Increase of high-risk tramadol use and harmful consequences in France from 2013 to 2018: Evidence from the triangulation of addictovigilance data.

AIMS: The aim of this paper is to assess recent developments in non-medical tramadol use, tramadol use disorder, illegal procurement and deaths. METHODS: This study used repeated cross-sectional analysis of data collected nationwide from 2013 to 2018. Analysis was conducted through multisource monitoring of the French Addictovigilance Network of: (1) validated reports of high-risk tramadol use, (2) record systems collecting information from toxicology experts investigating analgesic-related deaths (DTA) and deaths related to substance abuse (DRAMES), and pharmacists for forged prescriptions (OSIAP), and (3) survey of drug users, with investigation of patterns of use while visiting addiction-specialised institutions (OPPIDUM). RESULTS: Despite a plateauing level of tramadol exposure in the French population, the proportion of tramadol reports increased 1.7-fold (187 cases in 2018, 3.2% (95% confidence interval [CI]: 2.74-3.63%), versus 1.9% (95% CI: 1.49-2.42% in 2013). Trends were similar in OSIAP: 11.9% of forged prescriptions in 2018 (95% CI: 10.56-13.45%); 1.7-fold increase; in OPPIDUM: 0.76% (95% CI: 0.55-1.02); 2.2-fold increase; and DRAMES: 3.2% of drug abuse-related deaths in 2018 (95% CI: 1.89-5.16) versus 1.7% in 2013 (95% CI: 0.65-3.84). Tramadol was the primary opioid in analgesic-related deaths in DTA (45% in 2018). Two profiles of high-risk tramadol users were identified: (1) patients treated for pain or with tramadol persistence when pain disappeared (mainly women; mean age 44 years), and (2) individuals with non-medical use for psychoactive effects (mainly men; mean age 36 years). CONCLUSION: The triangulation of the data obtained through addictovigilance monitoring evidenced a recent increase in high-risk tramadol use. These findings have a practical impact on the limitation of the maximal duration of tramadol prescriptions.

Transcultural validation of a French-European version of the Prescription Opioid Misuse Index Scale (POMI-5F).

PURPOSE: The Prescription Opioid Misuse Index scale (POMI) is a brief questionnaire used to assess opioid prescription misuse. In view of the increase in the prescription of opioid analgesics for chronic noncancer pain (CNCP), this tool is particularly useful during medical consultations to screen opioid misuse in patients using opioids. We sought to generate and validate a French-European translation of the POMI. METHODS: We conducted an observational, longitudinal, and multicenter psychometric study with crosscultural validation. All adult CNCP patients who were treated with opioids for at least three months, were followed in pain clinics, and spoke French were eligible. From September 2015 to November 2017, we included 163 patients and analyzed 154. We performed a pretest on a sample of representative patients to evaluate acceptability and understanding of translation. Study patients completed the POMI scale at a pain clinic (test phase), and we assessed test-retest reliability after two to four weeks by a second completion of the POMI scale at home by patients (retest phase). We subsequently explored psychometric properties of the POMI (acceptability, internal consistency, reproducibility, and external validity). RESULTS: Due to poor internal consistency and reproducibility, items 4, 7, and 8 of the original POMI scale were removed, and we proposed a five-question French-European version (POMI-5F). The internal consistency of POMI-5F was good (Cronbach's α = 0.71), as was test-retest reliability (r = 0.65 [0.55-0.67]). The external validity of POMI-5F, compared with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, was moderate but significant (r = 0.45; P < 0.001). The optimal POMI-5F cut-off score to indicate misuse was 2/5 (sensitivity = 0.95 and specificity = 0.54). CONCLUSION: We generated and validated a French-European translation of the POMI scale, POMI-5F, for use by French researchers and physicians to identify opioid misuse in CNCP patients.

RéSUMé: OBJECTIF: L'échelle Prescription Opioid Misuse Index (POMI) est un questionnaire court utilisé pour évaluer le mésusage de la prescription d'opioïdes. Face à l'augmentation de la prescription d'antalgiques opioïdes pour les douleurs chroniques non cancéreuses (DCNC), cet outil est particulièrement utile lors des consultations médicales pour dépister le mésusage chez les patients utilisateurs d'opioïdes. Nous avons cherché à générer et à valider une traduction franco-européenne de la POMI. MéTHODES: Nous avons mené une étude psychométrique observationnelle, longitudinale et multicentrique avec une validation transculturelle. Tous les patients souffrant de DCNC, traités par opioïdes depuis au moins trois mois, suivis en structures douleur chronique et parlant le Français étaient éligibles. De septembre 2015 à novembre 2017, 163 patients ont été inclus et 154 analysés. Un pré-test a été réalisé sur un échantillon de patients représentatifs pour évaluer l'acceptabilité et la compréhension de la traduction. Les patients de l'étude ont rempli l'échelle POMI (phase TEST) au sein du centre investigateur et la fiabilité du test­retest a été évaluée après deux à quatre semaines par un second remplissage de l'échelle POMI à domicile par les patients (phase RETEST). Ensuite, les propriétés psychométriques de l'échelle POMI ont été explorées (acceptabilité, cohérence interne, reproductibilité et validité externe). RéSULTATS: En raison d'une faible cohérence interne et reproductibilité, les items 4, 7 et 8 de l'échelle POMI originale ont été supprimés, et nous avons proposé une version française (Europe) à cinq questions (POMI-5F). La cohérence interne de l'échelle POMI-5F était bonne (α de Cronbach = 0,71), tout comme la fiabilité test­retest (r = 0,65 [0,55­0,67]). La validité externe du POMI-5F, comparée à la cinquième édition du Manuel diagnostique et statistique des troubles mentaux (DSM-5), était modérée mais significative (r = 0,45; P < 0,001). Le score seuil optimal du POMI-5F pour indiquer un mésusage était de 2/5 (sensibilité = 0,95 et spécificité = 0,54). CONCLUSION: Nous avons généré et validé une traduction franco-européenne de l'échelle POMI, POMI-5F, pour une utilisation par les chercheurs et les médecins français afin d'identifier le mésusage des opioïdes chez les patients souffrant de DCNC.

Role of serotonin and norepinephrine transporters in antidepressant-induced arterial hypertension: a pharmacoepidemiological-pharmacodynamic study.

PURPOSE: Some reports have described arterial hypertension (AH) in patients treated by serotonin reuptake inhibitor (SRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants. The mechanism remains discussed, some authors suggesting a role of SERT (SERotonin Transporter) inhibition whereas others discussing NET (NorEpinephrine Transporter) involvement. The present study used the pharmacoepidemiological-pharmacodynamic (PE-PD) method to investigate the role of these transporters in SRI- and SNRI-induced AH. METHODS: The study involved two successive approaches: first, a PE study (disproportionality analysis) investigating in VigiBase®, the World Health Organization Individual Case safety Report (ICSR) database, the relationships between exposure to SRI AND SNRI, and reports of AH. The primary analysis compared patients receiving one SRI (or one SNRI) with non-users. Secondary analyses were performed according to the pharmacological classes. Results are expressed as reporting odds ratios (ROR) with 95% CI and information component (IC), an indicator for disproportionate Bayesian reporting. Second, we performed a PD study using linear regression analyses to explore the association between the AH signal and binding affinities for NET and SERT (expressed as their pKi ratio) of SRIs and SNRIs. RESULTS: A significant ROR value was found for each individual SRI (except fluvoxamine) and each individual SNRI. ROR values were also significant for SRIs and SNRIs in general with higher values for SNRIs than for SRIs. Similar trends were found using IC. A significant correlation was found between the signal of AH and the NET/SERT pKi ratio (y = 6.57x - 2.55, R2 = 0.68, Pearson coefficient correlation = 0.82). CONCLUSION: The present study found a positive association between the NET/SERT pKi ratio and the occurrence of arterial hypertension with SRI and SNRI antidepressants. These results are important for the selection of antidepressants in hypertensive and/or at risk depressive patients as well as for future development of antidepressants devoid of hypertensive effect.

Antidepressants and movement disorders: a postmarketing study in the world pharmacovigilance database.

BACKGROUND: Antidepressants-induced movement disorders are rare and imperfectly known adverse drug reactions. The risk may differ between different antidepressants and antidepressants' classes. The objective of this study was to assess the putative association of each antidepressant and antidepressants' classes with movement disorders. METHODS: Using VigiBase®, the WHO Pharmacovigilance database, disproportionality of movement disorders' reporting was assessed among adverse drug reactions related to any antidepressant, from January 1967 to February 2017, through a case/non-case design. The association between nine subtypes of movement disorders (akathisia, bruxism, dystonia, myoclonus, parkinsonism, restless legs syndrome, tardive dyskinesia, tics, tremor) and antidepressants was estimated through the calculation first of crude Reporting Odds Ratio (ROR), then adjusted ROR on four potential confounding factors: age, sex, drugs described as able to induce movement disorders, and drugs used to treat movement disorders. RESULTS: Out of the 14,270,446 reports included in VigiBase®, 1,027,405 (7.2%) contained at least one antidepressant, among whom 29,253 (2.8%) reported movement disorders. The female/male sex ratio was 2.15 and the mean age 50.9 ± 18.0 years. We found a significant increased ROR for antidepressants in general for all subtypes of movement disorders, with the highest association with bruxism (ROR 10.37, 95% CI 9.62-11.17) and the lowest with tics (ROR 1.49, 95% CI 1.38-1.60). When comparing each of the classes of antidepressants with the others, a significant association was observed for all subtypes of movement disorders except restless legs syndrome with serotonin reuptake inhibitors (SRIs) only. Among antidepressants, mirtazapine, vortioxetine, amoxapine, phenelzine, tryptophan and fluvoxamine were associated with the highest level to movement disorders and citalopram, paroxetine, duloxetine and mirtazapine were the most frequently associated with movement disorders. An association was also found with eight other antidepressants. CONCLUSIONS: A potential harmful association was found between movement disorders and use of the antidepressants mirtazapine, vortioxetine, amoxapine, phenelzine, tryptophan, fluvoxamine, citalopram, paroxetine, duloxetine, bupropion, clomipramine, escitalopram, fluoxetine, mianserin, sertraline, venlafaxine and vilazodone. Clinicians should beware of these adverse effects and monitor early warning signs carefully. However, this observational study must be interpreted as an exploratory analysis, and these results should be refined by future epidemiological studies.

Detecting the diverted use of psychoactive drugs by adolescents and young adults: A pilot study.

PURPOSE: The increasing trend of diversion of nonprescription drugs (NPDs) by adolescents or young adults is worrying. We implemented this pilot study before a national investigation to identify requests for suspected recreational use of psychoactive drugs made by young subjects to community pharmacies. METHODS: Thirty-eight French community pharmacies were asked to complete questionnaire (with age, gender of subjects; name, form, quantity of drugs) for each suspect request formulated by subjects under 26. Besides, pharmacists were asked about the regulatory measures they thought useful to decrease this diverted use by young people. Nineteen pharmacies participated. The study covered from December 12, 2016 to January 23, 2017. RESULTS: Forty-one requests mentioning 51 drugs were reported. They concerned males (85%) aged 20 years old on average, including 6 minors. The most frequent age class was that comprised between 18 and 20 years old. Codeine-containing drugs (29 reports) and promethazine (17 reports), the main components of the popular cocktail "Purple drank," were the most requested, followed by dextromethorphan (3 reports). Fifteen drugs were requested in syrup form. One request concerned the prescription drug ketamine. Pharmacists suggested to schedule the concerned NPDs to prescription-only drugs and to increase the education of students as well as the public. CONCLUSIONS: Codeine and promethazine, the main components of the popular cocktail Purple drank, were the most requested. Suspect requests of psychoactive drugs made by adolescents or young adults in community pharmacies should be carefully surveyed and combined to the monitoring of falsified prescriptions.

[The current aspects of the use of ecstasy/MDMA in France]. / Les aspects actuels de l'usage de l'ecstasy/MDMA en France.

Methylenedioxymethamphetamine (MDMA), the active compound of ecstasy, has been used for several years, especially by young adults to benefit of psychostimulant properties. By raising the level of neuromodulators in the synapsis, MDMA can cause psychiatric and physical injuries. After reduced supplies in 2009 (number of ecstasy seizures equal to 10 percent of those recorded in 2002), judicial authorities now observed an increased availability (a half more part of seizures in 2012 than 2010). From its "Spontaneous Notifications" data base and "deaths in connection with the abuse of medicine and substances (DRAMES)", "observation of illegal drugs and misuse of psychotropic medications" (OPPIDUM), and "observation of drug dependencies in ambulatory medicine" (OPEMA) national inquiries, the French Addictovigilance network (CEIP-A) highlighted the increasing consumption of MDMA. The way of use appeared quite unchanged: users were mainly young men between 25 and 30 years; they favored an occasional use but mainly combined other products such as alcohol, cannabis and other stimulants. Severity of the clinical cases, based on hospital care and forensic data, could be consistent with the higher amounts of MDMA measured in pills.

Population awareness of risks related to medicinal product use in Vientiane Capital, Lao PDR: a cross-sectional study for public health improvement in low and middle income countries.

BACKGROUND: While essential medicines have been made more available in all but the most remote areas in low and middle income countries (L/MICs) over the past years, inappropriate and incorrect use of good quality medicines remains a key impediment for public health. In addition, as medicines have a potential to cause harm (medicine risks), adequate awareness by medicine users of the risks of adverse reactions is essential, especially as self-medication is common in L/MICs. This study aimed to investigate the awareness of Lao residents regarding medicine risks in Vientiane Capital, Lao People's Democratic Republic. METHODS: Face-to-face interviews using structured questionnaires of 144 residents older than 16 years were carried out in 12 randomly selected villages out of the 146 villages of Vientiane Capital with at least one health facility. RESULTS: The respondents were mainly (85.0 %) the heads of households or their husband/spouse . The majority of the respondents were unaware (61.8 %) of medicine risks. Compared to residents living in the urban district of Xaysetha, living in peri-urban and even more in rural areas were identified as factors associated with being unaware of medicine risks [adjusted odds ratio (aOR) =3.3, 95 % Confidence Interval (CI) = 1.1-9.4]) and aOR =7.5 (95 % CI = 2.3-24.2), respectively]. In addition, more than half of the respondents had never heard of poor quality medicines, with a higher rate in rural/peri-urban compared to urban districts (55.6 % vs 38.9 %, respectively, p = 0.02). Finally, approximately one third of all respondents thought that traditional medicines could not cause harm. CONCLUSIONS: Overall, these results suggest a lack of awareness about medicinal product risks. Differences according to the place of residence are apparent and could be partly explained by a lower level of training of healthcare providers in contact with the population in the rural districts in particular. Communication on medicinal product risks to patients through well-trained healthcare providers could probably make a valuable contribution towards the appropriate use of medicines in L/MICs.

Evaluation of abuse and dependence in addiction monitoring systems: tramadol as an example.

The objective of this paper is to present an evaluation of the potential for abuse of and dependence on a drug from the data obtained from the different pharmacoepidemiological tools used by the French network for evaluation and information on pharmacodependence and addiction monitoring taking the example of tramadol. Comparison of the data from spontaneous reports with surveys in specific populations and with evaluations of indicators of diverted uses does not highlight a major problem of tramadol abuse and dependence in terms of public health, but stresses the importance of paying attention to the signal. This example of addiction monitoring of tramadol illustrates the interest of comparing results obtained from different validated sources. The implementation of repeated observational programs of abuse of and dependence on psychoactive drugs is an important aid to health authorities to define the content of the information to be delivered or regulatory decisions to reduce these problematic uses.

Low-dose ketamine infusion to facilitate opioid tapering in chronic non-cancer pain with opioid-use disorder: a historical cohort study.

BACKGROUND: Long-term opioid use is associated with pharmacological tolerance, a risk of misuse and hyperalgesia in patients with chronic pain (CP). Tapering is challenging in this context, particularly with comorbid opioid-use disorder (OUD). The antihyperalgesic effect of ketamine, through N-methyl-D-aspartate (NMDA) antagonism, could be useful. We aimed to describe the changes in the dose of opioids consumed over 1 year after a 5-day hospitalisation with ketamine infusion for CP patients with OUD. METHODS: We performed a historical cohort study using a medical chart from 1 January 2014 to 31 December 2019. Patients were long-term opioid users with OUD and CP, followed by the Pain Center of the University Hospital of Toulouse, for which outpatient progressive tapering failed. Ketamine was administered at a low dose to initiate tapering during a 5-day hospitalisation. RESULTS: 59 patients were included, with 64% of them female and a mean age of 48±10 years old. The most frequent CP aetiologies were back pain (53%) and fibromyalgia (17%). The baseline opioid daily dose was 207 mg (±128) morphine milligram equivalent (MME). It was lowered to 92±72 mg MME at discharge (p<0.001), 99±77 mg at 3 months (p<0.001) and 103±106 mg at 12 months. More than 50% tapering was achieved immediately for 40 patients (68%), with immediate cessation for seven patients (12%). 17 patients were lost to follow-up. CONCLUSIONS: A 5-day hospitalisation with a low-dose ketamine infusion appeared useful to facilitate opioid tapering in long-term opioid users with CP and OUD. Ketamine was well tolerated, and patients did not present significant withdrawal symptoms. Prospective and comparative studies are needed to confirm our findings.

Discordance between pain specialists and patients on the perception of dependence on pain medication: A multi-centre cross-sectional study.

AIM: Patients with chronic non-cancer pain are referred to pain centres to improve their pain treatment. The discontinuation of pain medications in case of poor efficacy can be difficult to accept for patients, particularly opioid analgesics. Previous research has described that from the patients' perspective, the psychological relief of a negative effect of chronic pain and withdrawal symptoms of prescription opioids represent drivers of persistent use and first stage of opioid use disorder, despite insufficient pain relief. There is no validated tool to investigate this psychological dependence. This study aimed to assess discordance between patients and pain specialists in their perception of dependence on pain medication and investigate associations with characteristics of patients, type of pain and iatrogenic pharmacodependence. METHODS: Self-administered questionnaires (patients and physicians) were administered in six pain centres in France. A question on perceived dependence on pain medications was addressed to the patient and the physician in a matched pair. Discordance between them was evaluated by the Cohen kappa coefficient. Demographics, pain, anxiety and depression, pain medication withdrawal symptoms, diverted use, and craving represented variables studied in a multivariate model as potentially associated with patient-physician discordance. RESULTS: According to the 212 pairs of completed questionnaires, a perceived dependence was reported by the majority of patients (65.6%) and physicians (68.4%). However, the concordance was fair (kappa=0.38; CI [95%]: 0.25-0.51). Almost all patients (89.3%) were treated with an opioid analgesic. A higher likelihood of discordance was observed when patients suffered from nociplastic pain (odds ratio [OR]: 2.72, 95% [CI]: 1.29-5.84). CONCLUSION: Medical shared-decision for changing pain treatment could be improved by taking into account the perception of patient dependence on medications for pain relief and or psychoactive effects, particularly in nociplastic pain for which the treatment is challenging.

Substance use disorder of equimolar oxygen-nitrous oxide mixture in French sickle-cell patients: results of the PHEDRE study.

BACKGROUND: In many countries, nitrous oxide is used in a gas mixture (EMONO) for short-term analgesia. Cases of addiction, with significant misuse, have been reported in hospitalized patients. Patients suffering from sickle cell disease (SCD) could represent a high-risk population for substance use disorder (SUD) due to their significant pain crisis and repeated use of EMONO. The objective of the PHEDRE study was to assess the prevalence of SUD for EMONO in French SCD patients. RESULTS: A total of 993 patients were included. Among 339 EMONO consumers, only 38 (11%) had a SUD, with very few criteria, corresponding mainly to a mild SUD due to a use higher than expected (in quantity or duration) and relational tensions with the care teams. Almost all patients (99.7%) were looking for an analgesic effect, but 68% of patients were also looking for other effects. The independent risks factors associated with at least one SUD criterion were: the feeling of effects different from the expected therapeutic effects of EMONO, at least one hospitalization for vaso occlusive crisis in the past 12 months and the presence of a SUD for at least one other analgesic drug. CONCLUSIONS: The use of EMONO was not problematic for the majority of patients. Manifestations of SUD that led to tensions with healthcare teams should alert and lead to an evaluation, to distinguish a true addiction from a pseudoaddiction which may be linked to an insufficient analgesic treatment related to an underestimation of pain in SCD patients. TRIAL REGISTRATION: Clinical Trials, NCT02580565. Registered 16 October 2015, https://clinicaltrials.gov/.

["Serious" adverse drug reactions with tramadol: a 2010-2011 pharmacovigilance survey in France]. / Effets indésirables « graves ¼ du tramadol : bilan 2010-2011 de pharmacovigilance en France.

OBJECTIVE: Tramadol is a weak opioid used as a step 2 analgesic, approved in France for moderate to severe pain. After dextropropoxyphene withdrawal, a national pharmacovigilance follow-up of tramadol was decided by the French Drug Agency. METHODS: All Serious Adverse Drug Reactions (SADR) notified with tramadol to the French PharmacoVigilance Centres (CRPV) and pharmaceutical companies between August 1(st), 2010 and July 31(th), 2011 were analyzed. RESULTS: During the study period, 296 cases of SADR were notified to CRPV and 59 to pharmaceutical companies. Apart from opiate-related SADR, tramadol induced serotoninergic SADR, including seizures or serotoninergic syndromes. Several « unlabelled ¼ SADR were also identified: some of them, like hyponatremia or hypoglycemia, are poorly known by health professionals. Other were never published: peripheral edema or pancreatitis. CONCLUSION: This study shows that besides well-known opioid or serotoninergic ADR, tramadol can also induce 2 other relatively unknown ADR: hypoglycemia and hyponatremia.

[Not Available]. / Effets indésirables « graves ¼ du tramadol : bilan 2010-2011 de pharmacovigilance en France.

OBJECTIVE: Tramadol is a weak opioid used as a step 2 analgesic, approved in France for moderate to severe pain. After dextropropoxyphene withdrawal, a national pharmacovigilance follow-up of tramadol was decided by the French Drug Agency. METHODS: All Serious Adverse Drug Reactions (SADR) notified with tramadol to the French PharmacoVigilance Centres (CRPV) and pharmaceutical companies between August 1(st), 2010 and July 31(th), 2011 were analyzed. RESULTS: During the study period, 296 cases of SADR were notified to CRPV and 59 to pharmaceutical companies. Apart from opiate-related SADR, tramadol induced serotoninergic SADR, including seizures or serotoninergic syndromes. Several « unlabelled ¼ SADR were also identified: some of them, like hyponatremia or hypoglycemia, are poorly known by health professionals. Other were never published: peripheral edema or pancreatitis. CONCLUSION: This study shows that besides well-known opioid or serotoninergic ADR, tramadol can also induce 2 other relatively unknown ADR: hypoglycemia and hyponatremia.

[Increase of overdose and deaths related to methadone during COVID-19 epidemic in 2020]. / Augmentation des surdoses et décès en lien avec la consommation de méthadone durant la crise sanitaire liée au COVID-19 en 2020.

INTRODUCTION: Due to the risk of overdoses increase especially with methadone, a reinforced monitoring has been set up by the French Addictovigilance Network following the first lockdown related to coronavirus disease 2019 (COVID-19). In this context, we managed a specific study to analyze overdoses related to methadone in 2020 compared to 2019. MATERIAL AND METHODS: We analyzed methadone-related overdoses which occurred in 2019 and 2020 from two sources: DRAMES program (deaths with toxicological analysis) and the French pharmacovigilance database (BNPV) (overdoses that did not lead to death). RESULTS: Data from DRAMES program in 2020 show methadone as the first drug involved in deaths as well as an increase in deaths: in number (n=230 versus n=178), in proportion (41% versus 35%) and number of deaths per 1000 exposed subjects (3.4 versus 2.8). According to BNPV, the number of overdose increased in 2020 compared to 2019 (98 versus 79; i.e., 1.2-fold increase) particularly during several target periods: first lockdown, end of lockdown/summer period and second lockdown. In 2020, a higher number of cases were observed in April (n=15) and May (n=15). Overdoses and deaths occurred in subjects enrolled in treatment programs or not (naïve subjects/occasional users who obtained methadone from street market or family/friends). Overdoses resulted from different factors: overconsumption, multiple drug use with depressants drugs or cocaine, injection, consumption for sedative, recreational purposes or voluntary drug poisoning. DISCUSSION/CONCLUSION: All these data show an increase of morbidity and mortality related to methadone during COVID-19 epidemic. This trend has been observed in other countries.

Descriptive analysis of sickle cell patients living in France: The PHEDRE cross-sectional study.

BACKGROUND: Sickle cell disease (SCD) induces chronic haemolytic anaemia and intermittent vaso-occlusion that results in tissue ischaemia causing acute, severe pain episodes that can lead to frequent hospitalizations. These consequences can have repercussions on family, social, school and/or professional life. Here, we present some of the results of the PHEDRE study (Pharmacodépendance Et DREpanocytose-drug dependence and sickle-cell disease), which is the largest study of patients with SCD in France. This paper intends to describe characteristics of the French SCD population. We also aimed to assess the impact of the disease on the lives of patients using objective and subjective variables. METHODS: The PHEDRE study was a national multicentric observational study. Adults, adolescents and children with a confirmed SCD diagnosis were included in the study by their referring doctor. Then, they were interviewed by phone about their socioeconomic status, about the impact of the disease on their lives and about their analgesic and psychoactive drug use. RESULTS: The study population consisted of 872 patients (28% were minors). Seventy-two percent of adults were active, and all minors were in school. Many patients presented criteria of severe SCD. Seventy-five percent were homozygous SS, 15% were double heterozygotes SC and 8% were heterozygotes Sßthal, 87% received specific treatment, 58% were hospitalized at least once for vaso-occlusive crisis in the past 12 months, and the number of analgesic drugs taken averaged 3.8. Seventy-five percent of patients reported academic or professional consequences related to their SCD, and 52% reported social consequences. CONCLUSIONS: The impact of SCD on patients' lives can be significant, nevertheless their social integration seems to be maintained. We highlighted respect of recommendations regarding analgesic treatments and only a few patients used tobacco, alcohol or cannabis. TRIAL REGISTRATION: Clinical Trials, NCT02580565; https://clinicaltrials.gov/ Registered 16 October 2015.

[Buprenorphine for the treatment of opioid dependence: a study on generic substitution conducted in community pharmacies]. / La buprénorphine pour le traitement de la dépendance aux opiacés: une étude sur la substitution par les génériques menée en pharmacie d'officine.

OBJECTIVE: To describe the evolution of buprenorphine prescription form characteristics before and after the application of a measure of the French Social Security system aimed to encourage the use of generic drugs. METHOD: All buprenorphine prescription forms issued to sixty-two patients subjected to follow-up in 6 community pharmacies were analysed between October 2007 and February 2008. RESULTS: Patients maintained on Subutex during the whole follow-up were more numerous (n=39), younger, and received a higher daily dose of buprenorphine (10.5 mg versus 7.8 mg), compared to patients maintained on generic (n=13). For patients receiving again Subutex after have been treated by a generic (n=10), daily doses remained unchanged. CONCLUSION: It seems that the patients stabilized on generic present less serious pharmacodependence and less psychiatric comorbidity than those maintained on Subutex. Substituting a buprenorphine speciality with another should not induce any treatment unsettlement.

Efficacy of multimodal analgesic treatment of severe traumatic acute pain in mice pretreated with chronic high dose of buprenorphine inducing mechanical allodynia.

Managing severe acute nociceptive pain in buprenorphine-maintained individuals for opioid use disorder management is challenging owing to the high affinity and very slow dissociation of buprenorphine from µ-opioid receptors that hinders the use of full agonist opioid analgesics. In a translational approach, the aim of this study was to use an animal setting to investigate the effects of a chronic high dose of buprenorphine treatment on nociceptive thresholds before and after applying a severe acute nociceptive traumatic surgery stimulus and to screen postoperative pharmacological analgesic strategies. A chronic treatment of mice with a high dose of buprenorphine (BUP HD, 2 × 200 µg/kg/day; i.p.) revealed significant mechanical allodynia. One and two days after having discontinued buprenorphine administration and having induced a severe nociceptive acute pain by a closed tibial fracture, acute administration of morphine at a dose which has analgesic effects in absence of pretreatment (4.5 mg/kg; i.p.), was ineffective to reduce pain in the BUP HD group. However, mimicking multimodal analgesia strategy used in human postoperative context, the combination of morphine (administered at the same dose) with a NMDA receptor antagonist (ketamine) or an NSAID (ketoprofen) produced antinociceptive responses in these animals. The mouse model of closed tibial fracture could be useful to identify analgesic strategies of postoperative pain for patients with chronic exposure to opioids and suffering from hyperalgesia.

Teaching Basic Knowledge on Substance Use Disorders: The Impact of e-Learning on Health Professionals.

PURPOSE: Recent evolution toward a medical perspective on patients with substance use disorders (SUDs) has led to a lack of medical training in substance abuse. To increase this knowledge, a distance learning course ("e-learning") was implemented to teach the general concepts of SUDs to medical residents and health professionals before delivering on-campus courses. The purpose was to evaluate the impact on participants' basic knowledge. METHODS: The e-learning on the general concepts of SUDs was based on short voiced presentations and additional educational material. It was proposed to 2 populations: medical residents in general practice and health professionals in continuing education. All of the participants answered questionnaires before and after the distance learning course to evaluate their basic knowledge of SUDs. These questionnaires were analyzed along with a satisfaction questionnaire to assess both the acquired knowledge about SUDs and the satisfaction level. FINDINGS: Participants moved toward higher test scores independently of their initial background and for all the educational objectives targeted by the teachers. The mean progression on a 20-point scale between the pretest and posttest questionnaires was 5.48 (2.63) for health professionals and 5.90 (2.20) for residents in general practice. Satisfaction was rated 4 or 5 on a 5-point Likert scale by at least 84.2% of participants. IMPLICATIONS: This study is the first evaluation of an online pedagogical tool on SUDs. The positive feedback from participants encourages pursuing development of this e-learning. Used before on-campus courses, it provides an attractive educational option to overcome the usual limitations of online classes.