Opioid

Opioids are a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant. Opioids work in the brain to produce a variety of effects, including pain relief. As a class of substances, they act on opioid receptors to produce morphine-like effects.^[2][3]

The terms 'opioid' and 'opiate' are sometimes used interchangeably, but there are key differences based on the manufacturing processes of these medications.^[4]

Medically they are primarily used for

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

Because opioids are addictive and may result in fatal overdose, most are controlled substances. In 2013, between 28 and 38 million people used opioids illicitly (0.6% to 0.8% of the global population between the ages of 15 and 65).^[12] In 2011, an estimated 4 million people in the United States used opioids recreationally or were dependent on them.^[13] As of 2015, increased rates of recreational use and addiction are attributed to over-prescription of opioid medications and inexpensive illicit heroin.^[14][15][16] Conversely, fears about overprescribing, exaggerated side effects, and addiction from opioids are similarly blamed for under-treatment of pain.^[17][18]

Terminology

Opioids include opiates, an older term that refers to such drugs derived from opium, including morphine itself.^[19] 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.^[20] The terms opiate and narcotic are sometimes encountered as synonyms for opioid. Opiate is properly limited to the natural alkaloids found in the resin of the opium poppy although some include semi-synthetic derivatives.^[19][21] Narcotic, derived from words meaning 'numbness' or 'sleep', as an American legal term, refers to cocaine and opioids, and their source materials; it is also loosely applied to any illegal or controlled psychoactive drug.^[22][23] 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.^[24][25]

Medical uses

Pain

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.^[26][27][28] Other opioids are usually reserved for the relief of moderate to severe pain.^[27]

Acute pain

Opioids are effective for the treatment of acute pain (such as pain following surgery).^[29] 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.^[30] 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.^[31]

Chronic non-cancer pain

Guidelines have suggested that the risk of opioids is likely greater than their benefits when used for most non-cancer chronic conditions including

In treating chronic pain, opioids are an option to be tried after other less risky pain relievers have been considered, including paracetamol/acetaminophen or NSAIDs like ibuprofen or naproxen.^[35] Some types of chronic pain, including the pain caused by fibromyalgia or migraine, are preferentially treated with drugs other than opioids.^[36][37] The efficacy of using opioids to lessen chronic neuropathic pain is uncertain.^[38]

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.^[39] Opioids can also cause heightened sensitivity to headache pain.^[39] 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.^[39]

Opioids are being used more frequently in the management of non-malignant

Codeine was once viewed as the "gold standard" in cough suppressants, but this position is now questioned.^[47] Some recent placebo-controlled trials have found that it may be no better than a placebo for some causes including acute cough in children.^[48][49] as a consequence, it is not recommended for children.^[49] Additionally, there is no evidence that hydrocodone is useful in children.^[50] Similarly, a 2012 Dutch guideline regarding the treatment of acute cough does not recommend its use.^[51] (The opioid analogue dextromethorphan, long claimed to be as effective a cough suppressant as codeine,^[52] has similarly demonstrated little benefit in several recent studies.^[53])

Low dose morphine may help chronic cough but its use is limited by side effects.^[54]

Diarrhea

In cases of diarrhea-predominate

The ability to suppress diarrhea also produces constipation when opioids are used beyond several weeks.[55] Naloxegol, a peripherally-selective opioid antagonist is now available to treat opioid induced constipation.^[56]

Shortness of breath

Opioids may help with

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.^[61]

Hyperalgesia

Opioid-induced hyperalgesia (OIH) has been evident in patients after chronic opioid exposure.^[62][63]

Adverse effects

Each year 69,000 people worldwide die of opioid overdose, and 15 million people have an opioid addiction.^[65]

In older adults, opioid use is associated with increased adverse effects such as "sedation, nausea, vomiting, constipation, urinary retention, and falls".^[66] As a result, older adults taking opioids are at greater risk for injury.^[67] 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.^[68]

Prescription of opioids for acute low back pain and management of osteoarthritis seem to have long-term adverse effects^[69][70]

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.^[71] Studies of long term opioids have found that many stop them, and that minor side effects were common.^[72] Addiction occurred in about 0.3%.^[72] In the United States in 2016 opioid overdose resulted in the death of 1.7 in 10,000 people.^[73]

Reinforcement disorders

Tolerance

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.^[74] 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.^[75]

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

• calcium channel blockers^[76][77][78]
• intrathecal magnesium^[79][80] and zinc^[81]
• NMDA antagonists, such as dextromethorphan, ketamine,^[82] and memantine.^[83]
• cholecystokinin antagonists, such as proglumide^[84][85][86]
• Newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.^[87]

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

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

Critical patients who received regular doses of opioids experience iatrogenic withdrawal as a frequent syndrome.[91]

Addiction

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.^[92][93]

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.^[72]

Problems with opioids include the following:

1. Some people find that opioids do not relieve all of their pain.^[94]
2. Some people find that opioids side effects cause problems which outweigh the therapy's benefit.^[72]
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.^[72]
4. Long-term opioid use can cause opioid-induced hyperalgesia, which is a condition in which the patient has increased sensitivity to pain.^[95]

All of the opioids can cause side effects.

Tolerance to nausea occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol once at night) are very effective.^{[citation needed]} 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;^[96][97] it also produces analgesia that may allow lower doses of opioids with reduced nausea and vomiting.^[98][99]

• 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.^[100]

Patients with chronic pain using opioids had small improvements in pain and physically functioning and increased risk of vomiting.^[101]

Drowsiness

Tolerance to

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

Itching

• Antihistamines (e.g. fexofenadine)

Constipation

Opioid-induced constipation (OIC) develops in 90 to 95% of people taking opioids long-term.^[104] Since tolerance to this problem does not generally develop, most people on long-term opioids need to take a laxative or enemas.^[105]

Treatment of OIC is successional and dependent on severity.

Opioid rotation is one method suggested to minimise the impact of constipation in long-term users.^[114] 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

• Respiratory stimulants:
  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.^[120]

Patients with cardiac, respiratory disease and/or obstructive sleep apnoea are at increased risk for OIRD.^[121]

Increased pain sensitivity

Opioid-induced hyperalgesia – where individuals using opioids to relieve pain

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.^[128] 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.^{[129][130][131]}

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

Other adverse effects

Low sex hormone levels

Clinical studies have consistently associated medical and recreational opioid use with

Use of opioids may be a risk factor for failing to return to work.[138]^[139]

Persons performing any safety-sensitive task should not use opioids.

People who take opioids long term have increased likelihood of being unemployed.[141] 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.^[142]

Increased accident-proneness

Opioid use may increase

Opioids have been shown to reduce attention, more so when used with antidepressants and/or anticonvulsants.[146]

Rare side effects

Infrequent adverse reactions in patients taking opioids for pain relief include: dose-related respiratory depression (especially with more

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.[147]

With other depressant drugs

The concurrent use of opioids with other depressant drugs such as

Opioid effects (adverse or otherwise) can be reversed with an opioid antagonist such as

Naltrexone does not appear to increase risk of serious adverse events, which confirms the safety of oral naltrexone.[152] Mortality or serious adverse events due to rebound toxicity in patients with naloxone were rare.^[153]

Pharmacology

Opioids bind to specific

The

Functional selectivity

A new strategy of drug development takes receptor signal transduction into consideration. This strategy strives to increase the activation of desirable signalling pathways while reducing the impact on undesirable pathways. This differential strategy has been given several names, including functional selectivity and biased agonism. The first opioid that was intentionally designed as a biased agonist and placed into clinical evaluation is the drug oliceridine. It displays analgesic activity and reduced adverse effects.^[162]

Opioid comparison

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

Binding profiles

Usage

Opioid prescriptions in the US increased from 76 million in 1991 to 207 million in 2013.^[185]

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.^[186] 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.^[187] Certain populations have been affected by the opioid addiction crisis more than others, including First World communities^[188] and low-income populations.^[189] Public health specialists say that this may result from the unavailability or high cost of alternative methods for addressing chronic pain.^[190] 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.^[191] 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.^[192] 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.

History

Naturally occurring opioids

Opioids are among the world's oldest known drugs.^[193] 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.^{[194][195][196]}

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".^{[197][198][199]} Opium was known to the Egyptians, and is mentioned in the Ebers Papyrus as an ingredient in a mixture for the soothing of children,^[200][199] and for the treatment of breast abscesses.^[201]

Opium was also known to the Greeks.^[200] It was valued by

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)[199] By 1590 AD, opium poppies were a staple spring crop in the Subahs of Agra region.^[206]

The physician Paracelsus (c. 1493–1541) is often credited with reintroducing opium into medical use in Western Europe, during the German Renaissance. He extolled opium's benefits for medical use. He also claimed to have an "arcanum", a pill which he called laudanum, that was superior to all others, particularly when death was to be cheated. ("Ich hab' ein Arcanum – heiss' ich Laudanum, ist über das Alles, wo es zum Tode reichen will.")^[207] Later writers have asserted that Paracelsus' recipe for laudanum contained opium, but its composition remains unknown.^[207]

Laudanum

The term laudanum was used generically for a useful medicine until the 17th century. After Thomas Sydenham introduced the first liquid tincture of opium, "laudanum" came to mean a mixture of both opium and alcohol.^[207] Sydenham's 1669 recipe for laudanum mixed opium with wine, saffron, clove and cinnamon.^[208] Sydenham's laudanum was used widely in both Europe and the Americas until the 20th century.^[200][208] Other popular medicines, based on opium, included Paregoric, a much milder liquid preparation for children; Black-drop, a stronger preparation; and Dover's powder.^[208]

The opium trade

Opium became a major colonial commodity, moving legally and illegally through trade networks involving India, the Portuguese, the Dutch, the British and China, among others.^[209] The British East India Company saw the opium trade as an investment opportunity in 1683 AD.^[206] 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.^[206][210] 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.^{[211][210][209][212]}

Morphine

In the 19th century, two major scientific advances were made that had far-reaching effects. Around 1804, German pharmacist Friedrich Sertürner isolated morphine from opium. He described its crystallization, structure, and pharmacological properties in a well-received paper in 1817.^{[211][213][208][214]} Morphine was the first alkaloid to be isolated from any medicinal plant, the beginning of modern scientific drug discovery.^[211][215]

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.^{[216][208][199][217][218]}

Morphine was initially hailed as a wonder drug for its ability to ease pain.

Codeine

Codeine was discovered in 1832 by Pierre Jean Robiquet. Robiquet was reviewing a method for morphine extraction, described by Scottish chemist William Gregory (1803–1858). Processing the residue left from Gregory's procedure, Robiquet isolated a crystalline substance from the other active components of opium. He wrote of his discovery: "Here is a new substance found in opium ... We know that morphine, which so far has been thought to be the only active principle of opium, does not account for all the effects and for a long time the physiologists are claiming that there is a gap that has to be filled."^[223] His discovery of the alkaloid led to the development of a generation of antitussive and antidiarrheal medicines based on codeine.^[224]

Semisynthetic and synthetic opioids

Synthetic opioids were invented, and biological mechanisms for their actions discovered, in the 20th century.

Heroin received little attention until it was independently synthesized by Felix Hoffmann (1868–1946), working for Heinrich Dreser (1860–1924) at Bayer Laboratories.^[225] 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.^{[211][226][227]}

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.^[228] Next, Martin Freund and Edmund Speyer developed oxycodone, also from thebaine, at the University of Frankfurt in 1916.^[229] 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.^[228]

The first fully synthetic opioid was

Criminalization and medical use

Non-clinical use of opium was criminalized in the United States by the Harrison Narcotics Tax Act of 1914, and by many other laws.^[232][233] 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.^[211] The Controlled Substances Act of 1970 eventually relaxed the harshness of the Harrison Act.^{[citation needed]}

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.^[234]

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".^[235][236] 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.^{[211][237][235]}

The release of

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.[237] 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.^[239]

"Remove the Risk"

In April 2019 the U.S.

Definition

The term "opioid" originated in the 1950s.^[241] 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".^[242] 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".^[243] 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".^[244] 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)".^[2] 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.^[19]

Efforts to reduce recreational use in the US

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.^{[190][245][246][247]}

As of 2015, prescription drug monitoring programs exist in every state, except for Missouri.^[248] 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.^[249] The Centers for Disease Control and Prevention was tasked with establishing and publishing a new guideline, and was heavily lobbied.^[250] 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.^[34] 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.^[251]

On 10 August 2017, Donald Trump declared the opioid crisis a (non-FEMA) national public health emergency.^[252]

Global shortages

Opioids can produce strong feelings of euphoria^[255] and are frequently used recreationally. Traditionally associated with illicit opioids such as heroin, prescription opioids are misused recreationally.

There are a number of broad classes of opioids:[260]

• Natural
  opium poppy, primarily morphine, codeine, and thebaine, but not papaverine and noscapine
  which have a different mechanism of action
• diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphine dipropionate), desomorphine, acetylpropionylmorphine, dibenzoylmorphine, diacetyldihydromorphine;^[261][262]
• 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;
• 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
  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.^[263]

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.[266] 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.^[267] Inflammatory pain is also blunted by endogenous opioid peptides activating peripheral opioid receptors.^[268]

It was discovered in 1953,^{[citation needed]} 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

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	Skeletal molecular images
Adrenorphin
Amidorphin
Casomorphin
DADLE
DAMGO
Dermorphin
Endomorphin
Morphiceptin
Nociceptin
Octreotide
Opiorphin
TRIMU 5

Endogenous opioids

Opioid-peptides that are produced in the body include:

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.

Opium alkaloids and derivatives

Opium alkaloids

Phenanthrenes naturally occurring in (opium):

Preparations of mixed opium

Ethers of morphine

Semi-synthetic alkaloid derivatives

Synthetic opioids

Anilidopiperidines

Benzimidazoles

Benzimidazoles opioids are also known as nitazenes.

Phenylpiperidines

Diphenylpropylamine derivatives

Benzomorphan derivatives

Oripavine derivatives

Morphinan derivatives

Others

Allosteric modulators

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

Opioid antagonists

Tables of opioids

Table of morphinan opioids

Table of morphinan opioids: click to

Morphine 2,4-Dinitrophenylmorphine 6-MDDM Chlornaltrexamine Desomorphine Dihydromorphine Hydromorphinol Methyldesorphine N-Phenethylnormorphine RAM-378 3,6-diesters of morphine Acetylpropionylmorphine Dihydroheroin Dibenzoylmorphine Dipropanoylmorphine Heroin Nicomorphine Codeine-dionine family Codeine 6-MAC Benzylmorphine Codeine methylbromide Dihydroheterocodeine Ethylmorphine Heterocodeine Pholcodine Myrophine Methyldihydromorphine Morphinones and morphols 14-Cinnamoyloxycodeinone 14-Ethoxymetopon 14-Methoxymetopon PPOM 7-Spiroindanyloxymorphone Acetylmorphone Codeinone Conorphone Codoxime Thebacon Hydrocodone Hydromorphone Metopon Morphinone N-Phenethyl-14-Ethoxymetopon Oxycodone Oxymorphone Pentamorphone Semorphone Various semi-synthetics Chloromorphide 14-Hydroxydihydrocodeine Acetyldihydrocodeine Dihydrocodeine Nalbuphine Nicocodeine Nicodicodeine Oxymorphazone 1-Iodomorphine Active opiate metabolites M6G 6-MAM Norcodeine Normorphine Morphine-N-oxide Synthetic morphinans Cyclorphan DXA Levorphanol Levophenacylmorphan Levomethorphan Norlevorphanol Oxilorphan Phenomorphan Furethylnorlevorphanol Xorphanol Butorphanol Cyprodime Drotebanol Orvinols & Oripavine derivatives 6,14-Endoethenotetrahydrooripavine 7-PET Acetorphine BU-48 Buprenorphine Cyprenorphine Dihydroetorphine Etorphine Norbuprenorphine Thienorphine Opioid antagonists & inverse agonists 5'-Guanidinonaltrindole Diprenorphine Levallorphan MNTX Nalfurafine Nalmefene Naloxazone Naloxone Nalorphine Naltrexone Naltriben Naltrindole 6β-Naltrexol-d4 3-Iodobenzoyl Naltrexamine Morphinan dimers Pseudomorphine Naloxonazine Norbinaltorphimine Somniferine

Table of non-morphinan opioids

Table of non-morphinan opioids: click to

Benzomorphans 8-CAC Alazocine Bremazocine Dezocine Ketazocine Metazocine Pentazocine Phenazocine Cyclazocine 4-Phenylpiperidines 4-Fluoromeperidine Allylnorpethidine Anileridine Benzethidine Carperidine Difenoxin Diphenoxylate Etoxeridine Furethidine Hydroxypethidine Morpheridine Oxpheneridine Pethidine Pheneridine Phenoperidine Piminodine Properidine Sameridine Allylprodine α-Meprodine MPPP PEPAP α-Prodine Prosidol Trimeperidine Acetoxyketobemidone Droxypropine Ketobemidone Methylketobemidone Propylketobemidone Alvimopan Loperamide Picenadol Open chain opioids Dipipanone Methadone Normethadone Phenadoxone Dimepheptanol Levacetylmethadol Dextromoramide Levomoramide Racemoramide Diethylthiambutene Dimethylthiambutene Ethylmethylthiambutene Piperidylthiambutene Pyrrolidinylthiambutene Thiambutene Tipepidine Dextropropoxyphene Dimenoxadol Dioxaphetyl butyrate Levopropoxyphene Norpropoxyphene Diampromide Phenampromide Propiram Methiodone Isoaminile Lefetamine R-4066 Anilidopiperidines 3-Allylfentanyl 3-Methylfentanyl 3-Methylthiofentanyl 4-Phenylfentanyl Alfentanil α-Methylacetylfentanyl α-Methylfentanyl α-Methylthiofentanyl β-Hydroxyfentanyl β-Hydroxythiofentanyl β-Methylfentanyl Brifentanil Carfentanil Fentanyl Lofentanil Mirfentanil Ocfentanil Ohmefentanyl Parafluorofentanyl Phenaridine Remifentanil Sufentanil Thiofentanyl Trefentanil Various others Ethoheptazine Metheptazine Metethoheptazine Proheptazine Bezitramide Piritramide Clonitazene Etonitazene 18-MC 7-Hydroxymitragynine Akuammine Eseroline Hodgkinsine Mitragynine Pericine BW373U86 DPI-221 DPI-287 DPI-3290 SNC-80 AD-1211 AH-7921 Azaprocin Bromadol BRL-52537 Bromadoline C-8813 Ciramadol Doxpicomine Enadoline Faxeladol GR-89696 Herkinorin ICI-199441 ICI-204448 J-113397 JTC-801 LPK-26 Methopholine MT-45 NDMC NNC 63-0532 Nortilidine O-Desmethyltramadol Prodilidine Profadol Ro64-6198 SB-612111 SC-17599 RWJ-394674 TAN-67 Tapentadol Tifluadom Tramadol Trimebutine U-50488 U-69593 Viminol W-18 Alvimopan JDTic MCOPPB Beta-amine ketone 'compound 29'

See also

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

References