opioid

File:Opiates v opioids.pngs and opioids with chemical structures indicated. Many classical opiates are also referred to as opioids in modern nomenclature.]]

Opioids include opiates, an older term that refers to such drugs derived from opium, including morphine itself.{{Cite book|url=https://books.google.com/books?id=iwwo5gx8aX8C&q=903|title=Encyclopedia of Molecular Pharmacology|last=Offermanns|first=Stefan|publisher=Springer Science & Business Media|year=2008|isbn=978-3-540-38916-3|edition=2|volume=1|page=903|quote=In the strict sense, opiates are drugs derived from opium and include the natural products morphine, codeine, thebaine and many semi-synthetic congeners derived from them. The term opioids applies to any substance, whether endogenous or synthetic, peptidic or non-peptidic, that produces morphine-like effects through action on opioid receptors.}} Opiate is properly limited to the natural alkaloids found in the resin of the opium poppy although some include semi-synthetic derivatives.{{Cite book|title = Compact Clinical Guide to Cancer Pain Management: An Evidence-Based Approach for Nurses|url = https://books.google.com/books?id=7ob0jFPNhOMC|publisher = Springer Publishing Company|date = 26 September 2012|isbn = 978-0-8261-0974-3 | first1 = Pamela Stitzlein | last1 = Davies | first2 = Yvonne M. | last2 = D'Arcy }} Other opioids are semi-synthetic and synthetic drugs such as hydrocodone, oxycodone, and fentanyl; antagonist drugs such as naloxone; and endogenous peptides such as endorphins.{{Cite book|chapter-url=https://books.google.com/books?id=ybtX0GZGhk8C&pg=PA85|title=Opioids in Medicine: A Comprehensive Review on the Mode of Action and the Use of Analgesics in Different Clinical Pain States|last=Freye|first=Enno|publisher=Springer Science & Business Media|year=2008|isbn=978-1-4020-5947-6|page=85|chapter=Part II. Mechanism of action of opioids and clinical effects|quote=Opiate is a specific term that is used to describe drugs (natural and semi-synthetic) derived from the juice of the opium poppy. For example morphine is an opiate but methadone (a completely synthetic drug) is not. Opioid is a general term that includes naturally occurring, semi-synthetic, and synthetic drugs, which produce their effects by combining with opioid receptors and are competitively antagonized by nalaxone. In this context the term opioid refers to opioid agonists, opioid antagonists, opioid peptides, and opioid receptors.}} The terms opiate and narcotic are sometimes encountered as synonyms for opioid. Narcotic, derived from words meaning 'numbness' or 'sleep', originally referred to any psychoactive compound with numbing or paralyzing properties.{{cite book |last1=Anstie |first1=Francis Edmund |title=Stimulants and Narcotics, Their Mutual Relations: With Special Researches on the Action of Alcohol, Aether and Chloroform on the Vital Organism |year=1865 |publisher=Lindsay and Blakiston |page=152 |url=https://books.google.com/books?id=rBULAAAAIAAJ&pg=PA152 |language=en}} As an American legal term, narcotic refers to cocaine and opioids, and their source materials; it is also loosely applied to any illegal or controlled psychoactive drug.{{Cite web|title = 21 U.S. Code § 802 – Definitions|url = https://www.law.cornell.edu/uscode/text/21/802|website = LII / Legal Information Institute|access-date = 12 February 2016|archive-date = 25 January 2021|archive-url = https://web.archive.org/web/20210125183014/https://www.law.cornell.edu/uscode/text/21/802|url-status = live}}{{Cite web|title = Definition of NARCOTIC|url = http://www.merriam-webster.com/dictionary/narcotic|website = www.merriam-webster.com|access-date = 12 February 2016|archive-date = 14 November 2020|archive-url = https://web.archive.org/web/20201114184715/https://www.merriam-webster.com/dictionary/narcotic|url-status = live}} In some jurisdictions all controlled drugs are legally classified as narcotics. The term can have pejorative connotations and its use is generally discouraged where that is the case.{{Cite book|title = Pharmacology and Pharmacotherapeutics|url = https://books.google.com/books?id=h2drCgAAQBAJ|publisher = Elsevier Health Sciences|isbn = 978-81-312-4371-8| vauthors = Satoskar RS, Rege N, Bhandarkar SD |year = 2015}}{{Cite book|title = Behavioral and Psychopharmacologic Pain Management|url = https://books.google.com/books?id=RORnRRghGeYC|publisher = Cambridge University Press|isbn = 978-1-139-49354-3|first1 = Michael H.|last1 = Ebert|first2 = Robert D.|last2 = Kerns |year = 2010}}

The weak opioid codeine, in low doses and combined with one or more other drugs, is commonly available in prescription medicines and without a prescription to treat mild pain.{{cite journal | vauthors = Moore RA, Wiffen PJ, Derry S, Maguire T, Roy YM, Tyrrell L | title = Non-prescription (OTC) oral analgesics for acute pain - an overview of Cochrane reviews | journal = The Cochrane Database of Systematic Reviews | volume = 11 | issue = 11 | pages = CD010794 | date = November 2015 | pmid = 26544675 | pmc = 6485506 | doi = 10.1002/14651858.CD010794.pub2 }}{{cite web |title=Codeine |url=https://www.drugs.com/codeine.html |publisher=Drugs.com |access-date=31 January 2023 |date=15 May 2022 |archive-date=16 July 2017 |archive-url=https://web.archive.org/web/20170716200041/https://www.drugs.com/codeine.html |url-status=live }} Other opioids are usually reserved for the relief of moderate to severe pain.{{Cite book| url = https://books.google.com/books?id=a7CqcE1ZrFkC| title = Textbook of Pediatric Emergency Medicine| last1 = Fleisher| first1 = Gary R.| last2 = Ludwig| first2 = Stephen | date = 2010| publisher = Lippincott Williams & Wilkins| isbn = 978-1-60547-159-4| page = 61}}

Opioids are effective for the treatment of acute pain (such as pain following surgery).{{cite journal | vauthors = Alexander GC, Kruszewski SP, Webster DW | title = Rethinking opioid prescribing to protect patient safety and public health | journal = JAMA | volume = 308 | issue = 18 | pages = 1865–6 | date = November 2012 | pmid = 23150006 | doi = 10.1001/jama.2012.14282 }} For immediate relief of moderate to severe acute pain, opioids are frequently the treatment of choice due to their rapid onset, efficacy and reduced risk of dependence. However, a new report showed a clear risk of prolonged opioid use when opioid analgesics are initiated for an acute pain management following surgery or trauma.{{cite journal | vauthors = Mohamadi A, Chan JJ, Lian J, Wright CL, Marin AM, Rodriguez EK, von Keudell A, Nazarian A | title = Risk Factors and Pooled Rate of Prolonged Opioid Use Following Trauma or Surgery: A Systematic Review and Meta-(Regression) Analysis | journal = The Journal of Bone and Joint Surgery. American Volume | volume = 100 | issue = 15 | pages = 1332–1340 | date = August 2018 | pmid = 30063596 | doi = 10.2106/JBJS.17.01239 | s2cid = 51891341 }} They have also been found to be important in palliative care to help with the severe, chronic, disabling pain that may occur in some terminal conditions such as cancer, and degenerative conditions such as rheumatoid arthritis. In many cases opioids are a successful long-term care strategy for those with chronic cancer pain.

Just over half of all states in the US have enacted laws that restrict the prescribing or dispensing of opioids for acute pain.{{Cite journal|last1=Davis|first1=Corey S.|last2=Lieberman|first2=Amy Judd|last3=Hernandez-Delgado|first3=Hector|last4=Suba|first4=Carli|date=1 January 2019|title=Laws limiting the prescribing or dispensing of opioids for acute pain in the United States: A national systematic legal review|journal=Drug and Alcohol Dependence|volume=194|pages=166–172|doi=10.1016/j.drugalcdep.2018.09.022|issn=1879-0046|pmid=30445274|s2cid=53567522}}

Guidelines have suggested that the risk of opioids is likely greater than their benefits when used for most non-cancer chronic conditions including headaches, back pain, and fibromyalgia.{{cite journal | vauthors = Franklin GM | title = Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology | journal = Neurology | volume = 83 | issue = 14 | pages = 1277–84 | date = September 2014 | pmid = 25267983 | doi = 10.1212/WNL.0000000000000839 | doi-access = free }} Thus they should be used cautiously in chronic non-cancer pain.{{cite journal | vauthors = Okie S | title = A flood of opioids, a rising tide of deaths | journal = The New England Journal of Medicine | volume = 363 | issue = 21 | pages = 1981–5 | date = November 2010 | pmid = 21083382 | doi = 10.1056/NEJMp1011512 | s2cid = 7092234 | doi-access = free }}
Responses to Okie's perspective: {{cite journal | vauthors = Rich JD, Green TC, McKenzie MS | title = Opioids and deaths | journal = The New England Journal of Medicine | volume = 364 | issue = 7 | pages = 686–687 | date = February 2011 | pmid = 21323559 | doi = 10.1056/NEJMc1014490 | pmc = 10347760 }} If used the benefits and harms should be reassessed at least every three months.{{cite journal | vauthors = Dowell D, Haegerich TM, Chou R | title = CDC Guideline for Prescribing Opioids for Chronic Pain--United States, 2016 | journal = JAMA | volume = 315 | issue = 15 | pages = 1624–45 | date = April 2016 | pmid = 26977696 | pmc = 6390846 | doi = 10.1001/jama.2016.1464 }}

In treating chronic pain, opioids are an option to be tried after other less risky pain relievers have been considered, including paracetamol or NSAIDs like ibuprofen or naproxen.{{Cite journal |last1=Yang |first1=Juan |last2=Bauer |first2=Brent A |last3=Wahner-Roedler |first3=Dietlind L |last4=Chon |first4=Tony Y |last5=Xiao |first5=Lizu |date=17 February 2020 |title=The Modified WHO Analgesic Ladder: Is It Appropriate for Chronic Non-Cancer Pain? |journal=Journal of Pain Research |volume=13 |pages=411–417 |doi=10.2147/JPR.S244173 |pmc=7038776 |pmid=32110089 |doi-access=free }} Some types of chronic pain, including the pain caused by fibromyalgia or migraine, are preferentially treated with drugs other than opioids.For information on the use and overuse of opioids to treat migraines, see {{Citation |author1 = American Academy of Neurology |author1-link = American Academy of Neurology |date = February 2013 |title = Five Things Physicians and Patients Should Question |publisher = American Academy of Neurology |work = Choosing Wisely: an initiative of the ABIM Foundation |url = http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-neurology/ |access-date = 1 August 2013 |archive-date = 1 September 2013 |archive-url = https://web.archive.org/web/20130901115555/http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-neurology/ |url-status = live }}, which cites

• {{cite journal | vauthors = Silberstein SD | title = Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology | journal = Neurology | volume = 55 | issue = 6 | pages = 754–62 | date = September 2000 | pmid = 10993991 | doi = 10.1212/WNL.55.6.754 | doi-access = free }}
• {{cite journal | vauthors = Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, Sándor PS | title = EFNS guideline on the drug treatment of migraine--revised report of an EFNS task force | journal = European Journal of Neurology | volume = 16 | issue = 9 | pages = 968–81 | date = September 2009 | pmid = 19708964 | doi = 10.1111/j.1468-1331.2009.02748.x | author8 = European Federation of Neurological Societies | s2cid = 9204782 | doi-access = free }}
• {{Citation |author=Institute for Clinical Systems Improvement |year=2011 |title=Headache, Diagnosis and Treatment of |publisher=Institute for Clinical Systems Improvement |url=https://www.icsi.org/guidelines__more/catalog_guidelines_and_more/catalog_guidelines/catalog_neurological_guidelines/headache/ |ref=none |access-date=18 December 2013 |archive-url=https://web.archive.org/web/20131029201313/https://www.icsi.org/guidelines__more/catalog_guidelines_and_more/catalog_guidelines/catalog_neurological_guidelines/headache/ |archive-date=29 October 2013 |url-status=dead }}{{cite journal | vauthors = Painter JT, Crofford LJ | title = Chronic opioid use in fibromyalgia syndrome: a clinical review | journal = Journal of Clinical Rheumatology | volume = 19 | issue = 2 | pages = 72–7 | date = March 2013 | pmid = 23364665 | doi = 10.1097/RHU.0b013e3182863447 }} The efficacy of using opioids to lessen chronic neuropathic pain is uncertain.{{cite journal | vauthors = McNicol ED, Midbari A, Eisenberg E | title = Opioids for neuropathic pain | journal = The Cochrane Database of Systematic Reviews | volume = 8 | issue = 8 | pages = CD006146 | date = August 2013 | pmid = 23986501 | pmc = 6353125 | doi = 10.1002/14651858.CD006146.pub2 }}

Opioids are contraindicated as a first-line treatment for headache because they impair alertness, bring risk of dependence, and increase the risk that episodic headaches will become chronic.{{Citation |author1 = American Headache Society |author1-link = American Academy of Dermatology |date = September 2013 |title = Five Things Physicians and Patients Should Question |publisher = American Headache Society |work = Choosing Wisely: an initiative of the ABIM Foundation |url = http://www.choosingwisely.org/doctor-patient-lists/american-headache-society/ |access-date = 10 December 2013 |url-status = dead |archive-url = https://web.archive.org/web/20131203001051/http://www.choosingwisely.org/doctor-patient-lists/american-headache-society/ |archive-date = 3 December 2013 |df = dmy-all }}, which cites

• {{cite journal | vauthors = Bigal ME, Lipton RB | title = Excessive opioid use and the development of chronic migraine | journal = Pain | volume = 142 | issue = 3 | pages = 179–82 | date = April 2009 | pmid = 19232469 | doi = 10.1016/j.pain.2009.01.013 | s2cid = 27949021 }}
• {{cite journal | vauthors = Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB | title = Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study | journal = Headache | volume = 48 | issue = 8 | pages = 1157–68 | date = September 2008 | pmid = 18808500 | doi = 10.1111/j.1526-4610.2008.01217.x | doi-access = free }}
• {{cite journal | vauthors = Scher AI, Stewart WF, Ricci JA, Lipton RB | title = Factors associated with the onset and remission of chronic daily headache in a population-based study | journal = Pain | volume = 106 | issue = 1–2 | pages = 81–9 | date = November 2003 | pmid = 14581114 | doi = 10.1016/S0304-3959(03)00293-8 | s2cid = 29000302 | url = https://zenodo.org/record/1260009 }}
• {{cite journal | vauthors = Katsarava Z, Schneeweiss S, Kurth T, Kroener U, Fritsche G, Eikermann A, Diener HC, Limmroth V | title = Incidence and predictors for chronicity of headache in patients with episodic migraine | journal = Neurology | volume = 62 | issue = 5 | pages = 788–90 | date = March 2004 | pmid = 15007133 | doi = 10.1212/01.WNL.0000113747.18760.D2 | s2cid = 20759425 }} Opioids can also cause heightened sensitivity to headache pain. When other treatments fail or are unavailable, opioids may be appropriate for treating headache if the patient can be monitored to prevent the development of chronic headache.

Opioids are being used more frequently in the management of non-malignant chronic pain.{{cite journal | vauthors = Manchikanti L, Helm S, Fellows B, Janata JW, Pampati V, Grider JS, Boswell MV | title = Opioid epidemic in the United States | journal = Pain Physician | volume = 15 | issue = 3 Suppl | pages = ES9-38 | date = July 2012 | doi = 10.36076/ppj.2012/15/ES9 | pmid = 22786464 | doi-access = free }}{{cite journal | vauthors = Chou R, Ballantyne JC, Fanciullo GJ, Fine PG, Miaskowski C | title = Research gaps on use of opioids for chronic noncancer pain: findings from a review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline | journal = The Journal of Pain | volume = 10 | issue = 2 | pages = 147–59 | date = February 2009 | pmid = 19187891 | doi = 10.1016/j.jpain.2008.10.007 | doi-access = free }}{{cite web |url=http://www.painjournalonline.com/article/S0304-3959(06)00316-2/abstract |title=PAIN |publisher=Painjournalonline.com |date=1 September 2015 |access-date=7 January 2016 |archive-date=6 August 2020 |archive-url=https://web.archive.org/web/20200806025801/http://journals.lww.com/pain/pages/default.aspx |url-status=live }} This practice has now led to a new and growing problem with addiction and misuse of opioids.{{cite journal | vauthors = Kissin I | title = Long-term opioid treatment of chronic nonmalignant pain: unproven efficacy and neglected safety? | journal = Journal of Pain Research | volume = 6 | pages = 513–29 | date = 28 September 2015 | pmid = 23874119 | pmc = 3712997 | doi = 10.2147/JPR.S47182 | doi-access = free }} Because of various negative effects the use of opioids for long-term management of chronic pain is not indicated unless other less risky pain relievers have been found ineffective. Chronic pain which occurs only periodically, such as that from nerve pain, migraines, and fibromyalgia, frequently is better treated with medications other than opioids. Paracetamol and nonsteroidal anti-inflammatory drugs including ibuprofen and naproxen are considered safer alternatives.{{cite journal | vauthors = Dhalla IA, Gomes T, Mamdani MM, Juurlink DN | title = Opioids versus nonsteroidal anti-inflammatory drugs in noncancer pain | journal = Canadian Family Physician | volume = 58 | issue = 1 | pages = 30 | date = January 2012 | pmid = 22267615 | pmc = 3264005 }} They are frequently used combined with opioids, such as paracetamol combined with oxycodone (Percocet) and ibuprofen combined with hydrocodone (Vicoprofen), which boosts the pain relief but is also intended to deter recreational use.{{cite journal | vauthors = Marret E, Beloeil H, Lejus C | title = [What are the benefits and risk of non-opioid analgesics combined with postoperative opioids?] | journal = Annales Françaises d'Anesthésie et de Réanimation | volume = 28 | issue = 3 | pages = e135-51 | date = March 2009 | pmid = 19304445 | doi = 10.1016/j.annfar.2009.01.006 }}{{cite journal | vauthors = Franceschi F, Iacomini P, Marsiliani D, Cordischi C, Antonini EF, Alesi A, Giacobelli D, Zuccalà G | title = Safety and efficacy of the combination acetaminophen-codeine in the treatment of pain of different origin | journal = European Review for Medical and Pharmacological Sciences | volume = 17 | issue = 16 | pages = 2129–35 | date = August 2013 | pmid = 23893177 | url = http://www.europeanreview.org/wp/wp-content/uploads/2129-2135.pdf | access-date = 26 February 2016 | archive-date = 26 October 2020 | archive-url = https://web.archive.org/web/20201026093553/http://www.europeanreview.org/wp/wp-content/uploads/2129-2135.pdf | url-status = live }}

Codeine was once viewed as the "gold standard" in cough suppressants, but this position is now questioned.{{cite book| first1 = K. Fan | last1 = Chung | first2 = John | last2 = Widdicombe |title=Pharmacology and therapeutics of cough|year=2008|publisher=Springer|location=Berlin|isbn=978-3-540-79842-2|page=248|url=https://books.google.com/books?id=Z4kXCSRq0OAC&pg=PA248}} Some recent placebo-controlled trials have found that it may be no better than a placebo for some causes including acute cough in children.{{cite journal | vauthors = Bolser DC, Davenport PW | title = Codeine and cough: an ineffective gold standard | journal = Current Opinion in Allergy and Clinical Immunology | volume = 7 | issue = 1 | pages = 32–6 | date = February 2007 | pmid = 17218808 | pmc = 2921574 | doi = 10.1097/ACI.0b013e3280115145 }} As a consequence, it is not recommended for children.{{cite journal | vauthors = Goldman RD | title = Codeine for acute cough in children | journal = Canadian Family Physician | volume = 56 | issue = 12 | pages = 1293–4 | date = December 2010 | pmid = 21156892 | pmc = 3001921 }} Additionally, there is no evidence that hydrocodone is useful in children.{{cite journal | vauthors = Paul IM | title = Therapeutic options for acute cough due to upper respiratory infections in children | journal = Lung | volume = 190 | issue = 1 | pages = 41–4 | date = February 2012 | pmid = 21892785 | doi = 10.1007/s00408-011-9319-y | s2cid = 23865647 }} Similarly, a 2012 Dutch guideline regarding the treatment of acute cough does not recommend its use.{{cite journal | vauthors = Verlee L, Verheij TJ, Hopstaken RM, Prins JM, Salomé PL, Bindels PJ | title = [Summary of NHG practice guideline 'Acute cough'] | journal = Nederlands Tijdschrift voor Geneeskunde | volume = 156 | pages = A4188 | date = 2012 | pmid = 22917039 }} (The opioid analogue dextromethorphan, long claimed to be as effective a cough suppressant as codeine,{{cite journal | vauthors = Matthys H, Bleicher B, Bleicher U | title = Dextromethorphan and codeine: objective assessment of antitussive activity in patients with chronic cough | journal = The Journal of International Medical Research | volume = 11 | issue = 2 | pages = 92–100 | date = 1983 | pmid = 6852361 | doi = 10.1177/030006058301100206 | s2cid = 30521239 }} has similarly demonstrated little benefit in several recent studies.{{Cite web|url=http://www.medscape.com/viewarticle/803288|title=Do Cough Remedies Work?|website=Medscape|access-date=10 April 2016|vauthors=Van Amburgh JA|archive-date=31 March 2019|archive-url=https://web.archive.org/web/20190331131156/https://www.medscape.com/viewarticle/803288|url-status=live}})

Low dose morphine may help chronic cough but its use is limited by side effects.{{cite journal | vauthors = Bolser DC | title = Pharmacologic management of cough | journal = Otolaryngologic Clinics of North America | volume = 43 | issue = 1 | pages = 147–55, xi | date = February 2010 | pmid = 20172264 | pmc = 2827356 | doi = 10.1016/j.otc.2009.11.008 }}

In cases of diarrhea-predominate irritable bowel syndrome, opioids may be used to suppress diarrhea.{{Cite journal |date=2017-09-02 |title=Opioids in Gastroenterology: Treating Adverse Effects and Creating Therapeutic Benefits |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC5565678/ |journal=Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association |volume=15 |issue=9 |pages=1338–1349 |doi=10.1016/j.cgh.2017.05.014 |issn=1542-7714 |pmc=5565678 |pmid=28529168}} Loperamide is a peripherally selective opioid available without a prescription used to suppress diarrhea.

The ability to suppress diarrhea also produces constipation when opioids are used beyond several weeks.{{cite journal | vauthors = Webster LR | title = Opioid-Induced Constipation | journal = Pain Medicine | volume = 16 | pages = S16-21 | date = October 2015 | issue = Suppl 1 | pmid = 26461071 | doi = 10.1111/pme.12911 | doi-access = free }} Naloxegol, a peripherally-selective opioid antagonist is now available to treat opioid induced constipation.{{Cite web|title = Press Announcements - FDA approves Movantik for opioid-induced constipation|url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm414620.htm|website = www.fda.gov|access-date = 18 February 2016|archive-date = 16 February 2017|archive-url = https://web.archive.org/web/20170216212729/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm414620.htm|url-status = live}}

Opioids may help with shortness of breath particularly in advanced diseases such as cancer and COPD among others.{{cite journal | vauthors = Gallagher R | title = The use of opioids for dyspnea in advanced disease | journal = CMAJ | volume = 183 | issue = 10 | pages = 1170 | date = July 2011 | pmid = 21746829 | pmc = 3134725 | doi = 10.1503/cmaj.110024 }}{{cite journal | vauthors = Wiseman R, Rowett D, Allcroft P, Abernethy A, Currow DC | title = Chronic refractory dyspnoea--evidence based management | journal = Australian Family Physician | volume = 42 | issue = 3 | pages = 137–40 | date = March 2013 | pmid = 23529525 }} However, findings from two recent systematic reviews of the literature found that opioids were not necessarily more effective in treating shortness of breath in patients who have advanced cancer.{{cite journal | title = Interventions for Breathlessness in Patients With Advanced Cancer | journal =JAMA Oncology | date = 2020-11-19 | pmid = 33289989 | doi = 10.23970/ahrqepccer232 | last1 = Dy | first1 = Sydney M. | last2 = Gupta | first2 = Arjun | last3 = Waldfogel | first3 = Julie M. | last4 = Sharma | first4 = Ritu | last5 = Zhang | first5 = Allen | last6 = Feliciano | first6 = Josephine L. | last7 = Sedhom | first7 = Ramy | last8 = Day | first8 = Jeff | last9 = Gersten | first9 = Rebecca A. | last10 = Davidson | first10 = Patricia M. | last11 = Bass | first11 = Eric B. | doi-access = free }}{{cite journal | vauthors = Feliciano JL, Waldfogel JM, Sharma R, Zhang A, Gupta A, Sedhom R, Day J, Bass EB, Dy SM | title = Pharmacologic Interventions for Breathlessness in Patients With Advanced Cancer: A Systematic Review and Meta-analysis | journal = JAMA Network Open | volume = 4 | issue = 2 | pages = e2037632 | date = February 2021 | pmid = 33630086 | pmc = 7907959 | doi = 10.1001/jamanetworkopen.2020.37632 }}

Though not typically a first line of treatment, opioids, such as oxycodone and methadone, are sometimes used in the treatment of severe and refractory restless legs syndrome.{{Cite web |title=Restless Legs Syndrome {{!}} Baylor Medicine |url=https://www.bcm.edu/healthcare/specialties/neurology/parkinsons-disease-and-movement-disorders/restless-legs-syndrome |access-date=2023-11-06 |website=www.bcm.edu |language=en |archive-date=5 November 2023 |archive-url=https://web.archive.org/web/20231105232250/https://www.bcm.edu/healthcare/specialties/neurology/parkinsons-disease-and-movement-disorders/restless-legs-syndrome |url-status=live }}

Hyperalgesia

{{main|Opioid-induced hyperalgesia}}

Opioid-induced hyperalgesia (OIH) has been evident in patients after chronic opioid exposure.{{cite journal | vauthors = Higgins C, Smith BH, Matthews K | title = Evidence of opioid-induced hyperalgesia in clinical populations after chronic opioid exposure: a systematic review and meta-analysis | journal = British Journal of Anaesthesia | volume = 122 | issue = 6 | pages = e114–e126 | date = June 2019 | pmid = 30915985 | doi = 10.1016/j.bja.2018.09.019 | s2cid = 81293413 | url = https://discovery.dundee.ac.uk/ws/files/28488556/3rd_submission.pdf | access-date = 24 April 2020 | archive-date = 18 September 2020 | archive-url = https://web.archive.org/web/20200918073747/https://discovery.dundee.ac.uk/ws/files/28488556/3rd_submission.pdf | url-status = live }}{{Cite journal|last1=Yang|first1=David Z.|last2=Sin|first2=Billy|last3=Beckhusen|first3=Joshua|last4=Xia|first4=Dawei|last5=Khaimova|first5=Rebecca|last6=Iliev|first6=Ilia|date=May–June 2019 |title=Opioid-Induced Hyperalgesia in the Nonsurgical Setting: A Systematic Review|journal=American Journal of Therapeutics|volume=26|issue=3|pages=e397–e405|doi=10.1097/MJT.0000000000000734|issn=1536-3686|pmid=29726847|s2cid=19181545}}

{{See also|Opioid overdose}}{{quote box

| title = Adverse effects of opioids|Common and short term

• Itching
• Nausea
• Vomiting
• Constipation
• Drowsiness
• Dry mouth

Other

• Cognitive effects
• Opioid dependence
• Dizziness
• Loss of appetite
• Delayed gastric emptying
• Decreased sex drive
• Impaired sexual function
• Decreased testosterone levels
• Depression
• Immunodeficiency
• Increased pain sensitivity
• Irregular menstruation
• Increased risk of falls
• Slowed breathing
• Coma

}}

Each year 69,000 people worldwide die of opioid overdose, and 15 million people have an opioid addiction.{{cite journal | vauthors = Parthvi R, Agrawal A, Khanijo S, Tsegaye A, Talwar A | title = Acute Opiate Overdose: An Update on Management Strategies in Emergency Department and Critical Care Unit | journal = American Journal of Therapeutics | volume = 26 | issue = 3 | pages = e380–e387 | date = May–June 2019 | pmid = 28952972 | doi = 10.1097/MJT.0000000000000681 | s2cid = 24720660 }}

In older adults, opioid use is associated with increased adverse effects such as "sedation, nausea, vomiting, constipation, urinary retention, and falls".{{cite journal | vauthors = Baumann S | title = A nursing approach to pain in older adults | journal = Medsurg Nursing | volume = 18 | issue = 2 | pages = 77–82; quiz 83 | year = 2009 | pmid = 19489204 }} As a result, older adults taking opioids are at greater risk for injury.{{cite journal | vauthors = Buckeridge D, Huang A, Hanley J, Kelome A, Reidel K, Verma A, Winslade N, Tamblyn R | title = Risk of injury associated with opioid use in older adults | journal = Journal of the American Geriatrics Society | volume = 58 | issue = 9 | pages = 1664–70 | date = September 2010 | pmid = 20863326 | doi = 10.1111/j.1532-5415.2010.03015.x | s2cid = 25941322 }} Opioids do not cause any specific organ toxicity, unlike many other drugs, such as aspirin and paracetamol. They are not associated with upper gastrointestinal bleeding and kidney toxicity.{{cite journal | vauthors = Schneider JP | url = http://www.musculoskeletalnetwork.com/pain/content/article/1145622/1551411 | title = Rational use of opioid analgesics in chronic musculoskeletal pain | journal = J Musculoskel Med | date = 2010 | volume = 27 | pages = 142–148 | access-date = 14 April 2010 | archive-date = 3 March 2012 | archive-url = https://web.archive.org/web/20120303062000/http://www.musculoskeletalnetwork.com/pain/content/article/1145622/1551411 | url-status = live }}

Prescription of opioids for acute low back pain and management of osteoarthritis seem to have long-term adverse effects{{cite journal | vauthors = Sanger N, Bhatt M, Singhal N, Ramsden K, Baptist-Mohseni N, Panesar B, Shahid H, Hillmer A, D Elia A, Luo C, Rogers V, Arunan A, Baker-Beal L, Haber S, Henni J, Puckering M, Sun S, Ng K, Sanger S, Mouravaska N, Samaan MC, de Souza R, Thabane L, Samaan Z | title = Adverse Outcomes Associated with Prescription Opioids for Acute Low Back Pain: A Systematic Review and Meta-Analysis | journal = Pain Physician | volume = 22 | issue = 2 | pages = 119–138 | date = March 2019 | pmid = 30921976 }}{{cite journal | vauthors = Fuggle N, Curtis E, Shaw S, Spooner L, Bruyère O, Ntani G, Parsons C, Conaghan PG, Corp N, Honvo G, Uebelhart D, Baird J, Dennison E, Reginster JY, Cooper C | title = Safety of Opioids in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis | journal = Drugs & Aging | volume = 36 | issue = Suppl 1 | pages = 129–143 | date = April 2019 | pmid = 31073926 | pmc = 6509215 | doi = 10.1007/s40266-019-00666-9 }}

According to the USCDC, methadone was involved in 31% of opioid related deaths in the US between 1999–2010 and 40% as the sole drug involved, far higher than other opioids.{{Cite journal|url = http://emedicine.medscape.com/article/815784-overview#showall|title = Opioid Toxicity|date = 23 November 2015|access-date = 24 February 2016|website = Medscape|last = Stephens|first = Everett|quote = The CDC reported that methadone contributed to 31.4% of opioid-related deaths in the United States from 1999–2010. Methadone also accounted for 39.8% of all single-drug opioid-related deaths. The overdose death rate associated with methadone was significantly higher than that associated with other opioid-related deaths among multidrug and single-drug deaths.|archive-date = 4 December 2020|archive-url = https://web.archive.org/web/20201204205814/https://emedicine.medscape.com/article/815784-overview#showall|url-status = live}} Studies of long term opioids have found that many stop them, and that minor side effects were common.{{cite journal | vauthors = Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C, Schoelles KM | title = Long-term opioid management for chronic noncancer pain | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD006605 | date = January 2010 | volume = 2018 | pmid = 20091598 | pmc = 6494200 | doi = 10.1002/14651858.CD006605.pub2 | veditors = Noble M }} Addiction occurred in about 0.3%. In the United States in 2016 opioid overdose resulted in the death of 1.7 in 10,000 people.{{cite web|title=Drug Overdose Deaths in the United States, 1999–2016|url=https://www.cdc.gov/nchs/data/databriefs/db294.pdf|website=CDC|access-date=23 December 2017|archive-date=16 January 2021|archive-url=https://web.archive.org/web/20210116031228/https://www.cdc.gov/nchs/data/databriefs/db294.pdf|url-status=live}}

{{Main|Opioid use disorder}}

Tolerance is a process characterized by neuroadaptations that result in reduced drug effects. While receptor upregulation may often play an important role other mechanisms are also known.{{cite journal | vauthors = Pradhan AA, Walwyn W, Nozaki C, Filliol D, Erbs E, Matifas A, Evans C, Kieffer BL | title = Ligand-directed trafficking of the δ-opioid receptor in vivo: two paths toward analgesic tolerance | journal = The Journal of Neuroscience | volume = 30 | issue = 49 | pages = 16459–68 | date = December 2010 | pmid = 21147985 | pmc = 3086517 | doi = 10.1523/JNEUROSCI.3748-10.2010 }} Tolerance is more pronounced for some effects than for others; tolerance occurs slowly to the effects on mood, itching, urinary retention, and respiratory depression, but occurs more quickly to the analgesia and other physical side effects. However, tolerance does not develop to constipation or miosis (the constriction of the pupil of the eye to less than or equal to two millimeters). This idea has been challenged, however, with some authors arguing that tolerance does develop to miosis.{{cite journal | vauthors = Kollars JP, Larson MD | title = Tolerance to miotic effects of opioids | journal = Anesthesiology | volume = 102 | issue = 3 | pages = 701 | date = March 2005 | pmid = 15731628 | doi = 10.1097/00000542-200503000-00047 | doi-access = free }}

Tolerance to opioids is attenuated by a number of substances, including:

• calcium channel blockers{{cite journal | vauthors = Santillán R, Maestre JM, Hurlé MA, Flórez J | title = Enhancement of opiate analgesia by nimodipine in cancer patients chronically treated with morphine: a preliminary report | journal = Pain | volume = 58 | issue = 1 | pages = 129–32 | date = July 1994 | pmid = 7970835 | doi = 10.1016/0304-3959(94)90192-9 | s2cid = 35138704 }}{{cite journal | vauthors = Santillán R, Hurlé MA, Armijo JA, de los Mozos R, Flórez J | title = Nimodipine-enhanced opiate analgesia in cancer patients requiring morphine dose escalation: a double-blind, placebo-controlled study | journal = Pain | volume = 76 | issue = 1–2 | pages = 17–26 | date = May 1998 | pmid = 9696455 | doi = 10.1016/S0304-3959(98)00019-0 | s2cid = 30963675 }}{{cite journal | vauthors = Smith FL, Dombrowski DS, Dewey WL | title = Involvement of intracellular calcium in morphine tolerance in mice | journal = Pharmacology, Biochemistry, and Behavior | volume = 62 | issue = 2 | pages = 381–8 | date = February 1999 | pmid = 9972707 | doi = 10.1016/S0091-3057(98)00168-3 | s2cid = 37434490 }}
• intrathecal magnesium{{cite journal | vauthors = McCarthy RJ, Kroin JS, Tuman KJ, Penn RD, Ivankovich AD | title = Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats | journal = Anesthesia and Analgesia | volume = 86 | issue = 4 | pages = 830–6 | date = April 1998 | pmid = 9539610 | doi = 10.1097/00000539-199804000-00028 | url = http://www.anesthesia-analgesia.org/cgi/reprint/86/4/830 | doi-access = free | access-date = 12 November 2007 | archive-date = 11 February 2010 | archive-url = https://web.archive.org/web/20100211210920/http://www.anesthesia-analgesia.org/cgi/reprint/86/4/830 | url-status = live }}{{cite journal | vauthors = Morrison AP, Hunter JM, Halpern SH, Banerjee A | title = Effect of intrathecal magnesium in the presence or absence of local anaesthetic with and without lipophilic opioids: a systematic review and meta-analysis | journal = British Journal of Anaesthesia | volume = 110 | issue = 5 | pages = 702–12 | date = May 2013 | pmid = 23533255 | doi = 10.1093/bja/aet064 | doi-access = free }} and zinc{{cite journal | vauthors = Larson AA, Kovács KJ, Spartz AK | title = Intrathecal Zn2+ attenuates morphine antinociception and the development of acute tolerance | journal = European Journal of Pharmacology | volume = 407 | issue = 3 | pages = 267–72 | date = November 2000 | pmid = 11068022 | doi = 10.1016/S0014-2999(00)00715-9 }}
• NMDA antagonists, such as dextromethorphan, ketamine,{{cite journal | vauthors = Wong CS, Cherng CH, Luk HN, Ho ST, Tung CS | title = Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at mu-opioid receptors | journal = European Journal of Pharmacology | volume = 297 | issue = 1–2 | pages = 27–33 | date = February 1996 | pmid = 8851162 | doi = 10.1016/0014-2999(95)00728-8 }} and memantine.{{cite journal | vauthors = Malec D, Mandryk M, Fidecka S | title = Interaction of memantine and ketamine in morphine- and pentazocine-induced antinociception in mice | journal = Pharmacological Reports | volume = 60 | issue = 2 | pages = 149–55 | date = Mar–Apr 2008 | pmid = 18443375 | url = http://www.if-pan.krakow.pl/pjp/pdf/2008/2_149.pdf | access-date = 17 September 2011 | archive-date = 30 September 2020 | archive-url = https://web.archive.org/web/20200930223437/http://www.if-pan.krakow.pl/pjp/pdf/2008/2_149.pdf | url-status = live }}
• cholecystokinin antagonists, such as proglumide{{cite journal | vauthors = McCleane GJ | title = The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine | journal = The Clinical Journal of Pain | volume = 19 | issue = 3 | pages = 200–1 | year = 2003 | pmid = 12792559 | doi = 10.1097/00002508-200305000-00008 | s2cid = 29229782 }}{{cite journal | vauthors = Watkins LR, Kinscheck IB, Mayer DJ | title = Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide | journal = Science | volume = 224 | issue = 4647 | pages = 395–6 | date = April 1984 | pmid = 6546809 | doi = 10.1126/science.6546809 | bibcode = 1984Sci...224..395W }}{{cite journal | vauthors = Tang J, Chou J, Iadarola M, Yang HY, Costa E | title = Proglumide prevents and curtails acute tolerance to morphine in rats | journal = Neuropharmacology | volume = 23 | issue = 6 | pages = 715–8 | date = June 1984 | pmid = 6462377 | doi = 10.1016/0028-3908(84)90171-0 | s2cid = 33168040 }}
• Newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.{{cite journal | vauthors = Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW | title = Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes | journal = Expert Opinion on Investigational Drugs | volume = 16 | issue = 7 | pages = 935–50 | date = July 2007 | pmid = 17594181 | doi = 10.1517/13543784.16.7.935 | s2cid = 22321634 }}

Tolerance is a physiologic process where the body adjusts to a medication that is frequently present, usually requiring higher doses of the same medication over time to achieve the same effect. It is a common occurrence in individuals taking high doses of opioids for extended periods, but does not predict any relationship to misuse or addiction.

Physical dependence is the physiological adaptation of the body to the presence of a substance, in this case opioid medication. It is defined by the development of withdrawal symptoms when the substance is discontinued, when the dose is reduced abruptly or, specifically in the case of opioids, when an antagonist (e.g., naloxone) or an agonist-antagonist (e.g., pentazocine) is administered. Physical dependence is a normal and expected aspect of certain medications and does not necessarily imply that the patient is addicted.

The withdrawal symptoms for opiates may include severe dysphoria, craving for another opiate dose, irritability, sweating, nausea, rhinorrea, tremor, vomiting and myalgia. Slowly reducing the intake of opioids over days and weeks can reduce or eliminate the withdrawal symptoms. The speed and severity of withdrawal depends on the half-life of the opioid; heroin and morphine withdrawal occur more quickly than methadone withdrawal. The acute withdrawal phase is often followed by a protracted phase of depression and insomnia that can last for months. The symptoms of opioid withdrawal can be treated with other medications, such as clonidine.{{cite journal | vauthors = Hermann D, Klages E, Welzel H, Mann K, Croissant B | title = Low efficacy of non-opioid drugs in opioid withdrawal symptoms | journal = Addiction Biology | volume = 10 | issue = 2 | pages = 165–9 | date = June 2005 | pmid = 16191669 | doi = 10.1080/13556210500123514 | s2cid = 8017503 }} Physical dependence does not predict drug misuse or true addiction, and is closely related to the same mechanism as tolerance. While there is anecdotal claims of benefit with ibogaine, data to support its use in substance dependence is poor.{{cite journal | vauthors = Brown TK | title = Ibogaine in the treatment of substance dependence | journal = Current Drug Abuse Reviews | volume = 6 | issue = 1 | pages = 3–16 | date = March 2013 | pmid = 23627782 | doi = 10.2174/15672050113109990001 }}

Critical patients who received regular doses of opioids experience iatrogenic withdrawal as a frequent syndrome.{{Cite journal|last1=Duceppe|first1=Marc-Alexandre|last2=Perreault|first2=Marc M.|last3=Frenette|first3=Anne Julie|last4=Burry|first4=Lisa D.|last5=Rico|first5=Philippe|last6=Lavoie|first6=Annie|last7=Gélinas|first7=Céline|last8=Mehta|first8=Sangeeta|last9=Dagenais|first9=Maryse|last10=Williamson|first10=David R.|date=April 2019|title=Frequency, risk factors and symptomatology of iatrogenic withdrawal from opioids and benzodiazepines in critically Ill neonates, children and adults: A systematic review of clinical studies|journal=Journal of Clinical Pharmacy and Therapeutics|volume=44|issue=2|pages=148–156|doi=10.1111/jcpt.12787|issn=1365-2710|pmid=30569508|doi-access=free}}

Drug addiction is a complex set of behaviors typically associated with misuse of certain drugs, developing over time and with higher drug dosages. Addiction includes psychological compulsion, to the extent that the affected person persists in actions leading to dangerous or unhealthy outcomes. Opioid addiction includes insufflation or injection, rather than taking opioids orally as prescribed for medical reasons.

In European nations such as Austria, Bulgaria, and Slovakia, slow-release oral morphine formulations are used in opiate substitution therapy (OST) for patients who do not well tolerate the side effects of buprenorphine or methadone. Buprenorphine can also be used together with naloxone for a longer treatment of addiction. In other European countries including the UK, this is also legally used for OST although on a varying scale of acceptance.

Slow-release formulations of medications are intended to curb misuse and lower addiction rates while trying to still provide legitimate pain relief and ease of use to pain patients. Questions remain, however, about the efficacy and safety of these types of preparations. Further tamper resistant medications are currently under consideration with trials for market approval by the FDA.{{cite journal | vauthors = Bannwarth B | title = Will abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose? | journal = Drugs | volume = 72 | issue = 13 | pages = 1713–23 | date = September 2012 | pmid = 22931520 | doi = 10.2165/11635860-000000000-00000 | s2cid = 26082561 }}{{cite journal | vauthors = Schneider JP, Matthews M, Jamison RN | title = Abuse-deterrent and tamper-resistant opioid formulations: what is their role in addressing prescription opioid abuse? | journal = CNS Drugs | volume = 24 | issue = 10 | pages = 805–10 | date = October 2010 | pmid = 20839893 | doi = 10.2165/11584260-000000000-00000 | s2cid = 17830622 }}

The amount of evidence available only permits making a weak conclusion, but it suggests that a physician properly managing opioid use in patients with no history of substance use disorder can give long-term pain relief with little risk of developing addiction, or other serious side effects.

Problems with opioids include the following:

1. Some people find that opioids do not relieve all of their pain.{{cite journal | vauthors = Xu Y, Johnson A | title = Opioid therapy pharmacogenomics for noncancer pain: efficacy, adverse events, and costs | journal = Pain Research and Treatment | volume = 2013 | pages = 943014 | year = 2013 | pmid = 24167729 | pmc = 3791560 | doi = 10.1155/2013/943014 | doi-access = free }}
2. Some people find that opioids side effects cause problems which outweigh the therapy's benefit.
3. Some people build tolerance to opioids over time. This requires them to increase their drug dosage to maintain the benefit, and that in turn also increases the unwanted side effects.
4. Long-term opioid use can cause opioid-induced hyperalgesia, which is a condition in which the patient has increased sensitivity to pain.{{cite journal | vauthors = Brush DE | title = Complications of long-term opioid therapy for management of chronic pain: the paradox of opioid-induced hyperalgesia | journal = Journal of Medical Toxicology | volume = 8 | issue = 4 | pages = 387–92 | date = December 2012 | pmid = 22983894 | pmc = 3550256 | doi = 10.1007/s13181-012-0260-0 }}

All of the opioids can cause side effects.{{cite journal | vauthors = Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E | title = Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects | journal = CMAJ | volume = 174 | issue = 11 | pages = 1589–94 | date = May 2006 | pmid = 16717269 | pmc = 1459894 | doi = 10.1503/cmaj.051528 }} Common adverse reactions in patients taking opioids for pain relief include nausea and vomiting, drowsiness, itching, dry mouth, dizziness, and constipation.{{cite book | veditors = Doyle D, Hanks G, Cherney I, Calman K |title=Oxford Textbook of Palliative Medicine |publisher=Oxford University Press |year=2004 |isbn=978-0-19-856698-4 |edition=3rd}}

Tolerance to nausea occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol once at night) are very effective.{{Citation needed|date=November 2010}} Due to severe side effects such as tardive dyskinesia, haloperidol is now rarely used. A related drug, prochlorperazine is more often used, although it has similar risks. Stronger antiemetics such as ondansetron or tropisetron are sometimes used when nausea is severe or continuous and disturbing, despite their greater cost. A less expensive alternative is dopamine antagonists such as domperidone and metoclopramide. Domperidone does not cross the blood–brain barrier and produce adverse central antidopaminergic effects, but blocks opioid emetic action in the chemoreceptor trigger zone. This drug is not available in the U.S.

Some antihistamines with anticholinergic properties (e.g. orphenadrine, diphenhydramine) may also be effective. The first-generation antihistamine hydroxyzine is very commonly used, with the added advantages of not causing movement disorders, and also possessing analgesic-sparing properties. Δ⁹-tetrahydrocannabinol relieves nausea and vomiting;{{cite journal | vauthors = Malik Z, Baik D, Schey R | title = The role of cannabinoids in regulation of nausea and vomiting, and visceral pain | journal = Current Gastroenterology Reports | volume = 17 | issue = 2 | pages = 429 | date = February 2015 | pmid = 25715910 | doi = 10.1007/s11894-015-0429-1 | s2cid = 32705478 }}{{cite journal | vauthors = Abrams DI, Guzman M | title = Cannabis in cancer care | journal = Clinical Pharmacology and Therapeutics | volume = 97 | issue = 6 | pages = 575–86 | date = June 2015 | pmid = 25777363 | doi = 10.1002/cpt.108 | s2cid = 2488112 }} it also produces analgesia that may allow lower doses of opioids with reduced nausea and vomiting.{{Cite web|url=https://www.ucsf.edu/news/2011/12/11077/ucsf-study-finds-medical-marijuana-could-help-patients-reduce-pain-opiates|title=UCSF Study Finds Medical Marijuana Could Help Patients Reduce Pain with Opiates|website=UC San Francisco|date=6 December 2011|access-date=4 March 2016|archive-date=17 December 2020|archive-url=https://web.archive.org/web/20201217075151/https://www.ucsf.edu/news/2011/12/11077/ucsf-study-finds-medical-marijuana-could-help-patients-reduce-pain-opiates|url-status=live}}{{cite journal | vauthors = Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL | title = Cannabinoid-opioid interaction in chronic pain | journal = Clinical Pharmacology and Therapeutics | volume = 90 | issue = 6 | pages = 844–51 | date = December 2011 | pmid = 22048225 | doi = 10.1038/clpt.2011.188 | s2cid = 4823659 }}

• 5-HT₃ antagonists (e.g. ondansetron)
• Dopamine antagonists (e.g. domperidone)
• Anti-cholinergic antihistamines (e.g. diphenhydramine)
• Δ⁹-tetrahydrocannabinol (e.g. dronabinol)

Vomiting is due to gastric stasis (large volume vomiting, brief nausea relieved by vomiting, oesophageal reflux, epigastric fullness, early satiation), besides direct action on the chemoreceptor trigger zone of the area postrema, the vomiting centre of the brain. Vomiting can thus be prevented by prokinetic agents (e.g. domperidone or metoclopramide). If vomiting has already started, these drugs need to be administered by a non-oral route (e.g. subcutaneous for metoclopramide, rectally for domperidone).

• Prokinetic agents (e.g. domperidone)
• Anti-cholinergic agents (e.g. orphenadrine)

Evidence suggests that opioid-inclusive anaesthesia is associated with postoperative nausea and vomiting.{{cite journal | vauthors = Frauenknecht J, Kirkham KR, Jacot-Guillarmod A, Albrecht E | title = Analgesic impact of intra-operative opioids vs. opioid-free anaesthesia: a systematic review and meta-analysis | journal = Anaesthesia | volume = 74 | issue = 5 | pages = 651–662 | date = May 2019 | pmid = 30802933 | doi = 10.1111/anae.14582 | s2cid = 73469631 | url = https://serval.unil.ch/notice/serval:BIB_6A01A1CDCF6A | doi-access = free | access-date = 15 September 2022 | archive-date = 15 December 2023 | archive-url = https://web.archive.org/web/20231215100415/https://serval.unil.ch/en/notice/serval:BIB_6A01A1CDCF6A | url-status = live }}

Patients with chronic pain using opioids had small improvements in pain and physically functioning and increased risk of vomiting.{{Cite journal|last1=Busse|first1=Jason W.|last2=Wang|first2=Li|last3=Kamaleldin|first3=Mostafa|last4=Craigie|first4=Samantha|last5=Riva|first5=John J.|last6=Montoya|first6=Luis|last7=Mulla|first7=Sohail M.|last8=Lopes|first8=Luciane C.|last9=Vogel|first9=Nicole|last10=Chen|first10=Eric|last11=Kirmayr|first11=Karin|date=2018-12-18|title=Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis|journal=JAMA|language=en|volume=320|issue=23|pages=2448–2460|doi=10.1001/jama.2018.18472|pmid=30561481|pmc=6583638|issn=0098-7484|doi-access=free}}

Tolerance to drowsiness usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps. Certain opioids such as fentanyl, morphine and diamorphine (heroin) tend to be particularly sedating, while others such as oxycodone, codeine, and tilidine tend to produce comparatively less sedation, but individual patients responses can vary markedly and some degree of trial and error may be needed to find the most suitable drug for a particular patient. Otherwise, treatment with CNS stimulants is generally effective.{{cite journal | vauthors = Reissig JE, Rybarczyk AM | title = Pharmacologic treatment of opioid-induced sedation in chronic pain | journal = The Annals of Pharmacotherapy | volume = 39 | issue = 4 | pages = 727–31 | date = April 2005 | pmid = 15755795 | doi = 10.1345/aph.1E309 | s2cid = 39058371 }}{{cite journal | vauthors = Corey PJ, Heck AM, Weathermon RA | title = Amphetamines to counteract opioid-induced sedation | journal = The Annals of Pharmacotherapy | volume = 33 | issue = 12 | pages = 1362–6 | date = December 1999 | pmid = 10630837 | doi = 10.1345/aph.19024 | s2cid = 23733242 }}

• Stimulants (e.g. caffeine, modafinil, amphetamine, methylphenidate)

Itching tends not to be a severe problem when opioids are used for pain relief, but antihistamines are useful for counteracting itching when it occurs. Non-sedating antihistamines such as fexofenadine are often preferred as they avoid increasing opioid induced drowsiness. However, some sedating antihistamines such as orphenadrine can produce a synergistic pain relieving effect permitting smaller doses of opioids be used. Consequently, several opioid/antihistamine combination products have been marketed, such as Meprozine (meperidine/promethazine) and Diconal (dipipanone/cyclizine), and these may also reduce opioid induced nausea.

• Antihistamines (e.g. fexofenadine)

Opioid-induced constipation (OIC) develops in 90 to 95% of people taking opioids long-term.{{cite news|author1=Canadian Agency for Drugs and Technologies in Health|title=Dioctyl Sulfosuccinate or Docusate (Calcium or Sodium) for the Prevention or Management of Constipation: A Review of the Clinical Effectiveness|date=26 June 2014|pmid=25520993}} Since tolerance to this problem does not generally develop, most people on long-term opioids need to take a laxative or enemas.{{cite journal | vauthors = McCarberg BH | title = Overview and treatment of opioid-induced constipation | journal = Postgraduate Medicine | volume = 125 | issue = 4 | pages = 7–17 | date = July 2013 | pmid = 23782897 | doi = 10.3810/pgm.2013.07.2651 | s2cid = 42872181 }}

Treatment of OIC is successional and dependent on severity.{{cite journal | vauthors = Kumar L, Barker C, Emmanuel A | title = Opioid-induced constipation: pathophysiology, clinical consequences, and management | journal = Gastroenterology Research and Practice | volume = 2014 | pages = 141737 | year = 2014 | pmid = 24883055 | pmc = 4027019 | doi = 10.1155/2014/141737 | doi-access = free }} The first mode of treatment is non-pharmacological, and includes lifestyle modifications like increasing dietary fiber, fluid intake (around {{convert|1.5|L|usfloz|abbr=on}} per day), and physical activity. If non-pharmacological measures are ineffective, laxatives, including stool softeners (e.g., polyethylene glycol), bulk-forming laxatives (e.g., fiber supplements), stimulant laxatives (e.g., bisacodyl, senna), and/or enemas, may be used. A common laxative regimen for OIC is the combination of docusate and bisacodyl.{{cite book| first1 = Patrick Craig | last1 = Alguire |author2=American College of Physicians|author3=Clerkship Directors in Internal Medicine|title=Internal Medicine Essentials for Clerkship Students 2|url=https://books.google.com/books?id=_oNOMxckD4QC&pg=PA272|year=2009|publisher=ACP Press|isbn=978-1-934465-13-4|pages=272–}}{{cite book| first1 = Jennifer A. | last1 = Elliott | first2 = Howard S. | last2 = Smith |title=Handbook of Acute Pain Management|url=https://books.google.com/books?id=Em7OBQAAQBAJ&pg=PA89|date=19 April 2016|publisher=CRC Press|isbn=978-1-4665-9635-1|pages=89–}}{{update inline|date=August 2019}} Osmotic laxatives, including lactulose, polyethylene glycol, and milk of magnesia (magnesium hydroxide), as well as mineral oil (a lubricant laxative), are also commonly used for OIC.

If laxatives are insufficiently effective (which is often the case),{{cite journal | vauthors = Poulsen JL, Brock C, Olesen AE, Nilsson M, Drewes AM | title = Evolving paradigms in the treatment of opioid-induced bowel dysfunction | journal = Therapeutic Advances in Gastroenterology | volume = 8 | issue = 6 | pages = 360–72 | date = November 2015 | pmid = 26557892 | pmc = 4622283 | doi = 10.1177/1756283X15589526 }} opioid formulations or regimens that include a peripherally-selective opioid antagonist, such as methylnaltrexone bromide, naloxegol, alvimopan, or naloxone (as in oxycodone/naloxone), may be tried.{{cite journal | vauthors = Davis MP, Goforth HW | title = Oxycodone with an opioid receptor antagonist: A review | journal = Journal of Opioid Management | volume = 12 | issue = 1 | pages = 67–85 | year = 2016 | pmid = 26908305 | doi = 10.5055/jom.2016.0313 }} A 2018 (updated in 2022) Cochrane review found that the evidence was moderate for alvimopan, naloxone, or methylnaltrexone bromide but with increased risk of adverse events.{{Cite journal |last1=Candy |first1=Bridget |last2=Jones |first2=Louise |last3=Vickerstaff |first3=Victoria |last4=Larkin |first4=Philip J. |last5=Stone |first5=Patrick |date=2022-09-15 |title=Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care |journal=The Cochrane Database of Systematic Reviews |volume=2022 |issue=9 |pages=CD006332 |doi=10.1002/14651858.CD006332.pub4 |issn=1469-493X |pmc=9476137 |pmid=36106667 }} Naloxone by mouth appears to be the most effective.{{cite journal | vauthors = Luthra P, Burr NE, Brenner DM, Ford AC | title = Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and network meta-analysis | journal = Gut | volume = 68 | issue = 3 | pages = 434–444 | date = May 2018 | pmid = 29730600 | doi = 10.1136/gutjnl-2018-316001 | s2cid = 13677764 | url = http://eprints.whiterose.ac.uk/132159/2/gutjnl-2018-316001R2%20Clean%20copy.pdf | access-date = 23 September 2019 | archive-date = 6 August 2020 | archive-url = https://web.archive.org/web/20200806000501/http://eprints.whiterose.ac.uk/132159/2/gutjnl-2018-316001R2 | url-status = live }} A daily 0.2 mg dose of naldemedine has been shown to significantly improve symptoms in patients with OIC.{{cite journal | vauthors = Esmadi M, Ahmad D, Hewlett A | title = Efficacy of naldemedine for the treatment of opioid-induced constipation: A meta-analysis | journal = Journal of Gastrointestinal and Liver Diseases | volume = 28 | issue = 1 | pages = 41–46 | date = March 2019 | pmid = 30851171 | doi = 10.15403/jgld.2014.1121.281.any | doi-access = free }}

Opioid rotation is one method suggested to minimise the impact of constipation in long-term users.{{cite journal | vauthors = Dorn S, Lembo A, Cremonini F | title = Opioid-induced bowel dysfunction: epidemiology, pathophysiology, diagnosis, and initial therapeutic approach | journal =The American Journal of Gastroenterology Supplements | volume = 2 | issue = 1 | pages = 31–7 | date = September 2014 | pmid = 25207610 | doi = 10.1038/ajgsup.2014.7 }} While all opioids cause constipation, there are some differences between drugs, with studies suggesting tramadol, tapentadol, methadone and fentanyl may cause relatively less constipation, while with codeine, morphine, oxycodone or hydromorphone constipation may be comparatively more severe.

Respiratory depression is the most serious adverse reaction associated with opioid use, but it usually is seen with the use of a single, intravenous dose in an opioid-naïve patient. In patients taking opioids regularly for pain relief, tolerance to respiratory depression occurs rapidly, so that it is not a clinical problem. Several drugs have been developed which can partially block respiratory depression, although the only respiratory stimulant currently approved for this purpose is doxapram, which has only limited efficacy in this application.{{cite journal | vauthors = Yost CS | title = A new look at the respiratory stimulant doxapram | journal = CNS Drug Reviews | volume = 12 | issue = 3–4 | pages = 236–49 | year = 2006 | pmid = 17227289 | pmc = 6506195 | doi = 10.1111/j.1527-3458.2006.00236.x }}{{cite journal | vauthors = Tan ZM, Liu JH, Dong T, Li JX | title = [Clinical observation of target-controlled remifentanil infusion combined with propofol and doxapram in painless artificial abortion] | journal = Nan Fang Yi Ke da Xue Xue Bao = Journal of Southern Medical University | volume = 26 | issue = 8 | pages = 1206–8 | date = August 2006 | pmid = 16939923 }} Newer drugs such as BIMU-8 and CX-546 may be much more effective.{{cite journal | vauthors = Manzke T, Guenther U, Ponimaskin EG, Haller M, Dutschmann M, Schwarzacher S, Richter DW | title = 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia | journal = Science | volume = 301 | issue = 5630 | pages = 226–9 | date = July 2003 | pmid = 12855812 | doi = 10.1126/science.1084674 | bibcode = 2003Sci...301..226M | s2cid = 13641423 }}{{cite journal | vauthors = Wang X, Dergacheva O, Kamendi H, Gorini C, Mendelowitz D | title = 5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function | journal = Hypertension | volume = 50 | issue = 2 | pages = 368–76 | date = August 2007 | pmid = 17576856 | doi = 10.1161/HYPERTENSIONAHA.107.091033 | doi-access = free }}{{cite journal | vauthors = Ren J, Poon BY, Tang Y, Funk GD, Greer JJ | title = Ampakines alleviate respiratory depression in rats | journal = American Journal of Respiratory and Critical Care Medicine | volume = 174 | issue = 12 | pages = 1384–91 | date = December 2006 | pmid = 16973981 | doi = 10.1164/rccm.200606-778OC }}{{non-primary source needed|date=May 2017}}

• Respiratory stimulants: carotid chemoreceptor agonists (e.g. doxapram), 5-HT₄ agonists (e.g. BIMU8), δ-opioid agonists (e.g. BW373U86) and AMPAkines (e.g. CX717) can all reduce respiratory depression caused by opioids without affecting analgesia, but most of these drugs are only moderately effective or have side effects which preclude use in humans. 5-HT_1A agonists such as 8-OH-DPAT and repinotan also counteract opioid-induced respiratory depression, but at the same time reduce analgesia, which limits their usefulness for this application.
• Opioid antagonists (e.g. naloxone, nalmefene, diprenorphine)

The initial 24 hours after opioid administration appear to be the most critical with regard to life-threatening OIRD, but may be preventable with a more cautious approach to opioid use.{{Cite journal|last1=Cozowicz|first1=Crispiana|last2=Chung|first2=Frances|last3=Doufas|first3=Anthony G.|last4=Nagappa|first4=Mahesh|last5=Memtsoudis|first5=Stavros G.|date=October 2018|title=Opioids for Acute Pain Management in Patients With Obstructive Sleep Apnea: A Systematic Review|journal=Anesthesia and Analgesia|volume=127|issue=4|pages=988–1001|doi=10.1213/ANE.0000000000003549|issn=1526-7598|pmid=29958218|s2cid=49614405}}

Patients with cardiac, respiratory disease and/or obstructive sleep apnoea are at increased risk for OIRD.{{Cite journal|last1=Gupta|first1=Kapil|last2=Nagappa|first2=Mahesh|last3=Prasad|first3=Arun|last4=Abrahamyan|first4=Lusine|last5=Wong|first5=Jean|last6=Weingarten|first6=Toby N.|last7=Chung|first7=Frances|date= 14 December 2018|title=Risk factors for opioid-induced respiratory depression in surgical patients: a systematic review and meta-analyses|journal=BMJ Open|volume=8|issue=12|pages=e024086|doi=10.1136/bmjopen-2018-024086|issn=2044-6055|pmc=6303633|pmid=30552274}}

{{Main|Opioid-induced hyperalgesia}}

Opioid-induced hyperalgesia – where individuals using opioids to relieve pain paradoxically experience more pain as a result of that medication – has been observed in some people. This phenomenon, although uncommon, is seen in some people receiving palliative care, most often when dose is increased rapidly.{{cite journal | vauthors = Wilson GR, Reisfield GM | title = Morphine hyperalgesia: a case report | journal = The American Journal of Hospice & Palliative Care | volume = 20 | issue = 6 | pages = 459–61 | year = 2003 | pmid = 14649563 | doi = 10.1177/104990910302000608 | s2cid = 22690630 }}{{cite journal | vauthors = Vella-Brincat J, Macleod AD | title = Adverse effects of opioids on the central nervous systems of palliative care patients | journal = Journal of Pain & Palliative Care Pharmacotherapy | volume = 21 | issue = 1 | pages = 15–25 | year = 2007 | pmid = 17430825 | doi = 10.1080/J354v21n01_05 | s2cid = 17757207 }} If encountered, rotation between several different opioid pain medications may decrease the development of increased pain.{{cite journal | vauthors = Mercadante S, Arcuri E | title = Hyperalgesia and opioid switching | journal = The American Journal of Hospice & Palliative Care | volume = 22 | issue = 4 | pages = 291–4 | year = 2005 | pmid = 16082916 | doi = 10.1177/104990910502200411 | s2cid = 39647898 }}{{cite journal | vauthors = Fine PG | title = Opioid insights:opioid-induced hyperalgesia and opioid rotation | journal = Journal of Pain & Palliative Care Pharmacotherapy | volume = 18 | issue = 3 | pages = 75–9 | year = 2004 | pmid = 15364634 | doi = 10.1080/J354v18n03_08 | s2cid = 45555785 }} Opioid induced hyperalgesia more commonly occurs with chronic use or brief high doses but some research suggests that it may also occur with very low doses.{{cite journal | vauthors = Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L | title = A comprehensive review of opioid-induced hyperalgesia | journal = Pain Physician | volume = 14 | issue = 2 | pages = 145–61 | date = 2011 | doi = 10.36076/ppj.2011/14/145 | pmid = 21412369 | url = http://www.painphysicianjournal.com/current/pdf?article=MTQ0Ng%3D%3D&journal=60 | doi-access = free | access-date = 11 November 2016 | archive-date = 14 December 2020 | archive-url = https://web.archive.org/web/20201214085159/https://painphysicianjournal.com/current/pdf?article=MTQ0Ng==&journal=60 | url-status = live }}{{cite journal | vauthors = Tompkins DA, Campbell CM | title = Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon? | journal = Current Pain and Headache Reports | volume = 15 | issue = 2 | pages = 129–36 | date = April 2011 | pmid = 21225380 | pmc = 3165032 | doi = 10.1007/s11916-010-0171-1 }}

Side effects such as hyperalgesia and allodynia, sometimes accompanied by a worsening of neuropathic pain, may be consequences of long-term treatment with opioid analgesics, especially when increasing tolerance has resulted in loss of efficacy and consequent progressive dose escalation over time. This appears to largely be a result of actions of opioid drugs at targets other than the three classic opioid receptors, including the nociceptin receptor, sigma receptor and Toll-like receptor 4, and can be counteracted in animal models by antagonists at these targets such as J-113,397, BD-1047 or (+)-naloxone respectively.{{cite journal | vauthors = Díaz JL, Zamanillo D, Corbera J, Baeyens JM, Maldonado R, Pericàs MA, Vela JM, Torrens A | title = Selective sigma-1 (sigma1) receptor antagonists: emerging target for the treatment of neuropathic pain | journal = Central Nervous System Agents in Medicinal Chemistry | volume = 9 | issue = 3 | pages = 172–83 | date = September 2009 | pmid = 20021351 | doi = 10.2174/1871524910909030172 }} No drugs are currently approved specifically for counteracting opioid-induced hyperalgesia in humans and in severe cases the only solution may be to discontinue use of opioid analgesics and replace them with non-opioid analgesic drugs. However, since individual sensitivity to the development of this side effect is highly dose dependent and may vary depending which opioid analgesic is used, many patients can avoid this side effect simply through dose reduction of the opioid drug (usually accompanied by the addition of a supplemental non-opioid analgesic), rotating between different opioid drugs, or by switching to a milder opioid with a mixed mode of action that also counteracts neuropathic pain, particularly tramadol or tapentadol.{{cite journal | vauthors = Mitra S | title = Opioid-induced hyperalgesia: pathophysiology and clinical implications | journal = Journal of Opioid Management | volume = 4 | issue = 3 | pages = 123–30 | year = 2018 | pmid = 18717507 | doi = 10.5055/jom.2008.0017 }}{{Cite book | vauthors = Baron R | title = Sensory Nerves | volume = 194 | issue = 194 | pages = 3–30 | year = 2009 | pmid = 19655103 | doi = 10.1007/978-3-540-79090-7_1 | isbn = 978-3-540-79089-1 | series = Handbook of Experimental Pharmacology | chapter = Neuropathic Pain: A Clinical Perspective }}{{cite journal | vauthors = Candiotti KA, Gitlin MC | title = Review of the effect of opioid-related side effects on the undertreatment of moderate to severe chronic non-cancer pain: tapentadol, a step toward a solution? | journal = Current Medical Research and Opinion | volume = 26 | issue = 7 | pages = 1677–84 | date = July 2010 | pmid = 20465361 | doi = 10.1185/03007995.2010.483941 | s2cid = 9713245 }}

• NMDA receptor antagonists such as ketamine
• SNRIs such as milnacipran
• Anticonvulsants such as gabapentin or pregabalin

Clinical studies have consistently associated medical and recreational opioid use with hypogonadism (low sex hormone levels) in different sexes. The effect is dose-dependent. Most studies suggest that the majority (perhaps as much as 90%) of chronic opioid users develop hypogonadism. A 2015 systematic review and meta-analysis found that opioid therapy suppressed testosterone levels in men by about 165 ng/dL (5.7 nmol/L) on average, which was a reduction in testosterone level of almost 50%.{{cite journal | vauthors = Bawor M, Bami H, Dennis BB, Plater C, Worster A, Varenbut M, Daiter J, Marsh DC, Steiner M, Anglin R, Coote M, Pare G, Thabane L, Samaan Z | title = Testosterone suppression in opioid users: a systematic review and meta-analysis | journal = Drug Alcohol Depend | volume = 149 | issue = | pages = 1–9 | date = April 2015 | pmid = 25702934 | doi = 10.1016/j.drugalcdep.2015.01.038 | url = | doi-access = free }} Conversely, opioid therapy did not significantly affect testosterone levels in women. However, opioids can also interfere with menstruation in women by limiting the production of luteinizing hormone (LH). Opioid-induced hypogonadism likely causes the strong association of opioid use with osteoporosis and bone fracture, due to deficiency in estradiol. It also may increase pain and thereby interfere with the intended clinical effect of opioid treatment. Opioid-induced hypogonadism is likely caused by their agonism of opioid receptors in the hypothalamus and the pituitary gland.{{cite journal |vauthors=Coluzzi F, Billeci D, Maggi M, Corona G |title=Testosterone deficiency in non-cancer opioid-treated patients |journal=Journal of Endocrinological Investigation |volume=41 |issue=12 |pages=1377–1388 |date=December 2018 |pmid=30343356 |pmc=6244554 |doi=10.1007/s40618-018-0964-3}} One study found that the depressed testosterone levels of heroin addicts returned to normal within one month of abstinence, suggesting that the effect is readily reversible and is not permanent.{{Citation needed|date=April 2016}} {{As of|2013}}, the effect of low-dose or acute opioid use on the endocrine system is unclear.{{cite journal | vauthors = Fountas A, Chai ST, Kourkouti C, Karavitaki N | title = MECHANISMS OF ENDOCRINOLOGY: Endocrinology of opioids | journal = European Journal of Endocrinology | volume = 179 | issue = 4 | pages = R183–R196 | date = October 2018 | pmid = 30299887 | doi = 10.1530/EJE-18-0270 | doi-access = free }}{{cite journal | vauthors = Brennan MJ | title = The effect of opioid therapy on endocrine function | journal = The American Journal of Medicine | volume = 126 | issue = 3 Suppl 1 | pages = S12-8 | date = March 2013 | pmid = 23414717 | doi = 10.1016/j.amjmed.2012.12.001 }}{{cite journal | vauthors = Colameco S, Coren JS | title = Opioid-induced endocrinopathy | journal = The Journal of the American Osteopathic Association | volume = 109 | issue = 1 | pages = 20–5 | date = January 2009 | pmid = 19193821 }}{{cite journal | vauthors = Smith HS, Elliott JA | title = Opioid-induced androgen deficiency (OPIAD) | journal = Pain Physician | volume = 15 | issue = 3 Suppl | pages = ES145-56 | date = July 2012 | pmid = 22786453 }} Long-term use of opioids can affect the other hormonal systems as well.

Use of opioids may be a risk factor for failing to return to work.{{cite journal | vauthors = Brede E, Mayer TG, Gatchel RJ | title = Prediction of failure to retain work 1 year after interdisciplinary functional restoration in occupational injuries | journal = Archives of Physical Medicine and Rehabilitation | volume = 93 | issue = 2 | pages = 268–74 | date = February 2012 | pmid = 22289236 | doi = 10.1016/j.apmr.2011.08.029 }}{{cite journal | vauthors = Volinn E, Fargo JD, Fine PG | title = Opioid therapy for nonspecific low back pain and the outcome of chronic work loss | journal = Pain | volume = 142 | issue = 3 | pages = 194–201 | date = April 2009 | pmid = 19181448 | doi = 10.1016/j.pain.2008.12.017 }}

Persons performing any safety-sensitive task should not use opioids.{{Citation |author1 = American College of Occupational and Environmental Medicine |author1-link = American College of Occupational and Environmental Medicine |date = February 2014 |title = Five Things Physicians and Patients Should Question |publisher = American College of Occupational and Environmental Medicine |work = Choosing Wisely: an initiative of the ABIM Foundation |url = http://www.choosingwisely.org/doctor-patient-lists/american-college-of-occupational-and-environmental-medicine/ |access-date = 24 February 2014 |archive-date = 11 September 2014 |archive-url = https://web.archive.org/web/20140911001813/http://www.choosingwisely.org/doctor-patient-lists/american-college-of-occupational-and-environmental-medicine/ |url-status = live }}, which cites

• {{cite book | vauthors = Weiss MS, Bowden K, Branco F | veditors = Hegmann KT |title=Occupational medicine practice guidelines : evaluation and management of common health problems and functional recovery in workers|date=2011|publisher=American College of Occupational and Environmental Medicine |chapter=Opioids Guideline |page=11|location=Elk Grove Village, IL|isbn=978-0-615-45227-2|edition=3rd|type=online March 2014|display-authors=etal}} Health care providers should not recommend that workers who drive or use heavy equipment including cranes or forklifts treat chronic or acute pain with opioids. Workplaces which manage workers who perform safety-sensitive operations should assign workers to less sensitive duties for so long as those workers are treated by their physician with opioids.

People who take opioids long term have increased likelihood of being unemployed.{{cite journal | vauthors = Cherubino P, Sarzi-Puttini P, Zuccaro SM, Labianca R | title = The management of chronic pain in important patient subgroups | journal = Clinical Drug Investigation | volume = 32 | pages = 35–44 | date = February 2012 | issue = Suppl 1 | pmid = 23389874 | doi = 10.2165/11630060-000000000-00000 | s2cid = 47576095 }} Taking opioids may further disrupt the patient's life and the adverse effects of opioids themselves can become a significant barrier to patients having an active life, gaining employment, and sustaining a career.

In addition, lack of employment may be a predictor of aberrant use of prescription opioids.{{cite journal | vauthors = White KT, Dillingham TR, González-Fernández M, Rothfield L | title = Opiates for chronic nonmalignant pain syndromes: can appropriate candidates be identified for outpatient clinic management? | journal = American Journal of Physical Medicine & Rehabilitation | volume = 88 | issue = 12 | pages = 995–1001 | date = December 2009 | pmid = 19789432 | doi = 10.1097/PHM.0b013e3181bc006e | s2cid = 43241757 }}

Opioid use may increase accident-proneness. Opioids may increase risk of traffic accidents{{cite journal | vauthors = Kaye AM, Kaye AD, Lofton EC | title = Basic concepts in opioid prescribing and current concepts of opioid-mediated effects on driving | journal = The Ochsner Journal | volume = 13 | issue = 4 | pages = 525–32 | year = 2013 | pmid = 24358001 | pmc = 3865831 }}{{cite journal | vauthors = Orriols L, Delorme B, Gadegbeku B, Tricotel A, Contrand B, Laumon B, Salmi LR, Lagarde E | title = Prescription medicines and the risk of road traffic crashes: a French registry-based study | journal = PLOS Medicine | volume = 7 | issue = 11 | pages = e1000366 | date = November 2010 | pmid = 21125020 | pmc = 2981588 | doi = 10.1371/journal.pmed.1000366 | veditors = Pirmohamed M | doi-access = free }} and accidental falls.{{cite journal | vauthors = Miller M, Stürmer T, Azrael D, Levin R, Solomon DH | title = Opioid analgesics and the risk of fractures in older adults with arthritis | journal = Journal of the American Geriatrics Society | volume = 59 | issue = 3 | pages = 430–8 | date = March 2011 | pmid = 21391934 | pmc = 3371661 | doi = 10.1111/j.1532-5415.2011.03318.x }}

Reduced Attention

Opioids have been shown to reduce attention, more so when used with antidepressants and/or anticonvulsants.{{cite journal | vauthors = Allegri N, Mennuni S, Rulli E, Vanacore N, Corli O, Floriani I, De Simone I, Allegri M, Govoni S, Vecchi T, Sandrini G, Liccione D, Biagioli E | title = Systematic Review and Meta-Analysis on Neuropsychological Effects of Long-Term Use of Opioids in Patients With Chronic Noncancer Pain | journal = Pain Practice | volume = 19 | issue = 3 | pages = 328–343 | date = March 2019 | pmid = 30354006 | doi = 10.1111/papr.12741 | s2cid = 53023743 }}

Infrequent adverse reactions in patients taking opioids for pain relief include: dose-related respiratory depression (especially with more potent opioids), confusion, hallucinations, delirium, urticaria, hypothermia, bradycardia/tachycardia, orthostatic hypotension, dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus (with high doses), and flushing (due to histamine release, except fentanyl and remifentanil). Both therapeutic and chronic use of opioids can compromise the function of the immune system. Opioids decrease the proliferation of macrophage progenitor cells and lymphocytes, and affect cell differentiation (Roy & Loh, 1996). Opioids may also inhibit leukocyte migration. However the relevance of this in the context of pain relief is not known.

{{excerpt|Opioids and pregnancy}}

Physicians treating patients using opioids in combination with other drugs keep continual documentation that further treatment is indicated and remain aware of opportunities to adjust treatment if the patient's condition changes to merit less risky therapy.

The concurrent use of opioids with other depressant drugs such as benzodiazepines or ethanol increases the rates of adverse events and overdose.{{cite journal | vauthors = Gudin JA, Mogali S, Jones JD, Comer SD | title = Risks, management, and monitoring of combination opioid, benzodiazepines, and/or alcohol use | journal = Postgraduate Medicine | volume = 125 | issue = 4 | pages = 115–30 | date = July 2013 | pmid = 23933900 | pmc = 4057040 | doi = 10.3810/pgm.2013.07.2684 }} Despite this, opioids and benzodiazepines are concurrently dispensed in many settings.{{cite journal | vauthors = Islam MM, Wollersheim D | title = A comparison of opioids and benzodiazepines dispensing in Australia | journal = PLOS ONE | volume = 14 | issue = 8 | pages = e0221438 | date = 2019 | pmid = 31425552 | doi = 10.1371/journal.pone.0221438 | pmc = 6699700 | bibcode = 2019PLoSO..1421438I | doi-access = free }}{{cite journal | vauthors = Islam MM, Wollersheim D | title = Trends and Variations in Concurrent Dispensing of Prescription Opioids and Benzodiazepines in Australia: A Retrospective Analysis | journal = Contemporary Drug Problems | volume = 47 | date = 2020 | issue = 2 | pages = 136–148 | doi = 10.1177/0091450920919443 | s2cid = 218780209 }} As with an overdose of opioid alone, the combination of an opioid and another depressant may precipitate respiratory depression often leading to death.{{Cite journal |title=Effects of anesthetics, sedatives, and opioids on ventilatory control |vauthors=Stuth EA, Stucke AG, Zuperku EJ |journal=Comprehensive Physiology |year=2012 |isbn=978-0-470-65071-4 |volume=2 |pages=2281–2367 |doi=10.1002/cphy.c100061 |pmid=23720250 |issue=4}} These risks are lessened with close monitoring by a physician, who may conduct ongoing screening for changes in patient behavior and treatment compliance.

{{Main|Opioid antagonist}}

Opioid effects (adverse or otherwise) can be reversed with an opioid antagonist such as naloxone or naltrexone.{{cite journal | vauthors = Gowing L, Ali R, White JM | title = Opioid antagonists with minimal sedation for opioid withdrawal | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD002021 | date = May 2017 | issue = 5 | pmid = 28553701 | pmc = 6481395 | doi = 10.1002/14651858.CD002021.pub4 }} These competitive antagonists bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This displaces the agonist, attenuating or reversing the agonist effects. However, the elimination half-life of naloxone can be shorter than that of the opioid itself, so repeat dosing or continuous infusion may be required, or a longer acting antagonist such as nalmefene may be used. In patients taking opioids regularly it is essential that the opioid is only partially reversed to avoid a severe and distressing reaction of waking in excruciating pain. This is achieved by not giving a full dose but giving this in small doses until the respiratory rate has improved. An infusion is then started to keep the reversal at that level, while maintaining pain relief. Opioid antagonists remain the standard treatment for respiratory depression following opioid overdose, with naloxone being by far the most commonly used, although the longer acting antagonist nalmefene may be used for treating overdoses of long-acting opioids such as methadone, and diprenorphine is used for reversing the effects of extremely potent opioids used in veterinary medicine such as etorphine and carfentanil. However, since opioid antagonists also block the beneficial effects of opioid analgesics, they are generally useful only for treating overdose, with use of opioid antagonists alongside opioid analgesics to reduce side effects, requiring careful dose titration and often being poorly effective at doses low enough to allow analgesia to be maintained.

Naltrexone does not appear to increase risk of serious adverse events, which confirms the safety of oral naltrexone.{{Cite journal|last1=Bolton|first1=Monica|last2=Hodkinson|first2=Alex|last3=Boda|first3=Shivani|last4=Mould|first4=Alan|last5=Panagioti|first5=Maria|last6=Rhodes|first6=Sarah|last7=Riste|first7=Lisa|last8=van Marwijk|first8=Harm|date= 15 January 2019|title=Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis|journal=BMC Medicine|volume=17|issue=1|pages=10|doi=10.1186/s12916-018-1242-0|issn=1741-7015|pmc=6332608|pmid=30642329 |doi-access=free }} Mortality or serious adverse events due to rebound toxicity in patients with naloxone were rare.{{Cite journal|last1=Greene|first1=Jennifer Anne|last2=Deveau|first2=Brent J.|last3=Dol|first3=Justine S.|last4=Butler|first4=Michael B.|date=April 2019|title=Incidence of mortality due to rebound toxicity after 'treat and release' practices in prehospital opioid overdose care: a systematic review|journal=Emergency Medicine Journal |volume=36|issue=4|pages=219–224|doi=10.1136/emermed-2018-207534|issn=1472-0213|pmid=30580317|doi-access=free}}

{{See also|Opioid receptor}}

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.

File:Morphine structure.svgs of the morphine molecule]]

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{{Citation needed|date=March 2013}}. 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.

File:INTA.svg: selective agonist of KOR-DOR and KOR-MOR heteromers. Does not recruit β-arrestin II. Antinociceptive devoid of aversion, tolerance, and dependence in mice.{{cite journal | vauthors = Le Naour M, Lunzer MM, Powers MD, Kalyuzhny AE, Benneyworth MA, Thomas MJ, Portoghese PS | title = Putative kappa opioid heteromers as targets for developing analgesics free of adverse effects | journal = Journal of Medicinal Chemistry | volume = 57 | issue = 15 | pages = 6383–92 | date = August 2014 | pmid = 24978316 | pmc = 4136663 | doi = 10.1021/jm500159d }}]]

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.{{cite journal | vauthors = 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 | title = A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 344 | issue = 3 | pages = 708–17 | date = March 2013 | pmid = 23300227 | doi = 10.1124/jpet.112.201616 | s2cid = 8785003 }}

{{Main|Equianalgesic}}

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.

{{Global estimates of illicit drug users}}

Opioid prescriptions in the US increased from 76 million in 1991 to 207 million in 2013.{{cite web|last1=Volkow|first1=Nora D.|title=America's Addiction to Opioids: Heroin and Prescription Drug Abuse|url=https://www.drugabuse.gov/about-nida/legislative-activities/testimony-to-congress/2016/americas-addiction-to-opioids-heroin-prescription-drug-abuse#_ftn5|website=DrugAbuse.GOV|publisher=National Institute on Drug Abuse|access-date=30 April 2017|archive-date=25 May 2018|archive-url=https://web.archive.org/web/20180525140114/https://www.drugabuse.gov/about-nida/legislative-activities/testimony-to-congress/2016/americas-addiction-to-opioids-heroin-prescription-drug-abuse#_ftn5|url-status=live}}

In the 1990s, opioid prescribing increased significantly. Once used almost exclusively for the treatment of acute pain or pain due to cancer, opioids are now prescribed liberally for people experiencing chronic pain. This has been accompanied by rising rates of accidental addiction and accidental overdoses leading to death. According to the International Narcotics Control Board, the United States and Canada lead the per capita consumption of prescription opioids.{{cite web|url=http://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2012/Narcotic_Drugs_Report_2012.pdf|title=Narcotic Drugs Stupéfiants Estupefacientes|year=2012|publisher=INTERNATIONAL NARCOTICS CONTROL BOARD|access-date=6 March 2017|archive-date=21 October 2020|archive-url=https://web.archive.org/web/20201021021358/http://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2012/Narcotic_Drugs_Report_2012.pdf|url-status=live}} The number of opioid prescriptions per capita in the United States and Canada is double the consumption in the European Union, Australia, and New Zealand.{{cite web |url=http://www.painpolicy.wisc.edu/opioid-consumption-data |title=Opioid Consumption Data | Pain & Policy Studies Group |publisher=Painpolicy.wisc.edu |access-date=7 January 2016 |archive-date=30 January 2019 |archive-url=https://web.archive.org/web/20190130174221/http://www.painpolicy.wisc.edu/opioid-consumption-data |url-status=dead }} Certain populations have been affected by the opioid addiction crisis more than others, including First World communities{{cite journal | vauthors = Dell CA, Roberts G, Kilty J, Taylor K, Daschuk M, Hopkins C, Dell D | title = Researching Prescription Drug Misuse among First Nations in Canada: Starting from a Health Promotion Framework | journal = Substance Abuse | volume = 6 | pages = 23–31 | year = 2012 | pmid = 22879752 | pmc = 3411531 | doi = 10.4137/SART.S9247 }} and low-income populations.{{cite web |url=http://www.ices.on.ca/Newsroom/News-Releases/2011/Socially-disadvantaged-Ontarians-being-prescribed-opiods |title=Socially disadvantaged Ontarians being prescribed opioids on an ongoing basis and at doses that far exceed Canadian guidelines |publisher=Ices.on.ca |date=25 January 2011 |access-date=7 January 2016 |archive-date=12 November 2019 |archive-url=https://web.archive.org/web/20191112211545/https://www.ices.on.ca/Newsroom/News-Releases/2011/Socially-disadvantaged-Ontarians-being-prescribed-opiods |url-status=dead }} Public health specialists say that this may result from the unavailability or high cost of alternative methods for addressing chronic pain.{{cite web|url=http://www.cpso.on.ca/CPSO/media/uploadedfiles/policies/policies/Opioid_report_final.pdf|title=Avoiding Abuse, Achieving a Balance: Tackling the Opioid Public Health Crisis|publisher=College of Physicians and Surgeons of Ontario|date=8 September 2010|access-date=6 March 2017|url-status=dead|archive-url=https://web.archive.org/web/20160607203830/http://www.cpso.on.ca/CPSO/media/uploadedfiles/policies/policies/Opioid_report_final.pdf|archive-date=7 June 2016}} Opioids have been described as a cost-effective treatment for chronic pain, but the impact of the opioid epidemic and deaths caused by opioid overdoses should be considered in assessing their cost-effectiveness.{{cite journal | vauthors = Backhaus I, Mannocci A, La Torre G | title = A Systematic Review of Economic Evaluation Studies of Drug-Based Non-Malignant Chronic Pain Treatment | journal = Current Pharmaceutical Biotechnology | volume = 20 | issue = 11 | pages = 910–919 | date = 2019 | pmid = 31322067 | doi = 10.2174/1389201020666190717095443 | s2cid = 197664630 }} Data from 2017 suggest that in the U.S. about 3.4 percent of the U.S. population are prescribed opioids for daily pain management.{{cite journal | vauthors = Mojtabai R | title = National trends in long-term use of prescription opioids | journal = Pharmacoepidemiology and Drug Safety | volume = 27 | issue = 5 | pages = 526–534 | date = May 2018 | pmid = 28879660 | doi = 10.1002/pds.4278 | s2cid = 19047621 | doi-access = free }} Calls for opioid deprescribing have led to broad scale opioid tapering practices with little scientific evidence to support the safety or benefit for patients with chronic pain.

{{clear}}

File:Raw opium.jpg

Opioids are among the world's oldest known drugs.{{cite journal | vauthors = Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S | title = Crystal structure of the µ-opioid receptor bound to a morphinan antagonist | journal = Nature | volume = 485 | issue = 7398 | pages = 321–6 | date = March 2012 | pmid = 22437502 | pmc = 3523197 | doi = 10.1038/nature10954 | bibcode = 2012Natur.485..321M | quote = Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. }} 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.{{cite book |last1=Colledge |first1=Sue |last2=Conolly |first2=James |title=The Origins and Spread of Domestic Plants in Southwest Asia and Europe |date=10 August 2007 |publisher=Left Coast Press |location=Walnut Creek, CA |isbn=978-1-59874-988-5 |pages=179–181 |url=https://books.google.com/books?id=D2nym35k_EcC&pg=PA179 |access-date=28 August 2018 |archive-date=15 December 2023 |archive-url=https://web.archive.org/web/20231215100411/https://books.google.com/books?id=D2nym35k_EcC&pg=PA179#v=onepage&q&f=false |url-status=live }}{{cite news |last1=Kunzig |first1=Robert |last2=Tzar |first2=Jennifer |title=La Marmotta |url=http://discovermagazine.com/2002/nov/cover |access-date=28 August 2018 |work=Discover |date=1 November 2002 |archive-date=22 January 2019 |archive-url=https://web.archive.org/web/20190122004705/http://discovermagazine.com/2002/nov/cover |url-status=live }}{{cite book |last1=Chevalier |first1=Alexandre |last2=Marinova |first2=Elena |last3=Pena-Chocarro |first3=Leonor |title=Plants and People: Choices and Diversity through Time |date=1 April 2014 |publisher=Oxbow Books |isbn=978-1-84217-514-9 |pages=97–99 |url=https://books.google.com/books?id=R5f9AwAAQBAJ&pg=PA97 |access-date=28 August 2018 |archive-date=15 December 2023 |archive-url=https://web.archive.org/web/20231215100411/https://books.google.com/books?id=R5f9AwAAQBAJ&pg=PA97#v=onepage&q&f=false |url-status=live }}

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".{{cite journal |vauthors=Kritikos PG, Papadaki SP |title=The history of the poppy and of opium and their expansion in antiquity in the eastern Mediterranean area |journal=Bulletin on Narcotics |date=1967 |volume=XIX |issue=4 |url=https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1967-01-01_3_page004.html |access-date=23 August 2018 |archive-date=16 December 2020 |archive-url=https://web.archive.org/web/20201216123419/https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1967-01-01_3_page004.html |url-status=live }}{{cite journal |last1=Sonnedecker |first1=Glenn |title=Emergence of the Concept of Opiate Addiction |journal=Journal Mondial de Pharmacie |date=1962 |volume=3 |pages=275–290 }}{{cite journal | vauthors = Brownstein MJ | title = A brief history of opiates, opioid peptides, and opioid receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 12 | pages = 5391–3 | date = June 1993 | pmid = 8390660 | pmc = 46725 | doi = 10.1073/pnas.90.12.5391 | bibcode = 1993PNAS...90.5391B | doi-access = free }}

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.{{cite journal | vauthors = Rosso AM |title=Poppy and Opium in Ancient Times: Remedy or Narcotic? |journal=Biomedicine International |date=2010 |volume=1 |pages=81–87 |citeseerx=10.1.1.846.221 }}

Opium was also known to the Greeks.{{cite journal |last1=Duarte |first1=Danilo Freire |title=Uma breve história do ópio e dos opióides |journal=Revista Brasileira de Anestesiologia |date=February 2005 |volume=55 |issue=1 |doi=10.1590/S0034-70942005000100015 |url=http://www.scielo.br/pdf/rba/v55n1/en_v55n1a15.pdf |doi-access=free |access-date=13 September 2019 |archive-date=10 January 2021 |archive-url=https://web.archive.org/web/20210110091519/http://www.scielo.br/pdf/rba/v55n1/en_v55n1a15.pdf |url-status=live }}

It was valued by Hippocrates ({{circa|460}} – {{circa|370 BC}}) and his students for its sleep-inducing properties, and used for the treatment of pain.{{cite journal | vauthors = Astyrakaki E, Papaioannou A, Askitopoulou H | title = References to anesthesia, pain, and analgesia in the Hippocratic Collection | journal = Anesthesia and Analgesia | volume = 110 | issue = 1 | pages = 188–94 | date = January 2010 | pmid = 19861359 | doi = 10.1213/ane.0b013e3181b188c2 | s2cid = 25919738 | doi-access = free }} 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.{{cite journal | vauthors = Türe H, Türe U, Gögüs FY, Valavanis A, Yasargil MG |title=987 The Art of Alleviating Pain in Greek Mythology |journal= European Journal of Pain|date=September 2006 |volume=10 |issue=S1 |pages=S255b–S255 |doi=10.1016/S1090-3801(06)60990-7 |s2cid=26539333 |quote=Sedare dolorem opus divinum est – an old Latin inscription – means "alleviating pain is the work of the divine". This inscription is often attributed to either Hippocrates of Kos or Galen of Pergamum, but it is most likely an anonymous proverb }} The medical use of opium is later discussed by Pedanius Dioscorides ({{circa|40}} – 90 AD), a Greek physician serving in the Roman army, in his five-volume work, De Materia Medica.{{cite book |last1=Osbaldeston |first1=Tess Anne |title=Dioscorides (translation) |date=2000 |publisher=Ibidis Press |location=Johannesburg, South Africa |isbn=978-0-620-23435-1 |pages=607–611 }}

During the Islamic Golden Age, the use of opium was discussed in detail by Avicenna ({{circa|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.{{cite journal | vauthors = Heydari M, Hashempur MH, Zargaran A | title = Medicinal aspects of opium as described in Avicenna's Canon of Medicine | journal = Acta medico-historica Adriatica | volume = 11 | issue = 1 | pages = 101–12 | date = 2013 | pmid = 23883087 | url = https://www.researchgate.net/publication/251877190 | access-date = 28 August 2018 | archive-date = 13 February 2023 | archive-url = https://web.archive.org/web/20230213141437/https://www.researchgate.net/publication/251877190 | url-status = live }}

Exactly when the world became aware of opium in India and China is uncertain, but opium was mentioned in the Chinese medical work K'ai-pao-pen-tsdo (973 AD) By 1590 AD, opium poppies were a staple spring crop in the Subahs of Agra region.{{cite journal |vauthors=Asthana SN |title=The Cultivation of the Opium Poppy in India |date=1954 |journal=Bulletin on Narcotics |issue=3 |url=https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1954-01-01_3_page002.html#s020 |access-date=5 September 2018 |archive-date=6 August 2020 |archive-url=https://web.archive.org/web/20200806090211/https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1954-01-01_3_page002.html#s020 |url-status=live }}

The physician Paracelsus ({{circa|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.{{cite journal |vauthors=Sigerist HE |title=Laudanum in the Works of Paracelsus |journal=Bull. Hist. Med. |date=1941 |volume=9 |pages=530–544 |url=http://www.samorini.it/doc1/alt_aut/sz/sigerist-laudanum-in-the-work-of-paracelsus.pdf |access-date=5 September 2018 |archive-date=9 October 2022 |archive-url=https://ghostarchive.org/archive/20221009/http://www.samorini.it/doc1/alt_aut/sz/sigerist-laudanum-in-the-work-of-paracelsus.pdf |url-status=live }}

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.{{cite journal | vauthors = Hamilton GR, Baskett TF | title = In the arms of Morpheus the development of morphine for postoperative pain relief | journal = Canadian Journal of Anaesthesia | volume = 47 | issue = 4 | pages = 367–74 | date = April 2000 | pmid = 10764185 | doi = 10.1007/BF03020955 | doi-access = free }} 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.

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.{{cite journal |last1=Farooqui |first1=Amar |title=The Global Career of Indian Opium and Local Destinies |journal=Almanack |date=December 2016 |issue=14 |pages=52–73 |doi=10.1590/2236-463320161404 |url=http://www.scielo.br/pdf/alm/n14/2236-4633-alm-14-00052.pdf |access-date=5 September 2018 |archive-date=27 July 2018 |archive-url=https://web.archive.org/web/20180727030153/http://www.scielo.br/pdf/alm/n14/2236-4633-alm-14-00052.pdf |url-status=live }}

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.{{cite journal |last1=Deming |first1=Sarah |title=The Economic Importance of Indian Opium and Trade with China on Britain's Economy, 1843–1890 |journal=Economic Working Papers |date=2011 |volume=25 |issue=Spring |url=https://www.whitman.edu/Documents/Academics/Economics/Working%20Paper%20Contents/WP_25.pdf |access-date=5 September 2018 |archive-date=12 November 2020 |archive-url=https://web.archive.org/web/20201112023133/https://www.whitman.edu/Documents/Academics/Economics/Working |url-status=dead }} 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.{{cite journal |last1=Rinde |first1=Meir |title=Opioids' Devastating Return |url=https://www.sciencehistory.org/distillations/magazine/opioids-devastating-return |journal=Distillations |date=2018 |volume=4 |issue=2 |pages=12–23 |access-date=23 August 2018 |archive-date=5 September 2018 |archive-url=https://web.archive.org/web/20180905215044/https://www.sciencehistory.org/distillations/magazine/opioids-devastating-return |url-status=live }}{{Cite journal |last1=Mills |first1=James H. |title=Review of 'Opium and Empire in Southeast Asia: Regulating Consumption in British Burma' |journal=Reviews in History |date=2016 |doi=10.14296/RiH/2014/2010 |url=https://www.recensio.net/rezensionen/zeitschriften/reviews-in-history/2016/october/opium-and-empire-in-southeast-asia |access-date=5 September 2018 |publisher=Palgrave Macmillan |isbn=978-0-230-29646-6 |series=Cambridge imperial and post-colonial studies series |archive-date=1 October 2020 |archive-url=https://web.archive.org/web/20201001123812/https://www.recensio.net/rezensionen/zeitschriften/reviews-in-history/2016/october/opium-and-empire-in-southeast-asia |url-status=live |doi-access=free }}

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.{{cite journal | vauthors = Krishnamurti C, Rao SC | title = The isolation of morphine by Serturner | journal = Indian Journal of Anaesthesia | volume = 60 | issue = 11 | pages = 861–862 | date = November 2016 | pmid = 27942064 | pmc = 5125194 | doi = 10.4103/0019-5049.193696 | doi-access = free }}{{cite book|last1=Courtwright|first1=David T.|title=Forces of habit drugs and the making of the modern world|date=2009|publisher=Harvard University Press|location=Cambridge, Mass.|isbn=978-0-674-02990-3|pages=36–37|edition=1|url=https://books.google.com/books?id=GHqV3elHYvMC&pg=PA36}}

Morphine was the first alkaloid to be isolated from any medicinal plant, the beginning of modern scientific drug discovery.{{cite journal | vauthors = 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 | title = Discovery and resupply of pharmacologically active plant-derived natural products: A review | journal = Biotechnology Advances | volume = 33 | issue = 8 | pages = 1582–1614 | date = December 2015 | pmid = 26281720 | pmc = 4748402 | doi = 10.1016/j.biotechadv.2015.08.001 }}

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.{{cite journal | vauthors = Kotwal A | title = Innovation, diffusion and safety of a medical technology: a review of the literature on injection practices | journal = Social Science & Medicine | volume = 60 | issue = 5 | pages = 1133–47 | date = March 2005 | pmid = 15589680 | doi = 10.1016/j.socscimed.2004.06.044 }}{{cite book| first1 = Clayton J. | last1 = Mosher |title=Drugs and Drug Policy: The Control of Consciousness Alteration|date=2013|publisher=SAGE Publications|isbn=978-1-4833-2188-2|page=123|url=https://books.google.com/books?id=2UQXBAAAQBAJ&pg=PA123}}{{cite book |last1=Fisher |first1=Gary L. |title=Encyclopedia of substance abuse prevention, treatment, & recovery|date=2009|publisher=SAGE|location=Los Angeles|isbn=978-1-4522-6601-5|page=564|url=https://books.google.com/books?id=DFR2AwAAQBAJ&pg=PT598}}

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.{{cite book |last1=Schechter |first1=Neil L. |title=Pain in Infants, Children, and Adolescents |date=1993 |publisher=Williams & Wilkins |isbn=978-0-683-07588-5 |url=https://books.google.com/books?id=Qh19Z6WLsqUC&pg=PA189 |access-date=6 September 2018 |archive-date=15 December 2023 |archive-url=https://web.archive.org/web/20231215100439/https://books.google.com/books?id=Qh19Z6WLsqUC&pg=PA189#v=onepage&q&f=false |url-status=live }} 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.{{cite journal |last1=Hicks |first1=Robert D. |title=Frontline Pharmacies |url=https://www.sciencehistory.org/distillations/magazine/frontline-pharmacies |journal=Chemical Heritage Magazine |publisher=Chemical Heritage Foundation |date=2011 |access-date=29 October 2018 |archive-date=30 September 2020 |archive-url=https://web.archive.org/web/20200930032439/https://www.sciencehistory.org/distillations/magazine/frontline-pharmacies |url-status=live }}{{cite news |last1=Trickey |first1=Erick |title=Inside the Story of America's 19th-Century Opiate Addiction |url=https://www.smithsonianmag.com/history/inside-story-americas-19th-century-opiate-addiction-180967673/ |access-date=6 September 2018 |work=Smithsonian |date=4 January 2018 |archive-date=23 December 2020 |archive-url=https://web.archive.org/web/20201223090543/https://www.smithsonianmag.com/history/inside-story-americas-19th-century-opiate-addiction-180967673/ |url-status=live }} It was also prescribed frequently for women, for menstrual pain and diseases of a "nervous character".{{rp|85}}

At first it was assumed (wrongly) that this new method of application would not be addictive.{{cite book |last1=Booth |first1=Martin |title=Opium : a history |url=https://archive.org/details/opiumhistory00boot |url-access=registration |publisher=St. Martin's Press |isbn=978-0-312-20667-3 |edition=1st U.S.|date=12 June 1999 }}

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."{{cite journal |last1=Wisniak |first1=Jaime |title=Pierre-Jean Robiquet |journal=Educación Química |date=March 2013 |volume=24 |pages=139–149 |doi=10.1016/S0187-893X(13)72507-2 |doi-access=free }} His discovery of the alkaloid led to the development of a generation of antitussive and antidiarrheal medicines based on codeine.{{cite book |last1=Filan |first1=Kenaz |title=The power of the poppy : harnessing nature's most dangerous plant ally |date=2011 |publisher=Park Street Press |isbn=978-1-59477-399-0 |page=69 |url=https://books.google.com/books?id=JV4oDwAAQBAJ&pg=PT69 |access-date=30 October 2018 |archive-date=15 December 2023 |archive-url=https://web.archive.org/web/20231215100411/https://books.google.com/books?id=JV4oDwAAQBAJ&pg=PT69#v=onepage&q&f=false |url-status=live }}

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.

Heroin received little attention until it was independently synthesized by Felix Hoffmann (1868–1946), working for Heinrich Dreser (1860–1924) at Bayer Laboratories.{{cite web|title=Felix Hoffmann|url=https://www.sciencehistory.org/historical-profile/felix-hoffmann|website=Science History Institute|access-date=21 March 2018|date=June 2016|archive-date=21 March 2018|archive-url=https://web.archive.org/web/20180321130305/https://www.sciencehistory.org/historical-profile/felix-hoffmann|url-status=live}} 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.{{cite book |last1=Cooper |first1=Raymond |last2=Deakin |first2=Jeffrey John |title=Botanical miracles : chemistry of plants that changed the world |date=22 February 2016 |publisher=CRC Press |isbn=978-1-4987-0428-1 |page=137 |url=https://books.google.com/books?id=aXGmCwAAQBAJ&pg=PA137 |access-date=30 October 2018 |archive-date=15 December 2023 |archive-url=https://web.archive.org/web/20231215100915/https://books.google.com/books?id=aXGmCwAAQBAJ&pg=PA137#v=onepage&q&f=false |url-status=live }}{{cite journal | vauthors = Sneader W | title = The discovery of heroin | journal = Lancet | volume = 352 | issue = 9141 | pages = 1697–9 | date = November 1998 | pmid = 9853457 | doi = 10.1016/S0140-6736(98)07115-3 | s2cid = 1819676 | url = https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(98)07115-3.pdf | quote = Bayer registered the name heroin in June, 1898. | access-date = 30 October 2018 | archive-date = 17 December 2020 | archive-url = https://web.archive.org/web/20201217133639/https://www.thelancet.com/ | url-status = live }}

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.{{cite book |last1=Newton |first1=David E. |title=Youth substance abuse : a reference handbook |date=2016 |publisher=ABC-CLIO |location=Santa Barbara, CA |isbn=978-1-4408-3983-2 |pages=41–60 |url=https://books.google.com/books?id=NNGuDAAAQBAJ&pg=PA41 |access-date=30 October 2018 |archive-date=15 December 2023 |archive-url=https://web.archive.org/web/20231215100916/https://books.google.com/books?id=NNGuDAAAQBAJ&pg=PA41 |url-status=live }}

Next, Martin Freund and Edmund Speyer developed oxycodone, also from thebaine, at the University of Frankfurt in 1916.{{cite news |last1=Crow |first1=James Mitchell |title=Addicted to the cure |url=https://www.chemistryworld.com/features/new-opioid-drugs/2500163.article |access-date=30 October 2018 |work=Chemistry World |date=3 January 2017 |archive-date=7 November 2020 |archive-url=https://web.archive.org/web/20201107132726/https://www.chemistryworld.com/features/new-opioid-drugs/2500163.article |url-status=live }}

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.

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.{{cite book|title=Methadone Matters: Evolving Community Methadone Treatment of Opiate Addiction|date=2003|publisher=CRC Press|isbn=978-0-203-63309-0|page=13|url=https://books.google.com/books?id=A8ObB64ZKWoC&pg=PA13|url-status=live|archive-url=https://web.archive.org/web/20151223052336/https://books.google.com/books?id=A8ObB64ZKWoC&pg=PA13|archive-date=23 December 2015}}

In 1959 the Belgian physician Paul Janssen developed fentanyl, a synthetic opioid with 30 to 50 times the potency of heroin.{{cite web |title=Fact Sheet: Fentanyl and Synthetic Opioids |url=http://www.drugpolicy.org/sites/default/files/Synthetic-Opioids-Fact-Sheet.pdf |website=Drug Policy Alliance |access-date=30 October 2018 |date=September 2016 |archive-date=29 August 2020 |archive-url=https://web.archive.org/web/20200829142150/https://www.drugpolicy.org/sites/default/files/Synthetic-Opioids-Fact-Sheet.pdf |url-status=dead }}

Nearly 150 synthetic opioids are now known.

Non-clinical use of opium was criminalized in the United States by the Harrison Narcotics Tax Act of 1914, and by many other laws.{{cite web |title=Laws Learn about the laws concerning opioids from the 1800s until today |url=https://www.naabt.org/laws.cfm |website=The National Alliance of Advocates for Buprenorphine Treatment |access-date=30 October 2018 |archive-date=22 December 2020 |archive-url=https://web.archive.org/web/20201222164151/https://www.naabt.org/laws.cfm |url-status=live }}{{cite web |last1=White |first1=William L. |title=The Early Criminalization of Narcotic Addiction |url=http://www.williamwhitepapers.com/pr/dlm_uploads/2014-The-Early-Criminalization-of-Narcotic-Addiction.pdf |website=William White Papers |access-date=30 October 2018 |archive-date=26 October 2020 |archive-url=https://web.archive.org/web/20201026041222/http://www.williamwhitepapers.com/pr/dlm_uploads/2014-The-Early-Criminalization-of-Narcotic-Addiction.pdf |url-status=dead }} The use of opioids was stigmatized, and it was seen as a dangerous substance, to be prescribed only as a last resort for dying patients. The Controlled Substances Act of 1970 eventually relaxed the harshness of the Harrison Act.{{citation needed|date=October 2018}}

In the United Kingdom the 1926 report of the Departmental Committee on Morphine and Heroin Addiction under the Chairmanship of the President of the Royal College of Physicians reasserted medical control and established the "British system" of control—which lasted until the 1960s.{{cite book | vauthors = Mars S | title = Making Health Policy | chapter = Peer pressure and imposed consensus: the making of the 1984 Guidelines of Good Clinical Practice in the Treatment of Drug Misuse | series = Clio Medica | volume = 75 | issue = 2 | pages = 149–83 | date = 2003 | doi = 10.1163/9789004333109_009 | pmid = 16212730 | isbn = 978-90-04-33310-9 }}

In the 1980s the World Health Organization published guidelines for prescribing drugs, including opioids, for different levels of pain. In the U.S., Kathleen Foley and Russell Portenoy became leading advocates for the liberal use of opioids as painkillers for cases of "intractable non-malignant pain".{{cite news |last1=Jacobs |first1=Harrison |title=This one-paragraph letter may have launched the opioid epidemic |url=https://www.businessinsider.com/porter-and-jick-letter-launched-the-opioid-epidemic-2016-5 |access-date=30 October 2018 |work=Business Insider |date=26 May 2016 |archive-date=6 August 2020 |archive-url=https://web.archive.org/web/20200806022110/https://www.businessinsider.com/porter-and-jick-letter-launched-the-opioid-epidemic-2016-5 |url-status=live }}{{cite journal | vauthors = Portenoy RK, Foley KM | title = Chronic use of opioid analgesics in non-malignant pain: report of 38 cases | journal = Pain | volume = 25 | issue = 2 | pages = 171–86 | date = May 1986 | pmid = 2873550 | doi = 10.1016/0304-3959(86)90091-6 | s2cid = 23959703 }}

With little or no scientific evidence to support their claims, industry scientists and advocates suggested that people with chronic pain would be resistant to addiction.{{cite journal | vauthors = Meldrum ML | title = The Ongoing Opioid Prescription Epidemic: Historical Context | journal = American Journal of Public Health | volume = 106 | issue = 8 | pages = 1365–6 | date = August 2016 | pmid = 27400351 | pmc = 4940677 | doi = 10.2105/AJPH.2016.303297 }}

The release of OxyContin in 1996 was accompanied by an aggressive marketing campaign promoting the use of opioids for pain relief. Increasing prescription of opioids fueled a growing black market for heroin. Between 2000 and 2014 there was an "alarming increase in heroin use across the country and an epidemic of drug overdose deaths".{{cite book |last1=Quinones |first1=Sam |title=Dreamland : the true tale of America's opiate epidemic |date=2015 |publisher=Bloomsbury Press |isbn=978-1-62040-251-1}}

As a result, health care organizations and public health groups, such as Physicians for Responsible Opioid Prescribing, have called for decreases in the prescription of opioids. In 2016, the Centers for Disease Control and Prevention (CDC) issued a new set of guidelines for the prescription of opioids "for chronic pain outside of active cancer treatment, palliative care, and end-of-life care" and the increase of opioid tapering.{{cite journal | vauthors = Dowell D, Haegerich TM, Chou R | title = CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016 | journal = MMWR. Recommendations and Reports | volume = 65 | issue = 1 | pages = 1–49 | date = March 2016 | pmid = 26987082 | doi = 10.15585/mmwr.rr6501e1 | doi-access = free | pmc = 6390846 }}

In April 2019 the U.S. Food and Drug Administration announced the launch of a new education campaign to help Americans understand the important role they play in removing and properly disposing of unused prescription opioids from their homes. This new initiative is part of the FDA's continued efforts to address the nationwide opioid crisis (see below) and aims to help decrease unnecessary exposure to opioids and prevent new addiction. The [https://www.fda.gov/drugs/ensuring-safe-use-medicine/safe-opioid-disposal-remove-risk-outreach-toolkit "Remove the Risk" campaign] is targeting women ages 35–64, who are most likely to oversee household health care decisions and often serve as the gatekeepers to opioids and other prescription medications in the home.{{Cite web |date=2020-03-24 |title=FDA launches public education campaign to encourage safe removal of unused opioid pain medicines from homes |url=https://www.fda.gov/news-events/press-announcements/fda-launches-public-education-campaign-encourage-safe-removal-unused-opioid-pain-medicines-homes |access-date=2023-12-15 |website=FDA |language=en |archive-date=2 December 2020 |archive-url=https://web.archive.org/web/20201202175658/https://www.fda.gov/news-events/press-announcements/fda-launches-public-education-campaign-encourage-safe-removal-unused-opioid-pain-medicines-homes |url-status=live }}

{{Main|Opioid epidemic}}

The term "opioid" originated in the 1950s.{{Cite web|title = opioid: definition of opioid in Oxford dictionary (American English) (US)|url = http://www.oxforddictionaries.com/us/definition/american_english/opioid|archive-url = https://web.archive.org/web/20140627150404/http://www.oxforddictionaries.com/us/definition/american_english/opioid|url-status = dead|archive-date = 27 June 2014|website = www.oxforddictionaries.com|access-date = 14 February 2016|quote = Opioid: 1950s: from opium + -oid.}} 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".{{cite journal | vauthors = Wikler A, Martin WR, Pescor FT, Eades CG | title = Factors regulating oral consumption of an opioid (Etonitazene) by morphine-addicted rats | journal = Psychopharmacologia | volume = 5 | pages = 55–76 | date = October 1963 | pmid = 14082382 | doi = 10.1007/bf00405575 | s2cid = 38073529 | quote = In this paper, the term, 'opioid', is used in the sense originally proposed by DR. 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".{{cite journal | vauthors = Martin WR | title = Opioid antagonists | journal = Pharmacological Reviews | volume = 19 | issue = 4 | pages = 463–521 | date = December 1967 | pmid = 4867058 }} 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".{{cite book|title=Textbook of Pharmacology |chapter=Opioid analgesics and antagonists | vauthors = Mehdi B | veditors = Seth SD, Seth V|page=III.137 |publisher=Elsevier India |year=2008 |isbn=978-81-312-1158-8}} 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.

In 2011, the Obama administration released a white paper describing the administration's plan to deal with the opioid crisis. The administration's concerns about addiction and accidental overdosing have been echoed by numerous other medical and government advisory groups around the world.{{cite web|title=Epidemic: Responding to America's Prescription Drug Abuse Crisis |url=http://www.whitehouse.gov/sites/default/files/ondcp/issues-content/prescription-drugs/rx_abuse_plan.pdf|archive-url=https://web.archive.org/web/20120303154035/http://www.whitehouse.gov/sites/default/files/ondcp/issues-content/prescription-drugs/rx_abuse_plan.pdf|publisher=The White House|date=2011|url-status=dead|archive-date=3 March 2012}}{{cite web |url=http://www.ccsa.ca/resource%20library/canada-strategy-prescription-drug-misuse-report-en.pdf |title=First Do No Harm: Responding to Canada's Prescription Drug Crisis |date=March 2013 |access-date=8 March 2017 |archive-date=2 March 2019 |archive-url=https://web.archive.org/web/20190302235040/http://www.ccsa.ca/resource |url-status=live }}{{cite web |url=http://www.delhidailynews.com/news/UK--Task-Force-offers-ideas-for-opioid-addiction-solutions-1402491160/ |title=UK: Task Force offers ideas for opioid addiction solutions |publisher=Delhidailynews.com |date=11 June 2014 |access-date=7 January 2016 |archive-url=https://web.archive.org/web/20170606021651/http://www.delhidailynews.com/news/UK--Task-Force-offers-ideas-for-opioid-addiction-solutions-1402491160/ |archive-date=6 June 2017 |url-status=dead }}

As of 2015, prescription drug monitoring programs exist in every state, except for Missouri.{{cite news|url=https://www.kansascity.com/news/politics-government/article209982404.html|title=Every state but Missouri has opioid drug tracking. Why are senators against it?|newspaper=The Kansas City Star|first=Allison|last=Kite|date=29 April 2018|access-date=5 November 2018|archive-date=27 December 2020|archive-url=https://web.archive.org/web/20201227122856/https://www.kansascity.com/news/politics-government/article209982404.html|url-status=live}} These programs allow pharmacists and prescribers to access patients' prescription histories in order to identify suspicious use. However, a survey of US physicians published in 2015 found that only 53% of doctors used these programs, while 22% were not aware that the programs were available to them.{{cite journal | vauthors = Rutkow L, Turner L, Lucas E, Hwang C, Alexander GC | title = Most primary care physicians are aware of prescription drug monitoring programs, but many find the data difficult to access | journal = Health Affairs | volume = 34 | issue = 3 | pages = 484–92 | date = March 2015 | pmid = 25732500 | doi = 10.1377/hlthaff.2014.1085 | doi-access = free }} The Centers for Disease Control and Prevention was tasked with establishing and publishing a new guideline, and was heavily lobbied.{{cite web | first = Matthew | last = Perrone | agency = Associated Press | url = http://www.philly.com/philly/news/nation_world/20151220_Painkiller_politics__Effort_to_curb_prescribing_under_fire.html | title = Painkiller politics: Effort to curb prescribing under fire | publisher = Philly.com | access-date = 7 January 2016 | date = 20 December 2015 | archive-date = 22 December 2018 | archive-url = https://web.archive.org/web/20181222044942/http://www.philly.com/philly/news/nation_world/20151220_Painkiller_politics__Effort_to_curb_prescribing_under_fire.html | url-status = live }} In 2016, the United States Centers for Disease Control and Prevention published its Guideline for Prescribing Opioids for Chronic Pain, recommending that opioids only be used when benefits for pain and function are expected to outweigh risks, and then used at the lowest effective dosage, with avoidance of concurrent opioid and benzodiazepine use whenever possible. Research suggests that the prescription of high doses of opioids related to chronic opioid therapy (COT) can at times be prevented through state legislative guidelines and efforts by health plans that devote resources and establish shared expectations for reducing higher doses.{{cite journal | vauthors = Von Korff M, Dublin S, Walker RL, Parchman M, Shortreed SM, Hansen RN, Saunders K | title = The Impact of Opioid Risk Reduction Initiatives on High-Dose Opioid Prescribing for Patients on Chronic Opioid Therapy | journal = The Journal of Pain | volume = 17 | issue = 1 | pages = 101–10 | date = January 2016 | pmid = 26476264 | pmc = 4698093 | doi = 10.1016/j.jpain.2015.10.002 }}

On 10 August 2017, Donald Trump declared the opioid crisis a (non-FEMA) national public health emergency.{{cite news | first1 = Joel | last1 = Achenbach | first2 = John | last2 = Wagner | first3 = Lenny | last3 = Bernstein | url = https://www.washingtonpost.com/politics/trump-declares-opioid-crisis-is-a-national-emergency-pledges-more-money-and-attention/2017/08/10/5aaaae32-7dfe-11e7-83c7-5bd5460f0d7e_story.html | title = Trump says opioid crisis is a national emergency, pledges more money and attention | newspaper = Washington Post | access-date = 11 August 2017 | archive-date = 24 November 2020 | archive-url = https://web.archive.org/web/20201124103354/https://www.washingtonpost.com/politics/trump-declares-opioid-crisis-is-a-national-emergency-pledges-more-money-and-attention/2017/08/10/5aaaae32-7dfe-11e7-83c7-5bd5460f0d7e_story.html | url-status = live }}

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.{{cite web |title=Feasibility Study on Opium Licensing in Afghanistan for the Production of Morphine and Other Essential Medicines |date=September 2005 |publisher=ICoS |url=http://www.isn.ethz.ch/Digital-Library/Publications/Detail/?id=13751&lng=en |access-date=3 March 2015 |archive-date=3 March 2016 |archive-url=https://web.archive.org/web/20160303235641/http://www.isn.ethz.ch/Digital-Library/Publications/Detail/?id=13751&lng=en |url-status=live }} 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 poppy-based drugs. The World Health Organization is now working with administrations from various countries to train healthworkers and to develop national regulations regarding drug prescription to facilitate a greater prescription of poppy-based medicines.{{cite web |title=Assuring Availability of Opioid Analgesics |publisher=World Health Organization |url=http://www.euro.who.int/document/e76503.pdf |url-status=dead |archive-url=https://web.archive.org/web/20091201034539/http://www.euro.who.int/document/e76503.pdf |archive-date=1 December 2009 }}

Another idea to increase morphine availability is proposed by the Senlis Council, 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 those in severe pain and unable to access poppy-based drugs under the current system.

{{See also|Opioid use disorder|Recreational drug use}}

File:US timeline. Prescription opioid pain reliever deaths.jpg

Opioids can produce strong feelings of euphoria{{cite journal | vauthors = Ghelardini C, Di Cesare Mannelli L, Bianchi E | title = The pharmacological basis of opioids | journal = Clinical Cases in Mineral and Bone Metabolism | volume = 12 | issue = 3 | pages = 219–21 | date = 2015 | pmid = 26811699 | pmc = 4708964 | doi = 10.11138/ccmbm/2015.12.3.219 | quote = The opioid effects transcending analgesia include sedation, respiratory depression, constipation and a strong sense of euphoria. }} and are frequently used recreationally. Traditionally associated with illicit opioids such as heroin, prescription opioids are misused recreationally.

Drug misuse and non-medical use include the use of drugs for reasons or at doses other than prescribed. Opioid misuse can also include providing medications to persons for whom it was not prescribed. Such diversion may be treated as crimes, punishable by imprisonment in many countries.{{cite journal | vauthors = Barrett SP, Meisner JR, Stewart SH | title = What constitutes prescription drug misuse? Problems and pitfalls of current conceptualizations | journal = Current Drug Abuse Reviews | volume = 1 | issue = 3 | pages = 255–62 | date = November 2008 | pmid = 19630724 | doi = 10.2174/1874473710801030255 | url = http://www.bentham.org/cdar/openaccsesarticle/cdar%201-3/0002CDAR.pdf | url-status = dead | archive-url = https://web.archive.org/web/20100615214225/http://bentham.org/cdar/openaccsesarticle/cdar%201-3/0002CDAR.pdf | archive-date = 15 June 2010 }}{{cite journal | vauthors = McCabe SE, Boyd CJ, Teter CJ | title = Subtypes of nonmedical prescription drug misuse | journal = Drug and Alcohol Dependence | volume = 102 | issue = 1–3 | pages = 63–70 | date = June 2009 | pmid = 19278795 | pmc = 2975029 | doi = 10.1016/j.drugalcdep.2009.01.007 }} In 2014, almost 2 million Americans abused or were dependent on prescription opioids.{{cite web|title=Prescription Opioid Overdose Data {{!}} Drug Overdose {{!}} CDC Injury Center|url=https://www.cdc.gov/drugoverdose/data/overdose.html|website=www.cdc.gov|access-date=17 January 2017|date=31 August 2018|archive-date=24 August 2019|archive-url=https://web.archive.org/web/20190824072528/https://www.cdc.gov/drugoverdose/data/overdose.html|url-status=live}}{{Cite web |title=Chronic Pain Management and Opioid Misuse: A Public Health Concern (Position Paper) |url=https://www.aafp.org/about/policies/all/chronic-pain-management-opiod-misuse.html |access-date=2023-09-09 |website=American Academy of Family Physicians |language=en-US |archive-date=4 October 2023 |archive-url=https://web.archive.org/web/20231004124424/https://www.aafp.org/about/policies/all/chronic-pain-management-opiod-misuse.html |url-status=live }}

There are a number of broad classes of opioids:{{cite web | url= https://www.sciencedaily.com/terms/opioid.htm | title= Opioid drug | website= Science Daily | access-date= 2021-06-25 | archive-date= 19 April 2021 | archive-url= https://web.archive.org/web/20210419134504/https://www.sciencedaily.com/terms/opioid.htm | url-status= live }}

• Natural opiates: alkaloids contained in the resin of the opium poppy, primarily morphine, codeine, and thebaine, but not papaverine and noscapine which have a different mechanism of action
• Esters of morphine opiates: slightly chemically altered but more natural than the semi-synthetics, as most are morphine prodrugs, diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphine dipropionate), desomorphine, acetylpropionylmorphine, dibenzoylmorphine, diacetyldihydromorphine;{{cite web|title=Esters of Morphine|url=http://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1953-01-01_2_page009.html|publisher=United Nations Office on Drugs and Crime|access-date=10 March 2012|year=1953|archive-date=24 December 2018|archive-url=https://web.archive.org/web/20181224151550/http://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1953-01-01_2_page009.html|url-status=live}}{{Cite web|url = http://www.eopiates.com/opioids/classification/esters-of-morphine-opioids.html|archive-url = https://web.archive.org/web/20230213170706/http://www.eopiates.com/opioids/classification/esters-of-morphine-opioids.html|url-status = dead|archive-date = 13 February 2023|title = Esters of Morphine Opioids|date = 28 May 2014|access-date = 12 February 2016|website = eOpiates}}
• Semi-synthetic opioids: created from either the natural opiates or morphine esters, such as hydromorphone, hydrocodone, oxycodone, oxymorphone, ethylmorphine and buprenorphine;
• Fully synthetic opioids: such as fentanyl, pethidine, levorphanol, methadone, tramadol, tapentadol, and dextropropoxyphene;
• Endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins.
• Endogenous opioids, non-peptide: Morphine, and some other opioids, which are produced in small amounts in the body, are included in this category.
• Natural opioids, non-animal, non-opiate: the leaves from Mitragyna speciosa (kratom) contain a few naturally-occurring opioids, active via Mu- and Delta receptors. Salvinorin A, found naturally in the Salvia divinorum plant, is a kappa-opioid receptor agonist.{{Cite journal|last1=Roth|first1=Bryan L.|last2=Baner|first2=Karen|last3=Westkaemper|first3=Richard|last4=Siebert|first4=Daniel|last5=Rice|first5=Kenner C.|last6=Steinberg|first6=SeAnna|last7=Ernsberger|first7=Paul|last8=Rothman|first8=Richard B.|date=2002-09-03|title=Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=99|issue=18|pages=11934–11939|doi=10.1073/pnas.182234399|issn=0027-8424|pmid=12192085|pmc=129372|bibcode=2002PNAS...9911934R|doi-access=free}}

Tramadol and tapentadol, which act as monoamine uptake inhibitors also act as mild and potent agonists (respectively) of the μ-opioid receptor.{{cite journal | vauthors = Raffa RB, Buschmann H, Christoph T, Eichenbaum G, Englberger W, Flores CM, Hertrampf T, Kögel B, Schiene K, Straßburger W, Terlinden R, Tzschentke TM | title = Mechanistic and functional differentiation of tapentadol and tramadol | journal = Expert Opinion on Pharmacotherapy | volume = 13 | issue = 10 | pages = 1437–49 | date = July 2012 | pmid = 22698264 | doi = 10.1517/14656566.2012.696097 | s2cid = 24226747 }} Both drugs produce analgesia even when naloxone, an opioid antagonist, is administered.{{cite journal | vauthors = Rojas-Corrales MO, Gibert-Rahola J, Micó JA | title = Tramadol induces antidepressant-type effects in mice | journal = Life Sciences | volume = 63 | issue = 12 | pages = PL175-80 | year = 1998 | pmid = 9749830 | doi = 10.1016/S0024-3205(98)00369-5 }}

Some minor opium alkaloids and various substances with opioid action are also found elsewhere, including molecules present in kratom, Corydalis, and Salvia divinorum plants and some species of poppy aside from Papaver somniferum. There are also strains which produce copious amounts of thebaine, an important raw material for making many semi-synthetic and synthetic opioids. Of all of the more than 120 poppy species, only two produce morphine.

Amongst analgesics there are a small number of agents which act on the central nervous system but not on the opioid receptor system and therefore have none of the other (narcotic) qualities of opioids although they may produce euphoria by relieving pain—a euphoria that, because of the way it is produced, does not form the basis of habituation, physical dependence, or addiction. Foremost amongst these are nefopam, orphenadrine, and perhaps phenyltoloxamine or some other antihistamines. Tricyclic antidepressants have painkilling effect as well, but they're thought to do so by indirectly activating the endogenous opioid system. Paracetamol is predominantly a centrally acting analgesic (non-narcotic) which mediates its effect by action on descending serotoninergic (5-hydroxy triptaminergic) pathways, to increase 5-HT release (which inhibits release of pain mediators). It also decreases cyclo-oxygenase activity. It has recently been discovered that most or all of the therapeutic efficacy of paracetamol is due to a metabolite, AM404, which enhances the release of serotonin and inhibits the uptake of anandamide.{{Citation needed|date=June 2010}}

Other analgesics work peripherally (i.e., not on the brain or spinal cord). Research is starting to show that morphine and related drugs may indeed have peripheral effects as well, such as morphine gel working on burns. Recent investigations discovered opioid receptors on peripheral sensory neurons.{{cite journal | vauthors = Stein C, Schäfer M, Machelska H | title = Attacking pain at its source: new perspectives on opioids | journal = Nature Medicine | volume = 9 | issue = 8 | pages = 1003–8 | date = August 2003 | pmid = 12894165 | doi = 10.1038/nm908 | s2cid = 25453057 }} A significant fraction (up to 60%) of opioid analgesia can be mediated by such peripheral opioid receptors, particularly in inflammatory conditions such as arthritis, traumatic or surgical pain.{{cite journal | vauthors = Stein C, Lang LJ | title = Peripheral mechanisms of opioid analgesia | journal = Current Opinion in Pharmacology | volume = 9 | issue = 1 | pages = 3–8 | date = February 2009 | pmid = 19157985 | doi = 10.1016/j.coph.2008.12.009 }} Inflammatory pain is also blunted by endogenous opioid peptides activating peripheral opioid receptors.{{cite journal | vauthors = Busch-Dienstfertig M, Stein C | title = Opioid receptors and opioid peptide-producing leukocytes in inflammatory pain--basic and therapeutic aspects | journal = Brain, Behavior, and Immunity | volume = 24 | issue = 5 | pages = 683–94 | date = July 2010 | pmid = 19879349 | doi = 10.1016/j.bbi.2009.10.013 | s2cid = 40205179 }}

It was discovered in 1953,{{Citation needed|date=August 2011}} that humans and some animals naturally produce minute amounts of morphine, codeine, and possibly some of their simpler derivatives like heroin and dihydromorphine, in addition to endogenous opioid peptides. Some bacteria are capable of producing some semi-synthetic opioids such as hydromorphone and hydrocodone when living in a solution containing morphine or codeine respectively.

Many of the alkaloids and other derivatives of the opium poppy are not opioids or narcotics; the best example is the smooth-muscle relaxant papaverine. Noscapine is a marginal case as it does have CNS effects but not necessarily similar to morphine, and it is probably in a category all its own.

Dextromethorphan (the stereoisomer of levomethorphan, a semi-synthetic opioid agonist) and its metabolite dextrorphan have no opioid analgesic effect at all despite their structural similarity to other opioids; instead they are potent NMDA antagonists and sigma 1 and 2-receptor agonists and are used in many over-the-counter cough suppressants.

Salvinorin A is a unique selective, powerful ĸ-opioid receptor agonist. It is not properly considered an opioid nevertheless, because:

1. chemically, it is not an alkaloid; and
2. it has no typical opioid properties: absolutely no anxiolytic or cough-suppressant effects. It is instead a powerful hallucinogen.

Opioid-peptides that are produced in the body include:

{{div col|colwidth=30em}}

• Endorphins
• Enkephalins
• Dynorphins
• Endomorphins

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β-endorphin is expressed in Pro-opiomelanocortin (POMC) cells in the arcuate nucleus, in the brainstem and in immune cells, and acts through μ-opioid receptors. β-endorphin has many effects, including on sexual behavior and appetite. β-endorphin is also secreted into the circulation from pituitary corticotropes and melanotropes. α-neoendorphin is also expressed in POMC cells in the arcuate nucleus.

Met-enkephalin is widely distributed in the CNS and in immune cells; [met]-enkephalin is a product of the proenkephalin gene, and acts through μ and δ-opioid receptors. leu-enkephalin, also a product of the proenkephalin gene, acts through δ-opioid receptors.

Dynorphin acts through κ-opioid receptors, and is widely distributed in the CNS, including in the spinal cord and hypothalamus, including in particular the arcuate nucleus and in both oxytocin and vasopressin neurons in the supraoptic nucleus.

Endomorphin acts through μ-opioid receptors, and is more potent than other endogenous opioids at these receptors.

Phenanthrenes naturally occurring in (opium):

{{div col|colwidth=30em}}

• Codeine
• Morphine
• Thebaine
• Oripavine{{cite journal | vauthors = Odell LR, Skopec J, McCluskey A | title = Isolation and identification of unique marker compounds from the Tasmanian poppy Papaver somniferum N. Implications for the identification of illicit heroin of Tasmanian origin | journal = Forensic Science International | volume = 175 | issue = 2–3 | pages = 202–8 | date = March 2008 | pmid = 17765420 | doi = 10.1016/j.forsciint.2007.07.002 }}

{{div col end}}

Preparations of mixed opium alkaloids, including papaveretum, are still occasionally used.

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• Diacetylmorphine (morphine diacetate; heroin)
• Nicomorphine (morphine dinicotinate)
• Dipropanoylmorphine (morphine dipropionate)
• Diacetyldihydromorphine
• Acetylpropionylmorphine
• Desomorphine
• Methyldesorphine
• Dibenzoylmorphine

{{div col end}}

{{div col|colwidth=30em}}

• Dihydrocodeine
• Ethylmorphine
• Heterocodeine

{{div col end}}

{{div col|colwidth=30em}}

• Buprenorphine
• Etorphine
• Hydrocodone
• Hydromorphone
• Oxycodone (sold as OxyContin)
• Oxymorphone

{{div col end}}

{{div col|colwidth=30em}}

• Fentanyl (see also list of fentanyl analogues)
• Alphamethylfentanyl
• Alfentanil
• Sufentanil
• Remifentanil
• Carfentanyl
• Ohmefentanyl
• Ohmecarfentanil

{{div col end}}

{{main|List of benzimidazole opioids}}

{{div col|colwidth=30em}}

• Metodesnitazene (Metazene)
• Etodesnitazene (Etazene)
• Etonitazepyne
• Etonitazepipne
• Nitazene opioids, which are a subgroup of benzimidazoles opioids
• Metonitazene
• Etonitazene
• Isotonitazene
• Clonitazene

{{div col end}}

{{div col|colwidth=30em}}

• Pethidine (meperidine)
• Ketobemidone
• MPPP
• Allylprodine
• Prodine
• PEPAP
• Promedol

{{div col end}}

{{div col|colwidth=30em}}

• Propoxyphene
• Dextropropoxyphene
• Dextromoramide
• Bezitramide
• Piritramide
• Methadone
• Dipipanone
• Levomethadyl acetate (LAAM)
• Difenoxin
• Diphenoxylate
• Loperamide (does cross the blood–brain barrier but is quickly pumped into the non-central nervous system by P-Glycoprotein. Mild opiate withdrawal in animal models exhibits this action after sustained and prolonged use including rhesus monkeys, mice, and rats.)

{{div col end}}

{{div col|colwidth=30em}}

• Dezocine—agonist/antagonist
• Pentazocine—agonist/antagonist
• Phenazocine

{{div col end}}

{{div col|colwidth=30em}}

• Buprenorphine—partial agonist
• Dihydroetorphine
• Etorphine

{{div col end}}

{{div col|colwidth=30em}}

• Butorphanol—agonist/antagonist
• Nalbuphine—agonist/antagonist
• Levorphanol
• Levomethorphan
• Racemethorphan

{{div col end}}

{{div col|colwidth=30em}}

• Lefetamine
• Meptazinol
• Mitragynine
• Tilidine
• Tramadol
• Tapentadol
• Eluxadoline
• Bucinnazine
• 7-Hydroxymitragynine

{{div col end}}

Plain allosteric modulators do not belong to the opioids, instead they are classified as opioidergics.

{{div col|colwidth=30em}}

• Nalmefene
• Naloxone
• Naltrexone
• Methylnaltrexone (Methylnaltrexone is only peripherally active as it does not cross the blood–brain barrier in sufficient quantities to be centrally active. As such, it can be considered the antithesis of loperamide.)
• Naloxegol (Naloxegol is only peripherally active as it does not cross the blood–brain barrier in sufficient quantities to be centrally active. As such, it can be considered the antitheses of loperamide.)

{{div col end}}

• Froehde reagent
• Opiate comparison
• Opioid epidemic
• Opioid tapering

{{Reflist}}

• [http://www.painpillabuse.com Opioid Withdrawal Symptoms] {{Webarchive|url=https://web.archive.org/web/20180810141013/http://www.painpillabuse.com/ |date=10 August 2018 }}—Information about Opioid and opiate withdrawal issues
• [https://web.archive.org/web/20110428180333/http://www.who.int/medicines/areas/quality_safety/GLs_Ens_Balance_NOCP_Col_EN_sanend.pdf World Health Organization guidelines for the availability and accessibility of controlled substances]
• [https://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1er.htm CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016]
• [http://whqlibdoc.who.int/hq/2011/WHO_EMP_MAR_2011.4_eng.pdf Reference list to the previous publication]
• [https://web.archive.org/web/20110521204911/http://www.who.int/medicines/areas/quality_safety/guide_nocp_sanend/en/index.html Links to all language versions of the previous publication]
• Video: Opioid side effects [http://vimeo.com/46549874 (Vimeo)] [https://www.youtube.com/watch?v=1IrJk4780gc (YouTube)]—A short educational film about the practical management of opioid side effects.

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