The Discriminative Effects of Tramadol in Humans

• Sponsor: National Institute on Drug Abuse (NIDA) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00499746
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 4
• Duration (Months): 45
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This research is part of a set of studies whose purpose is to test whether tramadol can be used for the treatment of opioid addiction. Tramadol is already available in the United States as a pain medicine marketed as Ultram. It has effects similar to morphine, and it may also have effects similar to other drugs like stimulants. The doses of tramadol used in this study are higher than those generally used for the treatment of pain. To be in this study a participant must be a user of opioids (drugs like heroin) and stimulants (drugs like cocaine), but cannot be addicted to either. The person must be between 21-55 years old, and generally healthy. Up to 12 people will take part in this study.

Condition or Disease	Intervention/Treatment	Phase
Opioid Abuse; Opioid Addiction; Stimulant Abuse; Stimulant Addiction	Drug: tramadol; Drug: placebo; Drug: Hydromorphone; Drug: Methylphenidate	Phase 1/Phase 2

Detailed Description

This is a human laboratory study that tests the effects of tramadol as a step in the possible development of this medication as a new treatment for opioid dependence. Tramadol is a mild/moderate mu agonist opioid currently marketed as an analgesic that has a unique profile of effects. One of the primary metabolites of tramadol, mono-O-demethyltramadol (referred to as M1) exerts opioid agonist effects at the mu receptor. In addition, tramadol and M1 produce reuptake blockade of monoamines, and this latter effect may positively influence its analgesic efficacy, in addition to influencing the subjective effects produced by tramadol. Preclinical evidence suggests that tramadol's effects on monoamine reuptake may have antidepressant qualities as well. Given tramadol's diverse pharmacodynamic profile, a systematic characterization of its subjective effects in opioid-experienced subjects would provide valuable information regarding its abuse liability, and its potential utility as a treatment for opioid dependence.

The characterization of an opioid medication's profile can be accomplished through a variety of experimental procedures. One useful procedure for assessing the profile of an opioid is a drug discrimination procedure. In this methodology, subjects are first trained to discriminate reference drugs such as placebo and an opioid agonist, and then administered doses of a novel compound to determine how like (or unlike) it is to the reference training conditions. Our laboratory has a long history of using this drug discrimination methodology to study and to characterize opioids with varying opioid receptor activity profiles. Studies have generally included either two or three training conditions in humans. Using this technique in volunteers, studies have characterized the profile of a number of opioids including (for example) butorphanol, nalbuphine, pentazocine, and buprenorphine.

While most of these studies testing the effects of mixed agonist-antagonist opioids have used an opioid agonist and placebo as the training conditions, tramadol's profile of effects suggests that there may be a non-opioid component of action at serotonin and norepinephrine sites that will be useful to distinguish. In particular, it is of interest to determine the extent to which tramadol is identified as being like a prototypic mu agonist opioid, whether it is substantially identified as being like a non-opioid compound, and if this non-opioid component is related to enhancement of monoamine effects. In order to provide a meaningful non-opioid contrast training condition, this study will compare different doses of tramadol to training conditions of placebo, a mu agonist opioid, and a prototypic stimulant.

Overall, this evaluation will provide a greater understanding of the subjective effect profile of tramadol in comparison to a prototypic mu opioid and a prototypic stimulant. If tramadol is to be useful in the treatment of opioid dependence, a thorough assessment of its subjective effects in experienced opioid and stimulant abusers is warranted.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Medications Development for Drug Abuse Disorders
• Study Start Date: Nov 1, 2007
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Tramadol oral dose, once per day	Drug: tramadol; oral dose, once per day; Other Names: Ultram
Placebo Comparator: Placebo oral dose, once per day	Drug: placebo; oral dose, once per day; Other Names: sugar pill
Active Comparator: hydromorphone oral dose, once per day	Drug: Hydromorphone; oral dose, once per day; Other Names: Dilaudid
Active Comparator: methylphenidate oral dose, once per day	Drug: Methylphenidate; oral dose, once per day; Other Names: stimulant

Outcome Measures

Primary Outcome Measures

1. Acquisition of Discrimination Assessed by Accuracy of the Discrimination Test [1 day]

   The acquisition of discrimination was to test whether volunteers could identify each training drug condition by the correct letter code. Results are the percentage of correct responses with a range of 0% to 100%.

2. Discrimination Effects Assessed by Operant Responses [1 day]

   Volunteers emitted operant responses on computer keys that corresponded to the training letter, on a fixed interval 1 second schedule for 8.5 minutes. The range is from 0 to 500 operant responses.

3. Discrimination Effects Assessed by Point Distribution [1day]

   In point distribution, volunteers distributed 50 points among three training drug letters depending on how certain they were of the identity of the administrated drug. Maximum total is 50 points.

4. Discrimination Effects Assessed by Discrete Choice [1 day]

   During discrete choice, volunteers were given three choices (placebo, hydromorphone, methylphenidate) and were asked to choose which of the training drugs they thought they received. The outcome measure illustrates the percentage of participants who chose either placebo, hydromorphone, or methylphenidate during each drug condition (i.e., Placebo, Hydromorphone 8 mg, Tramadol 50 mg, etc.), ranging from 0-100. The outcome measure represents the percentage of participants who chose either placebo, opioid agonist, or stimulant across each drug condition.

Secondary Outcome Measures

1. Physiologic Effects Assessed by the Pharmacological Class Questionnaire [Measure at 120 min after drug administration]

   During the peak (assessed at 120 min) of each drug administration, participants were asked to complete the pharmacological class questionnaire. The pharmacological class questionnaire had volunteers indicate which drug class was most similar to the drug condition they received. Ten drug classes were listed with descriptive labels and examples of each: placebo, opiates (or opioid agonist), phenothiazines, barbiturates, antidepressants, opiate antagonists, hallucinogens, benzodiazepines, stimulants, and other. Of these choices, participants chose 3: placebo, opioid agonist, and stimulant. The outcome measure represents the percentage of participants who chose either placebo, opioid agonist, or stimulant across each drug condition.

2. Physiological Effects Assessed by Peak Change From Baseline Pupil Diameter [Measure at 120 min after drug administration]

   Change in pupil diameter (mm) at peak (120 min) compared to baseline measure of pupil diameter

3. Peak Change From Baseline Opioid Agonist Effects Assessed by the Visual Analog Scale (VAS) [Measure at 120 min after drug administration]

   The Visual Analog Scale (VAS) measures subjective ratings of opioid agonist effects. The scale on this measure ranges from 0 being "Not at all" to 100 being "Extremely". On this scale, higher scores indicate a stronger drug effect. The outcome measure illustrates a difference from peak (120 min) to baseline measure on VAS.

4. Peak Change From Baseline Stimulant Effects Assessed by the Visual Analog Scale (VAS) [Measure at 120 min after drug administration]

   The Visual Analog Scale (VAS) measures subjective ratings of stimulant effects. The scale on this measure ranges from 0 being "Not at all" to 100 being "Extremely". On this scale, higher scores indicate a stronger drug effect. The outcome measure illustrates a difference from peak (120 min) to baseline measure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Months to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Study subjects are male and female non-dependent opioid users with active stimulant use.

• Between the ages of 21-55

• In good physical health

• Without significant psychiatric illness besides their drug use.

• Females are required to provide a negative pregnancy test prior to study participation.

Exclusion Criteria:

• Subjects are excluded if they have evidence of significant medical (e.g., insulin dependent diabetes mellitus) or psychiatric (e.g., schizophrenia) illness.

• Subjects with a history of seizures will be excluded.

• Persons with current history of significant alcohol or sedative/hypnotic drug use will be excluded from study participation.

• Applicants seeking treatment for their substance abuse will not be admitted to the study, and will be provided information about treatment services available.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Behavioral Pharmacology Research Unit	Baltimore	Maryland	United States	21224

Sponsors and Collaborators

• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Eric C Strain, M.D., Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eric Strain, MD, Professor, Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT00499746
• Other Study ID Numbers: NIDA-18125-3; R01DA018125; DPMCDA
• First Posted: Jul 11, 2007
• Last Update Posted: Oct 17, 2017
• Last Verified: Sep 1, 2017

• Keywords provided by Eric Strain, MD, Professor, Johns Hopkins University: drug discrimination; opioid pharmacology; behavioral pharmacology; human research
• Additional relevant MeSH terms: Opioid-Related Disorders; Behavior, Addictive; Tramadol; Hydromorphone; Methylphenidate

Study Results

Participant Flow

Arm/Group Title	All Participants
Arm/Group Description	Participant flow is reported in single group due to the number of randomized sequences. In Phase 1 and Phase 2, each participant received two exposures of each training drug in randomize order (placebo, Hydromorphone 8 mg, Methylphenidate 60 mg). In Phase 3, each participant received randomized exposure to placebo, Hydromorphone (4 and 8 mg), Methylphenidate (30 and 60 mg), tramadol (50, 100, 200, and 400 mg).
Period Title: Phase 1(6-9 One Day Sessions)
STARTED	20
COMPLETED	8
NOT COMPLETED	12
Period Title: Phase 1(6-9 One Day Sessions)
STARTED	8
COMPLETED	8
NOT COMPLETED	0
Period Title: Phase 1(6-9 One Day Sessions)
STARTED	8
COMPLETED	8
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Group 1
Arm/Group Description
Overall Participants	8
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.3 (2.3)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	8 100%
Region of Enrollment (participants) [Number]
United States	8 100%

Outcome Measures

1. Primary Outcome

Title	Acquisition of Discrimination Assessed by Accuracy of the Discrimination Test
Description	The acquisition of discrimination was to test whether volunteers could identify each training drug condition by the correct letter code. Results are the percentage of correct responses with a range of 0% to 100%.
Time Frame	1 day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo 0 mg	Hydromorphone 8 mg	Methylphenidate 60 mg
Arm/Group Description
Measure Participants	8	8	8
Mean (Full Range) [percent of correct response]	87	87.5	90

2. Primary Outcome

Title	Discrimination Effects Assessed by Operant Responses
Description	Volunteers emitted operant responses on computer keys that corresponded to the training letter, on a fixed interval 1 second schedule for 8.5 minutes. The range is from 0 to 500 operant responses.
Time Frame	1 day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo 0 mg	Hydromorphone 4 mg	Hydromorphone 8 mg	Methylphenidate 30 mg	Methylphenidate 60 mg	Tramadol 50 mg	Tramadol 100 mg	Tramadol 200 mg	Tramadol 400 mg
Arm/Group Description
Measure Participants	8	8	8	8	8	8	8	8	8
Placebo	455.5 (9.6)	116.6 (76.4)	0.0 (0.0)	0.0 (0.0)	0.0 (0.0)	464.1 (4.2)	341.3 (74.8)	86.6 (62.0)	115.6 (75.7)
Hydromorphone	0.0 (0.0)	341.3 (74.7)	453.4 (9.0)	0.0 (0.0)	0.0 (0.0)	0.0 (0.0)	118.1 (77.3)	367.0 (60.2)	282.9 (83.4)
Methylphenidate	0.0 (0.0)	0.0 (0.0)	0.0 (0.0)	465.4 (4.7)	465.8 (3.0)	0.0 (0.0)	0.0 (0.0)	0.0 (0.0)	59.9 (59.9)

3. Primary Outcome

Title	Discrimination Effects Assessed by Point Distribution
Description	In point distribution, volunteers distributed 50 points among three training drug letters depending on how certain they were of the identity of the administrated drug. Maximum total is 50 points.
Time Frame	1day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo 0 mg	Hydromorphone 4 mg	Hydromorphone 8 mg	Methylphenidate 30 mg	Methylphenidate 60 mg	Tramadol 50 mg	Tramadol 100 mg	Tramadol 200 mg	Tramadol 400 mg
Arm/Group Description
Measure Participants	8	8	8	8	8	8	8	8	8
Placebo	50.0 (0.0)	11.9 (7.8)	0.0 (0.0)	0.0 (0.0)	0.0 (0.0)	50.0 (0.0)	37.5 (8.2)	9.4 (6.6)	12.5 (8.2)
Hydromorphone	0.0 (0.0)	38.1 (7.8)	50.0 (0.0)	0.0 (0.0)	0.0 (0.0)	0.0 (0.0)	12.5 (8.2)	38.3 (6.5)	31.3 (9.1)
Methylphenidate	0.0 (0.0)	0.0 (0.0)	0.0 (0.0)	50.0 (0.0)	50.0 (0.0)	0.0 (0.0)	0.0 (0.0)	0.0 (0.0)	6.3 (6.3)

4. Primary Outcome

Title	Discrimination Effects Assessed by Discrete Choice
Description	During discrete choice, volunteers were given three choices (placebo, hydromorphone, methylphenidate) and were asked to choose which of the training drugs they thought they received. The outcome measure illustrates the percentage of participants who chose either placebo, hydromorphone, or methylphenidate during each drug condition (i.e., Placebo, Hydromorphone 8 mg, Tramadol 50 mg, etc.), ranging from 0-100. The outcome measure represents the percentage of participants who chose either placebo, opioid agonist, or stimulant across each drug condition.
Time Frame	1 day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo 0 mg	Hydromorphone 4 mg	Hydromorphone 8 mg	Methylphenidate 30 mg	Methylphenidate 60 mg	Tramadol 50 mg	Tramadol 100 mg	Tramadol 200 mg	Tramadol 400 mg
Arm/Group Description
Measure Participants	8	8	8	8	8	8	8	8	8
Placebo	100	25	0	0	0	100	75	25	25
Hydromorphone	0	75	100	0	0	0	25	75	63
Methylphenidate	0	0	0	100	100	0	0	0	12

5. Secondary Outcome

Title	Physiologic Effects Assessed by the Pharmacological Class Questionnaire
Description	During the peak (assessed at 120 min) of each drug administration, participants were asked to complete the pharmacological class questionnaire. The pharmacological class questionnaire had volunteers indicate which drug class was most similar to the drug condition they received. Ten drug classes were listed with descriptive labels and examples of each: placebo, opiates (or opioid agonist), phenothiazines, barbiturates, antidepressants, opiate antagonists, hallucinogens, benzodiazepines, stimulants, and other. Of these choices, participants chose 3: placebo, opioid agonist, and stimulant. The outcome measure represents the percentage of participants who chose either placebo, opioid agonist, or stimulant across each drug condition.
Time Frame	Measure at 120 min after drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo 0 mg	Hydromorphone 4 mg	Hydromorphone 8 mg	Methylphenidate 30 mg	Methylphenidate 60 mg	Tramadol 50 mg	Tramadol 100 mg	Tramadol 200 mg	Tramadol 400 mg
Arm/Group Description
Measure Participants	8	8	8	8	8	8	8	8	8
Placebo	100	25	0	0	0	100	75	37	25
Opioid Agonist	0	75	100	0	0	0	25	63	63
Stimulant	0	0	0	100	100	0	0	0	12

6. Secondary Outcome

Title	Physiological Effects Assessed by Peak Change From Baseline Pupil Diameter
Description	Change in pupil diameter (mm) at peak (120 min) compared to baseline measure of pupil diameter
Time Frame	Measure at 120 min after drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo 0 mg	Hydromorphone 4 mg	Hydromorphone 8 mg	Methylphenidate 30 mg	Methylphenidate 60 mg	Tramadol 50 mg	Tramadol 100 mg	Tramadol 200 mg	Tramadol 400 mg
Arm/Group Description
Measure Participants	8	8	8	8	8	8	8	8	8
Mean (Standard Error) [mm]	-0.5 (0.2)	-1.2 (0.2)	-1.9 (0.2)	-0.6 (0.3)	-0.3 (0.2)	-0.5 (0.1)	-0.2 (0.1)	-0.8 (0.3)	-0.8 (0.3)

7. Secondary Outcome

Title	Peak Change From Baseline Opioid Agonist Effects Assessed by the Visual Analog Scale (VAS)
Description	The Visual Analog Scale (VAS) measures subjective ratings of opioid agonist effects. The scale on this measure ranges from 0 being "Not at all" to 100 being "Extremely". On this scale, higher scores indicate a stronger drug effect. The outcome measure illustrates a difference from peak (120 min) to baseline measure on VAS.
Time Frame	Measure at 120 min after drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo 0 mg	Hydromorphone 4 mg	Hydromorphone 8 mg	Methylphenidate 30 mg	Methylphenidate 60 mg	Tramadol 50 mg	Tramadol 100 mg	Tramadol 200 mg	Tramadol 400 mg
Arm/Group Description
Measure Participants	8	8	8	8	8	8	8	8	8
Mean (Standard Error) [units on a scale]	1.4 (0.7)	2.9 (1.0)	4.8 (2.1)	2.1 (0.5)	3.4 (1.2)	0.4 (0.4)	1.6 (0.7)	2.1 (1.0)	3.8 (1.8)

8. Secondary Outcome

Title	Peak Change From Baseline Stimulant Effects Assessed by the Visual Analog Scale (VAS)
Description	The Visual Analog Scale (VAS) measures subjective ratings of stimulant effects. The scale on this measure ranges from 0 being "Not at all" to 100 being "Extremely". On this scale, higher scores indicate a stronger drug effect. The outcome measure illustrates a difference from peak (120 min) to baseline measure.
Time Frame	Measure at 120 min after drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo 0 mg	Hydromorphone 4 mg	Hydromorphone 8 mg	Methylphenidate 30 mg	Methylphenidate 60 mg	Tramadol 50 mg	Tramadol 100 mg	Tramadol 200 mg	Tramadol 400 mg
Arm/Group Description
Measure Participants	8	8	8	8	8	8	8	8	8
Mean (Standard Error) [units on a scale]	1.4 (0.8)	3.6 (1.0)	3.6 (1.2)	8.0 (1.6)	10.6 (2.3)	0.6 (0.4)	0.9 (0.5)	4.9 (2.0)	6.9 (2.1)

Adverse Events

Arm/Group Title	All Participants
Arm/Group Description
All Cause Mortality
	All Participants
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Participants
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Other (Not Including Serious) Adverse Events
	All Participants
	Affected / at Risk (%)	# Events
Total	0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.