Heritability of Opioid Effects: A Twin Study

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00672438

Enrollment

242

Registered

2008-05-06

Start date

2008-05-31

Completion date

2010-06-30

Last updated

2017-01-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pain

Brief summary

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.

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.

Interventions

DRUGAlfentanil

Target controlled intravenous infusion of alfentanil at a plasma concentration of 100ng/ml

OTHERSaline placebo infusion

Intravenous infusion of normal saline

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Yes

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

Design outcomes

Primary

Measure	Time frame	Description
Heat Pain Threshold	Participants underwent the pain testing measures at training prior to study procedures, at baseline and during each of the infusions.	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	Participants underwent the pain testing measures at training prior to study procedures, at baseline and during each of the infusions.	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	Participants underwent the pain testing measures at training prior to study procedures, at baseline and during each of the infusions.	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	Measured throughout the study session ~ 5 hours	Breaths per minute counted by direct observation and additionally recorded / external electronic monitoring.
Transcutaneous Partial Pressure of Carbon Dioxide	Measured continuously throughout the study session ~ 5 hours	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

Measure	Time frame	Description
Average Drug Liking	At the end of each infusion stage. 2 times total.	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	At the end of each infusion stage. 2 times total.	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.
Sedation	The trail making test was performed at training prior to study procedures, at baseline, and during each of the infusions.	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.
Sedation by Patient Report	At the end of each infusion stage. 2 times total.	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.
Maximum Drug Disliking	At the end of each infusion stage. 2 times total.	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.
Average Nausea	At the end of each infusion stage. 2 times total.	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	At the end of each infusion stage. 2 times total.	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	At the end of each infusion stage. 2 times total.	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	At the end of each infusion stage. 2 times total.	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.

Countries

United States

Participant flow

Recruitment details

Twins were recruited by a joint effort of SRI International and Stanford University School of Medicine. Initial contact and primary enrollment was the responsibility of study staff of SRI International. Recruitment was mainly achieved through the Twin Research Registry and advertisements broadcasted by regional radio stations

Pre-assignment details

Participants were required to fast overnight except for clear liquids that were allowed up to 2 hours before starting the drug infusion. Subjects were also required to have at least 6 hours of night-time sleep before a study session. Some participants withdrew prior to study participation.

Participants by arm

Arm	Count
Alfentanil Infusion Prior to Saline Placebo Infusion 50% of participants were randomized to receive an infusion of alfentanil prior to a saline placebo infusion. All other procedures were identical in both groups.	122
Saline Placebo Infusion Prior to Alfentanil Infusion 50% of participants were randomized to receive a saline placebo infusion prior to an infusion of alfentanil. All other procedures were identical in both groups.	120
Total	242

Baseline characteristics

Characteristic	Alfentanil Infusion Prior to Saline Placebo Infusion	Saline Placebo Infusion Prior to Alfentanil Infusion	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	122 Participants	120 Participants	242 Participants
Gender Female	76 Participants	74 Participants	150 Participants
Gender Male	46 Participants	46 Participants	92 Participants
Region of Enrollment United States	122 participants	120 participants	242 participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	0 / 228
serious Total, serious adverse events	0 / 228

Outcome results

Primary

Cold Pain Threshold

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.

Time frame: Participants underwent the pain testing measures at training prior to study procedures, at baseline and during each of the infusions.