Cocaine is an alkaloid substance found in the leaves of the Erythroxylum coca plant that grows mainly in the tropical region of South and Central America.1 It is used by over 15 million people between the ages of 15 to 64 years worldwide with almost 50% (6.4 million) coming from North America.2 It is the drug responsible for most emergency room visits accounting for 40.3% visits versus 36% and 20.6% for marijuana and heroin respectively.3 Cocaine is classified by the FDA as a schedule II medication due to its addictive properties as well as its extensive adverse effect on the pulmonary, respiratory and cardiovascular systems. While in the body, cocaine enhances the activity of monoamine neurotransmitters such as dopamine and norepinephrine in the central and peripheral nervous systems by blocking its reuptake in the presynaptic cleft.4 The consequent increase of dopamine in the mesocorticolimbic reward circuit is responsible for its (cocaine) positive psychological effects.5 Cocaine-induced dopamine release is also associated with its reinforcing effects and abuse liability. Its great abuse potential is also in part due to its ability to rapidly cross the blood brain barrier and deliver a short-term intense and pleasurable ‘high’.6,7 Depending on the route of administration, the psychological effects of cocaine can be felt within 30 seconds after an Intravenous ingestion to about 90 minutes if orally consumed.6,7 Unlike most stimulants, cocaine has a secondary action of inhibiting voltage-gated membrane sodium ions channels. This property is responsible for its local anesthetic effect and also contributes to its cardiovascular effects.
Currently, psychotherapy defined as ‘a psychological treatment that aims to change problematic thoughts, feelings, and behaviors through creating a new understanding of thoughts and feelings that appear related to the presenting difficulty’8 is recommended as the first line of therapy for cocaine dependence. There are many types of psychotherapy that have been used in the treatment of addictive disorders including but not limited to cognitive behavioral therapy (CBT), supportive expressive therapy (SE), interpersonal therapy (IPT), motivational interviewing (MI) and drug counseling (DC).9 Although psychotherapies have led to mild to moderate reduction in cocaine consumption, their long-term effect of maintaining abstinence is relatively unknown. There is no consensus or evidence depicting the superiority of any psychotherapy over the other ones.
Crits-christoph et al10 designed a trial to determine the effectiveness of 4 psychotherapies in the treatment of cocaine-dependent patients. In this multicenter study, 487 patients were randomized into one of the four treatment groups: individual drug counseling (IDC) plus group drug counseling (GDC), CBT plus GDC, SE plus GDC or GDC alone. Intervention included a 6 month active phase of treatment and a 3 month booster phase and follow-up of 3 months. All treatment groups recorded significant improvements from baseline mean (SD) 30 days cocaine use of 10.4 (7.8) days (median, 8.0; range, 1-30; n=487) to 3.4 (6.5) days (median, 0; range, 0-30; n = 387) at 12 months. Among the four groups, IDC plus GDC was superior on the number of cocaine-use days and also on the Addiction Severity Index-Drug Use Composite score. The authors noted that despite the low average drug use found in in the IDC-treated patients during the 12 month trial, abstinence was not maintained in most patients as only 36%achieved 3 consecutive cocaine-free months.
Discovering an effective pharmacotherapy for cocaine use disorder remains a top research priority nationally since there are currently no FDA approved medication for the treatment of cocaine dependence. While several classes of medications have shown some efficacy in some phase two clinical trials, none has been proven to show consistency and lasting efficacy. Recent progress in the understanding of the effect of cocaine on the brain has given insight on medications that might prove efficacious. Pharmacotherapy for cocaine use disorder is geared mainly on two objectives; to assist patient in achieving an initial stage of abstinence and to help those patients avoid relapsing.11 Cocaine withdrawal symptoms such as irritability, sleep disturbance and fatigue are usually a stumbling block for patients that are trying to attain abstinence.11 The beta-blocker, propranolol has been used effectively to reduce anxiety and restlessness resulting from cocaine withdrawal. Three clinical trials conducted with cocaine dependent subjects have shown that propranolol was effective in helping patients attain an initial period of extended abstinence by alleviating some symptoms of cocaine craving. Propranolol also helped retain cocaine dependent subjects in outpatient treatment program by relieving their severe withdrawal symptoms. However, recent reports have recommended against the use of propranolol in patient exposed to cocaine due to its aggravating effects on cocaine-induced coronary vasoconstriction.12
Relapse prevention is the more difficult phase of pharmacotherapy, and it usually involves multiple trials by patients before relapse is completely avoided.11,13 Potential pharmacotherapy for cocaine dependence must be able to either inhibit cocaine-induced euphoria or reduce cocaine craving.13 Animal studies have shown that medications that inhibit the effects of excitatory amino acids like glutamate, or potentiate the inhibitory effects of GABA in the mesocorticolimbic dopamine system can reduce the reinforcing effects that are associated with cocaine abuse.11,14 A model drug will thus be one that enhances GABA in the central nervous system, inhibits cocaine-induced dopamine release, increase brain stimulation reward thresholds and attenuate the formation and expression of cocaine-associated triggers. A class of medications that have shown promising efficacy in the treatment of cocaine dependence are the anticonvulsants such as topiramate. Topiramate might be an excellent choice of medication to help attain sustained abstinence and relapse prevention due to its dual activity on both GABA and glutamate neurotransmission. Topiramate works by enhancing the cerebral levels of GABA and facilitating GABA neurotransmission, 15 while also inhibiting glutamate neurotransmission by antagonizing AMPA and kainate receptors.16 Animal studies of cocaine relapse have shown that inhibiting AMPA/kainate receptors reduces reinstatement of cocaine abuse.16
In 2013, Johnson et al17 published a report on the efficacy of topiramate for the treatment of cocaine addiction. This was a double-blind, randomized, placebo-controlled, 12-week trial that ran between November 2005 and July 2011 at the University of Virginia clinical research facilities. Participants were randomized in a 1:1 ratio into a treatment group of either daily oral topiramate or equivalent placebo. Participants were screened for 2 weeks to determine their eligibility for the trial and to record a baseline history of self-reported cocaine use which was also verified by urine drug screens. Eligibility criteria included recent history of cocaine use (defined as one or more positive urine specimen during screening), diagnosed cocaine dependence according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, and ages 18 years or older. Participants with alcohol dependence were allowed in the trial except for those with marked withdrawal symptoms that required clinical interventions. Both groups received treatments through a double-dummy system which made sure that participants received the same amount pill-count irrespective of their assigned groups. During the first 6 weeks, oral topiramate and its equivalent placebo was titrated up from 50mg/day up to a maximum dose of 300mg/day. Investigators were allowed to titrate down to a minimum of 200mg/day in cases where participants were intolerable to adverse events. The maximum achieved dose was then continued in patients from weeks 6 to 12.
The primary outcome was the weekly difference from baseline in the proportion of cocaine nonuse days during weeks 6 to 12, which was computed using an algorithm created by Elkashef et al. This algorithm determined the number of study days in which each participant used cocaine by analyzing the results of urine specimen and the number of self-reported cocaine use. The secondary outcome was urinary cocaine-free weeks during weeks 6 to 12; defined as 3 benzoylecgonine (cocaine metabolite) free urine samples by a participant in 1 week. Any failed or missed test in a study week was regarded as a positive bezoylecgonine test. Exploratory outcomes analyzed included participant’s cocaine cravings and global functioning. Craving was measured using both the Cocaine Selective Severity Assessment scale (measures the intensity and frequency of the urge to use cocaine in the past 24 hours) and the Brief Substance Craving Scale, while the Clinical Global Impression-Observer and Clinical Global Impression-Self scales assessed the severity of the participant’s cocaine dependence symptoms and its improvement during the course of the trial.
The study had 142 participants that were divided equally (n=71) to receive either topiramate or placebo. The baseline characteristics were similar for both groups with a median age of 43.6 and 43.8; male population of 71.8% and 73.2% and the mean 30 days self-reported cocaine use of 13.3 and 12.3, for topiramate and placebo groups respectively. Out of the 142 randomized participants, 13 failed enrollment by not returning to the clinic for the first double-blind visit. Of the 129 participants remaining, 72 completed the trial with 38 and 34 from the topiramate and placebo group respectively. Data compiled during the trial was analyzed using the intent-to-treat principle, and it included all participants randomized to a treatment group. Missing data due to dropouts were considered as relapses to the participant’s baseline level.
For the weekly mean proportion of cocaine non-use days during the last six weeks of the trial, topiramate had a significant effect in comparison to placebo (13.3% vs 5.3%; 95% CI, 1.4%-14.6%;effect size, 0.48; F=5.66; P=.02). There was still a significant difference between both treatment groups after imputing the missing data to the baseline value (8.9% vs 3.7%; 95% CI, 0.2%-10.1%; effect size, 0.35; F=4.15; P=.04). For the secondary outcome of urinary cocaine-free weeks between the sixth and twelfth weeks, it was noted that those in the topiramate treatment group were more likely to record urinary cocaine-free weeks when compared to the placebo group (16.6% vs 5.8%; odds ratio [OR], 3.21; 95% CI, 1.24-8.32; F=5.77; P=.02). When the results was extrapolated to include the duration of the trial (weeks 1 to 12), the topiramate treatment group still had the greater likelihood of recording urinary cocaine-free weeks in comparison to placebo (13.5% vs 6.7%; OR, 2.17; 95% CI, 1.00-4.71; P= .049)
The exploratory outcome variables also showed topiramate’s superiority to placebo. The 2 craving subscales of the Cocaine Selective Severity Assessment scale, when comparing topiramate versus placebo, recorded values of 0.573 vs 0.402 (OR, 2.00; 95% CI, 1.01-3.97; P=.048) for having ‘reportedly no desire at all for cocaine in the 24 hours’; 0.572 vs 0.379 (OR, 2.19; 95% CI, 1.08-4.42; P=.03) for having ‘reportedly no urge at all to use cocaine in the last 24 hours’; and 0.553 vs 0.364 (OR, 2.16; 95% CI, 108-4.34; P= .03) for having ‘reportedly no desire and no urge at all for cocaine in the last 24 hours.’ The Brief Substance Craving Scale measured the intensity, frequency and duration of craving in the past 24 hours and recorded a value of 0.499 vs 0.300 (OR, 2.33; 95% CI, 1.15-4.71; P=.02) for having ‘reportedly no craving at all’ for the topiramate and placebo group respectively.
The clinical Global Impression-Observer scale (done by clinicians), also showed an association with topiramate treatment and significant decrease in participants’ levels of cocaine dependence, estimating a mean difference of -1.74 (95% CI, -3.12 to -0.35; P=.02) for topiramate vs placebo. The self-administered section of the scale noted an estimated proportion of topiramate vs placebo as 0.502 vs 0.310 (OR, 2.25; 95% CI, 1.05-4.83; P = .04) for having ‘reportedly no symptoms or borderline symptoms and 0.704 vs 0.550 (OR, 1.95; 95% CI, 0.91-4.17; P = .09) for being ‘reportedly very much improved or much improved’ in the global severity and improvement of cocaine dependence.
The number of adverse events was similar for both treatment groups with 60 participants from the topiramate group reporting adverse events in comparison to 57 participants from placebo. The most frequently occurred adverse events were decreased weight (63.5% and 49.3%), fatigue (45.1% and 35.2%), headache (38.0% and 38.0%), paresthesia (50.7% and 21.1%), taste perversion (42.3% and 23.9%) and diarrhea (33.8% and 25.4%) for topiramate and placebo respectively. Participants also reports difficulty with concentration, with the topiramate group significantly higher than the placebo group at 26.8% vs 11.% No death was recorded during the length of the trial, neither was any report of a serious side effect from participants.
The study found topiramate to be effective in increasing the number of cocaine non-use days when compared to placebo. Participants that received topiramate were also more likely to have urinary cocaine-free weeks as determined by the absence of benzoylecgonine (cocaine metabolite) in the urine. Additionally, participants from the topiramate treatment group reported significant reductions in the intensity and frequency of cravings in the past 24 hours and an improvement in their overall global functioning in comparison to the placebo treatment group. Limitations of the study include a low retention rate, lack of follow-up with participants, and a short duration of trial. By week 11 of the trial, the retention rates were only 63.5% and 53.0% for topiramate and placebo recipients respectively. Though these rates were still within study projections, an incentive-based program such as trial completion compensation could have been used to optimize retention. In addition, the study only lasted 12 weeks and this gave the investigators only 6 weeks to measure the efficacy of topiramate since the optimal dose of 300mg per day was not achieved until the sixth week. A lengthier period of study will enable investigators to properly assess topiramate’s therapeutic effects as well as the sustainability of such effect after the discontinuation of therapy.
Although this study is not without its limitations, it provides promising reports that can position topiramate as an effective choice in the treatment of cocaine dependence. The effect size of topiramate (0.48) is impressive mainly because other medications such as naltrexone and acamprosate have been approved by the Food and Drug administration for the treatment of another addictive disorder with a much lower effect size of 0.12 and 0.36 respectively. Further studies will be needed to assess the long-term efficacy of topiramate and also to determine if such effects are sustainable after medication discontinuation.
Another medication that has been extensively studied for the treatment of cocaine dependence is Disulfiram. Disulfiram is primarily used to treat chronic alcoholism and it works by causing an unpleasant reaction to alcohol consumption through its blockade of the enzyme aldehyde dehydrogenase which leads high levels of acetaldehyde in the body. Disulfiram was evaluated as a possible treatment option for cocaine dependence due to its ability to prevent the breakdown of cocaine and dopamine in the body.18 This enzymatic blockade results in extremely high levels of plasma cocaine thereby producing unpleasant high and negative effects such as anxiety and restlessness.18, 19 Clinical trials done on Disulfiram 250mg daily for the treatment of cocaine dependence have so far produced conflicting reports. Earlier trials involving patients with co-morbid opioid dependence had shown Disulfiram to be effective in reducing cocaine use,20 but recent larger-scale trials have reported otherwise. There are also general health and safety concerns in patients who do not refrain completely from cocaine use because of its (disulfiram) interaction with cocaine and alcohol.20
Oliveto et al21 examined the dose-related effectiveness of Disulfiram for the treatment of cocaine dependence in 161 patients who had co-morbid opioid dependence and were stabilized on methadone treatment. This was a 14-week, multi-center, double blind, randomized, placebo-controlled clinical trial. Patients were stabilized on methadone during the first two weeks, and were randomly assigned to receive Disulfiram at doses 0, 62.5, 125, or 250 mg/day from weeks 3 to 14. They were also given weekly individual cognitive behavioral therapy. Patients were required to report for a thrice-weekly urine test that tested for benzoylecgonine and to report any cocaine use each week. A total of 104 patients completed the study. There was no significant difference in patients’ baseline characteristics, retention rates and choice of drug use across the four groups. From weeks 2 to 14, the amount of cocaine-positive urine samples were increased over time in the 62.5 (t = 3.74, df = 4806, p = 0.0002; slope = 0.08) and 125 (t = 5.45, df = 4806, p < 0.0001; slope = 0.18) mg disulfiram groups relative to placebo (slope = -0.05), but decreased over time in both the 250mg disulfiram and placebo groups ( t = -1.33, df = 4806, p = 0.18; slope = -0.10 and -0.05, respectively. While, there was no significant difference over time found in the amount of self-reported cocaine use in the 62.5 (t=1.17, df = 1068, p = 0.24; slope = -0.009) and 250 (t = -1.28, df = 1076, p = 0.20; slope = -0.074) mg disulfiram groups relative to placebo (slope = -0.04), an increase was discovered in the 125mg disulfiram group (t = 2.02, df = 954.1, p = 0.04; slope = 0.013). The study concluded that disulfiram at doses less than 250mg per day may be contraindicated for the treatment of cocaine dependence. More clinical trials were recommended to examine the effectiveness of disulfiram at doses higher that 250mg per day. Modafinil, a wake-promoting agent approved by the Food and Drug Administration for the treatment of narcolepsy has also been studied for the treatment of cocaine dependence. Its glutamate-enhancing effects was hypothesized to be efficacious in cocaine dependence based on reports that showed that chronic cocaine consumption reduces glutamatergic synaptic strengths in the nucleus accumbens22 and also reduces extracellular glutamate levels.23 This is further strengthened by the fact that the stimulating effects of modafinil are largely opposite to cocaine withdrawal symptoms, and modafinil would be expected to alleviate the severity of these symptoms. Since severe cocaine withdrawal symptoms predicts poor treatment outcome, reversal of these symptoms by modafinil therapy is expected to improve cocaine abstinence and relapse prevention.24 Dackis et al25 assessed the effect of modafinil on the clinical outcome of cocaine-dependent patients who were concurrently receiving standardized psychosocial treatment. In a double-blind, placebo-controlled format, 62 cocaine-dependent patients that were predominantly African-Americans were randomized to receive 400mg daily dose of Modafinil or equivalent placebo tablets for 8 weeks while also undergoing twice-weekly cognitive behavioral therapy. Modafinil-treated patients submitted significantly more benzoylecgonine-free samples when compared to placebo treated patients (42.3% vs. 24.0%). Additionally, greater proportion of patients in the modafinil group (32%) attained prolonged abstinence (defined as 3 consecutive weeks of cocaine-free urine samples) in comparison to placebo (13%) during the length of the trial (X2 = 3.84, df = 1, p = 0.05). The authors concluded that modafinil was significantly effective in attaining cocaine abstinence but recommended confirmation of these findings using a bigger sample size. Bupropion is an antidepressant that is also used for smoking cessation. It is a norepinephrine and dopamine reuptake blocker that promotes positive mood due to increased levels of dopamine in the mesolimbic system. Consequently, bupropion might be effective in treating cocaine dependence by ameliorating the effects of an impaired dopaminergic system which is associated with chronic administration of cocaine. An earlier study by Margolin et al26 to test bupropion's efficacy in cocaine-dependent patient concurrently undergoing methadone therapy showed no overall difference in cocaine use between bupropion and placebo treatment groups. Poling et al27 then set to out determine the efficacy of bupropion for cocaine dependence when compared with contingency management (CM) in methadone maintained subjects. This 25-week, placebo-controlled, double-blind trial randomly assigned 106 opiate dependent subjects into 1 of 4 treatment groups: CM and placebo (CMP), CM and 300mg/d of bupropion (CMB), voucher control and placebo (VCP), or voucher control and bupropion (VCB). Contingency management involved rewarding subjects with a monetary-based voucher for each cocaine and opioid-free urine sample. Vouchers were also given out for completing finishing abstinence-related activities. Eligible subjects must meet DSM-IV diagnoses criteria for opioid dependence, self-report opiate and cocaine use in the prior weeks before study, and have laboratory results confirming the use of opioid and cocaine in the previous month before study resumption. Exclusion criteria included current diagnosis of dependence on alcohol or any substance other than tobacco, opiates and cocaine; history of psychosis; past seizure episode; history of anorexia nervosa or bulimia; current use of psychoactive medications; elevated liver enzymes levels; and pregnant or nursing mother. Primary outcome was the results of cocaine and opiate urine sample screening performed three times weekly. Participants began methadone therapy from week 1 with an initial dose of 30mg and titrated up to a target dose of 60mg by the end of the week. Those not adequately maintained on 60mg were further titrated up to a maximum dose of 120mg. Subjects remained on methadone therapy throughout the duration of the study. Bupropion was initiated for participants in the active medication group during the second week of the trial at an initial dose of 75mg/d, and titrated up by 75mg every other day until a target dose of 300mg was achieved by week's end. Participants remained on this dose for the remaining 23 weeks of the study. Participants in the CM groups received vouchers for every negative urine samples regardless of whether they were receiving bupropion or placebo. Participant received $3 worth of vouchers for the first negative sample and this amount was increased by $1 up to a maximum of $15 per sample for each consecutive sample that came back opioid and cocaine free. The voucher amount was reset back to $3 in the event of a positive sample or a missed test. Reward vouchers were provided for negative samples from weeks 1 to 13 only though urine samples continued to be tested thrice weekly from weeks 14 to 25. Vouchers were also awarded to participants for the completion of weekly abstinence-related activities. Activities were created with the goal of facilitating abstinence in participants and they included programs like 'attend an Alcoholics Anonymous meeting' or 'meet with staff regarding graduate equivalency diploma classes.' Participant received $3 voucher for a completed activity and the voucher was increased by $1 for each continuous completion of activity up to a threshold of $10 per activity. Similar to the urine testing, every failed or unverified activity resulted in the decrease of the voucher amount back to $3. Voucher rewards for abstinence related activities lasted through the 25 weeks of the study. Participant in the VC group were given $3 vouchers for every sample submitted without regards to the results of the sample and an increase of $1 per week for submitting all 3 samples. There were no significant differences across the four groups in demographics and baseline characteristics. Retention rates were also similar with 60% of CMP, 56% of CMB, 63% of VCP and 56% of VCB participants retained through the duration of the study. The study reports that cocaine-positive urine samples were significantly reduced from weeks 3 to 13 in the CMB participants, and the reduction was maintained even after reinforcements for negative urine samples were discontinue from weeks 14 to 25 (slope = 0.006, P < .001). Conversely, there was a significant increase of cocaine-positive urine samples among CMP patients from weeks 3 to 13 though the rate of increase slowed down in weeks 14 to 25. Both VCP and VCB patients had increasing probability of a cocaine positive result from weeks 3 through 25. HLM Poisson analysis of cocaine results from weeks 24 to 25 reported an observed probability of a cocaine-positive sample as 0.33 (CMB), 0.57 (CMP), 0.66 (VCB) and 0.74 (VCP). The CMB group had significantly less positive results in than all other groups (P < .001 for all). The average continuous cocaine-free weeks was also higher for the CMB group with 3.04 (VCP), 4.9 (VCB), 4.30 (CMP) and 6.7 (CMB). Limitation of the study includes self-administration of the evening dose by participants at home. Investigators had to rely on patient reports to monitor compliance. Additionally, there was no analysis done to measure the effect of bupropion on cocaine withdrawal symptoms even though it was hypothesized as part of bupropion's action. Nevertheless, the authors believe that this study accurately showed a significant improvement in treatment outcomes when combining CM with bupropion therapy. Even though the mechanism behind the synergistic effect of the dual therapy is unknown, it is suggested that their efficacy might be due to a complimentary action of bupropion helping participants attain initial abstinence while CM helps maintain abstinence through it reinforcing incentives. More studies are needed to help outline bupropion's mechanism of action specific to the treatment of cocaine dependence, and evaluate concerns about the long-term efficacy of CM. Finally, a promising anti-cocaine vaccine is currently in the preliminary stages of clinical trials. Its proposed mechanism of action is through production of cocaine specific antibodies that directly binds with circulating cocaine molecules in the body. Binding with cocaine molecules will adversely affect their ability to easily cross the blood brain barrier. Prevention of cocaine molecules of rapidly getting into the brain will in-turn reduces cocaine-induced euphoria and reinforcing properties. This is particularly intriguing as it offers an alternative therapy that is potentially free of both psychoactive effects and drug-drug interactions that are associated with other therapies. Martell et al28 was a 24-week, randomized, double-blind, placebo-controlled, phase 2b efficacy trial that was done to determine the safety and efficacy of a novel vaccine for the treatment of cocaine dependence. Participants were randomized equally to receive either vaccine or placebo during the trial. The primary objective was determining the efficacy of the vaccine in the reduction of cocaine use when compared to placebo. This was achieved by collecting and analyzing participants' urine samples each week using an intent-to-treat analysis. Secondary objectives included determining the safety and tolerability of the vaccine, as well as reaffirming previously confirmed immunogenicity using levels of IgG anticocaine antibodies present in the body. The researchers hypothesized a decrease in cocaine use of about 25% in the placebo group and 50% in the vaccinated group, and concluded that 60 participants were needed in each treatment group to achieve a statistical power of 0.8 with alpha level of .05. Eligible participants had to be between the ages of 18 to 55 years, diagnosed with cocaine and opioid dependence using the DSM-IV criteria, had a recent positive urine sample for cocaine, and without a clinically unstable chronic condition. Female participants had to either be non-childbearing or agreeable to the use of contraception. Exclusion criteria included major medical or psychiatric illness, current infection or fever, current use of psychotropic medications, blood transfusion within 3 months of screening, and corticosteroid therapy within 30 days of screening. Participants received either 360??g of active vaccine (succinylnorcocaine-recombinant cholera toxin B-subunit protein) or equivalent placebo (saline) in a 0.5mL injection administered intramuscularly. They were given 5 doses at weeks 0,2,4,8 and 12 and efficacy assessment did not commence until the eighth week when significant levels of IgG anticocaine antibody levels were expected. Participants were also on methadone maintenance therapy which started approximately 2 weeks before the first dose of vaccination with a stabilized mean (SD) dose of 83 (16) mg daily by week 8 of the study. By week 21, participants were either detoxified or transferred to another methadone treatment program. There was also weekly 30 to 45 minutes cognitive behavioral relapse-prevention therapy sessions that was run by trained counselors. Participants' urine samples were tested for benzoylecgonine (BE) during screening, methadone initiation and thrice weekly through the length of the trial to detect cocaine usage. Vaccine efficacy was analyzed using hierarchical linear modeling (HLM) to compare participants' weekly urine samples. Out of the 115 participants randomized, 94 (82%) were retained throughout the 24 weeks span of the trial. Retention was comparable in both vaccine (55) and placebo (47) groups. Demographically, participant were similar in age, sex and ethnicity but majority of the participants were whites in both treatment groups (>80%). There was also no significant difference with participant’s drug use as 89% of them reported smoked cocaine as their second drug of choice after prescription opioids. Furthermore, both treatment groups recorded similar opioid-free urine samples and methadone dosage after the first 2 weeks of methadone maintenance therapy. Out of the 58 participants randomized to the active vaccine treatment group, 55 completed the 5 doses of vaccinations. 21(38%) attained efficacious serum IgG antibody levels of 43??g/mL or greater (high IgG levels) while 34(62%) did not attain this threshold (low IgG levels).
There was a significant difference in the weekly cocaine-free urine samples as the study progressed from weeks 1 to 16 between the active vaccine (vaccine X time interaction; Z = 8.7, P= .001) and placebo (placebo X time interaction: Z = 5.4, P < .001) groups. However, HLM analyses reported no significant difference in the amount of cocaine-free urine samples between both groups from weeks 16 to 24. This was due to the expected drop in serum IgG antibody levels weeks after the last dose of the administered vaccine. From weeks 9 to 16, participants with high IgG levels had a significant higher results of cocaine-free urine samples than participants with low IgG levels and placebo (45% vs 35%) respectively. The vaccine proved to be safe as there were no reported serious adverse events related to the vaccine. The most common adverse events reported were injection site induration (3% vs 0%), site tenderness (10% vs 6%), feeling cold (12% vs 7%), hot flashes (19% vs 12%), hyperhidrosis (15% vs 10%) and nausea (14% vs 2%) for the vaccine and placebo groups respectively. The study found a significant reduction of cocaine usage by participants who had high IgG levels of 43??g/mL or greater which was predetermined as critical to the vaccine's efficacy and its ability to minimize cocaine's euphoric effect. However, only 38% of vaccinated participants were able to attain this target antibody level, and they (IgG levels) substantially reduced between weeks 16 to 24. While this is a step in the right direction, optimization of this vaccine is needed to deliver improved efficacy. The vaccine will have to be improved so as to increase the proportion of the population that can attain a therapeutic level of antibodies. Furthermore, an optimized version of the vaccine must also be able to maintain the above-mentioned levels of antibodies for an extended period of time in order to effectively maintain abstinence in patients. In conclusion, there are still no medications approved by the Food and Drug Administration for the treatment of cocaine dependence. Recent advances in the understanding of cocaine addiction and its effects (physical and psychosocial) on dependent individuals have led to the discovery of promising pharmacotherapy. So far, none of the medications have demonstrated consistent and convincing evidence of their efficacy in the treatment of cocaine dependence. Furthermore, majority of the clinical trials performed so far have involved a small sample size. Hence, larger studies are needed that will not only have a bigger population size, but will also been conducted long enough to determine the sustainability of these medications. 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