Supervised injectable opioid treatment (SIOT) is a promising alternative for people living with opioid use disorder (OUD) who have not sufficiently benefitted from oral opioid substitution treatment. Yet, SIOT utilization remains limited in Germany. We propose that this is due to beliefs, or schemas, on SIOT among people living with OUD. Drawing from medical sociology and social psychology, this study explores the emergence and evolution of such schemas on SIOT.
We conducted semi-structured interviews with 34 individuals currently in or eligible for SIOT in two German outpatient treatment facilities and paralleled an inductive qualitative content analysis with the exploration of individual cases.
The analysis revealed that peer-to-peer interaction and individuals\' practical experiences in therapy are crucial in constructing and changing idiosyncratic and shared schemas of SIOT. When facing ambiguous information, cognitive strategies like subtyping served to mitigate uncertainty.
This research has important practical implications for integrating experiential knowledge into clinical care and improve information sharing among people living with OUD. A nuanced understanding of the complex network of informal advice-seeking and -giving among people living with OUD is indispensable to adequately expand treatment modalities of proven effectiveness.

Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy.

Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy.

Although many anti-seizure medications (ASMs) are available, treatment failure, known as drug-resistant epilepsy (DRE), still occurs in around 30% of children with epilepsy. Second-line ASMs are usually used as substitution therapy in DRE to control seizures, although international consensus is not available yet. Previous studies focus on comparing the ASMs, whether as add-on or substitution therapy, mainly conducted in newly diagnosed epilepsy. However, the study that investigated first-line ASMs as substitution therapy compared to second-line ones, particularly among DRE children, is still lacking. A randomized controlled trial (RCT) enrolling 102 participants, aged 1-18, at three referral hospitals in Indonesia will be conducted, dividing them into intervention and control groups. The intervention group will be treated with first-line ASMs as the substitution therapy, while the other in the control group will get second-line ASMs. The primary outcome measure is the proportion difference of responders between groups who get first-line and second-line ASMs in 14 weeks of intervention. Clinical trial registration: ClinicalTrials.gov, identifier NCT05697614.

BACKGROUND: The treatment of opiate addiction is an unmet medical need. Repeated exposure to opiates disrupts cognitive performance. Opioid substitution therapy, with, e.g., methadone, may further exacerbate the cognitive deficits. Growing evidence suggests that mitragynine, the primary alkaloid from the Kratom (Mitragyna speciosa) leaves, may serve as a promising alternative therapy for opiate addiction. However, the knowledge of its health consequences is still limited.
OBJECTIVE: We aimed to examine the cognitive effects of mitragynine substitution in morphine-withdrawn rats. Furthermore, we asked whether neuronal addiction markers like the brain-derived neurotrophic factor (BDNF) and Ca2+/calmodulin-dependent kinase II alpha (αCaMKII) might mediate the observed effects.
METHODS: Male Sprague-Dawley rats were given morphine at escalating doses before treatment was discontinued to induce a spontaneous morphine withdrawal. Then, vehicle or mitragynine (5 mg/kg, 15 mg/kg, or 30 mg/kg) substitution was given for 3 days. A vehicle-treated group was used as a control. Withdrawal signs were scored after 24 h, 48 h, and 72 h, while novel object recognition (NOR) and attentional set-shifting (ASST) were tested during the substitution period.
RESULTS: Discontinuation of morphine significantly induced morphine withdrawal signs and cognitive deficit in the ASST. The substitution with mitragynine was able to alleviate the withdrawal signs. Mitragynine did not affect the recognition memory in the NOR but significantly improved the reversal learning deficit in the morphine-withdrawn rats.
CONCLUSIONS: These data support the idea that mitragynine could be used as safe medication therapy to treat opiate addiction with beneficial effects on cognitive deficits.

Increasing evidence suggests an essential role of the endocannabinoid system in modulating cognitive abilities, mood, stress, and sleep. The psychoactive effects of cannabis are described as euphoric, calming, anxiolytic, and sleep-inducing and positively affect the mood, but can also adversely affect therapy. The responses to cannabinoid medications depend on the patient\'s endocannabinoid system activity, the proportion of phytocannabinoids, the terpenoid composition, and the dose used. There is some evidence for a therapeutic use of phytocannabinoids in psychiatric conditions. THC and CBD may have opposing effects on anxiety. Current guidelines recommend caution in using THC in patients with anxiety or mood disorders. In a small number of clinical trials, cannabinoids used to treat cancer, HIV, multiple sclerosis, hepatitis C, Crohn\'s disease, and chronic neuropathic pain report decreases in anxiety or depression symptoms and presented sedative and anxiolytic effects. Several studies have investigated the influence of potential genetic factors on psychosis and schizophrenia development after cannabis use. THC may increase the risk of psychosis, especially in young patients with an immature central nervous system. There is limited evidence from clinical trials that cannabinoids are effective therapy for sleep disorders associated with concomitant conditions. There is evidence for a possible role of cannabis as a substitute for alcohol and drugs, also in the context of the risks of opioid use (e.g., opioid-related mortality). In this narrative review of the recent evidence, we discuss the prospects of using the psychoactive effects of cannabinoids in treating mental and psychiatric disorders. However, this evidence is weak for some clinical conditions and well-designed randomized controlled trials are currently lacking. Furthermore, some disorders may be worsened by cannabis use.

The last decades have seen a major gain in understanding the action of cannabinoids and the endocannabinoid system in reward processing and the development of addictive behavior. Cannabis-derived psychoactive compounds such as Δ9-tetrahydrocannabinol and synthetic cannabinoids directly interact with the reward system and thereby have addictive properties. Cannabinoids induce their reinforcing properties by an increase in tonic dopamine levels through a cannabinoid type 1 (CB1) receptor-dependent mechanism within the ventral tegmental area. Cues that are conditioned to cannabis smoking can induce drug-seeking responses (ie, craving) by eliciting phasic dopamine events. A dopamine-independent mechanism involved in drug-seeking responses involves an endocannabinoid/glutamate interaction within the corticostriatal part of the reward system. In conclusion, pharmacological blockade of endocannabinoid signaling should lead to a reduction in drug craving and subsequently should reduce relapse behavior in addicted individuals. Indeed, there is increasing preclinical evidence that targeting the endocannabinoid system reduces craving and relapse, and allosteric modulators at CB1 receptors and fatty acid amide hydrolase inhibitors are in clinical development for cannabis use disorder. Cannabidiol, which mainly acts on CB1 and CB2 receptors, is currently being tested in patients with alcohol use disorder and opioid use disorder.
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En las últimas décadas se ha observado un gran progreso en el conocimiento acerca de la acción de los cannabinoides y del sistema endocannabinoide en el procesamiento de recompensas y el desarrollo de conductas adictivas. Los compuestos psicoactivos derivados del cannabis como el Δ9-tetrahidrocannabinol y los cannabinoides sintéticos interactúan directamente con el sistema de recompensa y, por lo tanto, tienen propiedades adictivas. Los cannabinoides inducen sus propiedades reforzadoras mediante un aumento en los niveles de dopamina tónica a través de un mecanismo dependiente del receptor cannabinoide 1 (CB1) dentro del área tegmental ventral. Las señales que están condicionadas con fumar cannabis pueden inducir respuestas de búsqueda de drogas (es decir, craving) al provocar liberación fásica de dopamina. Un mecanismo independiente de la dopamina implicado en las respuestas de búsqueda de droga incluye una interacción endocannabinoide / glutamato dentro de la parte cortico-estriatal del sistema de recompensa. En conclusión, el bloqueo farmacológico de la señalización endocannabinoide debería conducir a una reducción del craving por droga y, posteriormente, debería reducir las recaídas en las personas adictas. De hecho, existe una creciente evidencia preclínica de que el elegir como blanco el sistema endocannabinoide reduce el craving y la recaída. Los moduladores alostéricos de los receptores CB1 y los inhibidores de amida hidrolasa de ácidos grasos están en desarrollo clínico para el trastorno por consumo de cannabis. Actualmente se está probando el cannabidiol, que actúa principalmente sobre los receptores CB1 y CB2, en pacientes con trastorno por consumo de alcohol y de opioides.
Les avancées de ces 10 dernières années nous ont permis de mieux comprendre l\'action des cannabinoïdes et du système endocannabinoïde dans le processus de récompense et le développement de l’addiction. Le Δ9-tétrahydrocannabinol, comme les autres composés psychoactifs dérivés du cannabis, et les cannabinoïdes synthétiques interagissent directement avec le système de récompense et ont donc des propriétés addictives. La capacité de renforcement des cannabinoïdes s’exerce par un mécanisme dépendant du récepteur cannabinoïde 1 (CB1R) dans la zone tegmentale ventrale qui augmente les taux de dopamine en mode d’activation tonique. La consommation de cannabis entraîne des signaux qui peuvent induire des réactions toxicomaniaques (sensation de manque) en provoquant le mode d’activation phasique dopaminergique. Dans les réponses toxicomaniaques, le mécanisme d’action est indépendant de la dopamine et implique une interaction endocannabinoïde/glutamate dans la partie corticostriatale du système de récompense. En conclusion, bloquer pharmacologiquement la signalisation des endocannabinoïdes devrait diminuer la sensation de manque et donc diminuer les rechutes chez les personnes dépendantes. En effet, de plus en plus de données précliniques montrent qu’en ciblant le système endocannabinoïde, la sensation de manque et les rechutes diminuent. Des modulateurs allostériques au niveau des récepteurs CB1 et des inhibiteurs de l\'hydrolase des amides d\'acides gras sont en cours de développement clinique pour les troubles liés à la consommation de cannabis. Agissant principalement sur les récepteurs CB1 et CB2, le cannabidiol est actuellement testé chez des patients souffrant de troubles liés à la consommation d\'alcool et d\'opiacés.

The United States of America is currently in an opioid epidemic. Heroin remains the most lethal opioid option with its death rate increasing by over 500% in the last decade. The rewarding and reinforcing effects of heroin are thought to be mediated by its ability to increase dopamine concentration in the nucleus accumbens shell. By activating Gi/o-coupled μ-opioid receptors, opioids are thought to indirectly excite midbrain dopamine neurons by removing an inhibitory GABAergic tone. The partial μ-opioid receptor agonist buprenorphine is a substitution-based therapy for heroin dependence that is thought to produce a steady-state level of μ-opioid receptor activation. But it remains unclear how buprenorphine alters dopamine release relative to heroin and how buprenorphine alters the dopamine-releasing effects of heroin. Because buprenorphine is a partial agonist at the μ-opioid receptor and heroin is a full agonist, we predicted that buprenorphine would function as a weak dopamine releaser relative to heroin, while functioning as a competitive antagonist if administered in advance of heroin.
We performed fast-scan cyclic voltammetry in awake and behaving rats to measure how heroin, buprenorphine HCl, and their combination affect transient dopamine release events in the nucleus accumbens shell. We also performed a complimentary pharmacokinetic analysis comparing opioid plasma levels at time points correlated to our neurochemical findings.
Both buprenorphine and heroin produced changes in the frequency of transient dopamine release events, although the effect of buprenorphine was weak and only observed at a low dose. In comparison with vehicle, the frequency of dopamine release events maximally increased by ~25% following buprenorphine treatment and by ~60% following heroin treatment. Distinct neuropharmacological effects were observed in the high-dose range. The frequency of dopamine release events increased linearly with heroin dose but biphasically with buprenorphine dose. We also found that buprenorphine pretreatment occluded the dopamine-releasing effects of heroin, but plasma levels of buprenorphine had returned to baseline at this time point.
These findings support the notion that low-dose buprenorphine is a weak dopamine releaser relative to heroin and that buprenorphine pretreatment can block the dopamine-releasing effects of heroin. The finding that high-dose buprenorphine fails to increase dopamine release might explain its relatively low abuse potential among opioid-dependent populations. Because high-dose buprenorphine decreased dopamine release before occluding heroin-evoked dopamine release, and buprenorphine was no longer detected in plasma, we conclude that the mechanisms through which buprenorphine blocks heroin-evoked dopamine release involve multifaceted pharmacokinetic and pharmacodynamic interactions.

BACKGROUND: Congenital chloride diarrhea (CCD) is a rare inherited disorder of intestinal electrolyte transport that results in a large wastage of electrolytes and water. Advances in substitution therapy using sodium chloride (NaCl) and potassium chloride (KCl) have dramatically improved survival for patients with CCD. Slow-release KCl is widely prescribed as a potassium supplement; however, it has also occasionally been used in suicide attempts, as potassium poisoning can generate life-threatening hyperkalemia.
METHODS: A 26-year-old female presented to the emergency department (ED) with self-poisoning, having taken 30 tablets of slow-release KCl (total: 240 mmol potassium) following an auditory hallucination. The patient had been undergoing substitution therapy with NaCl and KCl for CCD and been followed up in the pediatric department. One month prior, she developed insomnia and anxiety and had consulted a psychiatrist. At the ED, although her general condition was good, she appeared agitated. Her serum potassium level was 7.0 mmol/L, indicating hyperkalemia, and electrocardiographic changes showed tenting of the T-waves. She responded to the administration of calcium gluconate, sodium bicarbonate, and insulin with glucose, and the serum potassium level improved. Finally, she was diagnosed with schizophrenia.
CONCLUSIONS: In CCD management, physicians should pay careful attention to patients\' extraintestinal issues, including psychological disorders that may emerge in adulthood.

A fixed dose combination (FDC) product containing two components can be authorized for the use in 3 conceptual scenarios (1) as substitution for a treatment regimen containing both components given separately (substitution therapy) or (2) as replacement for a treatment regimen where the patient currently receives one of the components (add-on therapy) or (3) initial treatment of patients naïve to both components (initial combination therapy).
Trends in European Medicine Agency (EMA) and Food and Drug Administration (FDA) approvals of FDC products for the 3 scenarios were explored by comparing the therapeutic indications retrieved from the EMA and FDA websites for FDCs approved between January 2000 and April 2017 within 5 selected therapeutic areas: type 2 diabetes mellitus (T2DM), asthma, chronic obstructive pulmonary disease, hypertension, and human immunodeficiency virus (HIV) infection.
Approval decisions between EMA and FDA were largely aligned for the substitution therapy and add-on therapy scenarios. Discrepancies were found for the initial combination therapy scenario.
Since EMA and FDA rely on similar conceptional models when approving FDCs, the reasons behind this general disparity are not clear, but may be found in the lack of evidence from the registration studies. Sponsors and health authorities should work collaboratively on closing that gap.