Utilizing buprenorphine&amp;ndash;naloxone to treat illicit and prescription-opioid dependence

Mauger, Sofie; Fraser, R. S. S.; Gill, Kathryn

doi:10.2147/ndt.s39692

Cited by 23 publications

(23 citation statements)

References 104 publications

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“…For these studies, we evaluated the µ-, δ-, and κ-opioid receptors (MOR, DOR, and KOR, respectively), which play essential roles in nociception and have resulted in the availability of a diverse pharmacology, including naloxone, which is commonly used to reverse opioid overdose, but is also used for the treatment of addiction and for chronic pain management in combination with partial agonists (62, 63). Naloxone binds to all of the opioid receptors with high affinity, and it is commonly described as competitive antagonist (64).…”

Section: Resultsmentioning

confidence: 99%

“…Although the full range of the behavioral effects of TBPB remains to be established, it clearly has antipsychotic-like activity and shows efficacy in decreasing Aβ production (57), which suggests that these beneficial effects likely arise from the distinct and selective set of G proteins that TBPB enables M1R to activate. Similarly, the highly selective agonistic properties of naloxone toward opioid receptors may underlie the success of its use as an adjuvant for weak opioid agonists for the management of pain and dependence (62, 63), and this can likely be exploited further. Thus, it is conceivable that optimal therapeutic efficacy could be achieved through the selective activation of only a subset of the G proteins within the repertoire of a GPCR, possibly circumventing adverse side effects.…”

Section: Discussionmentioning

confidence: 99%

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Distinct profiles of functional discrimination among G proteins determine the actions of G protein–coupled receptors

et al. 2015

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Members of the G protein coupled receptor (GPCR) family play key roles in many physiological functions and have been extensively exploited pharmacologically to treat diseases. Individual GPCRs exert diverse and distinct effects on cellular physiology and transduce signals by activating heterotrimeric G proteins. Mammalian genomes encode 16 different G protein alpha subunits, and each one of them has distinct properties. Here, we developed a single-platform, optical strategy for the direct monitoring of G protein activation in live cells, and using it we profiled the activities of individual GPCRs across a range of different G proteins, simultaneously quantifying both magnitude of their signaling and activation rates. We report that GPCRs engage multiple G proteins with varying efficacy and kinetics, generating fingerprint-like profiles that define individual receptors. We found that different classes of GPCR ligands, including full and partial agonists, allosteric modulators, and antagonists distinctly affected these fingerprints to functionally bias GPCR signaling. Finally, we showed that intracellular signaling modulators further altered the G protein–coupling profiles of GPCRs, which suggests that their differential expression may alter signaling outcomes in a cell-specific manner. . These observations suggest that the diversity of the effects of GPCRs on cellular physiology may be determined by their differential engagement of multiple G proteins with varying signal magnitudes and activation kinetics, properties that may be exploited pharmacologically.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Distinct profiles of functional discrimination among G proteins determine the actions of G protein–coupled receptors

et al. 2015

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“…In response to this trend, the Rhode Island Governor's Overdose Prevention Task Force was formed in 2015 and tasked with identifying strategies for decreasing the rate of fatal overdose (Rhode Island Governor's Overdose Prevention and Intervention Task Force, 2015). A key element of the strategy recommended by the Task Force is increased access to buprenorphine/naloxone, partial opioid antagonist used in medication-assisted therapy (MAT), an effective treatment for opioid use disorder (Mauger, Fraser, & Gill, 2014) that effectively reduces drug-related harm and risk of overdose death (Otiashvili et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Exposure to fentanyl-contaminated heroin and overdose risk among illicit opioid users in Rhode Island: A mixed methods study

Carroll

Marshall

Rich

et al. 2017

International Journal of Drug Policy

198

137

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Background Illicit fentanyl use has become wide spread in the US, causing high rates of overdose deaths among people who use drugs. This study describes patterns and perceptions of fentanyl exposure among opioid users in Rhode Island. Methods A mixed methods study was conducted via questionnaire with a convenience sample of 149 individuals using illicit opioids or misusing prescription opioids in Rhode Island between January and November 2016. Of these, 121 knew of fentanyl and reported known or suspected exposure to fentanyl in the past year. Semi-structured interviews were conducted with the first 47 participants. Results Study participants were predominantly male (64%) and white (61%). Demographic variables were similar across sample strata. Heroin was the most frequently reported drug of choice (72%). Self-reported exposure to illicit fentanyl in the past year was common (50.4%, n=61). In multivariate models, regular (at least weekly) heroin use was independently associated with known or suspected fentanyl exposure in the past year (adjusted prevalence ratio (APR)=4.07, 95% CI: 1.24-13.3, p=0.020). In interviews, users described fentanyl as unpleasant, potentially deadly, and to be avoided. Participants reporting fentanyl exposure routinely experienced or encountered non-fatal overdose. Heroin users reported limited ability to identify fentanyl in their drugs. Harm reduction strategies used to protect themselves from fentanyl exposure and overdose, included test hits, seeking prescription opioids in lieu of heroin, and seeking treatment with combination buprenorphine/naloxone. Participants were often unsuccessful in accessing structured treatment programs. Conclusion Among illicit opioid users in Rhode Island, known or suspected fentanyl exposure is common, yet demand for fentanyl is low. Fentanyl-contaminated drugs are generating user interest in effective risk mitigation strategies, including treatment. Responses to the fentanyl epidemic should be informed by the perceptions and experiences of local users. The rapid scale-up of buprenorphine/naloxone provision may slow the rate of fentanyl-involved overdose deaths.

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“…It is well known that Bup/nx is a partial μ-opioid agonist combined with the opioid antagonist naloxone in a 4:1 ratio. According to some [47], this combination is safe and beneficial to treat illicit and prescription-opioid dependence. Bup/nx has a lower abuse potential, carries less stigma, and allows for more flexibility than methadone.…”

Section: Discussionmentioning

confidence: 99%

Hypothesizing that a Pro-Dopaminergic Regulator (KB220z™ Liquid Variant) can Induce "Dopamine Homeostasis" and Provide Adjunctive Detoxification Benefits in Opiate/Opioid Dependence

Blum

Whitney²,

Fried

et al. 2016

Clin Med Rev Case Rep

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In order to explore the initiation of detoxification of addictive patients to opiates/opioids (along with some other anti-withdrawal agents), we developed a protocol to be utilized in treatment centers particularly with heavily dependent opiate/opioid subjects. Out of 17 subjects, only three received Buprenorphine/Naloxone (Bup/nx) along with KB220Z. In this pilot, we first used a dose of KB220Z of 2 oz twice daily before meals along with clonidine and benzodiazepines and other anti-nausea and sleep aids including Gabapentin. The dose of KB220Z was maintained for 6 days in five individuals. In a second scenario, we utilized a higher dose of 4 oz every 6 hours, over a 6-day period. The higher dose was employed in another 12 patients. It is noteworthy that only 3 people have relapsed utilizing these two protocols during the first two weeks of the study, allowing for the remaining 82% to be maintained on KB220Z. The patients have been maintained without any additional Bup/nx for a minimum of 120 days and in one subject, 214 days. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates utilizing data from the Clinical opiate Withdrawal Scale (COWS) pre and post KB220Z. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates. While this does not constitute an acceptable controlled experiment, it does provide some preliminary evidence that agrees with an earlier study. Moreover, because of the utilization of standard detoxifying agents in this detoxification protocol, we cannot make any inference to KB220Z’s effects. However, out of 17 subjects, only three required Bup/nx suggesting an interesting finding. If further confirmed in larger studies, the utilization for opiate/opioid detoxification may provide a novel way to eliminate the need for addictive opioids during withdrawal and detoxification. This paradigm shift may translate to a reduction in utilizing powerful and addictive opioids like buprenorphine and methadone (especially in these patients at high genetic risk for addiction) as not only detoxifying agents, but also maintenance drugs. While extensive research is required, this pilot paves the way for future investigations that could assist in the reduction of addictive opiate/opioid use and mortalities amongst both the young and old in America.

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Utilizing buprenorphine–naloxone to treat illicit and prescription-opioid dependence

Cited by 23 publications

References 104 publications

Distinct profiles of functional discrimination among G proteins determine the actions of G protein–coupled receptors

Distinct profiles of functional discrimination among G proteins determine the actions of G protein–coupled receptors

Exposure to fentanyl-contaminated heroin and overdose risk among illicit opioid users in Rhode Island: A mixed methods study

Hypothesizing that a Pro-Dopaminergic Regulator (KB220z™ Liquid Variant) can Induce "Dopamine Homeostasis" and Provide Adjunctive Detoxification Benefits in Opiate/Opioid Dependence

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