Mobile Health App and Web Platform (eDOL) for Medical Follow-Up of Patients With Chronic Pain: Cohort Study Involving the French eDOL National Cohort After 1 Year.

BACKGROUND: Chronic pain affects approximately 30% of the general population, severely degrades quality of life and professional life, and leads to additional health care costs. Moreover, the medical follow-up of patients with chronic pain remains complex and provides only fragmentary data on painful daily experiences. This situation makes the management of patients with chronic pain less than optimal and may partly explain the lack of effectiveness of current therapies. Real-life monitoring of subjective and objective markers of chronic pain using mobile health (mHealth) programs could better characterize patients, chronic pain, pain medications, and daily impact to help medical management. OBJECTIVE: This cohort study aimed to assess the ability of our mHealth tool (eDOL) to collect extensive real-life medical data from chronic pain patients after 1 year of use. The data collected in this way would provide new epidemiological and pathophysiological data on chronic pain. METHODS: A French national cohort of patients with chronic pain treated at 18 pain clinics has been established and followed up using mHealth tools. This cohort makes it possible to collect the determinants and repercussions of chronic pain and their evolutions in a real-life context, taking into account all environmental events likely to influence chronic pain. The patients were asked to complete several questionnaires, body schemes, and weekly meters, and were able to interact with a chatbot and use educational modules on chronic pain. Physicians could monitor their patients' progress in real time via an online platform. RESULTS: The cohort study included 1427 patients and analyzed 1178 patients. The eDOL tool was able to collect various sociodemographic data; specific data for characterizing pain disorders, including body scheme; data on comorbidities related to chronic pain and its psychological and overall impact on patients' quality of life; data on drug and nondrug therapeutics and their benefit-to-risk ratio; and medical or treatment history. Among the patients completing weekly meters, 49.4% (497/1007) continued to complete them after 3 months of follow-up, and the proportion stabilized at 39.3% (108/275) after 12 months of follow-up. Overall, despite a fairly high attrition rate over the follow-up period, the eDOL tool collected extensive data. This amount of data will increase over time and provide a significant volume of health data of interest for future research involving the epidemiology, care pathways, trajectories, medical management, sociodemographic characteristics, and other aspects of patients with chronic pain. CONCLUSIONS: This work demonstrates that the mHealth tool eDOL is able to generate a considerable volume of data concerning the determinants and repercussions of chronic pain and their evolutions in a real-life context. The eDOL tool can incorporate numerous parameters to ensure the detailed characterization of patients with chronic pain for future research and pain management. TRIAL REGISTRATION: ClinicalTrials.gov NCT04880096; https://clinicaltrials.gov/ct2/show/NCT04880096.

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.

Real-Life Testing of the Prescription Opioid Misuse Index in French Primary Care.

Analgesic opioid (AO) misuse by patients ranges from 0% to 50%. General practitioners are the first prescribers of AO. Our objective was to validate the Prescription Opioid Misuse Index (POMI) in primary care. We conducted a psychometric study in patients with chronic pain who had been taking AOs for at least 3 months and were followed in general practice. Patients responded to the POMI at inclusion and after 2 weeks. The reference used was the DSM-V. Sixty-nine GPs included 160 patients (87 women, 54.4%), mean age 56.4 ± 15.2 years. The total POMI score was 1.50 ± 1.27, and 73/160 (45.6.0%) had a score ≥ 2 (misuse threshold). Internal validity was measured with the Kuder-Richardson coefficient, which was 0.44. Correlations between each item and the total score ranged from 0.06 to 0.35. Test-retest reliability was determined from 145 patients: Lin's concordance coefficient was 0.57 [0.46, 0.68]. Correlation with the DSM-V (Spearman's coefficient) was 0.52. The POMI does not have sufficient psychometric properties to be recommended as a tool to identify the misuse of AOs in primary care. This study clearly showed that there is a need to create a monitoring tool specific to primary care.

Cross-sectional study of the prevalence of prescription opioids misuse in French patients with chronic non-cancer pain: An update with the French version of the POMI scale.

Public health issues related to chronic pain management and the risks of opioid misuse and abuse remain a challenge for practitioners. Data on the prevalence of disorders related to the use of prescribed opioids in patients suffering from chronic pain remains rather patchy, in particular because of the absence of a gold standard for their clinical assessment. We estimated the prevalence of prescription opioid misuse (POM), using a specific and validated opioid misuse scale (POMI-5F scale), in adults with chronic non-cancer pain. Nine-hundred-fifty-one (951) patients with opioids prescription and followed-up in pain clinics and addictology centers for chronic non-cancer pain (CNCP) completed the survey interview. The results suggest that 44.4% of participants have POM, accompanied by overuse (42.5%), use of opioids for effects other than analgesia (30.9%), withdrawal syndrome (65.7%), and craving (6.9%). The motivations cited for POM, apart from pain relief, were to calm down, relax and improve mood. POM was shown to be related to male sex (OR 1.52), young age (OR 2.21) and the presence of nociplastic pain (OR 1.62) of severe intensity (OR 2.31), codeine use (OR 1.72) and co-prescription of benzodiazepines (OR 1.59). Finally, despite the presence of three subgroups of misusers, no factor was associated with the intensity of misuse, reinforcing the view that distinguishing between strong and weak opioids is not appropriate in the context of use disorder. Almost half of patients with CNCP misuse their prescribed opioid. Practitioners should be attentive of profiles of patients at risk of POM, such as young, male patients suffering from severe nociplastic pain, receiving prescription for codeine and a co-prescription for benzodiazepine. We encourage French-speaking practitioners to use the POMI-5F scale to assess the presence of POM in their patients receiving opioid-based therapy. Clinical Trial Registration clinicaltrials.gov, identifier NCT03195374.

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.

eDOL mHealth App and Web Platform for Self-monitoring and Medical Follow-up of Patients With Chronic Pain: Observational Feasibility Study.

BACKGROUND: Chronic pain affects approximately 30% of the general population, severely degrades quality of life (especially in older adults) and professional life (inability or reduction in the ability to work and loss of employment), and leads to billions in additional health care costs. Moreover, available painkillers are old, with limited efficacy and can cause significant adverse effects. Thus, there is a need for innovation in the management of chronic pain. Better characterization of patients could help to identify the predictors of successful treatments, and thus, guide physicians in the initial choice of treatment and in the follow-up of their patients. Nevertheless, current assessments of patients with chronic pain provide only fragmentary data on painful daily experiences. Real-life monitoring of subjective and objective markers of chronic pain using mobile health (mHealth) programs can address this issue. OBJECTIVE: We hypothesized that regular patient self-monitoring using an mHealth app would lead physicians to obtain deeper understanding and new insight into patients with chronic pain and that, for patients, regular self-monitoring using an mHealth app would play a positive therapeutic role and improve adherence to treatment. We aimed to evaluate the feasibility and acceptability of a new mHealth app called eDOL. METHODS: We conducted an observational study to assess the feasibility and acceptability of the eDOL tool. Patients completed several questionnaires using the tool over a period of 2 weeks and repeated assessments weekly over a period of 3 months. Physicians saw their patients at a follow-up visit that took place at least 3 months after the inclusion visit. A composite criterion of the acceptability and feasibility of the eDOL tool was calculated after the completion of study using satisfaction surveys from both patients and physicians. RESULTS: Data from 105 patients (of 133 who were included) were analyzed. The rate of adherence was 61.9% (65/105) after 3 months. The median acceptability score was 7 (out of 10) for both patients and physicians. There was a high rate of completion of the baseline questionnaires and assessments (mean 89.3%), and a low rate of completion of the follow-up questionnaires and assessments (63.8% (67/105) and 61.9% (65/105) respectively). We were also able to characterize subgroups of patients and determine a profile of those who adhered to eDOL. We obtained 4 clusters that differ from each other in their biopsychosocial characteristics. Cluster 4 corresponds to patients with more disabling chronic pain (daily impact and comorbidities) and vice versa for cluster 1. CONCLUSIONS: This work demonstrates that eDOL is highly feasible and acceptable for both patients with chronic pain and their physicians. It also shows that such a tool can integrate many parameters to ensure the detailed characterization of patients for future research works and pain management. TRIAL REGISTRATION: ClinicalTrial.gov NCT03931694; http://clinicaltrials.gov/ct2/show/NCT03931694.

Analgesic opioid use disorders in patients with chronic non-cancer pain: A holistic approach for tailored management.

Chronic pain is a major public health issue that frequently leads to analgesic opioid prescriptions. These prescriptions could cause addiction issues in high-risk patients with associated comorbidities, especially those of a psychiatric, addictive, and social nature. Pain management in dependent patients is complex and is yet to be established. By combining the views of professionals from various specialties, we conducted an integrative review on this scope. This methodology synthesizes knowledge and results of significant practical studies to provide a narrative overview of the literature. The main results consisted in first proposing definitions that could allow shared vocabulary among health professionals regardless of their specialties. Next, a discussion was conducted around the main strategies for managing prescription opioid dependence, as well as pain in the context of opioid dependence and associated comorbidities. As a conclusion, we proposed to define the contours of holistic management by outlining the main guidelines for creating a multidisciplinary care framework for multi-comorbid patients with chronic pathologies.

Prevalence of chronic pain in opioid-maintained patients using the capture-recapture method: a nationwide population-based study.

Few studies all based on classical surveys have provided prevalence estimates of chronic pain (CP) in opioid-maintained patients (OMPs) but often had a limited patient sample size and a great variability in the prevalence estimates. This study sought to assess the prevalence of CP in the exhaustive population of OMPs using the capture-recapture method applied to the French nationwide health care database. Capture-recapture methods are increasingly used to estimate the prevalence of chronic conditions but have never been used in the specific context of CP in OMPs. Three large medical-administrative sources were used: the prescription drug database (A-list), the national hospital discharge database (M-list), and the pain center database (C-list). Between 2015 and 2016, 160,429 OMPs aged 15 years and older were identified and age- and sex-matched with 160,429 non-OMPs. All patients treated with analgesic drugs for ≥6 months (A-list) or diagnosed with CP (M- and C-list) were included. Capture-recapture analyses were performed to yield CP estimates with their 95% confidence intervals using log-linear models. In 2015 to 2016, 12,765 OMPs and 2938 non-OMPs with CP were captured. Most patients were male (67%) in OMPs and non-OMPs; median ages for OMPs and non-OMPs were 46 (interquartile range: 38-51) and 48 (41-53) years, respectively. The CP prevalence estimated in OMPs and non-OMPs ranged from 23.6% (14.9-46.2) to 32.1% (28.6-36.3) and from 7.28% (3.98-18.4) to 9.32% (7.42-12.1), respectively. This first study on CP in the exhaustive population of OMPs using the capture-recapture method demonstrated a high prevalence of CP in OMPs, 3- to 4-fold than in the general population.

Ketamine and Magnesium for Refractory Neuropathic Pain: A Randomized, Double-blind, Crossover Trial.

BACKGROUND: Ketamine is often used for the management of refractory chronic pain. There is, however, a paucity of trials exploring its analgesic effect several weeks after intravenous administration or in association with magnesium. The authors hypothesized that ketamine in neuropathic pain may provide pain relief and cognitive-emotional benefit versus placebo and that a combination with magnesium may have an additive effect for 5 weeks. METHODS: A randomized, double-blind, crossover, placebo-controlled study (NCT02467517) included 20 patients with neuropathic pain. Each ketamine-naïve patient received one infusion every 35 days in a random order: ketamine (0.5 mg/kg)/placebo or ketamine (0.5 mg/kg)/magnesium sulfate (3g) or placebo/placebo.The primary endpoint was the area under the curve of daily pain intensity for a period of 35 days after infusion. Secondary endpoints included pain (at 7, 15, 21 and 28 days) and health-related, emotional, sleep, and quality of life questionnaires. RESULTS: Daily pain intensity was not significantly different between the three groups (n = 20) over 35 days (mean area under the curve = 185 ± 100, 196 ± 92, and 187 ± 90 pain score-days for ketamine, ketamine/magnesium, and placebo, respectively, P = 0.296). The effect size of the main endpoint was -0.2 (95% CI [-0.6 to 0.3]; P = 0.425) for ketamine versus placebo, 0.2 (95% CI [-0.3 to 0.6]; P = 0.445) for placebo versus ketamine/magnesium and -0.4 (95% CI [-0.8 to 0.1]; P = 0.119) for ketamine versus ketamine/magnesium. There were no significant differences in emotional, sleep, and quality of life measures. During placebo, ketamine, and ketamine/magnesium infusions, 10%, 20%, and 35% of patients respectively reported at least one adverse event. CONCLUSIONS: The results of this trial in neuropathic pain refuted the hypothesis that ketamine provided pain relief at 5 weeks and cognitive-emotional benefit versus placebo and that a combination with magnesium had any additional analgesic effect.

Dextromethorphan and memantine after ketamine analgesia: a randomized control trial.

PURPOSE: Intravenous ketamine is often prescribed in severe neuropathic pain. Oral N-methyl-D-aspartate receptor (NMDAR) antagonists might prolong pain relief, reducing the frequency of ketamine infusions and hospital admissions. This clinical trial aimed at assessing whether oral dextromethorphan or memantine might prolong pain relief after intravenous ketamine. PATIENTS AND METHODS: A multicenter randomized controlled clinical trial included 60 patients after ketamine infusion for refractory neuropathic pain. Dextromethorphan (90 mg/day), memantine (20 mg/day) or placebo was given for 12 weeks (n=20 each) after ketamine infusion. The primary endpoint was pain intensity at one month. Secondary endpoints included pain, sleep, anxiety, depression, cognitive function and quality of life evaluations up to 12 weeks. RESULTS: At 1 month, dextromethorphan maintained ketamine pain relief (Numeric Pain Scale: 4.01±1.87 to 4.05±2.61, p=0.53) and diminished pain paroxysms (p=0.03) while pain intensity increased significantly with memantine and placebo (p=0.04). At 3 months, pain remained lower than at inclusion (p=0.001) and was not significantly different in the three groups. Significant benefits were observed on cognitive-affective domains and quality of life for dextromethorphan and memantine (p<0.05). CONCLUSIONS: Oral dextromethorphan given after ketamine infusion extends pain relief during one month and could help patients to better cope with pain. Future studies should include larger populations stratified on pharmacogenetics screening. Optimization of an oral drug that could extend ketamine antihyperalgesia, with fewer hospital admissions, remains a prime challenge in refractory neuropathic pain.

Milnacipran poorly modulates pain in patients suffering from fibromyalgia: a randomized double-blind controlled study.

INTRODUCTION: Fibromyalgia is characterized by widespread and chronic pain, and its prevalence is increasing worldwide. Milnacipran, an antidepressant, is often prescribed for fibromyalgia with a possible beneficial effect on central pain modulation. The aim of this study was to evaluate if milnacipran could modify the status of conditioned pain modulation (CPM) in patients suffering from fibromyalgia. DESIGN AND SETTING: Randomized, double-blind controlled trial. SUBJECTS AND METHODS: Women with fibromyalgia received milnacipran 100 mg or placebo. The primary end point was the evolution of CPM with treatments after a 30-second painful stimulus. Secondary outcomes included the predictability of milnacipran efficacy from CPM performance, evolution of global pain, mechanical sensitivity, thermal pain threshold, mechanical allodynia, cognitive function, and tolerance. RESULTS: Fifty-four women with fibromyalgia (46.7±10.6 years) were included and randomized, and 24 patients were analyzed in each group. At inclusion, CPM was dysfunctional (CPM30=-0.5±1.9), and global pain was 6.5±1.8. After treatment, there was a nonsignificant CPM difference between milnacipran and placebo (CPM30=-0.46±1.22 vs -0.69±1.43, respectively, p=0.55) and 18.8% vs 6.3% (p=0.085) patients did reactivate CPM after milnacipran vs placebo. Initial CPM was not a predictor of milnacipran efficacy. Global pain, mechanical and thermal thresholds, allodynia, cognition, and tolerance were not significantly different between both groups. CONCLUSION: Milnacipran did not display a significant analgesic effect after 1-month treatment, but the tendency of milnacipran to reactivate CPM in a number of patients must be explored with longer treatment duration in future studies and pleads for possible subtypes of fibromyalgia patients.

Prevalence of chronic pain with or without neuropathic characteristics in France using the capture-recapture method: a population-based study.

Capture-recapture methods are increasingly used to determine the prevalence of numerous chronic conditions but have never been used in the context of chronic pain (CP). This study sought to provide up-to-date estimates of the prevalence of people experiencing CP ± neuropathic characteristics in France using the capture-recapture method. In 2013 to 2015, 3 data sources were used: the French prescription drug database (D-list), the national hospital discharge database (H-list), and the French pain center database (P-list). Patients aged 18 years and older treated with analgesic drugs for ≥6 months (D-list) or with a diagnosis of CP ± neuropathic characteristics (H- and P-lists) were included. Two successive capture-recapture analyses were conducted, with log-linear regression for each analysis performed. A total of 63,557 and 9852 distinct cases of CP and chronic neuropathic pain were captured, respectively. The estimated prevalence of CP and chronic neuropathic pain in the adults ranged from 27.2% (95% confidence interval: 26.1-28.4) to 32.7% (26.0-43.3) and from 5.55% (2.89-19.0) to 7.30% (6.40-8.41), respectively. Most patients were female, median ages were 67 (55-80) and 63 (51-76) years for chronic and neuropathic pain, respectively. The analgesic drugs most frequently used in CP patients were paracetamol (62.1%), weak opioids (39.7%), and nonsteroidal anti-inflammatory drugs (32.7%), whereas in neuropathic pain patients, anticonvulsants (45.3%), tricyclic antidepressants (18.1%), and serotonin-norepinephrine reuptake inhibitors (13.3%) were more frequently used. This first electronic health record-based study on CP using the capture-recapture method revealed a high prevalence of CP, with a significant proportion of neuropathic pain patients.

Effect of ketamine combined with magnesium sulfate in neuropathic pain patients (KETAPAIN): study protocol for a randomized controlled trial.

BACKGROUND: Neuropathic pain is difficult to treat, and the efficacy of recommended drugs remains limited. N-methyl-D-aspartate receptors are implicated, and antagonists are a pharmacological option. Ketamine is widely used in French pain clinics, but without consensus or recommendations. Furthermore, the association of ketamine with magnesium has been poorly studied. The aim of the present study is to evaluate the benefit of ketamine with or without magnesium in refractory neuropathic pain. METHODS/DESIGN: A randomized, double-blind, crossover, placebo-controlled study will be performed in Clermont-Ferrand University Hospital, Clermont-Ferrand, France. The aim is to evaluate the effect of ketamine with or without magnesium in 22 patients with neuropathic pain. Intravenous ketamine/placebo, ketamine/magnesium sulfate, or placebo/placebo will be administered consecutively to each patient, in random order, once at 5-week intervals. The primary endpoint is the AUC of pain intensity assessed on a 0-10 Numeric Pain Rating Scale for a 5-week period. Data analysis will be performed on an intention-to-treat basis, and all statistical tests (except primary analysis) will be performed with an α risk of 5% (two-sided). DISCUSSION: Considering the poor efficacy of the drugs available for neuropathic pain, ketamine with or without magnesium sulfate may be a valuable therapeutic option that needs to be standardized. TRIAL REGISTRATION: EudraCT number- 2015-000142-29 . Registered on April 9, 2015; version 1.4.

Codeine Shopping Behavior in a Retrospective Cohort of Chronic Noncancer Pain Patients: Incidence and Risk Factors.

Codeine is a widely used opioid analgesic but studies on its misuse in chronic noncancer pain (CNCP) are still lacking. The aim of this study was to assess the incidence of codeine shopping behavior in CNCP patients and to identify the associated risk factors. This was a population-based retrospective cohort study from the French health insurance claims database from 2004 to 2014. The main outcome was the one-year incidence of codeine shopping behavior defined as ≥1 day of overlapping prescriptions written by ≥2 different prescribers and filled in ≥3 different pharmacies. A total of 1,958 CNCP patients treated with codeine were included, with a mean age of 62.7 ± 16.1 years, 36.8% men. The 1-year incidence rate of codeine shopping behavior was 4.03% (95% confidence interval [CI], 3.07-5.28). In multivariate analysis, risk factors associated with shopping behavior were younger age (≤40 years) (hazard ratio [HR] = 7.29; 95% CI, 4.28-12.42), mental health disorders (HR = 2.25; 95% CI, 1.08-4.67), concurrent use of anxiolytic benzodiazepines (HR = 3.12; 95% CI, 1.55-6.26), and previous use of strong opioids (HR = 2.94; 95% CI, 1.24-6.98). The incidence of codeine shopping behavior in CNCP patients was 4% and risk factors identified were shared with those of opioid abuse. PERSPECTIVE: Shopping behavior for codeine was not infrequent in CNCP patients. The risk factors identified in this study are similar to those identified for opioid abuse in other studies. Appropriate use of codeine from the perspectives of patients and healthcare providers should be encouraged.

Incidence of tramadol shopping behavior in a retrospective cohort of chronic non-cancer pain patients in France.

PURPOSE: Opioid analgesic use in chronic non-cancer pain (CNCP) is increasingly prevalent, but the benefits and risks are inadequately understood. In France, tramadol is one of the most used prescription opioids, but studies on its misuse liability in CNCP are still lacking. The aim was to assess the incidence of tramadol shopping behavior in CNCP patients and to identify the associated risk factors. METHODS: A retrospective cohort of CNCP patients aged 18 years and older treated by tramadol for at least six consecutive months between 2005 and 2013 from a sample of the French Health Insurance database was established. Doctor shopping was defined as at least 1 day of overlapping prescriptions written by two or more different prescribers and filled in at least three different pharmacies. RESULTS: A total of 3505 CNCP patients were included with a majority of women (66.4%) and a mean age of 66.4 ± 14.7 years. The median tramadol treatment duration was 260 [interquartile range: 211-356] days. The 1-year incidence rate of tramadol shopping behavior was 1.0% [95%CI: 0.7-1.5]. On multivariate analysis, risk factors associated with tramadol shopping behavior were age (hazard ratio [HR] = 7.4 [95%CI: 2.8-19.7] for age <40, HR = 2.8 [95%CI: 1.0-7.7] for 40 ≤ age < 50, versus age ≥50), low-income status (HR = 8.5 [95%CI: 3.6-20.5]), and prior use of strong opioids (HR = 5.7 [95%CI: 1.9-17.0]). CONCLUSION: Tramadol shopping behavior incidence appears low in CNCP patients but may represent a public health concern given the widespread use of tramadol. Education and best monitoring of high-risk patients are needed to reduce doctor shopping. Copyright © 2016 John Wiley & Sons, Ltd.

Rationale and design of a randomized double-blind clinical trial in breast cancer: dextromethorphan in chemotherapy-induced peripheral neuropathy.

BACKGROUND: Anti-cancer chemotherapy often induces peripheral neuropathy and consequent cognitive and quality of life impairment. Guidelines recommend antiepileptics or antidepressants but their efficacy is limited.Dextromethorphan, a N-methyl-D-aspartate receptor antagonist, has shown its efficacy in painful diabetic neuropathy and in post-operative pain but has not been studied in chemotherapy-induced peripheral neuropathy. This clinical trial evaluates the effect of dextromethorphan on pain, cognition and quality of life in patients who suffer from neuropathic pain induced by chemotherapy for breast cancer. It also assesses the impact of dextromethorphan genetic polymorphism on analgesia. METHODS AND DESIGN: This trial is a randomized, placebo-controlled, double-blind clinical study in two parallel groups (NCT02271893). It includes 40 breast cancer patients suffering from chemotherapy-induced peripheral neuropathy. They are randomly allocated to dextromethorphan (maximal dose 90 mg/day) or placebo for 4 weeks. The primary endpoint is pain intensity measured after 4 weeks of treatment on a (0-10) Numeric Pain Rating Scale. Secondary outcomes include assessment of neuropathic pain, cognitive function, anxiety/depression, sleep and quality of life. Data analysis is performed using mixed models and the tests are two-sided, with a type I error set at α=0.05. DISCUSSION: Considering the poor efficacy of available drugs in chemotherapy-induced neuropathic pain, dextromethorphan may be a valuable therapeutic option. Pharmacogenetics may provide predictive factors of dextromethorphan response in patients suffering from breast cancer.

Rationale and design of a multicenter randomized clinical trial with memantine and dextromethorphan in ketamine-responder patients.

The N-methyl-D-aspartate receptor plays an important role in central sensitization of neuropathic pain and N-methyl-D-aspartate receptor antagonists, such as ketamine, memantine and dextromethorphan may be used for persistent pain. However, ketamine cannot be repeated too often because of its adverse events. A drug relay would be helpful in the outpatient to postpone or even cancel the next ketamine infusion. This clinical trial evaluates if memantine and/or dextromethorphan given as a relay to ketamine responders may maintain or induce a decrease of pain intensity and have a beneficial impact on cognition and quality of life. This trial is a multi-center, randomized, controlled and single-blind clinical study (NCT01602185). It includes 60 ketamine responder patients suffering from neuropathic pain. They are randomly allocated to memantine, dextromethorphan or placebo. After ketamine infusion, 60 patients received either memantine (maximal dose 20 mg/day), or dextromethorphan (maximal dose 90 mg/day), or placebo for 12 weeks. The primary endpoint is pain measured on a (0-10) Numeric Rating Scale 1 month after inclusion. Secondary outcomes include assessment of neuropathic pain, sleep, quality of life, anxiety/depression and cognitive function at 2 and 3 months. Data analysis is performed using mixed models and the tests are two-sided, with a type I error set at α=0.05. This study will explore if oral memantine and/or dextromethorphan may be a beneficial relay in ketamine responders and may diminish ketamine infusion frequency. Preservation of cognitive function and quality of life is also a central issue that will be analyzed in these vulnerable patients.

Oral magnesium treatment in patients with neuropathic pain: a randomized clinical trial.

Studies in animals and in patients have suggested that magnesium (Mg), a physiological blocker of N-methyl-D-aspartate receptor, could have an antinociceptive effect in painful situations. This randomised, double-blind, controlled trial in two parallel groups aims at studying oral Mg effects in patients with neuropathic pain. It explores the impact of Mg (6x419 mg Mg chloride/capsule per day for a month), versus placebo (lactose) on pain [Neuropathic Pain Symptom Inventory (NPSI) and numerical scale (NS)], and on quality of life indicators after 4 weeks treatment, in 45 patients suffering from neuropathic pain. After 4 weeks, NPSI, NS and quality of life are not different in the Mg and placebo groups, while the frequency of pain paroxysms diminishes and the emotional component improves in the Mg group compared to baseline. This clinical trial displays a large placebo response and could not demonstrate any significant difference in pain alleviation after a month of oral treatment between Mg and placebo in patients suffering from neuropathic pain. Frequency of pain paroxysms and emotional impact will be explored in future studies as they constitute major aspects of pain alleviation in chronic pain conditions.

Median effective dose (ED50) of nefopam and ketoprofen in postoperative patients: a study of interaction using sequential analysis and isobolographic analysis.

BACKGROUND: The analgesic efficacy of ketoprofen has been shown after moderate- and severe-pain surgery, and the analgesic efficacy of nefopam has been shown after moderate-pain surgery. The aim of this study was to define the median effective analgesic doses of each drug and to determine whether the interaction of nefopam and of ketoprofen is synergistic. METHODS: Seventy-two patients scheduled to undergo moderately painful surgery were enrolled in one of three groups. The dose of nefopam and ketoprofen received by a particular patient was determined by the response of the previous patient of the same group, using an up-and-down technique. Initial doses were 18 and 40 mg, with dose adjustment intervals of 2 and 5 mg, in the nefopam and ketoprofen groups, respectively. The initial doses of nefopam and ketoprofen were 8 and 20 mg, respectively, in the nefopam-ketoprofen group, with the same dose adjustment intervals. Analgesic efficacy was defined as a decrease to less than 3 on a 0-10 numeric pain scale, 45 min after the beginning of drug infusion. RESULTS: The median effective analgesic dose (median value and 95% confidence interval) of nefopam and ketoprofen were, respectively, 28 mg (17-39 mg) and 30 mg (14-46 mg). The median effective analgesic dose of the combination was 1.75 mg (0.9-2.3 mg) for nefopam and 4.3 mg (2.2-6.5 mg) for ketoprofen. CONCLUSION: The isobolographic analysis demonstrated that the combination of the two drugs produces effective analgesia with an important synergistic interaction.

The median effective dose of nefopam and morphine administered intravenously for postoperative pain after minor surgery: a prospective randomized double-blinded isobolographic study of their analgesic action.

UNLABELLED: The aim of this study was to characterize the nature of analgesic interaction between nefopam and morphine administered i.v. for postoperative pain after minor surgery. To do so, we defined the median effective analgesic dose (ED(50)) for each drug and also the median ED(50) of their combination and compared them using the isobolographic method. Determination of median effective doses was performed by the up-and-down sequential drug administration in a two-stage study. First, in a prospective, randomized, double-blinded study, we enrolled 60 patients with mild to moderate pain after minor surgery; this was followed by an open study enrolling 30 patients. The end-point was a pain score less than 3 on a Numerical Pain Scale (0-10). Initial doses were 16 mg in group N, 5 mg in group M, and 7.5 mg of N combined with 2.5 mg of M in group N+M. The testing interval was 2 mg in group N, 1 mg in group M, and 1.5 mg of N combined with 0.5 mg of M in group N+M. ED(50) (95% confidence interval) was 5 mg (4-6 mg) for morphine, 18 mg (16-18 mg) for nefopam, and 4 mg (3.5-4.5 mg) with 12 mg (10.5-13.5 mg) for the combination of morphine and nefopam administered at a 3:1 dose ratio. Isobolographic analysis demonstrated a significant infra-additive interaction. The incidence of side effects did not differ significantly among morphine, nefopam, and their combination. These findings suggest that the combination of nefopam and morphine does not offer any advantage compared to each drug administered i.v. or alone after minor surgery. This study is the first to define the ED(50) of nefopam and morphine in postoperative patients. In conclusion, the addition of nefopam has a morphine-sparing effect, but the combination is infra-additive. IMPLICATIONS: Pharmacologic interaction between nefopam and morphine shows infra-additivity but their combination may be clinically useful as morphine consumption is decreased in postoperative patients.