Development and use of methylnaltrexone,a peripherally acting opioid antagonist,to treat side effects related to opioid use

Opioid medications are used extensively as potent analgesics for treating moderate to severe pain. Although opioids offer reliable pain relief, their use is associated with a number of adverse effects, especially constipation. Conventional measures for ameliorating opioid‐induced adverse effects are often insufficient. Thus, reducing the severity of these adverse effects is of utmost importance for patients who require the benefits of opioid analgesics. Since opioids mediate pain‐relieving and adverse effects through the same classes of receptors, i.e., mu, delta, and kappa, it has been challenging to dissociate beneficial effects from detrimental ones. Methylnaltrexone is the first peripherally acting opioid receptor antagonist to receive FDA approval. This compound offers the therapeutic potential to block or reverse the undesired side effects of opioids that are mediated by receptors located in the periphery (e.g., in the gastrointestinal tract), without affecting analgesia or precipitating opioid withdrawal symptoms, which are mediated predominantly by receptors in the central nervous system. This review provides a history of the development of methylnaltrexone, discusses studies that relate to opioid bowel dysfunction, and explores other uses of this compound. Drug Dev Res, 2009. © 2009 Wiley‐Liss, Inc.     

Emerging infectious diseases - a therapeutic challenge

Introduction: Despite its central role in acute pain management, the exclusive use of opioids has been challenged recently in view of its immediate and long-term side effects. Development of chronic postsurgical pain syndromes, hyperalgesia and immunomodulation are some particular concerns as they may be related to opioid exposure, intertwined with patient characteristics and other factors. Application of a multimodal approach, administration of preventive analgesia and paradigm shift in surgical techniques all mandate a revisit of evidence-based perioperative pain management.

Areas covered: Adjuvant analgesics are drugs indicated for primary non-pain conditions, but have been found efficacious in analgesia either when used alone or in combination with other analgesics. Among a diverse group of adjuvant analgesics, systemic administration of ketamine, magnesium, gabapentinoids, steroids, α2 agonists and lidocaine are reviewed, with recent evidence compared with earlier systematic reviews or meta-analyses from a Medline search (1990 – Apr 2010).

Expert opinion: For acute pain management, adjuvant analgesics in appropriate doses and monitored care are beneficial in improving analgesic efficacy and reduce opioid-related side effects with good safety and tolerability. However, the quest for an optimal regime for administration and individualizing treatment remains.     

The toxic effect of opioid analgesics on human sperm motility in vitro

Opioid analgesics are the most common therapeutic analgesic for acute pain. In this study, the toxicological and pharmacological features of a group of opioid analgesics were characterized by the motility of human sperm. Aliquots of sperm were incubated with various concentrations of opioid analgesics in vitro. Computer-assisted sperm analysis was used to assess sperm motility at 15 minutes, 2 hours, and 4 hours after drug addition to the medium. Butorphanol and dezocine showed marked reduction of motility after incubation with sperm for 15 minutes. Butorphanol was more effective than dezocine in immobilizing sperm. Other opioids studied, such as fentanyl, alfentanil, and sufentanil, showed only partial inhibitory activity. Based on the data reported herein, we have found that butorphanol and dezocine exert a sperm-immobilizing effect. However, fentanyl, alfentanil, and sufentanil exhibit only partial inhibition of sperm motility. Given the increasing use of opioids and their potential effect on sperm motility, these findings are greatly relevant to male reproductive health.     

Hospital admission medication reconciliation in high-risk prescription opioid users

BackgroundNo studies have assessed the clinical significance of medication reconciliation in surgical patients using high-risk extended-release/long-acting (ER/LA) opioid medications.ObjectivesWe assessed differences in the perioperative use of opioid analgesics in patients who underwent medication reconciliation upon hospital admission compared to patients who did not and identified predictors of perioperative use of opioids.MethodsRetrospective observational quasi-experimental study including adult non-cancer patients who underwent elective surgery at UCSF Medical Center in the period January 2017 through December 2019 and received at least one opioid analgesic during surgical hospitalization. The primary study outcome was perioperative use of opioids measured in daily oral morphine equivalents (OME). Secondary outcomes were predictors of perioperative use of opioids after adjusting for baseline differences between groups.ResultsWe identified 402 patients. Of them, 59.5% were female. The mean patient age was 58.5 years. Most patients underwent neurological or orthopedic surgery (each 40.8%). Over 94.3% of our patients underwent medication reconciliation upon hospital admission, with 78.4% completed by a pharmacy staff. Medication reconciliation evidenced that 5.5% patients were not taking the ER/LA opioids on their medication history list. Inactive ER/LA opioids were discontinued during hospitalization. None of the patients with inactive ER/LA opioids had those opioids restarted at hospital discharge. In addition, patients (26.9%) were successfully converted from ER/LA to SA opioids. After adjusting for patients’ demographic and clinical characteristics, surgical procedure type and post-operative pain, opioid formulation conversion was the main predictor of perioperative use of opioids per hospitalization day. Switching patients from ER/LA to SA opioids reduced the mean daily use of OME by 66.03 units (p < 0.02) without adversely impacting postoperative pain.ConclusionsMedication reconciliation upon hospital admission reduced unnecessary exposure to opioids in hospitalized surgical patients.     

Characteristics of methadone maintenance treatment patients prescribed opioid analgesics

ABSTRACT

Background: Opioid analgesic use and disorders have dramatically increased among the general American population and those receiving methadone maintenance treatment (MMT). Most research among MMT patients focuses on opioid analgesics misuse or disorders; few studies focus on MMT patients prescribed opioid analgesics. We describe demographic, clinical, and substance use characteristics of MMT patients prescribed opioid analgesics and compare them with MMT patients not prescribed opioid analgesics. Methods: We conducted a cross-sectional secondary data analysis using screening interviews from a parent study. From 2012 to 2015, we recruited adults from 3 MMT Bronx clinics. Questionnaire data included patterns of opioid analgesic use, substance use, comorbid illnesses, and demographic characteristics. Our main dependent variable was patients' report of currently taking prescribed opioid analgesics. To compare characteristics between MMT patients prescribed and not prescribed opioid analgesics, we conducted chi-square tests, t tests, and Mann-Whitney U tests. Results: Of 611 MMT patients, most reported chronic pain (62.0%), hepatitis C virus (HCV) infection (52.1%), and current use of illicit substances (64.2%). Of the 29.8% who reported currently taking prescribed opioid analgesics, most misused their opioid analgesics (57.5%). Patients prescribed (versus not prescribed) opioid analgesics were more likely to report human immunodeficiency virus (HIV) infection (adjusted odds ratio [aOR] = 1.6, 95% confidence interval [CI]: 1.1–2.3) and chronic pain (aOR = 7.6, 95% CI: 4.6–12.6). Conclusion: Among MMT patients primarily in 3 Bronx clinics, nearly one third reported taking prescribed opioid analgesics. Compared with patients not prescribed opioid analgesics, those prescribed opioid analgesics were more likely to report chronic pain and HIV infection. However, between these patients, there was no difference in illicit substance use. These findings highlight the complexity of addressing chronic pain in MMT patients.     

Erectile Dysfunction in Opioid Users: Lack of Association with Serum Testosterone

ABSTRACT

This study describes the prevalence of erectile dysfunction (ED) among 57 men using illicit opioids who presented to a primary care program for buprenorphine therapy. Participants’ mean age was 40 years and 34% reported ED. Low total testosterone was detected in 17% of those reporting ED, but total testosterone was not significantly associated with ED. Examining multiple comorbidities and laboratory parameters, only older age was significantly associated with ED (r = .27, P< .05). ED is highly prevalent among men abusing opioids, but low total testosterone is rarely the cause.     

Alcohol,marijuana, and opioid use disorders: 5-Year patterns and characteristics of emergency department encounters

ABSTRACT

Background: Changes in substance use patterns stemming from opioid misuse, ongoing drinking problems, and marijuana legalization may result in new populations of patients with substance use disorders (SUDs) using emergency department (ED) resources. This study examined ED admission trends in a large sample of patients with alcohol, marijuana, and opioid use disorders in an integrated health system. Methods: In a retrospective design, electronic health record (EHR) data identified patients with ≥1 of 3 common SUDs in 2010 (n = 17,574; alcohol, marijuana, or opioid use disorder) and patients without SUD (n = 17,574). Logistic regressions determined odds of ED use between patients with SUD versus controls (2010–2014); mixed-effect models examined 5-year differences in utilization; moderator models identified subsamples for which patients with SUD may have a greater impact on ED resources. Results: Odds of ED use were higher at each time point (2010–2014) for patients with alcohol (odds ratio [OR] range: 5.31–2.13, Ps < .001), marijuana (OR range: 5.45–1.97, Ps < .001), and opioid (OR range: 7.63–4.19, Ps < .001) use disorders compared with controls; odds decreased over time (Ps < .001). Patients with opioid use disorder were at risk of high ED utilization; patients were 7.63 times more likely to have an ED visit in 2010 compared with controls and remained 5.00 (average) times more likely to use ED services. ED use increased at greater rates for patients with alcohol and opioid use disorders with medical comorbidities relative to controls (Ps < .045). Conclusions: ED use is frequent in patients with SUDs who have access to private insurance coverage and integrated medical services. ED settings provide important opportunities in health systems to identify patients with SUDs, particularly patients with opioid use disorder, to initiate treatment and facilitate ongoing care, which may be effective for reducing excess medical emergencies and ED encounters.     

Designing safer analgesics: a focus on μ-opioid receptor pathways

ABSTRACT

Introduction: The recent dramatic increase in intentional and unintentional deaths attributed to opioids has refocused attention on the therapeutic ratio (risk–benefit ratio) of opioid analgesics. Almost all traditional opioid analgesics produce their effects (therapeutic and adverse) via the activation of μ-opioid receptor (MOR) pathways. It is therefore important to examine the question of whether this natural endogenous pathway can still be activated, but with greater safety.

Areas covered: Other comprehensive reviews have focused on pharmacokinetic (e.g. peripheral restriction) and pharmacodynamic (e.g. functional selectivity, biased ligand) approaches. Herein, the authors focus on a different approach, specifically, multi-mechanistic ‘atypical opioids’ that synergistically combines MOR activation plus one or more non-opioid mechanism of analgesic action.

Expert opinion: Four ‘atypical opioid’ analgesics on the market act as μ-opioid receptor pathway agonists but have a non-opioid mechanism of action that significantly contributes to the analgesic effect. The multi-mechanistic action of these products confers particular clinical utility in that they provide effective analgesia with relatively lower opioid load, and they are generally associated with fewer or less severe opioid-related adverse effects and less abuse compared to traditional opioid analgesics.