Involvement of the transient receptor potential A1 in morphine-induced conditioned place preference and physical dependence in mice.

The main side effects of opioid use are physiological and psychological dependence. The transient receptor potential channels, including transient receptor potential ankyrin 1 (TRPA1), are involved in various neurological disorders. We aimed to evaluate the effect of TRPA1 inhibition on morphine-induced conditioned place preference (CPP) and physical dependence. For induction of CPP, morphine (10 and 20 mg/kg) was administrated for four consecutive days to male BALB/c mice. The effects of HC030031 (TRPA1 antagonist, 10, 25, and 50 mg/kg) on the expression and reinstatement of morphine-induced CPP were evaluated. For induction of physical dependence, morphine was injected three times a day for 3 days. Withdrawal-related behaviors such as jumping and defecation were precipitated by the administration of naloxone to morphine-dependent mice. The effect of HC030031 on jumping and defecation was assessed. The results showed that 20 mg/kg of morphine elicited a significant CPP. HC030031 reduced the expression of morphine CPP without any change in the locomotor activity. It also decreased the reinstatement of morphine CPP. HC030031 mitigated morphine withdrawal via reducing jumping and defecation. The present study demonstrated that HC030031 decreased morphine-associated CPP and physical dependence. It is presumed that TRPA1 has interaction with the main pharmacological effects of morphine.

New approaches to the design of analgesic medicinal substances.

A gamma-pyrone derivative, comenic acid, activates the opioid-like receptor-mediated signaling pathway that modulates the NaV1.8 channels in the primary sensory neuron membrane. These channels are responsible for the generation of the nociceptive signal; therefore, gamma-pyrones have great therapeutic potential as analgesics, and this effect deserves a deeper understanding. The novelty of our approach to the design of a medicinal substance is based on a combination of the data obtained from living neurons using very sensitive physiological methods and the results of quantum chemical calculations. This approach allows the correlation of the molecular structure of gamma-pyrones with their ability to evoke a physiological response of the neuron. Comenic acid can bind to two calcium cations. One of them is chelated by the carbonyl and hydroxyl functional groups, while the other forms a salt bond with the carboxylate anion. Calcium-bound gamma-pyrones have fundamentally different electrostatic properties from free gamma-pyrone molecules. These two calcium ions are key elements involved in ligand-receptor binding. It is very likely that ion-ionic interactions between these cations and anionic functional groups of the opioid-like receptor activate the latter. The calculated intercationic distance of 9.5 Å is a structural criterion for effective ligand-receptor binding of calcium-bound gamma-pyrones.

Participation of the opioid receptor - nitric oxide - cGMP - K+ channel pathway in the peripheral antinociceptive effect of nalbuphine and buprenorphine in rats.

The aim of this study was to examine if the peripheral antinociceptive effects of the opioid agonist/antagonist nalbuphine and buprenorphine involve the sequential participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats (180-220 g) were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous (s.c.) injection into the dorsal surface of the paw of vehicles or increasing doses of nalbuphine (50-200 µg/paw) or buprenorphine (1-5 µg/paw) 20 min before formalin injection into the paw. Nalbuphine antinociception was reversed by the s.c. injection into the paw of the inhibitor of NO synthesis (NG-nitro-l-arginine methyl ester (L-NAME)), by the inhibitor of guanylyl cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)), by the Kir6.1-2, ATP-sensitive K+ channel inhibitors (glibenclamide and glipizide), by the KCa2.1-3, small conductance Ca2+-activated K+ channel blocker (apamin), by the KCa1.1, large conductance Ca2+-activated K+ channel blocker (charybdotoxin), and by the KV, voltage-dependent K+ channel inhibitors (4-aminopyridine (4-AP) and tetraethylammonium chloride (TEA)). The antinociceptive effect produced by buprenorphine was blocked by the s.c. injection of 4-AP and TEA but not by L-NAME, ODQ, glibenclamide, glipizide, apamin, or charybdotoxin. The present results provide evidence for differences in peripheral mechanisms of action between these opioid drugs.

[Investigation of the medical and social situation of patients managed by opiate replacement regimens for over 10 years by their GP]. / Enquête sur la situation médico-sociale de patients suivis pour un traitement substitutif aux opiacés depuis plus de 10ans par leur médecin généraliste.

OBJECTIVE: Management with opiate replacement regimens (ORRs) of patients presenting to primary care settings with opiate addiction has become a long-term follow-up. The aim of this survey study was to describe patients who had been prescribed ORRs for at least 10 years by their general practitioner (GP). METHOD: In 2011, two questionnaires were sent to a sample of 38 GPs prescribing ORRs in Northern France. Doctors' questionnaires collected their typology and opinions on their patients receiving opiate substitution treatments for over 10 years. Patients' questionnaires were completed in the presence of the patient. RESULTS: Twenty-three doctors' and 83 patients' questionnaires were suitable for analysis. The average number of listed ORR patients was 14.2 and 3.6 had been managed for 10 years or more. Misuse persisted: 30.5% of GPs considered that it was carried out by at least by 15% of patients. Average dosages were 60.3 mg for methadone and 7.0 mg for buprenorphine. Employment (46.3% of patients had a salary), dwelling and family live (46.3% of patients were in charge of children) were favored. Nevertheless, precariousness persisted: 32% of patients were indebted and help of social workers was not systematically searched. One third of the patients were alcohol and cannabis misusers, 70% were smoking and 34.5% multiple drug misusers. An important number of patients were taking anxiolytics (37.8%) and hypnotics (30.5%). CONCLUSION: After 10 years of follow-up for an ORR by a GP, the social situation of patients seems to have stabilized, but psychoactive drugs consumption remains important.

Pharmacists' different profiles characterization about opioid substitution treatments.

INTRODUCTION: Delivering practices of opioid substitution treatment (OST) in community pharmacies are heterogeneous. This study aims at drawing up an inventory and at characterizing different populations of pharmacists, regarding their practices and perceptions. METHODS: We distributed a questionnaire to pharmacists, which was divided into two parts: socio-demographic questions, and 49 binary questions collecting pharmacists' perceptions. Statistical analyses were performed using SAS 9.3 and SPAD7 software. The categorical variables were expressed as numbers and percentages. We characterized the different profiles of pharmacists using a multivariate analysis method. RESULTS: We analyzed 303 questionnaires; 60.8% of our cross-section of pharmacists consider that OSTs are a treatment for chronic disease, a treatment in which they consider that they play a key role. Regarding OSTs, 89.3% felt "comfortable" with current regulations, while 77.3% have mastered possible interactions with other drugs. 16.8% of pharmacists equate the act of delivering OSTs as a "legal narcotic deal". Regarding the patients, 49.2% of pharmacists consider them as "different", and 39.1% fear that they cause relationship problems. Most pharmacists perceive the role they are meant to play, although a lack of training and the need for recommendations have been highlighted. PCA allowed us to characterize 4 different profiles of pharmacists. CONCLUSION: Continuous training adapted to the different profiles we drew up will be offered in order to allow pharmacists to deepen their knowledge about drug dependence and related care support.

[Characteristics of subjects under opiate maintenance treatment in primary care using the OPEMA data 2013]. / Caractéristiques des sujets sous traitement de substitution vus en médecine générale d'après l'enquête nationale OPEMA 2013.

AIM: The objective of the study is to describe the characteristics of subjects under opiate maintenance treatment by general practionners (GPs). METHOD: Data analysis from observatory for pharmacodependency in ambulatory medicine survey (observation des pharmacodépendances en médecine ambulatoire [OPEMA]) program in 2013 of the subjects under high dosage buprenorphine (HDB) and methadone prescribed or obtained illegally reported by GPs in France. RESULTS: Survey concerned consumers with 862, 433 and 429 of high dosage buprenorphine and respectively methadone. The average age is 39±9 years respectively, and 36±8 years; over 70% are male; 55% have paid employment and over 30% report social benefits; 9% are in temporary housing. In both groups, more than 50% have anxiety and depression; over 25% have associated somatic disorders and digestive diseases, respiratory, pain is the most common. Almost 99% use oral route; nearly 100% have a daily consumption and about 20% of the alcohol concomitantly; 24% of HDB use benzodiazepines and 18% of the methadone group (P=0.06); 33% of the population using methadone consume illicit psychoactive substances and 21% for HDB population (P<0.0001), in particular cannabis (P<0.0001). Heroin and cocaine are also consumed. CONCLUSION: The population consuming opiate maintenance treatments shows social, somatic and psychiatric vulnerability. Misuse associated forms and consumption of other psychoactive substances and illegal drugs are observed. Despite the complexity of management of these patients, general practitioners have a major role to play.

[Patterns of prescription of opioid analgesics in Hôtel-Dieu de France of Beyrouth]. / Les modalités de prescription d'analgésiques opiacés par les médecins de l'Hôtel-Dieu de France de Beyrouth.

OBJECTIVES: Use of chronic opioid therapy has increased substantially over the past few years, even though opioid therapy is associated with potentially serious harms, including opioid-related adverse effects and outcomes. Prescription of opioids for chronic pain, particularly nonmalignant chronic pain, remains controversial. In the midst of this controversy, patterns of actual prescription and influences on these patterns are not well understood. This study aims to describe the frequency of prescription of opioid analgesics in a university hospital, the attitudes of doctors towards this category of drugs, and the follow-up modalities of patients taking these drugs. The study also explores the association between the practitioners' characteristics and the modalities of prescription. DESIGN AND METHODS: A survey was delivered to 112 doctors and surgeons in the hospital during the four months between August and December 2013 and it was returned by 55 (49.0%). The survey consists of three parts. The first part addresses the frequency and reluctance of doctors' prescription of opioids and other analgesics for acute and chronic pain. The second part studies the doctors' attitudes and concerns towards opioids. It explores the belief of the doctors in the efficacy of this category of drugs, their confidence in prescribing such medications and the eventual side effects they might worry about. The third part of the survey studies the modalities of evaluation prior to the prescription and the modalities of follow-up of the patients receiving a long-term opioid treatment. RESULTS: Overall, 76.4% of doctors reported they sometimes, frequently, or always, prescribe opioids, which, using the Wilcoxon test, proved to be a significantly lower frequency than for prescribing of minor analgesics or nonsteroidal anti-inflammatory drugs (NSAIDS). Similarly, 60.1% reported a reluctance to prescribe opioids for chronic nonmalignant pain, which was a significantly greater reluctance than for cancer pain. The age and sex of the participants were unrelated to prescribing, but those with specialty training and use of practice guidelines were more likely to prescribe opioids and were less reluctant to do so. A majority of practitioners felt that opioids are effective for the treatment of chronic nonmalignant pain and that they have the sufficient training to prescribe them adequately; however, they still worry about the long-term prescription of opioids, particularly fearing the psychological dependence this treatment might cause. Using a series of Spearman correlation tests, we found that practitioners who thought they were adequately trained and who believed in the efficacy of long-term opioid treatment were more likely to prescribe them but that the worries about side effects decreased the frequency of prescription. A significant proportion of practitioners do not evaluate addiction risk factors of patients before prescribing opioids. The results concerning the modalities of follow-up of prescription were very heterogeneous with 87% of practitioners not explaining and 65% not screening for adverse effects. We similarly found that the frequency of follow-up and the management of patients who were exhibiting signs of dependence were very diverse. CONCLUSION: The results of this study were compatible with those of other recent studies about opioid prescription. The doctors practicing in the university hospital Hôtel-Dieu de France de Beyrouth present comparable prescription patterns, independent of their personal or professional characteristics, and they are more confident in their prescription when professionally trained for it. However, they exhibit a notable heterogeneity in their attitudes towards opioids and in their modalities of evaluating patients receiving long-term treatment. These results suggest a need for additional training in the management of this category of drugs.

[Bronchial diseases and heroin use. A systematic review]. / Pathologies bronchiques et usage d'héroïne. Revue systématique.

INTRODUCTION: Heroin use can cause respiratory complications including asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis (BD). OBJECTIVES: A general review of the literature presenting the data on the relationships between heroin consumption and bronchial complications, while underlining the difficulties of diagnosis and management. DOCUMENTARY SOURCES: Medline, 1980-2022, keywords "asthma" or "bronchospasm" or "COPD" or "bronchiectasis" and "heroin" or "opiate" or "opiates", with limits pertaining to "Title/Abstract". Concerning asthma, 26 studies were included, as were 16 for COPD and 5 for BD. RESULTS: Asthma and COPD are more prevalent among heroin addicts, who are less compliant than other patients with their treatment. The authors found a positive association between frequency of asthma exacerbations, admission to intensive care and heroin inhalation. Late diagnosis of COPD worsens the course of the disease; emphysema and BD are poor prognostic factors. CONCLUSION: Bronchial diseases in heroin users can be identified by means of respiratory function exploration and chest CT scans. These tests should be performed frequently in view of optimizing their care, which includes their weaning themselves from addictive substances.

[Development of a targeted educational activity in addictology: From design to use in specialized structures in the Normandy region]. / Élaboration d'une activité éducative ciblée en addictologie : de la conception à l'utilisation dans les structures spécialisées de la région Normandie.

OBJECTIVE: Risk and damage reduction is a public health issue and allows to consider addiction as a chronic pathology in which patients have the opportunity to become actors of their own care, a philosophy shared with Therapeutic Education. In this context, our objective is to develop a tool adapted to the populations of patients/users in specialized structures, meeting the criteria of a Targeted Educational Activity, to allow them a better understanding and management of their addiction to opiates on a daily basis. METHOD: In a multi-professional setting, involving pharmacists, doctors and nurses, an exploratory phase was conducted in order to identify the theme, the target population and the tool format. Then, the tool was built and validated with the ambition of responding pedagogically to the problems encountered daily by patients/users. RESULTS: The pedagogical tool, called "Le QUIZZ à moindre risque", contains 51 questions categorized in 2 structured parts on the reduction of risks related to opiate consumption and substitution drugs. Focused on the problems of patients/users, it helps them achieve greater autonomy in their health and a better quality of life, with and despite the illness. The proposed format makes it a tool that can be freely consulted by patients/users according to their practices and needs; it can also be used in group workshops conducted with the caregivers. CONCLUSION: The tool developed aims to (i) enable opiate users to acquire skills to improve the management of their consumption and the risks involved and (ii) strengthen communication between patients/users and caregivers by offering them the opportunity to be actors of their care. The tool is currently being tested and evaluated in many cities in Normandy and its optimization will allow for an improvement in care that meets the challenges and needs.

[Prolonged-release buprenorphine formulations: Perspectives for clinical practice]. / Buprénorphine d'action prolongée : quelles perspectives pour la pratique clinique ?

Buprenorphine and methadone are the two main opioids agonist treatments approved for opioid use disorder. Buprenorphine is a partial agonist of the mu-opioid receptors, which has been merely available through sublingual form until now. In practice, the use of buprenorphine is smoother than that of methadone, and it induces reduced risks of overdose. However, sublingual buprenorphine also exposes to risks (e.g., withdrawal, misuse) and constraints (e.g., daily intake). Three new galenic formulations of prolonged-release buprenorphine (PRB) are being commercialized and should allow some improvements in patients' comfort and safety. This narrative review aims to describe the main technical features and efficacy and safety data of these PRBs, as well as patients' and professionals' expectancies and concerns, using data of the scientific literature and the regulatory texts. PRBs consist of one subcutaneous implant and two subcutaneous injection depots. Sixmo®/Probuphine® is a six-month-long implant which needs to be surgically placed and removed and is approved for subjects previously treated with a maximum daily dose of 8mg of sublingual buprenorphine, and can be used only for two successive periods of six months before the subject needs to be switched back to sublingual form. Sublocade® is a one-month-long depot formulation that is indicated in switch from sublingual buprenorphine, and which proposes only two dose schemes, i.e., 100 and 300mg monthly. Buvidal®/Brixadi® is a one-week- or one-month-long depot formulation with multiple dosages, which can be used in initiation or in switched from sublingual formulations. While opioid users report some concerns with a risk of coercive use of long-acting forms of buprenorphine, both users and professionals deem that these new specialties could be particularly appreciated in stabilized patients bothered with the daily intake of the treatments, or specific situations at risk of treatment dropout (e.g., following hospital discharge or prison release).

[Asthma and cannabis, cocaine or heroin use]. / Asthme et usage de cannabis, de cocaïne ou d'héroïne.

INTRODUCTION: The use of cannabis, cocaine or heroin can be responsible for many respiratory complications including asthma. OBJECTIVES: The aim of this systematic literature review of data was to expose the relations between cannabis, cocaine or heroin use and asthma. RESULTS: Cannabis, cocaine or heroin use by inhalation may be responsible for respiratory symptoms (cough, wheezing), asthma onset, acute asthma exacerbations (which may require intubation and invasive ventilation) or deaths related to asthma. Lower adherence to asthma treatment is also observed. Cannabis induces a rapid bronchodilator effect. In contrast, its chronic use may induce a decrease in specific airway conductance. Studies on forced expiratory volume in one second (FEV1) reduction or decline are discordant. CONCLUSION: Cannabis, cocaine or heroin use must be considered in cases of acute respiratory symptoms or asthma exacerbation in young persons and practitioners must help illicit substance users to stop their consumption.

[Multidisciplinary meetings determining the imputability of xenobiotics in causes of death: What contribution to pharmacovigilance data?] / Réunions pluridisciplinaires déterminant l'imputabilité des xénobiotiques dans les causes de la mort : quel apport aux données de pharmacovigilance ?

PURPOSE: In case of xenobiotics induced toxic deaths analyzed at the university hospital of Rennes, a multidisplinary team of forensic analysts, toxicologists, anatomopathologists and pharmacologists assess xenobiotics' contribution to the death. METHODS: A death contribution score (SCRIM) is collectively established during meetings for each death involving xenobiotic drugs. Graded between 1 and 6, lower was this score, more certain was the imputability. Among deaths with the highest imputability, drug poisonings were isolated. RESULTS: Analysis of 266 deaths presented at meetings over the period 2010-2017 highlight a lot of drug medicine poisonings (60%). The main classes implicated are: opioid substitution treatments (24%) followed by anxiolytics (23%), antidepressants (16%), legal opioids (16%) and antipsychotics (14%). Analysis of these cases by Rennes regional pharmacovigilance center permits to obtain a qualitative signal by establishing a local overview of the main risk classes but also to highlight a specific signal, in particular for oxycodone and antihistamines. CONCLUSIONS: This multidisciplinary approach shows that a majority of toxic deaths are attributed to drugs. Mortality attributed to oxycodone and antihistamines is a specific signal that should be closely monitored.

[Feedback from two French addiction centers and national survey on the intranasal naloxone (Nalscue®) in the prevention of opioid overdoses]. / Retour d'expérience de deux CSAPA et enquête nationale sur la naloxone intranasale (Nalscue®) dans la prévention des overdoses aux opioïdes.

OBJECTIVE: France has temporarily authorized addictology centers to use a form of intranasal naloxone (Nalscue®) to prevent opioid overdoses. The objectives of this work are to present both the characteristics of the patients included in this device in two hospitals centers and the results of the national survey on addiction center's contribution to this new risk reduction tool. METHODS: Patient data are those requested under Nalscue® study (inclusion period July 2016 to January 2018). The survey is an online questionnaire distributed to all addiction centers with an email address. RESULTS: Over this period, in the two addiction centers, 370 kits (35% of the national total) were distributed to 330 patients including 312 opioid users. Of these users, 15% report injecting and 85% are poly-consumers. In 14% of the cases, a patient's relative was formed to administrate the Nalscue®. Forty kits (30 given away, 6 lost, 4 administered) were renewed to 35 users. Of the 462 addiction centers contacted, 82 (18%) responded. Among 76 structures specialized in opioid addictions, two did not feel concerned and one had no knowledge of the antidote. Fifty-five structures were formed by the pharmaceutical firm. Nine hundred forty-seven patients (58% of the total) were included by 37 centers. Forty-four centers ordered 2458 kits and dispensed 1116 (including kits given out of study). Thirteen structures reported use of Nalscue®. CONCLUSION: The interest of intranasal naloxone is no longer to be demonstrated in a context of opioid overdose, but the preauthorized framework did not allow a major diffusion of the antidote within the population most at risk. Let us hope that the availability in pharmacy can promote its distribution and thus reduce the number of deaths.

[Not Available]. / Abus et dépendances aux produits psychoactifs : étude de consommations à travers l'enquête OPPIDUM 2004 du réseau des CEIP.

The purpose of this study was to identify the characteristics of psychotropic drug use and abuse by drugs addicts. The results are based on data from OPPIDUM (Observation des Produits Psychotropes Illicites ou Détournés de leur Utilisation Médicamenteuse), an annual survey primarily concerned with the consumption of licit and illicit drugs. The study involved 3373 patients recruited during october 2004 from 109 health centers. The main trends observed were an increasing interest for opioid maintenance treatment by methadone versus buprenorphine high dosage (patients treated by methadone are mainly represented for the first year of the OPPIDUM program), some changes in illicit drugs uses (increase in sniff and decrease in intravenous injection) and changes in the grading of the most consumpted benzodiazepines (decrease in flunitrazepam consumption and increase in clonazepam consumption). Main warnings concern the buprenorphine illicit use leading to firstly dependence and the illicit use of some benzodiazepines, especially clonazepam.

[Misuse and dependence on prescription opioids: Prevention, identification and treatment]. / Mésusage et dépendance aux opioïdes de prescription : prévention, repérage et prise en charge.

Since the 1990s, the use of prescription opioids has largely spread, which has brought a real progress in the treatment of pain. The long-term use of prescription opioid is sometimes required, and may lead to pharmacological tolerance and withdrawal symptoms, i.e. pharmacological dependence on prescription opioids. Occasionally, this may also lead to misuse of prescription opioids (MPO). MPO preferentially occurs in vulnerable individuals, i.e., those with a young age, history of other addictive or psychiatric disorders, especially anxious and depressive disorders. MPO is associated with numerous complications, including an increased risk of fatal overdose. Prevention of MPO begins before the opioid prescription, with the identification of potential vulnerability factors. A planned and personalized monitoring should be systematically implemented. In vulnerable patients, contractualizing the prescription is warranted. During follow-up, the relevance of the prescription should be regularly reconsidered, according to the benefit observed on pain and the potential underlying signs of MPO. Patients with suspected MPO should be referred early to pain or addiction centers. The treatment of MPO should be based on multidisciplinary strategies, involving both the addiction and pain aspects: progressive opioid withdrawal, non-pharmacological measures against pain, or switching to medication-assisted treatment of addiction (i.e., buprenorphine or methadone).

[Management of neuropathic pain]. / Prise en charge de la douleur neuropathique.

Neuropathic pain is often underestimated and not adequately treated. The DN4 scale is very useful for its identification since it will benefit from pharmacological and non-pharmacological specific alternative care. The pathophysiological mechanisms involve the hyperexcitability of nociceptive pathways or decreased inhibitory descending controls that will be the target of pharmacological treatments. Frontline molecules are antidepressants (tricyclics and mixed serotonin and norepinephrine reuptake inhibitors) and antiepileptics (α2δ calcium channel inhibitors). However, these drugs will only have a partial efficacy on pain. The therapeutic strategy is based on reasonable goals, starting with a monotherapy adapted to the patient's symptoms and comorbidities and increased step by step. Patient compliance to contract is essential and requires clear and complete information. The impact on profession, social and family integration should rapidly be taken into account. In case of inefficiency, a change of the first-line treatment or an association could be considered. Some indications justify a specific therapy. Patients with resistant chronic pain should be sent to a specialized centre. New drugs are being studied and non-pharmacological support must be evaluated.