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Kappa opioid receptor antagonism: Are opioids the answer for treatment resistant depression?

ABSTRACT: Past trials of buprenorphine (BUP) in the treatment of major depressive disorder (MDD) have displayed favorable results, although its clinical utility was limited by the risk of abuse or physical dependence. By combining BUP with samidorphan (SAM), the euphoric high is negated by an opposing mechanism, which theoretically reduces addictive-like properties while allowing the antidepressant properties to remain. As such, the objective of this article is to analyze the results of BUP/SAM premarketing clinical trials as adjunctive treatment for treatment-resistant MDD.A comprehensive PubMed/MEDLINE search was conducted through November 9, 2017, using the following search terms: depression, samidorphan, buprenorphine, ALKS-5461. Additional data were obtained from Clinicaltrials.gov and resources included in the present study. All English-language clinical trials evaluating the combination of BUP/SAM in the treatment of MDD were included.A few premarketing studies have evaluated the efficacy and safety of BUP/SAM combination as adjunctive treatment in patients with treatment-resistant MDD. The FORWARD-1 through FORWARD-5 trials concluded (1) the most effective dosing ratio of BUP/SAM to reduce abuse potential was 1:1; (2) statistically significant changes in scores from baseline on the Montgomery-Asberg Depression Rating Scale were noted for the 2 mg/2 mg dose compared with placebo; and (3) the most commonly reported adverse effects were nausea, dizziness, and fatigue.Buprenorphine/samidorphan has shown favorable results for efficacy and tolerability in premarketing studies evaluating its use as adjunctive therapy for treatment-resistant MDD. Its novel mechanism targeting the opioid pathway may serve as a promising antidepressant devoid of abuse potential.

SUBMITTER: Peckham AM

PROVIDER: S-EPMC6063454 | biostudies-other | 2018 Jul

REPOSITORIES: biostudies-other

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Kappa opioid receptor antagonism: Are opioids the answer for treatment resistant depression?

Peckham Alyssa M AM De La Cruz Austin A Dufresne Robert L RL

The mental health clinician 20180629 4

<h4>Introduction</h4>Past trials of buprenorphine (BUP) in the treatment of major depressive disorder (MDD) have displayed favorable results, although its clinical utility was limited by the risk of abuse or physical dependence. By combining BUP with samidorphan (SAM), the euphoric high is negated by an opposing mechanism, which theoretically reduces addictive-like properties while allowing the antidepressant properties to remain. As such, the objective of this article is to analyze the results ...[more]

PMID: 30155392

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Project description:Although opioids are potent analgesics, a consequence of chronic opioid use is hyperalgesia during withdrawal, which may contribute to opioid misuse. Dynorphin, the endogenous ligand of κ-opioid receptors (KORs), is upregulated in opioid-dependent rats and in animal models of chronic pain. However, the role of KORs in opioid withdrawal-induced hyperalgesia remains to be determined. We hypothesized that KOR antagonism would reverse opioid withdrawal-induced hyperalgesia in opioid-dependent rats. Male and female Wistar rats received daily injections of heroin (2-6 mg/kg, SC) and were tested for mechanical sensitivity in the electronic von Frey test 4-6 h into withdrawal. Female rats required significantly more heroin than male rats to reach comparable levels of both heroin-induced analgesia and hyperalgesia (6 mg/kg vs. 2 mg/kg). Once hyperalgesia was established, we tested the effects of the KOR antagonists nor-binaltorphimine (norBNI; 30 mg/kg, SC) and 5'-guanidinonaltrindole (5'GNTI; 30 mg/kg, SC). When the animals continued to receive their daily heroin treatment (or saline treatment in the repeated saline group) five times per week throughout the experiment, both KOR antagonists reversed heroin withdrawal-induced hyperalgesia. The anti-hyperalgesia effect of norBNI was more prolonged in males than in females (14 days vs. 7 days), whereas 5'GNTI had more prolonged effects in females than in males (14 days vs. 4 days). The behavioral effects of 5'GNTI coincided with higher 5'GNTI levels in the brain than in plasma when measured at 24 h, whereas 5'GNTI did not reverse hyperalgesia at 30 min posttreatment when 5'GNTI levels were higher in plasma than in the brain. Finally, we tested the effects of 5'GNTI on naloxone-induced and spontaneous signs of opioid withdrawal and found no effect in either male or female rats. These findings indicate a functional role for KORs in heroin withdrawal-induced hyperalgesia that is observed in rats of both sexes.

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Kappa opioid receptor antagonism: Are opioids the answer for treatment resistant depression?

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Kappa opioid receptor antagonism: Are opioids the answer for treatment resistant depression?

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