Opioid analgesics as drugs of abuse

The medical use of opium as a pain-relieving drug dates back to the third century. Arab physicians used extracts of the oriental poppy to treat diarrhoea and probably introduced it to the Far East. However, because of its erratic absorption from the gastrointestinal tract, its use as an effective analgesic only became possible with the introduction of the hypodermic syringe in the middle of the last century.

Opium is obtained from the dried juice from the seed capsule of the oriental poppy, Papaver somniferum. The dried juice contains up to 17% morphine and 4% codeine by weight, as well as other, non-additive alkaloids that lack analgesic activity such as noscapine, papaverine, and thebaine. Papaveretum is a standardized preparation of opium containing 50% morphine.

The term ''opioid'' is used to designate a group of drugs that have opium-like or morphine-like properties. The term ''opiate analgesic'' is often used as an alternative. The term ''narcotic analgesic'' is now obsolete; it was formerly used to describe potent opiate analgesics which had sedative properties.

The opioids produce their pharmacological effects by interacting with a closely related group of peptide receptors, thereby suggesting that endogenous opioid-like polypeptides exist, which presumably have a physiological function.

In recent years there has been a major research effort, so far without success, to produce potent, centrally acting analgesics that do not have an abuse potential. The discovery of various types of opioid receptor, which may have different effects on central neurotransmitter function, may ultimately lead to the development of such a drug. In the meantime, the most widely used opioids, for example morphine, heroin (also called diacetylmorphine) and codeine are therapeutically effective but are liable to be abused and produce dependence. The structure of some of the morphine-like analgesics and their antagonists are shown in Figure 15.2.

Substitution of an allyl group on the nitrogen atom of morphine produces drugs which act as antagonists, such substances thereby reversing the analgesia, euphoria and respiratory depressant effects of such agonists as morphine and heroin. The structurally related antagonist naltrexone is frequently used as an antagonist of morphine and related opioid agonists. Other structural analogues of morphine, such as nalorphine, act as partial agonists. When nalorphine, for example, is injected into an animal, it will produce analgesia, but will also counteract such an effect of morphine should this pure agonist be given concurrently. All the opioids exert their pharmacological effects by binding to specific receptors located in the brain and on peripheral organs. The seminal studies of Kosterlitz and Hughes in the 1970s clearly demonstrated the relationship between opioid receptor occupancy and the ability of a drug to inhibit electrically stimulated contractions of the guinea pig ileum in vitro.

Later studies showed that the opiates have a high affinity for specific building sites in the brain and gastrointestinal tract which is both saturable and stereospecific. However, there does not appear to be a direct relationship between the affinity of an agonist for the central opioid receptors and its analgesic potency. This can be partly explained by the relative lack of accessibility of many opiates to the brain owing to their low lipophilicity, but other factors, such as the differences in their affinity for the various types of opioid receptors, must also be considered. Ligand-binding studies, subcellular fractionation to determine the location of the receptors at the cellular level, and the application of histochemical and immunocy-tochemical techniques to map the distribution of the receptors in the brain have now enabled a detailed assessment to be made of their distribution, and possible function, in man and other mammals.

The highest concentration of opioid receptors appears to be in the sensory, limbic and hypothalamic regions of the brain, with particularly high concentrations being found in the amygdala and the periaqueductal grey



Chemical groups inserted in positions: 3 6 17


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