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Heritability of Opioid Effects: A Twin Study

This study has been completed.
Sponsor:
Collaborator:
SRI International
Information provided by (Responsible Party):
Martin Angst, Stanford University
ClinicalTrials.gov Identifier:
NCT00672438
First received: May 2, 2008
Last updated: June 10, 2016
Last verified: June 2016
  Purpose
Proposed twin study will test to what degree inter-individual differences in pain sensitivity and amount of pain relief in response to opioid therapy are inherited or alternatively, are due to environmental factors. This knowledge is important to guide future studies trying to explain such inter-individual differences. For example, finding that differences are largely due to environmental factors would discourage genomic studies and emphasize epidemiological studies.

Condition Intervention
Pain
Drug: Alfentanil
Other: Saline placebo infusion

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Official Title: Heritability of Opioid Effects: A Twin Study

Resource links provided by NLM:


Further study details as provided by Stanford University:

Primary Outcome Measures:
  • Heat Pain Threshold [ Time Frame: Participants underwent the pain testing measures at training prior to study procedures, at baseline and during each of the infusions. ] [ Designated as safety issue: No ]

    Degrees Centigrade

    Heat pain was induced with a thermal sensory analyzer (TSA-II, Medoc Advanced Medical Systems, Durham, North Carolina). A thermode was placed in contact with skin at the volar forearm. Starting at a comfortable temperature, the thermode temperature was increased at a measured rate. Study participants pushed a button of a hand-held device at the onset of pain at which point the thermode immediately reduced the temperature.


  • Cold Pain Threshold [ Time Frame: Participants underwent the pain testing measures at training prior to study procedures, at baseline and during each of the infusions. ] [ Designated as safety issue: No ]

    Time in seconds

    Sensitivity to cold-pressor pain was tested by asking subjects to immerse their hand up to the wrist in ice water (1-2 C) continuously re-circulated within a 12-L container with the palm of the hand in full contact with the bottom of the container.They were asked to indicate the onset of pain - reported as pain threshold.


  • Cold Pain Tolerance [ Time Frame: Participants underwent the pain testing measures at training prior to study procedures, at baseline and during each of the infusions. ] [ Designated as safety issue: No ]

    Time in seconds

    Sensitivity to cold-pressor pain was tested by asking subjects to immerse their hand up to the wrist in ice water (1-2 C) continuously re-circulated within a 12-L container with the palm of the hand in full contact with the bottom of the container.They were asked to remove their hand from the water bath when it was no longer tolerable - reported as pain tolerance.


  • Respiratory Rate [ Time Frame: Measured throughout the study session ~ 5 hours ] [ Designated as safety issue: No ]
    Breaths per minute counted by direct observation and additionally recorded / external electronic monitoring.

  • Transcutaneous Partial Pressure of Carbon Dioxide [ Time Frame: Measured continuously throughout the study session ~ 5 hours ] [ Designated as safety issue: No ]
    Partial pressure of transcutaneous carbon dioxide (CO2) was measured with aid of a pO2/pCO2-electrode (Perimed Inc., North Royalton, OH) mounted to the anterior chest wall.


Secondary Outcome Measures:
  • Sedation [ Time Frame: The trail making test was performed at training prior to study procedures, at baseline, and during each of the infusions. ] [ Designated as safety issue: No ]
    Sedative opioid effects were assessed with the trail-making test (TMT) (Angst et al., 2004; Oswald and Roth, 1987). The TMT is a paper-and pencil test consisting of 4 different matrices listing numbers 1-90 in a 9 × 10 format. Subsequent numbers are located in neighboring rows or columns. Matrices were allocated randomly. Subjects had to connect numbers 1-90 as quickly as possible and the time to completion was recorded.

  • Average Nausea [ Time Frame: At the end of each infusion stage. 2 times total. ] [ Designated as safety issue: No ]
    At the end of an infusion stage participants were asked to rate the average severity of nausea on a 100-mm visual analog scale (VAS) anchored by the words "not at all" and "as much as possible." This means that the scale is 100mm long where one extreme end of the scale represents "0", and 0 represents no nausea experienced. The other extreme end of the scale represents "100", and 100 represents as much nausea as possible. Participants are asked to indicate what point on that continuum best represents their average experience.

  • Maximum Nausea [ Time Frame: At the end of each infusion stage. 2 times total. ] [ Designated as safety issue: No ]
    At the end of an infusion stage participants were asked to rate the maximum severity of nausea on a 100-mm visual analog scale (VAS) anchored by the words "not at all" and "as much as possible." This means that the scale is 100mm long where one extreme end of the scale represents "0", and 0 represents no nausea experienced. The other extreme end of the scale represents "100", and 100 represents as much nausea as possible. Participants are asked to indicate what point on that continuum best represents their maximum experience of nausea.

  • Average Pruritis [ Time Frame: At the end of each infusion stage. 2 times total. ] [ Designated as safety issue: No ]
    At the end of an infusion stage participants were asked to rate the average severity of pruritis on a 100-mm visual analog scale (VAS) anchored by the words "not at all" and "as much as possible." This means that the scale is 100mm long where one extreme end of the scale represents "0", and 0 represents no pruritis experienced. The other extreme end of the scale represents "100", and 100 represents as much pruritis as possible. Participants are asked to indicate what point on that continuum best represents their average experience of pruritis.

  • Maximum Pruritis [ Time Frame: At the end of each infusion stage. 2 times total. ] [ Designated as safety issue: No ]
    At the end of an infusion stage participants were asked to rate the maximum severity of pruritis on a 100-mm visual analog scale (VAS) anchored by the words "not at all" and "as much as possible." This means that the scale is 100mm long where one extreme end of the scale represents "0", and 0 represents no pruritis experienced. The other extreme end of the scale represents "100", and 100 represents as much pruritis as possible. Participants are asked to indicate what point on that continuum best represents their maximun experience of pruritis.

  • Average Drug Liking [ Time Frame: At the end of each infusion stage. 2 times total. ] [ Designated as safety issue: No ]
    At the end of an infusion stage participants were asked, "How much did you like the drug on average (100-mm VAS, 0 _ "not at all," 100 _ "as much as possible")? The VAS scale is 100mm long where one extreme end of the scale represents "0", and 0 indicates the participant did not like the drug experience. The other extreme end of the scale represents "100", and 100 indicates that the participant liked the drug experience as much as possible. Participants are asked to indicate what point on that continuum best represents the their experience.

  • Maximum Drug Liking [ Time Frame: At the end of each infusion stage. 2 times total. ] [ Designated as safety issue: No ]
    At the end of an infusion stage participants were asked, "What was the maximum that you liked the drug at any moment (VAS)? (100-mm VAS, 0 _ "not at all," 100 _ "as much as possible")? The VAS scale is 100mm long where one extreme end of the scale represents "0", and 0 indicates the participant did not like the drug experience. The other extreme end of the scale represents "100", and 100 indicates that the participant liked the drug experience as much as possible. Participants are asked to indicate what point on that continuum best represents the their experience.

  • Maximum Drug Disliking [ Time Frame: At the end of each infusion stage. 2 times total. ] [ Designated as safety issue: No ]
    At the end of an infusion stage participants were asked, "What was the maximum that you disliked the drug at any moment (VAS)? (100-mm VAS, 0 _ "not at all," 100 _ "as much as possible")? The VAS scale is 100mm long where one extreme end of the scale represents "0", and 0 indicates the participant did not like the drug experience. The other extreme end of the scale represents "100", and 100 indicates that the participant liked the drug experience as much as possible. Participants are asked to indicate what point on that continuum best represents the most they disliked the drug experience.

  • Sedation by Patient Report [ Time Frame: At the end of each infusion stage. 2 times total. ] [ Designated as safety issue: No ]
    Sedation was assessed by measuring cognitive speed and by asking participants to indicate on a 100-mm visual analog scale (VAS) how sedated they felt. This means that the scale is 100mm long where one extreme end of the scale represents "0", and 0 represents no sedation was experienced. The other extreme end of the scale represents "100", and 100 represents as much sedation as possible. Participants are asked to indicate what point on that continuum best represents their experience of sedation.


Enrollment: 242
Study Start Date: May 2008
Study Completion Date: June 2010
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Saline placebo infusion
Subjects will receive an intravenous infusion of normal saline.
Other: Saline placebo infusion
Intravenous infusion of normal saline
Experimental: Alfentanil infusion
Subjects will receive an intravenous infusion of alfentanil.
Drug: Alfentanil
Target controlled intravenous infusion of alfentanil at a plasma concentration of 100ng/ml
Other Name: Alfenta

Detailed Description:

The principal hypothesis to be evaluated is that the degree of analgesia provided by opioids in humans displays substantial familial aggregation, and is, in fact, heritable. These studies will use a classical twin paradigm to determine the role of genetics and the environment in influencing analgesia and a range of other opioid effects.

Specific Aims: (1) Determine the degree to which opioid analgesic responses show familial aggregation and make preliminary estimates of heritability using both a heat and cold pressor pain model, and (2) determine the degree to which non-analgesic opioid responses show familial aggregation and make preliminary estimates of heritability. Side effects such as sedation, nausea, respiratory depression, and pruritus, as well as the positive affective response, a measure of abuse potential, will be monitored. Monozygotic (MZ) and dizygotic (DZ) twin pairs (125 total pairs) will be tested under controlled pain laboratory conditions for their responses to opioid infusion using the complementary pain models while monitoring side effects and additional psychometric indices of mood, sleep, and abuse potential. The selected models provide unique mechanistic information because they involve different peripheral and/or central pain pathways. DNA samples will be collected for zygosity testing and banked for future studies.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:Monozygotic or dizygotic twins ages 18-70

Exclusion Criteria:(1) Clinically relevant systemic diseases such as psychiatric, neurological, and dermatological conditions interfering with the collection and interpretation of study data (2) History of addiction (3) Allergy to study medication (4) Chronic intake of medication potentially interfering with pain processing (except oral contraceptives) (5) Intake of over-the-counter analgesics within the two days prior to study (6) Reynaud's disease (7) Pregnancy (8) Participation in other study within last 30 days (9) Personnel with direct access to addicting drugs

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00672438

Locations
United States, California
Stanford University School of Medicine
Stanford, California, United States, 94305
Sponsors and Collaborators
Martin Angst
SRI International
Investigators
Principal Investigator: Martin S Angst Stanford University
  More Information

Responsible Party: Martin Angst, Professor of Anesthesia, Stanford University
ClinicalTrials.gov Identifier: NCT00672438     History of Changes
Other Study ID Numbers: SU-04212008-1119  13018 
Study First Received: May 2, 2008
Results First Received: May 28, 2013
Last Updated: June 10, 2016
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Alfentanil
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anesthetics, Intravenous
Anesthetics, General
Anesthetics

ClinicalTrials.gov processed this record on December 08, 2016