How are opioids classified?
There are various ways to categorised opioids. Some group opioids by the type of receptors they effect (e.g. mu-opioid receptors) or by their binding and affinity to receptors (e.g. agonists), or by both (e.g. mu-opioid receptor agonists). Others describe opioids based on their mode of synthesis (e.g. synthetic opioids) or perceived potencies (e.g. "strong" or "weak" opioids) or legal schedules, which can vary by country and in some cases individual states. This variation in classifications can confuse those who take, prescribe, develop, and research opioids.
Types of receptors
Opioids exert their effects on metabotropic opioid receptors, including mu (MOP), delta (DOP), or kappa (KOP) receptors, and the more recently discovered nociceptin receptor (NOP). MOP, DOP, and KOP are considered conventional opioid receptors, while NOP receptors are considered opioid‐related receptors. This is because NOP receptors have distinct pharmacology, while also exhibiting a high degree of structural homology to conventional opioid receptors.
All four receptors are G-protein coupled receptors (GPCRs), the largest class of membrane proteins in the human genome. GPCRs exert their effects by increasing intracellular concentrations of cyclic adenosine monophosphate (cAMP) and modifying the permeability of ion channels, causing downstream effects. In humans, opioid receptors are widespread in the central and peripheral nervous systems. In the Oxford Catalogue of Opioids most drugs (57%) targeted MOP receptors (see Table 3 in Richards et al. 2021).
Action at receptors
Opioids can be categorised depending on their receptor binding and affinity, including full agonists, partial agonists, mixed agonists, inverse agonists, and antagonists. Agonists interact with opioid receptors, usually MOPs, to elicit a graded response (e.g. analgesia following the administration of morphine). Substances that bind to opioid receptors but have no agonist activity and prevent the effects of opioid agonists are known as antagonists. Some drugs have both agonist and antagonist effects (partial agonists). In the Oxford Catalogue of Opioids, the majority of drugs (82%) were agonists at one or more receptors (see Table 3 in Richards et al. 2021).
Mode of synthesis
Extracts from Papaver somniferum, or the opium poppy, contain opioid alkaloids (e.g. morphine and codeine). Modifications of morphine-like alkaloid derivatives led to the production of semi-synthetic opioids (e.g. heroin and oxycodone). Later, fully synthetic opioids were derived from morphinan (e.g. levorphanol), diphenylheptane (e.g. methadone), benzomorphan (e.g. pentazocine), and phenylpiperidine (e.g. fentanyl).
In the Oxford Catalogue of Opioids, there were seven naturally occurring alkaloids (i.e. codeine, morphine, narceine, noscapine, oripavine, paraveretum, and thebaine). However most (82%) were synthetic opioids and 16% were semi-synthetic opioids.
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Alexander SPH, Christopoulos A, Davenport AP, et al. THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors. Br J Pharmacol. 2019 Dec;176 Suppl 1(Suppl 1):S21-S141. doi: 10.1111/bph.14748.
Richards GC, Sitkowski K, Heneghan C, Aronson JK. The Oxford Catalogue of Opioids: A systematic synthesis of opioid drug names and their pharmacology. Br J Clin Pharmacol. 2021. doi: 10.1111/bcp.14786