Opioids

Drug Class: Opioids > Opioid Agonist > Analgesic.

Opioids are substances that bind to and influence opioid receptors on cell membranes located principally in the central and peripheral nervous system and gastrointestinal tract. Opioids are the most powerful analgesics known to exist.

Humans have been using opioids to relieve pain since at least 4,000 BC. These early users made a small slit in the seedpods of the poppy plant, Papaver somniferum, then scraped the latex that dripped from the incision to create opium. The alkaloids morphine and codeine are the active opiate ingredients in opium. Thebaine is a less potent opiate alkaloid.

Modern pharmacologists create opioids from alkaloids extracted from the poppy seeds and the poppy straw, harvested with field mowers. These opioids can be natural, synthetic or semi-synthetic. Drug manufacturers create semi-synthetic from morphine, codeine and thebaine. Fully synthetic opioids are made from drugs not related to the opium plant but are included in the opioid classification because of their action.

Modern opioids include morphine, codeine, hydrocodone, oxycodone, methadone, fentanyl and heroin.

Structure

Morphine, the archetype of the opioid class, consists of a benzene ring with a phenolic hydroxyl group at position 3, plus an alcohol hydroxyl group at position 6 and at the nitrogen atom. Both hydroxyl groups can be converted to either ethers or esters: codeine, for example, is morphine O-methylated at position 3 while heroin is morphine O-acetylated at position 6.

Distribution

Opioids are distributed throughout body tissues, including breast milk, and cross-placental barriers. This wide distribution allows opioids to bind to peripheral opioid receptors. Analgesia is therefore enhanced through central and peripheral mechanisms.

Metabolism and Excretion

Morphine is metabolized in the liver and the gut mucosa through glucuronidation. Morphine glucuronidation varies greatly between individuals, affecting metabolism rates.

The kidneys excrete most opioids, especially morphine, hydromorphone and meperidine. Morphine-6-glucuronide levels can rise to toxic levels in patients with renal dysfunction; these patients should use morphine with caution.

Opioid Receptors

Opioids bind to receptors on neurons scattered through the nervous and immune systems. Researchers have identified four major opioid receptors: mu, kappa, delta and the most recently discovered, OFQ/N.

Opioid drugs mimic endogenous opioids, which bind to and change the shape of receptors. When an opioid docks onto a receptor, it causes a chemical cascade eventually resulting in a burst of dopamine.

Candace Pert discovered opiate receptors in the brain. In 1973, she administered radioactive morphine to a mouse and then followed the course of morphine to the rodent's brain, where it docked to a neuron. A graduate student at the time, Pert named the receptor mu, the Greek word for the first letter in the word morphine.

More than 20 medications that bind to opioid receptors are now available. Most act as full agonists to mu receptors to create maximal response and analgesia.

Opioids may be full agonists, partial agonists, antagonists or mixed agonist/antagonist. There is low ceiling effect associated with partial agonists and antagonists but no ceiling to the analgesia opioid agonists provide. Antagonists are non-selective and have a higher affinity to receptor cells than agonists do, making them effective for initiating the detoxification process in opioid-dependent individuals.

Agonists bind to mu, kappa and delta receptors to cause morphine-like actions. Partial agonists bind to mu receptors to produce morphine-like actions. Antagonists bind to mu, delta and kappa receptors but do not produce morphine-like actions, so they do not produce euphoria and sedation. Mixed agonists/antagonists bind to kappa receptors to produce this effect but do not bind to mu and delta receptors.