Substitution Therapies Research Articles

A novel strategy to elicit enduring anti-morphine immunity and relief from addiction by targeting Acr1 protein nano vaccine through TLR-2 to dendritic cells

Morphine addiction poses a significant challenge to global healthcare. Current opioid substitution therapies, such as buprenorphine, naloxone and methadone are effective but often lead to dependence. Thus, exploring alternative treatments for opioid addiction is crucial. We have developed a novel vaccine that presents morphine and Pam3Cys (a TLR-2 agonist) on the surface of Acr1 nanoparticles. This vaccine has self-adjuvant properties and targets TLR-2 receptors on antigen-presenting cells, particularly dendritic cells. Our vaccination strategy promotes the proliferation and differentiation of morphine-specific B-cells and Acr1-reactive CD4 T-cells. Additionally, the vaccine elicited the production of high-affinity anti-morphine antibodies, effectively eliminating morphine from the bloodstream and brain in mice. It also reduced the expression of addiction-associated μ-opioid receptor and dopamine genes. The significant increase in memory CD4 T-cells and B-cells indicates the vaccine's ability to induce long-lasting immunity against morphine. This vaccine holds promise as a prophylactic measure against morphine addiction.

Deactivating permanent pacemakers in pacemakerdependent patients with terminal illness: an ethical perspective

Medical guidelines state that both implantable cardioverter defibrillator (ICD) and pacemaker deactivation may be ethically permissible when the patient requests their withdrawal based on the respect for the patient’s autonomy. However, they also state that most physicians make an ethical distinction between deactivating ICDs and deactivating permanent pacemakers in pacemaker-dependent patients, being reasonably uncomfortable when confronted with a petition for pacing deactivation in these patients. If a difference between both actions exists, what principles explain this ethical distinction? We analyze this question from the perspective of the bioethical principles and the standpoint of the distinction between substitution and replacement therapies for ethical decisions. Even if we recognize appropriate insights in these proposals, they are insufficient to provide an adequate ethical justification in case of pacemaker deactivation in pacemaker-dependent patients. We propose the burden of therapy and the configuration of the moral act as determinant factors in arriving at a solid answer. In these cases, it is necessary to arrive at a description as precise as possible of the moral action that is performed and to ask what is the basic intentionality that moves such action. Furthermore, we propose the communication virtues as an important aspect to practice in cases of request of a pacemaker withdrawal.

An overview of legal and policy barriers to opioid analgesics access and opioid agonist therapy in Morocco

PurposeThrough its 1922 Act on poisonous substances and more recent national normative guidance, Morocco attempts to address high prevalence of HIV among people who inject illegal opioids, and to lift legal and policy barriers to the availability of opioid-based essential controlled medicines. This paper aims to map the Moroccan opioid regulation environment, with a focus on responses to the legal and illegal markets.Design/methodology/approachThe policy paper focuses on legal provisions for the control of opioids for pain relief and methadone for substitution therapies. It reviews existing reported data from official national, regional and international sources, studies and grey literature. It allows, by presenting the current state of affairs, to measure the limited pace of policy changes.FindingsThe authors provide a clear mapping of the laws and regulations restricting access to opioids in Morocco; the health impacts on populations; and an overall overview of institutional barriers to policy change despite more efforts such as the introduction of opioid agonist therapies.Research limitations/implicationsDue to limited available data and sources, the policy paper exploits the maximum of existing evidence from national and international sources to provide an overall review of opioid control policies in Morocco.Originality/valueTo the best of the authors’ knowledge, this policy paper is among the first to explore the legal environment of opioid use and control in Morocco, to highlight policy reforms, and to analyse the barriers to access to opioids.

Intravitreal gene therapy restores the autophagy-lysosomal pathway and attenuates retinal degeneration in cathepsin D-deficient mice

Loss of vision due to progressive retinal degeneration is a hallmark of neuronal ceroid lipofuscinoses (NCL), a group of fatal neurodegenerative lysosomal storage diseases. Enzyme substitution therapies represent promising treatment options for NCLs caused by dysfunctions of soluble lysosomal enzymes. Here, we compared the efficacy of a cell-based enzyme substitution strategy and a gene therapy approach to attenuate the retinal pathology in cathepsin D- (CTSD) deficient mice, an animal model of CLN10 disease. Levels of enzymatically active CTSD in mutant retinas were significantly higher after an adeno-associated virus vector-mediated CTSD transfer to retinal glial cells and retinal pigment epithelial cells than after intravitreal transplantations of a CTSD overexpressing clonal neural stem cell line. In line with this finding, the gene therapy treatment restored the disrupted autophagy-lysosomal pathway more effectively than the cell-based approach, as indicated by a complete clearance of storage, significant attenuation of lysosomal hypertrophy, and normalized levels of the autophagy marker sequestosome 1/p62 and microtubule-associated protein 1 light chain 3-II. While the cell-based treatment did not prevent the rapidly progressing loss of various retinal cell types, the gene therapy approach markedly attenuated retinal degeneration as demonstrated by a pronounced rescue of photoreceptor cells and rod bipolar cells.

ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy.

Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.

Analysis of hip joint cross-shear under variable activities using a novel virtual joint model within Visual3D.

Cross-shear forces occur between bearing surfaces at the hip and have been identified as a key contributor to prosthesis wear. Understanding the variation in relative motion paths between both individuals and activities, is a possible explanation for increased revision rates for younger patients and could assist in improved pre-clinical testing regimes. Additionally, there is little information for the pre-clinical testing of cartilage substitution therapies for younger more active individuals. The calculation of motion paths has previously relied on computational modelling software which can be complex and time-consuming. The aim of this study was to determine whether the motion paths calculations could be integrated into gait analysis software to improve batch processing, reduce analysis time and ultimately improve the efficiency of the analysis of cross-shear variation for a broader range of activities. A novel Virtual Joint model was developed within Visual3D for calculating motion paths. This model was compared to previous computational methods and found to provide a competitive solution for cross shear analysis (accuracy <0.01 mm error between methods). The virtual hip model was subsequently applied to 13 common activities to investigate local aspect ratio's, velocities and accelerations. Surprisingly walking produced the harshest cross shear motion paths in subjects. Within walking, of additional interest was that the localised change in acceleration for subjects was six times greater compared to the same point on an equivalent smoothed simulator cycle. The Virtual hip developed in Visual 3D provides a time saving technique for visualising and processing large data sets directly from motion files. The authors postulate that rather than focussing on a generalised smoothed cross-shear model that pre-clinical testing of more delicate structures should consider localised changes in acceleration as these may be more important in the assessment of cartilage substitutes sensitive to shear.

Developing a local service to improve the provision of palliative care to people who use substances

AimsTo develop a new service model that engages and improves the provision of palliative care to PWUS.BackgroundAlthough people who use substances (PWUS) continue to die prematurely compared to the general population, they are now more likely to die from chronic diseases rather than from drug-related deaths. Challenges to providing palliative care to PWUS include delayed care-seeking behaviours, complex drug interactions and lack of healthcare provider experience.MethodAn informal factorial analysis elucidated population needs through: a review of local databases to estimate the prevalence of palliative need, a thematic review into the deaths of patients in specialist drug services and, a survey of health practitioners’ knowledge and attitudes. These informed the service development phase which involves three key components: 1. A systems approach to increasing patient identification, incorporating key multi-disciplinary stakeholders across hospital- and community-based care 2. Targeted training of healthcare providers and 3. Medicines management for symptom palliation amidst concurrent substance use (including substitution treatments).ResultThe palliative needs of PWUS are under-identified: the local substance service was not partaking in the palliative referral pathway. Only 7% of a local hospice's annual caseload was recognised as having substance use problems. The care pathway was described as fragmented. Although &gt;80% of surveyed palliative care practitioners had experienced caring for PWUS, confidence and knowledge around managing withdrawal, pain and opioid substitution therapies was poor.ConclusionA new pathway is designed to identify PWUS and in their last year of life at key treatment points e.g., accident and emergency, ward-based care. The pathway will then streamline referrals to relevant specialist services depending on complexity of palliative/dependency need. Teaching resources and prescribing guidelines have been developed in collaboration with secondary care pain specialists.

Global, regional, and national consumption of controlled opioids: a cross-sectional study of 214 countries and non-metropolitan territories.

Introduction:The consumption of opioids has increased globally since the 1990s. Previous studies of global opioid consumption have concentrated on morphine alone or a subset of opioids, with a focus on cancer pain and palliative care. In this study, we have determined the global, regional, and national consumption of all controlled opioids, including anaesthetics, analgesics, antidiarrheals, opioid substitution therapies, and cough suppressants.Methods:We conducted a cross-sectional study using data from the International Narcotics Control Board (INCB). We calculated mean opioid consumption (mg/person) globally, regionally, and nationally for 2015–2017, where consumption refers to the total amount of controlled opioids distributed for medical purposes and excludes recreational use. We ranked countries by total consumption and quantified the types of opioids consumed globally.Results:Between 2015 and 2017, 90% of the world’s population consumed only 11% of controlled opioids. An average of 32 mg/person was consumed annually, but this was not equally distributed across the world. Consumption was the highest in Germany (480 mg/person), followed by Iceland (428 mg/person), the United States (398 mg/person) and Canada (333 mg/person). Oxycodone (35%) was the most heavily consumed controlled opioid globally, followed by morphine (15.9%), methadone (15.8%) and tilidine (14%).Conclusion:Large disparities persist in most of the world in accessing essential opioid medicines. Consumption patterns should continue to be monitored, and collaborative strategies should be developed to promote access and the appropriate prescribing of opioids in all countries and non-metropolitan territories.

Haemophilia, state of the art and new therapeutic opportunities, a regulatory perspective.

Haemophilia A and B are rare bleeding disorders. Over the past decades, they have been transformed from debilitating diseases to manageable conditions in the Western world. However, optimizing haemophilia care remains challenging in developing countries. Several challenges and unmet needs remain in the treatment of the haemophilia limiting the QoL of patients. These challenges are now being addressed by extended half‐life recombinant factors, rebalancing and substitution therapies. Gene therapy and genome editing show promise for a definite clinical cure. Here, we provide an overview of new therapeutic opportunities for haemophilia and their advances and limitations from a regulatory perspective. The database on human medicines from the European Medicines Agency (EMA) was used and data from rare disease (orphan) designations and EPARs were retrieved for the analysis. Clinical trial databases were used to query all active studies on haemophilia. Gene therapy medicinal products based on AAV and lentiviral vectors are in development and clinical trials have reported substantial success in ameliorating bleeding tendency in haemophilia patients. The prospect of gene editing for correction of the underlying mutation is on the horizon and has considerable potential. With regard to the benefit of the gene therapy medicinal products, more long‐term efficacy and safety data are awaited. We are entering an era of innovation and abundance in treatment options for those affected by bleeding disorders, but issues remain about the affordability and accessibility to patients.

Relationship between Dose and Retention of Methadon Maintenance Therapy to Drug Dependence Patients in Primary Health Care

Methadon maintenance therapy is one of the substitution therapies needed as an approach to harm reduction or the reduction of the adverse effects of drug abuse. This study aims to fix the infinitive relationship doses with retention of drug dependence patients on methadon maintenance therapies program (PTRM) in Kramat Jati Primary Health Care in 2009-2018. A cross-sectional study is conducted using secondary data from medical records subsequently significance analysis. This research involves 136 patients who were included in the inclusion criteria. Results shown mean initial doses received is 27,65 mg (10-40 mg), after 2 weeks of therapy mean doses received are 51,6 mg (range 22,5 – 85 mg). Average lowest and highest maintenance dose which received is 30,9 mg (range 0,25-115 mg) dan 84,39 mg (range 7,77-126,92 mg). This research shows the retention value 1 year or more reaches 64,71%. Maintenance doses 2 weeks (P=0,005), lowest maintenance doses (P=0,000), average maintenance doses (P=0,004), and history misses doses (P=0,000) have significance with retention. The conclusion that the more optimal maintenance doses received, even more in methadone maintenance therapies. Otherwise, lower missed doses frequency better to patients retention in methadon maintenance therapies.

Risk perceptions and recovery threats for clients with a history of methadone maintenance therapy dropout

ABSTRACT Background: Methadone treatment is one of the opioid substitution therapies (OSTs) used to manage opioid use disorder (OUD). Clients on methadone treatment experience a high attrition rate from OST programs due to diverse barriers such as access to methadone treatment, treatment modality, transportation, and stigma. Methods: The aim of this project is to explore the experiences and perspectives of clients on methadone treatment who had previously dropped out of an OST program. We used an explorative qualitative design to interview 22 participants currently receiving methadone treatment at a clinic in a small city in western Canada. Results: Four phases designated as critical moments in their lives were identified from their narratives: 1) pre-addiction phase; 2) early substance use; 3) first methadone treatment; and 4) methadone treatment failure and reenrollment. Conclusion: Understanding clients’ experiences on OST treatment and presenting them temporally on a prevention-rehabilitation continuum expands possibilities for community-based interventions focussing on the individual, their family, and the community on substance use prevention, harm reduction activities, and supported treatment and recovery.

P1729HEMODYNAMIC AND AUTONOMIC PERFORMANCE IN CHRONIC DIALYSIS AND RENAL TRANSPLANT PATIENTS. IS THERE AN IMPROVEMENT?

Abstract Background and Aims Chronic kidney disease (CKD) is a major public health problem, with high prevalence worldwide. It’s associated with high morbidity and mortality, especially in the advanced stage when substitution therapies are needed. It’s well established that Ps with end-stage kidney disease have increased mortality due to an elevated incidence of cardiovascular diseases (CVD). The best treatment for this population it’s definitely the kidney transplant (KT), mostly because it improves the quality of life and reduces global and CV mortality compared with Ps treated with chronic dialysis (Dx). There is not a convincing explanation about the physiological mechanisms involved in this improvement. Impedance cardiography (IC) it’s a well established, validated method to asses hemodynamics parameters. Study and describe the differences between hemodynamic and autonomic profiles between KT and Dx Ps using IC. Method We studied 331 Ps as part of a cardiovascular evaluation program in Ps with ESKD which is being carried out in our institution (CEMIC, Buenos Aires). Of these, 190 were on Dx and 141 on KT. Non-invasive hemodynamic assessment was performed using IC (Z Logic- Exxer SA) in supine and standing position, taking into account the following variables: heart rate (HR), thoracic fluid content (TFC), stroke volume (SV), systemic vascular resistance index (SVRI), arterial compliance index (ACI), and pre-ejection period (PEP). Ps in the Dx group were studied on the interdialytic day. We evaluated the autonomic profile by studying the variability of HR (Kubios Finland) for three minutes, with measurements of the spectral components, high frequency (HF), low frequency (LF), total power (totpowar) and the ratio LF/HF. We compared absolute supine variables and then the differences between supine and standing positions. Exclusions criteria: less than six months of KT or Dx; incomplete basic hemodynamic study or lack of data; amputation; previous KT. Results We included 107 Ps of Dx and 118 of KT. No significant differences were detected in terms of age, sex, diabetes, and antihypertensive treatment. Ps on Dx had more prevalence of hypertension and CVD. Those in KT group had a median time of 72,5 months of transplantation and 46 months of prior dialysis time, with a media of eGFR (CKD-Epi) of 56 ml/min/1,72 m2. Ps on Dx had a median of 22 months on substitution treatment. The hemodynamic evaluation showed that KT Ps had lower HR (p=o,oo1), higher ACI (p=0,002) and PEP (p=0,05), and a tendency of higher SV (p=0,07). The autonomic evaluation showed no significant differences between the two groups, though the totpowar had a tendency to be higher in the KT group with a median of 367(200-625) compared with 248 (103-465) in the Dx group (p=0,07). The changes in the variables during the standing position evidenced that Ps on Dx had a lower elevation of HR (p=0,04) and SVRI (p&amp;lt;0,001). We assessed the prevalence of orthostatic hypotension defined as a reduction of the SBP in 20 mmHg and/or the DBP in 10 mmHg after standing up. The Dx group had a prevalence of 30% and the KT group of 20%, but the difference was not significant. Conclusion Ps with KT seems to have a better hemodynamic profile than those on Dx, mainly, a better vascular response with a more physiological- compensatory elevation of HR and VSRI when they stand up. Although the autonomic activity showed no significant statistical difference, the total power, an expression of the whole autonomic activity, showed us a clear tendency in favor of KT, which needs to be confirmed with a larger size sample.

A call for consensus in defining efficacy in clinical trials for opioid addiction: combined results from a systematic review and qualitative study in patients receiving pharmacological assisted therapy for opioid use disorder

BackgroundGiven the complex nature of opioid addiction treatment and the rising number of available opioid substitution and antagonist therapies (OSAT), there is no ‘gold standard’ measure of treatment effectiveness, and each successive trial measures a different set of outcomes which reflect success in arbitrary or opportune terms. We sought to describe the variation in current outcomes employed across clinical trials for opioid addiction, as well as determine whether a discrepancy exists between the treatment targets that patients consider important and how treatment effectiveness is measured in the literature.MethodsWe searched nine commonly used databases (e.g., EMBASE, MEDLINE) from inception to August 1, 2015. Outcomes used across trials were extracted and categorized according to previously established domains. To evaluate patient-reported goals of treatment, semi-structured interviews were conducted with 18 adults undergoing methadone treatment.ResultsWe identified 60 trials eligible for inclusion. Once outcomes were categorized into eight broad domains (e.g., abstinence/substance abuse), we identified 21 specific outcomes with furthermore 53 subdomains and 118 measurements. Continued opioid use and treatment retention were the most commonly reported measures (46%, n = 28). The majority of patients agreed that abstinence from opioids was a primary goal in their treatment, although they also stressed goals under-reported in clinical trials.ConclusionsThere is inconsistency in the measures used to evaluate the effectiveness of OSATs. Individual and population level decision making is being guided by a standard of effect considered useful to researchers yet in direct conflict with what patients deem important.Trial registrationPROSPERO, CRD42013006507.

A Sociohistorical Overview of Harm Reduction Development in Croatia

Harm reduction is viewed as a public health aspect of drug policy in Croatia. The development of needle exchange programs and opioid substitution therapies are discussed herein by sketching the basic contours of the Croatian social and cultural context in which these activities have taken place over the past several decades. Along with the critical reflection of the approaches in which drug use in Croatia is considered in the matrix of anomie and disorganization explanations, two phases were identified in the development of harm reduction programs. The first phase marked the initial establishment of these programs in the context of strong growth in the number of heroin users in the 1990s, while the second phase allowed for the further development of these programs during the 2000s. It has been shown that, in contrast to anomie and social disorganization related approaches, the economic and political development trends of Croatian society are not clearly unambiguous in relation to the development of harm reduction programs, thus indicating that consideration of harm reduction development is more appropriate to link to the decentralization of related activities and the incorporation of these programs into intravenous drug use population's social insurance. In this way, immediate and non-patronizing access to the intravenous drug use population throughout Croatia is enabled. However, although embedded in the prohibitionist government's drug policy, the current implementation of the harm reduction programs in Croatia is still characterized by the unpredictability of official drug policy action as well as the general changes in drug use, with problems associated with the use of new psychoactive substances representing the greatest challenge.

Opioid substitution therapy for people living in German prisons\u2014inequality compared with civic sector

BackgroundThe above-average proportion of people with opioid use disorder living in prisons is a worldwide reality, and the need to treat these people was recognized internationally more than 20 years ago. Studies have shown that substitution therapies are best suited to treat opioid use disorder and reduce the risk of HIV and hepatitis C transmission and overdose. However, huge health inequalities exist in and outside of prison due to the different implementation of opioid substitution therapy (OST). People living in prisons are entitled to the best possible health care. This is established by the Universal Declaration of Human Rights and by the International Convention on Economic, Social and Cultural Rights. Solely the imprisonment, and not the loss of fundamental human rights, constitutes the punishment.MethodsA qualitative literature search using PubMed and Google Scholar was performed in order to identify relevant publications.ResultsThis review shows the inequality in availability of opioid substitution therapy for people living in prison compared with people outside of prison in Germany. It also gives possible reasons and evidence for this inequality, showing that continuing or initiating OST in prison is more beneficial for the health of people living in prison than abstinence-oriented treatment only.ConclusionIt is important that drug use disorder is treated as a serious illness also in prison. Joint efforts are needed to provide people living in prison with the best possible treatment and to minimize the adverse effects of drug use. Therefore, with laws, policies, and programs that conform to international human rights standards, each state must ensure that people living in prison receive the same health care as people outside of prison.

The Effects of Opioids on HIV Neuropathogenesis.

HIV associated neurocognitive disorders (HAND) are a group of neurological deficits that affect approximately half of people living with HIV (PLWH) despite effective antiretroviral therapy (ART). There are currently no reliable molecular biomarkers or treatments for HAND. Given the national opioid epidemic, as well as illegal and prescription use of opioid drugs among PLWH, it is critical to characterize the molecular interactions between HIV and opioids in cells of the CNS. It is also important to study the role of opioid substitution therapies in the context of HIV and CNS damage in vitro and in vivo. A major mechanism contributing to HIV neuropathogenesis is chronic, low-level inflammation in the CNS. HIV enters the brain within 4–8 days after peripheral infection and establishes CNS reservoirs, even in the context of ART, that are difficult to identify and eliminate. Infected cells, including monocytes, macrophages, and microglia, produce chemokines, cytokines, neurotoxic mediators, and viral proteins that contribute to chronic inflammation and ongoing neuronal damage. Opioids have been shown to impact these immune cells through a variety of molecular mechanisms, including opioid receptor binding and cross desensitization with chemokine receptors. The effects of opioid use on cognitive outcomes in individuals with HAND in clinical studies is variable, and thus multiple biological mechanisms are likely to contribute to the complex relationship between opioids and HIV in the CNS. In this review, we will examine what is known about both HIV and opioid mediated neuropathogenesis, and discuss key molecular processes that may be impacted by HIV and opioids in the context of neuroinflammation and CNS damage. We will also assess what is known about the effects of ART on these processes, and highlight areas of study that should be addressed in the context of ART.

Discriminative Stimulus and Low Abuse Liability Effects of Novel Endomorphin Analogs Suggest a Potential Treatment Indication for Opioid Use Disorder.

Opioid dependence can be difficult to manage using existing pharmacotherapies. A long-acting opioid with low abuse liability that substitutes for a shorter-acting opioid may improve treatment of opioid use disorders (OUDs). We recently characterized an endomorphin (EM) analog (ZH853) that produced a longer duration of antinociception compared with morphine, but did not produce self-administration or several other adverse effects preclinically. Here, we further characterized ZH853 in tests of antinociception, abuse liability, and drug discrimination. A conditioned place preference (CPP) procedure, that included a locomotor activity assessment, was used to test abuse liability in rats. Subsequently, dopamine (DA) cell-somas located in the ventral tegmental area (VTA) from these rats were assessed by size using immunohistochemistry and Stereo Investigator software. A hot-plate antinociception test in male and female mice confirmed central penetration. Morphine-substitution effects of several EM analogs (ZH850, ZH831, and ZH853) were tested in a drug discrimination (DD) procedure in rats. Morphine produced dose-dependent CPP and locomotor sensitization and reduced the size of DA cell somas in VTA, whereas ZH853 did not produce any of these effects relative to control. The antinociceptive effects of ZH853 were μ-receptor selective since β-funaltrexamine antagonized these effects. Rats responded on a morphine-trained lever when injected with ZH831 and ZH853 during DD experiments. The favorable morphine-substitution effects of these EM analogs relative to their low abuse liability indicate promising novel compounds that may improve treatment of OUD. SIGNIFICANCE STATEMENT: In this experiment, we investigated the preclinical effects of novel endomorphin analogs for use as substitution therapies for opioid use disorder, a problem that has contributed to an opioid overdose epidemic. Several endomorphin analogs substituted for morphine without producing adverse effects, including reward behaviors associated with abuse liability. These compounds have the potential to become important additional tools to treat opioid use disorders.

Cigarette smoking in subjects maintained with methadone or buprenorphine: The role of psychiatric symptoms and psychological distress

ObjectiveThe relationship between cigarette smoking, psychiatric symptoms/psychological distress in subjects maintained with methadone or buprenorphine was studied. Methods1049 subjects with a diagnosis of heroin use disorder were enrolled. The Symptom Checklist-90-Revised (SCL-90-R) and the General Health Questionnaire-12 (GHQ-12) were administered. The analyses were run in the whole sample and stratified for substitution therapies. ResultsIn the whole sample as well as among subjects maintained with methadone, the number of cigarettes smoked daily was associated with SCL-90-R Global score (whole sample: p = 0.001; ΔR2 = 0.012; subjects maintained with methadone: p ≤ 0.001; ΔR2 = 0.019) and with GHQ-12 (whole sample: p = 0.001; ΔR2 = 0.013; subjects maintained with methadone: p = 0.01; ΔR2 = 0.010) while among subjects maintained with buprenorphine, the number of cigarettes smoked daily was associated with SCL-90-R Global score (p = 0.05; ΔR2 = 0.020). ConclusionPsychiatric symptoms were associated with the number of cigarettes smoked daily among subjects maintained with methadone and among those maintained with buprenorphine, thus deserving clinical attention.

Comparing the Effects of Methadone, Buprenorphine, and Opium Tincture Maintenance Therapy on Sexual Function.

BackgroundOpioid use disorder is a major concern to public health, and opioid maintenance treatment on methadone or buprenorphine is a widely used approach. On the other hand, in recent years, there has been more regards for the use of opium tincture for detoxification and maintenance treatment of opioid dependence in certain parts of the world. The purpose of our research was to compare sexual impairments of methadone maintenance treatment (MMT), buprenorphine maintenance treatment (BMT), and opium tincture maintenance treatment (OMT) in patients.MethodsThe study sample consisted of opium-addicted men candidates for maintenance treatment in an addiction quitting clinic in Tehran, Iran, from November 2017 to February 2018. Participants (n = 84) were randomly assigned to three groups (of the equal number), receiving either methadone tablet, buprenorphine sublingual tablet, and opium tincture. The average score for sexual function was evaluated using the Arizona Sexual Experiences Scale (ASEX) at the beginning and after 3 months after treatment.FindingsAlthough there was no significant different in ASEX scores between the groups at the beginning and end of the study (P > 0.05), but the difference was significant in each group in comparing by themselves.ConclusionThese results showed that sexual dysfunction became better after opioid substitution therapies, and no differences were observed on sexual dysfunction between the three groups.

Does sex hormone treatment reverse the sex-dependent stress regulation? A longitudinal study on hypothalamus-pituitary-adrenal (HPA) axis activity in transgender individuals

BackgroundStudies in mammals indicate a role for sex hormones in the regulation of hypothalamic–pituitary–adrenal (HPA)-axis reactivity. However, in humans, experimental paradigms investigating long-term exposure to sex hormones are sparse, limiting the understanding of the influence of sex hormones on HPA-axis activity. Gender-affirming hormone therapy (GAHT) in transgender persons enables to study the physiological role of sex steroids partially uncoupled from the distinct genetic background of men and women. MethodsTen transwomen (male genotype and female gender identity) and 15 transmen (female genotype and male gender identity) were investigated at baseline and following three months of GAHT by means of the combined dexamethasone (dex)/CRH-test. Linear mixed-effects model analysis was used to assess changes over time and to identify determinants of HPA-axis reactivity. ResultsIn response to CRH, overall ACTH (+18%) as well as cortisol (+15%) output were increased in transwomen after 3-months of estrogen and antiandrogen treatment, while the opposite was the case for transmen after testosterone treatment (-15% and -58%, respectively). The ACTH/Cortisol-ratio indicated that testosterone attenuated sensitivity for ACTH at the adrenal level in transmen. Interestingly, copeptin levels before CRH administration were a strong predictor of overall cortisol secretion. ConclusionsThis is the first study demonstrating long-term effects of a complete reversal of the sex-hormonal milieu on HPA-axis activity in humans. Our findings hereby expand the current knowledge of the physiology of HPA-axis regulation. and may be particularly relevant for transgender and cisgender people undergoing hormonal suppression or substitution therapies.