The Discriminative Effects of Tramadol in Humans

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.

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.