ABSTRACT
INTRODUCTION: d-Propoxyphene, which was previously available in many single-agent and combination products, was recently voluntarily withdrawn from the US market following an FDA recommendation based partly on the concern that the risk associated with QT prolongation exceeded the clinical benefit of the drug. The drug had previously been withdrawn from European markets. These recent actions prompt the question: what is known about QT prolongation and analgesic drugs? AREAS COVERED: A systematic search was conducted of 50 opioid and non-opioid analgesic drugs using PubMed, the FDA website, and the Internet. Search terms for opioids, NSAIDs, acetaminophen and other analgesics were used (including both generic and brand names), along with QTc, QTc prolongation, QTc interval, hERG, torsades de pointes (TdP), ventricular arrhythmias, and other relevant terms. EXPERT OPINION: There is a paucity of available information on the QT interval for most analgesics. Of those for which there is a lot of data, only methadone, oxycodone, and LAAM (levo--acetylmethadol) appear to have a known and accepted level of effect on the QT interval.
Subject(s)
Analgesics/adverse effects , Dextropropoxyphene/adverse effects , Long QT Syndrome/chemically induced , Analgesics/chemistry , Animals , Dextropropoxyphene/chemistry , Humans , Structure-Activity RelationshipABSTRACT
Non-medical abuse of prescription opioid medications is not a new phenomenon, but such use has been increasing in recent years. Various methods have been used and continue to be developed in an effort to limit diversion and abuse of opioid medications. A number of these methods will be described for opioid analgesic and addiction treatment formulations using relevant historical examples (e.g. propoxyphene, pentazocine, buprenorphine) as well as examples of formulations currently being considered or under development (e.g. oxycodone plus naltrexone, sustained-release buprenorphine). The focus, though not exclusively, will be on those formulations that represent a combination of an opioid agonist with an antagonist. These methods must take into consideration the pharmacokinetic profile of the agonist and antagonist, the expected primary route of abuse of the medication and the medication combination, the dose of medication that is likely to be abused, the availability of alternative drugs of abuse, and the population of potential abusers that is being targeted with the revised formulation.
Subject(s)
Drug Compounding/methods , Drug Prescriptions , Pharmaceutical Preparations/chemistry , Substance-Related Disorders/prevention & control , Buprenorphine/chemistry , Dextropropoxyphene/chemistry , Humans , Narcotics/chemistry , Pentazocine/chemistry , Tilidine/chemistryABSTRACT
A simple, efficient, and rapid method is described for separation of the enantiomers of propoxyphene by capillary electrophoresis with neutral cyclodextrins as chiral separators. This method has several advantages over the crystallization method employed by some forensic laboratories, including unambiguous results, ease of use, and smaller sample-size requirement. The method enables baseline separation of the propoxyphene enantiomers in approximately six minutes, which is less than one-third of the time required for a previously published method.
Subject(s)
Cyclodextrins/chemistry , Dextropropoxyphene/chemistry , Electrophoresis, Capillary/methods , Analgesics, Opioid/chemistry , Molecular Structure , Stereoisomerism , Time FactorsABSTRACT
The main objective of this study was to develop an effective potentiometric saturation titration protocol for determining the aqueous intrinsic solubility and the solubility-pH profile of ionizable molecules, with the specific aim of overcoming incomplete dissolution conditions, while attempting to shorten the data collection time. A modern theory of dissolution kinetics (an extension of the Noyes-Whitney approach) was applied to acid-base titration experiments. A thermodynamic method was developed, based on a three-component model, to calculate interfacial, diffusion-layer, and bulk-water reactant concentrations in saturated solutions of ionizable compounds perturbed by additions of acid/base titrant, leading to partial dissolution of the solid material. Ten commercial drugs (cimetidine, diltiazem hydrochloride, enalapril maleate, metoprolol tartrate, nadolol, propoxyphene hydrochloride, quinine hydrochloride, terfenadine, trovafloxacin mesylate, and benzoic acid) were chosen to illustrate the new titration methodology. It was shown that the new method is about 10 times faster in determining equilibrium solubility constants, compared to the traditional saturation shake-flask methods.
