Opioid

Template:Short description Template:Cs1 config Template:Use dmy dates Template:Infobox drug class Opioids are a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, including pain relief.<ref name="Hemmings-2013">Template:Cite book</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The terms 'opioid' and 'opiate' are sometimes used interchangeably, but the term 'opioid' is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain.<ref>Template:Cite book</ref> Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum.<ref> {{#invoke:citation/CS1|citation |CitationClass=web }} </ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medically they are primarily used for pain relief, including anesthesia.<ref name="Stromgaard-2009" /> Other medical uses include suppression of diarrhea, replacement therapy for opioid use disorder, and suppressing cough. The opioid receptor antagonist naloxone is used to reverse opioid overdose.<ref name="Stromgaard-2009">Template:Cite book</ref> Extremely potent opioids such as carfentanil are approved only for veterinary use.<ref name="Walzer 2014">Template:Cite book</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> Opioids are also frequently used recreationally for their euphoric effects or to prevent withdrawal.<ref>Template:Cite book</ref> Opioids can cause death and have been used, alone and in combination, in a small number of executions in the United States.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Side effects of opioids may include itchiness, sedation, nausea, respiratory depression, constipation, and euphoria. Long-term use can cause tolerance, meaning that increased doses are required to achieve the same effect, and physical dependence, meaning that abruptly discontinuing the drug leads to unpleasant withdrawal symptoms.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The euphoria attracts recreational use, and frequent, escalating recreational use of opioids typically results in addiction. An overdose or concurrent use with other depressant drugs like benzodiazepines can result in death from respiratory depression.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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. Partial agonists, like the anti-diarrhea drug loperamide and antagonists, like naloxegol for opioid-induced constipation, do not cross the blood–brain barrier, but can displace other opioids from binding to 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).<ref name="WDR-2015">Template:Cite book</ref> By 2021, that number rose to 60 million.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2011, an estimated 4 million people in the United States used opioids recreationally or were dependent on them.<ref name="ASAM-2021">Template:Cite book</ref> As of 2015, increased rates of recreational use and addiction are attributed to over-prescription of opioid medications and inexpensive illicit heroin.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Conversely, fears about overprescribing, exaggerated side effects, and addiction from opioids are similarly blamed for under-treatment of pain.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

File:Opioid dependence.webm

Educational video on opioid dependence.

Terminology

File:Opiates v opioids.png

Opiates 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.<ref name="Offermanns">Template:Cite book</ref> Opiate is properly limited to the natural alkaloids found in the resin of the opium poppy although some include semi-synthetic derivatives.<ref name="Offermanns" /><ref name="Davies-2012">Template:Cite book</ref> 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.<ref name="Freye-2008">Template:Cite book</ref> 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.<ref>Template:Cite book</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite book</ref><ref>Template:Cite book</ref>

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.<ref>Template:Cite journal</ref><ref name="Fleisher"/><ref name="drugs">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Other opioids are usually reserved for the relief of moderate to severe pain.<ref name="Fleisher">Template:Cite book</ref>

Acute pain

Opioids are effective for the treatment of acute pain (such as pain following surgery).<ref name="pmid23150006">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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 headaches, back pain, and fibromyalgia.<ref>Template:Cite journal</ref> Thus they should be used cautiously in chronic non-cancer pain.<ref name="Okie S (2010)">Template:Cite journal
Responses to Okie's perspective: Template:Cite journal</ref> If used the benefits and harms should be reassessed at least every three months.<ref name="auto">Template:Cite journal</ref>

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.<ref name="pmid32110089">Template:Cite journal</ref> Some types of chronic pain, including the pain caused by fibromyalgia or migraine, are preferentially treated with drugs other than opioids.<ref name="AANfive">For information on the use and overuse of opioids to treat migraines, see Template:Citation, which cites

• Template:Cite journal
• Template:Cite journal
• Template:Citation</ref><ref>Template:Cite journal</ref> The efficacy of using opioids to lessen chronic neuropathic pain is uncertain.<ref name="pmid23986501">Template:Cite journal</ref>

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.<ref name="AHSfive">Template:Citation, which cites

• Template:Cite journal
• Template:Cite journal
• Template:Cite journal
• Template:Cite journal</ref> Opioids can also cause heightened sensitivity to headache pain.<ref name="AHSfive"/> 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.<ref name="AHSfive"/>

Opioids are being used more frequently in the management of non-malignant chronic pain.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> This practice has now led to a new and growing problem with addiction and misuse of opioids.<ref name="Okie S (2010)"/><ref>Template:Cite journal</ref> 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.<ref name="AANfive" /> Paracetamol and nonsteroidal anti-inflammatory drugs including ibuprofen and naproxen are considered safer alternatives.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Other

Cough

Codeine was once viewed as the "gold standard" in cough suppressants, but this position is now questioned.<ref>Template:Cite book</ref> Some recent placebo-controlled trials have found that it may be no better than a placebo for some causes including acute cough in children.<ref>Template:Cite journal</ref><ref name="CFP10" /> As a consequence, it is not recommended for children.<ref name="CFP10">Template:Cite journal</ref> Additionally, there is no evidence that hydrocodone is useful in children.<ref>Template:Cite journal</ref> Similarly, a 2012 Dutch guideline regarding the treatment of acute cough does not recommend its use.<ref name="Dutch2012">Template:Cite journal</ref> (The opioid analogue dextromethorphan, long claimed to be as effective a cough suppressant as codeine,<ref>Template:Cite journal</ref> has similarly demonstrated little benefit in several recent studies.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>)

Low dose morphine may help chronic cough but its use is limited by side effects.<ref>Template:Cite journal</ref>

Diarrhea

In cases of diarrhea-predominate irritable bowel syndrome, opioids may be used to suppress diarrhea.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Shortness of breath

Opioids may help with shortness of breath particularly in advanced diseases such as cancer and COPD among others.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Restless legs syndrome

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Hyperalgesia {{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

Opioid-induced hyperalgesia (OIH) has been evident in patients after chronic opioid exposure.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Adverse effects

Each year 69,000 people worldwide die of opioid overdose, and 15 million people have an opioid addiction.<ref>Template:Cite journal</ref>

In older adults, opioid use is associated with increased adverse effects such as "sedation, nausea, vomiting, constipation, urinary retention, and falls".<ref>Template:Cite journal</ref> As a result, older adults taking opioids are at greater risk for injury.<ref>Template:Cite journal</ref> 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.<ref name="musculoskeletalnetwork.com">Template:Cite journal</ref>

Prescription of opioids for acute low back pain and management of osteoarthritis seem to have long-term adverse effects<ref name="pmid30921976">Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> Studies of long term opioids have found that many stop them, and that minor side effects were common.<ref name="Long-term opioid management">Template:Cite journal</ref> Addiction occurred in about 0.3%.<ref name="Long-term opioid management"/> In the United States in 2016 opioid overdose resulted in the death of 1.7 in 10,000 people.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Reinforcement disorders

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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.<ref>Template:Cite journal</ref> 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.<ref name="pmid15731628">Template:Cite journal</ref>

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

• calcium channel blockers<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
• intrathecal magnesium<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and zinc<ref>Template:Cite journal</ref>
• NMDA antagonists, such as dextromethorphan, ketamine,<ref>Template:Cite journal</ref> and memantine.<ref>Template:Cite journal</ref>
• cholecystokinin antagonists, such as proglumide<ref name="pmid12792559">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
• Newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.<ref>Template:Cite journal</ref>

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 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.<ref name=oxford/> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Critical patients who received regular doses of opioids experience iatrogenic withdrawal as a frequent syndrome.<ref>Template:Cite journal</ref>

Addiction

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.<ref name=oxford/>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name="Long-term opioid management"/>

Problems with opioids include the following:

1. Some people find that opioids do not relieve all of their pain.<ref>Template:Cite journal</ref>
2. Some people find that opioids side effects cause problems which outweigh the therapy's benefit.<ref name="Long-term opioid management"/>
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.<ref name="Long-term opioid management"/>
4. Long-term opioid use can cause opioid-induced hyperalgesia, which is a condition in which the patient has increased sensitivity to pain.<ref>Template:Cite journal</ref>

All of the opioids can cause side effects.<ref name="Furlan">Template:Cite journal</ref> Common adverse reactions in patients taking opioids for pain relief include nausea and vomiting, drowsiness, itching, dry mouth, dizziness, and constipation.<ref name="Furlan"/><ref name=oxford>Template:Cite book</ref>

Nausea and vomiting

Tolerance to nausea occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol once at night) are very effective.Template: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;<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> it also produces analgesia that may allow lower doses of opioids with reduced nausea and vomiting.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>

• 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.<ref>Template:Cite journal</ref>

Patients with chronic pain using opioids had small improvements in pain and physically functioning and increased risk of vomiting.<ref>Template:Cite journal</ref>

Drowsiness

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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

Itching

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)

Constipation

Opioid-induced constipation (OIC) develops in 90 to 95% of people taking opioids long-term.<ref>Template:Cite news</ref> Since tolerance to this problem does not generally develop, most people on long-term opioids need to take a laxative or enemas.<ref>Template:Cite journal</ref>

Treatment of OIC is successional and dependent on severity.<ref name="KumarBarker2014">Template:Cite journal</ref> The first mode of treatment is non-pharmacological, and includes lifestyle modifications like increasing dietary fiber, fluid intake (around Template:Convert per day), and physical activity.<ref name="KumarBarker2014" /> 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.<ref name="KumarBarker2014" /> A common laxative regimen for OIC is the combination of docusate and bisacodyl.<ref name="KumarBarker2014" /><ref name="AlguirePhysicians2009">Template:Cite book</ref><ref name="ElliottSmith2016">Template:Cite book</ref>Template:Update inline 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.<ref name="AlguirePhysicians2009" /><ref name="ElliottSmith2016" />

If laxatives are insufficiently effective (which is often the case),<ref name="PoulsenBrock2015">Template:Cite journal</ref> 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.<ref name="KumarBarker2014" /><ref name="ElliottSmith2016" /><ref name="Davis, MD, FCCP, FAAHPMGoforth, MD2016">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> Naloxone by mouth appears to be the most effective.<ref>Template:Cite journal</ref> A daily 0.2 mg dose of naldemedine has been shown to significantly improve symptoms in patients with OIC.<ref>Template:Cite journal</ref>

Opioid rotation is one method suggested to minimise the impact of constipation in long-term users.<ref>Template:Cite journal</ref> 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 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Newer drugs such as BIMU-8 and CX-546 may be much more effective.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>Template:Non-primary source needed

• 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.<ref>Template:Cite journal</ref>

Patients with cardiac, respiratory disease and/or obstructive sleep apnoea are at increased risk for OIRD.<ref>Template:Cite journal</ref>

Increased pain sensitivity

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> If encountered, rotation between several different opioid pain medications may decrease the development of increased pain.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name="pmid20021351">Template:Cite journal</ref> 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.<ref name="pmid18717507">Template:Cite journal</ref><ref name="pmid19655103">Template:Cite book</ref><ref name="pmid20465361">Template:Cite journal</ref>

• 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 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%.<ref name="pmid25702934">Template:Cite journal</ref> Conversely, opioid therapy did not significantly affect testosterone levels in women.<ref name="pmid25702934" /> 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.<ref name="pmid30343356">Template:Cite journal</ref> 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.Template:Citation needed Template:As of, the effect of low-dose or acute opioid use on the endocrine system is unclear.<ref name="Fountas R183–R196">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Long-term use of opioids can affect the other hormonal systems as well.<ref name="Fountas R183–R196"/>

Disruption of work

Use of opioids may be a risk factor for failing to return to work.<ref name="pmid22289236">Template:Cite journal</ref><ref name="pmid19181448">Template:Cite journal</ref>

Persons performing any safety-sensitive task should not use opioids.<ref name="ACOEMfive">Template:Citation, which cites

• Template:Cite book</ref> 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.<ref name="ACOEMfive"/> 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.<ref name="ACOEMfive"/>

People who take opioids long term have increased likelihood of being unemployed.<ref name="pmid23389874">Template:Cite journal</ref> 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.<ref name="pmid19789432">Template:Cite journal</ref>

Increased accident-proneness

Opioid use may increase accident-proneness. Opioids may increase risk of traffic accidents<ref>Template:Cite journal</ref><ref name="pmid21125020">Template:Cite journal</ref> and accidental falls.<ref name="pmid21391934">Template:Cite journal</ref>

Reduced Attention

Opioids have been shown to reduce attention, more so when used with antidepressants and/or anticonvulsants.<ref>Template:Cite journal</ref>

Rare side effects

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).<ref name=oxford/> 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.

Interactions

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.<ref name="Gudin"/>

With other depressant drugs

The concurrent use of opioids with other depressant drugs such as benzodiazepines or ethanol increases the rates of adverse events and overdose.<ref name="Gudin">Template:Cite journal</ref> Despite this, opioids and benzodiazepines are concurrently dispensed in many settings.<ref name="pmid31425552">Template:Cite journal</ref><ref>Template:Cite journal</ref> As with an overdose of opioid alone, the combination of an opioid and another depressant may precipitate respiratory depression often leading to death.<ref>Template:Cite journal</ref> These risks are lessened with close monitoring by a physician, who may conduct ongoing screening for changes in patient behavior and treatment compliance.<ref name="Gudin"/>

Opioid antagonist

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

Opioid effects (adverse or otherwise) can be reversed with an opioid antagonist such as naloxone or naltrexone.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> Mortality or serious adverse events due to rebound toxicity in patients with naloxone were rare.<ref>Template:Cite journal</ref>

Pharmacology

Opioid comparison

Drug	Relative Potency <ref>Template:Cite book</ref>	Nonionized Fraction	Protein Binding	Lipid Solubility <ref>Template:Cite book</ref><ref>Template:Cite book</ref><ref name="MusazziMatera2015">Template:Cite journal</ref>
Morphine	1	++	+++	+++
Pethidine (meperidine)	0.1	+	+++	+++
Hydromorphone	10		+	+++
Alfentanil	10–25	++++	++++	+++
Fentanyl	50–100<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>	+	+++	++++
Remifentanil	250Template:Citation needed	+++	+++	++
Sufentanil	500–1000	++	++++	++++
Etorphine	1000–3000
Carfentanil	10000

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.svg

Locants 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 receptorTemplate:Citation needed. 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

INTA: selective agonist of KOR-DOR and KOR-MOR heteromers. Does not recruit β-arrestin II. Antinociceptive devoid of aversion, tolerance, and dependence in mice.<ref name="pmid24978316">Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

Opioid comparison

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

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

Template:Nowrap

Compound	Template:Abbrlink	Template:Abbrlink	Template:Abbrlink	Ref
3-HO-PCP	60	2,300	140	<ref name="pmid6088255">Template:Cite journal</ref>
7-Hydroxymitragynine	13.5	155	123	<ref name="pmid11960505">Template:Cite journal </ref>
β-Chlornaltrexamine	0.90	115	0.083	<ref name="pmid8114680">Template:Cite journal</ref>
β-Endorphin	1.0	1.0	52	<ref name="pmid8114680" />
β-Funaltrexamine	0.33	48	2.8	<ref name="pmid8114680" />
(+)-cis-3-methylfentanyl	0.24	Template:NtshTemplate:Abbr	Template:NtshTemplate:Abbr	<ref>Template:Cite journal</ref>
Alazocine	2.7	4.1	3.2	<ref name="pmid11197347">Template:Cite journal</ref>
(−)-Alazocine	3.0	15	4.7	<ref name="pmid2986989">Template:Cite journal</ref>
(+)-Alazocine	1,900	19,000	1,600	<ref name="pmid2986989" />
Alfentanil	39	21,200	Template:NtshTemplate:Abbr	<ref name="CorbettPaterson1993">Template:Cite book</ref>
Binaltorphimine	1.3	5.8	0.79	<ref name="CorbettPaterson1993" />
Template:Abbrlink	18	0.66	55	<ref name="pmid8114680" />
Bremazocine	0.75	2.3	0.089	<ref name="pmid8114680" />
(−)-Bremazocine	0.62	0.78	0.075	<ref name="CorbettPaterson1993" />
Buprenorphine	4.18	25.8	12.9	<ref name="pmid7562497">Template:Cite journal</ref>
Butorphanol	1.7	13	7.4	<ref name="pmid2986989" />
BW-3734	26	0.013	17	<ref name="pmid8114680" />
Carfentanil	0.024	3.3	43	<ref name="pmid11197347" />
Cebranopadol	0.7	18	2.6	<ref name="pmid24713140">Template:Cite journal</ref>
Codeine	79	Template:Ntsh>1,000	Template:Ntsh>1,000	<ref name="pmid8114680" />
CTOP	0.18	Template:Ntsh>1,000	Template:Ntsh>1,000	<ref name="pmid8114680" />
Cyclazocine	0.45	6.3	5.9	<ref name="pmid2986989" />
Cyprodime	9.4	356	176	<ref name="CorbettPaterson1993" />
DADLE	16	0.74	Template:Ntsh>1,000	<ref name="pmid8114680" />
DAMGO	2.0	Template:Ntsh>1,000	Template:Ntsh>1,000	<ref name="pmid8114680" />
[[(D-Ala2)Deltorphin II|[[[:Template:Small]]-Ala2]Deltorphin II]]	Template:Ntsh>1,000	3.3	Template:Ntsh>1,000	<ref name="pmid8114680" />
Dermorphin	0.33	Template:Ntsh>1,000	Template:Ntsh>1,000	<ref name="pmid8114680" />
(+)-Desmetramadol (O-DSMT)	17	690	1,800	<ref name="pmid8955860">Template:Cite journal</ref><ref name="pmid10991912">Template:Cite journal</ref>
Dextropropoxyphene	34.5	380	1,220	<ref name="pmid7562497" />
Dezocine	3.6	290	460	<ref name="pmid11197347" />
Dihydroetorphine	0.45	1.82	0.57	<ref name="pmid8719422">Template:Cite journal</ref>
Dihydromorphine	2.5	137	223	<ref>Template:Cite journal</ref>
Diprenorphine	0.072	0.23	0.017	<ref name="pmid8114680" />
DPDPE	Template:Ntsh>1,000	14	Template:Ntsh>1,000	<ref name="pmid8114680" />
DSLET	39	4.8	Template:Ntsh>1,000	<ref name="pmid8114680" />
Dynorphin A	32	Template:Ntsh>1,000	0.5	<ref name="pmid8114680" />
Ethylketazocine	3.1	101	0.40	<ref name="pmid8114680" />
(−)-Ethylketazocine	2.3	5.2	2.2	<ref name="pmid2986989" />
(+)-Ethylketazocine	2,500	Template:Ntsh>10,000	1,600	<ref name="pmid2986989" />
Etorphine	0.23	1.4	0.13	<ref name="pmid8114680" />
Fentanyl	0.39	Template:Ntsh>1,000	255	<ref name="pmid8114680" />
Hydrocodone	11.1	962	501	<ref name="pmid7562497" />
Hydromorphone	0.47	18.5	24.9	<ref name="pmid11197347" />
ICI-204488	Template:Ntsh>1,000	Template:Ntsh>1,000	0.71	<ref name="pmid8114680" />
Leu-enkephalin	3.4	4.0	Template:Ntsh>1,000	<ref name="pmid8114680" />
Levacetylmethadol	9.86	169	1,020	<ref name="pmid7562497" />
Lofentanil	0.68	5.5	5.9	<ref name="pmid8114680" />
Met-enkephalin	0.65	1.7	Template:Ntsh>1,000	<ref name="pmid8114680" />
Metazocine	3.8	44.3	13.3	<ref name="pmid11197347" />
Methadone	1.7	435	405	<ref name="pmid7562497" />
Dextromethadone	19.7	960	1,370	<ref name="pmid7562497" />
Levomethadone	0.945	371	1,860	<ref name="pmid7562497" />
Methallorphan	Template:NtshTemplate:Abbr	Template:NtshTemplate:Abbr	Template:NtshTemplate:Abbr	Template:Abbr
Dextrallorphan	1,140	2,660	34.6	<ref name="pmid7562497" />
Levallorphan	0.213	2.18	1,100	<ref name="pmid7562497" />
Methorphan	Template:NtshTemplate:Abbr	Template:NtshTemplate:Abbr	Template:NtshTemplate:Abbr	Template:Abbr
Dextromethorphan	1,280	11,500	7,000	<ref name="pmid7562497" />
Levomethorphan	11.2	249	225	<ref name="pmid7562497" />
Mitragynine	7.24	60.3	1,100	<ref name="pmid11960505" />
Mitragynine pseudoindoxyl	0.087	3.02	79.4	<ref name="pmid11960505" />
Morphanol	Template:NtshTemplate:Abbr	Template:NtshTemplate:Abbr	Template:NtshTemplate:Abbr	Template:NtshTemplate:Abbr
Dextrorphan	420	Template:Nts	Template:Nts	<ref name="pmid7562497" />
Levorphanol	0.42	3.61	4.2	<ref name="pmid7562497" />
Morphiceptin	56	Template:Ntsh>1,000	Template:Ntsh>1,000	<ref name="pmid8114680" />
Morphine	1.8	90	317	<ref name="CorbettPaterson1993" />
Morphine, (−)-	1.24	145	23.4	<ref name="pmid7562497" />
Morphine, (+)-	Template:Ntsh>10,000	Template:Ntsh>100,000	Template:Ntsh>300,000	<ref name="pmid7562497" />
MR-2266	1.0	3.0	0.16	<ref name="pmid11197347" />
Nalbuphine	11	Template:Ntsh>1,000	3.9	<ref name="pmid8114680" />
Nalmefene	0.24	16	0.083	<ref name="pmid15988468">Template:Cite journal</ref>
Nalorphine	0.97	148	1.1	<ref name="pmid8114680" />
Naloxonazine	0.054	8.6	11	<ref name="pmid8114680" />
Naloxone	1.1	16	12	<ref name="pmid2986989" />
(−)-Naloxone	0.93	17	2.3	<ref name="pmid8114680" />
(+)-Naloxone	Template:Ntsh>1,000	Template:Ntsh>1,000	Template:Ntsh>1,000	<ref name="pmid8114680" />
Naltrexone	1.0	149	3.9	<ref name="pmid8114680" />
Naltriben	12	0.013	13	<ref name="pmid8114680" />
Naltrindole	64	0.02	66	<ref name="pmid8114680" />
Norbinaltorphimine	2.2	65	0.027	<ref name="pmid8114680" />
Normorphine	4.0	310	149	<ref name="CorbettPaterson1993" />
Ohmefentanyl	0.0079	10	32	<ref name="CorbettPaterson1993" />
Oxycodone	8.69	901	1,350	<ref name="pmid7562497" />
Oxymorphindole	111	0.7	228	<ref name="pmid11197347" />
Oxymorphone	0.78	50	137	<ref name="CorbettPaterson1993" />
Pentazocine	5.7	31	7.2	<ref name="pmid8114680" />
Pethidine (meperidine)	385	Template:Nts	5,140	<ref name="CorbettPaterson1993" />
Phenazocine	0.20	5.0	2.0	<ref name="pmid19027293">Template:Cite journal</ref>
PLO17	30	Template:Ntsh>1,000	Template:Ntsh>1,000	<ref name="pmid8114680" />
Quadazocine	0.99	2.6	0.5	<ref name="Gharagozlou">Template:Cite journalTemplate:Cite journalTemplate:Cite journal</ref>
Salvinorin A	Template:Ntsh>10,000	Template:Ntsh>10,000	16	<ref name="pmid12192085">Template:Cite journal</ref>
Samidorphan	0.052	2.6	0.23	<ref name="pmid19282177">Template:Cite journal</ref>
Template:Abbrlink	33	1.7	Template:Ntsh>1,000	<ref name="pmid8114680" />
Spiradoline	21	Template:Ntsh>1,000	0.036	<ref name="pmid8114680" />
Sufentanil	0.15	50	75	<ref name="pmid8114680" />
Tianeptine	383	Template:Ntsh>10,000	Template:Ntsh>10,000	<ref name="pmid25026323">Template:Cite journal</ref>
Tifluadom	32	189	2.1	<ref name="pmid2986989" />
Tramadol	Template:Nts	Template:Nts	Template:Nts	<ref name="pmid7562497" />
(+)-Tramadol	Template:Nts	Template:Nts	Template:Nts	<ref name="pmid7562497" />
(−)-Tramadol	Template:Nts	Template:Nts	Template:Nts	<ref name="pmid7562497" />
U-47700	11.1	1,220	287	<ref>Template:Cite journal</ref>
U-50488	Template:Ntsh>1,000	Template:Ntsh>1,000	0.12	<ref name="pmid8114680" />
U-69593	Template:Ntsh>1,000	Template:Ntsh>1,000	0.59	<ref name="pmid8114680" />
U-77891	2	105	2,300	<ref name="Fujimoto">Template:Cite journal</ref>
Xorphanol	0.25	1.0	0.4	<ref name="Gharagozlou" />
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. Assays were done mostly with cloned or cultured rodent receptors.

Usage

Template:Global estimates of illicit drug users Opioid prescriptions in the US increased from 76 million in 1991 to 207 million in 2013.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Certain populations have been affected by the opioid addiction crisis more than others, including First World communities<ref>Template:Cite journal</ref> and low-income populations.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Public health specialists say that this may result from the unavailability or high cost of alternative methods for addressing chronic pain.<ref name="cpso.on.ca">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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

File:Raw opium.jpg

A sample of raw opium

Opioids are among the world's oldest known drugs.<ref>Template:Cite journal</ref> 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.<ref name="Colledge">Template:Cite book</ref><ref name="Kunzig">Template:Cite news</ref><ref name="Chevalier">Template:Cite book</ref>

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".<ref name="Kritikos">Template:Cite journal</ref><ref name="Sonnedecker">Template:Cite journal</ref><ref name=":Brownstyein">Template:Cite journal</ref> Opium was known to the Egyptians, and is mentioned in the Ebers Papyrus as an ingredient in a mixture for the soothing of children,<ref name="Duarte"/><ref name=":Brownstyein"/> and for the treatment of breast abscesses.<ref name="Rosso">Template:Cite journal</ref>

Opium was also known to the Greeks.<ref name="Duarte">Template:Cite journal</ref> It was valued by Hippocrates (Template:Circa – Template:Circa) and his students for its sleep-inducing properties, and used for the treatment of pain.<ref name="Astyrakaki">Template:Cite journal</ref> 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.<ref name="Türe">Template:Cite journal</ref> The medical use of opium is later discussed by Pedanius Dioscorides (Template:Circa – 90 AD), a Greek physician serving in the Roman army, in his five-volume work, De Materia Medica.<ref name="Osbaldeston">Template:Cite book</ref>

During the Islamic Golden Age, the use of opium was discussed in detail by Avicenna (Template:Circa – 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.<ref name="Heydari">Template:Cite journal</ref><ref name="Duarte"/>

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)<ref name=":Brownstyein"/> By 1590 AD, opium poppies were a staple spring crop in the Subahs of Agra region.<ref name="Asthana">Template:Cite journal</ref>

The physician Paracelsus (Template:Circa–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.")<ref name="Sigerist"/> Later writers have asserted that Paracelsus' recipe for laudanum contained opium, but its composition remains unknown.<ref name="Sigerist">Template:Cite journal</ref>

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.<ref name="Sigerist"/> Sydenham's 1669 recipe for laudanum mixed opium with wine, saffron, clove and cinnamon.<ref name="Hamilton">Template:Cite journal</ref> Sydenham's laudanum was used widely in both Europe and the Americas until the 20th century.<ref name="Duarte"/><ref name="Hamilton"/> Other popular medicines, based on opium, included Paregoric, a much milder liquid preparation for children; Black-drop, a stronger preparation; and Dover's powder.<ref name="Hamilton"/>

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.<ref name="Farooqui">Template:Cite journal</ref> The British East India Company saw the opium trade as an investment opportunity in 1683 AD.<ref name="Asthana"/> 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.<ref name="Asthana"/><ref name="Deming">Template:Cite journal</ref> 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.<ref name="Distillations">Template:Cite journal</ref><ref name="Deming"/><ref name="Farooqui"/><ref name="Mills">Template:Cite journal</ref>

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.<ref name="Distillations"/><ref name="Krishnamurti">Template:Cite journal</ref><ref name="Hamilton"/><ref name=Court2009>Template:Cite book</ref> Morphine was the first alkaloid to be isolated from any medicinal plant, the beginning of modern scientific drug discovery.<ref name="Distillations"/><ref name="Atanasov">Template:Cite journal</ref>

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.<ref name="Kotwal">Template:Cite journal</ref><ref name="Hamilton"/><ref name=":Brownstyein" /><ref name=Clay2013>Template:Cite book</ref><ref>Template:Cite book</ref>

Morphine was initially hailed as a wonder drug for its ability to ease pain.<ref name="Trickey"/> It could help people sleep,<ref name="Distillations"/> and had other useful side effects, including control of coughing and diarrhea.<ref name="Schechter">Template:Cite book</ref> 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.<ref name="Hicks">Template:Cite journal</ref><ref name="Trickey">Template:Cite news</ref> It was also prescribed frequently for women, for menstrual pain and diseases of a "nervous character".<ref name="Booth"/>Template:Rp At first it was assumed (wrongly) that this new method of application would not be addictive.<ref name="Distillations"/><ref name="Booth">Template:Cite book</ref>

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."<ref name="Wisniak">Template:Cite journal</ref> His discovery of the alkaloid led to the development of a generation of antitussive and antidiarrheal medicines based on codeine.<ref name="Filan">Template:Cite book</ref>

Semi-synthetic and synthetic opioids

Synthetic opioids were invented, and biological mechanisms for their actions discovered, in the 20th century.<ref name=":Brownstyein" /> 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.<ref name="Distillations"/>

Heroin received little attention until it was independently synthesized by Felix Hoffmann (1868–1946), working for Heinrich Dreser (1860–1924) at Bayer Laboratories.<ref name="HoffmanBio">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="Distillations"/><ref name="Cooper">Template:Cite book</ref><ref name="Sneader">Template:Cite journal</ref>

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.<ref name="Newton">Template:Cite book</ref> Next, Martin Freund and Edmund Speyer developed oxycodone, also from thebaine, at the University of Frankfurt in 1916.<ref name="Crow">Template:Cite news</ref> 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.<ref name="Newton"/>

The first fully synthetic opioid was meperidine (Demerol), found serendipitously by German chemist Otto Eisleb (or Eislib) at IG Farben in 1932.<ref name="Newton"/> Meperidine was the first opioid to have a structure unrelated to morphine, but with opioid-like properties.<ref name=":Brownstyein"/> Its analgesic effects were discovered by Otto Schaumann in 1939.<ref name="Newton"/> 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.<ref>Template:Cite book</ref> In 1959 the Belgian physician Paul Janssen developed fentanyl, a synthetic opioid with 30 to 50 times the potency of heroin.<ref name="Distillations"/><ref name="DPA">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Nearly 150 synthetic opioids are now known.<ref name="Newton"/>

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.<ref name="LAWS">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="White">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="Distillations"/> The Controlled Substances Act of 1970 eventually relaxed the harshness of the Harrison Act.Template: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.<ref name="Mars">Template:Cite book</ref>

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".<ref name="Jacobs">Template:Cite news</ref><ref name="Portenoy">Template:Cite journal</ref> 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.<ref name="Distillations"/><ref name="Meldrum">Template:Cite journal</ref><ref name="Jacobs"/>

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".<ref name="Meldrum"/><ref name="Distillations"/><ref name="Quinones">Template:Cite book</ref>

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.<ref name="Meldrum"/> 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.<ref name="Dowell">Template:Cite journal</ref>

Society and culture

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Definition

The term "opioid" originated in the 1950s.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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".<ref>Template:Cite journal</ref> 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".<ref>Template:Cite journal</ref> 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".<ref name=Mehdi>Template:Cite book</ref> 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)".<ref name="Hemmings-2013"/> 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.<ref name="Offermanns"/>

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.<ref name="cpso.on.ca"/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

As of 2015, prescription drug monitoring programs exist in every state, except for Missouri.<ref>Template:Cite news</ref> 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.<ref>Template:Cite journal</ref> The Centers for Disease Control and Prevention was tasked with establishing and publishing a new guideline, and was heavily lobbied.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="auto"/> 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.<ref>Template:Cite journal</ref>

On 10 August 2017, Donald Trump declared the opioid crisis a (non-FEMA) national public health emergency.<ref>Template:Cite news</ref>

Global shortages

Morphine and other poppy-based medicines have been identified by the World Health Organization as essential in the treatment of severe pain. As of 2002, seven countries (USA, UK, Italy, Australia, France, Spain and Japan) use 77% of the world's morphine supplies, leaving many emerging countries lacking in pain relief medication.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.

Recreational use

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

Prescription opioid pain reliever overdose deaths in the United States over years

Opioids can produce strong feelings of euphoria<ref>Template:Cite journal</ref> 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.<ref name=misuse>Template:Cite journal</ref><ref>Template:Cite journal</ref> In 2014, almost 2 million Americans abused or were dependent on prescription opioids.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Veterinary use

In the 17th century Robert Boyle investigated opium as a poison by giving opium to a dog. This experiment is the earliest documented use of an opioid in a domestic animal. In 1659, Christopher Wren and Boyle induced stupor in a dog via intravenous administration. Friedrich Wilhelm Adam Sertürner after isolating morphine from opium administered an aqueous alcoholic solution of morphine to four dogs and a mouse — one dog died and the others experienced sedation, convulsion, and emesis. Frederick Hobday was the first to report the varied effects of morphine in different species: in 1908 Hobday reported that morphine causes delirium in cats and horses but for dogs it induced anaesthesia. Hobday proposed that dogs be given 1/16th of a grain per pound to induce analgesia and anaesthesia in dogs. Despite the understanding of morphine's use in dogs it was not considered useful for other animals and in 1917, Howard Jay Milks wrote that morphine did not induce analgesia in animals other than dogs. Milks did report that 2 to 5 grains of morphine induced sedation in horses. Most research afterwards was more concerned with adverse effects of morphine as opposed to analgesic potential and opioids were not frequently used until the 1980s in veterinary practice, when an increased awareness of providing analgesia began to occur. Common routes for administration of opioids in veterinary medicine are intra-articular, intravenous, subcutaneous, intramuscular, intranasal, and transdermal. Common opioids in veterinary medicine are: morphine, fentanyl, and buprenorphine. Livestock are not usually given opioids due to a stand down period where an animal cannot be used for milking or slaughter following administration and strict regulations that require precise record keeping on administration ofr opioids.<ref>Template:Cite book</ref>

Classification

There are a number of broad classes of opioids:<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

• 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;<ref name=unodc>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

• 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.<ref>Template:Cite journal</ref>

Tramadol and tapentadol, which act as monoamine uptake inhibitors also act as mild and potent agonists (respectively) of the μ-opioid receptor.<ref>Template:Cite journal</ref> Both drugs produce analgesia even when naloxone, an opioid antagonist, is administered.<ref>Template:Cite journal</ref>

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.Template:Citation needed

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.<ref name="Stein C, Schäfer M, Machelska H (2003)">Template:Cite journal</ref> 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.<ref name="Stein C, Lang LJ (2009)">Template:Cite journal</ref> Inflammatory pain is also blunted by endogenous opioid peptides activating peripheral opioid receptors.<ref name="Busch-Dienstfertig M, Stein C (2010)">Template:Cite journal</ref>

It was discovered in 1953,Template: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 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	Skeletal molecular images
Adrenorphin	Chemical structure of Adrenorphin
Amidorphin	Chemical structure of Amidorphin.
Casomorphin	Chemical structure of Bovine β-casomorphin.
DADLE	Chemical structure of DADLE.
DAMGO	Chemical structure of DAMGO.
Dermorphin	Chemical structure of Dermorphin.
Endomorphin	Chemical structure of Endomorphin 1.
Morphiceptin	Chemical structure of Morphiceptin.
Nociceptin	Chemical structure of Nociceptin.
Octreotide	Chemical structure of Octreotide.
Opiorphin	Chemical structure of Opiorphin.
TRIMU 5	Chemical structure of TRIMU 5.

Endogenous opioids

Opioid-peptides that are produced in the body include: Template:Div col

• Endorphins
• Enkephalins
• Dynorphins
• Endomorphins

Template:Div col end 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.

Opium alkaloids and derivatives

Opium alkaloids

Phenanthrenes naturally occurring in (opium): Template:Div col

• Codeine
• Morphine
• Thebaine
• Oripavine<ref name="Odell 2007">Template:Cite journal</ref>

Template:Div col end Preparations of mixed opium alkaloids, including papaveretum, are still occasionally used.

Esters of morphine

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

Ethers of morphine

• Dihydrocodeine
• Ethylmorphine
• Heterocodeine

Semi-synthetic alkaloid derivatives

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

Synthetic opioids

Anilidopiperidines

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

Benzimidazoles

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

Phenylpiperidines

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

Diphenylpropylamine derivatives

• 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.)

Benzomorphan derivatives

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

Oripavine derivatives

• Buprenorphine—partial agonist
• Dihydroetorphine
• Etorphine

Morphinan derivatives

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

Others

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

Allosteric modulators

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

Opioid antagonists

• 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.)

Tables of opioids

Table of morphinan opioids

Table of morphinan opioids: click to

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

Table of non-morphinan opioids

Table of non-morphinan opioids: click to

Benzomorphans Chemical structure of 8-Carboxamidocyclazocine. 8-CAC Chemical structure of Allylnormetazocine. Alazocine Chemical structure of Bremazocine. Bremazocine Chemical structure of Dezocine. Dezocine Chemical structure of Ketazocine. Ketazocine Chemical structure of Metazocine. Metazocine Chemical structure of Pentazocine. Pentazocine Chemical structure of Phenazocine. Phenazocine Chemical structure of Cyclazocine. Cyclazocine 4-Phenylpiperidines Chemical structure of 4-Fluoromeperidine. 4-Fluoromeperidine Chemical structure of WIN-7681. Allylnorpethidine Chemical structure of Anileridine. Anileridine Chemical structure of Benzethidine. Benzethidine Chemical structure of Carperidine. Carperidine Chemical structure of Difenoxin. Difenoxin Chemical structure of Diphenoxylate. Diphenoxylate Chemical structure of Etoxeridine. Etoxeridine Chemical structure of Furethidine. Furethidine Chemical structure of Hydroxypethidine. Hydroxypethidine Chemical structure of Morpheridine. Morpheridine Chemical structure of Oxpheneridine. Oxpheneridine Chemical structure of Pethidine. Pethidine Chemical structure of Pheneridine. Pheneridine Chemical structure of Phenoperidine. Phenoperidine Chemical structure of Piminodine. Piminodine Chemical structure of Properidine. Properidine Chemical structure of Sameridine. Sameridine Chemical structure of Allylprodine. Allylprodine Chemical structure of α-meprodine. α-Meprodine Chemical structure of Desmethylprodine. MPPP Chemical structure of PEPAP. PEPAP Chemical structure of α-prodine. α-Prodine Chemical structure of Prosidol. Prosidol Chemical structure of Trimeperidine. Trimeperidine Chemical structure of Acetoxyketobemidone. Acetoxyketobemidone Chemical structure of Droxypropine. Droxypropine Chemical structure of Ketobemidone. Ketobemidone Chemical structure of Methylketobemidone. Methylketobemidone Chemical structure of Propylketobemidone. Propylketobemidone Chemical structure of Alvimopan. Alvimopan Chemical structure of Loperamide. Loperamide Chemical structure of Picenadol. Picenadol Open chain opioids Chemical structure of Dipipanone. Dipipanone Chemical structure of Methadone. Methadone Chemical structure of Normethadone. Normethadone Chemical structure of Phenadoxone. Phenadoxone Chemical structure of Dimepheptanol. Dimepheptanol Chemical structure of Levacetylmethadol. Levacetylmethadol Chemical structure of Dextromoramide. Dextromoramide Chemical structure of Levomoramide. Levomoramide Chemical structure of Racemoramide. Racemoramide Chemical structure of Diethylthiambutene Diethylthiambutene Chemical structure of Dimethylthiambutene. Dimethylthiambutene Chemical structure of Ethylmethylthiambutene. Ethylmethylthiambutene Chemical structure of Piperidylthiambutene Piperidylthiambutene Chemical structure of Pyrrolidinylthiambutene. Pyrrolidinylthiambutene Chemical structure of Thiambutene. Thiambutene Chemical structure of Tipepidine. Tipepidine Chemical structure of Dextropropoxyphene. Dextropropoxyphene Chemical structure of Dimenoxadol. Dimenoxadol Chemical structure of Dioxaphetyl butyrate. Dioxaphetyl butyrate Chemical structure of Levopropoxyphene. Levopropoxyphene Chemical structure of Norpropoxyphene. Norpropoxyphene Chemical structure of Diampromide. Diampromide Chemical structure of Phenampromide. Phenampromide Chemical structure of Propiram. Propiram Chemical structure of IC-26 structure. Methiodone Chemical structure of Isoaminile. Isoaminile Chemical structure of Lefetamine. Lefetamine Chemical structure of R-4066. R-4066 Anilidopiperidines Chemical structure of 3-allylfentanyl. 3-Allylfentanyl Chemical structure of 3-Methylfentanyl. 3-Methylfentanyl Chemical structure of 3-Methylthiofentanyl. 3-Methylthiofentanyl Chemical structure of 4-Phenylfentanyl. 4-Phenylfentanyl Chemical structure of Alfentanil. Alfentanil Chemical structure of α-methylacetylfentanyl. α-Methylacetylfentanyl Chemical structure of α-methylfentanyl. α-Methylfentanyl Chemical structure of α-methylthiofentanyl. α-Methylthiofentanyl Chemical structure of β-hydroxyfentanyl. β-Hydroxyfentanyl Chemical structure of β-hydroxythiofentanyl. β-Hydroxythiofentanyl Chemical structure of β-methylfentanyl. β-Methylfentanyl Chemical structure of Brifentanil. Brifentanil Chemical structure of Carfentanil. Carfentanil Chemical structure of Fentanyl. Fentanyl Chemical structure of Lofentanil. Lofentanil Chemical structure of Mirfentanil. Mirfentanil Chemical structure of Ocfentanil. Ocfentanil Chemical structure of Ohmefentanyl. Ohmefentanyl Chemical structure of Parafluorofentanyl. Parafluorofentanyl Chemical structure of Phenaridine. Phenaridine Chemical structure of Remifentanil. Remifentanil Chemical structure of Sufentanil. Sufentanil Chemical structure of Thiofentanyl. Thiofentanyl Chemical structure of Trefentanil. Trefentanil Various others Chemical structure of Ethoheptazine. Ethoheptazine Chemical structure of Metheptazine. Metheptazine Chemical structure of Metethoheptazine. Metethoheptazine Chemical structure of Proheptazine. Proheptazine Chemical structure of Bezitramide. Bezitramide Chemical structure of Piritramide. Piritramide Chemical structure of Clonitazene. Clonitazene Chemical structure of Etonitazene. Etonitazene Chemical structure of 18-Methoxycoronaridine. 18-MC Chemical structure of 7-Hydroxymitragynine. 7-Hydroxymitragynine Chemical structure of Akuammine. Akuammine Chemical structure of Eseroline. Eseroline Chemical structure of Hodgkinsine. Hodgkinsine Chemical structure of Mitragynine. Mitragynine Chemical structure of Pericine. Pericine Chemical structure of BW373U86. BW373U86 Chemical structure of DPI-221. DPI-221 Chemical structure of DPI-287. DPI-287 Chemical structure of DPI-3290. DPI-3290 Chemical structure of SNC-80. SNC-80 Chemical structure of AD-1211. AD-1211 Chemical structure of AH-7921. AH-7921 Chemical structure of Azaprocin. Azaprocin Chemical structure of Bromadol. Bromadol Chemical structure of BRL-52537. BRL-52537 Chemical structure of Bromadoline. Bromadoline Chemical structure of C-8813. C-8813 Chemical structure of Ciramadol. Ciramadol Chemical structure of Doxpicomine. Doxpicomine Chemical structure of Enadoline. Enadoline Chemical structure of Faxeladol. Faxeladol Chemical structure of GR-89696. GR-89696 Chemical structure of Herkinorin. Herkinorin Chemical structure of ICI-199441. ICI-199441 Chemical structure of ICI-204448. ICI-204448 Chemical structure of J-113397. J-113397 Chemical structure of JTC-801. JTC-801 Chemical structure of LPK-26. LPK-26 Chemical structure of Methopholine. Methopholine Chemical structure of MT-45. MT-45 Chemical structure of N-Desmethylclozapine. NDMC Chemical structure of NNC Template:Not a typo. NNC 63-0532 Chemical structure of Nortilidine. Nortilidine Chemical structure of O-Desmethyltramadol. O-Desmethyltramadol Chemical structure of Prodilidine. Prodilidine Chemical structure of Profadol. Profadol Chemical structure of Ro64-6198. Ro64-6198 Chemical structure of SB-612111. SB-612111 Chemical structure of SC-17599. SC-17599 Chemical structure of RWJ-394,674. RWJ-394674 Chemical structure of TAN-67. TAN-67 Chemical structure of Tapentadol. Tapentadol Chemical structure of Tifluadom. Tifluadom Chemical structure of Tramadol. Tramadol Chemical structure of Trimebutine. Trimebutine Chemical structure of U-50488. U-50488 Chemical structure of U-69593. U-69593 Chemical structure of Viminol. Viminol Chemical structure of W-18. W-18 Chemical structure of Alvimopan. Alvimopan Chemical structure of JDTic. JDTic Chemical structure of MCOPPB. MCOPPB Chemical structure of Beta-amine ketone 'compound 29' Beta-amine ketone 'compound 29'

See also

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

External links

• World Health Organization guidelines for the availability and accessibility of controlled substances
• CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016
• Reference list to the previous publication
• Links to all language versions of the previous publication