scholarly journals Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4163 ◽  
Author(s):  
Wolfgang Sadee ◽  
John Oberdick ◽  
Zaijie Wang
Keyword(s):  
Opioid Dependence ◽  
Pain Therapy ◽  
Active Form ◽  
Opioid Analgesics ◽  
Opioid Antagonist ◽  
Opioid Antagonists ◽  
Opioid Use ◽  
Opioid Agonist ◽  
Opposing Effects

Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct μ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-μ) to a ligand-free active form (MOR-μ*), which mediates MOR signaling. Moreover, MOR-μ converts spontaneously to MOR-μ* (basal signaling). Persistent upregulation of MOR-μ* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-μ and MOR-μ* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6β-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-μ*, naltrexone but not 6β-naltrexol suppresses MOR-μ*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-μ*with high potency, whereas 6β-naltrexol must compete with agonists at MOR-μ, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose–response curve may also result from opposing effects on MOR-μ and MOR-μ*. In contrast, we find that 6β-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6β-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.

scholarly journals Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

2020 ◽  
Author(s):  
Wolfgang Sadee ◽  
John Oberdick ◽  
Zaijie Wang
Keyword(s):  
Opioid Dependence ◽  
Pain Therapy ◽  
Active Form ◽  
Opioid Analgesics ◽  
Opioid Antagonist ◽  
Opioid Antagonists ◽  
Opioid Use ◽  
Opioid Agonist ◽  
Opposing Effects

Opioid analgesics are effective pain therapeutics but cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct m opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-m) to a ligand-free active form (MOR-m*), which mediates MOR signaling. Moreover, MOR-m converts spontaneously to MOR-m* (basal signaling). Persistent upregulation of MOR-m* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-m and MOR-m* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6b-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-m*, naltrexone but not 6b-naltrexol suppresses MOR-m*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-m*with high potency, whereas 6BN must compete with agonists at MOR-m, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose-response curve may also result from opposing effects on MOR-m and MOR-m*. In contrast, we find that 6b-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6b-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.

scholarly journals Pain-facilitating medullary neurons contribute to opioid-induced respiratory depression

2012 ◽  
Vol 108 (9) ◽  
pp. 2393-2404 ◽  
Author(s):  
Ryan S. Phillips ◽  
Daniel R. Cleary ◽  
Julia W. Nalwalk ◽  
Seksiri Arttamangkul ◽  
Lindsay B. Hough ◽  
...  
Keyword(s):  
Respiratory Depression ◽  
Opioid Analgesic ◽  
Opioid Analgesics ◽  
Opioid Peptide ◽  
Pain Modulation ◽  
Opioid Antagonist ◽  
Opioid Agonist ◽  
Ventromedial Medulla ◽  
Cell Firing ◽  
Opposing Effects

Respiratory depression is a therapy-limiting side effect of opioid analgesics, yet our understanding of the brain circuits mediating this potentially lethal outcome remains incomplete. Here we studied the contribution of the rostral ventromedial medulla (RVM), a region long implicated in pain modulation and homeostatic regulation, to opioid-induced respiratory depression. Microinjection of the μ-opioid agonist DAMGO in the RVM of lightly anesthetized rats produced both analgesia and respiratory depression, showing that neurons in this region can modulate breathing. Blocking opioid action in the RVM by microinjecting the opioid antagonist naltrexone reversed the analgesic and respiratory effects of systemically administered morphine, showing that this region plays a role in both the analgesic and respiratory-depressant properties of systemically administered morphine. The distribution of neurons directly inhibited by RVM opioid microinjection was determined with a fluorescent opioid peptide, dermorphin-Alexa 594, and found to be concentrated in and around the RVM. The non-opioid analgesic improgan, like DAMGO, produced antinociception but, unlike DAMGO, stimulated breathing when microinjected into the RVM. Concurrent recording of RVM neurons during improgan microinjection showed that this agent activated RVM ON-cells, OFF-cells, and NEUTRAL-cells. Since opioids are known to activate OFF-cells but suppress ON-cell firing, the differential respiratory response to these two analgesic drugs is best explained by their opposing effects on the activity of RVM ON-cells. These findings show that pain relief can be separated pharmacologically from respiratory depression and identify RVM OFF-cells as important central targets for continued development of potent analgesics with fewer side effects.

scholarly journals Clinically Relevant Infusion Rates of μ-Opioid Agonist Remifentanil Cause Bradypnea in Decerebrate Dogs but not Via Direct Effects in the pre-Bötzinger Complex Region

2010 ◽  
Vol 103 (1) ◽  
pp. 409-418 ◽  
Author(s):  
Sanda Mustapic ◽  
Tomislav Radocaj ◽  
Antonio Sanchez ◽  
Zoran Dogas ◽  
Astrid G. Stucke ◽  
...  
Keyword(s):  
Opioid Analgesic ◽  
Plasma Concentrations ◽  
Respiratory Neurons ◽  
Opioid Antagonist ◽  
Direct Effects ◽  
Opioid Agonist ◽  
Homocysteic Acid ◽  
Respiratory Rhythmogenesis ◽  
Bötzinger Complex

Systemic administration of μ-opioids at clinical doses for analgesia typically slows respiratory rate. Mu-opioid receptors (MORs) on pre-Bötzinger Complex (pre-BötC) respiratory neurons, the putative kernel of respiratory rhythmogenesis, are potential targets. The purpose of this study was to determine the contribution of pre-BötC MORs to the bradypnea produced in vivo by intravenous administration of clinically relevant infusion rates of remifentanil (remi), a short-acting, potent μ-opioid analgesic. In decerebrate dogs, multibarrel micropipettes were used to record pre-BötC neuronal activity and to eject the opioid antagonist naloxone (NAL, 0.5 mM), the glutamate agonist d-homocysteic acid (DLH, 20 mM), or the MOR agonist [d-Ala2, N-Me-Phe4, gly-ol5]-enkephalin (DAMGO, 100 μM). Inspiratory and expiratory durations ( TI and TE) and peak phrenic nerve activity (PPA) were measured from the phrenic neurogram. The pre-BötC was functionally identified by its rate altering response (typically tachypnea) to DLH microinjection. During intravenous remi-induced bradypnea (∼60% decrease in central breathing frequency, fB), bilateral injections of NAL in the pre-BötC did not change TI, TE, fB, and PPA. Also, NAL picoejected onto single pre-BötC neurons depressed by intravenous remi had no effect on their discharge. In contrast, ∼60 μg/kg of intravenous NAL rapidly reversed all remi-induced effects. In a separate group of dogs, microinjections of DAMGO in the pre-BötC increased fB by 44%, while subsequent intravenous remi infusion more than offset this DAMGO induced tachypnea. These results indicate that μ-opioids at plasma concentrations that cause profound analgesia produce their bradypneic effect via MORs located outside the pre-BötC region.

Tramadol for maintenance in opioid dependence: A retrospective chart revie

2017 ◽  
Vol 13 (5) ◽  
pp. 329 ◽  
Author(s):  
Siddharth Sarkar, MD, DNB ◽  
Rakesh Lal, MD ◽  
Mohit Varshney, MD ◽  
Yatan Pal Singh Balhara, MD, DNB, MNAMS
Keyword(s):  
Opioid Dependence ◽  
Maintenance Treatment ◽  
Evidence Base ◽  
Prescription Opioid ◽  
Opioid Use ◽  
Opioid Agonist ◽  
Heroin Use ◽  
Select Group ◽  
Treatment Centre ◽  
Icd 10

Background and aims: Tramadol is an opioid agonist which can be potentially used for maintenance treatment of patients with opioid use disorders. This chart review presents the characteristics of individuals with an ICD 10 diagnosis of opioid dependence who were maintained on tramadol for a period of at least 6 months.Methods: Records of patients seeking treatment for opioid dependence from the outpatient clinic of the National Drug Dependence Treatment Centre, Ghaziabad, India were screened. One hundred consecutive patients who received tramadol for more than 6 months were included.Results: The sample comprised exclusively of males and had a mean age of 40.9 years. The median dose of tramadol at initiation and continuation was 300 mg/ day. Sixty-two patients achieved complete abstinence during the course of treatment. Greater age, longer duration of opioid use, and better follow-up adherence were associated with abstinent status. The rates of abstinence were higher among those presenting with natural opioid use as compared to others (prescription opioid use or heroin use).Conclusion: Tramadol can be an alternative medication for harm reduction in select group of patients with opioid dependence. Further research is required to strengthen the evidence base of rational use of tramadol for maintenance treatment of patients with opioid dependence.

scholarly journals In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

2020 ◽  
Vol 21 (20) ◽  
pp. 7738
Author(s):  
Joanna Matalińska ◽  
Piotr F. J. Lipiński ◽  
Piotr Kosson ◽  
Katarzyna Kosińska ◽  
Aleksandra Misicka
Keyword(s):  
In Silico ◽  
Molecular Orbital Calculations ◽  
Opioid Use ◽  
Opioid Agonist ◽  
Hybrid Compound ◽  
In Silico Studies ◽  
Neurokinin 1 ◽  
Dynamics Simulations

AA3266 is a hybrid compound consisting of opioid receptor agonist and neurokinin-1 receptor (NK1R) antagonist pharmacophores. It was designed with the desire to have an analgesic molecule with improved properties and auxiliary anticancer activity. Previously, the compound was found to exhibit high affinity for μ- and δ-opioid receptors, while moderate binding to NK1R. In the presented contribution, we report on a deeper investigation of this hybrid. In vivo, we have established that AA3266 has potent antinociceptive activity in acute pain model, comparable to that of morphine. Desirably, with prolonged administration, our hybrid induces less tolerance than morphine does. AA3266, contrary to morphine, does not cause development of constipation, which is one of the main undesirable effects of opioid use. In vitro, we have confirmed relatively strong cytotoxic activity on a few selected cancer cell lines, similar to or greater than that of a reference NK1R antagonist, aprepitant. Importantly, our compound affects normal cells to smaller extent what makes our compound more selective against cancer cells. In silico methods, including molecular docking, molecular dynamics simulations and fragment molecular orbital calculations, have been used to investigate the interactions of AA3266 with MOR and NK1R. Insights from these will guide structural optimization of opioid/antitachykinin hybrid compounds.

scholarly journals Buprenorphine prescription, misuse and service provision: a global perspective

2009 ◽  
Vol 15 (5) ◽  
pp. 354-363 ◽  
Author(s):  
Roger Chun Man Ho ◽  
Kai Yang Chen ◽  
Birit Broekman ◽  
Anselm Mak
Keyword(s):  
Service Provision ◽  
Opioid Dependence ◽  
Global Perspective ◽  
Opioid Antagonist ◽  
Policy Recommendations ◽  
Opioid Misuse ◽  
Opioid Agonist ◽  
Training Requirements ◽  
Primary Care Settings ◽  
Recreational Use

SummaryBuprenorphine, a partial μ-opioid agonist and κ-opioid antagonist, is recommended as safe and effective maintenance treatment for opioid dependence. It offers the possibility of management in primary care settings. However, its prescription has led to diversion for illicit recreational use and resulted in medical complications and, rarely, fatal overdose in combination with other sedatives. The outcome of buprenorphine maintenance programmes varies from country to country and it is determined by the local therapeutic traditions, regulatory restrictions and existing service provision for opioid misusers. This article addresses the pharmacology of buprenorphine, the benefits and drawbacks of its prescription, service provision for opioid misuse around the world, policy recommendations, and prescribing training requirements.

scholarly journals Treatment of opioid use disorder in primary care

BMJ ◽  
2021 ◽  
pp. n784
Author(s):  
Megan Buresh ◽  
Robert Stern ◽  
Darius Rastegar
Keyword(s):  
Primary Care ◽  
Randomized Controlled Trials ◽  
Opioid Use Disorder ◽  
Opioid Antagonist ◽  
Controlled Trials ◽  
Opioid Use ◽  
Opioid Agonist ◽  
Randomized Controlled ◽  
Primary Care Settings ◽  
Illicit Opioid Use

AbstractOpioid use disorder (OUD) is a common, treatable chronic disease that can be effectively managed in primary care settings. Untreated OUD is associated with considerable morbidity and mortality—notably, overdose, infectious complications of injecting drug use, and profoundly diminished quality of life. Withdrawal management and medication tapers are ineffective and are associated with increased rates of relapse and death. Pharmacotherapy is the evidence based mainstay of OUD treatment, and many studies support its integration into primary care settings. Evidence is strongest for the opioid agonists buprenorphine and methadone, which randomized controlled trials have shown to decrease illicit opioid use and mortality. Discontinuation of opioid agonist therapy is associated with increased rates of relapse and mortality. Less evidence is available for the opioid antagonist extended release naltrexone, with a meta-analysis of randomized controlled trials showing decreased illicit opioid use but no effect on mortality. Treating OUD in primary care settings is cost effective, improves outcomes for both OUD and other medical comorbidities, and is highly acceptable to patients. Evidence on whether behavioral interventions improve outcomes for patients receiving pharmacotherapy is mixed, with guidelines promoting voluntary engagement in psychosocial supports, including counseling. Further work is needed to promote the integration of OUD treatment into primary care and to overcome regulatory barriers to integrating methadone into primary care treatment in the US.

scholarly journals Treatment of opioid dependence with buprenorphine: current update

2017 ◽  
Vol 19 (3) ◽  
pp. 299-308 ◽  
Keyword(s):  
Side Effects ◽  
Opioid Dependence ◽  
Maintenance Treatment ◽  
Partial Agonist ◽  
Opioid Antagonist ◽  
Clinical Effects ◽  
Opioid Maintenance Treatment ◽  
First Line ◽  
Opioid Agonist ◽  
Safety Issues

Opioid maintenance treatment is the first-line approach in opioid dependence. Both the full opioid agonist methadone (MET) and the partial agonist buprenorphine (BUP) are licensed for the treatment of opioid dependence. BUP differs significantly from MET in its pharmacology, side effects, and safety issues. For example, the risk of respiratory depression is lower than with MET. The risk of diversion and injection of BUP have been reduced by also making it available as a tablet containing the opioid antagonist naloxone. This review summarizes the clinical effects of BUP and examines possible factors that can support decisions regarding the use of BUP or MET in opioid-dependent people.

Opioids

2020 ◽  
pp. 109-148
Author(s):  
Darius A. Rastegar
Keyword(s):  
Respiratory Depression ◽  
Opioid Use Disorder ◽  
Opioid Antagonist ◽  
Opioid Use ◽  
Opioid Agonist ◽  
Level Of Consciousness ◽  
Long Acting ◽  
Self Help Groups ◽  
Prescription Pain Relievers

Opioids are a class of drugs that include heroin and prescription pain relievers that produce analgesia and euphoria. More than 2 million Americans have an opioid use disorder. Acute effects include analgesia, respiratory depression, miosis, and euphoria. Overdose is a serious complication of opioid use, characterized by depressed level of consciousness and respiratory depression. It can be treated with naloxone. Withdrawal symptoms include dysphoria, yawning, tearing, diarrhea, cramps, nausea, and piloerection. Buprenorphine, methadone, clonidine, and lofexidine can be used to ameliorate the symptoms of withdrawal. However, supervised withdrawal alone rarely leads to long-term abstinence. There are a number of psychosocial treatments, including self-help groups, outpatient therapy, and residential treatment; the data on their effectiveness are limited. Pharmacotherapy with an opioid agonist (methadone or buprenorphine) is the most effective treatment. Long-acting injectable naltrexone, an opioid antagonist, is also effective, but it is more difficult to initiate.

Ultra-low-dose opioid antagonists to enhance opioid analgesia

2006 ◽  
Vol 2 (5) ◽  
pp. 295 ◽  
Author(s):  
Paul Sloan, MD ◽  
Scott Hamann, PhD, MD
Keyword(s):  
Low Dose ◽  
Neuronal Cell ◽  
Opioid Antagonists ◽  
Cellular Mechanisms ◽  
Opioid Agonist ◽  
History Of ◽  
Primary Focus ◽  
Novel Model

This article will review decades of science contributing to current interest in opioid excitatory pharmacology. A long history of clinical confusion provided the stimulus for recent, detailed in vivo and in vitro investigations of the neuropharmacologic mechanisms involved in analgesic and hyperalgesic actions of opioid agonists and antagonists. Following the discovery of central nervous system opioid excitatory-hyperalgesic processes in animals, detailed neuronal cell culture experiments established opioid receptor/G protein/adenylate cyclase neurobiochemical mechanisms for bimodal inhibitory versus excitatory actions of opioids. Once this novel model was available to explain the cellular mechanisms responsible for the duality of opioid actions, clinical translation of this technology began to emerge, with a primary focus on selective antagonism of opioid excitatory actions with concomitant low-dose opioid antagonists. Encouraging results from recent animal and clinical studies will be discussed as further evidence that therapeutic pain management may be improved through enhancement of opioid agonist analgesia by cotreatment with ultra-low-dose opioid antagonists that selectively attenuate opioid-mediated hyperalgesia.

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