Search Results (20)

The use of opioids for cancer-related pain is essential but poses significant challenges due to the risk of misuse and the development of opioid use disorder (OUD). This review takes a multidisciplinary perspective based on the current scientific literature to analyze the pharmacological mechanisms, classification, and therapeutic roles of opioids in oncology. Key risk factors for opioid misuse—including psychiatric comorbidities, prior substance use, and insufficient clinical monitoring—are discussed in conjunction with validated tools for pain assessment and international guidelines. The review emphasizes the importance of integrating toxicological, pharmacological, physiological, and public health perspectives to promote rational opioid use. Pharmacogenetic variability is explored as a determinant of treatment response and addiction risk, underscoring the value of personalized medicine. Evidence-based strategies such as early screening, psychosocial interventions, and the use of buprenorphine-naloxone are presented as effective measures for managing OUD in cancer patients. Ultimately, this work advocates for safe, patient-centered opioid prescribing practices that ensure effective pain relief without compromising safety or quality of life. Full article

Background: Methadone and buprenorphine can reduce overdose-related mortality. Behavioral approaches can also reduce fatal overdoses. The current study examined the relationship between methadone and buprenorphine and overdose history and overdose prevention and treatment behaviors. Methods: Between December 2022 and August 2024, 647 individuals who used opioids in the prior month enrolled in a community recruited study on overdose. Participants were administered a face-to-face survey. Key behaviors assessed included overdose recency, testing drugs for potency, ingesting drugs slowly, using fentanyl test strips, using drugs alone, and carrying naloxone. Chi-square and logistic regression models examined the relationships between methadone and buprenorphine and overdose-related outcomes. Results: In total, 32.9% of participants were currently taking methadone and 15.5% buprenorphine. Most (69.2%) reported ever overdosing, and among those, 33.7% had overdosed within the prior 6 months. There were no significant associations between methadone or buprenorphine status and overdose prevention and care behaviors. In the multivariable logistic regression model, methadone use was associated with a lower odds ratio (aOR = 0.49, 95% CI = 0.30–0.79of a recent overdose compared to buprenorphine. Daily or almost daily crack use was associated with greater odds of a recent overdose (aOR = 2.21, 95% CI = 1.44–3.39. Discussion: Findings suggest the importance of promoting overdose prevention and care behaviors to people in drug treatment and training them to promote overdose prevention and care behaviors among their drug-using network members and other community members. Full article

Modified opioid agonist therapy (OAT) guidelines that were initially introduced during the COVID-19 pandemic allow prescribers to increase the number of take-home doses to fulfill their need for physical distancing and prevent treatment discontinuation. It is crucial to evaluate the consequence of administering higher take-home doses of OAT on treatment retention and opioid-related harms among OAT recipients to decide whether the new recommendations should be retained post-pandemic. This study used an agent-based model to simulate individuals dispensed daily or weekly OAT (methadone or buprenorphine/naloxone) with a prescription over a six-month treatment period. Within the model simulation, a subset of OAT recipients was deemed eligible for receiving increased take-home doses of OAT at varying points during their treatment time course. Model results demonstrated that the earlier dispensing of increased take-home doses of OAT were effective in achieving a slightly higher treatment retention among OAT recipients. Extended take-home doses also increased opioid-related harms among buprenorphine/naloxone-treated individuals. The model results also illustrated that expanding naloxone availability within OAT patients’ networks could prevent these possible side effects. Therefore, policymakers may need to strike a balance between expanding access to OAT through longer-duration take-home doses and managing the potential risks associated with increased opioid-related harms. Full article

The COVID-19 pandemic led to disruptions in care for vulnerable patients, in particular patients with opioid use disorder (OUD). We aimed to examine OUD-related ED visits before and during the COVID-19 pandemic and determine if patient characteristics for OUD-related ED visits changed in the context of the pandemic. We examined all visits to the three public safety net hospital EDs in Los Angeles County from April 2019 to February 2021. We performed interrupted time series analyses examining OUD-related ED visits from Period 1, April 2019 to February 2020, compared with Period 2, April 2020 to February 2021, by race/ethnicity and payor group. We considered OUD-related ED visits as those which included any of the following: discharge diagnosis related to OUD, patients administered buprenorphine or naloxone while in the ED, and visits where a patient was prescribed buprenorphine or naloxone on discharge. There were 5919 OUD-related ED visits in the sample. OUD-related visits increased by 4.43 (2.82–6.03) per 1000 encounters from the pre-COVID period (9.47 per 1000 in February 2020) to the COVID period (13.90 per 1000 in April 2020). This represented an increase of 0.41/1000 by white patients, 0.92/1000 by black patients, and 1.83/1000 by Hispanic patients. We found increases in OUD-related ED visits among patients with Medicaid managed care of 2.23/1000 and in LA County safety net patients by 3.95/1000 ED visits. OUD-related ED visits increased during the first year of the COVID pandemic. These increases were significant among black, white, and Hispanic patients, patients with Medicaid managed care, and LA County Safety net patients. These data suggest public emergency departments served as a stopgap for patients suffering from OUD in Los Angeles County during the pandemic and can be utilized to guide preventative interventions in vulnerable populations. Full article

The prevalence of opioid use among pregnant people has been increasing over the past few decades, with a parallel increase in the rate of neonatal abstinence syndrome. Opioid agonist treatment (OAT) including methadone and buprenorphine is the recommended management method for opioid use disorders during pregnancy. Methadone has been extensively studied during pregnancy; however, buprenorphine was introduced in the early 2000s with limited data on the use of different preparations during pregnancy. Buprenorphine-naloxone has been incorporated into routine practice; however, only a few studies have investigated the use of this medication during pregnancy. To determine the safety and efficacy of this medication, we conducted a systematic review of maternal and neonatal outcomes among buprenorphine-naloxone-exposed pregnancies. The primary outcomes of interest were birth parameters, congenital anomalies, and severity of neonatal abstinence syndrome. Secondary maternal outcomes included the OAT dose and substance use at delivery. Seven studies met the inclusion criteria. Buprenorphine-naloxone doses ranged between 8 and 20 mg, and there was an associated reduction of opioid use during pregnancy. There were no significant differences in gestational age at delivery, birth parameters, or prevalence of congenital anomalies between buprenorphine-naloxone-exposed neonates and those exposed to methadone, buprenorphine monotherapy, illicit opioids, or no opioids. In studies comparing buprenorphine-naloxone to methadone, there were reduced rates of neonatal abstinence syndrome requiring pharmacotherapy. These studies demonstrate that buprenorphine-naloxone is a safe and effective opioid agonist treatment for pregnant people with OUD. Further large-scale, prospective data collection is required to confirm these findings. Patients and clinicians may be reassured about the use of buprenorphine-naloxone during pregnancy. Full article

In the wake of COVID-19, morbidity and mortality due to Opioid Use Disorder (OUD) is beginning to emerge as a second wave of deaths of despair. Medication assisted treatment (MAT) for opioid use disorder MAT delivered by Emergency Medicine (EM) providers can decrease mortality due to OUD; however, there are numerous cited barriers to MAT delivery. We examined the impact of MAT training on these barriers among EM residents in an urban, tertiary care facility with a large EM residency. Training included the scripted and standardized content from the Provider Clinical Support System curriculum. Residents completed pre- and post-training surveys on knowledge, barriers, and biases surrounding OUD. We performed Wilcoxon matched-pairs signed-ranks test to detect statistical differences. Of 74 residents, 49 (66%) completed the pre-training survey, and 34 (69%) of these completed the follow-up survey. Residents reported improved preparedness to treat aspects of OUD across all areas queried, reported decreased perception of barriers to providing MAT, and increased comfort prescribing naloxone, counseling patients, prescribing buprenorphine, and treating opioid withdrawal. A didactic training on MAT was associated with residents reporting improved comfort providing buprenorphine and naloxone. As the wake of morbidity and mortality from both COVID and OUD continue to increase, programs should offer dedicated training on MAT. Full article

Opioid use disorder (OUD) is a chronic disease requiring long-term treatment and is associated with opioid overdose and increased risk of mortality. However, existing randomized clinical trials focused on short-term treatment engagement and detoxification rather than overdose or mortality risk due to limited follow-up time and ethical considerations. We used a hypothetical trial framework to conduct a retrospective cohort study to assess the effectiveness of time-varying buprenorphine-naloxone on opioid overdose and death. We identified 58,835 insured adult patients with OUD diagnosis in the US, 2010–2017. We fit a marginal structural model using inverse probability weighting methods to account for measured baseline and time-varying confounders, as well as selection bias due to possibly differential loss-to-follow-up. We found that receipt of buprenorphine-naloxone was associated with reduced risk of opioid overdose (hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.49, 0.91), death (HR = 0.24, 95% CI: 0.08, 0.75), and overdose or death (HR = 0.58, 95% CI: 0.40, 0.84). The E-value for death was 7.8, which was larger than the upper 95% CI of the association between each measured baseline variable and all-cause death, which implies that the unmeasured confounding itself may not explain away the estimated effect of treatment on the endpoint of all-cause mortality. Full article

Background: Online communities such as Reddit can provide social support for those recovering from opioid use disorder. However, it is unclear whether and how advice-seekers differ from other users. Our research addresses this gap by identifying key characteristics of r/suboxone users that predict advice-seeking behavior. Objective: The objective of this analysis is to identify and describe advice-seekers on Reddit for buprenorphine-naloxone use using text annotation, social network analysis, and statistical modeling techniques. Methods: We collected 5258 posts and their comments from Reddit between 2014 and 2019. Among 202 posts which met our inclusion criteria, we annotated each post to determine which were advice-seeking (n = 137) or not advice-seeking (n = 65). We also annotated each posting user’s buprenorphine-naloxone use status (current versus formerly taking and, if currently taking, whether inducting or tapering versus other stages) and quantified their connectedness using social network analysis. To analyze the relationship between Reddit users’ advice-seeking and their social connectivity and medication use status, we constructed four models which varied in their inclusion of explanatory variables for social connectedness and buprenorphine use status. Results: The stepwise model containing “total degree” (p = 0.002), “using: inducting/tapering” (p < 0.001), and “using: other” (p = 0.01) outperformed all other models. Reddit users with fewer connections and who are currently using buprenorphine-naloxone are more likely to seek advice than those who are well-connected and no longer using the medication, respectively. Importantly, advice-seeking behavior is most accurately predicted using a combination of network characteristics and medication use status, rather than either factor alone. Conclusions: Our findings provide insights for the clinical care of people recovering from opioid use disorder and the nature of online medical advice-seeking overall. Clinicians should be especially attentive (e.g., through frequent follow-up) to patients who are inducting or tapering buprenorphine-naloxone or signal limited social support. Full article

6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif originates from a [4 + 2] cycloaddition of morphinan-6,8-dienes with dienophiles. Certain 6,14-ethenomorphinans having extremely high affinity for opioid receptors are often non-selective for opioid receptor subtypes, but this view is now undergoing some revision. The agonist 20R-etorphine and 20R-dihydroetorphine are several thousand times more potent analgesics than morphine, whereas diprenorphine is a high-affinity non-selective antagonist. The partial agonist buprenorphine is used as an analgesic in the management of post-operative pain or in substitution therapy for opiate addiction, sometimes in combination with the non-selective antagonist naloxone. In the context of the current opioid crisis, we communicated a summary of several decades of work toward generating opioid analgesics with lesser side effects or abuse potential. Our summary placed a focus on Diels–Alder reactions of morphinan-6,8-dienes and subsequent transformations of the cycloadducts. We also summarized the pharmacological aspects of radiolabeled 6,14-ethenomorphinans used in molecular imaging of opioid receptors. Full article

The opioid epidemic is an ongoing public health crisis, and the United States health system is overwhelmed with increasing numbers of opioid-related overdoses. Methocinnamox (MCAM) is a novel mu opioid receptor antagonist with an extended duration of action. MCAM has potential to reduce the burden of the opioid epidemic by being used as an overdose rescue treatment and a long-term treatment for opioid use disorder (OUD). The currently available treatments for OUD include naloxone, naltrexone, and methadone. These treatments have certain limitations, which include short duration of action, patient non-compliance, and diversion. A narrative review was conducted using PubMed and Google Scholar databases covering the history of the opioid epidemic, pain receptors, current OUD treatments and the novel drug MCAM. MCAM could potentially be used as both a rescue and long-term treatment for opioid misuse. This is due to its pseudo-irreversible antagonism of the mu opioid receptor, abnormally long duration of action of nearly two weeks, and the possibility of using kappa or delta opioid receptor agonists for pain management during OUD treatment. MCAM’s novel pharmacokinetic and pharmacodynamic properties open a new avenue for treating opioid misuse. Full article

In our continuing effort to develop effective anti-heroin vaccines as potential medications for the treatment of opioid use disorder, herein we present the design and synthesis of the haptens: 1-AmidoMorHap (1), 1-AmidoMorHap epimer (2), 1 Amido-DihydroMorHap (3), and 1 Amido-DihydroMorHap epimer (4). This is the first report of hydrolytically stable haptenic surrogates of heroin with the attachment site at the C1 position in the 4,5-epoxymorophinan nucleus. We prepared respective tetanus toxoid (TT)–hapten conjugates as heroin vaccine immunogens and evaluated their efficacy in vivo. We showed that all TT–hapten conjugates induced high antibody endpoint titers against the targets but only haptens 2 and 3 can induce protective effects against heroin in vivo. The epimeric analogues of these haptens, 1 and 4, failed to protect mice from the effects of heroin. We also showed that the in vivo efficacy is consistent with the results of the in vitro drug sequestration assay. Attachment of the linker at the C1 position induced antibodies with weak binding to the target drugs. Only TT-2 and TT-3 yielded antibodies that bound heroin and 6-acetyl morphine. None of the TT–hapten conjugates induced antibodies that cross-reacted with morphine, methadone, naloxone, or naltrexone, and only TT-3 interacted weakly with buprenorphine, and that subtle structural difference, especially at the C6 position, can vastly alter the specificity of the induced antibodies. This study is an important contribution in the field of vaccine development against small-molecule targets, providing proof that the chirality at C6 in these epoxymorphinans is a vital key to their effectiveness. Full article

A multicenter-observational study was performed to assess the effectiveness of rac-methadone, levomethadone, and buprenorphine in opioid-dependent patients in polytherapy in Southern Italy. The primary endpoint was the reduction of urinary positivity to the substances and the maintaining doses. Patients (N = 266, age = 44.80 ± 5.65, male = 79.70%, female = 20.30%) have been recruited. At recruitment, 75% of them were on treatment with rac-methadone, levomethadone, and buprenorphine/naloxone. The patients were grouped into three clusters. The levomethadone patients of Cluster A (N patients = 211), after 180 days, showed stability in urinary methadone positivity, with a marked decrease in heroin −53 ± 4%, cannabinol’s −48 ± 2%, and cocaine −37 ± 6% positivity, with no differences between treatments. A lower QTcF value of 426 ± 8.4 ms was recorded in the levomethadone patients (delta = −19 ms) vs. rac-methadone, at significantly lower doses of levomethadone (−34%, −50.2% in males) (p < 0.05). The Cluster B data were collected from 37 patients, with a high prevalence of comorbidity infections (HIV/HCV/HPV), monitored for 21 months during COVID-19. High doses of levomethadone (58.33 ± 31.58 mg/day) were needed to stabilize those that were negative for opioids and cannabinoids, in contrast to the rac-methadone and buprenorphine/naloxone patients that showed positive toxicology. Eighteen patients of the Cluster C in double diagnosis (major depressive 38.90%, bipolar 27.78%, and schizophrenia 16.67%) were stabilized with high doses of racemate 97.5 ± 8 mg/day, 51.8 ± 5 mg/day of levomethadone (−46.8% vs. rac-methadone; −71% in men), and 2.5 ± 1 mg/day of buprenorphine/naloxone. Three patients in remission were treated with tapering doses of levomethadone. Significantly reduced QTcF values were recorded with levomethadone (delta −32 ms vs. rac-methadone) in the bipolar patients, as well as the schizophrenia patients in remission (delta −45.19 ms vs. rac-methadone). Our patients were safely stabilized. Levomethadone, compared to the racemate, contributes to reducing the illicit use, especially of opioids and cannabinoids at significantly lower doses with cardiovascular safety, which, in bipolar patients, is clinically significant. Full article

It is well established that a wide range of drugs of abuse acutely boost the signaling of the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis, where norepinephrine and epinephrine are major output molecules. This stimulatory effect is accompanied by such symptoms as elevated heart rate and blood pressure, more rapid breathing, increased body temperature and sweating, and pupillary dilation, as well as the intoxicating or euphoric subjective properties of the drug. While many drugs of abuse are thought to achieve their intoxicating effects by modulating the monoaminergic neurotransmitter systems (i.e., serotonin, norepinephrine, dopamine) by binding to these receptors or otherwise affecting their synaptic signaling, this paper puts forth the hypothesis that many of these drugs are actually acutely converted to catecholamines (dopamine, norepinephrine, epinephrine) in vivo, in addition to transformation to their known metabolites. In this manner, a range of stimulants, opioids, and psychedelics (as well as alcohol) may partially achieve their intoxicating properties, as well as side effects, due to this putative transformation to catecholamines. If this hypothesis is correct, it would alter our understanding of the basic biosynthetic pathways for generating these important signaling molecules, while also modifying our view of the neural substrates underlying substance abuse and dependence, including psychological stress-induced relapse. Importantly, there is a direct way to test the overarching hypothesis: administer (either centrally or peripherally) stable isotope versions of these drugs to model organisms such as rodents (or even to humans) and then use liquid chromatography-mass spectrometry to determine if the labeled drug is converted to labeled catecholamines in brain, blood plasma, or urine samples. Full article

Patients with chronic non-cancer pain (CNCP) often use opioids for long periods of time. This may lead to opioid use disorder (OUD) and psychiatric symptoms: mainly depression and anxiety. The current study investigated the effect of buprenorphine/naloxone (BuNa) rotation on opioid misuse, craving, psychiatric symptoms and pain in patients with CNCP and OUD. Forty-three participants with CNCP and OUD were converted from a full mu-receptor agonist opioid (mean morphine equivalent dose: 328.3 mg) to BuNa, in an inpatient setting. Opioid misuse, craving, co-occurring psychiatric symptoms, and pain perception were determined at baseline and after a two-month follow-up, using the following self-report questionnaires: Current Opioid Misuse Measurement (COMM), Visual Analog Scale (VAS-craving and VAS-pain) and Depression, Anxiety and Stress Scale (DASS), respectively. VAS-craving and VAS-pain were also determined immediately after conversion. A total of 37 participants completed the protocol. The mean COMM decreased from 17.1 to 6.7 (F = 36.5; p < 0.000), the mean VAS-craving decreased from 39.3 to 5.3 (−86.6%; F = 26.5, p < 0.000), the mean DASS decreased from 12.1 to 6.6 (F = 56.3, p < 0.000), and the mean VAS-pain decreased from 51.3 to 37.2 (−27.4%, F = 3.3; p = 0.043). Rotation to BuNa in patients with CNCP and OUD was accompanied by reductions in (i) opioid misuse, (ii) opioid craving, (iii) the severity of co-occurring psychiatric symptoms, and (iv) self-reported pain. BuNa as opioid agonist treatment may therefore be a beneficial strategy in CNCP patients with OUD. The limited sample size and the observational nature of this study underline the need for the replication of the current findings in large-scale, controlled studies. Full article

Opioid-associated overdoses and deaths due to respiratory depression are a major public health problem in the US and other Western countries. In the past decade, much research effort has been directed towards the development of G-protein-biased µ-opioid receptor (MOP) agonists as a possible means to circumvent this problem. The bias hypothesis proposes that G-protein signaling mediates analgesia, whereas ß-arrestin signaling mediates respiratory depression. SR-17018 was initially reported as a highly biased µ-opioid with an extremely wide therapeutic window. It was later shown that SR-17018 can also reverse morphine tolerance and prevent withdrawal via a hitherto unknown mechanism of action. Here, we examined the temporal dynamics of SR-17018-induced MOP phosphorylation and dephosphorylation. Exposure of MOP to saturating concentrations of SR-17018 for extended periods of time stimulated a MOP phosphorylation pattern that was indistinguishable from that induced by the full agonist DAMGO. Unlike DAMGO-induced MOP phosphorylation, which is reversible within minutes after agonist washout, SR-17018-induced MOP phosphorylation persisted for hours under otherwise identical conditions. Such delayed MOP dephosphorylation kinetics were also found for the partial agonist buprenorphine. However, buprenorphine, SR-17018-induced MOP phosphorylation was fully reversible when naloxone was included in the washout solution. SR-17018 exhibits a qualitative and temporal MOP phosphorylation profile that is strikingly different from any other known biased, partial, or full MOP agonist. We conclude that detailed analysis of receptor phosphorylation may provide novel insights into previously unappreciated pharmacological properties of newly synthesized MOP ligands. Full article