoing LARO-treatment and three who have previously undergone it. The material from the focus group and individual interviews is presented in the empirical section using thematic analysis. The empirical data were then analyzed with the help of previous research and Goffman’s theory of stigma. The study reveals several important aspects of individuals’ experiences with LARO treatment. Physical side effect and emotional numbness were highlighted as significant issues. Concurrent substance abuse also appears to be a major concern among the study’s participants. The process of medication retrieval and monitoring is another significant aspect of LARO treatment. While the treatment’s life-saving potential is acknowledged, participants also expressed a sense of dependency on the treatment as problematic. The study shows variability in how individuals undergoing LARO-treatment are affected by social contexts. On one hand, relationships with close ones and family sometimes remained functional or even improved. On the other hand, some relationships are described as deteriorated. All participants were cautious about whom they disclosed their treatment to. The study shows that the surrounding environment could be understanding in some cases. While in other cases, individuals were looked down upon. The participants’ experiences with the staff’s attitude are generally positive. The study discusses differing opinions on whether one can be considered drug-free while undergoing LARO treatment. Some respondents believe that one can be drug-free but highlight concurrent substance abuse as an obstacle. Other believe that one cannot be truly considered drug-free if receiving substitution treatment.

<p dir="ltr">Opioid use disorder (OUD) presents a challenging and nuanced condition with potential for debilitating social and physical consequences. Patients with OUD have access to treatment options, but they may encounter issues such as diversion, invasiveness, or poor adherence. With over 2.5 million adults in the US experiencing OUD as of 2021, the need for an OUD treatment that overcomes these challenges is clear. One available treatment method is Sublocade®, a PLGA-based in situ forming implant (ISFI) that releases buprenorphine. This treatment shows promise due to its physician administered extended release design, which addresses many current issues in OUD treatment. However, the practicality of this treatment remains a challenge due to its monthly injection requirement. To address this, we investigated how altering ISFI components impacts the timeframe of buprenorphine release from a PLGA-based ISFI. Our focus was on evaluating factors that lead to extended buprenorphine release while maintaining zero-order release. We varied polymer-to-solvent ratios, drug percentage, and solvent composition, assessing their effects through drug release studies. We also conducted SEM imaging and swelling/erosion studies to evaluate polymer behavior and implant microstructure, gaining further insights into drug release mechanisms. Our drug release studies revealed that higher buprenorphine content in the implant significantly reduced total drug release and linearized drug release patterns. Decreasing the polymer-to-solvent ratio similarly linearized drug release and reduced drug burst, although the overall amount of drug released over time remained similar. Introducing Triacetin (TA) as a solvent helped reduce drug burst and maintain release linearity in lower drug content implants. In higher drug content implants, TA appeared to increase drug release over time, likely due to degradation processes indicated by high swelling and increased degradation observed in SEM imaging. Erosion studies showed less implant erosion with higher drug loading, aligning with release study observations. In conclusion, solvent type and drug content significantly influence buprenorphine release in ISFI systems and should be carefully considered when designing extended release systems similar to Sublocade®.</p>

No description available.