Clinical trial NCT00499746: The Discriminative Effects of Tramadol in Humans
Official title: Medications Development for Drug Abuse Disorders
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Opioid Abuse
Opioid Addiction
Stimulant Abuse
Stimulant Addiction
Keywords: drug discrimination
opioid pharmacology
behavioral pharmacology
human research
Lead sponsor: National Institute on Drug Abuse (NIDA)
Sponsor class: NIH
First posted: 2007-07-11
Enrollment: 20
Sex: ALL
Minimum age (years): 21
Maximum age (years): 55
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Acquisition of Discrimination Assessed by Accuracy of the Discrimination Test
timeFrame: 1 day
measure: Discrimination Effects Assessed by Operant Responses
timeFrame: 1 day
measure: Discrimination Effects Assessed by Point Distribution
timeFrame: 1day
measure: Discrimination Effects Assessed by Discrete Choice
timeFrame: 1 day
Secondary outcomes:
measure: Physiologic Effects Assessed by the Pharmacological Class Questionnaire
timeFrame: Measure at 120 min after drug administration
measure: Physiological Effects Assessed by Peak Change From Baseline Pupil Diameter
timeFrame: Measure at 120 min after drug administration
measure: Peak Change From Baseline Opioid Agonist Effects Assessed by the Visual Analog Scale (VAS)
timeFrame: Measure at 120 min after drug administration
measure: Peak Change From Baseline Stimulant Effects Assessed by the Visual Analog Scale (VAS)
timeFrame: Measure at 120 min after drug administration
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Behavioral Pharmacology Research Unit
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Eric C Strain, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Duke AN, Bigelow GE, Lanier RK, Strain EC. Discriminative stimulus effects of tramadol in humans. J Pharmacol Exp Ther. 2011 Jul;338(1):255-62. doi: 10.1124/jpet.111.181131. Epub 2011 Apr 5.