Edward Gottheil

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.

Gender differences and similarities in African-American crack cocaine abusers

Recent interest in womens health and patient-treatment matching has focused attention on gender differences among substance abusers. This article seeks to extend research in this area to African-American crack cocaine abusers. It describes gender differences and similarities in a large sample (652 males and 595 females) of this important group of patients at a publicly funded, inner-city intensive outpatient clinic. As in previous studies on white working-class inpatients, few significant gender differences were found on demographic characteristics or drug use or treatment histories. Moreover, there were few differences in psychiatric symptomatology, and none in treatment participation or retention. In contrast to some reports, we did not find that women entered treatment with higher levels of depression than men. Most statistically significant differences we found were either too small to be of practical importance, or reflected conventional gender differences ( e. g., women were more likely to care for dependents). —J Nerv Ment Dis 183:260-266, 1995

Serotonin transporter (5-HTT) gene polymorphisms and susceptibility to cocaine dependence among African-American individuals

Studies indicate that the serotonin system, particularly the serotonin transporter (5‐HTT), may modulate the central effects of cocaine. We investigated whether a polymorphism in the 5′ promotor region (5‐HTTLPR) of the 5‐HTT gene confers susceptibility to cocaine dependence. One hundred and ninety‐seven cocaine‐dependent African‐American subjects and 101 controls were studied. Polymerase chain reaction based genotyping of a biallelic repeat polymorphism in the 5′ promotor region yielded 2 alleles containing 484 (S) and 528 bp (L) repeats, respectively. There were no significant differences between controls of European background (n = 40) and African‐American controls (n = 61) in distribution of genotypes (European: LL = 32.5%, LS = 40.0%, SS = 27.5%; African‐American: LL = 27.9%, LS = 57.4%, SS = 14.7%) (χ2= 3.60, df = 2, p = 0.16) or allele frequencies (European: L = 52.5%, S = 47.5%; African‐American: L = 56.6%, S = 43.4%) (χ2= 2.21, df = 1, p = 0.13). When cocaine patients were compared to an ethnically diverse control group (n = 101), frequencies of the L variant (65.0%) were significantly higher while the S variant (35.0%) was less frequent among cocaine patients compared to controls (L = 53.9%, S = 46.1%) (χ2= 6.83, df = 1, p < 0.01). Similarly, there were more cocaine patients with the LL genotype (41.1%) and less with the SS genotype (11.2%) compared to controls (LL = 29.7%, SS = 21.8%) (χ2= 7.43, df = 2, p < 0.05). However, after restricting controls to African‐American individuals only (n = 61), cocaine subjects and controls did not differ significantly with respect to genotype distribution (χ2= 4.24, df = 2, p = 0.12) or allele frequencies (χ2= 2.83, df = 1, p = 0.10). In conclusion, although comparisons with a heterogeneous control group indicated a possible association between allelic variants of 5‐HTTLPR and cocaine dependence among African‐American cocaine subjects, this relationship was not observed when the control group was limited to African‐American people only. Our findings need to be confirmed on larger samples of ethnically matched individuals.

Underreporting of Cocaine Use at Posttreatment Follow-up and the Measurement of Treatment Effectiveness

Substance abusers, especially cocaine abusers, may underreport their substance use in outcome interviews. Follow-up interviews were conducted and urine specimens were obtained on 633 persons 9 months after admission to a 3-month cocaine treatment program. Although 422 (67%) reported no use of cocaine in the past 30 days, 134 of these (32%) had cocaine-positive urines. This group did not differ on most characteristics at intake or follow-up from the 288 with cocaine-negative urines. The amount of treatment received did affect willingness to admit drug use. Of 132 treatment completers who reported no cocaine use at follow-up, 21 (16%) had positive urines. Of 91 early dropouts who also reported no cocaine use, 36 (40%) had positive urines. This differential rate of underreporting had the effect of seriously underrepresenting the effectiveness of treatment completion as compared with little or no treatment.

A retrospective case control study of alcohol relapse and spiritual growth.

In the context of an NIAAA/Fetzer Institute-funded study designed to look at the impact of spirituality in an inpatient alcohol treatment, this retrospective case control study investigated whether spiritual growth occurred during an inpatient phase of treatment for alcohol dependence, the degree to which spiritual gains (if noted) would be maintained at follow-up, and whether spiritual growth would be associated with follow-up sobriety. To accomplish this goal, thirty-six individuals who reported relapsing to alcohol at three-month follow-up were compared with thirty-six matched controls who reported abstinence at follow-up. Spiritual development and change was assessed via a set of six measures. Paired t-tests revealed that spiritual growth occurred across all measures during the treatment phase. Repeated measures analysis of variance (ANOVA) indicated that this growth was maintained at three-month follow-up. Two-way repeated measures ANOVA revealed that while non-relapsers maintained spiritual growth over the course of four weeks of treatment and in the three-month period following treatment, renewed alcohol use was associated with decreased spirituality.

Comparison of Pretreatment Characteristics and Treatment Outcomes for Alcohol-, Cocaine-, and Multisubstance-Dependent Patients

Abstract We investigated whether pretreatment characteristics and measures of outcome differed for alcohol-, cocaine-, and multisubstance-dependent patients receiving outpatient substance abuse treatment. One hundred and forty substance dependent individuals (32 alcohol, 76 cocaine, and 32 multisubstance) enrolled in a 12-week outpatient treatment program were compared across measures of addiction severity, personality, and treatment-readiness at admission. In-treatment, end-of-treatment and 9-month follow-up assessments of treatment outcome were then compared across the three groups. Outcome measures included reduction in problem severity, abstinence, retention, number of sessions attended, dropout, and counselor and patient ratings of treatment benefit. At admission, the multisubstance group had a higher proportion of positive urines, reported more severe drug, alcohol and psychiatric problems, and displayed higher impulsivity and anxiety scores than one or both of the other groups. However, multisubstance patients were more treatment ready in terms of adopting a total abstinence orientation than alcohol or cocaine patients. While a significant reduction in symptoms occurred for the total sample during treatment as well as at follow-up, comparisons of outcomes did not consistently favor any particular group. The three groups had equivalent improvements in eleven of fourteen during-treatment and five of seven follow-up measures. Despite pre-treatment differences, in severity and treatment-readiness, outcomes were more similar than different for alcohol-, cocaine-, and multisubstance-dependent patients. Clinicians should be cautious about forecasting treatment-outcomes for addicted patients based on their primary substances of abuse.

Denial and self-image confrontation in a case of anorexia nervosa.

If self-image confrontation is a useful therapeutic tool in combating denial, it should be maximally effective in a condition such as anorexia where, in addition to disturbances in body concept, the visible changes in body structure are so clearly evident. The patient in the case study presented here was followed in psychotherapy by one psychiatrist concurrently with self-image experience (SIE) sessions conducted by a different psychiatrist. During the course of 16 months of hospitalization, 54 SIE sessions were held. During each she was first shown sound motion picture films of herself responding and reacting to a brief, standard interview, and then she was asked a standard set of questions about her feelings in regard to the film sequences. Despite two serious setbacks in the 4th and 7th months of her hospitalization, the patients weight increased, she recognized some of her problems, and her plans for the future became more realistic. In the SIE sessions changes occurred in her attitudes toward her image on the screen and toward the procedure. Initially she continued to deny the evidence in the films about her condition. Later, however, her satisfaction gave way to disinterest and boredom, and then she became hostile to the procedure and rejecting of her image. Nevertheless she did not discontinue the sessions. Eventually she became able to take a more objective view of herself; to see both positive and negative features in the film; and to respond to aspects of her performance other than her physical appearance alone. Toward the end of her hospitalization, she was doubly shocked to see how terribly thin she had been earlier and how indifferent she had been to her condition. Her body image had changed, so that thinness became ugly rather than comforting to her. The changes in self-image which took place slowly against a great deal of resistance appeared to be associated with the continued and repeated self-image confrontations. These changes are discussed in the paper within the framework of a theory of self-consistency.

Patient Treatment Choice and Compliance: Data from a Substance Abuse Treatment Program

The authors tested the hypothesis that patients (treatment-seeking cocaine-dependent persons) given the opportunity to choose between treatment approaches would do better than patients randomly assigned to the same approaches in treatment retention and 9-month outcome. Subjects were 34 patients who voluntarily chose to enter individual therapy 1 hour per week (IND) and 33 who chose intensive group therapy for 3 hours, 3 times weekly (INT). There were no significant differences between these two groups on demographic, personality, or addiction severity variables or in treatment retention or 9-month outcome. Comparison with samples of 30 patients who had been randomly assigned to IND and 30 to INT did not confirm the hypothesis that patients who chose their treatment would either remain in treatment for longer periods of time or manifest improved 9-month outcomes. The authors raise several motivational issues.

Very low dose naltrexone addition in opioid detoxification: a randomized, controlled trial.

Although current treatments for opioid detoxification are not always effective, medical detoxification remains a required step before long‐term interventions. The use of opioid antagonist medications to improve detoxification has produced inconsistent results. Very low dose naltrexone (VLNTX) was recently found to reduce opioid tolerance and dependence in animal and clinical studies. We decided to evaluate safety and efficacy of VLNTX adjunct to methadone in reducing withdrawal during detoxification. In a multi‐center, double‐blind, randomized study at community treatment programs, where most detoxifications are performed, 174 opioid‐dependent subjects received NTX 0.125 mg, 0.250 mg or placebo daily for 6 days, together with methadone in tapering doses. VLNTX‐treated individuals reported attenuated withdrawal symptoms [F = 7.24 (2,170); P = 0.001] and reduced craving [F = 3.73 (2,107); P = 0.03]. Treatment effects were more pronounced at discharge and were not accompanied by a significantly higher retention rate. There were no group differences in use of adjuvant medications and no treatment‐related adverse events. Further studies should explore the use of VLNTX, combined with full and partial opioid agonist medications, in detoxification and long‐term treatment of opioid dependence.