Assessment of the antinociceptive, respiratory-depressant, and reinforcing effects of the low pKa fluorinated fentanyl analogs, FF3 and NFEPP.

RATIONALE: Recent studies report that fentanyl analogs with relatively low pKa values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception. OBJECTIVES: The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pKa values in terms of potency and efficacy in male and female Sprague-Dawley rats. METHODS: Nociception was produced by administration of Complete Freund's Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects. RESULTS: All compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects. CONCLUSIONS: Low pKa fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pKa relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.

Illicit fentanyls in the opioid street market: desired or imposed?

BACKGROUND: Illicitly manufactured fentanyl and its analogues are appearing in countries throughout the world, often disguised as heroin or counterfeit prescription pills, with resulting high overdose mortality. Possible explanations for this phenomenon include reduced costs and risks to heroin suppliers, heroin shortages, user preferences for a strong, fast-acting opioid and the emergence of Dark Web cryptomarkets. This paper addresses these potential causes and asks three questions: (1) can users identify fentanyl; (2) do users desire fentanyl; and (3) if users want fentanyl, can they express this demand in a way that influences the supply? ARGUMENT/ANALYSIS: Existing evidence, while limited, suggests that some users can identify fentanyl, although not reliably, and some desire it, but because fentanyl is frequently marketed deceptively as other drugs, users lack information and choice to express demand effectively. Even when aware of fentanyl's presence, drug users may lack fentanyl-free alternatives. Cryptomarkets, while difficult to quantify, appear to offer buyers greater information and competition than offline markets. However, access barriers and patterns of fentanyl-related health consequences make cryptomarkets unlikely sources of user influence on the fentanyl supply. Market condition data indicate heroin supply shocks and shortages prior to the introduction of fentanyl in the United States and parts of Europe, but the much lower production cost of fentanyl compared with heroin may be a more significant factor CONCLUSION: Current evidence points to a supply-led addition of fentanyl to the drug market in response to heroin supply shocks and shortages, changing prescription opioid availability and/or reduced costs and risks to suppliers. Current drug users in affected regions of the United States, Canada and Europe appear largely to lack both concrete knowledge of fentanyl's presence in the drugs they buy and access to fentanyl-free alternatives.

Fentanyl: A Whole New World?

This article seeks to document the latest danger in the opioid crisis: fentanyl and related synthetic opioids. Fifty times more potent than pure heroin, cheaper to manufacture in laboratories worldwide, and easily distributed by mail and couriers, fentanyl is flooding the illicit opioid markets throughout the country.

Trends in the use and abuse of branded and generic extended release oxycodone and fentanyl products in the United States.

BACKGROUND: A great deal of previous work on the pharmacoeconomics of alcohol, tobacco and illicit drug abuse indicates that as cost decreases, abuse increases and vice versa. The application of these cost principles to the abuse of prescribed medications is largely unknown. In this paper we assessed whether the introduction of generic products in the U.S. increased the therapeutic use and illicit abuse of extended release oxycodone products and the fentanyl patch. METHODS: As an index of therapeutic use, we purchased prescription data for each of the ZIP codes in which we had corresponding abuse data. To gather information about prescription drug abuse, we elicited cases with quarterly questionnaires completed by a key informant network. RESULTS: The introduction of generic extended release (ER) oxycodone and fentanyl patch did not significantly change the total prescriptions written for these products, but markedly altered the composition of sales: branded sales dropped precipitously over a very short time and this was compensated for by a corresponding increase in sales of generics. Surprisingly, the introduction of generic products did not increase the abuse of ER oxycodone or fentanyl products; the branded version was the drug of choice for at least 2 years. CONCLUSIONS: Our data suggest that drug costs alone do not increase the overall likelihood that a prescription opioid analgesic will be used therapeutically or abused. However, while generics are rapidly endorsed by insurance companies as a prescribed entity, abuse of the branded versions of ER oxycodone and fentanyl remains predominant for some time.

Relative efficiency of succinylcholine, xylazine, and carfentanil/xylazine mixtures to immobilize free-ranging moose.

We compared the efficiency of succinylcholine chloride, xylazine hydrochloride and carfentanil/xylazine mixtures in immobilizing 364 free-ranging moose (Alces alces) between 1987 and 1997 in Québec (Canada). With succinylcholine chloride (0.070, 0.062, 0.051 mg/kg of estimated body weight for calves, juveniles and adults), 63% of the 252 immobilization attempts led to complete immobilization and marking, whereas 7% of the darted animals died of respiratory paralysis during handling. The moose took an average of 13 min to lay down after darting (down time). Injection of xylazine (3.67-4.22 mg/kg) permitted sedation (the animal laid down but got up again when approached) or complete immobilization in 78% of the 40 darted adult moose, the mean down time being 8.7 min. No mortality was noted with this drug but 58% of the marked animals were only sedated. The use of RX821002A (0.058 mg/kg) as an antagonist, permitted a mean recovery time of 2.8 min after intravenous injection. With the carfentanil/xylazine mixtures (0.0071 and 0.181 mg/kg), 96% of the immobilization trials (n = 72) led to complete (88%) or partial (8%) immobilization, but 6% of the moose died several days after capture. The mean down time was 6.6 min, and injection of naltrexone (0.709 mg/kg) antagonized the effect of the immobilizing agent within 3.7 min. The respiratory rate was higher (P < 0.05) among moose immobilized with xylazine (35/min) than among those immobilized with carfentanil/xylazine mixtures (19/min) but this variation could be related to a longer pursuit time (z = 3.60; P < 0.01) and higher stress levels during handling. Rectal temperature also was higher with xylazine but the difference was small (39.7 vs. 39.3, P = 0.03) and did not differ significantly between the sexes (P > 0.05). Considering loss of materials and helicopter flight time due to non-successful marking trials, carfentanil/xylazine mixtures were the least expensive ($333 Cdn/animal).

Pharmacokinetic/dynamic assessment in drug development: application to the investigational opioid mirfentanil.

The safety, pharmacokinetics, and pharmacodynamics of the investigational partial opioid agonist, mirfentanil, were determined in a dose-escalating, Phase 1 study in healthy male volunteers. Hemodynamic, central nervous system, and respiratory monitoring were used for safety assessment. The electroencephalogram (EEG) was evaluated as a surrogate measure of drug effect. Butorphanol was chosen as the control drug. In the mirfentanil group (n = 8) the dose was increased in sequential subjects from 25 micrograms.kg-1.min-1 for 30 min to 450 micrograms.kg-1.min-1 for 15 min, and in the butorphanol group (n = 10) from 2 micrograms.kg-1.min-1 for 30 min to 25 micrograms.kg-1.min-1 for 15 min. In the mirfentanil group, serious side effects were observed at plasma concentrations more than 2000 ng/mL: heart rates exceeded 130 bpm (n = 2), epileptiform EEG potentials (n = 2), and a convulsion (n = 1). The clearance of mirfentanil was high (5.8-7.2 L/min), and the volume of distribution large (247-348 L). The EEG of the subjects receiving mirfentanil showed no changes typical for opioids. Butorphanol however, caused intermittent slowing in the delta and theta ranges. The results of our study define the upper limit of safe plasma concentrations in future mirfentanil studies.

Assessment of alfentanil by intravenous infusion as long-term sedation in intensive care.

The use of an alfentanil infusion for sedation of critically ill patients in intensive care was investigated in 16 patients who were entered consecutively into the study. The mean duration of stay was 8 days. Supplements of Diazemuls and muscle relaxants were administered if required. The success of the technique was judged by nursing and medical staff and, in particular, the wakefulness of patients was noted. No patient could recall events that occurred during their infusion. An outline protocol is described.

A simple instrument for biochemical studies of the living human brain.

A simple, relatively inexpensive radiation detection system was developed for measurement of positron-emitting receptor-binding drugs in the human brain. This high-efficiency coincidence counting system requires that only a few hundred microcuries of labeled drug be administered to the subject, thereby allowing for multiple studies without an excessive radiation dose. Measurement of the binding of [11C]-carfentanil, a high-affinity synthetic opiate, to opiate receptors in the presence and in the absence of a competitive opiate antagonist exemplifies the use of this system for estimating different degrees of receptor binding of drugs in the human brain. The instrument has also been used for measurement of the transport into the brain of other positron-emitting radiotracers, such as large neutral amino acids.

Clinical assessment and plasma pharmacokinetics associated with intramuscular or extradural alfentanil.

Patients with postoperative pain received alfentanil in doses of 15 micrograms kg-1 (n = 6) or 30 micrograms kg-1 (n = 6) via the extradural route or 15 micrograms kg-1 (n = 6) i.m. Effective analgesia was obtained in all patients in the extradural groups and in none in the i.m. group. Maximum pain relief developed within 10-15 min and the average duration of adequate analgesia was 78 min with the lower dose and 45 min with the higher dose, but this difference was not statistically significant. The 15-micrograms kg-1 extradural and i.m. groups showed the same pharmacokinetic pattern. Plasma concentrations were greater in the 30-micrograms kg-1 extradural group and this was associated with unwanted systemic effects. We conclude that the extradural administration of alfentanil can produce effective spinal analgesia. Its lipophilic property reduces the onset time, but does not modify its duration of action or impair absorption.