Novel Opipramol-Baclofen Combination Alleviates Depression and Craving and Facilitates Recovery From Substance Use Disorder-An Animal Model and a Human Study

Abstract

Substance use disorders (SUDs) are associated with depression and anxiety, with the latter being one of the major factors in substance-seeking and relapse. Due to dose-dependent sedative side effects there is limited efficacy of baclofen treatment for SUDs. Here we suggest the use of a novel combination of opipramol and baclofen (O/B) which is known to attenuate anxiety and depression, for the facilitation of recovery from SUDs. Since both opipramol and baclofen have a common downstream signal transduction, their individual doses could be reduced while still maintaining the benefits of the combination. We tested the O/B combination in both animals and patients. Rats treated with O/B showed significant attenuation in craving behavior and in relapse rate during withdrawal from cocaine. In a double-blind, placebo-controlled pilot study, conducted in a residential detoxification center, 14 males and 3 females, aged 28-60 years were assigned to a study (n = 6) and a placebo (n = 11) group (placebo group: 40 ± 10.5 years; O/B group 40 ± 10.8 years). The participants completed scales measuring depression, anxiety and craving symptoms and provided saliva samples for stress hormone examination [cortisol and dehydroepiandrosterone-sulfate (DHEA-S)]. Participants with polysubstance use disorder (PsUD) treated with O/B showed a reduction in cravings and depression and an increase in DHEA-S and in the DHEA-S/cortisol ratio. Our findings indicate a beneficial effect of O/B treatment. This study suggests a novel candidate for pharmacological treatment of patients with SUD and comorbid mood/anxiety disorders that may facilitate their rehabilitation.

Keywords: addiction; baclofen; opipramol; stress; substance-induced depressive disorder; therapeutic center; treatment.

FIGURE 1

Effects of a dose of 3.2 mg/kg of baclofen on extinction, withdrawal and reinstatement phases in a cocaine (Coc) self-administration (SA) rat model. (A) Effect of baclofen on cocaine-seeking during extinction and withdrawal phases. Rats (n = 6) were trained for cocaine (0.5 mg/kg) or saline SA on days 1–16. Coc-Saline, control, trained for cocaine SA and received saline at the withdrawal phase, and Coc-Baclofen, trained for cocaine SA and received baclofen (3.2 mg/kg) at the withdrawal phase. Baclofen treatment, given on days 17–18, significantly reduced cocaine-seeking behavior throughout extinction training, compared with saline-treated controls. A two-way ANOVA with repeated measures revealed a significant effect of treatment [F(1, 250) = 13.93, p = 0.0039], time [F(25, 250) = 4.77, p < 0.0001], and the interaction between them [F(25, 250) = 3.11, p < 0.0001] (Bonferroni, ***p < 0.001 day 17, **p < 0.01 day 18). A lack of baclofen administration on day 19 increased active lever presses immediately and resembled control. Baclofen administration on days 20–26 reduced active lever presses but not significantly. (B) Effect of Baclofen on cocaine-primed reinstatement. Rats received a priming injection of cocaine (10 mg/kg, i.p, day 27) and were placed in the SA chamber with no cocaine available in the relapse test. Baclofen treatment did not decrease active lever pressing compared to controls (Student’s t-test, p = 0.1323). Values are expressed as mean ± SEM.

FIGURE 2

Effect of opipramol (12.5 mg/kg) and low doses of baclofen (0.1 mg/kg) on extinction, withdrawal and reinstatement phases in a cocaine (Coc) self-administration (SA) rat model. (A) The fixed ratio 1 schedule (FR-1) of cocaine SA model that was used. Rats (n = 10–14) were trained (T) for cocaine (0.5 mg/kg) or saline SA on days 1–10. Next, we created two groups: Coc-Saline, control, trained for cocaine SA and received saline at the withdrawal phase, and Coc-Opipramol, trained for cocaine SA and received opipramol (12.5 mg/kg) throughout the withdrawal phase. (B) Effect of opipramol on cocaine-seeking during extinction and withdrawal phases. Opipramol treatment, given on days 11–20, significantly reduced cocaine-seeking behavior during extinction training, compared with saline-treated controls. A two-way ANOVA with repeated measures revealed a significant effect of treatment [F(1, 418) = 12.64, p = 0.0018], time [F(19, 418) = 15.49, p < 0.0001] and the interaction between them [F(19, 418) = 6.65, p < 0.0001] (Bonferroni, ***p < 0.001 days 11–14). (C) Effect of opipramol or baclofen on cocaine-primed reinstatement. Classification of treated rats according to “responders” or “non-responders” to chronic opipramol treatment revealed significantly decreased active lever presses for responder rats compared with non-responders or controls (Coc-Saline). A one-way ANOVA revealed a significant effect of treatment [F(4, 34) = 5.35, p = 0.0019] in the relapse test (Bonferroni, **p < 0.01 opipramol responders (R) vs. non-responders (NR), ^#p < 0.05 opipramol responders vs. controls). Baclofen administration did not decrease active lever presses compared to controls. Coc-Opipramol (T) included the total rats that received opipramol, i.e., opipramol responders [Coc-Opipramol (R)] and non-responders [Coc-Opipramol (NR)]. (D) Examination of baclofen (0.1 mg/kg) one injection to opipramol non-responder rats, before a second cocaine-primed reinstatement. A Student’s t-test did not reveal a significant treatment effect in the relapse test (p = 0.9207). Values are expressed as mean ± SEM.

FIGURE 3

Effect of the combination of opipramol and baclofen on extinction, withdrawal and reinstatement phases in a cocaine (Coc) self-administration rat (SA) model. (A) Effect of the selected treatment; opipramol (12.5 mg/kg) or opipramol (12.5 mg/kg) and baclofen (0.1 mg/kg) combination on cocaine-seeking during extinction and withdrawal phases. Opipramol alone and the combination treatments given on days 11–17 significantly reduced cocaine-seeking behavior during extinction training, compared with saline-treated controls. A two-way ANOVA with repeated measures revealed a significant effect of treatment [F(2, 1712) = 7.42, p = 0.001], time [F(16, 1712) = 16.97, p < 0.0001] and the interaction between them [F(32, 1712) = 7.75, p < 0.0001]. (Bonferroni, ***p < 0.001 days 11–16 opipramol treatment vs. controls, ^###p < 0.001 days 11–13 O/B treatment vs. controls). (B) Effect of opipramol or the combination of O/B on cocaine-primed reinstatement. Active lever presses were decreased in rats that were responders (R) to opipramol [Coc-Opipramol (R)] and in rats that received O/B combination (Coc-Opipramol + Baclofen) compared with opipramol non-responder (NR) rats [Coc-Opipramol (NR)] and controls (Coc-Saline). A one-way ANOVA revealed a significant effect of treatment [F(3, 89) = 28.97, p < 0.0001] in the relapse test (Bonferroni, ***^/###p < 0.001 opipramol responders and O/B vs. non-responders and controls, respectively). Values are expressed as mean ± SEM.

FIGURE 4

Effects of the various drug-combinations on Gabbr1 and Rac1 mRNA expression levels in the nucleus accumbens (NAc). (A) A Student’s t-test revealed a significant effect of opipramol treatment alone on the expression of Gabbr1 (**p = 0.0063). (B) Newman-Keuls post hoc test revealed a significant decrease in Rac1 mRNA expression levels in the opipramol responders (R) [Coc-Opipramol (R)] compared with the non-responder (NR) rats [Coc-Opipramol (NR)], as well as compared to high dose baclofen (3.2 mg/kg) alone treated rats (Coc-Baclofen), and compared to controls (Coc-Saine) (one-way ANOVA, *p < 0.05, ^#p < 0.05, and **p < 0.01, respectively). Values are expressed as mean ± SEM. (C) STRING software (version 11.0) revealed a complex of interacting proteins including Gabbr1, Rac1, and σ-1 receptor in a PPI enrichment analysis, p = 0.0272. The software indicates that the examined proteins are at least partially biologically connected.

FIGURE 5

Subject recruitment. Participants were randomly assigned to either the opipramol-baclofen (O/B) combination group or to the placebo group.

FIGURE 6

Study timeline. The clinical scales and saliva samples were collected on days 2 and 7 of the trial and 1 day before the release from the detox center. ASI, Addiction Severity Index; BSCS, Brief Substance Craving Scale; HDRS, Hamilton Depression Rating Scale; HARS, Hamilton Anxiety Rating Scale.

FIGURE 7

Effects of administering a combination of opipramol and baclofen on rehabilitation factors of patients with polysubstance use disorder (PsUD). (A) The individual magnitude of craving change tested by the Brief Substance Craving Scale (BSCS) questionnaire (score before/after O/B treatment was significantly improved in comparison with placebo treatment (Student’s t-test, p < 0.031). (B) A correlation between depression state and craving symptoms at the end of the trial (Pearson rank correlation, *p = 0.022, r = 0.36). (C) Dehydroepiandrosterone- sulfate (DHEA-S) levels were increased at the end of the treatment compared with placebo (Bonferroni, **p < 0.01) and over time (Bonferroni, ^##p < 0.01, admission vs. end of treatment, intermediate progress vs. end of treatment). A two-way ANOVA with repeated measures revealed a significant effect of time [F(2, 20) = 12.85, p = 0.0003] and interaction between treatment and time [F(2, 20) = 6.22, p = 0.0079], but did not reveal a significant effect of treatment [F(1, 20) = 2.27, p = 0.1628]. (D) DHEA-S and cortisol ratio were increased at the end of the treatment compared with placebo (Bonferroni, **p < 0.01). A two-way ANOVA with repeated measures revealed a significant effect of treatment [F(1, 16) = 9.2, p = 0.0162 and interaction between treatment and time [F(2, 16) = 3.67, p = 0.0488], but did not reveal a significant effect of time [F(2, 16) = 2.52, p = 0.1119].