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Molecules (Basel, Switzerland) Aug 2020Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their... (Review)
Review
Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their pharmacology, interactions, safety profiles, and how pharmacology is being manipulated to misuse these common medications, with the aim to expand on the subject outlined by the authors focusing on abuse prevention and prevalence rates. The reviewed literature was identified in several online databases through searches conducted with phrases created by combining the international non-proprietary names of the drugs with terms related to drug misuse. The results show that OTC opioids are misused as an alternative for illicit narcotics, or prescription-only opioids. The potency of codeine and loperamide is strongly dependent on the individual enzymatic activity of CYP2D6 and CYP3A4, as well as P-glycoprotein function. Codeine can also be utilized as a substrate for clandestine syntheses of more potent drugs of abuse, namely desomorphine ("Krokodil"), and morphine. The dangerous methods used to prepare these substances can result in poisoning from toxic chemicals and impurities originating from the synthesis procedure. OTC opioids are generally safe when consumed in accordance with medical guidelines. However, the intake of supratherapeutic amounts of these substances may reveal surprising traits of common medications.
Topics: Analgesics, Opioid; Codeine; Drug Misuse; Humans; Loperamide; Nonprescription Drugs
PubMed: 32867117
DOI: 10.3390/molecules25173905 -
JAMA Psychiatry Jul 2021Opioid use disorder (OUD) is a significant cause of morbidity and mortality in the US, yet many individuals with OUD do not receive treatment.
IMPORTANCE
Opioid use disorder (OUD) is a significant cause of morbidity and mortality in the US, yet many individuals with OUD do not receive treatment.
OBJECTIVE
To assess the cost-effectiveness of OUD treatments and association of these treatments with outcomes in the US.
DESIGN AND SETTING
This model-based cost-effectiveness analysis included a US population with OUD.
INTERVENTIONS
Medication-assisted treatment (MAT) with buprenorphine, methadone, or injectable extended-release naltrexone; psychotherapy (beyond standard counseling); overdose education and naloxone distribution (OEND); and contingency management (CM).
MAIN OUTCOMES AND MEASURES
Fatal and nonfatal overdoses and deaths throughout 5 years, discounted lifetime quality-adjusted life-years (QALYs), and costs.
RESULTS
In the base case, in the absence of treatment, 42 717 overdoses (4132 fatal, 38 585 nonfatal) and 12 660 deaths were estimated to occur in a cohort of 100 000 patients over 5 years, and 11.58 discounted lifetime QALYs were estimated to be experienced per person. An estimated reduction in overdoses was associated with MAT with methadone (10.7%), MAT with buprenorphine or naltrexone (22.0%), and when combined with CM and psychotherapy (range, 21.0%-31.4%). Estimated deceased deaths were associated with MAT with methadone (6%), MAT with buprenorphine or naltrexone (13.9%), and when combined with CM, OEND, and psychotherapy (16.9%). MAT yielded discounted gains of 1.02 to 1.07 QALYs per person. Including only health care sector costs, methadone cost $16 000/QALY gained compared with no treatment, followed by methadone with OEND ($22 000/QALY gained), then by buprenorphine with OEND and CM ($42 000/QALY gained), and then by buprenorphine with OEND, CM, and psychotherapy ($250 000/QALY gained). MAT with naltrexone was dominated by other treatment alternatives. When criminal justice costs were included, all forms of MAT (with buprenorphine, methadone, and naltrexone) were associated with cost savings compared with no treatment, yielding savings of $25 000 to $105 000 in lifetime costs per person. The largest cost savings were associated with methadone plus CM. Results were qualitatively unchanged over a wide range of sensitivity analyses. An analysis using demographic and cost data for Veterans Health Administration patients yielded similar findings.
CONCLUSIONS AND RELEVANCE
In this cost-effectiveness analysis, expanded access to MAT, combined with OEND and CM, was associated with cost-saving reductions in morbidity and mortality from OUD. Lack of widespread MAT availability limits access to a cost-saving medical intervention that reduces morbidity and mortality from OUD. Opioid overdoses in the US likely reached a record high in 2020 because of COVID-19 increasing substance use, exacerbating stress and social isolation, and interfering with opioid treatment. It is essential to understand the cost-effectiveness of alternative forms of MAT to treat OUD.
Topics: Adult; Buprenorphine; Combined Modality Therapy; Cost-Benefit Analysis; Delayed-Action Preparations; Female; Humans; Male; Methadone; Middle Aged; Naloxone; Opiate Overdose; Opiate Substitution Treatment; Opioid-Related Disorders; Psychotherapy; Treatment Outcome
PubMed: 33787832
DOI: 10.1001/jamapsychiatry.2021.0247 -
Nature Jan 2023Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side...
Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site found in µOR and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp residue in the Na site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at G subtypes and show strongly reduced arrestin recruitment-one (C6 guano) also shows the lowest G efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for G, G and G subtypes and arrestins, thus modulating their in vivo pharmacology.
Topics: Animals; Mice; Analgesics, Opioid; Arrestins; Cryoelectron Microscopy; Fentanyl; Ligands; Morphinans; Receptors, Opioid, mu; Binding Sites; Nociception; Drug Design
PubMed: 36450356
DOI: 10.1038/s41586-022-05588-y -
British Journal of Anaesthesia Oct 2019
Topics: Humans; Naloxone
PubMed: 31420087
DOI: 10.1016/j.bja.2019.07.007 -
Anesthesiology Jun 2020Intrathecal opioids are routinely administered during spinal anesthesia for postcesarean analgesia. The effectiveness of intrathecal morphine for postcesarean analgesia... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Intrathecal opioids are routinely administered during spinal anesthesia for postcesarean analgesia. The effectiveness of intrathecal morphine for postcesarean analgesia is well established, and the use of intrathecal hydromorphone is growing. No prospective studies have compared the effectiveness of equipotent doses of intrathecal morphine versus intrathecal hydromorphone as part of a multimodal analgesic regimen for postcesarean analgesia. The authors hypothesized that intrathecal morphine would result in superior analgesia compared with intrathecal hydromorphone 24 h after delivery.
METHODS
In this single-center, double-blinded, randomized trial, 138 parturients undergoing scheduled cesarean delivery were randomized to receive 150 µg of intrathecal morphine or 75 µg of intrathecal hydromorphone as part of a primary spinal anesthetic and multimodal analgesic regimen; 134 parturients were included in the analysis. The primary outcome was the numerical rating scale score for pain with movement 24 h after delivery. Static and dynamic pain scores, nausea, pruritus, degree of sedation, and patient satisfaction were assessed every 6 h for 36 h postpartum. Total opioid consumption was recorded.
RESULTS
There was no significant difference in pain scores with movement at 24 h (intrathecal hydromorphone median [25th, 75th] 4 [3, 5] and intrathecal morphine 3 [2, 4.5]) or at any time point (estimated difference, 0.5; 95% CI, 0 to 1; P = 0.139). Opioid received in the first 24 h did not differ between groups (median [25th, 75th] oral morphine milligram equivalents for intrathecal hydromorphone 30 [7.5, 45.06] vs. intrathecal morphine 22.5 [14.0, 37.5], P = 0.769). From Kaplan-Meier analysis, the median time to first opioid request was 5.4 h for hydromorphone and 12.1 h for morphine (log-rank test P = 0.200).
CONCLUSIONS
Although the hypothesis was that intrathecal morphine would provide superior analgesia to intrathecal hydromorphone, the results did not confirm this. At the doses studied, both intrathecal morphine and intrathecal hydromorphone provide effective postcesarean analgesia when combined with a multimodal analgesia regimen.
Topics: Adult; Analgesia, Epidural; Analgesia, Obstetrical; Analgesics, Opioid; Cesarean Section; Double-Blind Method; Female; Humans; Hydromorphone; Male; Morphine; Pain, Postoperative; Treatment Outcome
PubMed: 32251031
DOI: 10.1097/ALN.0000000000003283 -
Journal of Substance Abuse Treatment Nov 2022At age 16, I injected morphine for the first time, and then started injecting heroin. By most standards, I was highly functioning, although I eventually became addicted....
At age 16, I injected morphine for the first time, and then started injecting heroin. By most standards, I was highly functioning, although I eventually became addicted. I was and remain socioeconomically privileged, but my relationship to heroin resulted in behaviors and consequences that I never could have conceived of, and which I sometimes strain to remember occurred. My life now is stable and conventional. Some aspects of my past addiction are unerasable, but the most salient of those are the social and legal consequences of having a criminal record-not any hallmarks of a chronic brain disease or disorder. I do not consider myself "in recovery." Rather, I am recovered, by standards both my own and derived from clinical nosology. I have been in sustained remission for over a decade. Yet feelings are not facts, as is often said. I still use alcohol, and occasionally (though not recently) I have used other drugs, so there remains the possibility that my brain is indeed "diseased" and I am not objectively recovered, my self-assessment notwithstanding. My aim in writing about my lived experience of drug use, addiction, and recovery is to highlight the heterogeneity of people's experiences and the insight that personal narratives can provide. Debates about the brain disease model of addiction are often confined to academia, with the real-world, unintended consequences of the "disease" label seldom considered. Stigmatization of people with addiction comes from moralizing about drug use but may also originate from well-intended labels. I posit that we should not need labels to care about addicted people and make scientifically informed treatment accessible. Addicted people deserve help because they either need or want it, regardless of labels that presume to describe the etiology or likely trajectory of their problems. I conclude that some labels, even those needed for clinical classification of human behavior, may be pernicious. Clinicians and researchers have an obligation to reflect more deeply on the implications of the disease conceptualization of complex human behaviors such as addiction.
Topics: Adolescent; Behavior, Addictive; Brain Diseases; Heroin; Humans; Substance-Related Disorders
PubMed: 36108442
DOI: 10.1016/j.jsat.2022.108874 -
Canadian Family Physician Medecin de... Dec 2020
Topics: Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Dose-Response Relationship, Drug; Humans; Naloxone; Opioid-Related Disorders; Substance Withdrawal Syndrome
PubMed: 33334955
DOI: 10.46747/cfp.6612891 -
Pain Research & Management 2020Purified from the roots of the plant , sinomenine is traditionally used in China and Japan for treating rheumatism and arthritis. Previously, we have demonstrated that... (Review)
Review
Purified from the roots of the plant , sinomenine is traditionally used in China and Japan for treating rheumatism and arthritis. Previously, we have demonstrated that sinomenine possessed a broad analgesic spectrum in various chronic pain animal models and repeated administration of sinomenine did not generate tolerance. In this review article, we discussed sinomenine's analgesic mechanism with focus on its role on immune regulation and neuroimmune interaction. Sinomenine has distinct immunoregulative properties, in which glutamate, adenosine triphosphate, nitric oxide, and proinflammatory cytokines are thought to be involved. Sinomenine may alter the unbalanced neuroimmune interaction and inhibit neuroinflammation, oxidative stress, and central sensitization in chronic pain states. In conclusion, sinomenine has promising potential for chronic pain management in different clinical settings.
Topics: Analgesics; Animals; Chronic Pain; Humans; Morphinans; Neuroimmunomodulation
PubMed: 32454918
DOI: 10.1155/2020/1876862 -
Frontiers in Public Health 2023Opioid use disorder (OUD) is a major public health threat, contributing to morbidity and mortality from addiction, overdose, and related medical conditions. Despite our... (Review)
Review
Opioid use disorder (OUD) is a major public health threat, contributing to morbidity and mortality from addiction, overdose, and related medical conditions. Despite our increasing knowledge about the pathophysiology and existing medical treatments of OUD, it has remained a relapsing and remitting disorder for decades, with rising deaths from overdoses, rather than declining. The COVID-19 pandemic has accelerated the increase in overall substance use and interrupted access to treatment. If increased naloxone access, more buprenorphine prescribers, greater access to treatment, enhanced reimbursement, less stigma and various harm reduction strategies were effective for OUD, overdose deaths would not be at an all-time high. Different prevention and treatment approaches are needed to reverse the concerning trend in OUD. This article will review the recent trends and limitations on existing medications for OUD and briefly review novel approaches to treatment that have the potential to be more durable and effective than existing medications. The focus will be on promising interventional treatments, psychedelics, neuroimmune, neutraceutical, and electromagnetic therapies. At different phases of investigation and FDA approval, these novel approaches have the potential to not just reduce overdoses and deaths, but attenuate OUD, as well as address existing comorbid disorders.
Topics: Humans; Pandemics; Opiate Substitution Treatment; Opioid-Related Disorders; Buprenorphine; Naloxone; Drug Overdose
PubMed: 38332941
DOI: 10.3389/fpubh.2023.1274719 -
Molecules (Basel, Switzerland) Jun 2023Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of... (Review)
Review
Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of currently available opioids, together with the current 'opioid crisis', warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral opioid receptors as effective means of treating pain and avoiding the centrally mediated side effects represents a research area of substantial and continuous attention. Among clinically used analgesics, opioids from the class of morphinans (i.e., morphine and structurally related analogues) are of utmost clinical importance as analgesic drugs activating the mu-opioid receptor. In this review, we focus on peripheralization strategies applied to -methylmorphinans to limit their ability to cross the blood-brain barrier, thus minimizing central exposure and the associated undesired side effects. Chemical modifications to the morphinan scaffold to increase hydrophilicity of known and new opioids, and nanocarrier-based approaches to selectively deliver opioids, such as morphine, to the peripheral tissue are discussed. The preclinical and clinical research activities have allowed for the characterization of a variety of compounds that show low central nervous system penetration, and therefore an improved side effect profile, yet maintaining the desired opioid-related antinociceptive activity. Such peripheral opioid analgesics may represent alternatives to presently available drugs for an efficient and safer pain therapy.
Topics: Humans; Analgesics, Opioid; Morphinans; Pain; Analgesics; Morphine; Receptors, Opioid, mu
PubMed: 37375318
DOI: 10.3390/molecules28124761