Heritability of Opioid Effects: A Twin Study

Study Overview
=================
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.

Official Title
-----------------
Heritability of Opioid Effects: A Twin Study

Conditions
-----------------
Pain

Intervention / Treatment
-----------------
* Drug: Alfentanil
* Other: Saline placebo infusion


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Saline placebo infusion<br>Subjects will receive an intravenous infusion of normal saline. | Other: Saline placebo infusion<br>* Intravenous infusion of normal saline<br>|
| Experimental: Alfentanil infusion<br>Subjects will receive an intravenous infusion of alfentanil. | Drug: Alfentanil<br>* Target controlled intravenous infusion of alfentanil at a plasma concentration of 100ng/ml<br>* Other names: Alfenta;|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

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