Peter A. DeMaria

A genetic association study of the mu opioid receptor and severe opioid dependence.

Objectives Twin, family and adoption studies have suggested that vulnerability to opioid dependence may be a partially inherited trait (Cadoret et al., 1986; Merikangas et al., 1998; Tsuang et al., 1998, 2001). Studies using animal models also support a role for genetic factors in opioid dependence, and point to a locus of major effect on mouse chromosome 10 (Berrettini et al., 1994; Alexander et al., 1996), which harbors the mu opioid receptor gene (Mor1) (Kozak et al., 1994). The gene encoding the human mu opioid receptor (OPRM1) is thus an obvious candidate gene for contributing to opioid dependence. A recent report (Hoehe et al., 2000) found a significant association between a specific combination of OPRM1 single nucleotide polymorphisms (SNPs) and substance dependence. Methods In the current study, we genotyped 213 subjects with severe opioid dependence (89 African-Americans, 124 European-Americans) and 196 carefully screened ‘supercontrol’ subjects (96 African-Americans, 100 European-Americans) at five SNPs residing in the OPRM1 gene. The polymorphisms include three in the promoter region (T–1793A, –1699T insertion and A–1320G) and two in exon 1 (C+17T [Ala6Val] and A+118G [Asp40Asn]). Results Statistical analysis of the allele frequency differences between opioid-dependent and control subjects for each of the polymorphisms studied yielded P values in the range of 0.444–1.000. Haplotype analysis failed to identify any specific combination of SNPs associated with the phenotype. Conclusions Despite reasonable statistical power we found no evidence of association between the five mu opioid receptor polymorphisms studied and severe opioid dependence in our sample. There were, however, significant allele frequency differences between African-Americans and European-Americans for all five polymorphisms, irrespective of drug-dependent status. Linkage disequilibrium analysis of the African-American genotypes indicated linkage disequilibrium (P<0.0001) across the five-polymorphism, 1911 base pair region. In addition, only four haplotypes of these five polymorphisms are predicted to exist in African-Americans.

Human mu opioid receptor gene polymorphisms and vulnerability to substance abuse

Two polymorphisms of the human mu opioid receptor gene are described. A non‐coding region polymorphism (G to T) occurs at nucleotide 175 preceding the initiation of translation. A coding polymorphism in exon 1 (C to T) at nucleotide 229 changes an alanine residue to a valine residue. Frequencies of these polymorphisms were examined in groups of cocaine and/or opioid dependent individuals and matched controls. There were no significant differences between groups, although a trend (p= 0.05) towards a higher frequency of the 229 valine allele was observed in the substance abuse group, suggesting a need for large, well‐controlled studies of this polymorphism in severe substance abusers.

A functional prodynorphin promoter polymorphism and opioid dependence.

Objectives The prodynorphin gene (PDYN) promoter has a repeat polymorphism that is functionally important in association with substance abuse. We examined this polymorphism for association in our sample of 168 opioid-dependent patients and 122 ethnically and geographically matched controls. Methods Patients were selected from university-affiliated residential and non-residential addiction treatment programs in the Philadelphia area. A sample of blood was drawn from consenting individuals and genomic DNA was isolated. Polymerase chain reaction amplification of the PDYN promoter was performed and various genotypes were determined on the basis of differing sizes of the polymerase chain reaction products. The genotype and allele data were analyzed by Fishers exact test. Result A significant difference in genotype (P<0.0006) and allele (P<10−5) frequencies was found between the African American and European American populations. We did not detect any significant difference in genotype or allele frequencies between the patients and controls within the European American ethnic group. However, we detected a weak association (P=0.013) when we compared allele frequencies of patients and controls in the African American population. Conclusions These data suggest that the PDYN repeat polymorphism should be studied in additional opioid-dependent populations.

Relationship of Aggression, Sensation Seeking, and Impulsivity, With Severity of Cocaine Use

We investigated whether pretreatment measures of sensation seeking, impulsivity, and aggression were related to severity of cocaine use. Assessments of sensation seeking (SSS), impulsivity (BIS), and aggression (BDHI) were obtained for 140 African-American cocaine-dependent individuals entering outpatient treatment. We explored whether these variables were associated with addiction severity measures including quantity, frequency, and duration of cocaine use, scores on the Addiction Severity Index (ASI), and the admission urine drug screen status. A significant positive association was found between the total BDHI score and duration and frequency of cocaine use. Furthermore, SSS scores showed a significant positive correlation with frequency of cocaine use and cocaine positive admission urines. The BIS scores were significantly associated with 2 of the 7 ASI scales. Multiple regression analyses showed that the 3 measures contributed significantly toward predicting severity of cocaine use, but the contribution to the overall variance was modest. Measures of aggression and sensation seeking seem to be of clinical value in the assessment of cocaine abusers. However, these measures may need to be combined with other clinical and behavioral variables to accurately predict the severity of cocaine use.

Novel exonic μ-opioid receptor gene (OPRM1) polymorphisms not associated with opioid dependence

The μ‐opioid receptor (MOR) mediates reward and dependence associated with opioids and other commonly abused substances. Variability in the MOR gene, OPRM1, may influence risk for opioid dependence. In this study, associations between two single nucleotide polymorphisms (SNPs), dbSNP rs540825 and dbSNP rs562859, and opioid dependence were investigated. The two SNPs are located in the protein coding region of the novel exon X of an alternative splice variant of OPRM1, and can be detected using polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) methods. Genotyping at the two SNPs was performed for 170 severe opioid dependent individuals and 128 carefully screened controls. Although no differences were found between cases and controls, there were significant prevalence differences between African‐American (AA) subjects and European‐American (EA) subjects for SNP 540825 allele and genotype frequencies. The 540825 and 562859 polymorphisms were found to be in complete linkage disequilibrium (LD) for both ethnic groups, and LD existed between the 562859 SNP and the A−1320G SNP in the promoter region of OPRM1 in AAs, based on genotyping data previously carried out on the same subjects. LD between these two markers, separated by 55 kb, links the entire distance studied in this project. The results indicate that polymorphisms in the novel splice variant are not associated with opioid dependence, but are in LD with other polymorphisms in OPRM1.

Fluvoxamine as an Adjunct to Promote Methadone Dose Optimization

In order for methadone maintenance treatment to be effective, an adequate methadone serum level (MSL) must be attained. A number of factors can affect MSL, especially drugs that interact with the hepatic cytochrome P450 enzyme system. We report here 3 cases of patients who had difficulty stabilizing on methadone with continued complaints of opiate withdrawal symptoms, drug cravings, and continued opiate positive urine drug screens despite a methadone dose of 100 mg. Each had either low MSL or a high peak to trough MSL ratio (P/T ratio). Fluvoxamine, a selective serotonin reuptake inhibitor with potent cytochrome P450 enzyme inhibitory properties, was administered to each of the patients resulting in significant increases in MSL or a decrease in P/T ratio and leading to improvement in clinical status including cessation of opiate use. The mechanism and potential therapeutic role, as well as precautions, are discussed.

Using Buprenorphine to Treat Opioid-Dependent University Students Opportunities, Successes, and Challenges

Objective:The objective of this study was to characterize a population of opioid-dependent university students who were treated with buprenorphine, describe their treatment outcome, and discuss challenges the authors faced in working with this population in the setting of a university counseling center. Methods:We conducted a retrospective chart review of 27 opioid-dependent university students treated with buprenorphine at the universitys counseling center. Results:Students were predominantly white (85%, n = 23), male (63%, n = 17), average age of 22 years with an average of 33.4 ± 28.79 months (range = 4 to 132) opioid use before presentation. By self-report, 17 (63.0%) students reported heroin use, 9 (33.3%) students reported prescription opioid use, and 1 (3.7%) student reported use of both. Fifteen (56%) reported intravenous use. Treatment retention was high with students receiving an average of 12.00 + 11.49 months treatment (range = 1 to 36). During the course of treatment, 81% of all submitted urine drug screens were negative for opioids, 83.1% were negative for cocaine, 90.7% were negative for illicit (nonprescribed) benzodiazepines, and 59.1% were negative for marijuana. The average buprenorphine dose was 13.8 ± 5.69 mg (range = 4 to 24 mg). No serious adverse effects occurred. In working with this population, we found that continued marijuana use, engagement in treatment, financial concerns, and decision making around family involvement were ongoing challenges. Conclusions:Opioid-dependent university students are a unique group of substance users. Our results indicate that they can be safely and effectively treated with buprenorphine in a university counseling center.

The Implementation of Buprenorphine/Naloxone in College Health Practice.

Opiate abuse and dependence have become important concerns for college healthcare providers. The passage of the Drug Addiction Treatment Act of 2000 and the approval of the combination buprenorphine/naloxone for office-based treatment of opiate dependence have increased the options available for college students and their healthcare providers. The authors review the pharmacology of buprenorphine/naloxone and discuss how it can be implemented in college health practice. They also present a case report.