Minding the brain: the role of pharmacotherapy in substance-use disorder treatment.

With its medicalization as a brain-based disease, addiction has come to be regarded as amenable to biomedical treatment approaches, most commonly pharmacotherapy. Various vulnerabilities are recognized to contribute to maladaptive substance use, and have been linked to diverse neurobiological alterations that may be targeted with pharmacotherapy: withdrawal, craving and cue reactivity, and aberrant reward processing are the most significant. Here, we summarize current thinking regarding pharmacotherapy for substance-use disorders, grouping medications by the type of vulnerability they propose to address and providing insight into their neurobiological mechanisms. We also examine the limitations of the brain-based disease model in addiction treatment, especially as these shortcomings pertain to the place of pharmacotherapy in recovery. We conclude by sketching a framework whereby medications might be integrated fruitfully with other interventions, such as behavioral, existential, or peer-based treatments, targeting aspects of addiction beyond neurobiological deficits.

La medicalización de la adicción como una enfermedad de base cerebral, ha llegado a ser considerada como una condición sensible a un abordaje terapéutico biomédico, en especial con farmacoterapia. Se han reconocido diversas vulnerabilidades que contribuyen a la mala adaptación al uso de sustancias, las cuales se han vinculado con diversas alteraciones neurobiológicas y con blancos farmacológicos; las más importantes son la abstinencia, el craving y la reactividad a señales, junto con el procesamiento aberrante de la recompensa. En este artículo se resume el pensamiento actual relacionado con la farmacoterapia para los trastornos por uso de sustancias, se agrupan los medicamentos de acuerdo con el tipo de vulnerabilidad a la que ellos están dirigidos y se proporciona una visión acerca de sus mecanismos neurobiológicos. También se examinan las limitaciones del modelo de enfermedad cerebral en el tratamiento de las adicciones, especialmente porque estas alteraciones se relacionan con el papel que tiene la farmacoterapia en la recuperación. Para concluir se propone un esquema en que los medicamentos se pueden integrar de manera fructífera con otras intervenciones como los tratamientos conductuales, existenciales o basados en pares, focalizando aspectos de la adicción más allá de las alteraciones neurobiológicas.

Médicalisée comme une maladie cérébrale, l'addiction est maintenant considérée comme étant susceptible de répondre à des traitements biomédicaux, le plus souvent de la pharmacothérapie. Des vulnérabilités diverses, responsables de l'utilisation inadaptée de substances, sont liées à différentes altérations neurobiologiques et représentent des cibles pharmacologiques dont les plus significatives sont le sevrage, l'état de manque, la réactivité aux indices environnementaux et un fonctionnement anormal du circuit de la récompense. Nous résumons ici les concepts actuels sur la pharmacothérapie des troubles liés à l'utilisation de substances en regroupant les médicaments par type de vulnérabilité traitée et en donnant un aperçu de leurs mécanismes neurobiologiques. Nous analysons aussi les limites du modèle de maladie cérébrale dans le traitement des addictions, surtout lorsque ces failles concernent la place de la pharmacothérapie dans la guérison. Nous concluons en esquissant un cadre selon lequel les médicaments pourraient trouver leur place avec succès aux côtés d'autres traitements comme les traitements comportementaux, existentiels ou collégiaux et qui ciblent des aspects de l'addiction au-delà des déficits neurobiologiques.

Older, Less Regulated Medical Marijuana Programs Have Much Greater Enrollment Rates Than Newer 'Medicalized' Programs.

Twenty-three states and the District of Columbia have passed laws implementing medical marijuana programs. The nineteen programs that were in operation as of October 2014 collectively had over one million participants. All states (including D.C.) with medical marijuana laws require physicians directly or indirectly to authorize the use of marijuana at their discretion, yet little is known about how medical marijuana programs vary regarding adherence to basic principles of medical practice and associated rates of enrollment. To explore this, we analyzed marijuana programs according to seven components of traditional medical care and pharmaceutical regulation. We then examined enrollment rates, while controlling for potentially confounding state characteristics. We found that fourteen of the twenty-four programs were nonmedical and collectively enrolled 99.4 percent of participants nationwide, with enrollment rates twenty times greater than programs deemed to be "medicalized." Policy makers implementing or amending medical marijuana programs should consider the powerful relationship between less regulation and greater enrollment. Researchers should consider variations across programs when assessing programs' population-level effects.

Naltrexone-facilitated buprenorphine discontinuation: a feasibility trial.

RATIONALE: Buprenorphine is an effective and popular treatment for opioid dependence. It remains unclear, however, when or how to transition stable buprenorphine-maintained individuals to complete abstinence. This trial investigates the feasibility of using naltrexone to facilitate buprenorphine discontinuation in stable individuals who had tolerated a taper to 2mg or less but were unable to terminate entirely due to withdrawal-related distress. METHODS: The sample consisted of 6 buprenorphine-maintained individuals in sustained full remission, and who had tolerated a taper but were unable to discontinue altogether. A rapid induction procedure was performed, which included supervised buprenorphine discontinuation, oral naltrexone titration with a starting dose of 6.25mg, and administration of long-acting injectable naltrexone. Participants were followed weekly for 5weeks after the injection, with telephone follow-up occurring at 6months. RESULTS: The rapid induction procedure was well tolerated. There was no observed or reported clinical worsening over the course of study participation. Notably, no participants experienced an increase in Subjective Opioid Withdrawal Scale (SOWS) scores after the first oral dose of NTX as compared to day 1 (24hours after last dose of buprenorphine); instead, SOWS scores decreased between days 1 and 7 (p=0.043). All participants were able to discontinue buprenorphine and to remain opioid free during the trial and at follow-up. CONCLUSIONS: This preliminary trial represented for all participants the first successful attempt at buprenorphine discontinuation. Further research is needed to better understand if naltrexone is effective at facilitating buprenorphine discontinuation, as well as the feasibility of a sequential approach (buprenorphine stabilization to naltrexone) for opioid use disorders.

Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations.

As the nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment's abuse potential.

Improving temporal efficiency of outpatient buprenorphine induction.

Buprenorphine induction poses a barrier for physician adoption of office-based opioid dependence treatment. We conducted a retrospective chart review of the first 41 patients inducted at a newly established outpatient treatment program to examine the induction process and determine strategies associated with greater induction efficiency. Timed withdrawal scales, medication log, and notes enabled reconstruction of the initial day of buprenorphine treatment. To assess change with experience, consecutive patients were divided into three chronological groups for analyses (Phases 1-3). The time required for induction was substantial in Phase 1 (mean 5.5 hours), but temporal efficiency improved to a mean 1.5 hours spent at the program by Phase 3 (p < .001). Phase 2-3 patients arrived to the program after significantly longer opioid abstinence and were in greater withdrawal, with mean Clinical Opioid Withdrawal Scale scores of 6, 10, and 10 for Phases 1-3, respectively (p < .01). Patients in the later phases had less time delay to medication initiation, 5 minutes in Phase 3 compared to 133 minutes in Phase 1 (p < .001). The mean 7-mg buprenorphine dose administered in the office did not differ between groups, but occurred over a smaller time interval for later phases indicating more rapid titration. Patients in the later phases had more rapid withdrawal relief after buprenorphine initiation and were more likely to have used preinduction ancillary withdrawal medication. The study sheds light on the induction barrier and provides practical procedural information to inform clinical guidelines and hopefully mitigate procedural aspects of the induction barrier.

Imaging dopamine transmission in cocaine dependence: link between neurochemistry and response to treatment.

OBJECTIVE: Previous research has shown that dopamine signaling in the limbic striatum is crucial for selecting adaptive, motivated behavior and that disrupted dopamine transmission is associated with impulsive and maladaptive behavior. In humans, positron emission tomography (PET) imaging studies have shown that cocaine dependence is associated with the dysregulation of striatal dopamine signaling, which is linked to cocaine-seeking behavior. The goal of the present study was to investigate whether this association applies to the treatment setting. The authors hypothesized that dopamine signaling in the limbic striatum would be associated with response to a behavioral treatment that uses positive reinforcement to replace impulsive cocaine use with constructive personal goals. METHOD: Prior to treatment, cocaine-dependent subjects underwent two PET scans using [(11)C]raclopride, before and after the administration of a stimulant (methylphenidate), for measurement of striatal dopamine D(2/3) receptor binding and presynaptic dopamine release. RESULTS: Both of the outcome measures were lower in the volunteers who did not respond to treatment than in those who experienced a positive treatment response. CONCLUSIONS: These findings provide insight into the neurochemistry of treatment response and show that low dopamine transmission is associated with treatment failure. In addition, these data suggest that the combination of behavioral treatment with methods that increase striatal dopamine signaling might serve as a therapeutic strategy for cocaine dependence.

Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers.

BACKGROUND: Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double-blind, cross-over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs). METHODS: Intravenous heroin users (n = 12) lived in the hospital for 8-9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. RESULTS: Intravenous buprenorphine/naloxone was self-administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self-administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of 'drug liking' and 'desire to take the drug again' were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. CONCLUSIONS: These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment.

Dopamine type 2/3 receptor availability in the striatum and social status in human volunteers.

BACKGROUND: Previous positron emission tomography (PET) imaging studies in nonhuman primates have shown that striatal dopamine type 2/3 (D(2/3)) receptors correlate with social hierarchy in monkeys and that dominant animals exhibit higher levels of D(2/3) receptor binding. The goal of the present study was to examine this phenomena in human subjects using PET and the radiotracer [(11)C]raclopride. METHODS: Fourteen healthy volunteers were scanned with [(11)C]raclopride to measure D(2/3) receptor binding potential (BP). Social status was assessed using the Barratt Simplified Measure of Social Status. In addition, participants were asked to assess their level of social support using the Multidimensional Scale of Perceived Social Support (MSPSS). RESULTS: A correlation was seen between social status and dopamine D(2/3) receptors, where volunteers with the higher status had higher values for [(11)C]raclopride BP. A similar correlation was seen with the perceived social support, where higher [(11)C]raclopride BP correlated with higher scores on the MSPSS. CONCLUSIONS: The results of this study support the hypothesis that social status and social support is correlated with D(2/3) receptor binding.

Lower level of endogenous dopamine in patients with cocaine dependence: findings from PET imaging of D(2)/D(3) receptors following acute dopamine depletion.

OBJECTIVE: Previous positron emission tomography (PET) imaging studies have demonstrated that cocaine dependence is associated with a decrease in dopamine type 2 and 3 (D(2)/D(3)) receptor binding in cocaine-dependent individuals relative to healthy comparison subjects. However, given the nature of PET imaging, it is possible that the measured decrease in radiotracer binding results from an increase in baseline dopamine levels. The purpose of this study was to measure D(2)/D(3) receptors following acute dopamine depletion in cocaine-dependent volunteers relative to healthy comparison subjects. METHOD: Cocaine-dependent volunteers (N=15) and healthy matched comparison subjects (N=15) were scanned using PET, with the dopamine receptor radiotracer [(11)C]raclopride, at baseline and again following acute depletion of endogenous dopamine via alpha-methyl-para-tyrosine (AMPT) administration. Changes in radiotracer binding were measured in the subdivisions of the striatum (caudate, putamen, and ventral striatum) in addition to the striatum as a whole. RESULTS: Findings revealed that cocaine-dependent volunteers exhibited lower levels of endogenous dopamine relative to comparison subjects, which was measured as an increase in [(11)C]raclopride binding following AMPT administration. The increase in [(11)C]raclopride binding in the striatum was 11.1% (SD=4.4%) in healthy comparison subjects and 5.7% (SD=5.9%) in cocaine-dependent volunteers. Similar differences were seen in the subdivisions of the striatum. CONCLUSIONS: The decrease in striatal D(2)/D(3 )receptors associated with cocaine dependence cannot be attributed to higher levels of endogenous dopamine.

Dopamine D1 receptors in cocaine dependence measured with PET and the choice to self-administer cocaine.

The goal of this study was to determine D(1) receptor availability in human cocaine-dependent (CD) subjects and matched healthy controls (HCs). In addition, the CD subjects performed cocaine self-administration sessions in order to explore the association between D(1) receptor availability and cocaine-seeking behavior. Twenty-five CD subjects (40+/-4 years, 19M/6 F) and 23 matched HCs (38+/-4 years, 19M/4F) were scanned with PET and the radiotracer [(11)C]NNC 112. During the cocaine self-administration sessions, CD volunteers were given the choice to self-administer cocaine (0, 6, and 12 mg) or to receive a monetary voucher worth $5. D(1) receptor availability was measured in the limbic, associative, and sensori-motor striatum in addition to cortical brain regions. No difference in D(1) receptor availability was seen between the two groups. A negative association was seen between D(1) receptor BP(ND) in the limbic striatum and the choice for the 6 mg dose of cocaine (r=-0.47, p=0.02, corrected for age). These results do not support the hypothesis that cocaine dependence is associated with a reduction in D(1) receptor availability in the striatum. However, within the CD subjects, low D(1) receptor availability in the ventral striatum was associated with the choice to self-administer cocaine, suggesting that low D(1) receptor availability may be associated with an increased risk of relapse in cocaine dependence.

Dextromethorphan and quinidine combination for heroin detoxification.

Dextromethorphan (DM) is a low-affinity, non-competitive NMDA receptor antagonist that has shown promise in preclinical and preliminary clinical studies for the reduction of opioid withdrawal symptoms, but when used at higher doses, it is associated with deleterious side effects attributed to its metabolite, dextrorphan. A clinical trial was therefore conducted to test the withdrawal-suppressant effect of a combination of dextromethorphan with quinidine (DM/Q). Quinidine inhibits the metabolism of dextromethorphan, reducing dextrorphan levels. Opioid-dependent patients were admitted to an inpatient unit, stabilized for three days on morphine (25 mg, sc, every six hours), and randomly assigned on day 2 to DM/Q (30 mg/30 mg, twice a day) (n = 22) or matching placebo (n = 9) prior to the discontinuation of morphine on day 4. Withdrawal symptoms, measured with the Modified Himmelsbach Opioid Withdrawal Scale (MHOWS), increased significantly on days 4 and 5 (Z = 3.70, p = .0002), and by day 6, 90% of the sample (28/31) had dropped out of the study. There were no differences between treatment groups on either outcome measure. The combination of dextromethorphan and quinidine appears ineffective as a primary treatment for opioid withdrawal. Future studies should examine dextromethorphan as an adjunct to other anti-withdrawal medications and focus more on the relationship between dextrorphan levels and withdrawal suppression.

Use of dronabinol for cannabis dependence: two case reports and review.

Marijuana is the most commonly used illicit drug in the United States and throughout the world. Despite this, the number of laboratory studies that have assessed pharmacologic agents to target cannabis withdrawal symptoms or reduce the reinforcing effects of marijuana has been modest. Unlike alcohol, cocaine, opiates, or nicotine, there has been a minimal number of clinical pharmacologic treatment trials that have targeted marijuana use. Based on recent laboratory studies, dronabinol (delta-9-tetrahydrocannabinol) has been shown to reduce cannabis withdrawal symptoms and the subjective effects of marijuana. Given that agonist agents have been found to be effective for opiate and nicotine dependence, the clinical utility of dronabinol for cannabis dependence is a reasonable approach. Two case reports using dronabinol are presented. The potential benefit, as well as questions that arise from the use of this medication in cannabis-abusing populations, is presented. Also, future areas of research that might be explored are discussed.

Abuse of buprenorphine in the United States: 2003-2005.

This study examines trends in the reported abuse of two sublingual buprenorphine products, Subutex and Suboxone, in the United States. Quarterly counts of abuse cases were obtained from 18 regional poison control centers (PCCS) for 2003-2005. Seventy-seven abuse cases were reported, of which 7.8 percent involved Subutex and 92.2 percent involved Suboxone. The average quarterly ratio of abuse cases per 1,000 prescriptions dispensed was 0.08 (SD +/- 0.09) for Subutex, and 0.16 (SD +/- 0.08) for Suboxone. Findings suggest that these sublingual buprenorphine formulations have a low rate of abuse based on toxico-surveillance data.

Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine.

OBJECTIVE: Dopamine is an important mediator of the reinforcing effects of cocaine, and alterations in dopamine function might be involved in cocaine dependence. The goals of the present study were to characterize pre- and postsynaptic dopamine function in recently detoxified cocaine-dependent subjects. Specifically, dopamine response to an acute amphetamine challenge was assessed in striatal subregions in cocaine-dependent and healthy comparison participants using positron emission tomography (PET). Furthermore, the relationship between this dopamine response and the choice to self-administer cocaine in a laboratory model of relapse was investigated. METHOD: Twenty-four cocaine-dependent participants and 24 matched healthy subjects underwent [(11)C]raclopride scans under a baseline condition and following intravenous amphetamine administration (0.3 mg/kg). Cocaine-dependent participants also completed cocaine self-administration sessions in which a priming dose of cocaine was followed by the choice to either self-administer subsequent cocaine doses or receive a monetary reward. RESULTS: Cocaine dependence was associated with a marked reduction in amphetamine-induced dopamine release in each of the functional subregions of the striatum (limbic striatum: -1.2% in cocaine-dependent participants versus -12.4% in healthy subjects; associative striatum: -2.6% versus -6.7%, respectively; sensorimotor striatum: -4.3% versus -14.1%). Blunted dopamine transmission in the ventral striatum and anterior caudate was predictive of the choice for cocaine over money. CONCLUSIONS: Cocaine dependence is associated with impairment of dopamine function, and this impairment appears to play a critical role in relapse.