Biphalin-A Potent Opioid Agonist-As a Panacea for Opioid System-Dependent Pathophysiological Diseases?

Biphalin, one of the opioid agonists, is a dimeric analog of enkephalin with a high affinity for opioid receptors. Opioid receptors are widespread in the central nervous system and in peripheral neuronal and non-neuronal tissues. Hence, these receptors and their agonists, which play an important role in pain blocking, may also be involved in the regulation of other physiological functions. Biphalin was designed and synthesized in 1982 by Lipkowski as an analgesic peptide. Extensive further research in various laboratories on the antinociceptive effects of biphalin has shown its excellent properties. It has been demonstrated that biphalin exhibits an analgesic effect in acute, neuropathic, and chronic animal pain models, and is 1000 times more potent than morphine when administered intrathecally. In the course of the broad conducted research devoted primarily to the antinociceptive effect of this compound, it has been found that biphalin may also potentially participate in the regulation of other opioid system-dependent functions. Nearly 40 years of research on the properties of biphalin have shown that it may play a beneficial role as an antiviral, antiproliferative, anti-inflammatory, and neuroprotective agent, and may also affect many physiological functions. This integral review analyzes the literature on the multidirectional biological effects of biphalin and its potential in the treatment of many opioid system-dependent pathophysiological diseases.

Pregnant Smokers Receiving Opioid Agonist Therapy Have an Elevated Nicotine Metabolite Ratio: A Replication Study.

INTRODUCTION: Pregnant women exposed chronically to opioids smoked more cigarettes per day (CPD) and had a higher nicotine metabolite ratio (NMR), 3-hydroxycotinine/cotinine, a biomarker of nicotine metabolism and clearance, than those not receiving opioids. We examined CPD and NMR in a group of pregnant smokers, a quarter of whom were receiving opioid agonist therapy (OAT). AIMS AND METHODS: Pregnant smokers recruited to participate in a placebo-controlled trial of bupropion for smoking cessation provided a blood sample for measurement of NMR. RESULTS: Half (52.4%) of the 124 women with NMR data were African American. OAT-treated women (n = 34, 27.4%; 27 receiving methadone and 7 buprenorphine) were more likely to be white (79% vs. 30%, p < .001) and to have a lower mean PHQ-9 total score (2.91 [SD = 2.83] vs. 4.83 [SD = 3.82], p = .007). OAT-treated women reported smoking more CPD (9.50 [SD = 5.26] vs. 7.20 [SD = 3.65], p = .005) and had higher NMR (0.78 [SD = 0.36] vs. 0.56 [SD = 0.25], p = .001) than the non-OAT-treated group. In a linear regression analysis adjusting for race, depression severity, and CPD, NMR was greater in the OAT group (p = .025), among whom the daily methadone-equivalent dosage correlated with NMR (Spearman's ρ = 0.49, p = .003). CONCLUSIONS: Consistent with the findings of Oncken et al. (2019), we found that OAT smokers smoked more and had higher NMR than non-OAT smokers. As higher NMR is associated with a reduced likelihood of smoking cessation, the effects on NMR of both pregnancy and OAT could contribute to a lower smoking cessation rate in pregnant smokers receiving chronic opioid therapy. IMPLICATIONS: We replicated the finding that the NMR is significantly greater among pregnant smokers receiving OAT than those not receiving this treatment for opioid use disorder. Furthermore, we found that the dosage of the OAT was significantly associated with the NMR level. These findings may contribute to a poorer response to smoking cessation treatment in pregnant women treated with OAT, particularly those receiving high-dose therapy, and raise the question of whether novel approaches are needed to treat smoking in this subgroup of pregnant smokers.

Dispensation of attention deficit hyperactivity disorder (ADHD) medications in patients receiving opioid agonist therapy; a national prospective cohort study in Norway from 2015 to 2017.

BACKGROUND: It is estimated that up to a third of patients on opioid agonist therapy (OAT) have attention deficit hyperactivity disorder (ADHD). Treatment by ADHD medication, including a centrally acting stimulant (CAS) or atomoxetine is one of the essential approaches. This study evaluates the use of dispensed ADHD medications in the Norwegian OAT population in the period from 2015 to 2017. Types and doses of ADHD medications, co-dispensations of other potentially addictive drugs like benzodiazepines, z-hypnotics, gabapentinoids, and non-OAT opioids, as well as direct-acting antivirals (DAA) against hepatitis C infection, are investigated. METHODS: Information about all dispensed ADHD medication, OAT opioids, and the defined potentially addictive drugs were recorded from the Norwegian Prescription Database. Dispensation rates, the types, and the doses of dispensed ADHD medications were estimated by summarizing the number of dispensations, and the dispensed doses. Logistic regression analyses were employed to assess the associations between ADHD medication, and OAT opioid use, and dispensations of other potentially addictive drugs and DAAs against hepatitis C infection. RESULTS: A total of 9235 OAT patients were included. The proportion of patients who were dispensed ADHD medication increased from 3.5 to 4.6% throughout the study period. The three most dispensed CAS were short- and intermediate-acting methylphenidate (55%), lisdexamphetamine (24%), and dexamphetamine (17%) in 2017. Buprenorphine, rather than methadone, as OAT opioid (adjusted odds ratio: 1.6, CI: 1.2-2.1) was associated with being dispensed ADHD medication. Among patients who received CAS and OAT opioids each calendar year, the dispensed doses of methylphenidate increased from 63 mg/day in 2015 to 76 mg/day in 2017 (p = 0.01). Sixty percent of patients receiving ADHD medications were also dispensed other addictive drugs concomitantly in 2017. Similar results were found in 2015 and 2016. CONCLUSION: Co-prescription of ADHD medications was low among patients on OAT in Norway, considering a high prevalence of ADHD in this patient group. On the other hand, concurrent dispensations of multiple addictive drugs were common in this population. Understanding the underlying reasons for such prescribing is essential, and research on how to optimize ADHD medication of patients with ADHD receiving OAT is needed.

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

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.

Reduction in mortality risk with opioid agonist therapy: a systematic review and meta-analysis.

INTRODUCTION: Opioid agonist therapies are effective medications that can greatly improve the quality of life of individuals with opioid use disorder. However, there is significant uncertainty about the risks of cause-specific mortality in and out of treatment. OBJECTIVE: This systematic review and meta-analysis explored the association between methadone and buprenorphine with cause-specific mortality among opioid-dependent persons. METHODS: We searched six online databases to identify relevant cohort studies, calculating all-cause and overdose-specific mortality rates during periods in and out of treatment. We pooled mortality estimates using multivariate random effects meta-analysis of the crude mortality rate per 1000 person-years of follow-up as well as relative risks comparing mortality in vs. out of treatment. RESULTS: A total of 32 cohort studies (representing 150 235 participants, 805 423.6 person-years, and 9112 deaths) met eligibility criteria. Crude mortality rates were substantially higher among methadone cohorts than buprenorphine cohorts. Relative risk reduction was substantially higher with methadone relative to buprenorphine when time in-treatment was compared to time out-of-treatment. Furthermore, the greatest mortality reduction was conferred during the first 4 weeks of treatment. Mortality estimates were substantially heterogeneous and varied significantly by country, region, and by the nature of the treatment provider. CONCLUSION: Precautions are necessary for the safer implementation of opioid agonist therapy, including baseline assessments of opioid tolerance, ongoing monitoring during the induction period, education of patients about the risk of overdose, and coordination within healthcare services.

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates.

Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ∼10- to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abuse-free opioid analgesics.

Opioid agonist therapy during residential treatment of opioid use disorder: Cohort study on access and outcomes.

OBJECTIVE: To determine access to opioid agonist therapy (OAT) for those entering residential treatment for opioid use disorder; to report on treatment outcomes for those taking OAT and those not taking OAT; and to determine the association between OAT use and residential treatment completion. DESIGN: Retrospective cohort study. SETTING: Ontario. PARTICIPANTS: Patients with opioid use disorder admitted to publicly funded residential treatment programs in the province of Ontario between January 1, 2013, and December 31, 2016. MAIN OUTCOME MEASURES: Access to OAT during residential treatment using descriptive statistics. Treatment outcomes (ie, completed the program, voluntarily left early, involuntary discharged, and other) for the entire cohort and for the OAT and non-OAT groups using descriptive statistics. Association between OAT use at admission and treatment completion (a binary outcome) using bivariate and multivariate models. RESULTS: Among an identified cohort of 1910 patients with opioid use disorder, 52.8% entered programs that permitted access to OAT. Overall, 56.8% of patients completed treatment, 23.3% voluntarily left early (eg, were no-shows, dropped out), 17.0% were involuntarily discharged, and 2.9% were discharged early for other reasons. Those taking OAT were as likely to complete treatment as those not taking OAT (53.9% vs 57.5%, respectively; adjusted odds ratio of 1.07, 95% CI 0.77 to 1.38). CONCLUSION: This study demonstrates 2 large gaps in care for patients with opioid use disorder. First, these patients have poor access to OAT-the first-line treatment of opioid use disorder-while in publicly funded residential treatment programs; and second, many are involuntarily discharged from treatment. Additionally, this study indicates that patients taking OAT have similar likelihood of completing residential treatment as those not taking OAT do. Limitations of this study are that it is based on observational data for patients who self-selected before admission to use OAT or not, and it is likely not all confounders were accounted for.

Opiate agonist treatment to improve health of individuals with opioid use disorder in Lebanon.

BACKGROUND: Opioid agonist therapy has been widely used to reduce harms among individuals with opioid use disorder but its effectiveness has not been evaluated in the Middle East North African (MENA) region. This study aims to evaluate the effectiveness of a program using opioid agonist therapy in combination with psychosocial support on improving psychological and social well-being, reducing arrest, and reducing risky behavior in individuals with opioid use disorder in Lebanon. METHODS: A one-group pre-test post-test design study was performed at SKOUN Lebanese Addiction Centre between January 2013 and December 2014. Eighty-six out of 181 patients agreed to participate and completed the 3-month assessment and 38 concluded the 12-month assessment. Psychological (depression and anxiety, quality of life), substance dependence/abuse, behavioral (injecting behavior, sharing needles and paraphernalia), and social outcomes were evaluated at baseline, 3, and 12 months post-treatment. RESULTS: Remarkable statistical significance improvements were observed 3 months after treatment in most outcome variables including quality of life, anxiety, substance dependence, overdose, employment, and injecting behavior. Improvements were sustained 12 months after treatment. CONCLUSION: Results support expanding the access to opioid agonist therapy in other MENA countries to treat substance dependence and reduce harms among individuals with opioid use disorder.

Inhibition of Gßγ-subunit signaling potentiates morphine-induced antinociception but not respiratory depression, constipation, locomotion, and reward.

Inhibition of Gßγ-subunit signaling to phospholipase C ß3 has been shown to potentiate morphine-mediated antinociception while attenuating the development of tolerance and dependence in mice. The objective of this study was to determine the effect of Gßγ-subunit inhibition on antinociception and other pharmacological effects, such as respiratory depression, constipation, and hyperlocomotion, mediated by the µ-opioid receptor. The Gßγ-subunit inhibitor, gallein, was administered to C57BL/6J mice by intraperitoneal injection before morphine, and data were compared with mice treated with vehicle, morphine, or gallein alone. Morphine-induced antinociception was measured using the 55°C warm-water tail-withdrawal test. Pretreatment with gallein produced a dose-dependent potentiation of morphine-mediated antinociception, producing up to a 10-fold leftward shift in the morphine dose-response curve and extending the duration of antinociception induced by a single dose of morphine. Gallein pretreatment also prevented acute antinociceptive tolerance induced by morphine. In contrast, the dose-dependent respiratory depression and hyperlocomotion induced by morphine were not potentiated by gallein pretreatment. Similarly, gallein pretreatment did not potentiate morphine-conditioned place preference responses or morphine-induced constipation, as measured as a reduction in excreta. These results suggest that selectively inhibiting Gßγ-mediated signaling may selectively increase µ-opioid receptor-mediated antinociception without matching increases in adverse physiological effects.

Development and validation of a UPLC-MS/MS method for the determination of 7-hydroxymitragynine, a µ-opioid agonist, in rat plasma and its application to a pharmacokinetic study.

A simple, sensitive and specific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine the concentrations of 7-hydroxymitragynine in rat plasma. Following a single-step liquid-liquid extraction of plasma samples using chloroform, 7-hydroxymitragynine and the internal standard (tryptoline) were separated on an Acquity UPLC(TM) BEH C18 (1.7 µm, 2.1 × 50 mm) column using an isocratic elution at a flow rate of 0.2 mL/min. The mobile phase consisted of 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile (10:90, v/v). The run time was 2.5 min. The analysis was carried out under the multiple reaction-monitoring mode using positive electrospray ionization. Protonated ions [M + H](+) and their respective product ions were monitored at the following transitions: 415 → 190 for 7-hydroxymitragynine and 173 → 144 for the internal standard. The calibration curve was linear over the range of 10-4000 ng/mL (r(2) = 0.999) with a lower limit of quantification of 10 ng/mL. The extraction recoveries ranged from 62.0 to 67.3% at concentrations of 20, 600 and 3200 ng/mL). Intra- and inter-day assay precisions (relative standard deviation) were <15% and the accuracy was within 96.5-104.0%. This validated method was successfully applied to quantify 7-hydroxymitragynine in rat plasma following intravenous administration.

The role of opioid transmission in music-induced pleasure.

Studies conducted in rodents indicate a crucial role of the opioid circuit in mediating objective hedonic reactions to primary rewards. However, it remains unclear whether opioid transmission is also essential to experience pleasure with more abstract rewards, such as music. We addressed this question using a double-blind within-subject pharmacological design in which opioid levels were up- and downregulated by administering an opioid agonist (oxycodone) and antagonist (naltrexone), respectively, before healthy participants (n = 21) listened to music. Participants also performed a monetary incentive delay (MID) task to control for the effectiveness of the treatment and the specificity of the effects. Our results revealed that the pharmacological intervention did not modulate subjective reports of pleasure, nor the occurrence of chills. On the contrary, psychophysiological (objective) measures of emotional arousal, such as skin conductance responses (SCRs), were bidirectionally modulated in both the music and MID tasks. This modulation specifically occurred during reward consumption, with greater pleasure-related SCR following oxycodone than naltrexone. These findings indicate that opioid transmission does not modulate subjective evaluations but rather affects objective reward-related psychophysiological responses. These findings raise new caveats about the role of the opioidergic system in the modulation of pleasure for more abstract or cognitive forms of rewarding experiences, such as music.

δ-Opioid mechanisms for ADL5747 and ADL5859 effects in mice: analgesia, locomotion, and receptor internalization.

N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4'-piperidine]-4-yl) benzamide (ADL5859) and N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4'-piperidine]-4-yl)benzamide (ADL5747) are novel δ-opioid agonists that show good oral bioavailability and analgesic and antidepressive effects in the rat and represent potential drugs for chronic pain treatment. Here, we used genetic approaches to investigate molecular mechanisms underlying their analgesic effects in the mouse. We tested analgesic effects of ADL5859 and ADL5747 in mice by using mechanical sensitivity measures in both complete Freund's adjuvant and sciatic nerve ligation pain models. We examined their analgesic effects in δ-opioid receptor constitutive knockout (KO) mice and mice with a conditional deletion of δ-receptor in peripheral voltage-gated sodium channel (Nav)1.8-expressing neurons (cKO mice). Both ADL5859 and ADL5747, and the prototypical δ agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl]-(3-methoxyphenyl)methyl]-N,N-diethyl-benzamide (SNC80) as a control, significantly reduced inflammatory and neuropathic pain. The antiallodynic effects of all three δ-opioid agonists were abolished in constitutive δ-receptor KO mice and strongly diminished in δ-receptor cKO mice. We also measured two other well described effects of δ agonists, increase in locomotor activity and agonist-induced receptor internalization by using knock-in mice expressing enhanced green fluorescence protein-tagged δ receptors. In contrast to SNC80, ADL5859 and ADL5747 did not induce either hyperlocomotion or receptor internalization in vivo. In conclusion, both ADL5859 and ADL5747 showed efficient pain-reducing properties in the two models of chronic pain. Their effects were mediated by δ-opioid receptors, with a main contribution of receptors expressed on peripheral Nav1.8-positive neurons. The lack of in vivo receptor internalization and locomotor activation, typically induced by SNC80, suggests agonist-biased activity at the receptor for the two drugs.

Opioid agonist maintenance for probationers: patient-level predictors of treatment retention, drug use, and crime.

This study examined outcomes and their predictors among 181 probationers enrolling in opioid agonist maintenance with methadone or levo-alpha-acetylmethadol (LAAM). Participants were interviewed at treatment entry and 2-, 6-, and 12-month follow-ups. Treatment retention and frequency of heroin use, cocaine use, and income-generating criminal activity were examined using survival and longitudinal analyses. Participants reported marked reductions in drug use and crime relative to treatment entry. A number of patient characteristics associated with various outcomes were identified. The findings support engaging probationers in treatment and highlight patient factors that might influence outcomes.

How to design an opioid drug that causes reduced tolerance and dependence.

Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply "dialing up" signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance.

Can Treatment for Substance Use Disorder Prescribe the same Substance as that Used? The Case of Injectable Opioid Agonist Treatment.

This article examines injectable Opioid Agonist Treatment (iOAT), in which patients suffering from long-term, treatment refractory opioid use disorder (OUD) are prescribed injectable diacetylmorphine, the active ingredient of heroin. While iOAT is part of the continuum of care for OUD in some European countries and in some parts of Canada, it is not an available treatment in the United States. We suggest that one reason for this situation is the belief that a genuine treatment for substance use disorder cannot prescribe the same substance as that used. We examine possible rationales for this belief by considering four combinations of views on the constitutive causal basis of substance use disorders and the definition of effective treatment. We show that all but one combination counts iOAT as a genuine treatment and that there are good reasons to reject the one that does not. Specifically, we claim that medical interventions, such as iOAT, that significantly reduce the severity of a disorder deserve to be categorized as effective treatments and regarded as such in practice.

Medications Development for Treatment of Opioid Use Disorder.

This review describes methods for preclinical evaluation of candidate medications to treat opioid use disorder (OUD). The review is founded on the propositions that (1) drug self-administration procedures provide the most direct method for assessment of medication effectiveness, (2) procedures that assess choice between opioid and nondrug reinforcers are especially useful, and (3) states of opioid dependence and withdrawal profoundly influence both opioid reinforcement and effects of candidate medications. Effects of opioid medications and vaccines on opioid choice in nondependent and opioid-dependent subjects are reviewed. Various nonopioid medications have also been examined, but none yet have been identified that safely and reliably reduce opioid choice. Future research will focus on (1) strategies for increasing safety and/or effectiveness of opioid medications (e.g., G-protein-biased µ-opioid agonists), and (2) continued development of nonopioid medications (e.g., clonidine) that might serve as adjunctive agents to current opioid medications.