Opioid Analgesics—Morphine Type

Endogenous opioids are peptides that are cleaved from the precursors, proenkephalin, pro-opiomelanocortin, and prodynorphin. All contain the amino acid sequence of the pentapeptides [Met]- or [Leu]-enkephalin (A). The effects of the opioids can be abolished by antagonists (e. g., naloxone A), with the exception of buprenorphine. 

Mode of action of opioids. Most neurons react to opioids with a hyperpolarization, reflecting an increase in K+ conductance. Ca2 influx into nerve terminals during excitation is decreased, leading to a decreased release of transmitters and decreased synaptic activity (A). Depending on the cell population affected, this synaptic inhibition translates into a depressant or excitant effect (B). 

Effects of opioids (B). The analgesic effect results from actions at the level of the spinal cord (inhibition of nociceptive impulse transmission) and the brain (disinhibition Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms 

The attempt to quit repeated use of the drug results in withdrawal signs of both physical (e.g., cardiovascular disturbances) and psychological (e. g., restlessness, anxiety, depression) nature. 

Opioids meet the criteria of drugs producing dependence, that is, a psychological and physiological need to continue use of the drug as well as the compulsion to increase the dose. 

---

It is now widely accepted that there are at least three opioid receptor sub-types, mu kappa and delta. During the last decade increasing evidence has accumulated to support the hypothesis that a selective kappa opioid agonist will be a powerful analgesic without the clinically limiting side-effects that characterise morphine (e.g., respiratory depression, constipation, addiction)... 

Complete removal of the 4-phenyl substituent of the reversed ester of pethidine results in a drastic fall in potency as judged from tests in mice (see 23, R = Et). However, certain esters of l-methyl-4-piperidinol formed from aromatic acids display antinociceptive activities in the morphine to codeine range of potency (23).<68) A QSAR study of such esters has been made and a substitution pattern of the phenyl group defined for optimal activity/69 The relevance of these compounds to morphine-type analgesics is doubtful since the more active members show marginal or no affinity for opioid receptors of rat brain homogenates and display no physical dependence in monkeys. 

This drug is a morphine-type mixed agonist-antagonist opioid. It exerts analgesic effects by acting as partial agonist at the in receptor, and has little affinity for k receptors. 

Peptide transmitters Many peptides have been identified in the CNS, and some meet most or all of the criteria for acceptance as neurotransmitters. The best-defined ones are the opioid peptides (beta-endorphin, met- and leu-enkephalin, and dynorphin), which are distributed at all levels of the neuraxis. Some of the important therapeutic actions of opioid analgesics (eg, morphine) are mediated by receptors for these endogenous peptides. Substance P is localized in type C neurons involved in nociceptive sensory pathways in the spinal cord. Peptide transmitters differ from nonpeptide transmitters in that (1) the peptides are synthesized in the cell body and transported to the nerve ending via axonal transport, and (2) no reuptake or specific enzyme mechanisms have been identified for terminating their actions. 

The term opioid (synonym, narcotic analgesic) includes both natural and synthetic agents with morphine-type pain-relieving properties. Their action is exerted on the central nervous system and on smooth muscle. 

The major use of the narcotic analgesic is to relieve or manage moderate to severe acute and chronic pain. The ability of a narcotic analgesic to relieve pain depends on several factors, such as the drug, the dose, the route of administration, the type of pain, the patient, and the length of time the drug has been administered. Morphine is the most widely used opioid and an effective drug for... 

Nalorphine and levallorphan are examples. For example in patients with postoperative pain the analgesic effects of 10 mg of nalorphine is about the same as 10 mg of morphine. On the other hand naloxone and naltrexone seem to have no agonistic activity and some antagonistic affinity for all types of opioid receptors. Although antagonists could be expected to have effects by altering the actions of endogenous opioid peptides mostly such effects are not discernable. 

The action profile of synthetic opioids reinforced speculation, that more than one type of opioid receptor exists and is involved in the analgesic activity of these compounds. Martin and co-workers in 1960 investigated these differences in a specially developed test model, the chronic spinal dog (Martin et al., 1976). According to the analgesia and side-effect profile they postulated three types of opioid receptors, the p-receptor (ligand = morphine), the K-receptor (ligand = ketazocine) and the [Pg.128]

Dogrul, A., Yesilyurt, O., Isimer, A., Guzeldemir, M.E. L-type and T-type calcium channel blockade potentiate the analgesic effects of morphine and selective mu opioid agonist, but not to selective delta and kappa agonist at the level of the spinal cord in mice, Pain 2001, 93, 61-68. 

Hydromorphone is a semi-synthetic prescription drug that has similar pain-relieving properties to that of morphine and codeine. It is classified as an opioid or narcotic analgesic. It is an effective treatment for moderate-to-severe pain and is sometimes used in patients with a non-productive cough. It is used to treat several types of pain, including headache, cancer pain, and back pain. 

---