Opioids

Effects

Overview

Opioids are a class of psychoactive substances that resemble morphine or other opiates in their pharmacological effects. Opioids work by binding to opioid receptors, which are found in the central and peripheral nervous system and the gastrointestinal tract. The receptors in these organ systems mediate both the beneficial effects and the side effects of opioids. PW⚠ PsychonautWiki itself has flagged this text: citation needed.

Opioids are a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, including pain relief.[1][2] WP

The terms opioid and opiate are sometimes used interchangeably, but the term opioid is often used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain, while the term opiate is often used to refer to alkaloid compounds naturally found in the opium poppy plant Papaver somniferum.[1][3][4] WP

Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use disorder, and suppressing cough. The opioid receptor antagonist naloxone is used to reverse opioid overdose. Extremely potent opioids such as carfentanil are approved only for veterinary use. Opioids are also frequently used recreationally for their euphoric effects or to prevent withdrawal. Opioids can be fatal, and have been used, alone and in combination, in a small number of executions in the United States.[5–11] WP

Side effects of opioids may include itchiness, sedation, nausea, respiratory depression, constipation, and euphoria. Long-term use can cause tolerance, meaning that increased doses are required to achieve the same effect, and physical dependence, meaning that abruptly discontinuing the drug leads to unpleasant withdrawal symptoms. The euphoria attracts recreational use; frequent, escalating recreational use of opioids typically results in addiction. An overdose or concurrent use with other depressant drugs like benzodiazepines can result in death from respiratory depression.[12][13] WP

Opioid receptors are found principally in the central and peripheral nervous system and the gastrointestinal tract. These receptors mediate both the psychoactive and the somatic effects of opioids. Some partial agonists, like the anti-diarrhea drug loperamide and antagonists, like naloxegol for opioid-induced constipation, do not cross the blood–brain barrier, but can displace other opioids from binding to receptors in the myenteric plexus. Other agonists and antagonists cross the blood-brain barrier. WP

Because opioids are addictive and may result in fatal overdose, most are controlled substances. In 2013, between 28 and 38 million people used opioids illicitly (0.6–0.8% of the global population between the ages of 15 and 65). By 2021, that number rose to 60 million. In 2011, an estimated 4 million people in the United States used opioids recreationally or were dependent on them. As of 2015, increased rates of recreational use and addiction are attributed to over-prescription of opioid medications and inexpensive illicit heroin. Conversely, fears about overprescribing, exaggerated side effects, and addiction from opioids are similarly blamed for under-treatment of pain.[14–21] WP

History

Naturally occurring opioids

Opioids are among the world's oldest known drugs. The earliest known evidence of Papaver somniferum in a human archaeological site dates to the Neolithic period around 5,700–5,500 BCE. Its seeds have been found at Cueva de los Murciélagos in the Iberian Peninsula and La Marmotta in the Italian Peninsula.[27–30] WP

Use of the opium poppy for medical, recreational, and religious purposes can be traced to the fourth century BC, when ideograms on Sumerians clay tablets mention the use of "Hul Gil", a "plant of joy". Opium was known to the Egyptians, and is mentioned in the Ebers Papyrus as an ingredient in a mixture for the soothing of children, and for the treatment of breast abscesses.[31–35] WP

Opium was also known to the Greeks. It was valued by Hippocrates (c. 460 – c. 370 BC) and his students for its sleep-inducing properties, and used for the treatment of pain. The Latin saying "Sedare dolorem opus divinum est", trans. "Alleviating pain is the work of the divine", has been variously ascribed to Hippocrates and to Galen of Pergamum. The medical use of opium is later discussed by Pedanius Dioscorides (c. 40 – 90 AD), a Greek physician serving in the Roman army, in his five-volume work, De Materia Medica.[34][36][37][38] WP

During the Islamic Golden Age, the use of opium was discussed in detail by Avicenna (c. 980 – June 1037 AD) in The Canon of Medicine. The book's five volumes include information on opium's preparation, an array of physical effects, its use to treat a variety of illness, contraindications for its use, its potential danger as a poison and its potential for addiction. Avicenna discouraged opium's use except as a last resort, preferring to address the causes of pain rather than trying to minimize it with analgesics. Many of Avicenna's observations have been supported by modern medical research.[34][39] WP

Exactly when the world became aware of opium in India and China is uncertain, but opium was mentioned in the Chinese medical work Kaibao Bencao (973 AD) By 1590 AD, opium poppies were a staple spring crop in the Subahs of Agra region.[33][40] WP

The physician Paracelsus (c. 1493–1541) is often credited with reintroducing opium into medical use in Western Europe, during the German Renaissance. He extolled opium's benefits for medical use. He also claimed to have an "arcanum", a pill which he called laudanum, that was superior to all others, particularly when death was to be cheated. ("Ich hab' ein Arcanum – heiss' ich Laudanum, ist über das Alles, wo es zum Tode reichen will.") Later writers have asserted that Paracelsus' recipe for laudanum contained opium, but its composition remains unknown.[41] WP

Laudanum

The term laudanum was used generically for a useful medicine until the 17th century. After Thomas Sydenham introduced the first liquid tincture of opium, "laudanum" came to mean a mixture of both opium and alcohol. Sydenham's 1669 recipe for laudanum mixed opium with wine, saffron, clove and cinnamon. Sydenham's laudanum was used widely in both Europe and the Americas until the 20th century. Other popular medicines, based on opium, included Paregoric, a much milder liquid preparation for children; Black-drop, a stronger preparation; and Dover's powder.[34][41][42] WP

The opium trade

Opium became a major colonial commodity, moving legally and illegally through trade networks involving India, the Portuguese, the Dutch, the British and China, among others. The British East India Company saw the opium trade as an investment opportunity in 1683 AD. In 1773 the Governor of Bengal established a monopoly on the production of Bengal opium, on behalf of the East India Company. The cultivation and manufacture of Indian opium was further centralized and controlled through a series of acts, between 1797 and 1949. The British balanced an economic deficit from the importation of Chinese tea by selling Indian opium which was smuggled into China in defiance of Chinese government bans. This led to the First (1839–1842) and Second Opium Wars (1856–1860) between China and Britain.[40][43–46] WP

Morphine

In the 19th century, two major scientific advances were made that had far-reaching effects. Around 1804, German pharmacist Friedrich Sertürner isolated morphine from opium. He described its crystallization, structure, and pharmacological properties in a well-received paper in 1817. Morphine was the first alkaloid to be isolated from any medicinal plant, the beginning of modern scientific drug discovery.[42][45][47][48][49] WP

The second advance, nearly fifty years later, was the refinement of the hypodermic needle by Alexander Wood and others. Development of a glass syringe with a subcutaneous needle made it possible to easily administer controlled measurable doses of a primary active compound.[33][42][50][51][52] WP

Morphine was initially hailed as a wonder drug for its ability to ease pain. It could help people sleep, and had other useful side effects, including control of coughing and diarrhea. It was widely prescribed by doctors, and dispensed without restriction by pharmacists. During the American Civil War, opium and laudanum were used extensively to treat soldiers. It was also prescribed frequently for women, for menstrual pain and diseases of a "nervous character". At first it was assumed (wrongly) that this new method of application would not be addictive.[45][53–56] WP

Codeine

Codeine was discovered in 1832 by Pierre Jean Robiquet. Robiquet was reviewing a method for morphine extraction, described by Scottish chemist William Gregory (1803–1858). Processing the residue left from Gregory's procedure, Robiquet isolated a crystalline substance from the other active components of opium. He wrote of his discovery: "Here is a new substance found in opium... We know that morphine, which so far has been thought to be the only active principle of opium, does not account for all the effects and for a long time the physiologists are claiming that there is a gap that has to be filled." His discovery of the alkaloid led to the development of a generation of antitussive and antidiarrheal medicines based on codeine.[57][58] WP

Semi-synthetic and synthetic opioids

Synthetic opioids were invented, and biological mechanisms for their actions discovered, in the 20th century. Scientists have searched for non-addictive forms of opioids, but have created stronger ones instead. In England Charles Romley Alder Wright developed hundreds of opiate compounds in his search for a nonaddictive opium derivative. In 1874 he became the first person to synthesize diamorphine (heroin), using a process called acetylation which involved boiling morphine with acetic anhydride for several hours.[33][45] WP

Heroin received little attention until it was independently synthesized by Felix Hoffmann (1868–1946), working for Heinrich Dreser (1860–1924) at Bayer Laboratories. Dreser brought the new drug to market as an analgesic and a cough treatment for tuberculosis, bronchitis, and asthma in 1898. Bayer ceased production in 1913, after heroin's addictive potential was recognized.[45][59][60][61] WP

Several semi-synthetic opioids were developed in Germany in the 1910s. The first, oxymorphone, was synthesized from thebaine, an opioid alkaloid in opium poppies, in 1914. Next, Martin Freund and Edmund Speyer developed oxycodone, also from thebaine, at the University of Frankfurt in 1916. In 1920, hydrocodone was prepared by Carl Mannich and Helene Löwenheim, deriving it from codeine. In 1924, hydromorphone was synthesized by adding hydrogen to morphine. Etorphine was synthesized in 1960, from the oripavine in opium poppy straw. Buprenorphine was discovered in 1972.[62][63] WP

The first fully synthetic opioid was meperidine (Demerol), found serendipitously by German chemist Otto Eisleb (or Eislib) at IG Farben in 1932. Meperidine was the first opioid to have a structure unrelated to morphine, but with opioid-like properties. Its analgesic effects were discovered by Otto Schaumann in 1939. Gustav Ehrhart and Max Bockmühl, also at IG Farben, built on the work of Eisleb and Schaumann. They developed "Hoechst 10820" (later methadone) around 1937. In 1959 the Belgian physician Paul Janssen developed fentanyl, a synthetic opioid with 30 to 50 times the potency of heroin. Nearly 150 synthetic opioids are now known.[33][45][62][64][65] WP

Legal status

Definition

The term "opioid" originated in the 1950s. It combines "opium" + "-oid" meaning "opiate-like" ("opiates" being morphine and similar drugs derived from opium). The first scientific publication to use it, in 1963, included a footnote stating, "In this paper, the term, 'opioid', is used in the sense originally proposed by George H. Acheson (personal communication) to refer to any chemical compound with morphine-like activities". By the late 1960s, research found that opiate effects are mediated by activation of specific molecular receptors in the nervous system, which were termed "opioid receptors". The definition of "opioid" was later refined to refer to substances that have morphine-like activities that are mediated by the activation of opioid receptors. One modern pharmacology textbook states: "the term opioid applies to all agonists and antagonists with morphine-like activity, and also the naturally occurring and synthetic opioid peptides". Another pharmacology reference eliminates the morphine-like requirement: "Opioid, a more modern term, is used to designate all substances, both natural and synthetic, that bind to opioid receptors (including antagonists)". Some sources define the term opioid to exclude opiates, and others use opiate comprehensively instead of opioid, but opioid used inclusively is considered modern, preferred and is in wide use.[1][66–70] WP

Global shortages

Morphine and other poppy-based medicines have been identified by the World Health Organization as essential in the treatment of severe pain. As of 2002, seven countries (USA, UK, Italy, Australia, France, Spain and Japan) use 77% of the world's morphine supplies, leaving many emerging countries lacking in pain relief medication. The current system of supply of raw poppy materials to make poppy-based medicines is regulated by the International Narcotics Control Board under the provision of the 1961 Single Convention on Narcotic Drugs. The amount of raw poppy materials that each country can demand annually based on these provisions must correspond to an estimate of the country's needs taken from the national consumption within the preceding two years. In many countries, underprescription of morphine is rampant because of the high prices and the lack of training in the prescription of opiates. The World Health Organization is now working with administrations from various countries to train healthcare workers and to develop national regulations regarding drug prescription to facilitate a greater prescription of opiates.[71][72] WP

Another idea to increase morphine availability is proposed by the ICOS, who suggest, through their proposal for Afghan Morphine, that Afghanistan could provide cheap pain relief solutions to emerging countries as part of a second-tier system of supply that would complement the current INCB regulated system by maintaining the balance and closed system that it establishes while providing finished-product morphine to people in severe pain who are unable to access opiates under the current system. WP

Pharmacology

Pharmacology

Opioids bind to specific opioid receptors in the nervous system and other tissues. There are three principal classes of opioid receptors, μ, κ, δ (mu, kappa, and delta), although up to seventeen have been reported, and include the ε, ι, λ, and ζ (Epsilon, Iota, Lambda and Zeta) receptors. Conversely, σ (Sigma) receptors are no longer considered to be opioid receptors because their activation is not reversed by the opioid inverse-agonist naloxone, they do not exhibit high-affinity binding for classical opioids, and they are stereoselective for dextro-rotatory isomers while the other opioid receptors are stereo-selective for levo-rotatory isomers. In addition, there are three subtypes of μ-receptor: μ₁ and μ₂, and the newly discovered μ₃. Another receptor of clinical importance is the opioid-receptor-like receptor 1 (ORL1), which is involved in pain responses as well as having a major role in the development of tolerance to μ-opioid agonists used as analgesics. These are all G-protein coupled receptors acting on GABAergic neurotransmission. WP

The pharmacodynamic response to an opioid depends upon the receptor to which it binds, its affinity for that receptor, and whether the opioid is an agonist or an antagonist. For example, the supraspinal analgesic properties of the opioid agonist morphine are mediated by activation of the μ₁ receptor; respiratory depression and physical dependence by the μ₂ receptor; and sedation and spinal analgesia by the κ receptor. Each group of opioid receptors elicits a distinct set of neurological responses, with the receptor subtypes (such as μ₁ and μ₂ for example) providing even more [measurably] specific responses. Unique to each opioid is its distinct binding affinity to the various classes of opioid receptors (e.g. the μ, κ, and δ opioid receptors are activated at different magnitudes according to the specific receptor binding affinities of the opioid). For example, the opiate alkaloid morphine exhibits high-affinity binding to the μ-opioid receptor, while ketazocine exhibits high affinity to ĸ receptors. It is this combinatorial mechanism that allows for such a wide class of opioids and molecular designs to exist, each with its own unique effect profile. Their individual molecular structure is also responsible for their different duration of action, whereby metabolic breakdown (such as N-dealkylation) is responsible for opioid metabolism. WP⚠ Wikipedia itself has flagged this text: citation needed.

Functional selectivity

A new strategy of drug development takes receptor signal transduction into consideration. This strategy strives to increase the activation of desirable signalling pathways while reducing the impact on undesirable pathways. This differential strategy has been given several names, including functional selectivity and biased agonism. The first opioid that was intentionally designed as a biased agonist and placed into clinical evaluation is the drug oliceridine. It displays analgesic activity and reduced adverse effects.[97] WP

Opioid comparison

Extensive research has been conducted to determine equivalence ratios comparing the relative potency of opioids. Given a dose of an opioid, an equianalgesic table is used to find the equivalent dosage of another. Such tables are used in opioid rotation practices, and to describe an opioid by comparison to morphine, the reference opioid. Equianalgesic tables typically list drug half-lives, and sometimes equianalgesic doses of the same drug by means of administration, such as morphine: oral and intravenous. WP

Receptor binding · Wikipedia

Binding profiles of opioids at opioid receptors (Kᵢ, nM)

Chemistry

Pop culture

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References

1. Other Hemmings, Hugh C.; Egan, Talmage D. Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application: Expert Consult – Online and Print. 2013
2. Other Opioids. 2023-05-11
3. Other Opiate - Definitions from Dictionary.com
4. Other Alcohol and Drug Policy Commission: Opiates or Opioids — What's the difference?: State of Oregon
5. Other Stromgaard, Kristian; Krogsgaard-Larsen, Povl; Madsen, Ulf. Textbook of Drug Design and Discovery, Fourth Edition. 2009
6. Journal / agency Walzer C. Zoo Animal and Wildlife Immobilization and Anesthesia. 2014. doi:10.1002/9781118792919 · PMC2871358
7. Harm reduction site Carfentanil
8. Journal / agency Sterken J, Troubleyn J, Gasthuys F, Maes V, Diltoer M, Verborgh C. Intentional overdose of Large Animal Immobilon. European Journal of Emergency Medicine. October 2004. doi:10.1097/00063110-200410000-00013 · PMID 15359207
9. Other Lembke, Anna. Drug Dealer, MD: How Doctors Were Duped, Patients Got Hooked, and Why It's So Hard to Stop. 2016
10. Other New Execution Methods Can't Disguise Same Old Death Penalty Problems
11. Other Overview of Lethal Injection Protocols
12. Other Drug Facts: Prescription Opioids. June 2019
13. Journal / agency FDA requires strong warnings for opioid analgesics, prescription opioid cough products, and benzodiazepine labeling related to serious risks and death from combined use. 31 August 2016
14. Other World Drug Report 2015
15. Harm reduction site World Drug Report 2023
16. Other Advancing Access to Addiction Medications: Implications for Opioid Addiction Treatment
17. Journal / agency Tetrault JM, Butner JL. Non-Medical Prescription Opioid Use and Prescription Opioid Use Disorder: A Review. The Yale Journal of Biology and Medicine. September 2015. PMID 26339205 · PMC4553642
18. Journal / agency Tarabar AF, Nelson LS. The resurgence and abuse of heroin by children in the United States. Current Opinion in Pediatrics. April 2003. doi:10.1097/00008480-200304000-00013 · PMID 12640281
19. Other Gray, Eliza. Heroin Gains Popularity as Cheap Doses Flood the U.S. 4 February 2014
20. Journal / agency Maltoni M. Opioids, pain, and fear. Annals of Oncology. January 2008. doi:10.1093/annonc/mdm555 · PMID 18073220
21. Journal / agency McCarberg BH. Pain management in primary care: strategies to mitigate opioid misuse, abuse, and diversion. Postgraduate Medicine. March 2011. doi:10.3810/pgm.2011.03.2270 · PMID 21474900
22. Journal / agency Brennan, M. J. The effect of opioid therapy on endocrine function. The American Journal of Medicine. March 2013. doi:10.1016/j.amjmed.2012.12.001
23. Journal / agency Smith, H. S., Elliott, J. A. Opioid-induced androgen deficiency (OPIAD). Pain Physician. July 2012
24. Journal / agency Lee, M., Silverman, S. M., Hansen, H., Patel, V. B., Manchikanti, L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. April 2011
25. Other Why Heroin Relapse Often Ends In Death - Lauren F Friedman (Business Insider)
26. Journal / agency Siegel, S., Hinson, R. E., Krank, M. D., McCully, J. Heroin “Overdose” Death: Contribution of Drug-Associated Environmental Cues. Science. 23 April 1982. doi:10.1126/science.7200260
27. Journal / agency Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S. Crystal structure of the µ-opioid receptor bound to a morphinan antagonist. Nature. March 2012. doi:10.1038/nature10954 · PMID 22437502 · PMC3523197
28. Other Colledge, Sue; Conolly, James. The Origins and Spread of Domestic Plants in Southwest Asia and Europe. 10 August 2007
29. Other Kunzig, Robert; Tzar, Jennifer. La Marmotta. 1 November 2002
30. Other Chevalier, Alexandre; Marinova, Elena; Pena-Chocarro, Leonor. Plants and People: Choices and Diversity through Time. 1 April 2014
31. Journal / agency Kritikos PG, Papadaki SP. The history of the poppy and of opium and their expansion in antiquity in the eastern Mediterranean area. Bulletin on Narcotics. 1967
32. Journal / agency Sonnedecker, Glenn. Emergence of the Concept of Opiate Addiction. Journal Mondial de Pharmacie. 1962
33. Journal / agency Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proceedings of the National Academy of Sciences of the United States of America. June 1993. doi:10.1073/pnas.90.12.5391 · PMID 8390660 · PMC46725
34. Journal / agency Duarte, Danilo Freire. Uma breve história do ópio e dos opióides. Revista Brasileira de Anestesiologia. February 2005. doi:10.1590/S0034-70942005000100015
35. Journal / agency Rosso AM. Poppy and Opium in Ancient Times: Remedy or Narcotic?. Biomedicine International. 2010
36. Journal / agency Astyrakaki E, Papaioannou A, Askitopoulou H. References to anesthesia, pain, and analgesia in the Hippocratic Collection. Anesthesia and Analgesia. January 2010. doi:10.1213/ane.0b013e3181b188c2 · PMID 19861359
37. Journal / agency Türe H, Türe U, Gögüs FY, Valavanis A, Yasargil MG. 987 The Art of Alleviating Pain in Greek Mythology. European Journal of Pain. September 2006. doi:10.1016/S1090-3801(06)60990-7
38. Other Osbaldeston, Tess Anne. Dioscorides (translation). 2000
39. Journal / agency Heydari M, Hashempur MH, Zargaran A. Medicinal aspects of opium as described in Avicenna's Canon of Medicine. Acta medico-historica Adriatica. 2013. PMID 23883087
40. Journal / agency Asthana SN. The Cultivation of the Opium Poppy in India. Bulletin on Narcotics. 1954
41. Journal / agency Sigerist HE. Laudanum in the Works of Paracelsus. Bull. Hist. Med. 1941
42. Journal / agency Hamilton GR, Baskett TF. In the arms of Morpheus the development of morphine for postoperative pain relief. Canadian Journal of Anaesthesia. April 2000. doi:10.1007/BF03020955 · PMID 10764185
43. Journal / agency Farooqui, Amar. The Global Career of Indian Opium and Local Destinies. Almanack. December 2016. doi:10.1590/2236-463320161404
44. Journal / agency Deming, Sarah. The Economic Importance of Indian Opium and Trade with China on Britain's Economy, 1843–1890. Economic Working Papers. 2011
45. Journal / agency Rinde, Meir. Opioids' Devastating Return. Distillations. 2018
46. Journal / agency Mills, James H. Review of 'Opium and Empire in Southeast Asia: Regulating Consumption in British Burma'. Reviews in History. 2016. doi:10.14296/RiH/2014/2010
47. Journal / agency Krishnamurti C, Rao SC. The isolation of morphine by Serturner. Indian Journal of Anaesthesia. November 2016. doi:10.4103/0019-5049.193696 · PMID 27942064 · PMC5125194
48. Other Courtwright, David T. Forces of habit drugs and the making of the modern world. 2009
49. Journal / agency Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V, Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H. Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnology Advances. December 2015. doi:10.1016/j.biotechadv.2015.08.001 · PMID 26281720 · PMC4748402
50. Journal / agency Kotwal A. Innovation, diffusion and safety of a medical technology: a review of the literature on injection practices. Social Science & Medicine. March 2005. doi:10.1016/j.socscimed.2004.06.044 · PMID 15589680
51. Other Mosher, Clayton J. Drugs and Drug Policy: The Control of Consciousness Alteration. 2013
52. Other Fisher, Gary L. Encyclopedia of substance abuse prevention, treatment, & recovery. 2009
53. Other Trickey, Erick. Inside the Story of America's 19th-Century Opiate Addiction. 4 January 2018
54. Other Schechter, Neil L. Pain in Infants, Children, and Adolescents. 1993
55. Journal / agency Hicks, Robert D. Frontline Pharmacies. Chemical Heritage Magazine. 2011
56. Other Booth, Martin. Opium: a history. 12 June 1999
57. Journal / agency Wisniak, Jaime. Pierre-Jean Robiquet. Educación Química. March 2013. doi:10.1016/S0187-893X(13)72507-2
58. Other Filan, Kenaz. The power of the poppy: harnessing nature's most dangerous plant ally. 2011
59. Other Felix Hoffmann. June 2016
60. Other Cooper, Raymond; Deakin, Jeffrey John. Botanical miracles: chemistry of plants that changed the world. 22 February 2016
61. Journal / agency Sneader W. The discovery of heroin. Lancet. November 1998. doi:10.1016/S0140-6736(98)07115-3 · PMID 9853457
62. Other Newton, David E. Youth substance abuse: a reference handbook. 2016
63. Other Crow, James Mitchell. Addicted to the cure. 3 January 2017
64. Other Methadone Matters: Evolving Community Methadone Treatment of Opiate Addiction. 2003
65. Other Fact Sheet: Fentanyl and Synthetic Opioids. September 2016
66. Other opioid: definition of opioid in Oxford dictionary (American English) (US)
67. Journal / agency Wikler A, Martin WR, Pescor FT, Eades CG. Factors regulating oral consumption of an opioid (Etonitazene) by morphine-addicted rats. Psychopharmacologia. October 1963. doi:10.1007/bf00405575 · PMID 14082382
68. Journal / agency Martin WR. Opioid antagonists. Pharmacological Reviews. December 1967. PMID 4867058
69. Other Mehdi B. Textbook of Pharmacology. 2008
70. Other Offermanns, Stefan. Encyclopedia of Molecular Pharmacology. 2008
71. Other Feasibility Study on Opium Licensing in Afghanistan for the Production of Morphine and Other Essential Medicines. September 2005
72. Journal / agency Assuring Availability of Opioid Analgesics
73. Journal / agency Johnson N, Itzhak Y, Pasternak GW. Interaction of two phencyclidine opiate-like derivatives with 3H-opioid binding sites. European Journal of Pharmacology. June 1984. doi:10.1016/0014-2999(84)90171-7 · PMID 6088255
74. Journal / agency Takayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D, Koyama F, Matsumoto K, Moriyama T, Yamamoto LT, Watanabe K, Murayama T, Horie S. Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands. Journal of Medicinal Chemistry. April 2002. doi:10.1021/jm010576e · PMID 11960505
75. Journal / agency Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T. Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Molecular Pharmacology. February 1994. PMID 8114680
76. Journal / agency Alburges, ME. Utilization of a radioreceptor assay for the analysis of fentanyl analogs in urine. J Anal Toxicol. 1992. doi:10.1093/jat/16.1.36 · PMID 1322477
77. Journal / agency Filizola M, Villar HO, Loew GH. Molecular determinants of non-specific recognition of delta, mu, and kappa opioid receptors. Bioorganic & Medicinal Chemistry. January 2001. doi:10.1016/S0968-0896(00)00223-6 · PMID 11197347
78. Journal / agency Tam SW. (+)-[3H]SKF 10,047, (+)-[3H]ethylketocyclazocine, mu, kappa, delta and phencyclidine binding sites in guinea pig brain membranes. European Journal of Pharmacology. February 1985. doi:10.1016/0014-2999(85)90536-9 · PMID 2986989
79. Journal / agency Corbett AD, Paterson SJ, Kosterlitz HW. Opioids. 1993. doi:10.1007/978-3-642-77460-7_26
80. Journal / agency Codd EE, Shank RP, Schupsky JJ, Raffa RB. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. The Journal of Pharmacology and Experimental Therapeutics. September 1995. PMID 7562497
81. Journal / agency Linz K, Christoph T, Tzschentke TM, Koch T, Schiene K, Gautrois M, Schröder W, Kögel BY, Beier H, Englberger W, Schunk S, De Vry J, Jahnel U, Frosch S. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. The Journal of Pharmacology and Experimental Therapeutics. June 2014. doi:10.1124/jpet.114.213694 · PMID 24713140
82. Journal / agency Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B. Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittel-Forschung. November 1996. PMID 8955860
83. Journal / agency Potschka H, Friderichs E, Löscher W. Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy. British Journal of Pharmacology. September 2000. doi:10.1038/sj.bjp.0703562 · PMID 10991912 · PMC1572317
84. Journal / agency Katsumata S, Minami M, Nakagawa T, Iwamura T, Satoh M. Pharmacological study of dihydroetorphine in cloned mu-, delta- and kappa-opioid receptors. European Journal of Pharmacology. November 1995. doi:10.1016/0922-4106(95)90078-0 · PMID 8719422
85. Journal / agency Antkiewicz-Michaluk L, Vetulani J, Havemann U, Kuschinsky K. 3H-dihydromorphine binding sites in subcellular fractions of rat striatum. Pol J Pharmacol Pharm. 1982. PMID 6300816
86. Journal / agency Bart G, Schluger JH, Borg L, Ho A, Bidlack JM, Kreek MJ. Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity?. Neuropsychopharmacology. December 2005. doi:10.1038/sj.npp.1300811 · PMID 15988468
87. Journal / agency Wentland MP, Lou R, Lu Q, Bu Y, VanAlstine MA, Cohen DJ, Bidlack JM. Syntheses and opioid receptor binding properties of carboxamido-substituted opioids. Bioorganic & Medicinal Chemistry Letters. January 2009. doi:10.1016/j.bmcl.2008.10.134 · PMID 19027293
88. Journal / agency Gharagozlou P, Demirci H, David Clark J, Lameh J. Activity of opioid ligands in cells expressing cloned mu opioid receptors. BMC Pharmacology. January 2003. doi:10.1186/1471-2210-3-1 · PMID 12513698 · PMC140036
89. Journal / agency Gharagozlou P, Demirci H, Clark JD, Lameh J. Activation profiles of opioid ligands in HEK cells expressing delta opioid receptors. BMC Neuroscience. November 2002. doi:10.1186/1471-2202-3-19 · PMID 12437765 · PMC137588
90. Journal / agency Gharagozlou P, Hashemi E, DeLorey TM, Clark JD, Lameh J. Pharmacological profiles of opioid ligands at kappa opioid receptors. BMC Pharmacology. January 2006. doi:10.1186/1471-2210-6-3 · PMID 16433932 · PMC1403760
91. Journal / agency Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB. Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences of the United States of America. September 2002. doi:10.1073/pnas.182234399 · PMID 12192085 · PMC129372
92. Journal / agency Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, Ganorkar R, VanAlstine MA, Guo C, Cohen DJ, Bidlack JM. Syntheses of novel high affinity ligands for opioid receptors. Bioorganic & Medicinal Chemistry Letters. April 2009. doi:10.1016/j.bmcl.2009.02.078 · PMID 19282177 · PMC2791460
93. Journal / agency Schmid CL, Kennedy NM, Ross NC, Lovell KM, Yue Z, Morgenweck J, Cameron MD, Bannister TD, Bohn LM. Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics. Cell. November 2017. doi:10.1016/j.cell.2017.10.035 · PMID 29149605 · PMC5731250
94. Journal / agency Gassaway MM, Rives ML, Kruegel AC, Javitch JA, Sames D. The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist. Translational Psychiatry. July 2014. doi:10.1038/tp.2014.30 · PMID 25026323 · PMC4119213
95. Journal / agency Truver, M. T.; Smith, C. R.; Garibay, N.; Kopajtic, T. A.; Swortwood, M. J.; Baumann, M. H. Pharmacodynamics and pharmacokinetics of the novel synthetic opioid, U-47700, in male rats. Neuropharmacology. 2020. doi:10.1016/j.neuropharm.2020.108195 · PMID 32533977 · PMC7554234
96. Journal / agency Fujimoto RA, Boxer J, Jackson RH, Simke JP, Neale RF, Snowhill EW, Barbaz BJ, Williams M, Sills MA. Synthesis, opioid receptor binding profile, and antinociceptive activity of 1-azaspiro[4.5]decan-10-yl amides. Journal of Medicinal Chemistry. June 1989. doi:10.1021/jm00126a019 · PMID 2542556
97. Journal / agency DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD. A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. The Journal of Pharmacology and Experimental Therapeutics. March 2013. doi:10.1124/jpet.112.201616 · PMID 23300227

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