There are 28 clinical trials
Pain assessment in infants and toddlers is quite challenging since children in these populations are nonverbal or preverbal and cannot describe the presence and severity of pain that they perceive. Over the last decade, advances in the field have included the development of behavioral scoring systems for the assessment of acute pain . However, although they have been validated, these commonly used methods of pain assessment are largely subjective and rely on a highly trained observer. An objective continuous measure of pain would be an important addition to standard behavioral painscores which require nurses to monitor the child's behavioral responses.
The ability of skin conductance monitor to predict post-operative pain scores, sensitivity and specificity will be measured.. Effect of single nucleotide polymorphisms in the mu-opioid receptor A118G on post-operaive pain scores. --- A118G ---
Association of the mu-opioid receptor gene A118G polymorphisms with inter-individual differences in the pain scores with standardized treatments will be evaluated.. Inclusion Criteria: - Children 0 - 3 years of age inclusive - Presenting for palatal repair (palatoplasty) - American Society of Anesthesiologists (ASA) physical status of 1 or 2 Exclusion Criteria: - Children > 3 years of age - On chronic pain treatment - Pre-operative use of analgesics - Allergies to any anesthetics or analgesia products - Known obstructive sleep apnea - Diagnosis of Cystic fibrosis - American Society of Anesthesiologists (ASA) physical status ≥ 3 Inclusion Criteria: - Children 0 - 3 years of age inclusive - Presenting for palatal repair (palatoplasty) - American Society of Anesthesiologists (ASA) physical status of 1 or 2 Exclusion Criteria: - Children > 3 years of age - On chronic pain treatment - Pre-operative use of analgesics - Allergies to any anesthetics or analgesia products - Known obstructive sleep apnea - Diagnosis of Cystic fibrosis - American Society of Anesthesiologists (ASA) physical status ≥ 3 Pain After standard general anesthetic mask induction, 0.5 ml of blood will be drawn for genetic analysis when the intravenous catheter is sited. --- A118G ---
Description: The skin conductance monitor will be attached to the patient in the Post-Anesthesia Care Unit (PACU) for 1 hour and the skin condutance values will be analyzed off-line. Corresponding pain scores on a scale of 0-10 using the FLACC (Face, Legs, Activity, Cry and Consolibility) scale will be noted every 5 minutes for a period of 1 hour. The skin conductance values will be measured in microsiemens, also the frequency of the skin conductance responses per second will be measured. The ability of skin conductance monitor to predict post-operative pain scores, sensitivity and specificity will be measured.
Measure: skin conductance measurements Time: 2 yearsDescription: Association of the mu-opioid receptor gene A118G polymorphisms with inter-individual differences in the pain scores with standardized treatments will be evaluated.
Measure: Effect of single nucleotide polymorphisms in the mu-opioid receptor A118G on post-operaive pain scores Time: 2 yearsBreathlessness, the sensation of breathing discomfort, is a major problem in people with chronic obstructive pulmonary disease (COPD). Breathlessness that persists despite optimal management of the underlying disease(s) is said to be refractory. Preliminary evidence suggests that a small, regular dose of morphine helps to reduce safely the sensation of breathlessness. However, this research on morphine for breathlessness has not defined the best way to adjust the dose of the medication, or refined which people are most likely to have benefit, no response or side effects. This is a randomized, double-blind phase III trial in people with COPD and significant refractory breathlessness, which will explore several important questions: - Are regular, low dose opioids (morphine) at four possible doses over 3 weeks more effective than placebo medication (containing no active ingredient) at improving breathlessness? - Does the medication have any effect on daily activity, breathlessness, and quality of life? - What are the common side effects of this intervention? - Does the benefit from the drug outweigh the side effects it produces? - Are there specific characteristics of people who are more likely to receive benefit from sustained release morphine? Participants will be allocated to receive three weeks of morphine sulfate (and laxative, docusate with senna), or placebo (and placebo laxative). The dose of morphine may be increased each week for weeks two and three. All medicines will appear the same (blinded) and neither the doctor nor the participant will know which medication the participant is receiving. Participants will have a medical interview, physical examination to collect some general health information, and baseline measurements including; daily activity, symptoms, and quality of life. A small amount of blood may be required to check eligibility. Further blood samples may be taken at week 1 and 3 to enable testing on how individuals respond to opioids, further consent will be obtained for these samples. Data on benefits, side effects, and medical care will be collected during comprehensive weekly visits. Participants will also fill out a simple diary twice daily for weeks one to three of the study, and for one day each week during an optional 3 month extension stage. The outcome of this study may enable better management of symptoms and activity in people COPD with medicines that are shown to be effective and safe.
From the baseline sample, the UGT2B7*2 and *28 polymorphisms, P-glycoprotein (ABCB1 5SNPs in a haplotype block), the 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572, and mu opioid receptor (A118G) polymorphisms will be measured. --- A118G ---
Description: Rated on a 0-10 numerical rating scale (NRS) in a diary each evening. The primary endpoint is the difference between placebo, morphine sulfate 8 mg, or 16 mg after the first treatment week.
Measure: Change from baseline intensity of breathlessness over the previous 24 hours Time: Week 1Description: Rated on a 0-10 numerical rating scale (NRS) in a diary each evening.
Measure: Change from baseline unpleasantness of breathlessness over the previous 24 hours Time: Week 3Description: Rated on a 0-10 numerical rating scale (NRS) in a diary each morning.
Measure: Change from baseline intensity of breathlessness "right now" Time: Week 3Description: In addition to the NRS ratings, the intensity of breathlessness is rated on a 0-10 modified Borg scale in a evening diary.
Measure: Change from baseline in the intensity of breathlessness Time: Week 1Description: Collected in a diary in the evening, including of any rescue medication used.
Measure: Current medication use and compliance Time: At study end for up to 15 weeks.Description: Collected in a diary in the evening.
Measure: Number of participants with adverse events Time: At study end for up to 15 weeks.Description: Measured during two days at baseline and during at least five days of treatment week three.
Measure: Change from baseline physical activity using an accelerometer Time: Week 3Description: Measured using the revised Edmonton Symptoms Assessment Scale (ESAS-r).
Measure: Change from baseline in concurrent symptoms Time: Week 1Description: Measures the functional impact of breathlessness.
Measure: The modified Medical Research Council (mMRC) breathlessness scale Time: At study end for up to 15 weeks.Description: To explore whether longer term morphine treatment is associated with decreased levels of testosterone.
Measure: Change from baseline serum testosterone level Time: At the end of the 3 month follow-up stage, after up to 15 weeks.Description: From the baseline sample, the UGT2B7*2 and *28 polymorphisms, P-glycoprotein (ABCB1 5SNPs in a haplotype block), the 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572, and mu opioid receptor (A118G) polymorphisms will be measured. Interleukin 1ß, TNFalpha and Il-6 will be measured at baseline and at the end of the first treatment week.
Measure: Change from baseline pharmacogenomic opioid blood profile Time: Week 1Description: In a subset of 55 participants, blood parameters for morphine and its metabolites will be analysed (4 blood samples over 8 hours) at steady state of the treatment at the end of the week 1.
Measure: Pharmacodynamic/-kinetic blood samples Time: Week 1Description: Exhaled gas measured using a non-invasive capnometer.
Measure: Change from baseline end-tidal carbon dioxide Time: Week 3Description: Non-invasive measurement of the oxygen saturation, respiratory rate, and heart rate.
Measure: Change from baseline pulse oximetry Time: Week 3Description: Twenty (20) participants at the Sydney and Adelaide sites will be invited to undertake a simple, non-invasive home sleep study using the ResMed ApneaLink Plus device.
Measure: Change from baseline sleep quality Time: The final night of week 3Description: Rated on a 4 point Likert scale in a morning diary.
Measure: Change from baseline sleep quality Time: During the study for up to 15 weeks.Description: The questionnaires used are the Epworth Sleepiness Scale, Leeds Sleep Questionnaire, and the Karolinska Sleepiness Scale.
Measure: Change from baseline sleep quality and sleep-related problems Time: Week 3Description: Measure of the bowel function, during treatment with placebo / morphine sulfate 8 or 16 mg.
Measure: Change from baseline bowel function index Time: Week 1Description: Measured on the CRQ-SAS Dyspnoea sub-scale.
Measure: Change from baseline breathlessness-related quality of life Time: Week 3Description: Measured using the EQ-5D questionnaire.
Measure: Change from baseline health-related quality of life Time: During the study for up to 15 weeks.Description: Life-Space is a measure of where a person goes, the frequency of going there, and the dependency in getting there.
Measure: Change from baseline Life-space Time: During the study for up to 15 weeks.Description: A score of 0 to 100 (in increments of 10) is assigned to participants based on their ability to undertake a range of daily tasks. The score gives an indication of the participant condition in terms of physical ability.
Measure: Change from baseline Australian Karnofsky Performance Status Time: During the study for up to 15 weeks.Description: A 14-item questionnaire used to measure anxiety and/or depression.
Measure: Change from baseline Hospital Anxiety and Depression Scale Time: Week 3Description: Participant-rated seven point scale of the perception of their change, specifically their improvement since the commencement of the study.
Measure: Global Impression of Change Time: During the study for up to 15 weeks.Description: Participants will be asked for their preference to continue at study exit ('Is this a therapy which, on balance, you would continue to take for your breathlessness?')
Measure: Blinded patient preference to continue treatment Time: At study end after up to 15 weeks.Description: Data on all health care contacts including lenght of hospitalizations, emergency department visits, DRG codes, outpatient visits to general practitioner and community nurse, and date of death.
Measure: Health economy composite Time: During the study for up to 15 weeks.This is a study involving treatment for alcohol dependence among males of European or Asian decent. The ultimate aim of this line of investigation is to further establish a genetic link between alcohol dependence and treatment by defining an endophenotype associated with treatment response. The study will combine two inpatient alcohol challenge sessions along with 12 weeks of outpatient treatment using random assignment to either naltrexone or placebo.
Recent work at our center provides evidence that the mu-opioid receptor (OPRM1) gene polymorphism A118G (Asn40Asp) imparts a significant change in treatment response. --- A118G ---
To further consolidate our knowledge, we wish to test the relationship between A118G polymorphism and the subjective/objective measures to alcohol among alcoholics treated with naltrexone. --- A118G ---
This work is focused on subjects of European or Asian decent as the A118G polymorphism occurs in less than 1% of those of African decent. --- A118G ---
Identification of the genetic polymorphisms that could be correlated either with a better clinical response or with a major predisposition of patients to develop tolerance and/or side effects to the treatment with morphine.
Assessment of the rescue doses in the two groups homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene; group B: both homozygous and heterozygous patients for the less frequent allele. --- A118G ---
Valuation of the rescue doses necessary to maintain NRS<4 in the first 24 hours post-surgery in the two groups of patients, A e B. Group A: homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene (about 80%); group B: both homozygous and heterozygous patients for the less frequent allele (about 20%).. Variants at the loci OPRM1, COMT, UGTs, ESR1,towards median pain measure. --- A118G ---
- Allergies to morphine and derivates Anesthesia Surgery Valuation of the rescue doses necessary to maintain NRS<4 in the first 24 hours post-surgery in the two groups of patients, A e B. Group A: homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene (about 80%); group B: both homozygous and heterozygous patients for the less frequent allele (about 20%). --- A118G ---
Description: Valuation of the rescue doses necessary to maintain NRS<4 in the first 24 hours post-surgery in the two groups of patients, A e B. Group A: homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene (about 80%); group B: both homozygous and heterozygous patients for the less frequent allele (about 20%).
Measure: Assessment of the rescue doses in the two groups homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene; group B: both homozygous and heterozygous patients for the less frequent allele Time: first 24 h after surgeryDescription: Frequency of the variants at the loci OPRM1, COMT, UGTs, ESR1, both in patients with NRS ≤4 and in those having NRS >4 at least once during 24 hours.
Measure: Variants at the loci OPRM1, COMT, UGTs, ESR1,towards median pain measure Time: during 24 h postsurgeryDescription: Frequency of the variants at the loci OPRM1, COMT, UGTs, ESR1, both in patients with NRS ≤4 and in those having NRS >4 at least once during the period between 24-48 hours postsurgery.
Measure: Variants at the loci OPRM1, COMT, UGTs, ESR1,towards median pain measure Time: period between 24 - 48 h postsurgeryDescription: Pharmacokinetic study of both morphine and its principal active and/or toxic metabolites (M3G and M6G).
Measure: Pharmacokinetics of morphine during continuous administration after surgery Time: 48 h after surgeryDescription: Detection of the possible side effects after continuous morphine administration
Measure: Detection of the possible side effects. Time: 72 h postoprativelyDescription: Detection of the association between M3G/M6G ratio and polymorphisms of UGTs and its possible side effects.
Measure: Detection of the association between M3G/M6G ratio and polymorphisms of UGTs Time: within 72 h postoperativelyIdentification of the genetic polymorphisms that could be correlated either with a better clinical response or with a major predisposition of patients to develop tolerance and/or side effects to the treatment with morphine.
Assessment of the medium morphine dose (mg/kg/die)in the two groups homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene; group B: both homozygous and heterozygous patients for the less frequent allele. --- A118G ---
Valutation of the medium morphine dose (mg/kg/die) necessary to maintain NRS<4 in the first 24 hours post-surgery in the two groups of patients, A e B. Group A: homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene (about 80%); group B: both homozygous and heterozygous patients for the less frequent allele (about 20%).. Variants at the loci OPRM1, COMT, UGTs, ESR1,towards median pain measure. --- A118G ---
- Allergies to morphine and derivates Anesthesia Surgery Valuation of the medium morphine dose (mg/kg/die) necessary to maintain NRS<4 in the first 24 hours post-surgery in the two groups of patients, A e B. Group A: homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene (about 80%); group B: both homozygous and heterozygous patients for the less frequent allele (about 20%). --- A118G ---
Description: Valutation of the medium morphine dose (mg/kg/die) necessary to maintain NRS<4 in the first 24 hours post-surgery in the two groups of patients, A e B. Group A: homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene (about 80%); group B: both homozygous and heterozygous patients for the less frequent allele (about 20%).
Measure: Assessment of the medium morphine dose (mg/kg/die)in the two groups homozygous patients for the more frequent allele of the polymorphism A118G of OPRM1 gene; group B: both homozygous and heterozygous patients for the less frequent allele Time: first 24 h after surgeryDescription: Frequency of the variants at the loci OPRM1, COMT, UGTs, ESR1, both in patients with NRS ≤4 and in those having NRS >4 at least once during 24 hours.
Measure: Variants at the loci OPRM1, COMT, UGTs, ESR1,towards median pain measure Time: during 24 h postsurgeryDescription: Detection of the medium morphine dose (mg/kg/die) necessary to maintain NRS<4 though the first 48 hours after surgery.
Measure: Detection of the medium morphine dose Time: First 24 h after surgeryDescription: Pharmacokinetic study of both morphine and its principal active and/or toxic metabolites (M3G and M6G).
Measure: Pharmacokinetics of morphine with PCA after surgery Time: 48 h after surgeryDescription: Variants frequency at loci OPRM1, COMT, UGTs, ESR1 in the patients with Cmax and AUC of both morphine and M3G-M6G metabolites >2 standard deviations higher than expected population curve ("outliers").
Measure: Variants frequency at loci OPRM1, COMT, UGTs, ESR1 Time: Within 48h after surgeryTo determine if the mu opioid receptor gene (OPRM1) A118G polymorphism moderates the subjective-rewarding effects of intravenous (IV) nicotine in male and female smokers. The subjective effects of nicotine will be measured with a Drug Effects Questionnaire, including the ratings of "good effects" and "drug liking". We hypothesize that smokers with the AG/GG genotype for the OPRM1 A118G will have attenuated subjective-rewarding effects from IV nicotine when compared to those with AA genotype.
Sensitivity to Intravenous Nicotine: Genetic Moderators To determine if the mu opioid receptor gene (OPRM1) A118G polymorphism moderates the subjective-rewarding effects of intravenous (IV) nicotine in male and female smokers. --- A118G ---
We hypothesize that smokers with the AG/GG genotype for the OPRM1 A118G will have attenuated subjective-rewarding effects from IV nicotine when compared to those with AA genotype. --- A118G ---
primary hypotheses will test the influence of OPRM1 A118G status on subjective responses to IV nicotine, which will be measured with the drug effects questionnaire (DEQ).. null. --- A118G ---
Further, the functional OPRM1 A118G variant has been linked to rewarding effects of alcohol in alcohol users and to nicotine in female smokers. --- A118G ---
Since no previous studies examined the influence of the A118G variation on pure nicotine responses, the next logical step is to evaluate how this genetic polymorphism affects nicotine's rewarding, cognitive, and physiological effects using IV nicotine administration in male and female smokers. --- A118G ---
Pharmacogenetics has allowed clinicians to identify associations between an individual's genetic profile and his/her response to drugs. The A118G (c.188A>G)is a single nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1). The mutated protein, N40D, appears to increase the binding affinity and potency of beta-endorphin approximately 3-fold. Individuals carrying the variant receptor gene (A118G) may show differences in some of the functions mediated by beta-endorphin action at the altered OPRM1. Combined spinal-epidural (CSE) analgesia is a commonly utilized technique for labor analgesia. Analgesia is initiated with the intrathecal administration of a lipid-soluble opioid (e.g. fentanyl), sometimes combined with a local anesthetic. The mean (± SD) duration of analgesia after intrathecal fentanyl 25 microgram was 89 ± 43 min. The ED50 of intrathecal fentanyl for labor analgesia varies between 14 microgram to 18.2 microgram. The wide variability in the duration of analgesia, as was well the differences in ED50 may result from differences known to affect labor pain (e.g., ethnicity, parity, stage of labor). Another possible explanation for the differences in opioid requirements and duration, as well as incidence of side effects such as itching and nausea/vomiting, is that opioid responsiveness is determined by genetic variability of the µ-opioid receptor. The ED50 for intrathecal fentanyl labor analgesia was significantly lower for parturients carrying the A118G variant of the mu-opioid receptor, compared to parturients with the A118 wild type receptor. The purpose of this study is to determine whether polymorphism at nucleotide 118 of OPRM1 influences the duration of intrathecal opioid (fentanyl) labor analgesia, and intrathecal opioid (morphine) postoperative analgesia.
The A118G (c.188A>G)is a single nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1). --- A118G ---
Individuals carrying the variant receptor gene (A118G) may show differences in some of the functions mediated by beta-endorphin action at the altered OPRM1. --- A118G ---
The ED50 for intrathecal fentanyl labor analgesia was significantly lower for parturients carrying the A118G variant of the mu-opioid receptor, compared to parturients with the A118 wild type receptor. --- A118G ---
SNP genotyping: For identification of allelic distribution of the A118G SNP, 20-60 ng of DNA from individuals will be first amplified by PCR (on thermocycler apparatuses equipped with a 96 well-microtiter plate block) using primers designed in the vicinity of the SNPs. --- A118G ---
Description: Time from intrathecal drug administration to request for analgesia either in laboring women of after cesarean delivery
Measure: Duration of Intrathecal Fentanyl Analgesia Time: Time (0-1440 minutes) to first analgesia requestDescription: Time until request for supplemental analgesia following intrathecal morphine/fentanyl for cesarean delivery
Measure: Duration of Intrathecal Analgesia Following Cesarean Delivery Time: 0 to 72 hours following cesarean deliveryDescription: Visual analog pain scale (0 to 100) at 1st request for supplemental analgesia
Measure: Visual Analog Pain Scale (0 to 100) at Analgesia Request Following Intrathecal Intervention Time: VAS at analgesia requestDescription: Severity of pruritus during labor analgesia
Measure: Severity of Pruritus Following Fentanyl Time: Labor analgesiaDescription: Subjects reporting pruritus in the first 24 hours post cesarean delivery
Measure: Subjects With Pruritus at 24 Hours Post Morphine Time: 24 hours post cesarean deliveryThis study will examine the relationship between variations in a gene called OPRM1 and the response to alcohol. The OPRM1 (Mu-opioid Receptor-1) gene helps regulate brain pathways involved in experiencing pleasure. Brain pathways use a chemical called dopamine. Different forms of the OPRM1 gene may lead to differences in how dopamine is released and subsequently to differences in a person's response to alcohol. Healthy non-smokers between 21 and 45 years of age may be eligible for this study. Candidates are screened with a medical and psychiatric history and physical examination, blood and urine tests, and breathalyzer (breath alcohol test). A blood test is also done to determine the variant of OPRM1 gene. Participants undergo the following procedures in three study sessions: Session 1 " Breathalyzer test, urine test for illicit drugs and pregnancy test for women who can become pregnant. " Insertion of catheters (plastic tubes) into a vein in one arm for infusing alcohol and into the other arm for drawing blood samples. " Completion of questionnaires on how intoxicated the subject feels. " Blood draw for research studies. " Eye movement test (a visor with a digital camera tracks the subject's eye movements while he or she watches lights on a computer screen). " 45-minute alcohol infusion (up to 0,08 grams per deciliter - a level considered in most states as driving under the influence of alcohol). " Repeat breathalyzer, questionnaires, eye movement test and blood draw every 15 minutes during the infusion and again after the infusion is complete. " Subjects remain in the clinic until their blood alcohol content falls below 0.02 g/dL, determined by a breathalyzer test done every 15 minutes. Subjects can usually return home about 3 to 4 hours after the alcohol infusion stops. Sessions 2 and 3 The procedure is the same as for session 1, except subjects receive an infusion of alcohol one session and an infusion of saline (salt water) the other. Also, subjects undergo positron emission tomography (PET) scanning during the infusions. For this test, the subject lies on a bed that slides in and out of a doughnut-shaped scanner. A custom-molded mask is used to support the head and prevent it from moving during the scanning. A small amount of radioactive substance called C-11 raclopride is injected through one of the catheters to trace brain dopamine activity. ...
OPRM1 A118G SNP, Alcohol Response, and Striatal Dopamine. --- A118G ---
OPRM1 A118G SNP, Alcohol Response, and Striatal Dopamine This study will examine the relationship between variations in a gene called OPRM1 and the response to alcohol. --- A118G ---
A functional mu-opioid receptor (OPRM1) A118G single nucleotide polymorphism (SNP) alters the affinity of the mu-opioid receptor for its endogenous ligand, is in some studies associated with increased risk for alcohol and heroin addiction, and confers differential pain sensitivity and subjective responses to alcohol. --- A118G ---
This prompts the question whether the differential subjective response to alcohol observed as a function of the OPRM1 A118G genotype reflects differential activation of the mesolimbic DA release. --- A118G ---
The objective of this study is to examine the role of the A118G OPRM1 polymorphism for responses to a highly standardized intravenous alcohol challenge, with regard to psycho-physiological variables measured in the laboratory, and for brain dopamine release measured by 11C raclopride PET. --- A118G ---
The aims of the study are to test for treatment outcome differences in alcohol dependent subjects randomly assigned to 12 weeks of treatment with NTX (50mg/day) or placebo among those with one or two copies of the Asp40 allele of the mu-opioid receptor compared to those homozygous for the Asn40 allele. Thus, the design of the study is a 2X2 cell double-blind randomization to NTX or placebo stratified by genotype. To meet these aims, 150 alcohol dependent outpatients with one or two copies of the Asp40 variant of the mu-opioid receptor and 190 subjects homozygous for the Asn40 variant will be recruited across the four participating sites.
Recent work at our center provides evidence that the mu-opioid receptor (OPRM1) gene polymorphism A118G (Asn40Asp) imparts a significant change in treatment response. --- A118G ---
To further consolidate our knowledge, we wish to test the relationship between A118G polymorphism and the response to treatment with naltrexone. --- A118G ---
This work is focused on subjects of European or Asian descent as the A118G polymorphism occurs in less than 1% of those of African descent. --- A118G ---
Pain is a complex experience influenced by gender and genetics, and, by psychosocial and sensory experiences. Pain sensitivity is thus highly variable between individuals. In the present study we evaluate individuals´ pain perception in response to a number of different pain stimuli in 100 healthy volunteers (50 females and 50 males). The data will allow us to assess pain sensitivity, to predict pain responses and to investigate gender related differences in pain perception. A second aim is to evaluate the robustness of the different pain-tests since the tests are repeated with an interval of 2-4 weeks.
A118G SNP. --- A118G ---
Psychophysical assessments following induction of a first degree burn injury (47.0 C, 420 s, 12.5 sq.cm, lower leg) include: - pain during induction of burn injury - thermal thresholds - tactile thresholds - electrical thresholds - areas of secondary hyperalgesia - pressure algometric assessments - assessment of Diffuse Noxious Inhibitory Control (DNIC) efficiency - assessment of (DNIC) using cold pressor test Psychological assessments include: - HADS (Hospital Anxiety and Depression Scale) - PCS (Pain Catastrophizing Scale) - vulnerability score Genetics include: - A118G SNP Demographics include: - gender - height - weight --- A118G ---
This investigation will be the first study assessing genetic modulation of naltrexone's NTX effects upon the abuse liability of a stimulant drug (methamphetamine). The study team will assess the ability of oral NTX to block the reinforcing and positive subjective effects of intranasal (IN) methamphetamine (30mg/70kg). This investigation could identify an important Gene x Pharmacological interaction, contributing to the personalization of stimulant abuse pharmacotherapy.
Substance Use Disorders Methamphetamine Abuse Substance-Related Disorders A recent meta-analysis concluded that the OPRM1 A118G SNP (rs1799971) significantly moderates the treatment efficacy of Naltrexone (NTX) in treating alcohol abuse, increasing the treatment efficacy by over 2-fold among G-allele carriers (AG/GG). --- A118G ---
Medication effects on these validated predictors of abuse potential will be compared between A118G A allele homozygotes (AA) and G-allele carriers (AG/GG; an anticipated 25% of the total sample), in order to assess genetic moderation of treatment outcome. --- A118G ---
Description: To assess the reinforcing effects of methamphetamine, participants complete a drug vs. money self-administration procedure. The outcome measure for this procedure is their percentage of choices for drug (methamphetamine) choices.
Measure: Percentage of methamphetamine choices. Time: 1 day.Description: Participant ratings of methamphetamine "Liking," on a 100 mm visual analog scale. Participants are asked to indicate on a 100 mm line the extent to which they agree with the description of the drug provided. The 0 mm end of the line indicates "Not at All," while the 100 mm indicates "Extremely."
Measure: Positive subjective effects of methamphetamine. Time: 1 dayDespite preclinical evidence supporting the role of the endogenous opioid system in the reinforcing effects of nicotine, the efficacy of the opioid antagonist naltrexone (NTX) as a tobacco dependence treatment remains unresolved. Research is needed to identify those smokers for whom NTX will have the strongest beneficial effects on smoking behavior. The research bridges existing knowledge of genetic, pharmacologic, and behavioral responses to nicotine, and translates this knowledge to treatment for tobacco dependence. The immediate goal was to test whether genetic variation in the mu-opioid receptor gene predicts the effects of naltrexone (NTX) on nicotine reinforcement.
A key question was whether smokers differ in their responses based on the mu opioid receptor gene (OPRM1) Asn40Asp (A118G) variant. --- Asn40Asp --- --- A118G ---
Description: On day 4 of each study medication period, participants completed a cigarette choice procedure where the subject is asked to take 4 puffs from a nicotinized (nicotine-containing) or a denicotinized (no nicotine) cigarette every 30 minutes for 2 hours (maximum of 24 puffs). The outcome variable is the number of nicotine cigarette choices or puffs out of 24 total puffs during these cigarette choice procedures. Subjects who had the A/A genotype took an average of 18.5 puffs from the nicotine-containing cigarettes. Subjects with the A/G or G/G genotypes took an average of 16.2 puffs from the nicotine-containing cigarettes.
Measure: Number of Nicotine Cigarette Choices Taken During the Cigarette Choice Procedure. Time: 2 hoursThirty-two healthy volunteers will be submitted to experimental pain and on the 2 study days receive Oxycodone 20 mg po vs. placebo. Half of the volunteers will be poor metabolizers according to CYP2D6 genotype and half will be extensive metabolizers (EM) and have an enzyme with normal function. The study hypothesis is that PM will experience less pain relief than EM.
Among these are the A118G SNP in the μ-receptor gene OPRM1 and the C3435T and G2677T/A SNPs in the MDR-1 gene of P-glycoprotein. --- A118G ---
Patients undergoing surgery (thyroidectomy and hysterectomy) will postoperatively receive oxycodone intravenously (IV) as pain management with morphine as an escape medicine, if there is insufficient pain relief with oxycodone. Patients' pain and side effects will be registered and after 24 hours they will answer a questionnaire. All included patients will be genotyped accordingly to CYP2D6 and relevant single nucleotide polymorphisms (SNPs), and measures of plasma levels of oxycodone will be performed.
Among these are the A118G SNP in the μ-receptor gene OPRM1 and the C3435T and G2677T/A SNPs in the MDR-1 gene of P-glycoprotein. --- A118G ---
Background: - Small differences in genes may alter responses to drugs. One gene that has different forms is the mu opioid receptor gene. People with one form of this gene are more sensitive to alcohol. People with a different form are sometimes more sensitive to pain. Morphine and other prescription pain pills produce pain relief by acting at the mu opioid receptor. Researchers want to see the effect of morphine on brain reward and subjective effects. Morphine is a strong but short-acting pain medication that is sometimes used for anesthesia during surgery. Objectives: - To compare the effect of morphine on brain measures of dopamine release using imaging. Eligibility: - Individuals between 21 and 55 years of age who have previously taken pain pills prescribed to treat pain from a medical or dental procedure. Design: - This study has a screening phase and a study phase. The screening phase involves one or two visits of 5 to 6 hours. The study phase consists of 4 study visits. Each study visit will take about 8 hours. - Participants will be screened with a medical and psychiatric history and physical exam. They will be asked about drinking and drug-taking history, and any family history of alcoholism or drug abuse. Blood, urine, and breath samples will be collected. - During the first study visit, an MRI scan may be performed, questionnaires completed, and a blood sample collected for genetic testing. - During study visit 2, participants will test their pain sensitivity by placing one hand in cold water. Pupil diameter will be measured after the sensitivity test. After a blood sample is taken, participants will receive the morphine or a salt solution. The sensitivity test and pupil diameter test will be repeated. Final blood samples will be collected. A brief physical exam will also be performed. - During study visits 3 and 4, participants will receive morphine or a salt solution during a PET scan. Questionnaires to assess subjective effects will be administered. Final blood samples will be collected. A brief physical exam will also be performed. - Participants will stay in the clinic until the effects of the drug have worn off after study visits 2, 3, and 4. - About 1 week after the study session, participants will have a follow-up phone call.
OPRM1 A118G SNP Effect on Striatal Dopamine Response to an IV Opiate. --- A118G ---
A functional µ-opioid receptor (OPRM1) A118G single nucleotide polymorphism (SNP) has been associated with increased risk for heroin addiction in some studies. --- A118G ---
The objective of this study is to examine the role of the A118G OPRM1 polymorphism for responses to a challenge of an opiate (morphine) with regard to psycho-physiological variables measured in the laboratory and for brain dopamine release measured by [11C]raclopride PET. --- A118G ---
Description: Binding potential measured using regions-of-interest analysis of PET data. Parametric Binding Potential (BPND) images were obtained using the Simple Reference Tissue Model 2 (SRTM2) 33, with cerebellum as the reference region. Reduction in raclopride binding is attributed to competition with endogenous dopamine, and has been shown to be proportional to the magnitude of Dopamine (DA) release.
Measure: 11C Raclopride Binding Potential in Caudate Time: 90 minutes following injectionDescription: Binding potential measured using regions-of-interest analysis of PET data. Parametric Binding Potential (BPND) images were obtained using the Simple Reference Tissue Model 2 (SRTM2) 33, with cerebellum as the reference region. Reduction in raclopride binding is attributed to competition with endogenous dopamine, and has been shown to be proportional to the magnitude of Dopamine (DA) release.
Measure: 11C Raclopride Binding Potential in Nucleus Accumbens Time: 90 minutes following injectionDescription: Binding potential measured using regions-of-interest analysis of PET data. Parametric Binding Potential (BPND) images were obtained using the Simple Reference Tissue Model 2 (SRTM2) 33, with cerebellum as the reference region. Reduction in raclopride binding is attributed to competition with endogenous dopamine, and has been shown to be proportional to the magnitude of Dopamine (DA) release.
Measure: 11C Raclopride Binding Potential in Putamen Time: 90 minutes following injectionDescription: Binding potential measured using regions-of-interest analysis of PET data. Parametric Binding Potential (BPND) images were obtained using the Simple Reference Tissue Model 2 (SRTM2) 33, with cerebellum as the reference region. Reduction in raclopride binding is attributed to competition with endogenous dopamine, and has been shown to be proportional to the magnitude of Dopamine (DA) release.
Measure: 11C Raclopride Binding Potential in Ventral Pallidum Time: 90 minutes following injectionDescription: Area under the curve of the subjective perception-time course - Feel Drug. Subjective responses as measured by the Drug Effects Questionnaire [DEQ]. The DEQ consists of simple, face-valid, visual analog scale (VAS) questions on which people report their subjective states after ingesting a substance. The analog scale of responses ranges from "not at all" to "extremely", and the numeric scale ranges from 0 to 100. Due to skewness of individual time points; areas under the curve for these ratings across individual time points (0, 10, 20, 30, 40, 50 and 60 min) were compared instead. Possible range of values for the AUC are 0 to 5500.
Measure: Subjective Perception of Morphine Effect - Feel Drug Time: 60 minutes following injectionDescription: Area under the curve of the subjective perception-time course - Feel High. Subjective responses as measured by the Drug Effects Questionnaire [DEQ]. The DEQ consists of simple, face-valid, visual analog scale (VAS) questions on which people report their subjective states after ingesting a substance. The analog scale of responses ranges from "not at all" to "extremely", and the numeric scale ranges from 0 to 100. Due to skewness of individual time points; areas under the curve for these ratings across individual time points (0, 10, 20, 30, 40, 50 and 60 min) were compared instead. Possible range of values for the AUC are 0 to 5500.
Measure: Subjective Perception of Morphine Effect - Feel High Time: 60 minutes following injectionDescription: Area under the curve of the subjective perception-time course - Like Drug. Subjective responses as measured by the Drug Effects Questionnaire [DEQ]. The DEQ consists of simple, face-valid, visual analog scale (VAS) questions on which people report their subjective states after ingesting a substance. The analog scale of responses ranges from "not at all" to "extremely", and the numeric scale ranges from 0 to 100. Due to skewness of individual time points; areas under the curve for these ratings across individual time points (0, 10, 20, 30, 40, 50 and 60 min) were compared instead. Possible range of values for the AUC are 0 to 5500.
Measure: Subjective Perception of Morphine Effect - Like Drug Time: 60 minutes following injectionDescription: Area under the curve of the subjective perception-time course - Want More. Subjective responses as measured by the Drug Effects Questionnaire [DEQ]. The DEQ consists of simple, face-valid, visual analog scale (VAS) questions on which people report their subjective states after ingesting a substance. The analog scale of responses ranges from "not at all" to "extremely", and the numeric scale ranges from 0 to 100. Due to skewness of individual time points; areas under the curve for these ratings across individual time points (0, 10, 20, 30, 40, 50 and 60 min) were compared instead. Possible range of values for the AUC are 0 to 5500.
Measure: Subjective Perception of Morphine Effect - Want More Time: 60 minutes following injectionCaesarean delivery under general anaesthesia (GA) carries nowadays still 25% risk of insufficient depth of anaesthesia in a time before the fetus delivery. The reason is the lack of opioid administration. Opioids easily cross placental barrier and negatively influence newborn postpartum adaptation by respiratory depression. Introduction to GA is thus accompanied by exaggerated autonomic stress reaction with hypertension and tachycardia. The use of ultra-short acting opioid remifentanil should suppress stress response in mother without increasing the risk for newborn. There are only a few clinical data available. This study will be the first one systematically studying the influence of remifentanil in pregnant women with hypertension on hemodynamic stability and newborns safety. This study will also identify potential pharmacogenetic factors of individual variability in remifentanil response with respect of drug efficacy and safety in mother and newborn.
Method for assessment of opioid receptor polymorphism (A118G) will be implemented during the first year of the study. --- A118G ---
Description: newborn status (Apgar score + acid-base measurement from umbilical cord, clinical evaluation and scoring)
Measure: Newborn adaptation after delivery Time: 10 min after deliveryDescription: BIS (continuous bispectral EEG analysis)
Measure: Depth of anesthesia Time: 30 min from induction to general anesthesiaDescription: Changes in major hemodynamic parameters (Systolic Blood Pressure, Heart Rate, ST analysis)
Measure: Hemodynamic response to intubation and beginning of Cesarean operation Time: 30 min from induction to general anesthesiaA total of at least 48 healthy subjects with a history of social drinking will be recruited into this single-centre, randomized, double-blind, cross-over study. Subjects will be genetically stratified to result in equal numbers of A118G 'AA' homozygotes (n=24) and A118G 'G' carriers (n=24). Subjects will participate in all three treatment periods and will be randomized to receive each of the following for 5 days: Treatment A: Placebo, Treatment B: Naltrexone (NTX) 50 mg once daily (25 mg once daily for the first two days) and Treatment C: GSK1521498 10 mg once daily. A washout period will be of at least 14 days between treatments. Subjects will return for a follow-up visit 7-10 days after the final treatment session washout period has been completed. Subjects will attend the clinical research unit on days 1, 2, 3, 4 and 5 to monitor safety and tolerability for both drugs. Subjects will attend the clinical unit on days 4 and 5 for a two day assessment, using a series of pharmacodynamic measurements known to be sensitive to the effects of GSK1521498 and/or NTX: Functional brain response to alcohol and food cues; plasma cortisol; hedonic and consummatory eating behaviors; subjective response to an ethanol challenge; experimental pain threshold; and cognitive tests of attention bias towards alcohol and food cues.
A Randomized, Double-blind, Placebo-controlled, Crossover Study to Evaluate the Influence of the A118G Polymorphism in the mu Opioid Receptor Gene (OPRM1) on Effects of GSK1521498 and Naltrexone on Physiological and Behavioural Markers of Brain Function in Healthy Social Drinkers. --- A118G ---
To Evaluate the Influence of the A118G Polymorphism in the mu Opioid Receptor Gene (OPRM1) on Effects of GSK1521498 and Naltrexone on Physiological and Behavioural Markers of Brain Function in Healthy Social Drinkers A total of at least 48 healthy subjects with a history of social drinking will be recruited into this single-centre, randomized, double-blind, cross-over study. --- A118G ---
Subjects will be genetically stratified to result in equal numbers of A118G 'AA' homozygotes (n=24) and A118G 'G' carriers (n=24). --- A118G ---
Subjects will be genetically stratified to result in equal numbers of A118G 'AA' homozygotes (n=24) and A118G 'G' carriers (n=24). --- A118G --- --- A118G ---
To test that the OPRM1 A118G polymorphism modulates the effects of GSK1521498 10 mg on brain reward function and processing. --- A118G ---
Plasma cortisol concentrations will be measured under fasting conditions to test that the OPRM1 A118G polymorphism modulates the effect of GSK1521498 10mg on plasma cortisol. --- A118G ---
Description: To test that the OPRM1 A118G polymorphism modulates the effects of GSK1521498 10 mg on brain reward function and processing
Measure: Brain activation within the reward circuitry in response to consumption of food and alcohol cues, as measured by functional magnetic resonance imaging (fMRI) Time: Day 5 in each treatment periodDescription: Number of subjects with any adverse events during the treatment periods
Measure: Adverse events as a measure of safety and tolerability Time: Throughout the study, from Day 1 to Day 67Description: Systolic and diastolic BP will be measured
Measure: Blood pressure (BP) as a measure of safety and tolerability Time: Screening (Up to 30 days prior to Day 1), Day 1, Day 2, Day 5 in each treatment period and Follow-up visit.Description: 12-lead electrocardiograph (ECG) will be measured
Measure: 12-lead ECG and heart rate as a measure of safety and tolerability Time: Screening (Up to 30 days prior to Day 1), Day 1, Day 2, Day 5 in each treatment period and Follow-up visit.Description: Hematology/Chemistry assessments to be done at screening (fasted) and day 5 for each treatment session (un-fasted).
Measure: Clinical chemistry including liver enzymes and hematology as a measure of safety and tolerability Time: Screening (Up to 30 days prior to Day 1), Day 5 of each of the 3 treatment periods and Follow-up visitDescription: Mood anxiety will be assessed by The Beck Anxiety Inventory (BAI), The Beck Depression Inventory (BDI-II).
Measure: Psychiatric symptom questionnaires-Becks Depression & Anxiety Inventory (BDI-II & BAI) Time: Screening (Up to 30 days prior to Day 1), Day 1 (pre-dose and approximately 4 hours post dose), Day 2 (prior to discharge), Day 3 (prior to discharge), Day 5 (prior to discharge), in each treatment period and Follow-up visitDescription: Suicidality will be assessed by C-SSRS.
Measure: Psychiatric symptom questionnaires- Columbia Suicide Severity Rating Scale (C-SSRS) Time: Screening (Up to 30 days prior to Day 1), Day 1 (pre-dose and approximately 4 hours post dose), Day 2 (prior to discharge), Day 5 (prior to discharge), in each treatment period and Follow-up visitDescription: Mood anxiety and suicidality will be assessed by VAS.
Measure: Psychiatric symptom questionnaires- Bond and Lader Visual Analogue Scales (VAS). Time: Screening (Up to 30 days prior to Day 1), Day 1 (pre-dose and approximately 4 hours post dose), Day 2 (prior to discharge), Day 3 (prior to discharge), Day 4 (prior to discharge), Day 5 (prior to discharge), in each treatment period and Follow-up visitDescription: CANTAB attention tasks comprising of Simple Reaction Time (SRT), Choice Reaction Time (CRT) and Rapid Visual Information Processing (RVP) will be done to measure the power of attention
Measure: Computerized tests of reaction time (CANTAB) Time: Approximately 1 hour pre-dose on Day 1 and approximately 4 hours post dose on Day 1, Day 2 and Day 5 in each treatment periodDescription: Plasma cortisol concentrations will be measured under fasting conditions to test that the OPRM1 A118G polymorphism modulates the effect of GSK1521498 10mg on plasma cortisol
Measure: Plasma cortisol concentrations Time: Day 1 and Day 5 pre-dose, at approximately the same time, and on Day 5 post dose in each treatment period.Description: Pressure pain threshold and sensitivity will be measured in response to cutaneous pressure. Pressure pain thresholds and tolerance will be assessed at two tender points (left and right trapezius points, as defined by American College of Rheumatology)
Measure: Pressure pain threshold and sensitivity Time: Day 4 in each treatment period.Description: Eating behaviour will be assessed by ad libitum snacking , Menu choices and ad libitum intake of test buffet meals, Appetite Visual Analogue Scales (A-VAS) and Binge Eating Scale (BES)
Measure: Consummatory eating behaviour Time: Day 5 in each treatment period.Description: Response to sweet and high fat samples (tasting sweetened dairy products), will be performed in a fasted state. The Hedonic 9 point preference scale and Sensory Stimuli Scale will be performed after each sample has been tasted.
Measure: Hedonic taste preference Time: Day 5 in each treatment period.Description: It will be measured using self-report questionnaires Biphasic alcohol effects scale (BAES), Subjective High Assessment Scale (SHAS), Profile of Mood States (POMS-B), and Alcohol Rating Scale (ARS)
Measure: Subjective responses to intravenous doses of ethanol Time: Day 4 in each treatment periodDescription: The comparison will be done for the all efficacy endpoints as mentioned earlier which include Plasma cortisol; fMRI and cognitive measures of reward processing; pain threshold; hedonic and consummatory eating behaviour, subjective response to ethanol
Measure: To compare the placebo-controlled effects of GSK1521498 10 mg to the placebo-controlled effects of NTX 50 mg Time: Day 5 in each treatment period.This is a multi-center prospective comparative cohort study examining the safety, efficacy, pharmacokinetics, and pharmacogenomics of naltrexone for pregnant women with opioid use disorder. Pregnancy, delivery, and maternal and infant outcomes to 12 months post-delivery will be examined and compared with a cohort treated with buprenorphine/naloxone.
Mothers will be genotyped for the ORPM1 A118G SNP at 36 weeks gestation from a blood sample to see if genotype is associated with treatment response and risk for relapse.. Maternal saliva OPRM1 methylation status. --- A118G ---
Description: Maternal relapse of illicit and/or unprescribed drug use from maternal/provider report and or from urine toxicology testing at any point during the pregnancy and up to 12 months after delivery
Measure: Maternal drug use relapse Time: up to 12 months post-deliveryDescription: Number and type of side effects or adverse events such as injection site reactions, gastrointestinal upset, syncope, headaches, or dizziness reported by participant or provider
Measure: Naltrexone side effects or adverse events Time: up to 12 months post-deliveryDescription: Mean fetal heart rate (FHR), FHR variability, and episodic accelerations of FHR (count) from each routine care non-stress test (NST) in the third trimesters.
Measure: Fetal heart rate monitoring from NST Time: 27- 41 weeks gestationDescription: The biophysical profile uses electronic fetal heart rate monitoring to examine the fetus. There are five components measured during the biophysical examination (fetal breathing movements, gross body movement, fetal tone, amninotic fluid volume and whether the NST is reactive or nonreactive. A score of 2 points is given for each component The points are then added for a possible maximum score of 10. The test is continued until all criteria are met or 30 minutes have elapsed. HIgher scores are more favorable.
Measure: Biophysical profile score calculated from NST Time: 27 - 41 weeks gestationDescription: Hair cortisol levels will be obtained from maternal hair samples obtained at birth and 4 weeks after delivery, and compared between the naltrexone and buprenorphine groups. Higher hair cortisol levels in the mother may indicate exposure to higher levels of stress over the preceding 3 months period.
Measure: Maternal hair cortisol levels Time: Birth and 4 weeks post-deliveryDescription: Hair cortisol levels will be obtained from infant hair samples obtained at birth and 4 weeks after delivery, and compared between the naltrexone and buprenorphine groups. Higher hair cortisol levels in the infant may indicate exposure to higher levels of stress over the preceding 3 months period.
Measure: Infant hair cortisol levels Time: Birth and 4 weeks post-deliveryDescription: Fetal growth will be assessed at the time of routine growth scans at 18-20, and then q4 weeks until delivery. Fetal size will be compared to Intergrowth standards to produce z-scores and SGA (<10%ile) for averaged 2nd and 3rd trimester measurements.
Measure: Fetal growth based on ultrasound measurements Time: 18 - 41 weeks gestationDescription: Fetal, placental, or amniotic fluid anomalies identified during routine ultrasounds in the second and third trimesters will be documented.
Measure: Congenital fetal anomalies by ultrasound Time: 18 - 41 weeks gestationDescription: Infants will be routinely assessed at birth during the physical examination for any external anomalies.
Measure: Congenital anomalies by physical examination Time: BirthDescription: NAS diagnosis will be based on opioid withdrawal signs and symptoms in the infant after delivery as assessed by NAS withdrawal scores (either the Finnegan score or the via the ESC (Eat, Sleep, Console) assessment tool. The Finnegan scale assesses 21 of the most common signs of neonatal drug withdrawal syndrome and is scored on the basis of pathological significance and severity of the adverse symptoms, which sometimes requires pharmacological treatment. Measurements are performed every 4 hours, typically with 2-3 consecutive scores that are equal to or greater than 8, or 1-2 scores of 12 or greater, pharmacologic treatment for withdrawal is started. For the ESC assessment, clinicians assess whether or not the infant has poor feeding, is unable to sleep for at least 1 hour after feeding, and is consolable (rating of 1-3) due to symptoms of opioid withdrawal. Poor feeding, sleeping, or consolability triggers a huddle and possible start of pharmacologic treatment.
Measure: Diagnosis of Neonatal Abstinence Syndrome (NAS) Time: From birth to 30 daysDescription: The need for pharmacologic treatment will be recorded as Y/N as will the need for adjunctive agents.
Measure: Infant need for pharmacologic treatment Time: From birth to 30 daysDescription: The need for adjunctive agents will be recorded as Y/N
Measure: Infant need for adjunctive agent Time: From birth to 30 daysDescription: The total mgs of morphine/methadone needed for pharmacologic treatment and the total number of total opioid treatment days will be obtained from the birth hospitalization medical records.
Measure: Infant opioid replacement pharmacologic treatment Time: From birth to 30 daysDescription: Number of continuous days infant hospitalized after birth.
Measure: Infant birth hospitalization length of stay Time: From birth to 30 daysDescription: Growth parameters of infant weight in grams will be obtained by the clinician at birth, 4 weeks, and 12 months at each study visit. Percentiles will be calculated.
Measure: Infant weight Time: Birth, 4 weeks, and 12 monthsDescription: Growth parameters of infant length measured by the clinician in cm will be obtained at birth, 4 weeks, and 12 months at each study visit. Percentiles will be calculated.
Measure: Infant length Time: Birth, 4 weeks, and 12 monthsDescription: Growth parameters of infant head circumference in cm will be obtained by the clinician at birth, 4 weeks, and 12 months at each study visit. Percentiles will be calculated.
Measure: Infant head circumference Time: Birth, 4 weeks, and 12 monthsDescription: The NICU Network Neurobehavioral Scale (NNNS) is a comprehensive assessment of both neurologic integrity and behavioral functioning, including signs of stress. It assesses the full range of infant neurobehavioral performance (orientation to auditory and visual stimuli); infant stress (color changes, tremors, startles), neurologic functioning (reflexes, tone); some features of gestational age; self-soothing capacities; states and their organization. The 13 summary scores (i.e., orientation, habituation, hypertonicity, hypotonicity, excitability, arousal, lethargy, non-optimal reflexes, asymmetric reflexes, stress, self-regulation, quality of movement, handling) are typically used to summarize a clinical examination .
Measure: Infant neurobehavior-function assessed by the NNNS Time: 4 weeks of ageDescription: The Bayley III is a standard series of measurements used to assess the development of infants and toddlers, ages 1-42 months. It has 5 scales, 3 administered with child interaction - cognitive, motor, language, and 2 with parent questionnaires- social-emotional, adaptive behavior. A developmental quotient (DQ) is derived from the results.
Measure: Infant neurodevelopment assessed by Bayley III Time: 12 months of ageDescription: Naltrexone levels from maternal blood and plasma will be obtained at regular intervals for pharmacokinetic analysis.
Measure: Pharmacokinetic analysis of maternal naltrexone levels Time: 2nd trimester, 3rd trimester, delivery, 2-4 days after delivery, 4 weeks post-deliveryDescription: Naltrexone levels from infant blood and plasma will be obtained at regular intervals for pharmacokinetic analysis.
Measure: Pharmacokinetic analysis of infant naltrexone levels Time: Delivery, 2-4 days after delivery, 4 weeks post-deliveryDescription: Mothers will have a genome wide methylation profile at 36 weeks gestation from a blood sample.
Measure: Maternal DNA methylation profile Time: 36 weeks gestationDescription: Mothers will be genotyped for the ORPM1 A118G SNP at 36 weeks gestation from a blood sample to see if genotype is associated with treatment response and risk for relapse.
Measure: Mu opioid receptor (OPRM1) gene single nucleotide (SNP) genotype Time: 36 weeks gestationDescription: Mothers will have their OPRM1 methylation status examined via saliva samples to see if OPRM1 methylation is altered by maternal treatment.
Measure: Maternal saliva OPRM1 methylation status Time: Birth, 4 weeks postpartumDescription: Infants will have their OPRM1 methylation status examined via saliva samples at to see if OPRM1 methylation is altered by maternal treatment.
Measure: Infant saliva OPRM1 methylation status Time: Birth, 4 weeks postpartumDescription: Naltrexone levels will be measured from the breast milk of breastfeeding mothers who are on naltrexone.
Measure: Breast milk naltrexone level Time: 4 weeks postpartumDescription: Length of time mother continues medication assisted treatment (MAT) from provider or participant report
Measure: Retention in addiction treatment Time: up to 12 months post-deliveryDescription: Data on maternal healthcare utilization, including emergency room visits, primary care visits, and re-hospitalizations will be collected.
Measure: Maternal healthcare utilization Time: up to 12 months post-deliveryDescription: Data on infant healthcare utilization, including emergency room visits, primary care visits, and re-hospitalizations will be collected.
Measure: Infant healthcare utilization Time: up to 12 months post-deliveryThis study will elucidate the pharmacogenetic effects of the Asn40Asp SNP of the OPRM1 gene on biobehavioral and neural markers of response to naltrexone in individuals of East Asian descent, an ethnic group most likely to express the positive predictive allele.
Inclusion Criteria: - current (i.e., past month) alcohol dependence - East Asian ethnicity (i.e., Chinese, Korean, or Japanese) - Prospective genotyping for the A118G SNP of the mu opioid receptor (OPRM1) gene to allow for balanced groups on all three genotypes (AA, AG, GG) Exclusion Criteria: - lifetime DSM-IV of drug dependence (other than alcohol or nicotine) - current use of psychoactive drugs as determined by self-reports and verified using toxicology testing - lifetime diagnosis of bipolar disorder or any psychotic disorder - contraindications to an MRI scan (including left handedness) Inclusion Criteria: - current (i.e., past month) alcohol dependence - East Asian ethnicity (i.e., Chinese, Korean, or Japanese) - Prospective genotyping for the A118G SNP of the mu opioid receptor (OPRM1) gene to allow for balanced groups on all three genotypes (AA, AG, GG) Exclusion Criteria: - lifetime DSM-IV of drug dependence (other than alcohol or nicotine) - current use of psychoactive drugs as determined by self-reports and verified using toxicology testing - lifetime diagnosis of bipolar disorder or any psychotic disorder - contraindications to an MRI scan (including left handedness) Alcohol Use Disorder Alcohol Drinking Alcoholism Recent pharmacogenetic studies have advanced the gene coding for µ-opioid receptors (OPRM1) gene as a potential moderator of responses to naltrexone. --- A118G ---
Inclusion Criteria: - current (i.e., past month) alcohol dependence - East Asian ethnicity (i.e., Chinese, Korean, or Japanese) - Prospective genotyping for the A118G SNP of the mu opioid receptor (OPRM1) gene to allow for balanced groups on all three genotypes (AA, AG, GG) Exclusion Criteria: - lifetime DSM-IV of drug dependence (other than alcohol or nicotine) - current use of psychoactive drugs as determined by self-reports and verified using toxicology testing - lifetime diagnosis of bipolar disorder or any psychotic disorder - contraindications to an MRI scan (including left handedness) Inclusion Criteria: - current (i.e., past month) alcohol dependence - East Asian ethnicity (i.e., Chinese, Korean, or Japanese) - Prospective genotyping for the A118G SNP of the mu opioid receptor (OPRM1) gene to allow for balanced groups on all three genotypes (AA, AG, GG) Exclusion Criteria: - lifetime DSM-IV of drug dependence (other than alcohol or nicotine) - current use of psychoactive drugs as determined by self-reports and verified using toxicology testing - lifetime diagnosis of bipolar disorder or any psychotic disorder - contraindications to an MRI scan (including left handedness) Alcohol Use Disorder Alcohol Drinking Alcoholism Recent pharmacogenetic studies have advanced the gene coding for µ-opioid receptors (OPRM1) gene as a potential moderator of responses to naltrexone. --- A118G --- --- A118G ---
Description: Biphasic Alcohol Effects Scale (BAES) Alcohol Urge Questionnaire (AUQ)
Measure: Subjective Effects of Alcohol Time: During the alcohol administration and observation period which is expected to last a total of 4 hoursDescription: Alcohol taste cues task for fMRI
Measure: Neural response to alcohol cues Time: During the alcohol cue exposure fMRI paradigm which is expected to last 45 minutesDescription: Time to first drink and total number of drinks are the primary outcome variables for the alcohol self-administration task
Measure: Alcohol self-administration Time: Alcohol self-administration period will last 2 hoursThe purpose of this study is to determine if non-invasive salivary genetic screening of breastfeeding mothers taking codeine will allow for the successful identification of mother-infant pairs susceptible to adverse events and to prevent these adverse events by personalizing their medication to their genetics.
Incidence of the A118G polymorphism in the opioid receptor 1 (OPRM1) which has been associated with reduced response to morphine treatment.. null. --- A118G ---
Breathlessness is an overwhelming symptom affecting tens of thousands of Australians every day. For many people, it persists even when all the underlying causes have been optimally managed (chronic breathlessness). In these circumstances, it often occurs at rest or with minimal exertion. Evidence from a number of clinical studies suggests that a small, regular dose of morphine helps to reduce safely the sensation of breathlessness. However, it is not well established which patients derive more benefit and what is the net clinical effect of this treatment (weighing benefits and harms). This is a phase III, multi-site, randomised, double-blind, placebo-controlled trial with patients with chronic obstructive pulmonary disease (COPD) and severe chronic breathlessness which will explore several important questions: - Are regular, low doses of morphine at four possible doses over 3 weeks more effective than placebo at improving breathlessness? - Does increasing the dose in people who already are experiencing some benefit provide even greater reduction in worst breathlessness? - Does the medication have any effect on daily activity and quality of life? - What are the common or serious side effects of this intervention? - Does the benefit from the medication outweigh the side effects it produces? - Are there specific characteristics of people who are more likely to receive benefit from extended release morphine? Participants will receive once daily extended release morphine (plus laxative, docusate with senna), or placebo (placebo laxative) in addition to their usual medication for up to 3 weeks at increasing doses. Participants will have a medical interview and physical examination to collect some general health information, and baseline measurements including; daily activity, symptoms, and quality of life. A small amount of blood may be required to check eligibility. Further blood samples may be taken at week 1 and 3 to enable testing on how individuals respond to opioids, further consent will be obtained for these samples. Data on benefits, side effects, and medical care will be collected during comprehensive weekly visits. Participants will also fill out a simple diary twice daily for weeks one to three of the study, and for one day each week during an optional 6 month extension stage. The outcome of this study may enable better management of symptoms and activity in people COPD with medicines that are shown to be effective and safe.
Pharmacogenetic opioid profile - Mu receptor (A118G) polymorphism. --- A118G ---
The baseline blood samples will be analysed to detect the presence of Mu receptor (A118G) polymorphism. --- A118G ---
Description: Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, Stage1-3 (daily diary) and Stage 4 (weekly diary). The primary endpoint is: The difference between morphine sulphate 8mg and placebo (end of week1) The difference of morphine sulphate 16 mg and placebo (end of week 1)
Measure: Change from baseline worst breathlessness intensity over the previous 24 hours Time: Week 1Description: Difference from the baseline in the number of steps per day measured using the Fitbit(Charge HR). Measured at baseline, end of week 1, and end of week 3. The primary endpoint is: The difference between morphine sulphate 8mg and placebo (end of week 1) The difference between morphine sulphate 16mg and placebo (end of week 1) Comparison between baseline and end of week 3
Measure: Change from the baseline in the number of steps per day Time: Week 3Description: Measured at baseline and at the weekly visit for the randomisation phase, and then at the study exit in order to assess the theoretical risk of opioids worsening respiratory failure. Stages 1-4.
Measure: Change from baseline end-tidal carbon dioxide Time: Up to week 15Description: Measured at baseline and at the weekly visit for the randomisation phase, and then at the study exit in order to assess the theoretical risk of opioids worsening respiratory failure. Concomitant use of oxygen will be recorded. Stages 1-4.
Measure: Change from baseline pulse oximetry Time: Up to week 15Description: Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).
Measure: Change from baseline intensity of breathlessness "average" Time: Up to week 15Description: Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).
Measure: Change from baseline distress from breathlessness over the previous 24 hours Time: Up to week 15Description: Chronic Respiratory Questionnaire - Dyspnoea and Mastery Subscales. Baseline and end of Weeks 1-3.
Measure: Change from baseline perceived-impact of breathlessness Time: Up to week 3Description: Rated on the Modified Medical Research Council Breathlessness Scale (mMRC). Measured at baseline and at the conclusion of the study.
Measure: Change from baseline functional impact of breathlessness Time: Up to week 15Description: Measured using the Fitbit(Charge HR). Assessed at baseline (2 days), weeks 1 and 3.
Measure: Change from baseline sleep minutes Time: Week 3Description: Measured using the Fitbit(Charge HR). Given in number of movements per night (e.g. rolling over). Assessed at baseline (2 days), weeks 1 and 3.
Measure: Change from baseline sleep activity Time: Week 3Description: Measured using the Fitbit(Charge HR). Difference from baseline in the number of active minutes per day. Assessed at baseline (2 days), weeks 1 and 3.
Measure: Change from baseline in activity levels Time: Week 3Description: Measured using the Fitbit(Charge HR). Difference from baseline number of calories spent per day. Assessed at baseline (2 days), weeks 1 and 3.
Measure: Change from baseline total energy expenditure Time: Week 3Description: Measured using Australian-modified Karnofsky Performance Status (AKPS). Baseline, Stage1, Stage2, Stage3 and Stage 4.
Measure: Change from baseline performance status Time: Up to week 15Description: Measured using Barthel Index. Baseline and Stage 4.
Measure: Change from baseline activities of daily living Time: Up to week 15Description: Rated on a 4 point Likert scale. Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).
Measure: Change from baseline in sleep quality Time: Up to week 15Description: Thirty (30) participants at the Sydney and Adelaide sites will be invited to undertake a simple, non-invasive home sleep study using the ResMed ApneaLink Plus device. Baseline and Stage3.
Measure: Change from baseline in objective sleep testing Time: Week 3Description: Up to ten (10) participants will also undergo two (baseline and Stage 1) in-laboratory overnight sleep studies in Sydney and Adelaide.
Measure: Change from baseline Polysomnography Time: Week 3Description: Twenty (20) participants in Adelaide and Sydney. Baseline and on day 2 and 7 of the first week in an office-based simulator - AusEd.
Measure: Change from baseline Driving ability Time: Week 3 + 2 daysDescription: The baseline blood samples will be analysed to detect the presence of UGT2B7*2 and *28 polymorphisms.
Measure: Pharmacogenetic opioid profile - Number of participants with UGT2B7*2 and *28 polymorphisms Time: Baseline (1 day)Description: The baseline blood samples will be analysed to detect the presence of P-glycoprotein polymorphism (ABCB1 5SNPs in a haplotype block)
Measure: Pharmacogenetic opioid profile - Number of participants with P-glycoprotein polymorphism (ABCB1 5SNPs in a haplotype block) Time: Baseline (1 day)Description: The baseline blood samples will be analysed to detect the presence of 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism
Measure: Pharmacogenetic opioid profile - Number of participants with 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism Time: Baseline (1 day)Description: The baseline blood samples will be analysed to detect the presence of Mu receptor (A118G) polymorphism
Measure: Pharmacogenetic opioid profile - Mu receptor (A118G) polymorphism Time: Baseline (1 day)Description: In a subset of 55 participants, morphine peak plasma concentrations will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).
Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine Peak Plasma Concentration [Cmax] Time: Week 1Description: In a subset of 55 participants, morphine AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).
Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine Area Under the Curve (AUC) Time: Week 1Description: In a subset of 55 participants, M6G Peak Plasma Concentration will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).
Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-6-glucuronide (M6G) Peak Plasma Concentration [Cmax] Time: Week 1Description: In a subset of 55 participants, M6G AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).
Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-6-glucuronide (M6G) Area Under the Curve (AUC) Time: Week 1Description: In a subset of 55 participants, M3G Peak Plasma Concentration will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).
Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-3-glucuronide (M3G) Peak Plasma Concentration [Cmax] Time: Week 1Description: In a subset of 55 participants, M3G AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).
Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-3-glucuronide (M3G) Area Under the Curve (AUC) Time: Week 1Description: Baseline and study completion. To explore whether longer term morphine treatment is associated with decreased levels of testosterone.
Measure: Change from baseline serum testosterone level Time: Week 15Description: Rated on a Lickert Scale. Baseline, weeks 1-3 (daily diary), Stage 4 (weekly diary): Includes constipation, anxiety, appetite, nausea, vomiting, drowsiness, difficulty thinking clearly, problems passing urine, itch, other symptoms.
Measure: Adverse Effects Time: Up to 15 weeksDescription: Measured using the Edmonton Symptoms Assessment Scale (ESAS)
Measure: Change from baseline in concurrent symptoms Time: Up to 15 weeksDescription: Rated using the Hospital Anxiety and Depression Scale (HADS). At baseline, completion of randomization stage and study exit.
Measure: Change from the baseline anxiety and depression Time: Up to Week 15Description: Participant-rated 7 point scale of the perception of their change, specifically their improvement since the commencement of the study. Measured at the end of Stages 1-3 and conclusion.
Measure: Change in baseline global impression of change Time: Up to 15 weeksDescription: Measured with EQ-5D-5L questionnaire. Baseline, Stages 1-3, Stage 4, conclusion.
Measure: Change from baseline health-related quality of life Time: Up to 15 weeksDescription: Measured with the COPD Assessment Test (CAT) Baseline, Stages 1-3, Stage 4 and conclusion.
Measure: Change from baseline health-status in COPD Time: Week 3Description: Asked at the end of week 1 and at the conclusion/drop-out of the study. A 3-point Likert scale will be used.
Measure: Blinded-patient preference to continue the treatment [3-point Likert Scale] Time: Up to week 15Description: Scored using the Zarit Burden Interview (ZBI) 12 item short-form questionnaire. Baseline, end of weeks 1-3, stage 4.
Measure: Change from baseline caregiver Impact Time: Up to week 15Description: From randomisation to 28 days post treatment or death (whichever is the shorter period). Estimated based on all health-care contacts including length of hospitalizations, emergency department visits, DRG codes, community health visits, GP and community nurse visits, outpatient visits and date of death. These participant level data allow within trial modeling using bootstrapping methods of replicates for costs and consequences of alternative strategies, allowing for covariance between costs and effects. Incremental net monetary benefit and cost-effectiveness acceptability curves will be estimated at potential threshold values for an additional responder.
Measure: Economic Evaluation - Cost per responder Time: Up to week 4Description: Evaluation using the Subjective Opioid Withdrawal Scale (SOWS) for 3 consecutive days. After the completion of the study (Weeks 1-15).
Measure: Opioid Withdrawal Time: Up to week 15 + 3 daysA substantial body of evidence implicates the endogenous opioid system, and the mu opioid receptor (MOR) in particular, in the reinforcing effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the mu opioid receptor gene (OPRM1 Asp40) is associated with the ability to quit smoking, as well as nicotine reward and withdrawal symptoms. However, the precise mechanism through which this SNP influences nicotine dependence remains unresolved. This positron emission tomography (PET) study will examine whether this OPRM1 SNP alters MOR binding in response to nicotine in human smokers. Specifically, we will use [11 C]carfentanil PET imaging to assess the effects of intravenous (IV) nicotine versus saline (within-subject) on MOR binding potential in 24 chronic smokers genotyped prospectively and stratified by OPRM1 genotype.
Functional Characterization of OPRM1 A118G in Nicotine Dependence: IV Nicotine Study. --- A118G ---
Using theTEMA (test system for development of medications for alcoholism) it can be shown, that naltrexone administration reduces the willingness to perform work for alcohol infusion in a laboratory experiment.
Secondary objectives: - administration of naltrexone in comparison to placebo leads to a reduction of alcohol craving and real-life drinking - administration of naltrexone in comparison to placebo leads to reduction of the CDT-Level - administration of naltrexone in comparison to placebo leads to a change in perception of subjective alcohol effects - the effectiveness of naltrexone can be predicted by the A118G polymorphism of the OPRM1 - administration of naltrexone changes the baseline and alcohol-induced ability of motor inhibition - administration of naltrexone changes the baseline and alcohol-induced regional cerebral perfusion - administration of naltrexone changes the baseline and alcohol-induced cerebral resting state activity - changes of alcohol effects to the brain activity induced by naltrexone in comparison to placebo correlate with effects of naltrexone on the willingness to work for alcohol self-administration --- A118G ---
Description: Difference of cumulative number of work sets for alcohol in the "constant attention task" between first measurement (without medication) and second measurement (with medication)
Measure: Difference CAT Trials alcohol Time: one yearDescription: Difference of cumulative number of work sets for sodium chloride solution in the "constant attention task" between first measurement (without medication) and second measurement (with medication)
Measure: Difference CAT Trials sodium chloride solution Time: one yearDescription: Difference of the "break point" in the "progressive work" schedule for the work for alcohol between first measurement (without medication) and second measurement (with medication). The "break point" is the number of the last alcohol request before subjects stop to work for more alcohol.
Measure: break Point alcohol Time: one yearDescription: Maximal achieved blood alcohol concentration (BAC) in alcohol self-administration between first measurement (without medication) and second measurement (with medication)
Measure: max. BAC Time: one yearDescription: Drinking habits measured with Timeline Follow-back Interview over 45 days before study start (measured at screening) and over the entire study duration (between screening and the last day of medicinal product intake, ascertained at visit 5): drinking days, amount of alcohol per drinking day and number of days with alcohol consumption over 60 g (men) or 48 g (women)
Measure: Drinking habits Time: one yearDescription: CDT - level: (carbohydrate-deficient transferrin), measured at visit 1 and visit 5
Measure: CDT - level Time: one yearDescription: Alcohol craving in daily routine (OCD - scale) measured at visit 1 and visit 4
Measure: alcohol craving Time: one yearDescription: Difference in subjective alcohol effects between first measurement (without medication) and second measurement (with medication), measured with visual analogue scales ("Quizzer") before, during and after the alcohol infusion
Measure: subjective alcohol effects Time: one yearDescription: Capacity for motor impulse control during infusion of physiologic saline solution or alcohol as NIMPs (single-blinded), measured with the counting stroop task (in Verum and placebo group) at visit 3 and 4
Measure: motor impulse control Time: one yearDescription: Regional cerebral perfusion in ml/100 g tissue per Minute during infusion of sodium chloride solution or alcohol as NIMPs (single-blinded), measured with arterial spin labeling (ASL) under verum or placebo condition at visit 3 and 4
Measure: cerebral blood flow (CBF) Time: one yearDescription: Cerebral resting state activity during infusion of sodium chloride solution or alcohol as NIMPs (single-blinded), measured with BOLD fMRI (in Verum and placebo group) at visit 3 and 4
Measure: Cerebral resting state activity Time: one yearDescription: Medical survey concerning occurring adverse events at visit 1 to 5
Measure: adverse events Time: one yearDescription: ALAT (alanine aminotransferase) in µmol/ s*l before inclusion (screening visit), at visit 4 and after finishing all study relating interventions (visit 5)
Measure: ALAT Time: one yearDescription: ASAT (aspartate aminotransferase) in µmol/ s*l before inclusion (screening visit), at visit 4 and after finishing all study relating interventions (visit 5)
Measure: ASAT Time: one yearDescription: Gamma-GT in µmol/ s*l before inclusion (screening visit) and after finishing all study relating interventions (visit 5)
Measure: Gamma-GT Time: one yearDescription: standard blood cell count before inclusion (screening visit), at visit 4 and after finishing all study relating interventions (visit 5)
Measure: standard blood cell count Time: one yearDescription: creatinine in µmol/l before inclusion (screening visit)
Measure: creatinine Time: one yearDescription: lipase in µmol/ s*l before inclusion (screening visit) and after finishing all study relating interventions (visit 5)
Measure: lipase Time: one yearDescription: CRP (C-reactive protein) in mg / l before inclusion (screening visit) and after finishing all study relating interventions (visit 5)
Measure: CRP Time: one yearThe purpose of this study is to determine whether methamphetamine-dependent individuals will use less methamphetamine when treated with naltrexone. The study will also investigate whether individuals with the mu opioid receptor gene variant A118G will use less methamphetamine than individuals without A118G.
A Pilot Trial of Naltrexone for Methamphetamine Addiction - Role of the A118G SNP. --- A118G ---
The study will also investigate whether individuals with the mu opioid receptor gene variant A118G will use less methamphetamine than individuals without A118G. --- A118G ---
The study will also investigate whether individuals with the mu opioid receptor gene variant A118G will use less methamphetamine than individuals without A118G. --- A118G --- --- A118G ---
Drug therapy in patients with chronic low back pain is a major challenge for physicians. One of the problems is the lacking knowledge in prediction of drug efficacy in a chosen patient. Usually one of the classes of pain medication is given to patients with a similar clinical picture, although different pain mechanisms may be responsible for this clinical picture. Another reason for variable drug efficacy are genetic polymorphisms, this may be the reason why an unique drug produces different responses (from a lacking analgesic effect up to excessive effect or side-effects. Quantitative sensory testing is a method that documents alterations in the pain perception system. Linking genetic polymorphisms to quantitative sensory testing may give us a tool for anticipation of drug efficacy.
Methods Quantitative sensory testing: Heat pain threshold and tolerance, Ice water testing with central modulation of nociceptive input (DNIC), electrical pain detection and temporal summation (skin probe), pressure algometry with pain detection and threshold Drugs investigated: Imipramine, Oxycodone, Clobazam Blood samples: pharmacogenetics: Cytochrome variants CYP2D6, CYP2C19, CYP3A4, COMT haplotypes, CGH-1 variants, A118G of mu opioid receptor gene variants pharmacokinetics: kinetics of imipramine and desipramine --- A118G ---
The present clinical trial randomized will be to assess the link between the different haplotypes of CYP2C8 and CYP2C9 genes and the clinical efficacy of ibuprofen after lower third molar extractions. Onset, duration of postoperative analgesia, duration of anesthetic action on soft tissues, intraoperative bleeding, hemodynamic parameters, postoperative mouth opening and wound healing at the 7th postoperative day were evaluated. For this purpose, 200 healthy volunteers underwent removal of one lower third molar, under local anesthesia with articaine 4% (1:200,000 adrenaline) will be genotyped and phenotyped for these genes and their postoperative records with all data collected will be compared with the haplotypes found in the Brazilian population.
We will evaluate also the relationship between the different haplotypes of OPRM1 gene (SNP A118G), the salivary concentrations of pro-inflammatory cytokines (IL-2, IL-4, IL-6, IL-10 and TNF-±), and preoperative conditioned pain modulation. --- A118G ---
Description: Subjective evaluation of postsurgical pain, which was annotated by the volunteer after the surgery, in a Visual Analogue Scale (VAS, 0-100 mm). The subjective pain evaluations will be performed by patients at the following times after administration of the drug [0, 15, 30 and 45 min, 1; 1.5; 2; 3; 4; 5; 6; 7; 8; 10; 12; 16; 24 hr, 48, 72 and 96 h]. What will be taken into account on this outcome is the representation of the postsurgical pain, that will be noted on the Visual Analogue Scale (in millimeters) in respective moments.
Measure: Evaluation of changes in the postsurgical pain during the first 24 hours until 96 hours after the procedure Time: Seventh postoperative dayDescription: Quality of anesthesia during surgery based on a category 3point scale: 1) the patient reported no discomfort; 2) the patient reported discomfort, without the need to supplement the anesthesia; 3) reported some discomfort by the patient, requiring anesthesia complementation. Intraoral bleeding that will be evaluated by the surgeon according to a 3point scale (1: minimal, 2: normal and 3: Maximum), immediately after the following steps: injection of the first cartridge anesthesia, incision, mucoperiosteal detachment, osteotomies, tooth section, extraction, cleaning and suturing.
Measure: Quality of anesthesia Time: During the surgical procedureDescription: Intraoperative bleeding, rated by the surgeon according to a 3 point category rating scale (1 minimal bleeding; 2 normal bleeding; 3 excessive bleeding) (SISK, 1986), immediately after the following steps: injection of the first cartridge of articaine, tissue incision, flap reflection, bone removal (when this procedure was necessary), tooth extraction, cleaning of the operated site, and completion of suturing.
Measure: Intraoperative bleeding during the surgeries steps Time: During the surgical procedureDescription: Systolic blood pressure, diastolic, and mean to be verified and recorded at surgical moments previously described (injection of the first cartridge anesthesia, incision, mucoperiosteal detachment, osteotomies, tooth section, extraction, cleaning and suturing), carried out with the aid of a system for monitoring hemodynamic parameters.
Measure: Blood pressure variability during the surgeries steps Time: During the surgical procedureDescription: Heart rate to be verified and recorded surgical at moments described above, carried out with the aid of a system for monitoring hemodynamic parameters.
Measure: Heart rate variability during the surgeries steps Time: During the surgical procedureDescription: Oxygen saturation to be verified and recorded at surgical moments described above, carried out with the aid of a system for monitoring hemodynamic parameters.
Measure: Oxygen saturation variability during the surgeries steps Time: During the surgical procedureDescription: Subjective evaluation of postsurgical pain at the moment of the rescue medication consumption which was annotated by the volunteer after the surgery, in a Visual Analogue Scale (VAS, 0-100 mm).
Measure: Subjective evaluation of postsurgical pain at the moment of the rescue medication utilization Time: Seventh postoperative dayDescription: Mouth opening (mm) between the mesial-incisal corners of the upper and lower right central incisors at maximum opening of the jaws was measured and recorded before the surgery and during the second and seventh postoperative days.
Measure: Postoperative mouth opening Time: Second and Seventh postoperative daysDescription: Will only be considered those surgeries in which there is no difference in the duration time of the procedure between the patients. This time count will be started after the administration of the first local anesthetic. Unit of mesure used will be hours.
Measure: Onset and duration of surgery after administration of local anesthetic Time: During the surgeryDescription: Will be considered as adverse reactions: gastrointestinal irritation, nausea, vomiting, bleeding, allergy, headache, dizziness, drowsiness or any other type of reaction presented after surgery.
Measure: Incidence, type and severity of adverse reactions after the surgery Time: Seventh postoperative dayDescription: The total amount of rescue medication that was used by the patient during the postoperative period (Acetominophen- 750 mg) will be analyzed.
Measure: Total amount of rescue medication Time: Seventh postoperative dayDescription: It will apply the method used by Ustun et al. (2003), which takes into account the sum of the following measures (obtained with flexible tape measure): A) distance between the lateral corner of the eye and the gonion, B) away from the tragus corner of the mouth and C) away from the tragus to the soft tissue of pogonion. Preoperative sum of three measures will be considered as the baseline that way. The difference between the values obtained in the postoperative period and baseline indicate the facial edema in the 2nd and 7th days.
Measure: Measurement the facial edema Time: On the second day after surgery and on the seventh day after surgery.Background: Drugs like nalmefene interfere with opioid receptors. This might reduce drinking. The gene OPRM1 determines opioid receptor functions. Researchers want to see if nalmefene affects people s responses to alcohol cues. They also want to compare how nalmefene affects people with different forms of OPRM1. Objectives: To test nalmefene s effects on alcohol self-infusion and responses to alcohol cues. To test the role of different forms of OPRM1 on these effects. Eligibility: Healthy heavy drinkers ages 21 60: Women: over 15 drinks weekly Men: over 20 drinks weekly Design: Participants will be screened with: Medical history Physical exam Heart, blood, and urine tests Questionnaires Participants will have three 10-hour visits and one 2-hour follow-up visit. They will take a taxi. Visits are about 1 week apart. Before visits, participants cannot drink alcohol for 1 day or take medicine for 3 days. All study visits: Questionnaires Heart monitor Two-hour alcohol session: A needle guides a thin plastic tube into a vein in each arm. One tube receives alcohol. The other draws blood. Participants give themselves alcohol by pressing a button on a computer. Relaxing at the center until breath alcohol falls below 0.02 percent, or for 3 hours. Visits 2 and 3: Swallowing nalmefene or placebo. One-hour brain MRI: Participants lie on a table with a coil on their head. They press buttons in response to computer cues. Follow-up visit: participants will discuss their drinking habits.
Genetic variation at the micro-opioid receptor gene locus, OPRM1, specifically the A118G polymorphism, is associated with differential subjective responses to alcohol. --- A118G ---
Further, the A118G polymorphism has been shown to moderate the effect of opioid receptor modulators on alcohol consumption. --- A118G ---
However, the role of A118G on nalmefene s effectivenes, and the neural substrates underlying nalmefene s therapeutic effect remain to be explored in humans. --- A118G ---
Objective: To evaluate the effect of nalmefene on alcohol self-infusion and neural response to alcohol cues in healthy male and female heavy drinkers, and to examine the role of the OPRM1 A118G polymorphism on this effect. --- A118G ---
Background: - Tobacco smoking is one of the most preventable causes of morbidity and mortality in the world, but the addictive property of nicotine is such that fewer than 10 percent of people who attempt to quit smoking remain tobacco-free after 1 year. Researchers are studying the addictive properties of nicotine in an attempt to develop more successful medication therapies for smoking cessation. - Nicotine acts on chemical receptors in the brain, including opioid receptors that affect the perception of pain. Repeated nicotine administration can cause adaptations in the brain s opioid receptors, which heightens the addictive properties of nicotine and increases the likelihood and severity of withdrawal symptoms associated with smoking cessation. Researchers are interested in using positron emission tomography (PET) scanning to study brain chemical responses to nicotine in current smokers and nonsmokers. Objectives: - To study brain chemical activity related to cigarette smoking and nicotine administration. - To compare the brain chemical activity of current daily smokers with that of nonsmokers. Eligibility: - Individuals 21 to 50 years of age who are either current smokers (10 to 25 cigarettes daily for at least 2 years) or have had some exposure to tobacco but have never smoked regularly (may have had a maximum of 20 cigarettes in their lifetime and none in past year). Design: - Eligible participants will undergo initial medical and psychological screening and neuropsychological testing before beginning the main phase of the study. Participants will be required to abstain from alcohol and drugs (except caffeine, nicotine, and prescription drugs) for 24 hours before each session, and smokers will refrain from smoking after midnight on the night before each session. - Session 1: Participants will answer questions about nicotine craving and withdrawal symptoms, followed by a magnetic resonance imaging (MRI) scan to provide baseline information about brain activity. - Session 2 and 3: Participants will answer questions about nicotine craving and withdrawal symptoms, and then will smoke one cigarette (either active nicotine or placebo). Researchers will document participants consumption of the cigarette. After the cigarette is smoked, participants will have a PET scan. Blood samples will be drawn during the PET session.
Outcome Measures: 1) displacement [(11)C]carfentanil binding, secondary to the release of endorphins by nicotine; 2) upregulation of [(11)C]carfentanil specific binding in smokers compared with nonsmokers; 3) [(11)C]carfentanil specific binding as a function of the mu-opioid receptor A118G polymorphism; and 4) correlation between self-report measures of nicotine effect and [(11)C]carfentanil binding profile. --- A118G ---