Management of Pain Medication in Patients With a History of Bariatric Surgery: A Systematic Review.

CONTEXT: Obesity prevalence is persistently increasing worldwide. Among surgical therapeutic procedures, bypass surgery and sleeve gastrectomy have shown the best results regarding weight loss, prevention, and treatment of secondary complications. However, these surgeries are associated with an increased risk of malabsorption and metabolic changes that could further affect the pharmacokinetics of drugs. On the other hand, patients with a history of such surgeries are more likely to experience pain and request analgesic initiation or adaptation. The question of how to manage pain medication in these patients is challenging due to their narrow therapeutic indexes. OBJECTIVES: To summarize the current literature on the impact of bariatric surgery on the subsequent pharmacokinetics of analgesics and propose a multidisciplinary therapeutic attitude to optimize pain management in these patients. METHODS: We conducted a systematic review that included all pharmacological studies published after 2000. RESULTS: Unexpectedly, these surgeries seem to increase the bioavailability of drugs by long-term improvement of hepatic function. Yet, the medical community drastically lacks robust guidelines for pain management in those patients. This systematic review aims to bring together pharmacological studies related to the use of pain treatments in patients who underwent bypass surgery or sleeve gastrectomy. CONCLUSIONS: Caution should be exercised regarding the risk of overdose in every circumstance: treatment initiation, change of doses, or change of molecule. More prospective trials comparing the pharmacokinetics of medications in obese patients with and without prior bariatric surgery are needed.

Phenotyping Indices of CYP450 and P-Glycoprotein in Human Volunteers and in Patients Treated with Painkillers or Psychotropic Drugs.

Drug-metabolizing enzymes and drug transporters are key determinants of drug pharmacokinetics and response. The cocktail-based cytochrome P450 (CYP) and drug transporter phenotyping approach consists in the administration of multiple CYP or transporter-specific probe drugs to determine their activities simultaneously. Several drug cocktails have been developed over the past two decades in order to assess CYP450 activity in human subjects. However, phenotyping indices were mostly established for healthy volunteers. In this study, we first performed a literature review of 27 clinical pharmacokinetic studies using drug phenotypic cocktails in order to determine 95%,95% tolerance intervals of phenotyping indices in healthy volunteers. Then, we applied these phenotypic indices to 46 phenotypic assessments processed in patients having therapeutic issues when treated with painkillers or psychotropic drugs. Patients were given the complete phenotypic cocktail in order to explore the phenotypic activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A, and P-glycoprotein (P-gp). P-gp activity was evaluated by determining AUC0-6h for plasma concentrations over time of fexofenadine, a well-known substrate of P-gp. CYP metabolic activities were assessed by measuring the CYP-specific metabolite/parent drug probe plasma concentrations, yielding single-point metabolic ratios at 2 h, 3 h, and 6 h or AUC0-6h ratio after oral administration of the cocktail. The amplitude of phenotyping indices observed in our patients was much wider than those observed in the literature for healthy volunteers. Our study helps define the range of phenotyping indices with "normal" activities in human volunteers and allows classification of patients for further clinical studies regarding CYP and P-gp activities.

Cytochromes P450 and P-Glycoprotein Phenotypic Assessment to Optimize Psychotropic Pharmacotherapy: A Retrospective Analysis of Four Years of Practice in Psychiatry.

Altered cytochromes P450 enzymes (CYP) and P-glycoprotein transporter (P-gp) activity may explain variabilities in drug response. In this study, we analyzed four years of phenotypic assessments of CYP/P-gp activities to optimize pharmacotherapy in psychiatry. A low-dose probe cocktail was administered to evaluate CYP1A2, 2B6, 2D6, 2C9, 2C19, 3A4, and P-gp activities using the probe/metabolite concentration ratio in blood or the AUC. A therapeutic adjustment was suggested depending on the phenotyping results. From January 2017 to June 2021, we performed 32 phenotypings, 10 for adverse drug reaction, 6 for non-response, and 16 for both reasons. Depending on the CYP/P-gp evaluated, only 23% to 56% of patients had normal activity. Activity was decreased in up to 57% and increased in up to 60% of cases, depending on the CYP/P-gp evaluated. In 11/32 cases (34%), the therapeutic problem was attributable to the patient's metabolic profile. In 10/32 cases (31%), phenotyping excluded the metabolic profile as the cause of the therapeutic problem. For all ten individuals for which we had follow-up information, phenotyping allowed us to clearly state or clearly exclude the metabolic profile as a possible cause of therapeutic failure. Among them, seven showed a clinical improvement after dosage adaptation, or drug or pharmacological class switching. Our study confirmed the interest of CYP and P-gp phenotyping for therapeutic optimization in psychiatry.

Potential drug-drug interactions when managing status epilepticus patients in intensive care: A cohort study.

AIMS: The risk for drug-drug interactions (DDIs) associated with antiseizure drugs (ASDs) used to manage status epilepticus (SE) patients in the intensive care unit (ICU) has been poorly investigated. We aimed to quantify and describe those potential DDIs and determine SE patient risk profiles. METHODS: We conducted an observational bi-centric cohort study including all SE patients admitted to the ICU in the period 2016-2020. RESULTS: Overall, 431 SE patients were included and 5504 potential DDIs were identified including 1772 DDIs (33%) between ASDs, 2610 DDIs (47%) between ASDs and previous usual treatments (PUTs), and 1067 DDIs (20%) between ASDs and ICU treatments (ICUTs). DDIs were moderate (n = 4871), major (n = 562) or severe (n = 16). All patients exhibited potential DDIs, which were major-to-severe DDIs in 47% of the cases. DDIs were pharmacokinetic (n = 1972, 36%), mostly involving cytochrome P450 modulators, and pharmacodynamic (n = 3477, 64%), mainly leading to increased sedation. ASD/PUT DDIs were the most frequent and severe. Age, PUT and ASD drug numbers and length of ICU stay were significantly associated with increased DDI number. We identified four SE patient profiles with different DDI risks and outcomes including (1) epileptic or brain trauma patients, (2) withdrawal syndrome patients, (3) older patients with comorbidities and (4) self-poisoned patients with psychiatric disorders and/or past epilepsy. CONCLUSION: SE patients are subject to potential DDIs between ASDs, ASD/PUT and ASD/ICUT. Major-to-severe DDIs mostly occur between ASDs and PUTs. Physicians should pay attention to SE patient characteristics and history to limit DDI numbers and prevent their consequences.

Drug-induced meningitis: A review of the literature and comparison with an historical cohort of viral meningitis cases.

BACKGROUND: Drug-induced aseptic meningitis (DIAM) is potentially insufficiently considered by clinician, being of rare etiology, with there being no previously published exhaustive study describing its clinical and biological features. METHODS: Two independent academic clinicians searched all the case reports of DIAM from 1995 until 15th April, 2017. The search was limited to studies performed in humans, published in English or French. Clinical and biological data of subjects were compared with those of patients with documented viral meningitis. RESULTS: One hundred and fifty-one case reports fulfilled our inclusion criteria. Non-steroidal anti-inflammatory drugs were the commonest drug cause of AM n=49, followed by antibiotics n=46, biotherapy n=19 and finally immunomodulators n=15. The clinical and biological presentation of DIAM varies according to the causative etiological drug, especially with respect to the interval between exposure and presentation and cerebrospinal fluid (CSF) pleiocytosis. Clinical symptoms associated with meningitis were more prevalent in viral meningitis than in DIAM, except for fever and signs of encephalitis. Cerebrospinal fluid examination in DIAM reveals an increased CSF white cell count and an increased proportion of neutrophils and protein, compared with viral meningitis. DISCUSSION: We present an extensive review of the DIAM case reports, and highlight their clinical and biological characteristics according to the drugs involved. While comparing for the first time their characteristics with those of viral meningitis, this review hopes in facilitate earlier diagnosis and management of DIAM in clinical practice.

Evaluation of Phenotypic and Genotypic Variations of Drug Metabolising Enzymes and Transporters in Chronic Pain Patients Facing Adverse Drug Reactions or Non-Response to Analgesics: A Retrospective Study.

This retrospective study evaluates the link between an adverse drug reaction (ADR) or a non-response to treatment and cytochromes P450 (CYP), P-glycoprotein (P-gp) or catechol-O-methyltransferase (COMT) activity in patients taking analgesic drugs for chronic pain. Patients referred to a pain center for an ADR or a non-response to an analgesic drug between January 2005 and November 2014 were included. The genotype and/or phenotype was obtained for assessment of the CYPs, P-gp or COMT activities. The relation between the event and the result of the genotype and/or phenotype was evaluated using a semi-quantitative scale. Our analysis included 243 individual genotypic and/or phenotypic explorations. Genotypes/phenotypes were mainly assessed because of an ADR (n = 145, 59.7%), and the majority of clinical situations were observed with prodrug opioids (n = 148, 60.9%). The probability of a link between an ADR or a non-response and the genotypic/phenotypic status of the patient was evaluated as intermediate to high in 40% and 28.2% of all cases, respectively. The drugs in which the probability of an association was the strongest were the prodrug opioids, with an intermediate to high link in 45.6% of the cases for occurrence of ADRs and 36.0% of the cases for non-response. This study shows that the genotypic and phenotypic approach is useful to understand ADRs or therapeutic resistance to a usual therapeutic dosage, and can be part of the evaluation of chronic pain patients.

Changes in Alcohol Use after Metabolic and Bariatric Surgery: Predictors and Mechanisms.

PURPOSE OF REVIEW: This review synthesized the literature on predictors and mechanisms of post-bariatric alcohol problems, in order to guide future research on prevention and treatment targets. RECENT FINDINGS: Consistent evidence suggests an elevated risk of developing problems with alcohol following bariatric surgery. While there is a paucity of empirical data on predictors of problematic alcohol use after bariatric surgery, being male, a younger age, smoking, regular alcohol consumption, pre-surgical alcohol use disorder, and a lower sense of belonging have predicted alcohol misuse post-operatively. This review synthesizes potential mechanisms including specific bariatric surgical procedures, peptides and reinforcement/reward pathways, pharmacokinetics, and genetic influences. Finally, potential misperceptions regarding mechanisms are explored. Certain bariatric procedures elevate the risk of alcohol misuse post-operatively. Future research should serve to elucidate the complexities of reward signaling, genetically mediated mechanisms, and pharmacokinetics in relation to alcohol use across gender and developmental period by surgery type.

CYP450 activities before and after Roux-en-Y gastric bypass: correlation with their intestinal and liver content.

BACKGROUND: Several anatomic and physiologic changes occur after Roux-en-Y gastric bypass (RYGB) and its associated weight loss. At present, no single unified model can predict changes in drug metabolism associated with either RYGB surgery or weight loss. OBJECTIVE: The aim of this longitudinal human study was to measure the activity of the 5 most important Cytochrome P450 (CYP) involved in drug metabolism in patients with obesity before and after RYGB. Jejunal and liver biopsies obtained during bariatric surgery were used to measure CYP amount, and correlation between jejunal and hepatic content was estimated. SETTING: French university hospital. METHODS: Eleven volunteers with a mean body mass index of 44.1 (39.4-50.0) kg/m2 participated in the study. CYP1 A2, CYP2 C9, CYP2 C19, CYP2 D6, and CYP3 A4/A5 activities were measured with a cocktail approach before surgery (visit 1), 5 to 8 weeks after surgery (visit 2), and 25 to 30 weeks after surgery (visit 3). RESULTS: CYP3 A4/A5 and CYP2 C9 metabolic ratios were transitorily and significantly increased immediately after surgery (visit 2 versus 1). RYGB procedure does not lead to significant change in CYP activity 25 to 30 weeks after surgery (visit 3 versus 1). Samples obtained during surgery showed significant correlation between intestinal and liver contents of CYP2 C9 and CYP3 A4/A5. Except for liver CYP1 A2 content, CYP metabolic activities were not correlated to their intestinal or liver contents. CONCLUSIONS: This study showed that RYGB does not lead to a significant change in CYP activity 25 to 30 weeks after surgery. However, CYP3 A4/A5 and CYP2 C9 activities were transitorily and significantly increased in the immediate postoperative context (<1 mo), representing a situation at risk of reduced drug exposure for several drugs that have a narrow therapeutic window. In addition, considering high interindividual variability in liver contents and activity of CYP3 A4 and CYP2 C9, patients receiving drugs highly metabolized by these 2 CYPs should be closely monitored in the immediate postoperative period.

Glucocorticoids dosing in obese subjects: A systematic review.

Glucocorticoids (GCs) are amongst the most widely used and effective treatments to control inflammatory and autoimmune diseases. In obese subjects, drug dosing adjusted by body weight is problematic, all the more so as patients are at higher risk of GC metabolic side effects. We propose here to describe the determinants of drug pharmacokinetics (PK) in obese subjects and GC pharmacology, and to identify the existing PK studies that may help discussing the best size descriptor for GC dosing in obese subjects. A clinician and a pharmacist screened PubMed using the MeSH Terms: "glucocorticoids" OR "steroidal agents" AND "pharmacokinetics" AND "obesity" OR "overweight". The search was limited to the publications written in English language and to those performed in humans. A systematic search using the MeSH terms was performed until August 31st, 2017. Only three such PK studies have been published so far that compare dexamethasone, prednisolone and methylprednisolone in obese and normal weight subjects. The studies concur that GC partially distribute in the excess of body weight and that adjustment by total body weight (TBW) or by body weight (BW) excess would increase the initial plasma GC concentration after a loading dose and would thus be inappropriate. Contradictory results are observed regarding GC exposure or clearance according to the GC studied. Behind this overwhelming lack of conclusive evidence for adjusting GC by body weight, further PK studies are clearly needed for guiding their dosing. Furthermore, studies demonstrated an increased sensibility to GC, even when GC exposure was reduced, suggesting that adjustment by body weight may not only be unnecessary but also dangerous.

[Opioids prescription in the vulnerable populations : the children and the elderly. Practical guidelines]. / Prescription des opioïdes chez les patients vulnérables : les enfants et les personnes âgées. Recommandations pratiques.

Pain management in ambulatory care regularly requires the prescription of opioids. These drugs allow adequate analgesia achievement in many patients, but inefficiency and/or intolerable side effects may limit their use. Factors related to physiological particularities, comorbidities and comedication, as well as difficulties related to drug intake and pain assessment, make children and the elderly more vulnerable to variability in opioid response and problems of safety and efficacy profile. The purpose of this article is to remain the specificities of these two populations and to propose recommendations for the good use of opioids for ambulatory care.

La prise en charge de la douleur en médecine de ville nécessite régulièrement le recours à la prescription d'opioïdes. Une antalgie adéquate est obtenue chez de nombreux patients, mais une inefficacité et/ou des effets indésirables intolérables peuvent limiter leur utilisation. Les facteurs liés aux particularités physiologiques, aux comorbidités et aux comédications, les difficultés liées à la prise médicamenteuse et l'évaluation de la douleur, rendent l'enfant et le sujet âgé plus vulnérables à la variabilité de réponse aux opioïdes et aux problèmes de sécurité et d'efficacité. Le présent article a pour but de rappeler les spécificités de ces deux populations aux extrêmes de l'âge et de proposer des recommandations de bon usage des opioïdes pour la médecine ambulatoire.

Phenotypic Assessment of Drug Metabolic Pathways and P-Glycoprotein in Patients Treated With Antidepressants in an Ambulatory Setting.

OBJECTIVE: Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance. We also describe phenotypes in patients treated with antidepressants and evaluate the tolerance of a minimally invasive phenotyping approach. METHODS: From January 2015 to August 2015, 64 patients on a stable antidepressant regimen underwent a simultaneous assessment of steady-state antidepressant concentration and DME (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A) and P-glycoprotein transporter activity using a cocktail phenotyping approach. Psychiatric diagnoses were in accordance with DSM-5. RESULTS: We observed a high proportion of subjects (> 20%) with reduced activity of CYP2C19, CYP2D6, CYP3A4, and P-glycoprotein. As expected, higher CYP activity for major metabolic pathways was associated with lower concentration of the parent compound (CYP2C19 and escitalopram, P = .025; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .001), higher concentration of the metabolite (CYP2D6 and O-desmethylvenlafaxine, P = .007), and higher metabolite-to-parent drug ratio (CYP2C19 and escitalopram, P = .03; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .048; CYP2B6 and sertraline, P = .006). Phenotyping also highlighted the relevance of a minor metabolic pathway for venlafaxine (CYP3A4). Insufficient response and adverse reactions to antidepressants were not significantly associated with plasma antidepressant concentration, DME, or P-glycoprotein activity. Tolerance of the phenotypic test in ambulatory settings was found to be excellent. CONCLUSIONS: The phenotypic assessment of DMEs and a transporter is a valuable, well-tolerated method to explore the interindividual variability in drug disposition in clinical settings. The method is able to account for the inhibitory activity of antidepressants themselves and for polymedication, which is frequent in this population of refractory depressed patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02438072.

Effect of body weight and composition on efavirenz, atazanavir or darunavir concentration.

BACKGROUND: To compare the steady state plasma concentrations (Css) of three antiretroviral drugs in both normal and overweight patients, and to determine the relationship between Css and fat mass (FM) or lean body mass. METHODS: Patients treated for more than 6 months once daily with one of the antiretroviral drugs: efavirenz (EFV) 600mg, atazanavir boosted with ritonavir (ATV-r) 300mg/100mg, or darunavir boosted with ritonavir (DRV-r) 800mg/100mg, combined with two nucleoside analogues, were enrolled prospectively. One at steady state, plasma samples for the assessment of drug concentration were taken and body composition was assessed by bioelectrical impedance. RESULTS: One hundred and thirty-nine patients were enrolled (46, 45 and 48 in the groups EFV, ATV-r and DRV-r respectively). Their mean age was 46.2±10.4 years, 58% were male, 55.4% were from Sub Sahara African (SSA); body mass index (BMI) was 25.4±4.4kg/m2. Mean drug plasma Css of the three drugs did not differ according to BMI group. DRV-r Css tended to be higher in patients with BMI≥25kg/m2 (2896.7±1689 versus 2091.9±1038, P=0.09) and was significantly correlated with FM (r=0.3, P=0.02). In subgroup analysis, the effect of FM on DRV-r Css was significant in patients from SSA (r=0.4, P=0.04). CONCLUSIONS: Css result from many factors and body composition has been shown to only weakly influence interindividual variability but should be investigated in morbidly obese patients treated with DRV-r.

Binge eating behaviours in bipolar disorders.

BACKGROUND: Recent research, especially from the USA, suggests that comorbid binge eating (BE) behaviour and BE disorder are frequent in individuals with Bipolar Disorder (BD). Although basic clinical associations between BD and BE have been investigated, less is known about psychological or temperamental dimensions and qualitative aspects of eating habits. In a French cohort of patients with BD, we investigated the prevalence of BE behaviour and any associations with illness characteristics, anxiety, impulsivity, emotional regulation and eating habits. METHODS: 145 outpatients with BD (I and II) were assessed for the presence of BE behaviour using the Binge Eating Scale (BES). Characteristics identified in univariate analyses as differentiating BD cases with and without BE behaviour were then included in a backward stepwise logistic regression (BSLR) model. RESULTS: In this sample, 18.6% of BD patients met criteria for BE behaviour. Multivariate analysis (BSLR) indicated that shorter duration of BD, and higher levels of anxiety and emotional reactivity were observed in BD with compared to BD without BE behaviour. LIMITATIONS: Relatively small sample referred to specialist BD clinics and cross-sectional evaluation meant that it was not possible to differentiate between state and trait levels of impulsivity, emotional instability and disinhibition. These dimensions may also overlap with mood symptoms. CONCLUSION: BE behaviour is common in females and males with BD. Emotional dysregulation and anxiety may represent important shared vulnerability factors for worse outcome of BD and increased likelihood of BE behaviour.

Exploring venlafaxine pharmacokinetic variability with a phenotyping approach, a multicentric french-swiss study (MARVEL study).

BACKGROUND: It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the "in vivo" measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug-metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. METHODS/DESIGN: This study is a multicentre prospective non-randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2-3 and 6 h after cocktail administration for CYP2C19 and P-gp. Two follow-up visits will take place between 25 and 40 days and 50-70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland. DISCUSSION: By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants.

Morphine and metabolites plasma levels after administration of sustained release morphine in Roux-en-Y gastric bypass subjects versus matched control subjects.

BACKGROUND: Better knowledge of opioid pharmacology after Roux-en-Y gastric bypass (RYGB) is required for optimizing their use in this growing population. OBJECTIVE: The aim of this case-controlled pharmacokinetic (PK) study was to compare morphine and its glucuronidated metabolites (morphine-3-glucuronide and morphine-6-glucuronide) plasma PKs between patients with RYGB and their controls. SETTINGS: University hospital, Lariboisière Hospital, Paris. METHODS: Thirty milligrams of morphine as a sustained-release formulation was orally administered in 12 women who had undergone RYGB for at least 2 years (RYGB group) and in their nonsurgical controls matched for sex, body mass index (±2 points), and age (±5 yr). Morphine, morphine-3-glucuronide, and morphine-6-glucuronide plasma concentrations over a 12-hour period were determined by a validated method using liquid chromatography mass spectrometry in tandem. Drowsiness, respiratory rate, and oxygen saturation were monitored during the PK visit. RESULTS: Morphine oral area under the curve (for time 0-12 hr; 115.8 ± 108.0 nmol.hr/L and 86.9 ± 38.8 nmol.hr/L for RYGB group and control group, respectively, P = .71), morphine at maximal concentration, metabolites oral area under the curve (for time 0-12 hr), and other PK parameters were similar between groups. After drug administration, mean drowsiness was superior in RYGB group. Mean respiratory rate and oxygen saturation were similar in both groups. CONCLUSION: No dose adjustment seems to be needed for sustained release morphine when prescribed to RYGB patients.

Efficacy of Venlafaxine in Neuropathic Pain: A Narrative Review of Optimized Treatment.

PURPOSE: The prevalence of neuropathic pain is high in the general population, and high priority is given to the management of this pain condition. The treatment of neuropathic pain remains challenging, despite the publication of national and international recommendations. The purpose of this narrative review of venlafaxine (VLX) is to provide a better knowledge of the pharmacology of this drug and a clearer view of its efficacy and tolerability in neuropathic pain. METHODS: Two independent reviewers searched PubMed with the following search terms: serotonin and noradrenalin reuptake inhibitors OR VLX hydrochloride AND pain. The reviewers included all clinical studies that investigated VLX in neuropathic pain conditions and excluded animal studies, studies on fibromyalgia, studies that focused on the prevention of neuropathic pain, case reports, and studies that did not clearly describe neuropathic pain in the included patients. We describe the 13 studies that we analyzed. FINDINGS: Eleven were randomized clinical trials, and the comparator was placebo in 8 studies. Nine studies reported that VLX was effective against neuropathic pain. However, among the trials, only one against placebo included a large number of patients with >200 participants and one against prégabaline and carbamazepine had >200 patients. Most of the adverse events reported in the selected studies were consistent with known adverse events of VLX, and most were mild to moderate. However, most studies were of very short duration. IMPLICATIONS: Most of the clinical studies found that VLX was effective and well tolerated. However, given the limited number of study and the limitations of all these studies, further large clinical trials are needed. Currently, considering the limited therapeutic options for treating neuropathic pain and the highly variable nature of responses to all drugs, VLX has a place as a treatment option for neuropathic pain.