An increasing number of obese patients are undergoing surgery, particularly bariatric and orthopaedic surgery. The physiological differences between obese and normal-weight subjects may modify not ...only anaesthetic requirements during surgery but also post-operative analgesic management, raising a number of challenges in a critical period. In this review, we analyse studies of post-operative pain management with opioids in obese subjects. We discuss the genetic factors common to pain and obesity and the factors potentially modifying opioid pharmacokinetics and pharmacodynamics in obese patients, and we analyse the overall efficacy and safety of opioids for pain management during the post-operative period in obese patients. Both modifications to surgical methods and additional analgesic treatments to decrease the requirement for opioids may improve early rehabilitation and quality of care and reduce adverse effects in obese patients.
Introduction Methadone, a Mu-opioid receptor agonist, is currently used as a maintenance treatment in opioid dependant patients. However, its therapeutic index is narrow, and side effects are life ...threatening. Non-optimal dosing results in withdrawal symptoms and further heroin craving and use. The optimal dose is defined as the dose necessary to obtain a stable substitution. This optimal maximal dose can then be decreased, the final goal being to stop substitution. Objectives To identify factors to optimize the methadone optimal daily dose. Aims We aimed to identify genetic variants (SNP) associated with the methadone optimal dose. In a candidate gene approach, we focused on OPRM1 , which encodes the opioid receptor Mu, and on DRD2/ANKK1 SNP's, implied in the reward dopaminergic signalling. Methods Caucasians patients (n = 98) followed for methadone maintenance treatment were included in this prospective study. Candidate SNPs were genotyped ( ANKK1 : TaqI A; DRD2 : c.957C>T; OPRM1 : c.A118G). The plasmatic methadone level was determined using mass spectrometry in 59 patients. Results Two polymorphisms were significantly associated to the optimal methadone doses: OPRM1 c.A118G (p = 0.03) and DRD2 TaqI A (p = 0.035). The TaqIA polymorphism is located within ANKK1 , which encodes a serine threonine kinase which role remains elusive. Its molecular link to methadone pharmacodynamy remains to be established. None of these polymorphisms was associated neither to the current methadone doses, nor to the methadone plasmatic concentration. Conclusion This description is the first step to optimize the prescription of methadone in caucasian populations.
Abstract Quantitative RT-PCR (qRT-PCR) and Western blotting studies on transporters at the blood–brain barrier (BBB) of isolated brain microvessels have produced conflicting data on their cellular ...distribution. A major problem is identifying cells expressing the genes of interest, since isolated brain microvessels are composed of several cell types and may be contaminated with mRNA or proteins from astrocytes and neurons. We isolated rat brain microvessels and examined microscopically samples at each step of isolation to evaluate microvessel purity. The expression of specific markers of endothelial cells (Glut-1, Flk-1), pericytes (Ng2), neurons (synaptophysin, Syn) and astrocytes (Gfap) was measured by qRT-PCR in order to select the protocol giving the least astrocyte and neuron mRNAs and the most endothelial mRNAs. We also evaluated the gene expression of drug transporters (Mdr1a, Mdr1b, Mrp1–5, Bcrp and Oatp-2) at each step to optimize their location in cells at the BBB. The Mdr1a , Mrp4 , Bcrp and Oatp-2 gene profiles were similar to those of endothelium markers. The profiles of Mrp2 and Mrp3 closely resembled that of Ng2. Mrp5 and Mrp1 expression was not increased in the microvessel-enriched fraction, suggesting that they are ubiquitously expressed throughout the cortex parenchyma. We also evaluated by Western blotting the expression of P-gp, Mrp2, Gfap and Syn in the cortex and in the purest obtained microvessel fraction. Our results showed that P-gp expression strongly increased in microvessels whereas Mrp2 was not detected in any of the fraction. Surprisingly, Gfap expression increased in isolated microvessels whereas Syn was not detected. Our results showed that the strategy consisting of identifying gene expression at different steps of the protocol is useful to identify cells containing mRNA at the BBB and give overall similar results with protein expression.
Since the discovery of P-glycoprotein (P-gp) in brain microvessels composing the human blood-brain barrier (BBB), ATP-binding cassette (ABC) transporters have been recognized as bottlenecks in the ...development and delivery of neuropharmaceuticals. ABC transporters are expressed predominately at the plasma luminal membrane of brain capillary endothelial cells. These ABC transporters are responsible for the efflux of their substrates from the endothelial cells to the bloodstream against the concentration gradient and thus limit the entry of some drugs within the central nervous system (CNS). Advanced quantitative molecular biology tools allowed gene and protein quantification of the components of microvessels isolated from different species including human. Recently, positron emission tomography using radiolabelled probes that are substrates of ABC transporters allowed the determination of their functional activity at the human BBB. Here, we summarized new information regarding the relative expression, substrate recognition pattern for CNS drugs and functional activity of ABC transporters that are quantitatively expressed at the human BBB.
Aromatase inhibitors (AIs) are the first-line treatment in women with breast cancer for total estrogen depletion. Half the treated women may develop pain, and this condition may therefore be seen as ...a clinical model of pain related to estrogen deprivation. In this prospective multicenter study, we classified AI-related pain syndromes and identified their predictors. A 1-year, prospective, multicenter cohort study, with 6 visits, was carried out on 135 women with early-stage breast cancer and no pain at the start of AI treatment. At initial assessment, we investigated clinical (demographic and psychosocial, cancer characteristics and treatment, sleep, quality of life), biological (sex hormones, vitamin D, bone biomarkers, oxidative stress, immunologic and inflammatory markers), environmental, and genetic (polymorphism for pain mechanisms) risk factors for pain. During 1 year of follow-up, 77 women (57%) developed pain, leading to AI discontinuation in 12 cases. Five pain syndromes were identified: joint pain (36%), diffuse pain (22%), tendinitis (22%), neuropathic pain (9%), and mixed pain (11%), which are mostly persistent (57%), with diffuse and joint pains the most intense. Risk factors for the development of pain included higher levels of anxiety and impaired quality of life at the initial assessment, whereas cancer characteristics, genetic background, inflammation, and immunologic and hormonal status at baseline were not significant predictors.
This article presents a classification of AI-related pain syndromes induced by estrogen deprivation that were previously described as arthralgia, but not as neuropathic, diffuse, and mixed pain. This estrogen deprivation-related condition represents a clinical model of pain, and our study identified mostly psychological risk factors for pain development.
OBJECTIVES:Deaths due to asphyxia as well as following acute poisoning with severe respiratory depression have been attributed to buprenorphine in opioid abusers. However, in human and animal ...studies, buprenorphine exhibited ceiling respiratory effects, whereas its metabolite, norbuprenorphine, was assessed as being a potent respiratory depressor in rodents. Recently, norbuprenorphine, in contrast to buprenorphine, was shown in vitro to be a substrate of human P-glycoprotein, a drug-transporter involved in all steps of pharmacokinetics including transport at the blood–brain barrier. Our objectives were to assess P-glycoprotein involvement in norbuprenorphine transport in vivo and study its role in the modulation of buprenorphine-related respiratory effects in mice.
SETTING:University-affiliated research laboratory, INSERM U705, Paris, France.
SUBJECTS:Wild-type and P-glycoprotein knockout female Friend virus B-type mice.
INTERVENTIONS:Respiratory effects were studied using plethysmography and the P-glycoprotein role at the blood–brain barrier using in situ brain perfusion.
MEASUREMENTS AND MAIN RESULTS:Norbuprenorphine(≥1 mg/kg) and to a lesser extent buprenorphine (≥10 mg/kg) were responsible for dose-dependent respiratory depression combining increased inspiratory (TI) and expiratory times (TE). PSC833, a powerful P-glycoprotein inhibitor, significantly enhanced buprenorphine-related effects on TI (p < .01) and TE (p < .05) and norbuprenorphine-related effects on minute volume (VE, p < .05), TI, and TE (p < .001). In P-glycoprotein-knockout mice, buprenorphine-related effects on VE (p < .01), TE (p < .001), and TI (p < .05) and norbuprenorphine-related effects on VE (p < .05) and TI (p < .001) were significantly enhanced. Plasma norbuprenorphine concentrations were significantly increased in PSC833-treated mice (p < .001), supporting a P-glycoprotein role in norbuprenorphine pharmacokinetics. Brain norbuprenorphine efflux was significantly reduced in PSC833-treated and P-glycoprotein-knockout mice (p < .001), supporting P-glycoprotein-mediated norbuprenorphine transport at the blood–brain barrier.
CONCLUSIONS:P-glycoprotein plays a key-protective role in buprenorphine-related respiratory effects, by allowing norbuprenorphine efflux at the blood–brain barrier. Our findings suggest a major role for drug–drug interactions that lead to P-glycoprotein inhibition in buprenorphine-associated fatalities and respiratory depression.
Cytochrome P450 (P450) enzymes and ATP-binding cassette (ABC) transporters modulate the transport and metabolism of both endogenous and exogenous substrates and could play crucial roles in the human ...brain. In this study, we report the transcript expression profile of seven ABC transporters (ABCB1, ABCC1-C5, and ABCG2), 24 P450s (CYP1, CYP2, and CYP3 families and CYP46A1), and 14 related transcription factors aryl hydrocarbon receptor, nuclear receptor (NR)1I2/pregnane X receptor, NR1I3/constitutive androstane receptor and NR1C/peroxisome proliferator-activated receptor, NR1H/liver X receptor, NR2B/retinoid X receptor, and NR3A/estrogen receptor subfamilies in the whole brain, the dura mater, and 17 different encephalic areas. In addition, Western blotting and immunohistochemistry analysis were used to characterize the distribution of the P450s at the cellular and subcellular levels in some brain regions. Our results show the presence of a large variety of xenobiotic transporters and metabolizing enzymes in human brain and show for the first time their apparent selective distribution in different cerebral regions. The most abundant transporters were ABCC5 and ABCG2, which, interestingly, had a higher mRNA expression in the brain compared with that found in the liver. CYP46A1, CYP2J2, CYP2U1, CYP1B1, CYP2E1, and CYP2D6 represented more than 90% of the total P450 and showed selective distribution in different brain regions. Their presence in both microsomal and mitochondrial fractions was shown both in neuronal and glial cells in several brain areas. Thus, our study shows key enzymes of cholesterol and fatty acid metabolism to be present in the human brain and provides novel information of importance for elucidation of enzymes responsible for normal and pathological processes in the human brain.
Better knowledge of opioid pharmacology after Roux-en-Y gastric bypass (RYGB) is required for optimizing their use in this growing population.
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.
University hospital, Lariboisière Hospital, Paris.
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.
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.
No dose adjustment seems to be needed for sustained release morphine when prescribed to RYGB patients.
