An Open-label Study of Oral Minocycline for the Treatment of Patients With Co-occurring Opioid and Amphetamine-type Stimulant Dependence (COATS)

Additional data available to this project will come from contemporaneous and historical drug treatment clinical trials and treatment programs conducted at HUSM with similar populations of patients and proposed/described as other components of the cluster of research projects described in the overall Research University Team Grant proposal. Comparisons of treatment process and outcome measures collected in this proposed clinical trial with data collected in contemporaneous and historical controls will enhance our ability to evaluate the potential efficacy of minocycline as treatment agent for co-occurring opioid and amphetamine-type stimulant (ATS) dependence. Data from patients receiving other drug treatments at HUSM will be used as reference points to evaluate potential effect sizes of treatment effects associated with minocycline treatment. The preliminary data on treatment retention data, patient satisfaction, potential adverse effects, and efficacy will be used as preliminary/pilot research when designing and applying for funding support for future large scale randomized clinical trials aimed at the development of effective medically based treatments of opiate and ATS abuse or dependence.

Over the past decade, amphetamine-type stimulant (ATS) has also emerged as a major drug problem. Globally, ATS is now the second most commonly used illicit drug type and is more widely used than heroin. ATS abuse is especially prevalent and problematic in the Asian region, where ATS production, use, drug seizures, and demand for treatment have continued to increase. Injection of methamphetamine has been reported in Malaysia (Chawarski et al, 2006) and other south-east Asian countries (McKetin, 2008). In the most recent survey of out-of-treatment heroin IVDU in cities across Malaysia, more than 60% report current ATS use, and 29% inject ATS (Chawarski et al, 2012).

ATS use is associated with increased HIV transmission behavioral risks. The connection of heroin, methamphetamine and HIV in Malaysia is well documented (Chawarski et al, 2006). Increased needle sharing and risky sexual behaviors lead to increased prevalence of HIV infection. ATS use exacerbates HIV transmission risk through a number of mechanisms: ATS users report engaging in more frequent and more risky sexual behaviors while using ATS and in more frequent needle sharing. ATS is also associated with impairments of mood and executive functioning that may persist for prolonged periods and may contribute to relapse to drug use, thus all other problems.

Drug abuse has been a major problem in Kelantan for the past several decades (Suarn & NorAdam,1993) and ATS has been gaining momentum over the past decade. The number of individuals arrested annually for ATS in Kelantan increased over the past 5 years from 2900 in 2007 to 5300 in 2010. For the past 5 years, Kelantan has also led Malaysia in having the highest population prevalence of HIV infection, at 47 per 100,000 in 2008, nearly 4 times the prevalence reported for the rest of Malaysia. Kelantan also has the highest number of women with HIV in Malaysia with more than 1200 reported in 2008, suggesting that HIV is making the transition to the general population. A large proportion of treatment seeking drug users in Kelantan are HIV positives and are susceptible to high mortality (JKNK, 2012).

Minocycline is a broad-spectrum antibiotic derived from tetracycline. Minocycline is substantially more lipid-soluble than other tetracyclines, thus minocycline readily crosses the blood-brain barrier, and its potential efficacy for treating ATS dependence derives from its effects on dopamine on glutamate neurotransmission in the brain and its anti-inflammatory, neuro-protective and cognitive-enhancing effects in the brain (Dean et al, 2012). Glutamate along with dopamine plays a key role in the rewarding and addictive effects of amphetamine, methamphetamine, and other stimulants. Input from glutamatergic pathways in brain reward centers enhances dopaminergic transmission in these pathways and reward. Blockade of glutamate receptors in these regions prevents many of the behavioral effects of ATS or other stimulants and prevents reinstatement of stimulant use in animal studies. Glutamate plays a key role in learning and memory, and blockade of glutamate interferes with consolidation of memory for the rewarding effects of stimulants.