Genetic Effects on Dopamine Response to an Opiate
Condition: Polymorphism-Genetic; Pain; Addiction
MeSH terms: Behavior, Addictive
Intervention: Morphine; Placebo
Intervention MeSH terms: Morphine
Phase: Phase 2
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Crossover study - participants receive active and placebo treatments in randomized order.
Masking: Double (Participant, Investigator)
Masking description: Bliniding
Enrollment: 15.0
Sex: Male
Minimum age: 21 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: Opiate Receptor; Genotype; PET Imaging

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Male participants between 21-55 years of age.

               2. Good health as determined by medical history, physical exam, EKG and lab tests.

               3. Current non-smokers or light smokers or e-cigarette users (<20 cig/week) who can
                  easily abstain from smoking or using e-cigarettes for 1-2 days/week.

               4. Current non-drinkers or social drinkers who do not meet past or current DSM IV
                  criteria for alcohol abuse or alcohol dependence.

               5. An equal number of final participants will be of OPRM1 118 A/A vs. 118A/G or
                  118G/G genotype. This means that after the first group (n40) is complete then
                  only participants with the required genotype for the other group will be
                  included.

               6. Prior opiate use, at least one experience with one of the opiates listed in
                  Appendix 1 of the protocol.

               7. Comprehension/fluency with English Language.

        EXCLUSION CRITERIA:<TAB>

          1. Current or prior history of any significant disease, including cardiovascular,
             respiratory, gastrointestinal, hepatic, renal, endocrine, or reproductive disorders,
             or a positive hepatitis or HIV test at screening, disorders that could make
             administration of an opiate more risky (e.g., asthma, COPD, sleep apnea, or other
             breathing disorders; liver or kidney disease; thyroid disorder; trouble swallowing, or
             a blockage in the digestive tract (stomach or intestines); neurologic disorders (e.g.,
             a history of head injury or brain tumor, epilepsy or other seizure disorder, CVA,
             migraine in treatment, etc.); low blood pressure; hypertension; neuromuscular
             disorder; gallbladder disease; Addison's disease or other adrenal gland disorders;
             enlarged prostate, urination problems)

          2. Current Axis-I psychiatric illness as determined by the Structured Clinical Interview
             for DSM IV disorders (SCID).

          3. Current or prior history of any alcohol or drug dependence as determined by the
             Structured Clinical Interview for DSM IV disorders (SCID).

          4. Positive result on urine screen for illicit drugs.

          5. Medication Use:

               1. Current chronic prescription or over the counter medications or use of
                  prescription or OTC medications known to interact with dopamine receptors within
                  2 weeks of the study

               2. Drugs known to inhibit or induce enzymes that metabolize opiates should not be
                  used for 4 weeks prior to the study. These include chlorzoxazone, isoniazid,
                  metronidazole and disulfiram.

               3. Cough-and-cold preparations that contain anti-histamines or opiate pain medicines
                  will be withheld for at least 72 hours prior to each study session.

               4. Drugs that may interfere with the BOLD MRI signal within 2 weeks of the study.
                  These include, but may not be limited to: muscle relaxants or respiratory,
                  cardiovascular or anticonvulsant medications

          6. Morbid obesity (BMI >40 kg/m2)

          7. Previous negative effects of opioid administration

          8. Presence of certain implanted devices (cardiac pacemaker or neurostimulator, some
             artificial joints, metal pins, surgical clips or other implanted metal parts), body
             morphology, or claustrophobia. Justification: Implanted devices may increase the risk
             of MRI scanning and/or adversely affect the quality of the data; body morphology may
             prevent optimal positioning in the scanner and thus affect the quality of the data;
             participants with claustrophobia may find the MRI scan too unpleasant and may exhibit
             excess movement that will adversely affect the quality of the data. Assessment
             tool(s): Prospective participants will fill out an MRI screening questionnaire and
             undergo an interview with an MR technologist. Questions concerning suitability for
             scanning will be referred to the Medical Advisory Investigator. Prospective
             participants will be questioned about symptoms of claustrophobia and placed in the
             mock scanner during their first visit to assess for possible difficulty tolerating the
             confinement of the scanner and for ability to fit into the scanner.

          9. Conditions restricting participant's ability to lie flat for up to two hours (such as
             coagulopathies, superficial or deep vein thrombosis, or musculoskeletal
             abnormalities). Justification: PET scanning sessions require participants to lie flat
             on their backs and remain perfectly still for approximately two hours. Therefore,
             conditions that would make that difficult (e.g., chronic back pain, significant
             scoliosis) or dangerous (e.g., familial hypercoagulability syndrome, history of
             thrombosis) will be exclusionary. Assessment tool(s): History and physical examination
             by a qualified IRP clinician, supplemented with a trial of lying in the mock scanner
             to assess comfort.

         10. Head trauma leading to loss of consciousness for more than 5 min or hospitalization

         11. Exposure to ionizing radiation from research studies that, in combination with the
             study tracer, would result in cumulative exposure of >5 rem within the previous 12
             month period

         12. Self-reported and/or observed signs, symptoms, or diagnosis of Raynaud's or Buerger's
             disease (e.g., pain in hands or feet at times of rest, during/following cold exposure
             or stress, any significant color changes in hands or toes). Additionally, medical
             staff will be present to watch for these symptoms during the actual cold pressor test.