Atomoxetine as a pharmacological treatment for chronic cocaine and heroin abusers

Lead Research Organisation: University of Cambridge
Department Name: Psychology

Abstract

Drug addiction is a major medical, social and economic problem in our society and globally. Continued use of Class A drugs such as cocaine and heroin not only results in devastating effects on individuals' health and personal lives but also places an enormous burden on society through its repercussions for crime and health care provision. A key part of the solution to this problem is the provision of effective treatments for addiction in order to reduce relapse to drug use. Such treatments, at least for stimulant drugs such as cocaine, have yet to be developed. This issue is very much acknowledged by policy-makers, who have called for more research into interventions for stimulant abusers.

Within this context, the aim of our study is to investigate a potential pharmacological treatment for reducing the abuse of cocaine in a particularly difficult-to-treat group of drug-dependent patients. These are individuals dependent on both cocaine and heroin who, according to the Home Office, account for 99% of the total economic and social costs associated with drug abuse (approximately £15.3 billion per year). Treatments currently available for these patients consist mainly of opiate substitution treatments such as methadone, which are not effective in preventing patients from continuing with their use of cocaine, therefore jeopardising overall treatment success.

Based on our understanding of the pharmacology and brain processes involved in addictive behaviours and other neuropsychiatric disorders, we have identified atomoxetine as a promising drug candidate for remediating cocaine seeking in methadone-maintained heroin and stimulant drug abusers. Atomoxetine is a safe, non-stimulant and non-abused drug already used clinically for the treatment of juvenile and adult attention deficit hyperactivity disorder (ADHD). Atomoxetine targets the brain neurotransmitter noradrenaline, improving sustained attention and reducing impulsivity. Scientific evidence indicates that both thse effects could contribute to reducing drug-seeking behaviour.

We plan to carry out a 'proof-of-principle' study: A relatively small scale study to establish whether a drug candidate presents potential therapeutic properties before a larger scale clinical trial is instigated. We will determine the possible utility of atomoxetine in remediating cocaine seeking in methadone-maintained heroin and stimulant drug abusers in a double-blind, placebo controlled design. Before and after a 12 week treatment with atomoxetine or placebo, we will record sensitive behavioural and brain imaging measures of deficits in attentional bias to drug cues, sustained attention and self-control over impulsive behaviour. We will then be able to determine whether atomoxetine improves these indices for this group of drug dependent patients and whether these improvements correlate with reductions in cocaine- and heroin-seeking behaviours.

If our findings prove the potential efficacy of atomoxetine as a treatment for stimulant abuse, we will seek further funding and establish further collaborations with academic and non-academic organisations in order to progress to clinical trials. If successful, our work would contribute to the provision of an effective treatment for stimulant abuse and enhance the quality of life of drug-addicted individuals, their families and the societies in which they live. It would also help to reduce the vast socio-economic costs associated with drug addiction.

Technical Summary

Our overall objective is to conduct a proof-of-principle study to find a potential treatment for cocaine dependence, a largely unmet need, and to influence current treatment strategies for alleviating the vast socio-economic burden associated with drug abuse.

We will focus on a particularly difficult-to-treat group of drug-dependent patients: Individuals dependent on both cocaine and heroin. Treatments currently available for these patients consist mainly of opiate substitution treatments, which are not effective in reducing relapse to cocaine use, thus hindering overall treatment success.

We propose that atomoxetine, a safe, non-stimulant and non-abused drug already used clinically for the treatment of ADHD, could potentially be 'repurposed' to treat cocaine dependence. Atomoxetine improves sustained attention and reduces impulsivity, both effects which could contribute to reducing drug-seeking behaviour.

The possible utility of atomoxetine in remediating cocaine seeking in methadone-maintained cocaine and heroin abusers will be assessed using an experimental medicine approach, in a double-blind, placebo-controlled design (N=30 per group). Effects of atomoxetine on several measures of fronto-executive functioning, including Stroop bias to drug cues, sustained attention and the stop-signal reaction time in a combined fMRI paradigm will be assessed before and after 12 weeks of treatment with atomoxetine or placebo. Additional measures include clinical scales of compulsivity and impulsivity, self-reported drug intake as well as resting state MRI activity, peripheral biomarkers (including plasma cortisol), cardiovascular function and measures of integration into the community.

We predict that atomoxetine relative to placebo will reduce bias to both cocaine and heroin related cues, improve sustained attention and reduce impulsivity in this critical population of drug users. We anticipate that further controlled trials of atomoxetine would be warranted.

Planned Impact

This proof-of-principle study investigates the possible utility of atomoxetine in remediating cocaine seeking in methadone-maintained heroin and stimulant drug abusers. We anticipate that the findings from this study would provide sufficient confidence in the efficacy of atomoxetine as such treatment to warrant further controlled trials. Providing the successful outcome of our proof-of-principle study and the validation of atomoxetine as a treatment for stimulant abuse through clinical trials, there is a number non-academic beneficiaries of this study.

Beneficiaries in the long-term

-Drug dependent patients - Health and Wellbeing
Reduction in cocaine and heroin use by atomoxetine would involve major benefits for patients, including reduction in drug-related crime and other psychosocial consequences of drug addiction, as well as a reduction in the harm associated with the use of these drugs by injection. Atomoxetine may also facilitate drug users' integration into the community by improving attentional function, which seems to play an important role in this regard (ref). This effect of Atomoxetine may include remediation of cognitive side effects of methadone such as loss of concentration.

-Treatment providers and Department of Health - Improvement of Social Welfare and Public Services
The use of atomoxetine as an adjunct treatment to methadone maintenance would offer a cost-effective option for improving treatment adherence and overall treatment outcome.

-Home Office - Improvement of Social Welfare and Public Services
The proposed study aims to reduce the abuse of cocaine and in a particularly difficult-to-treat group of drug-dependent patients. These are individuals dependent on both cocaine and heroin who, according to the Home Office, account for 99% of the total economic and social costs associated with drug abuse.Therefore a reduction of cocaine and heroin abuse managed with atomoxetine would contribute to reducing the vast socio-economic cost associated with class A drug use.

-Commercial private sector
Repurposing an existing drug and validating its use for additional applications would have obvious benefits for the company producing such drug. Atomoxetine as a hydrochloride salt (atomoxetine HCl) is currently manufactured, marketed and sold in the United States under the brand name Strattera by Eli Lilly & Co, the original patent filing company, and current U.S. patent owner. Generics of atomoxetine are sold in all other countries; they are manufactured by Torrent Pharmaceuticals (Tomoxetin), Ranbaxy Laboratories (Attentin), Sun Pharmaceuticals and Intas Biopharmaceuticals.

-Society as a whole
The provision of an effective treatment for drug abuse will not only enhance the quality of life of drug-addicted individuals but also that of their families and the societies in which they live, this being in the UK or abroad.

Beneficiaries in the short-term

-Policy makers and health-care providers
This project takes on board the recommendations from bodies such as The UK Drug Policy Commission (UKDPC), calling for more research for interventions for stimulant abusers, and aspires to (a) transform evidence based policy in practice (b) influence and inform health-care providers and (c) contribute towards future evidence based policy-making.

-Drug users, their communities and general public.
Our research on addiction usually generates considerable media interest, an indicator of the general public interest in keeping abreast with the latest developments in addiction research.

-Academia-Industry partnerships
We anticipate that this study would progress into fully-powered studies to be conducted via academia-industry partnerships which would benefit all partners, this being through exchange of knowledge and expertise or financial or in-kind contributions.

Our proposed Pathways to Impact plan necessarily focuses on engaging the 'beneficiaries in the short-term' with this research.

Publications

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Barlow RL (2015) Markers of serotonergic function in the orbitofrontal cortex and dorsal raphé nucleus predict individual variation in spatial-discrimination serial reversal learning. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Ersche KD (2016) Carrots and sticks fail to change behavior in cocaine addiction. in Science (New York, N.Y.)

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Gillan CM (2015) Functional neuroimaging of avoidance habits in obsessive-compulsive disorder. in The American journal of psychiatry

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Horst NK (2019) D2 receptors and cognitive flexibility in marmosets: tri-phasic dose-response effects of intra-striatal quinpirole on serial reversal performance. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

 
Description West Anglia CLRN Research Capability Funding
Amount £1,697 (GBP)
Funding ID 116846 
Organisation National Institute for Health Research 
Department Leicestershire, Northamptonshire and Rutland Comprehensive Local Research Network
Sector Public
Country United Kingdom
Start 06/2013 
End 03/2016
 
Description BBC Horizon on OCD, AA-S, TWR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact BBC Horizon documentary entitled OCD: A Monster in my Mind


Raise public awareness of research in this area
Year(s) Of Engagement Activity 2015
URL http://www.bbc.co.uk/programmes/p030nypn
 
Description BBC World News on brain connectivity, TWR 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact BBC World News Interview entitled Brain's activity map makes stable 'fingerprint'. Concerning the Nature Neuroscience article


Raise public awareness of research in this area
Year(s) Of Engagement Activity 2015
URL http://www.bbc.co.uk/news/science-environment-34504848
 
Description Blog on danablog.org on mental health disorders in prisons, BJS 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Blog by the President of the International Neuroethics Society, entitled Mental Health Disorders in Prison: Neuroethical and Societal Issues


Raised awareness of research in this area
Year(s) Of Engagement Activity 2015
URL http://danablog.org/2015/07/28/mental-health-disorders-in-prison-neuroethical-and-societal-issues/
 
Description British Association for Psychopharmacology on secrets of success, TWR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Other audiences
Results and Impact Gave a talk entitled The ten secrets for success in science - lessons for trainees


Raised awareness of research in this area
Year(s) Of Engagement Activity 2015
 
Description British Neuroscience Association Festival of Neuroscience, TWR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach National
Primary Audience Other audiences
Results and Impact Gave a talk entitled Compulsivity and habit development in cocaine users. As part of the Drugs, addiction and freewill: do addicted individuals have free will?


Raised awareness of research in this area
Year(s) Of Engagement Activity 2015
URL http://www.bna2015.org/programme/details/?session=11518&theme=I
 
Description British Neuroscience Association Festival of Neuroscience, TWR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach National
Primary Audience Other audiences
Results and Impact Gave a talk entitled What has NEWMEDS taught us about translational science for schizophrenia and depression? As part of the Challenges and progress from the first calls of the EU innovative medicines initiative


Raised awareness of research in this area
Year(s) Of Engagement Activity 2015
URL http://www.bna2015.org/programme/details/?session=11513&theme=I
 
Description Cambridge and Bedford International Conference on mental Health, TWR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Other audiences
Results and Impact Gave a talk entitled The Neuroscience of Impulsivity


To raise awareness of research in this area
Year(s) Of Engagement Activity 2015
URL http://www.bcmhr-cu.org/content/programme-2015
 
Description International Convention of Psychological Science Symposium on addiction, TWR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Gave a talk entitled Voluntary, Habitual and Compulsive Substance Use. As part of the Symposium entitled Searching for the core of addiction: Translational perspectives


Raised awareness of research in this area
Year(s) Of Engagement Activity 2015
URL http://www.psychologicalscience.org/convention/icps_program/search/viewProgram.cfm?Abstract_ID=32919...
 
Description Science Museum Lates event on Human Enhancement, TWR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Gave 3 20 minutes talks to the Lates event at the Science Museum entitled Brain gain and smart drugs. Approximately 4000 people attended


Raised awareness of research in this area
Year(s) Of Engagement Activity 2015
URL http://www.sciencemuseum.org.uk/visitmuseum/plan_your_visit/events/festivals/you-have-been-upgraded....
 
Description Society for Neuroscience 2015, MV et al 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation poster presentation
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented a poster entitled Impaired cognitive flexibility is associated with reduced functional connectivity of dorsal fronto-striatal loop circuits in patients with Obsessive Compulsive Disorder (OCD)


Raise awareness of research in this area
Year(s) Of Engagement Activity 2015
URL https://www.sfn.org/annual-meeting/neuroscience-2015/sessions-and-events/program
 
Description Society for Neuroscience 2015, MV et al 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation poster presentation
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented a poster entitled Impaired cognitive flexibility is associated with reduced functional connectivity of dorsal fronto-striatal loop circuits in patients with Obsessive Compulsive Disorder (OCD)


Raise awareness of research in this area
Year(s) Of Engagement Activity 2015
URL https://www.sfn.org/annual-meeting/neuroscience-2015/sessions-and-events/program
 
Description The Times on smart drugs, BJS, TWR 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact The Times article entitled Smart drug helps you to sleep less and think more


Raise public awareness of research in this area
Year(s) Of Engagement Activity 2015
URL http://www.thetimes.co.uk/tto/health/news/article4532339.ece
 
Description Training session for Clinical Medicine trainees on OCD, TWR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Health professionals
Results and Impact Gave a seminar to 4 Clinical Medicine trainees from the Cambridge University Clinical School


Raised awareness of research in this area
Year(s) Of Engagement Activity 2015
 
Description University of Cambridge Research News on drug addiction, TWR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Media (as a channel to the public)
Results and Impact Gave a podcast on addiction to an A Level student working on the David Ross Educational Trust


Raised awareness of research in this area
Year(s) Of Engagement Activity 2015
URL https://www.cam.ac.uk/news/a-level-students-pick-cambridge-brains
 
Description Workshop "The role of atomoxetine in drug addiction treatment" 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact We held a Workshop event in June 2015, which included invited guests, clinicians and drug addiction experts who made constructive suggestions for the implications of the study into clinical practice and follow-up research, which we may now pursue.

suggestions for the implementation of the study into clinical practice and follow-up research, are now being pursued
Year(s) Of Engagement Activity 2015