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Narcotic Analgesics And Antagonists
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
The nalorphine-like antagonist property of Formula 33, observed in monkeys, does not appear to carry over completely to man. Trials with individuals physically dependent on narcotic analgesics appear to indicate that the compound does not precipitate an abstinence syndrome and these individuals do not seem to dislike it.66 However, α-1-2′-hydroxy-2, 5, 9-trimethyl-6, 7 benzomorphan (1-metazocine, Formula 34), equivalent to morphine in treating postoperative pain, is said to be little better than a placebo in supporting morphine dependence in man, but can produce morphine-like effects in postaddicts.65
Opioids and Related Agents
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
Pentazocine is a benzomorphan derivative of morphine with three to four times its analgesic potency and the same addictive potential. It is presumed to exert its agonistic actions at the κ- and δ-receptors and may precipitate withdrawal symptoms in patients taking narcotic analgesics regularly. I.V. injection of oral preparations of pentazocine and tripelenamine, an H1-blocking antihistamine, was a common form of drug abuse.* The tablets were crushed, dissolved in tap water, heated over a flame, and injected. The combination purportedly produced an effect similar to heroin at much lower cost. Because the method of sterilization was less than optimal, and the solution contained undissolved pieces of tablet binders and fillers, addicted individuals often developed skin decubiti, abscesses, and cellulitis. Continued injection resulted in serious pulmonary artery occlusion, pulmonary hypertension, and neurologic complications. As a consequence, oral pentazocine tablets were replaced with Talwin-NX® (pentazocine plus naloxone) to decrease this practice. Similarly to the combination with buprenorphine, the inhibitory action of naloxone on pentazocine’s analgesic effect is experienced only when the tablets are crushed and injected, since naloxone is not absorbed orally.†
CNS Receptors for Opioids
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
Richard J. Knopp, Mary Hunt, James K. Wamsley, Henry I. Yamamura
The behavioral rewarding effects of opiate drugs are clearly not shared with opioids selective for κ receptors. Early clinical studies (Jasinski et al., 1967) noted the association of dysphoric symptoms with benzomorphan opiates, such as pentazocine, cyclazocine, and ketocyclazocine. The adversive effects of selective κ agonists have been shown to be mediated by κ opioid receptors in animal (Mucha and Herz, 1985; Carr and Bak, 1988) and human (Pfeiffer et al., 1986) studies. The contrast between these observations of adversive activity compared to the highly rewarding effects of other opiates suggest the presence of distinct opioid systems mediating opposing cognitive states. The brain region(s) related to the adversive effects produced by κ opioid agonists has not been clearly defined, but the study by Carr and Bak (1988) suggests a possible thalamic location.
An evaluation of difelikefalin as a treatment option for moderate-to-severe pruritus in end stage renal disease
Published in Expert Opinion on Pharmacotherapy, 2021
Zoe M. Lipman, Gil Yosipovitch
Prior to our understanding of the opioid system’s role in pruritus, activation of peripheral KORs has been widely shown to reduce transmission of pain. Nalbuphine, the first known KOR agonist/MOR antagonist, has shown success in treating both pain and itch (including uremic pruritus); however, its mu-antagonism and action in the CNS can lead to negative side effects like depression and restlessness [27]. The first kappa-selective KOR agonist was ketocyclazocine (the namesake of the kappa opioid receptor), a benzomorphan [28]. Early studies of benzomorphans like ketocyclazocine and ethylketazocine, nalorphine, Mr2023, and pentazocine revealed analgesic effects in both mice and dogs against both chemical and pressure stimuli, but also revealed unwanted side effects like sedation and ataxia. These side effects were assumed to be due to the drugs’ residual effects on other opioid receptors like mu- and delta- [29]. Arylacetamide enadoline (Cl-977) was also a potent antinociceptive agent that displayed a similar binding affinity for KORs as the benzomorphan ethylketocyclazocine but with increased KOR selectivity, and in turn, produced less MOR-related sedative side effects [30]. However, despite its analgesic potential, later studies showed that it induced potent diuresis as well as dose-limiting neuropsychiatric effects [31].