A Phase 1/2 interventional study of tramadol and placebo in Opioid Abuse, Opioid Addiction and Stimulant Abuse, sponsored by National Institute on Drug Abuse (NIDA). Completed at 1 site in United States. Open to participants aged 21 Months to 55 Years. Per ClinicalTrials.gov, last updated 2017-10-17.
Sponsored by National Institute on Drug Abuse (NIDA) · Phase 1/2, Interventional, and Treatment
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.
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.
1,411 studies on the registry are indexed under Opioid-Related Disorders; 290 are open to participants now.
This study's enrollment of 20 is below the median of 63 across 1,123 interventional studies indexed under Opioid-Related Disorders.
Browse Opioid-Related Disorders studies →National Institute on Drug Abuse (NIDA) is the lead sponsor of 388 studies on the registry; 19 are open to participants now.
Of its 12 completed or terminated interventional studies of FDA-regulated products, 5 (42%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
oral dose, once per day
Drug: tramadol
oral dose, once per day
Drug: placebo
oral dose, once per day
Drug: Hydromorphone
oral dose, once per day
Drug: Methylphenidate
oral dose, once per day
Also known as: Ultram
oral dose, once per day
Also known as: sugar pill
oral dose, once per day
Also known as: Dilaudid
oral dose, once per day
Also known as: stimulant
Acquisition of Discrimination Assessed by Accuracy of the Discrimination Test
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
Discrimination Effects Assessed by Operant Responses
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
Discrimination Effects Assessed by Point Distribution
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
Discrimination Effects Assessed by Discrete Choice
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
Physiologic Effects Assessed by the Pharmacological Class Questionnaire
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
Physiological Effects Assessed by Peak Change From Baseline Pupil Diameter
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
Peak Change From Baseline Opioid Agonist Effects Assessed by the Visual Analog Scale (VAS)
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
Peak Change From Baseline Stimulant Effects Assessed by the Visual Analog Scale (VAS)
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
| Milestone | All Participants |
|---|---|
| Started | 20 |
| Completed | 8 |
| Not completed | 12 |
| Withdrew: Failed to perform study task | 7 |
| Withdrew: Withdrawal by subject | 3 |
| Withdrew: Investigator decision | 1 |
| Withdrew: Unable to determine | 1 |
| Milestone | All Participants |
|---|---|
| Started | 8 |
| Completed | 8 |
| Not completed | 0 |
| Milestone | All Participants |
|---|---|
| Started | 8 |
| Completed | 8 |
| Not completed | 0 |
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%.
| percent of correct response | Placebo 0 mg | Hydromorphone 8 mg | Methylphenidate 60 mg |
|---|---|---|---|
| Acquisition of Discrimination Assessed by Accuracy of the Discrimination Test | 87 (0 to 100) | 87.5 (0 to 100) | 90 (0 to 100) |
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.
| Responses | 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 |
|---|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| Points distributed | 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 |
|---|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| percentage of drug identification | 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 |
|---|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| percentage of drug identification | 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 |
|---|---|---|---|---|---|---|---|---|---|
| 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 |
Change in pupil diameter (mm) at peak (120 min) compared to baseline measure of pupil diameter
| mm | 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 |
|---|---|---|---|---|---|---|---|---|---|
| Physiological Effects Assessed by Peak Change From Baseline Pupil Diameter | -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 |
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.
| units on a scale | 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 |
|---|---|---|---|---|---|---|---|---|---|
| Peak Change From Baseline Opioid Agonist Effects Assessed by the Visual Analog Scale (VAS) | 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 |
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.
| units on a scale | 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 |
|---|---|---|---|---|---|---|---|---|---|
| Peak Change From Baseline Stimulant Effects Assessed by the Visual Analog Scale (VAS) | 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 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| All Participants | — | 0/8 (0%) | 0/8 (0%) |
| Age, Categorical(Participants) | Group 1 |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 8 |
| >=65 years | 0 |
| Age, Continuous(years) | Group 1 |
|---|---|
| Mean | 40.3 ± 2.3 |
| Sex: Female, Male(Participants) | Group 1 |
|---|---|
| Female | 0 |
| Male | 8 |
| Region of Enrollment(participants) | Group 1 |
|---|---|
| United States | 8 |
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