Paul Casadonte

Genetic susceptibility to heroin addiction: a candidate gene association study

Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify genetic variants that are associated with susceptibility to develop heroin addiction by analyzing 1350 variants in 130 candidate genes. All subjects had Caucasian ancestry. The sample consisted of 412 former severe heroin addicts in methadone treatment, and 184 healthy controls with no history of drug abuse. Nine variants, in six genes, showed the lowest nominal P values in the association tests (P < 0.01). These variants were in noncoding regions of the genes encoding the mu (OPRM1; rs510769 and rs3778151), kappa (OPRK1; rs6473797) and delta (OPRD1; rs2236861, rs2236857 and rs3766951) opioid receptors; the neuropeptide galanin (GAL; rs694066); the serotonin receptor subtype 3B (HTR3B; rs3758987) and the casein kinase 1 isoform epsilon (CSNK1E; rs1534891). Several haplotypes and multilocus genotype patterns showed nominally significant associations (e.g. OPRM1; P = 0.0006 and CSNK1E; P = 0.0007). Analysis of a combined effect of OPRM1 and OPRD1 showed that rs510769 and rs2236861 increase the risk of heroin addiction (P = 0.0005). None of these associations remained significant after adjustment for multiple testing. This study suggests the involvement of several genes and variants in heroin addiction, which is worthy of future study.

Buprenorphine Implants for Treatment of Opioid Dependence: A Randomized Controlled Trial

CONTEXT Limitations of existing pharmacological treatments for opioid dependence include low adherence, medication diversion, and emergence of withdrawal symptoms. OBJECTIVE To determine the efficacy of buprenorphine implants that provide a low, steady level of buprenorphine over 6 months for the treatment of opioid dependence. DESIGN, SETTING, AND PARTICIPANTS A randomized, placebo-controlled, 6-month trial conducted at 18 sites in the United States between April 2007 and June 2008. One hundred sixty-three adults, aged 18 to 65 years, diagnosed with opioid dependence. One hundred eight were randomized to receive buprenorphine implants and 55 to receive placebo implants. INTERVENTION After induction with sublingual buprenorphine-naloxone tablets, patients received either 4 buprenorphine implants (80 mg per implant) or 4 placebo implants. A fifth implant was available if a threshold for rescue use of sublingual buprenorphine-naloxone treatment was exceeded. Standardized individual drug counseling was provided to all patients. MAIN OUTCOME MEASURE The percentage of urine samples negative for illicit opioids for weeks 1 through 16 and for weeks 17 through 24. RESULTS The buprenorphine implant group had significantly more urine samples negative for illicit opioids during weeks 1 through 16 (P = .04). Patients with buprenorphine implants had a mean percentage of urine samples that tested negative for illicit opioids across weeks 1 through 16 of 40.4% (95% confidence interval [CI], 34.2%-46.7%) and a median of 40.7%; whereas those in the placebo group had a mean of 28.3% (95% CI, 20.3%-36.3%) and a median of 20.8%. A total of 71 of 108 patients (65.7%) who received buprenorphine implants completed the study vs 17 of 55 (30.9%) who received placebo implants (P < .001). Those who received buprenorphine implants also had fewer clinician-rated (P <.001) and patient-rated (P = .004) withdrawal symptoms, had lower patient ratings of craving (P <.001), and experienced a greater change on clinician global ratings of severity of opioid dependence (P<.001) and on the clinician global ratings of improvement (P < .001) than those who received placebo implants. Minor implant site reactions were the most common adverse events: 61 patients (56.5%) in the buprenorphine group and 29 (52.7%) in the placebo group. CONCLUSION Among persons with opioid dependence, the use of buprenorphine implants compared with placebo resulted in less opioid use over 16 weeks as assessed by urine samples. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00447564.

Heroin addiction in African Americans: a hypothesis-driven association study

Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify gene variants associated with heroin addiction in African Americans. The emphasis was on genes involved in reward modulation, behavioral control, cognitive function, signal transduction and stress response. We have performed a case–control association analysis by screening with 1350 variants of 130 genes. The sample consisted of 202 former severe heroin addicts in methadone treatment and 167 healthy controls with no history of drug abuse. Single nucleotide polymorphism (SNP), haplotype and multi‐SNP genotype pattern analyses were performed. Seventeen SNPs showed point‐wise significant association with heroin addiction (nominal P< 0.01). These SNPs are from genes encoding several receptors: adrenergic (ADRA1A), arginine vasopressin (AVPR1A), cholinergic (CHRM2), dopamine (DRD1), GABA‐A (GABRB3), glutamate (GRIN2A) and serotonin (HTR3A) as well as alcohol dehydrogenase (ADH7), glutamic acid decarboxylase (GAD1 and GAD2), the nucleoside transporter (SLC29A1) and diazepam‐binding inhibitor (DBI). The most significant result of the analyses was obtained for the GRIN2A haplotype G‐A‐T (rs4587976‐rs1071502‐rs1366076) with protective effect (Puncorrected = 9.6E‐ 05, Pcorrected = 0.058). This study corroborates several reported associations with alcohol and drug addiction as well as other related disorders and extends the list of variants that may affect the development of heroin addiction. Further studies will be necessary to replicate these associations and to elucidate the roles of these variants in drug addiction vulnerability.

Psychological and behavioral impact among intravenous drug users of learning HIV test results.

In 1984 as part of a New York City study to examine the prevalence of HIV infection in a substance-abusing population and to test the validity of HIV screening kits, 94 patients at the New York VAMC were tested. Results were made available to 50 (35 seronegative, 15 seropositive) patients in January 1986. Psychological and behavioral impact of learning test results was assessed using standardized psychiatric rating scales. A comparison group of 31 nontested subjects were also evaluated. Ratings were done preresults, approximately 1-2 weeks after results, and 8-10 weeks after informing patients of their HIV status. No major stress reactions were observed. Seropositives experienced a higher level of anxiety 1-2 weeks after learning results but anxiety generally diminished; they made significant behavior changes which were maintained. Seronegatives experienced relief and maintained IV drug risk reduction behavior. Anxiety about contracting AIDS increased in nontested subjects as the study progressed.

The Physician Clinical Support System-Buprenorphine (PCSS-B): A Novel Project to Expand/Improve Buprenorphine Treatment

ABSTRACTOpioid dependence is largely an undertreated medical condition in the United States. The introduction of buprenorphine has created the potential to expand access to and use of opioid agonist treatment in generalist settings. Physicians, however, often have limited training and experience providing this type of care. Some physicians believe having a mentoring relationship with an experienced provider during their initial introduction to the use of buprenorphine would ease implementation. Our goal was to describe the development, implementation, resources, and evaluation of the Physician Clinical Support System-Buprenorphine (PCSS-B), a federally funded program to improve access to and quality of treatment with buprenorphine. We provide a description of the PCSS-B, a national network of 88 trained physician mentors with expertise in buprenorphine treatment and skills in clinical education. We provide information regarding the use the PCSS-B core services including telephone, email and in-person support, a website, clinical guidances, a warmline and outreach to primary care and specialty organizations. Between July 2005 and July 2009, 67 mentors and 4 clinical experts reported providing mentoring services to 632 participants in 48 states, Washington DC and Puerto Rico. A total of 1,455 contacts were provided through email (45%), telephone (34%) and in-person visits (20%). Seventy-six percent of contacts addressed a clinical issue. Eighteen percent of contacts addressed a logistical issue. The number of contacts per participant ranged from 1–125. Between August 2005 and April 2009 there were 72,822 visits to the PCSS-B website with 179,678 pages viewed. Seven guidances were downloaded more than 1000 times. The warmline averaged more than 100 calls per month. The PCSS-B model provides support for a mentorship program to assist non-specialty physicians in the provision of buprenorphine and may serve as a model for dissemination of other types of care.

Pharmacists' and technicians' perceptions and attitudes toward dispensing buprenorphine/ naloxone to patients with opioid dependence.

OBJECTIVE To assess the perceptions and attitudes of pharmacists and pharmacy technicians involved in an office-based opioid dependence treatment program using buprenorphine/naloxone. DESIGN Cross-sectional attitudinal assessment. SETTING Community, outpatient hospital, and clinic pharmacies. PARTICIPANTS Pharmacists and technicians participating in a clinical trial of opioid dependence treatment using buprenorphine/naloxone. INTERVENTION Written and telephone surveys followed by interviews with open-ended items. MAIN OUTCOME MEASURES Attitudes and perceptions regarding opioid-dependent patients and use of buprenorphine/naloxone for treatment of opioid dependence. RESULTS Pharmacies in seven states (New York, Virginia, Illinois, Florida, Texas, California, and Washington) participated in the clinical trial. A total of 40 pharmacists and pharmacy technicians responded to the initial written survey, representing 27 of the 32 pharmacies (84%). Follow-up interviews were obtained from one individual at 30 of those pharmacies (93.8%). Most pharmacy personnel (77.5%) involved with this study were not more concerned about theft or break-ins and would be willing to participate in opioid dependence treatment as the medication became available commercially (70%). The majority of respondents (85%) indicated that patients did not cause problems at their pharmacies. Compared with their experiences in administering other narcotic medications, most respondents did not express increased concern regarding prescription forgery (75%) or diversion (80%) of buprenorphine/naloxone. CONCLUSION The majority of respondents expressed positive attitudes and perceptions regarding patients treated for opioid dependence with buprenorphine/naloxone.