Transdermal Rotigotine as Adjunct to Behavioral Therapy for Cocaine Use Disorder

Cocaine Use Disorder (CocUD) incurs a high socioeconomic burden, yet no Food and Drug Administration
(FDA)-approved pharmacotherapies are available for CocUD. We propose a proof of concept clinical trial of
multiple dopamine (DA) receptor (D2/D3/D4/D5) agonist rotigotine (RTG) that could improve cocaine abstinence
by increasing DA-dependent executive function (EF). EF is the set of cognitive abilities such as working memory,
information updating and mental flexibility required for goal attainment. In patients with CocUD and poor EF,
attention to and retention of psychoeducation information during cognitive behavioral therapy (CBT) could be
impaired, and drug-predictive cues may capture attention away from sobriety goals more readily. Indeed, low EF
has been linked to poor CocUD treatment outcomes. Such patients could benefit from DA-increasing medication
to help maintain abstinence. In fact, prescription stimulants that release DA have been shown to reduce cocaine
use, but are problematic because stimulants themselves have abuse potential. A multiple DA receptor agonist
may be a safer alternative to improve DA function and EF. Although RTG is FDA-approved for Parkinson’s
Disease treatment, RTG has been shown to improve cortical plasticity and EF in Alzheimer’s Disease. Moreover,
the sustained-release RTG patches promote steady state drug levels. Therefore, we propose a clinical trial of
six weeks of daily transdermal rotigotine (Neupro®) patches as an adjunct to CBT for cocaine use reduction in
CocUD. Cocaine use outcomes will be compared between n = 30 (completed) participants randomized to six
weeks of 4mg/d transdermal RTG, and n = 30 participants randomized to transdermal placebo. Per NIDA goals
of identifying alternative quality of life-related endpoints beyond abstinence in clinical trials, we will also attain
insights into RTG action by obtaining functional magnetic resonance imaging (fMRI) and neurocognition
assessments pertinent to EF prior and following dosing as secondary endpoints. This will garner evidence as to
whether RTG increases brain activation and overt behavioral signatures of EF. Such findings would provide
critical mechanistic evidence that RTG induces its abstinence-promoting effect by way of improving EF and/or
reducing impulsivity. Finally, in a step toward precision medicine for CocUD, we will determine how RTG benefits
brain and behavior as a function of baseline EF. Several lines of evidence from previous trials of DA agents
suggest that individuals with SUD and poor EF benefit most from DA enhancement, whereas participants with
normal to supranormal EF at baseline derive lesser or no benefit from DA enhancement on substance
abstinence. We will thus conduct a planned post-hoc analysis to detect differential change in EF and in EF-
related brain connectivity and function following RTG as a function of whether the participant scored above vs
below the median value of the RTG treatment arm in scores of a validated computerized cognitive battery that
probes EF. A finding in this post-hoc analysis that RTG selectively benefited individuals with lower EF would
augur a novel precision medicine approach in future clinical trials of other DA-promoting agents for CocUD.

Grant Number: 1U01DA057846-01
NIH Institute/Center: NIH
Principal Investigator: James Bjork