Category:Opioid analgesics

An opioid analgesic is a medicine that relieves pain by binding to one or more of the opioid receptors of the nervous system. The category is named for the opium poppy Papaver somniferum, the natural source of the prototype alkaloid morphine, and includes the natural opium alkaloids (morphine, codeine), the semi-synthetic morphine derivatives (hydromorphone, oxycodone, oxymorphone, hydrocodone, diacetylmorphine), the wholly synthetic agonists (the phenylpiperidines including meperidine and the fentanyl series; the diphenylheptane methadone), the atypical centrally acting agents (tramadol, tapentadol), and the partial agonist buprenorphine.

The medicinal use of opium is among the oldest documented in medicine. Sumerian tablets from the third millennium BCE name the poppy hul gil, the joy plant. Greek and Roman physicians (Hippocrates, Galen) prescribed opium extracts for pain, cough, and diarrhoea; the Persian polymath Avicenna cautioned in the eleventh century that the medicine was dangerous in overdose. The Swiss physician Paracelsus in the early sixteenth century introduced the tincture of opium in alcohol he called laudanum, which remained, until the nineteenth century, the standard preparation. The transformative event of the pharmacological era was the work of a twenty-one-year-old apothecary's apprentice. In 1804 Friedrich Sertürner of Paderborn in Westphalia isolated from opium a single crystalline alkaloid that produced the full range of opium's effect in a small fraction of the dose; he named it morphium for Morpheus, the Greek god of dreams.^[1] Morphine was the first alkaloid isolated from any plant, and Sertürner's report marks the conventional beginning of the science of alkaloid pharmacology.

The medicine reached the patient by way of a separate Scottish invention. In 1853 Alexander Wood of Edinburgh devised a hollow needle and a graduated syringe with which morphine could be injected under the skin, an order of magnitude more powerful and more reliably absorbed than any oral preparation. Hypodermic morphine was widely used in the American Civil War of 1861-1865 and produced an epidemic of dependence among the wounded that contemporaries called soldier's disease, the first opioid-use disorder of the industrial-medical era. The semi-synthetic opioids followed. C.R. Alder Wright at St Mary's Hospital in London synthesized diacetylmorphine in 1874 by acetylating morphine and tested it on a dog with disquieting results before abandoning the work. Twenty-four years later the German pharmaceutical company Bayer, whose chief chemist Heinrich Dreser had directed the parallel development of acetylsalicylic acid, marketed Wright's compound under the trade name Heroin (from heroisch, heroic) as a non-addictive cough suppressant and morphine substitute. The medicine was sold in pharmacies across Europe and North America until it became, within a decade, the most heavily diverted opioid in the world.

The wholly synthetic opioid was a wartime product of German industrial chemistry. In 1939 Otto Eisleb at IG Farbenindustrie in Frankfurt, screening compounds with anticholinergic structure, identified meperidine (pethidine, Dolantin), the first agent with morphine-like analgesic action that bore no chemical resemblance to morphine. The same firm's Max Bockmühl and Gustav Ehrhart in 1937 synthesized the diphenylheptane analogue that became, after wartime nomenclature change, methadone. Two decades later the Belgian physician-chemist Paul Janssen, working at his family pharmaceutical company in Beerse, modified the phenylpiperidine nucleus of meperidine to produce a series of agents of progressively greater potency: fentanyl (1960, approximately one hundred times the potency of morphine on a milligram basis), carfentanil (1974), sufentanil (1974), and alfentanil (1976).^[2] Fentanyl became the standard intraoperative analgesic and, in transdermal and transmucosal formulations, an important option in chronic pain; carfentanil, used in veterinary medicine to immobilise large animals, has appeared in the illicit market in milligram doses sufficient to kill a thousand people.

The molecular pharmacology of the opioid analgesics was established three decades after the synthetic agents had become routine. In 1973 three independent laboratories (those of Solomon Snyder and Candace Pert at Johns Hopkins, Eric Simon at NYU, and Lars Terenius at Uppsala) demonstrated that opioids bind to specific high-affinity receptors in brain tissue.^[3] The Scottish-trained pharmacologist Hans Kosterlitz and his Aberdeen graduate student John Hughes reported in 1975 the isolation of two endogenous pentapeptides, methionine- and leucine-enkephalin, that bound these receptors and were the body's own analgesic system; the longer endorphins followed within a year. The classical pharmacology recognises three opioid-receptor types named for the agents at which each was first studied: mu (μ, for morphine), delta (δ, for deferens), and kappa (κ, for ketocyclazocine), each cloned in the early 1990s, with a fourth nociceptin/orphanin receptor added later. Mu-receptor activation is responsible for most of the clinically useful and clinically problematic effects of the agonists in this category: analgesia, respiratory depression, miosis, constipation, euphoria, and the development of physical dependence on chronic use.

The pharmacology of the contemporary opioid is, in clinical use, dominated by the relation between analgesia and respiratory depression. The two effects are produced by activation of the same receptor and have not been successfully separated in any medicine of full agonist class, although the partial agonist buprenorphine approaches that separation at the expense of a ceiling on its analgesic effect. The atypical opioid tramadol, introduced by Grünenthal in 1977, is a weak mu agonist combined with a serotonin- and noradrenaline-reuptake inhibitor, and its descendant tapentadol (2008) retains the dual mechanism without the serotonergic component; both have a lower respiratory-depression profile than the corresponding-potency mu agonists and a different but real adverse-effect profile that includes serotonin syndrome (tramadol) and seizure (both). The mixed agonist-antagonists (pentazocine, nalbuphine, butorphanol) are now of limited use because their kappa-receptor activity produces dysphoria.

The opioid analgesics are, in the present clinical context, among the most consequential medicines to prescribe. The United States overdose mortality from opioid medicines, beginning with the 1996 introduction and aggressive marketing of controlled-release oxycodone under the trade name OxyContin and amplified after 2013 by illicit fentanyl analogues, has been documented as one of the few sustained declines in U.S. life expectancy of the post-war period.^[4] The contemporary prescriber works in a framework that has changed in the last decade: a presumption against chronic opioid use for non-cancer pain except where carefully considered, careful documentation of indication and duration, naloxone co-prescription, and an explicit clinical pathway to medicine-assisted treatment for opioid use disorder (buprenorphine, methadone, or extended-release naltrexone) when use becomes problematic.

By receptor activity:

• Full mu-receptor agonists, natural and semi-synthetic: morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, diacetylmorphine (heroin)
• Full mu-receptor agonists, synthetic phenylpiperidines (the fentanyl series and parent): meperidine, fentanyl, sufentanil, alfentanil, carfentanil, remifentanil
• Full mu-receptor agonists, diphenylheptane class: methadone
• Atypical centrally acting agents (mu agonist plus monoamine-reuptake inhibition): tramadol, tapentadol
• Partial agonist: buprenorphine
• Mixed agonist-antagonists (kappa agonist, mu antagonist or partial agonist): pentazocine, nalbuphine, butorphanol
• Peripheral mu agonists (acting on gut opioid receptors, not penetrating the central nervous system): loperamide (also listed under antidiarrheals), diphenoxylate
• Opium itself: opium (the tincture, as paregoric and as deodorised tincture of opium, remains in limited use)

The boundary of this category is "medicine whose principal indication is analgesia through opioid-receptor agonism." The opioid antagonists (naloxone, naltrexone, nalmefene), although they bind the same receptors, are not analgesics and are collected separately. Medications for the treatment of opioid use disorder are collected under medication-assisted treatment for opioid use disorder; methadone and buprenorphine appear in both that category and this one because their clinical roles are distinct in the two settings. The fixed-dose combination products in which an opioid is paired with paracetamol or with a non-steroidal anti-inflammatory (Vicodin, Percocet, Tylenol with Codeine, and the others) are collected here and also under fixed-dose combinations. Non-opioid analgesics (paracetamol, the NSAIDs, the gabapentinoids when used for pain) are collected under non-opioid analgesics and at their individual class pages.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.