Robert B. Raffa

Thermodynamic analysis of the drug-receptor interaction

Thermodynamic analysis of pharmacologic data potentially offers an insight into the molecular events underlying drug-receptor interactions not obtainable by other techniques. Embodied in thermodynamics are the laws governing the interconvertibility of heat and work and, hence, it is a particularly apt framework for the analysis of the transduction of information from ligand to biological tissue during the initiation of a drug effect. Implicit in thermodynamic analysis of pharmacologic data is quantitative measurement of the driving forces involved in the drug-receptor interaction (in place of less precise terms such as affinity). In addition, the cautious interpretation of thermodynamic analysis can give clues to the underlying mechanisms of the drug-receptor interaction that is beyond the resolving power of other parameters, such as the dissociation constant. The present review is an attempt to identify representative reports that have overtly analyzed pharmacologic data with thermodynamic analysis, to summarize the findings within and across studies (particularly regarding enthalpy- versus entropy-driven binding of agonists and antagonists), to point out and address some apparent inconsistencies that can arise, and to consider the application of thermodynamic analysis to data obtained using isolated tissue preparations.

Lack of antinociceptive efficacy of intracerebroventricular [D-Ala2,Glu4]deltorphin, but not [D-Pen2,D-Pen5]enkephalin, in the μ-opioid receptor deficient CXBX mouse

The antinociceptive efficacy of [D-Pen2,D-Pen5]enkephalin (DPDPE) (delta 1 agonist) and [D-Ala2,Glu4]deltorphin (delta 2 agonist) was evaluated following intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration in CD-1 and CXBK strains of mice using the radiant heat tail-flick test. Following i.c.v. administration, [D-Ala2,Glu4]deltorphin was effective in CD-1, but not CXBK, mice; DPDPE was approximately equiactive in both strains. While i.c.v. [D-Ala2,Glu4]deltorphin did not produce antinociception in the CXBK mouse, it effectively antagonized the antinociceptive actions of i.c.v. DPDPE. [D-Ala2,Glu4]deltorphin was effective following i.t. administration in both strains. These data suggest possible differences in the supraspinal populations of opioid delta receptor subtypes in the CXBK strain. On the basis of previously established selectivity of these agonists, the CXBK mouse may have a predominate population of supraspinal opioid delta 1, rather than delta 2, receptors.

The Basic Pharmacology of Opioids Informs the Opioid Discourse about Misuse and Abuse: A Review

Morphine and other opioids are widely used to manage moderate to severe acute pain syndromes, such as pain associated with trauma or postoperative pain, and they have been used to manage chronic pain, even chronic nonmalignant pain. However, recent years have seen a renewed recognition of the potential for overuse, misuse, and abuse of opioids. Therefore, prescribing opioids is challenging for healthcare providers in that clinical effectiveness must be balanced against negative outcomes—with the possibility that neither are achieved perfectly. The current discourse about the dual ‘epidemics’ of under-treatment of legitimate pain and the over-prescription of opioids is clouded by inadequate or inaccurate understanding of opioid drugs and the endogenous pain pathways with which they interact. An understanding of the basic pharmacology of opioids helps inform the clinician and other stakeholders about these simultaneously under- and over-used agents.

Concise review of the management of iatrogenic emesis using cannabinoids: emphasis on nabilone for chemotherapy-induced nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) is a prevalent, distressing, and burdensome side effect of cancer chemotherapy. It is estimated to affect the majority of patients receiving certain anti-cancer drug regimens and can be treatment-limiting, even for life-saving medications. Despite seemingly numerous options, such as antimuscarinic anticholinergics, antihistamines, 5-HT3 receptor antagonists, dopamine receptor antagonists, and neurokinin-1 receptor antagonists, preventative therapies are often inadequately effective, particularly for “delayed CINV”—leaving an important unmet clinical need. Cannabinoid receptor agonists, by virtue of their unique mechanism of action and efficacy and safety data reported in clinical trials, appear to offer a useful additional option. The mechanistic value of cannabinoids has been well known for many years, but these agents may have been underutilized in the past because of the notoriety and legal status of marijuana. While botanical marijuana contains nearly 500 components, including the psychoactive tetrahydrocannabinol (THC), nabilone is an established, single-entity synthetic cannabinoid receptor agonist that has become the focus of renewed interest. We review the basic pharmacology and clinical trial data of nabilone for use in prophylaxis and treatment of CINV.

Going beyond prescription pain relievers to understand the opioid epidemic: the role of illicit fentanyl, new psychoactive substances, and street heroin

ABSTRACT The opioid epidemic is associated with morbidity and mortality, and it has taken a vast toll on American society. While prescription opioid abuse is part of the opioid problem, it is by no means the entirety of it. Opioid abuse appears to have entered a technology-driven new world of clandestine labs all over the globe and many new synthetic analog, counterfeit, and adulterated drugs that arrive via the internet faster than the Drug Enforcement Administration (DEA) can catalog and outlaw them. To deal with opioid abuse, it must be recognized that it is more – far more – than a subset of chronic pain patients who become addicted. Indeed, to reduce the opioid epidemic to this population is to misunderstand it. The opioid epidemic involves illicit opioids, counterfeit opioids, new psychoactive substances, diverted opioids, and prescription opioids. The objective of this narrative review is to consider the roles of all substances that contribute to the opioid epidemic in America.

Abuse-deterrent opioids: an update on current approaches and considerations

Abstract Objective: Abuse and misuse of prescription opioids is a significant public health concern. This review examines the strategies used to confer abuse-deterrent properties on opioid abuse-deterrent formulations (ADFs), the characteristics and supporting data for each of the available ADFs, and the role of opioid ADFs as part of a comprehensive opioid risk management plan. Methods: A PubMed search was performed for articles published within the last 10 years using the search terms “abuse deterrent opioids”. Articles were limited to clinical studies and reviews focusing on United States (US) Food and Drug Administration (FDA)-approved opioid ADFs in the US. Results: There are currently nine extended-release and one immediate-release opioid pain medications with US FDA-approved ADF labelling. All use either physical and chemical barriers or agonist/antagonist combinations to deter manipulation and abuse. Evidence is mounting that introduction of opioid ADFs has been associated with decreased rates of abuse and diversion of opioids in the US. Conclusions: Although not sufficient by themselves to prevent prescription opioid abuse and misuse, opioid ADFs are an important component of a healthcare provider’s comprehensive opioid risk management plan (along with utilization of prescription drug monitoring programs, clinical assessment tools, urine tests, co-prescribing of naloxone to patients at risk of an overdose, access to non-pharmacological treatments and addiction/mental health resources, among others). Adoption of opioid ADFs should be considered as part of an overall public health opioid risk management plan involving all stakeholders to balance legitimate safe and effective use of opioids against misuse and abuse.

Safety of buprenorphine transdermal system in the management of pain in older adults

ABSTRACT Objectives: To evaluate whether buprenorphine transdermal system (BTDS; Butrans®) is an option for the treatment of chronic pain in older adults. Methods: This retrospective analysis of 16 placebo- and active-controlled and uncontrolled studies (N = 6566) evaluated the safety and tolerability profile in patients exposed to BTDS and compared the safety profiles associated with BTDS treatment in older patients ≥ 65 years of age (65 to 98 years) and younger patients < 65 years of age (18 to 64 years). Safety analyses included adverse events (AEs), laboratory values, and electrocardiograms. Results: Overall, the incidence of AEs was similar in the ≥ 65 year patient cohort (N = 1715) and the < 65 year patient cohort (N = 4843) (63.8% and 61.0%, respectively). The older patient cohort experienced more constipation, peripheral edema, and urinary tract infection, but fewer application-site AEs (eg, erythema, irritation, pruritus, rash) and headaches. A statistically significant treatment-by-age interaction was observed for fall, arthralgia, and localized and non-application site-related rash, suggesting a differential increase in the risk of these events among older patients treated with BTDS that cannot be explained by age or treatment alone. A similar trend was observed for accidents and injuries, and for falls, in patients treated with both BTDS and active controls (oxycodone/acetaminophen [OXY/APAP] and hydrocodone/acetaminophen [HCD/APAP]), suggesting an opioid class effect. However, due to small sample sizes of the active control groups, a statistical test of treatment-by-age interaction could not be conducted for the active controls. The incidences of serious AEs and of clinically significant increases in liver enzymes, such as AST, ALT and bilirubin were small, regardless of age. Conclusion: BTDS appears to be a viable option for the management of pain in older adults, but the benefits need to be tempered by potential risks among older adults.

Fixed-dose combinations at the front line of multimodal pain management: perspective of the nurse-prescriber

1Department of Pain Medicine, Beaumont Hospital, Beaumont, Dublin, Ireland; 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Association of Chronic Pain Patients, Houston, TX; Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA; 3Arthritis Center Twente, Enschede, The Netherlands; 4Department of Endocrinology, Diabetology and Osteology, Kantonsspital St Gallen, Switzerland; 5Centro de Salud Universitario Goya, Madrid, Spain; 6Kansas University Medical Center, Kansas City, and International Clinic Research, Leawood, KS, USA; 7Service de Medecine Interne et Consultation de la Douleur, Hopital Hotel Dieu, Paris Descartes University, Paris, France; 8Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia PA, USA

Pharmacokinetics of Oral and Intravenous Paracetamol (Acetaminophen) When Co-Administered with Intravenous Morphine in Healthy Adult Subjects

Background and ObjectiveSeveral features favor paracetamol (acetaminophen) administration by the intravenous rather than the oral route in the postoperative setting. This study compared the pharmacokinetics and bioavailability of oral and intravenous paracetamol when given with or without an opioid, morphine.MethodsIn this randomized, single-blind, parallel, repeat-dose study in healthy adults, subjects received four repeat doses of oral or intravenous 1000 mg paracetamol at 6-h intervals, and morphine infusions (0.125 mg/kg) at the 2nd and 3rd intervals. Comparisons of plasma pharmacokinetic profiles were conducted before, during, and after opioid co-administrations.ResultsTwenty-two subjects were included in the pharmacokinetic analysis. Observed paracetamol peak concentration (Cmax) and area under the plasma concentration-time curve over the dosing interval (AUC0–6) were reduced when oral paracetamol was co-administered with morphine (reduced from 11.6 to 7.25xa0µg/mL and from 31.00 to 25.51xa0µg·h/mL, respectively), followed by an abruptly increased Cmax and AUC0–6 upon discontinuation of morphine (to 13.5xa0µg/mL and 52.38xa0µg·h/mL, respectively). There was also a significantly prolonged mean time to peak plasma concentration (Tmax) after the 4th dose of oral paracetamol (2.84xa0h) compared to the 1st dose (1.48xa0h). However, pharmacokinetic parameters of paracetamol were not impacted when intravenous paracetamol was co-administered with morphine.ConclusionsMorphine co-administration significantly impacted the pharmacokinetics of oral but not intravenous paracetamol. The abrupt release of accumulated paracetamol at the end of morphine-mediated gastrointestinal inhibition following oral but not intravenous administration of paracetamol suggests that intravenous paracetamol provides a better option for the management of postoperative pain.ClinicalTrials.gov IdentifierNCT02848729.

Fast-Acting Sublingual Zolpidem for Middle-of-the-Night Wakefulness

Sleep disorders (somnipathies) are conditions characterized by disruptions of sleep quality or of sleep pattern. They can involve difficulty falling asleep (prolonged sleep onset latency), difficulty staying asleep (disturbance of sleep maintenance), sleep of poor quality (unrefreshing), or combinations of these and can lead to poor health and quality of life problems. A subtype of sleep-maintenance insomnia is middle-of-the-night wakefulness, a relatively common occurrence. Zolpidem, a nonbenzodiazepine benzodiazepine receptor agonist, allosterically modulates an ion channel and increases the influx of Cl−, thereby dampening the effect of excitatory (sleep disrupting) input. Recently, product label changes to some zolpidem containing products have been implemented by the FDA in order to reduce the risk associated with their morning after residual side effects. A new formulation of zolpidem tartrate (Intermezzo) sublingual tablet, an approved product indicated exclusively for the treatment of middle-of-the-night wakefulness and difficulty returning to sleep, did not have its label changed. We present a short summary of its basic science and clinical attributes in light of the recent regulatory changes for zolpidem products.