Aims We evaluated the immunogenicity, efficacy, and safety of succinylnorcocaine conjugated to cholera toxin B protein as a vaccine for cocaine dependence. Methods This 6-site, 24 week Phase III randomized double-blind placebo-controlled trial assessed efficacy during weeks 8 to 16. We measured urine cocaine metabolites thrice weekly as the main outcome. Results The 300 subjects (76% male, 72% African-American, mean age 46 years) had smoked cocaine on average for 13 days monthly at baseline. We hypothesized that retention might be better and positive urines lower for subjects with anti-cocaine IgG levels of ≥ 42 μg/mL (high IgG), which was attained by 67% of the 130 vaccine subjects receiving five vaccinations. Almost 3-times fewer high than low IgG subjects dropped out (7% vs 20%). Although for the full 16 weeks cocaine positive urine rates showed no significant difference between the three groups (placebo, high, low IgG), after week 8, more vaccinated than placebo subjects attained abstinence for at least two weeks of the trial (24% vs 18%), and the high IgG group had the most cocaine-free urines for the last 2 weeks of treatment (OR=3.02), but neither were significant. Injection site reactions of induration and tenderness differed between placebo and active vaccine, and the 29 serious adverse events did not lead to treatment related withdrawals, or deaths. Conclusions The vaccine was safe, but it only partially replicated the efficacy found in the previous study based on retention and attaining abstinence.

Opioid Use Disorder (OUD) is a significant public health concern, negatively impacting the medical, psychological, and social domains of an individual's life as well as creating substantial burdens for society. Effective treatment interventions are necessary for reduction of OUD and its consequences. Pharmacotherapy represents a central component of management. Areas covered: This review focuses on pharmacologic strategies for OUD treatment, discussing both primary as well as adjunctive therapy modalities. We will discuss both medications used during detoxification to treat withdrawal, as well as those used as maintenance therapy. Detox medications include alpha-2 adrenergic agonists, such as clonidine, as well as the μ-opioid agonist, methadone, and the μ-opioid partial agonist, buprenorphine. Opioid maintenance treatment (OMT) is also discussed, focusing on those medications meant to substitute abused opioids and includes the agonists, methadone and buprenorphine, as well as supervised intravenous heroin, and opioid antagonist, naltrexone. Expert opinion: Medication therapy for treatment of OUD has demonstrated efficacy and is of great clinical benefit. While agonist treatment with methadone or buprenorphine remains the gold standard, there is an important place for use of long-acting antagonist therapy with naltrexone. Continued investigation into treatment paradigms and behavioral platforms which optimize medication therapy is most needed.

Cocaine is a stimulant that leads to the rapid accumulation of catecholamines and serotonin in the brain due to prevention of their re-uptake into the neuron that released the neurotransmitter. Cocaine dependence is a public health concern and cause of significant morbidity and mortality worldwide. At present, there are no approved medications for the treatment of this devastating illness, and behavioral interventions have proven to be of limited use. However, there have been a number of recent trials testing promising agents including dopamine agonists, GABAergic medications and the cocaine vaccine. Here we discuss the most recent human clinical trials of potential medications for treatment of cocaine dependence, as well as pre-clinical studies for another promising agent, levo tetrahydropalmatine. Examination of these recent findings shows promise for GABAergic medications and the cocaine vaccine, as well as unique medications such as disulfiram, whose mechanism remains to be determined. Future work may also confirm specific subgroups of patients for treatment response based on clinical characteristics, biomarkers and pharmacogenetics. This review highlights the need for further, bigger studies in order to determine optimal clinical usage.

Background Medications decreasing central noradrenergic activity have been associated with attenuation of cocaine effects. Aims This pilot study examined the efficacy of doxazosin versus placebo for reducing cocaine use in treatment-seeking cocaine dependent persons. Methods We screened 108 cocaine dependent subjects and assigned 35 participants to receive either doxazosin (8mg/day) or placebo for 13 weeks. Participants were titrated on the study medication according to two different schedules. During the initial phase of the study, patients were titrated onto the study medication over an 8-week period (DOX-slow). After reviewing data from our human laboratory study, a second phase was initiated, wherein titration was accelerated to a 4-week period (DOX-fast). All participants received weekly cognitive behavioral therapy. Urine toxicology was performed thrice weekly. Results Baseline subject characteristics were comparable. Thirty subjects entered the study: 8 subjects in DOX-slow, 9 subjects in DOX-fast, and 13 subjects in placebo. Total number of cocaine-negative urines was significantly increased in the DOX-fast group; and percentage of total cocaine-negative urines by group were 10% for DOX-slow group, 35% for DOX-fast group, and 14% for placebo (chi-square=36.3, df=2, p<0.0001). The percentage of participants achieving two or more consecutive weeks of abstinence by group was 0% for DOX-slow group, 44% for DOX-fast group, and 7% for placebo (chi-square=7.35, df=2, p<0.023). Conclusions This pilot study suggests the potential efficacy of doxazosin when rapidly titrated in reducing cocaine use.

Comorbid PTSD and SUD amplifies their lethality and treatment complexity. Although they share important neurobiology, these patients uncommonly respond to a single pharmacotherapy such as sertraline or disulfiram and more typically require medication combinations and consideration of the specific type of SUD.

Research into cocaine pharmacotherapy must continue to show innovation. Given that medications targeting single neurotransmitter systems have demonstrated little efficacy in treatment of cocaine use disorder, the recent focus on pharmacotherapeutic agents with multiple neurobiochemical targets represents an exciting shift in trial design and approach. Additionally, consideration of pharmacogenetics may be helpful in identification of subpopulations of cocaine-dependent individuals who may preferentially respond to medications.

Substance use disorders (SUD) are a significant threat to both individual and public health. To date, SUD pharmacotherapy has focused primarily on agonist medications (i.e. nicotine replacement therapy for tobacco use disorder; methadone and buprenorphine for opioid use disorder), antagonist medications (i.e. naltrexone for opioid use disorder), and aversive therapy (i.e. disulfiram for alcohol use disorder). Pharmacotherapeutic approaches utilizing an immunological framework for medication development represent an important focus of study for treatment of these illnesses. Areas covered: This review discusses vaccines for treatment of substance use disorders. Using PubMed ( https://www.ncbi.nlm.nih.gov/pubmed/ ), we searched both preclinical and human clinical trials of vaccines for treatment of nicotine, cocaine, methamphetamine, and opioid use disorders. In addition, we searched for recently developed strategies for enhancement of the immunologic response through alteration of conjugate molecules and adjuvants. Expert commentary: Despite challenges in human clinical trials of SUD vaccines, a number of strategies have been introduced which may ultimately improve efficacy. These challenges, as well as their implications for vaccine development, are discussed. Additionally, the optimal conditions for research study and treatment are considered.

Buprenorphine can align addiction treatment with treatments for other chronic medical illnesses. However, preventing diversion will require graduate and continuing medical education and integrated care models for delivery of buprenorphine to those in need.