Genetic Effects on Dopamine Response to an Opiate

Phase 2

Completed

Conditions: Pain
Addiction
Polymorphism-Genetic

Interventions: Drug: Placebo
Drug: Morphine

Registration Number: NCT01878006

Lead Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Brief Summary: 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.

Detailed Description: Objectives

Mesolimbic dopamine (DA) release is a key signal for drug reward, and endogenous opioids are thought to exert their effects in part by modulating the activity of this system. A functional µ-opioid receptor (OPRM1) A118G single nucleotide polymorphism (SNP) has been associated with increased risk for heroin addiction in some studies. This polymorphism has been shown to confer differential pain sensitivity and to alter the release of DA following an alcohol challenge. 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.

Study Population

Healthy male participants who have had experience with oral prescription analgesics (e.g., Oxycontin, Vicodin, Percocet, oxycodone) will be recruited for the study. These volunteers will be screened to obtain samples of two groups of subjects: 1) persons homozygous for the major 118A allele (118AA genotype); 2) persons carrying one or two copies of the variant 118G allele (118AG or 118GG genotype, hereafter called 118GX). We will recruit up to 120 participants to obtain 40 completers per genotype for the study.

Design

We will compare the response of these groups to a challenge with morphine given intravenously. Participants will receive a standardized IV challenge of morphine (10.0 mg/70 kg over 1 minute; morphine concentration 2 mg/ml). Pre and post injection measures will be made in two areas: 1) subjective response as measured by standardized questionnaires, and 2) measures of physiological response, including pupil response to light, respiratory rate, oxygen saturation and a pain rating from putting a hand in cold water and blood chemistries. In addition, during this visit, participants will wear the AutoSense mobile physiological monitor; parameters measured by AutoSense include respiration rate, heart rate, heart-rate variability, skin conductance, and activity level. The injection will be repeated in all participants in the PET scanner, once with morphine and once with normal saline. Dopamine release will be assessed by determining the difference between the binding potential for \[11C\]raclopride, a positron emitter labeled ligand which binds preferentially to D2 receptors during saline administration and its binding potential during morphine administration.

Outcome measures

We hypothesize that 118GX subjects will have significantly different subjective response to the challenge than 118AA subjects as observed in participants receiving alcohol in a similar study (Ramchandani et al. 2011). However, the genotype effect on the response may be opposite from the effect of genotype on the alcohol response. We also hypothesize that the PET studies with \[11C\]raclopride will show that 118GX subjects have less dopamine release during morphine administration than 118 AA subjects.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 15

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Saline injection
Morphine	Morphine	Morphine injection 10 mg/70kg

Primary Outcome Measures

Name	Time	Method
11C Raclopride Binding Potential in Nucleus Accumbens	90 minutes following injection	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), with cerebellum as the reference region. BPND is computed in units of mCi/ml reflecting the radioactivity (milliCuries or mCi) per unit volume (milliliters or ml) in specific brain regions. 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.
11C Raclopride Binding Potential in Ventral Pallidum	90 minutes following injection	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), with cerebellum as the reference region. BPND is computed in units of mCi/ml reflecting the radioactivity (milliCuries or mCi) per unit volume (milliliters or ml) in specific brain regions. 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.
11C Raclopride Binding Potential in Caudate	90 minutes following injection	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), with cerebellum as the reference region. BPND is computed in units of mCi/ml reflecting the radioactivity (milliCuries or mCi) per unit volume (milliliters or ml) in specific brain regions. 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.
11C Raclopride Binding Potential in Putamen	90 minutes following injection	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), with cerebellum as the reference region. BPND is computed in units of mCi/ml reflecting the radioactivity (milliCuries or mCi) per unit volume (milliliters or ml) in specific brain regions. 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.

Secondary Outcome Measures

Name	Time	Method
Subjective Perception of Morphine Effect - Feel Drug	60 minutes following injection	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 (AUC) for these ratings across individual time points (0, 10, 20, 30, 40, 50 and 60 min) were compared. AUC is computed using the trapezoidal rule and has a range of values from 0 to 5500, where 0 reflects no subjective perception at any time point and 5500 reflects maximal subjective perception (score of 100) at all time points after drug administration.
Subjective Perception of Morphine Effect - Feel High	60 minutes following injection	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 (AUC) for these ratings across individual time points (0, 10, 20, 30, 40, 50 and 60 min) were compared. AUC is computed using the trapezoidal rule and has a range of values from 0 to 5500, where 0 reflects no subjective perception at any time point and 5500 reflects maximal subjective perception (score of 100) at all time points after drug administration.
Subjective Perception of Morphine Effect - Like Drug	60 minutes following injection	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 (AUC) for these ratings across individual time points (0, 10, 20, 30, 40, 50 and 60 min) were compared. AUC is computed using the trapezoidal rule and has a range of values from 0 to 5500, where 0 reflects no subjective perception at any time point and 5500 reflects maximal subjective perception (score of 100) at all time points after drug administration.
Subjective Perception of Morphine Effect - Want More	60 minutes following injection	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 (AUC) for these ratings across individual time points (0, 10, 20, 30, 40, 50 and 60 min) were compared. AUC is computed using the trapezoidal rule and has a range of values from 0 to 5500, where 0 reflects no subjective perception at any time point and 5500 reflects maximal subjective perception (score of 100) at all time points after drug administration.