Opioid

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

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.[3] Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum.[4][5]

Medically they are primarily used for pain relief, including anesthesia.[6] 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.[6] Extremely potent opioids such as carfentanil are approved only for veterinary use.[7][8][9] Opioids are also frequently used recreationally for their euphoric effects or to prevent withdrawal.[10] Opioids can be fatal, and have been used, alone and in combination, in a small number of executions in the United States.[11][12]

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.[13] The euphoria attracts recreational use; frequent, escalating recreational use of opioids typically results in addiction. An overdose or concurrent use with other depressant drugs like benzodiazepines can result in death from respiratory depression.[14]

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).[15] By 2021, that number rose to 60 million.[16] In 2011, an estimated 4 million people in the United States used opioids recreationally or were dependent on them.[17] As of 2015, increased rates of recreational use and addiction are attributed to over-prescription of opioid medications and inexpensive illicit heroin.[18][19][20] Conversely, fears about overprescribing, exaggerated side effects, and addiction from opioids are similarly blamed for under-treatment of pain.[21][22] File:Opioid dependence.webm

## Contents

* 1 Terminology
* 2 Medical uses
* 2.1 Pain
* 2.1.1 Acute pain
* 2.1.2 Chronic non-cancer pain
* 2.2 Other
* 2.2.1 Cough
* 2.2.2 Diarrhea
* 2.2.3 Shortness of breath
* 2.2.4 Restless legs syndrome
* 3 Adverse effects
* 3.1 Reinforcement disorders
* 3.1.1 Tolerance
* 3.1.2 Physical dependence
* 3.1.3 Addiction
* 3.2 Nausea and vomiting
* 3.3 Drowsiness
* 3.4 Itching
* 3.5 Constipation
* 3.6 Respiratory depression
* 3.7 Increased pain sensitivity
* 3.8 Other adverse effects
* 3.8.1 Low sex hormone levels
* 3.8.2 Disruption of work
* 3.8.3 Increased accident-proneness
* 3.8.4 Rare side effects
* 3.8.5 Pregnancy
* 4 Interactions
* 4.1 With other depressant drugs
* 4.2 Opioid antagonist
* 5 Pharmacology
* 5.1 Functional selectivity
* 5.2 Opioid comparison
* 5.3 Binding profiles
* 6 Usage
* 7 History
* 7.1 Naturally occurring opioids
* 7.2 Laudanum
* 7.3 The opium trade
* 7.4 Morphine
* 7.5 Codeine
* 7.6 Semi-synthetic and synthetic opioids
* 7.7 Criminalization and medical use
* 8 Society and culture
* 8.1 Definition
* 8.2 Efforts to reduce recreational use in the US
* 8.3 Global shortages
* 8.4 Recreational use
* 9 Veterinary use
* 10 Classification
* 10.1 Endogenous opioids
* 10.2 Opium alkaloids and derivatives
* 10.2.1 Opium alkaloids
* 10.2.2 Esters of morphine
* 10.2.3 Ethers of morphine
* 10.2.4 Semi-synthetic alkaloid derivatives
* 10.3 Synthetic opioids
* 10.3.1 Anilidopiperidines
* 10.3.2 Benzimidazoles
* 10.3.3 Phenylpiperidines
* 10.3.4 Diphenylpropylamine derivatives
* 10.3.5 Benzomorphan derivatives
* 10.3.6 Oripavine derivatives
* 10.3.7 Morphinan derivatives
* 10.3.8 Others
* 10.4 Allosteric modulators
* 10.5 Opioid antagonists
* 10.6 Tables of opioids
* 10.6.1 Table of morphinan opioids
* 10.6.2 Table of non-morphinan opioids
* 11 See also
* 12 References
* 13 External links

## Terminology

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.[23] Opiate is properly limited to the natural alkaloids found in the resin of the opium poppy although some include semi-synthetic derivatives.[23][24] 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.[25] 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.[26] 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.[27][28] 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.[29][30]

## 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.[31][32][33] Other opioids are usually reserved for the relief of moderate to severe pain.[32]

#### Acute pain

Opioids are effective for the treatment of acute pain (such as pain following surgery).[34] 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.[35] 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.[36]

#### 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.[37] Thus they should be used cautiously in chronic non-cancer pain.[38] If used the benefits and harms should be reassessed at least every three months.[39]

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.[40] Some types of chronic pain, including the pain caused by fibromyalgia or migraine, are preferentially treated with drugs other than opioids.[41][42] The efficacy of using opioids to lessen chronic neuropathic pain is uncertain.[43]

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.[44] Opioids can also cause heightened sensitivity to headache pain.[44] 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.[44]

Opioids are being used more frequently in the management of non-malignant chronic pain.[45][46][47] This practice has now led to a new and growing problem with addiction and misuse of opioids.[38][48] 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.[41] Paracetamol and nonsteroidal anti-inflammatory drugs including ibuprofen and naproxen are considered safer alternatives.[49] 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.[50][51]

### Other

#### Cough

Codeine was once viewed as the "gold standard" in cough suppressants, but this position is now questioned.[52] Some recent placebo-controlled trials have found that it may be no better than a placebo for some causes including acute cough in children.[53][54] As a consequence, it is not recommended for children.[54] Additionally, there is no evidence that hydrocodone is useful in children.[55] Similarly, a 2012 Dutch guideline regarding the treatment of acute cough does not recommend its use.[56] (The opioid analogue dextromethorphan, long claimed to be as effective a cough suppressant as codeine,[57] has similarly demonstrated little benefit in several recent studies.[58])

Low dose morphine may help chronic cough but its use is limited by side effects.[59]

#### Diarrhea

In cases of diarrhea-predominate irritable bowel syndrome, opioids may be used to suppress diarrhea.[60] 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.[61]

#### Shortness of breath

Opioids may help with shortness of breath particularly in advanced diseases such as cancer and COPD among others.[62][63] 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.[64][65]

#### 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.[66]

Hyperalgesia

Main article: Chemistry:Opioid-induced hyperalgesia

Opioid-induced hyperalgesia (OIH) has been evident in patients after chronic opioid exposure.[67][68]

## Adverse effects

See also: Opioid overdose

Adverse effects of opioids

Common and short term

* Itching[69]
* Nausea[69]
* Vomiting[69]
* Constipation[69]
* Drowsiness[69]
* Dry mouth[69]

Other

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

Each year 69,000 people worldwide die of opioid overdose, and 15 million people have an opioid addiction.[70]

In older adults, opioid use is associated with increased adverse effects such as "sedation, nausea, vomiting, constipation, urinary retention, and falls".[71] As a result, older adults taking opioids are at greater risk for injury.[72] 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.[73]

Prescription of opioids for acute low back pain and management of osteoarthritis seem to have long-term adverse effects[74][75]

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.[76] Studies of long term opioids have found that many stop them, and that minor side effects were common.[77] Addiction occurred in about 0.3%.[77] In the United States in 2016 opioid overdose resulted in the death of 1.7 in 10,000 people.[78]

### Reinforcement disorders

Main article: Medicine:Opioid use disorder

#### 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.[79] 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.[80]

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

* calcium channel blockers[81][82][83]
* intrathecal magnesium[84][85] and zinc[86]
* NMDA antagonists, such as dextromethorphan, ketamine,[87] and memantine.[88]
* cholecystokinin antagonists, such as proglumide[89][90][91]
* Newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.[92]

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.[93] 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.[94] Physical dependence does not predict drug misuse or true addiction, and is closely related to the same mechanism as tolerance. While there are anecdotal claims of benefit with ibogaine, data to support its use in substance dependence is poor.[95]

Critical patients who received regular doses of opioids experience iatrogenic withdrawal as a frequent syndrome.[96]

#### 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.[93]

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.[97][98]

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.[77]

Problems with opioids include the following:

1. Some people find that opioids do not relieve all of their pain.[99]
2. Some people find that opioids side effects cause problems which outweigh the therapy's benefit.[77]
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.[77]
4. Long-term opioid use can cause opioid-induced hyperalgesia, which is a condition in which the patient has increased sensitivity to pain.[100]

All of the opioids can cause side effects.[69] Common adverse reactions in patients taking opioids for pain relief include nausea and vomiting, drowsiness, itching, dry mouth, dizziness, and constipation.[69][93]

### 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. 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 commonly used, with the added advantages of not causing movement disorders, and also possessing analgesic-sparing properties. THC relieves nausea and vomiting;[101][102] it also produces analgesia that may allow lower doses of opioids with reduced nausea and vomiting.[103][104]

* 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.[105]

Patients with chronic pain using opioids had small improvements in pain and physically functioning and increased risk of vomiting.[106]

### 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.[107][108]

* 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.[109] Since tolerance to this problem does not generally develop, most people on long-term opioids need to take a laxative and/or enemas.[110]

Treatment of OIC is successional and dependent on severity.[111] The first mode of treatment is non-pharmacological, and includes lifestyle modifications like increasing dietary fiber, fluid intake (around 1.5 L (51 US fl oz) per day), and physical activity.[111] 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.[111] A common laxative regimen for OIC is the combination of docusate and bisacodyl.[111][112][113][needs update] 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.[112][113]

If laxatives are insufficiently effective (which is often the case),[114] 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.[111][113][115] 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.[116] Naloxone by mouth appears to be the most effective.[117] A daily 0.2 mg dose of naldemedine has been shown to significantly improve symptoms in patients with OIC.[118]

Opioid rotation is one method suggested to minimise the impact of constipation in long-term users.[119] 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.[120][121] Newer drugs such as BIMU-8 and CX-546 may be much more effective.[122][123][124][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-HT1A 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.[125]

Patients with cardiac, respiratory disease and/or obstructive sleep apnoea are at increased risk for OIRD.[126]

### Increased pain sensitivity

Main article: Chemistry:Opioid-induced hyperalgesia

Opioid-induced hyperalgesia – where individuals using opioids to relieve pain paradoxically experience more pain as a result of that medication – has been observed in some people. This phenomenon, although uncommon, is seen in some people receiving palliative care, most often when dose is increased rapidly.[127][128] If encountered, rotation between several different opioid pain medications may decrease the development of increased pain.[129][130] Opioid induced hyperalgesia more commonly occurs with chronic use or brief high doses, but some research suggests that it may also occur with small doses.[131][132]

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.[133] 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.[134][135][136]

* 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%.[137] Conversely, opioid therapy did not significantly affect testosterone levels in women.[137] 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.[138] 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. As of 2013[update], the effect of low-dose or acute opioid use on the endocrine system is unclear.[139][140][141][142] Long-term use of opioids can affect the other hormonal systems as well.[139]

#### Disruption of work

Use of opioids may be a risk factor for failing to return to work.[143][144]

Persons performing any safety-sensitive task should not use opioids.[145] 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.[145] 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.[145]

People who take opioids long term have increased likelihood of being unemployed.[146] 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.[147]

#### Increased accident-proneness

Opioid use may increase accident-proneness. Opioids may increase risk of traffic accidents[148][149] and accidental falls.[150]

Reduced Attention

Opioids have been shown to reduce attention, more so when used with antidepressants and/or anticonvulsants.[151]

#### 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).[93] 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.

#### Pregnancy

This section is an excerpt from Opioids and pregnancy[ edit ]

## 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.[152]

### 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.[152] Despite this, opioids and benzodiazepines are concurrently dispensed in many settings.[153][154] As with an overdose of opioid alone, the combination of an opioid and another depressant may precipitate respiratory depression often leading to death.[155] These risks are lessened with close monitoring by a physician, who may conduct ongoing screening for changes in patient behavior and treatment compliance.[152]

### Opioid antagonist

Opioid effects (adverse or otherwise) can be reversed with an opioid antagonist such as naloxone or naltrexone.[156] 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.[157] Mortality or serious adverse events due to rebound toxicity in patients with naloxone were rare.[158]

## Pharmacology

See also: Biology:Opioid receptor

Opioid comparison  Drug  | Relative
Potency
[159] | Nonionized
Fraction  | Protein
Binding  | Lipid
Solubility
[160][161][162]

|
|
|
|

Morphine | 1  | ++  | +++  | +++
Pethidine (meperidine)  | 0.1  | \+  | +++  | +++
Hydromorphone | 10  |  | \+  | +++
Alfentanil | 10–25  | ++++  | ++++  | +++
Fentanyl | 50–100[163][164][165] | \+  | +++  | ++++
Remifentanil | +++  | +++  | ++
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.

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 receptor . Each group of opioid receptors elicits a distinct set of neurological responses, with the receptor subtypes (such as μ1 and μ2 for example) providing even more [measurably] specific responses. Unique to each opioid is its distinct binding affinity to the various classes of opioid receptors (e.g. the μ, κ, and δ opioid receptors are activated at different magnitudes according to the specific receptor binding affinities of the opioid). For example, the opiate alkaloid morphine exhibits high-affinity binding to the μ-opioid receptor, while ketazocine exhibits high affinity to ĸ receptors. It is this combinatorial mechanism that allows for such a wide class of opioids and molecular designs to exist, each with its own unique effect profile. Their individual molecular structure is also responsible for their different duration of action, whereby metabolic breakdown (such as N-dealkylation) is responsible for opioid metabolism.

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.[166]

### 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.[167]

### Opioid comparison

Main article: Chemistry:Equianalgesic

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

### Binding profiles

Binding profiles of opioids at opioid receptors (Ki, nM) Compound | MOR | DOR | KOR | Ref

|
|
|
|

3-HO-PCP | 60 | 2,300 | 140 | [168]
7-Hydroxymitragynine | 13.5 | 155 | 123 | [169]
β-Chlornaltrexamine | 0.90 | 115 | 0.083 | [170]
β-Endorphin | 1.0 | 1.0 | 52 | [170]
β-Funaltrexamine | 0.33 | 48 | 2.8 | [170]
(+)-cis-3-methylfentanyl | 0.24 | ND | ND | [171]
Alazocine | 2.7 | 4.1 | 3.2 | [172]
(−)-Alazocine | 3.0 | 15 | 4.7 | [173]
(+)-Alazocine | 1,900 | 19,000 | 1,600 | [173]
Alfentanil | 39 | 21,200 | ND | [174]
Binaltorphimine | 1.3 | 5.8 | 0.79 | [174]
BNTX | 18 | 0.66 | 55 | [170]
Bremazocine | 0.75 | 2.3 | 0.089 | [170]
(−)-Bremazocine | 0.62 | 0.78 | 0.075 | [174]
Buprenorphine | 4.18 | 25.8 | 12.9 | [175]
Butorphanol | 1.7 | 13 | 7.4 | [173]
BW-3734 | 26 | 0.013 | 17 | [170]
Carfentanil | 0.024 | 3.3 | 43 | [172]
Cebranopadol | 0.7 | 18 | 2.6 | [176]
Codeine | 79 | >1,000 | >1,000 | [170]
CTOP | 0.18 | >1,000 | >1,000 | [170]
Cyclazocine | 0.45 | 6.3 | 5.9 | [173]
Cyprodime | 9.4 | 356 | 176 | [174]
DADLE | 16 | 0.74 | >1,000 | [170]
DAMGO | 2.0 | >1,000 | >1,000 | [170]
[D-Ala2]Deltorphin II | >1,000 | 3.3 | >1,000 | [170]
Dermorphin | 0.33 | >1,000 | >1,000 | [170]
(+)-Desmetramadol (O-DSMT) | 17 | 690 | 1,800 | [177][178]
Dextropropoxyphene | 34.5 | 380 | 1,220 | [175]
Dezocine | 3.6 | 290 | 460 | [172]
Dihydroetorphine | 0.45 | 1.82 | 0.57 | [179]
Dihydromorphine | 2.5 | 137 | 223 | [180]
Diprenorphine | 0.072 | 0.23 | 0.017 | [170]
DPDPE | >1,000 | 14 | >1,000 | [170]
DSLET | 39 | 4.8 | >1,000 | [170]
Dynorphin A | 32 | >1,000 | 0.5 | [170]
Ethylketazocine | 3.1 | 101 | 0.40 | [170]
(−)-Ethylketazocine | 2.3 | 5.2 | 2.2 | [173]
(+)-Ethylketazocine | 2,500 | >10,000 | 1,600 | [173]
Etorphine | 0.23 | 1.4 | 0.13 | [170]
Fentanyl | 0.39 | >1,000 | 255 | [170]
Hydrocodone | 11.1 | 962 | 501 | [175]
Hydromorphone | 0.47 | 18.5 | 24.9 | [172]
ICI-204488 | >1,000 | >1,000 | 0.71 | [170]
Leu-enkephalin | 3.4 | 4.0 | >1,000 | [170]
Levacetylmethadol | 9.86 | 169 | 1,020 | [175]
Lofentanil | 0.68 | 5.5 | 5.9 | [170]
Met-enkephalin | 0.65 | 1.7 | >1,000 | [170]
Metazocine | 3.8 | 44.3 | 13.3 | [172]
Methadone | 1.7 | 435 | 405 | [175]
Dextromethadone | 19.7 | 960 | 1,370 | [175]
Levomethadone | 0.945 | 371 | 1,860 | [175]
Methallorphan | ND | ND | ND | ND
Dextrallorphan | 1,140 | 2,660 | 34.6 | [175]
Levallorphan | 0.213 | 2.18 | 1,100 | [175]
Methorphan | ND | ND | ND | ND
Dextromethorphan | 1,280 | 11,500 | 7,000 | [175]
Levomethorphan | 11.2 | 249 | 225 | [175]
Mitragynine | 7.24 | 60.3 | 1,100 | [169]
Mitragynine pseudoindoxyl | 0.087 | 3.02 | 79.4 | [169]
Morphanol | ND | ND | ND | ND
Dextrorphan | 420 | 34,700 | 5,950 | [175]
Levorphanol | 0.42 | 3.61 | 4.2 | [175]
Morphiceptin | 56 | >1,000 | >1,000 | [170]
Morphine | 1.8 | 90 | 317 | [174]
Morphine, (−)- | 1.24 | 145 | 23.4 | [175]
Morphine, (+)- | >10,000 | >100,000 | >300,000 | [175]
MR-2266 | 1.0 | 3.0 | 0.16 | [172]
Nalbuphine | 11 | >1,000 | 3.9 | [170]
Nalmefene | 0.24 | 16 | 0.083 | [181]
Nalorphine | 0.97 | 148 | 1.1 | [170]
Naloxonazine | 0.054 | 8.6 | 11 | [170]
Naloxone | 1.1 | 16 | 12 | [173]
(−)-Naloxone | 0.93 | 17 | 2.3 | [170]
(+)-Naloxone | >1,000 | >1,000 | >1,000 | [170]
Naltrexone | 1.0 | 149 | 3.9 | [170]
Naltriben | 12 | 0.013 | 13 | [170]
Naltrindole | 64 | 0.02 | 66 | [170]
Norbinaltorphimine | 2.2 | 65 | 0.027 | [170]
Normorphine | 4.0 | 310 | 149 | [174]
Ohmefentanyl | 0.0079 | 10 | 32 | [174]
Oxycodone | 8.69 | 901 | 1,350 | [175]
Oxymorphindole | 111 | 0.7 | 228 | [172]
Oxymorphone | 0.78 | 50 | 137 | [174]
Pentazocine | 5.7 | 31 | 7.2 | [170]
Pethidine (meperidine) | 385 | 4,350 | 5,140 | [174]
Phenazocine | 0.20 | 5.0 | 2.0 | [182]
PLO17 | 30 | >1,000 | >1,000 | [170]
Quadazocine | 0.99 | 2.6 | 0.5 | [183]
Samidorphan | 0.052 | 2.6 | 0.23 | [184]
SIOM | 33 | 1.7 | >1,000 | [170]
Spiradoline | 21 | >1,000 | 0.036 | [170]
Sufentanil | 0.15 | 50 | 75 | [170]
Tianeptine | 383 | >10,000 | >10,000 | [185]
Tifluadom | 32 | 189 | 2.1 | [173]
Tramadol | 2,120 | 57,700 | 42,700 | [175]
(+)-Tramadol | 1,330 | 62,400 | 54,000 | [175]
(−)-Tramadol | 24,800 | 213,000 | 53,500 | [175]
U-47700 | 11.1 | 1,220 | 287 | [186]
U-50488 | >1,000 | >1,000 | 0.12 | [170]
U-69593 | >1,000 | >1,000 | 0.59 | [170]
U-77891 | 2 | 105 | 2,300 | [187]
Xorphanol | 0.25 | 1.0 | 0.4 | [183]
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

Global estimates of drug users in 2016
(in millions of users)[188] Substance | Best
estimate | Low
estimate | High
estimate

|
|
|

Amphetamine-
type stimulants | 34.16 | 13.42 | 55.24
Cannabis | 192.15 | 165.76 | 234.06
Cocaine | 18.20 | 13.87 | 22.85
Ecstasy | 20.57 | 8.99 | 32.34
Opiates | 19.38 | 13.80 | 26.15
Opioids | 34.26 | 27.01 | 44.54

Opioid prescriptions in the US increased from 76 million in 1991 to 207 million in 2013.[189]

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.[190] 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.[191] Certain populations have been affected by the opioid addiction crisis more than others, including First World communities[192] and low-income populations.[193] Public health specialists say that this may result from the unavailability or high cost of alternative methods for addressing chronic pain.[194] 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.[195] 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.[196] 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

A sample of raw opium

Opioids are among the world's oldest known drugs.[197] 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.[198][199][200]

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".[201][202][203] Opium was known to the Egyptians, and is mentioned in the Ebers Papyrus as an ingredient in a mixture for the soothing of children,[204][203] and for the treatment of breast abscesses.[205]

Opium was also known to the Greeks.[204] It was valued by Hippocrates (c. 460 – c. 370 BC) and his students for its sleep-inducing properties, and used for the treatment of pain.[206] 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.[207] The medical use of opium is later discussed by Pedanius Dioscorides (c. 40 – 90 AD), a Greek physician serving in the Roman army, in his five-volume work, De Materia Medica.[208]

During the Islamic Golden Age, the use of opium was discussed in detail by Avicenna (c. 980 – June 1037 AD) in The Canon of Medicine. The book's five volumes include information on opium's preparation, an array of physical effects, its use to treat a variety of illness, contraindications for its use, its potential danger as a poison and its potential for addiction. Avicenna discouraged opium's use except as a last resort, preferring to address the causes of pain rather than trying to minimize it with analgesics. Many of Avicenna's observations have been supported by modern medical research.[209][204]

Exactly when the world became aware of opium in India and China is uncertain, but opium was mentioned in the Chinese medical work Kaibao Bencao (zh) (973 AD)[203] By 1590 AD, opium poppies were a staple spring crop in the Subahs of Agra region.[210]

The physician Paracelsus (c. 1493–1541) is often credited with reintroducing opium into medical use in Western Europe, during the German Renaissance. He extolled opium's benefits for medical use. He also claimed to have an "arcanum", a pill which he called laudanum, that was superior to all others, particularly when death was to be cheated. ("Ich hab' ein Arcanum – heiss' ich Laudanum, ist über das Alles, wo es zum Tode reichen will.")[211] Later writers have asserted that Paracelsus' recipe for laudanum contained opium, but its composition remains unknown.[211]

### 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.[211] Sydenham's 1669 recipe for laudanum mixed opium with wine, saffron, clove and cinnamon.[212] Sydenham's laudanum was used widely in both Europe and the Americas until the 20th century.[204][212] Other popular medicines, based on opium, included Paregoric, a much milder liquid preparation for children; Black-drop, a stronger preparation; and Dover's powder.[212]

### 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.[213] The British East India Company saw the opium trade as an investment opportunity in 1683 AD.[210] 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.[210][214] 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.[215][214][213][216]

### 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.[215][217][212][218] Morphine was the first alkaloid to be isolated from any medicinal plant, the beginning of modern scientific drug discovery.[215][219]

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.[220][212][203][221][222]

Morphine was initially hailed as a wonder drug for its ability to ease pain.[223] It could help people sleep,[215] and had other useful side effects, including control of coughing and diarrhea.[224] 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.[225][223] It was also prescribed frequently for women, for menstrual pain and diseases of a "nervous character".[226]: 85 At first it was assumed (wrongly) that this new method of application would not be addictive.[215][226]

### 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."[227] His discovery of the alkaloid led to the development of a generation of antitussive and antidiarrheal medicines based on codeine.[228]

###  Semi-synthetic and synthetic opioids

Synthetic opioids were invented, and biological mechanisms for their actions discovered, in the 20th century.[203] 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.[215]

Heroin received little attention until it was independently synthesized by Felix Hoffmann (1868–1946), working for Heinrich Dreser (1860–1924) at Bayer Laboratories.[229] 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.[215][230][231]

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.[232] Next, Martin Freund and Edmund Speyer developed oxycodone, also from thebaine, at the University of Frankfurt in 1916.[233] 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.[232]

The first fully synthetic opioid was meperidine (Demerol), found serendipitously by German chemist Otto Eisleb (or Eislib) at IG Farben in 1932.[232] Meperidine was the first opioid to have a structure unrelated to morphine, but with opioid-like properties.[203] Its analgesic effects were discovered by Otto Schaumann in 1939.[232] 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.[234] In 1959 the Belgian physician Paul Janssen developed fentanyl, a synthetic opioid with 30 to 50 times the potency of heroin.[215][235] Nearly 150 synthetic opioids are now known.[232]

### 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.[236][237] 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.[215] The Controlled Substances Act of 1970 eventually relaxed the harshness of the Harrison Act. 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.[238]

In the 1980s the World Health Organization published guidelines for prescribing drugs, including opioids, for different levels of pain.[239][240] 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.[215][241][239]

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".[241][215][242]

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.[241] 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.[243]

## Society and culture

Main article: Chemistry:Opioid epidemic

### Definition

The term "opioid" originated in the 1950s.[244] 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".[245] 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".[246] 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".[247] 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)".[1] 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.[23]

### 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.[194][248][249][250]

As of 2015, prescription drug monitoring programs exist in every state except for Missouri.[251] 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.[252] The Centers for Disease Control and Prevention (CDC) was tasked with establishing and publishing a new guideline, and was heavily lobbied.[253] In 2016, the CDC 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.[39] 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.[254]

On 10 August 2017, Donald Trump declared the opioid crisis a (non-FEMA) national public health emergency.[255]

### 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.[256] The current system of supply of raw poppy materials to make poppy-based medicines is regulated by the International Narcotics Control Board under the provision of the 1961 Single Convention on Narcotic Drugs. The amount of raw poppy materials that each country can demand annually based on these provisions must correspond to an estimate of the country's needs taken from the national consumption within the preceding two years. In many countries, underprescription of morphine is rampant because of the high prices and the lack of training in the prescription of opiates. The World Health Organization is now working with administrations from various countries to train healthcare workers and to develop national regulations regarding drug prescription to facilitate a greater prescription of opiates.[257]

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

### Recreational use

See also: Medicine:Opioid use disorder and Recreational drug use

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

Opioids can produce strong feelings of euphoria[258] 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.[259][260] In 2014, almost 2 million Americans abused or were dependent on prescription opioids.[261][262]

## 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 of opioids.[263]

## Classification

There are a number of broad classes of opioids:[264]

* 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), acetylpropionylmorphine, dibenzoylmorphine, diacetyldihydromorphine;[265][266]
* Semi-synthetic opioids: created from either the natural opiates or morphine esters, such as hydromorphone, hydrocodone, oxycodone, oxymorphone, ethylmorphine, buprenorphine and desomorphine;
* 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.[267]

Tramadol and tapentadol, which act as monoamine uptake inhibitors also act as mild and potent agonists (respectively) of the μ-opioid receptor.[268] Both drugs produce analgesia even when naloxone, an opioid antagonist, is administered.[269]

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.

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.[270] 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.[271] Inflammatory pain is also blunted by endogenous opioid peptides activating peripheral opioid receptors.[272]

It was discovered in 1953, 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 |
Amidorphin |
Casomorphin |
DADLE |
DAMGO |
Dermorphin |
Endomorphin |
Morphiceptin |
Nociceptin |
Octreotide |
Opiorphin |
TRIMU 5 |

### Endogenous opioids

Opioid-peptides that are produced in the body include:

* Endorphins
* Enkephalins
* Dynorphins
* Endomorphins

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):

* Codeine
* Morphine
* Thebaine
* Oripavine[273]

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

Main article: Chemistry:List of benzimidazole opioids

* 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

Morphine

2,4-Dinitrophenylmorphine

6-MDDM

Chlornaltrexamine

Desomorphine

|
|
|
|

Dihydromorphine

Hydromorphinol

Methyldesorphine

N-Phenethylnormorphine

RAM-378

3,6-diesters of morphine

Acetylpropionylmorphine

Dihydroheroin

Dibenzoylmorphine

Dipropanoylmorphine

Heroin

Nicomorphine

Codeine-dionine family

Codeine

6-MAC

Benzylmorphine

Codeine methylbromide

Dihydroheterocodeine

Ethylmorphine

Heterocodeine

Pholcodine

Myrophine

Methyldihydromorphine

Morphinones and morphols

14-Cinnamoyloxycodeinone

14-Ethoxymetopon

14-Methoxymetopon

PPOM

7-Spiroindanyloxymorphone

Acetylmorphone

Codeinone

Conorphone

Codoxime

Thebacon

Hydrocodone

Hydromorphone

Metopon

Morphinone

N-Phenethyl-14-Ethoxymetopon

Oxycodone

Oxymorphone

Pentamorphone

Semorphone

Various semi-synthetics

Chloromorphide

14-Hydroxydihydrocodeine

Acetyldihydrocodeine

Dihydrocodeine

Nalbuphine

Nicocodeine

Nicodicodeine

Oxymorphazone

1-Iodomorphine

Active opiate metabolites

M6G

6-MAM

Norcodeine

Normorphine

Morphine-N-oxide

Synthetic morphinans

Cyclorphan

DXA

Levorphanol

Levophenacylmorphan

Levomethorphan

Norlevorphanol

Oxilorphan

Phenomorphan

Furethylnorlevorphanol

Xorphanol

Butorphanol

Cyprodime

Drotebanol

Orvinols & Oripavine derivatives

6,14-Endoethenotetrahydrooripavine

7-PET

Acetorphine

BU-48

Buprenorphine

Cyprenorphine

Dihydroetorphine

Etorphine

Norbuprenorphine

Thienorphine

Opioid antagonists & inverse agonists

5'-Guanidinonaltrindole

Diprenorphine

Levallorphan

MNTX

Nalfurafine

Nalmefene

Naloxazone

Naloxone

Nalorphine

Naltrexone

Naltriben

Naltrindole

6β-Naltrexol-d4

3-Iodobenzoyl Naltrexamine

Morphinan dimers

Pseudomorphine

Naloxonazine

Norbinaltorphimine

Somniferine

#### Table of non-morphinan opioids

Table of non-morphinan opioids: click to

| Benzomorphans

8-CAC

Alazocine

Bremazocine

Dezocine

Ketazocine

Metazocine

Pentazocine

Phenazocine

Cyclazocine

4-Phenylpiperidines

4-Fluoromeperidine

Allylnorpethidine

Anileridine

Benzethidine

Carperidine

Difenoxin

Diphenoxylate

Etoxeridine

Furethidine

Hydroxypethidine

Morpheridine

Oxpheneridine

Pethidine

Pheneridine

Phenoperidine

Piminodine

Properidine

Sameridine

Allylprodine

α-Meprodine

MPPP

PEPAP

α-Prodine

Prosidol

Trimeperidine

Acetoxyketobemidone

Droxypropine

Ketobemidone

Methylketobemidone

Propylketobemidone

Alvimopan

Loperamide

Picenadol

Open chain opioids

Dipipanone

Methadone

Normethadone

Phenadoxone

Dimepheptanol

Levacetylmethadol

Dextromoramide

Levomoramide

Racemoramide

Diethylthiambutene

Dimethylthiambutene

Ethylmethylthiambutene

Piperidylthiambutene

Pyrrolidinylthiambutene

Thiambutene

Tipepidine

Dextropropoxyphene

Dimenoxadol

Dioxaphetyl butyrate

Levopropoxyphene

Norpropoxyphene

Diampromide

Phenampromide

Propiram

Methiodone

Isoaminile

Lefetamine

R-4066

Anilidopiperidines

3-Allylfentanyl

3-Methylfentanyl

3-Methylthiofentanyl

4-Phenylfentanyl

Alfentanil

α-Methylacetylfentanyl

α-Methylfentanyl

α-Methylthiofentanyl

β-Hydroxyfentanyl

β-Hydroxythiofentanyl

β-Methylfentanyl

Brifentanil

Carfentanil

Fentanyl

Lofentanil

Mirfentanil

Ocfentanil

Ohmefentanyl

Parafluorofentanyl

Phenaridine

Remifentanil

Sufentanil

Thiofentanyl

Trefentanil

Various others

Ethoheptazine

Metheptazine

Metethoheptazine

Proheptazine

Bezitramide

Piritramide

Clonitazene

Etonitazene

18-MC

7-Hydroxymitragynine

Akuammine

Eseroline

Hodgkinsine

Mitragynine

Pericine

BW373U86

DPI-221

DPI-287

DPI-3290

SNC-80

AD-1211

AH-7921

Azaprocin

Bromadol

BRL-52537

Bromadoline

C-8813

Ciramadol

Doxpicomine

Enadoline

Faxeladol

GR-89696

Herkinorin

ICI-199441

ICI-204448

J-113397

JTC-801

LPK-26

Methopholine

MT-45

NDMC

NNC 63-0532

Nortilidine

O-Desmethyltramadol

Prodilidine

Profadol

Ro64-6198

SB-612111

SC-17599

RWJ-394674

TAN-67

Tapentadol

Tifluadom

Tramadol

Trimebutine

U-50488

U-69593

Viminol

W-18

Alvimopan

JDTic

MCOPPB

Beta-amine ketone 'compound 29'

## See also

* Froehde reagent
* Opiate comparison
* Opioid epidemic
* Opioid tapering

## References

1. ↑ 1.0 1.1 Hemmings, Hugh C.; Egan, Talmage D. (2013). Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application: Expert Consult – Online and Print. Elsevier Health Sciences. p. 253. ISBN 978-1-4377-1679-5. https://books.google.com/books?id=s8CXrbimviMC&pg=PA268. "Opiate is the older term classically used in pharmacology to mean a drug derived from opium. Opioid, a more modern term, is used to designate all substances, both natural and synthetic, that bind to opioid receptors (including antagonists)."
2. ↑ "Opioids" (in en). 2023-05-11. https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/opioids.
3. ↑ Hemmings, Hugh C.; Egan, Talmage D. (2014). Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application: Expert Consult - Online and Print. Elsevier Health Sciences. p. 253. ISBN 978-1-4377-1679-5. https://books.google.com/books?id=s8CXrbimviMC&pg=PA268. "Opiate is the older term classically used in pharmacology to mean a drug derived from opium. It has been used in the past to refer to drugs with opium-like effects, but that use is dated. Opioid, a more modern term, is used to designate all substances, both natural and synthetic, that bind to opioid receptors (including antagonists)."
4. ↑ "Opiate - Definitions from Dictionary.com". dictionary.reference.com. http://dictionary.reference.com/browse/Opiate.
5. ↑ "Alcohol and Drug Policy Commission : Opiates or Opioids — What's the difference?: State of Oregon". https://www.oregon.gov/adpc/pages/opiate-opioid.aspx.
6. ↑ 6.0 6.1 Stromgaard, Kristian; Krogsgaard-Larsen, Povl; Madsen, Ulf (2009). Textbook of Drug Design and Discovery, Fourth Edition. CRC Press. ISBN 978-1-4398-8240-5. https://books.google.com/books?id=YLPMBQAAQBAJ.
7. ↑ "52 Nondomestic Equids". Zoo Animal and Wildlife Immobilization and Anesthesia. The Canadian Veterinary Journal. 51 (2nd ed.). Ames, USA: John Wiley & Sons. 2014. pp. 723, 727. doi:10.1002/9781118792919. ISBN 978-1-118-79291-9. https://books.google.com/books?id=h0XxBQAAQBAJ&pg=PA723. Retrieved 8 July 2019.
8. ↑ "Carfentanil". https://www.drugbank.ca/drugs/DB01535.
9. ↑ "Intentional overdose of Large Animal Immobilon". European Journal of Emergency Medicine 11 (5): 298–301. October 2004. doi:10.1097/00063110-200410000-00013. PMID 15359207.
10. ↑ Lembke, Anna (2016). Drug Dealer, MD: How Doctors Were Duped, Patients Got Hooked, and Why It's So Hard to Stop. Johns Hopkins University Press. ISBN 978-1-4214-2140-7.
11. ↑ "New Execution Methods Can't Disguise Same Old Death Penalty Problems". https://www.acluohio.org/en/news/new-execution-methods-cant-disguise-same-old-death-penalty-problems.
12. ↑ "Overview of Lethal Injection Protocols". https://deathpenaltyinfo.org/executions/lethal-injection/overview-of-lethal-injection-protocols.
13. ↑ "Drug Facts: Prescription Opioids". June 2019. https://www.drugabuse.gov/publications/drugfacts/prescription-opioids.
14. ↑ "FDA requires strong warnings for opioid analgesics, prescription opioid cough products, and benzodiazepine labeling related to serious risks and death from combined use". 31 August 2016. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518697.htm.
15. ↑ "Status and Trend Analysis of Illict [sic] Drug Markets". World Drug Report 2015. http://www.unodc.org/documents/wdr2015/WDR15_Drug_use_health_consequences.pdf. Retrieved 26 June 2015.
16. ↑ "World Drug Report 2023". UNITED NATIONS OFFICE ON DRUGS AND CRIME. https://www.unodc.org/res/WDR-2023/WDR23_Exsum_fin_SP.pdf.
17. ↑ "Report III: FDA Approved Medications for the Treatment of Opiate Dependence: Literature Reviews on Effectiveness & Cost- Effectiveness, Treatment Research Institute". Advancing Access to Addiction Medications: Implications for Opioid Addiction Treatment. p. 41. http://www.asam.org/docs/default-source/advocacy/aaam_implications-for-opioid-addiction-treatment_final. Retrieved 14 February 2016.
18. ↑ "Non-Medical Prescription Opioid Use and Prescription Opioid Use Disorder: A Review". The Yale Journal of Biology and Medicine 88 (3): 227–33. September 2015. PMID 26339205.
19. ↑ "The resurgence and abuse of heroin by children in the United States". Current Opinion in Pediatrics 15 (2): 210–5. April 2003. doi:10.1097/00008480-200304000-00013. PMID 12640281.
20. ↑ Gray, Eliza (4 February 2014). "Heroin Gains Popularity as Cheap Doses Flood the U.S". Time. https://time.com/4505/heroin-gains-popularity-as-cheap-doses-flood-the-u-s/. Retrieved 12 February 2016.
21. ↑ "Opioids, pain, and fear". Annals of Oncology 19 (1): 5–7. January 2008. doi:10.1093/annonc/mdm555. PMID 18073220. http://annonc.oxfordjournals.org/content/19/1/5. Retrieved 14 February 2016. "[A] number of studies, however, have also reported inadequate pain control in 40%–70% of patients, resulting in the emergence of a new type of epidemiology, that of 'failed pain control', caused by a series of obstacles preventing adequate cancer pain management.... The cancer patient runs the risk of becoming an innocent victim of a war waged against opioid abuse and addiction if the norms regarding the two kinds of use (therapeutic or nontherapeutic) are not clearly distinct. Furthermore, health professionals may be worried about regulatory scrutiny and may opt not to use opioid therapy for this reason.".
22. ↑ "Pain management in primary care: strategies to mitigate opioid misuse, abuse, and diversion". Postgraduate Medicine 123 (2): 119–30. March 2011. doi:10.3810/pgm.2011.03.2270. PMID 21474900.
23. ↑ 23.0 23.1 23.2 Offermanns, Stefan (2008). Encyclopedia of Molecular Pharmacology. 1 (2 ed.). Springer Science & Business Media. p. 903. ISBN 978-3-540-38916-3. https://books.google.com/books?id=iwwo5gx8aX8C&q=903. "In the strict sense, opiates are drugs derived from opium and include the natural products morphine, codeine, thebaine and many semi-synthetic congeners derived from them. The term opioids applies to any substance, whether endogenous or synthetic, peptidic or non-peptidic, that produces morphine-like effects through action on opioid receptors."
24. ↑ Davies, Pamela Stitzlein; D'Arcy, Yvonne M. (26 September 2012). Compact Clinical Guide to Cancer Pain Management: An Evidence-Based Approach for Nurses. Springer Publishing Company. ISBN 978-0-8261-0974-3. https://books.google.com/books?id=7ob0jFPNhOMC.
25. ↑ Freye, Enno (2008). "Part II. Mechanism of action of opioids and clinical effects". Opioids in Medicine: A Comprehensive Review on the Mode of Action and the Use of Analgesics in Different Clinical Pain States. Springer Science & Business Media. p. 85. ISBN 978-1-4020-5947-6. https://books.google.com/books?id=ybtX0GZGhk8C&pg=PA85. "Opiate is a specific term that is used to describe drugs (natural and semi-synthetic) derived from the juice of the opium poppy. For example morphine is an opiate but methadone (a completely synthetic drug) is not. Opioid is a general term that includes naturally occurring, semi-synthetic, and synthetic drugs, which produce their effects by combining with opioid receptors and are competitively antagonized by nalaxone. In this context the term opioid refers to opioid agonists, opioid antagonists, opioid peptides, and opioid receptors."
26. ↑ Anstie, Francis Edmund (1865) (in en). Stimulants and Narcotics, Their Mutual Relations: With Special Researches on the Action of Alcohol, Aether and Chloroform on the Vital Organism. Lindsay and Blakiston. p. 152. https://books.google.com/books?id=rBULAAAAIAAJ&pg=PA152.
27. ↑ "21 U.S. Code § 802 – Definitions". https://www.law.cornell.edu/uscode/text/21/802.
28. ↑ "Definition of NARCOTIC". https://www.merriam-webster.com/dictionary/narcotic.
29. ↑ Pharmacology and Pharmacotherapeutics. Elsevier Health Sciences. 2015. ISBN 978-81-312-4371-8. https://books.google.com/books?id=h2drCgAAQBAJ.
30. ↑ Ebert, Michael H.; Kerns, Robert D. (2010). Behavioral and Psychopharmacologic Pain Management. Cambridge University Press. ISBN 978-1-139-49354-3. https://books.google.com/books?id=RORnRRghGeYC.
31. ↑ "Non-prescription (OTC) oral analgesics for acute pain - an overview of Cochrane reviews". The Cochrane Database of Systematic Reviews 11 (11). November 2015. doi:10.1002/14651858.CD010794.pub2. PMID 26544675.
32. ↑ 32.0 32.1 Fleisher, Gary R.; Ludwig, Stephen (2010). Textbook of Pediatric Emergency Medicine. Lippincott Williams & Wilkins. p. 61. ISBN 978-1-60547-159-4. https://books.google.com/books?id=a7CqcE1ZrFkC.
33. ↑ "Codeine". Drugs.com. 15 May 2022. https://www.drugs.com/codeine.html.
34. ↑ "Rethinking opioid prescribing to protect patient safety and public health". JAMA 308 (18): 1865–6. November 2012. doi:10.1001/jama.2012.14282. PMID 23150006.
35. ↑ "Risk Factors and Pooled Rate of Prolonged Opioid Use Following Trauma or Surgery: A Systematic Review and Meta-(Regression) Analysis". The Journal of Bone and Joint Surgery. American Volume 100 (15): 1332–1340. August 2018. doi:10.2106/JBJS.17.01239. PMID 30063596.
36. ↑ Davis, Corey S.; Lieberman, Amy Judd; Hernandez-Delgado, Hector; Suba, Carli (1 January 2019). "Laws limiting the prescribing or dispensing of opioids for acute pain in the United States: A national systematic legal review". Drug and Alcohol Dependence 194: 166–172. doi:10.1016/j.drugalcdep.2018.09.022. ISSN 1879-0046. PMID 30445274.
37. ↑ "Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology". Neurology 83 (14): 1277–84. September 2014. doi:10.1212/WNL.0000000000000839. PMID 25267983.
38. ↑ 38.0 38.1 "A flood of opioids, a rising tide of deaths". The New England Journal of Medicine 363 (21): 1981–5. November 2010. doi:10.1056/NEJMp1011512. PMID 21083382.
Responses to Okie's perspective: "Opioids and deaths". The New England Journal of Medicine 364 (7): 686–687. February 2011. doi:10.1056/NEJMc1014490. PMID 21323559.
39. ↑ 39.0 39.1 "CDC Guideline for Prescribing Opioids for Chronic Pain--United States, 2016". JAMA 315 (15): 1624–45. April 2016. doi:10.1001/jama.2016.1464. PMID 26977696.
40. ↑ Yang, Juan; Bauer, Brent A; Wahner-Roedler, Dietlind L; Chon, Tony Y; Xiao, Lizu (17 February 2020). "The Modified WHO Analgesic Ladder: Is It Appropriate for Chronic Non-Cancer Pain?". Journal of Pain Research 13: 411–417. doi:10.2147/JPR.S244173. PMID 32110089.
41. ↑ 41.0 41.1 For information on the use and overuse of opioids to treat migraines, see American Academy of Neurology (February 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation (American Academy of Neurology), http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-neurology/, retrieved 1 August 2013 , which cites
* "Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology 55 (6): 754–62. September 2000. doi:10.1212/WNL.55.6.754. PMID 10993991.
* "EFNS guideline on the drug treatment of migraine--revised report of an EFNS task force". European Journal of Neurology 16 (9): 968–81. September 2009. doi:10.1111/j.1468-1331.2009.02748.x. PMID 19708964.
* Institute for Clinical Systems Improvement (2011), Headache, Diagnosis and Treatment of, Institute for Clinical Systems Improvement, https://www.icsi.org/guidelines__more/catalog_guidelines_and_more/catalog_guidelines/catalog_neurological_guidelines/headache/, retrieved 18 December 2013
42. ↑ "Chronic opioid use in fibromyalgia syndrome: a clinical review". Journal of Clinical Rheumatology 19 (2): 72–7. March 2013. doi:10.1097/RHU.0b013e3182863447. PMID 23364665.
43. ↑ "Opioids for neuropathic pain". The Cochrane Database of Systematic Reviews 8 (8). August 2013. doi:10.1002/14651858.CD006146.pub2. PMID 23986501.
44. ↑ 44.0 44.1 44.2 American Headache Society (September 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation (American Headache Society), http://www.choosingwisely.org/doctor-patient-lists/american-headache-society/, retrieved 10 December 2013 , which cites
* "Excessive opioid use and the development of chronic migraine". Pain 142 (3): 179–82. April 2009. doi:10.1016/j.pain.2009.01.013. PMID 19232469.
* "Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study". Headache 48 (8): 1157–68. September 2008. doi:10.1111/j.1526-4610.2008.01217.x. PMID 18808500.
* "Factors associated with the onset and remission of chronic daily headache in a population-based study". Pain 106 (1–2): 81–9. November 2003. doi:10.1016/S0304-3959(03)00293-8. PMID 14581114. https://zenodo.org/record/1260009.
* "Incidence and predictors for chronicity of headache in patients with episodic migraine". Neurology 62 (5): 788–90. March 2004. doi:10.1212/01.WNL.0000113747.18760.D2. PMID 15007133.
45. ↑ "Opioid epidemic in the United States". Pain Physician 15 (3 Suppl): ES9-38. July 2012. doi:10.36076/ppj.2012/15/ES9. PMID 22786464.
46. ↑ "Research gaps on use of opioids for chronic noncancer pain: findings from a review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline". The Journal of Pain 10 (2): 147–59. February 2009. doi:10.1016/j.jpain.2008.10.007. PMID 19187891.
47. ↑ "PAIN". Painjournalonline.com. 1 September 2015. http://www.painjournalonline.com/article/S0304-3959(06)00316-2/abstract.
48. ↑ "Long-term opioid treatment of chronic nonmalignant pain: unproven efficacy and neglected safety?". Journal of Pain Research 6: 513–29. 28 September 2015. doi:10.2147/JPR.S47182. PMID 23874119.
49. ↑ "Opioids versus nonsteroidal anti-inflammatory drugs in noncancer pain". Canadian Family Physician 58 (1): 30. January 2012. PMID 22267615.
50. ↑ "[What are the benefits and risk of non-opioid analgesics combined with postoperative opioids?]". Annales Françaises d'Anesthésie et de Réanimation 28 (3): e135-51. March 2009. doi:10.1016/j.annfar.2009.01.006. PMID 19304445.
51. ↑ "Safety and efficacy of the combination acetaminophen-codeine in the treatment of pain of different origin". European Review for Medical and Pharmacological Sciences 17 (16): 2129–35. August 2013. PMID 23893177. http://www.europeanreview.org/wp/wp-content/uploads/2129-2135.pdf. Retrieved 26 February 2016.
52. ↑ Chung, K. Fan; Widdicombe, John (2008). Pharmacology and therapeutics of cough. Berlin: Springer. p. 248. ISBN 978-3-540-79842-2. https://books.google.com/books?id=Z4kXCSRq0OAC&pg=PA248.
53. ↑ "Codeine and cough: an ineffective gold standard". Current Opinion in Allergy and Clinical Immunology 7 (1): 32–6. February 2007. doi:10.1097/ACI.0b013e3280115145. PMID 17218808.
54. ↑ 54.0 54.1 "Codeine for acute cough in children". Canadian Family Physician 56 (12): 1293–4. December 2010. PMID 21156892.
55. ↑ "Therapeutic options for acute cough due to upper respiratory infections in children". Lung 190 (1): 41–4. February 2012. doi:10.1007/s00408-011-9319-y. PMID 21892785.
56. ↑ "[Summary of NHG practice guideline 'Acute cough']". Nederlands Tijdschrift voor Geneeskunde 156: A4188. 2012. PMID 22917039.
57. ↑ "Dextromethorphan and codeine: objective assessment of antitussive activity in patients with chronic cough". The Journal of International Medical Research 11 (2): 92–100. 1983. doi:10.1177/030006058301100206. PMID 6852361.
58. ↑ "Do Cough Remedies Work?". http://www.medscape.com/viewarticle/803288.
59. ↑ "Pharmacologic management of cough". Otolaryngologic Clinics of North America 43 (1): 147–55, xi. February 2010. doi:10.1016/j.otc.2009.11.008. PMID 20172264.
60. ↑ "Opioids in Gastroenterology: Treating Adverse Effects and Creating Therapeutic Benefits". Clinical Gastroenterology and Hepatology 15 (9): 1338–1349. 2017-09-02. doi:10.1016/j.cgh.2017.05.014. ISSN 1542-7714. PMID 28529168.
61. ↑ "Opioid-Induced Constipation". Pain Medicine 16 (Suppl 1): S16-21. October 2015. doi:10.1111/pme.12911. PMID 26461071.
62. ↑ "The use of opioids for dyspnea in advanced disease". CMAJ 183 (10): 1170. July 2011. doi:10.1503/cmaj.110024. PMID 21746829.
63. ↑ "Chronic refractory dyspnoea--evidence based management". Australian Family Physician 42 (3): 137–40. March 2013. PMID 23529525.
64. ↑ Dy, Sydney M.; Gupta, Arjun; Waldfogel, Julie M.; Sharma, Ritu; Zhang, Allen; Feliciano, Josephine L.; Sedhom, Ramy; Day, Jeff et al. (2020-11-19). "Interventions for Breathlessness in Patients With Advanced Cancer". JAMA Oncology. doi:10.23970/ahrqepccer232. PMID 33289989.
65. ↑ "Pharmacologic Interventions for Breathlessness in Patients With Advanced Cancer: A Systematic Review and Meta-analysis". JAMA Network Open 4 (2): e2037632. February 2021. doi:10.1001/jamanetworkopen.2020.37632. PMID 33630086.
66. ↑ "Restless Legs Syndrome | Baylor Medicine" (in en). https://www.bcm.edu/healthcare/specialties/neurology/parkinsons-disease-and-movement-disorders/restless-legs-syndrome.
67. ↑ "Evidence of opioid-induced hyperalgesia in clinical populations after chronic opioid exposure: a systematic review and meta-analysis". British Journal of Anaesthesia 122 (6): e114–e126. June 2019. doi:10.1016/j.bja.2018.09.019. PMID 30915985. https://discovery.dundee.ac.uk/ws/files/28488556/3rd_submission.pdf. Retrieved 24 April 2020.
68. ↑ Yang, David Z.; Sin, Billy; Beckhusen, Joshua; Xia, Dawei; Khaimova, Rebecca; Iliev, Ilia (May–June 2019). "Opioid-Induced Hyperalgesia in the Nonsurgical Setting: A Systematic Review". American Journal of Therapeutics 26 (3): e397–e405. doi:10.1097/MJT.0000000000000734. ISSN 1536-3686. PMID 29726847.
69. ↑ 69.0 69.1 69.2 69.3 69.4 69.5 69.6 69.7 "Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects". CMAJ 174 (11): 1589–94. May 2006. doi:10.1503/cmaj.051528. PMID 16717269.
70. ↑ "Acute Opiate Overdose: An Update on Management Strategies in Emergency Department and Critical Care Unit". American Journal of Therapeutics 26 (3): e380–e387. May–June 2019. doi:10.1097/MJT.0000000000000681. PMID 28952972.
71. ↑ "A nursing approach to pain in older adults". Medsurg Nursing 18 (2): 77–82; quiz 83. 2009. PMID 19489204.
72. ↑ "Risk of injury associated with opioid use in older adults". Journal of the American Geriatrics Society 58 (9): 1664–70. September 2010. doi:10.1111/j.1532-5415.2010.03015.x. PMID 20863326.
73. ↑ "Rational use of opioid analgesics in chronic musculoskeletal pain". J Musculoskel Med 27: 142–148. 2010. http://www.musculoskeletalnetwork.com/pain/content/article/1145622/1551411. Retrieved 14 April 2010.
74. ↑ "Adverse Outcomes Associated with Prescription Opioids for Acute Low Back Pain: A Systematic Review and Meta-Analysis". Pain Physician 22 (2): 119–138. March 2019. PMID 30921976.
75. ↑ "Safety of Opioids in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis". Drugs & Aging 36 (Suppl 1): 129–143. April 2019. doi:10.1007/s40266-019-00666-9. PMID 31073926.
76. ↑ Stephens, Everett (23 November 2015). Opioid Toxicity. http://emedicine.medscape.com/article/815784-overview#showall. Retrieved 24 February 2016. "The CDC reported that methadone contributed to 31.4% of opioid-related deaths in the United States from 1999–2010. Methadone also accounted for 39.8% of all single-drug opioid-related deaths. The overdose death rate associated with methadone was significantly higher than that associated with other opioid-related deaths among multidrug and single-drug deaths.".
77. ↑ 77.0 77.1 77.2 77.3 77.4 "Long-term opioid management for chronic noncancer pain". The Cochrane Database of Systematic Reviews 2018 (1). January 2010. doi:10.1002/14651858.CD006605.pub2. PMID 20091598.
78. ↑ "Drug Overdose Deaths in the United States, 1999–2016". https://www.cdc.gov/nchs/data/databriefs/db294.pdf.
79. ↑ "Ligand-directed trafficking of the δ-opioid receptor in vivo: two paths toward analgesic tolerance". The Journal of Neuroscience 30 (49): 16459–68. December 2010. doi:10.1523/JNEUROSCI.3748-10.2010. PMID 21147985.
80. ↑ "Tolerance to miotic effects of opioids". Anesthesiology 102 (3): 701. March 2005. doi:10.1097/00000542-200503000-00047. PMID 15731628.
81. ↑ "Enhancement of opiate analgesia by nimodipine in cancer patients chronically treated with morphine: a preliminary report". Pain 58 (1): 129–32. July 1994. doi:10.1016/0304-3959(94)90192-9. PMID 7970835.
82. ↑ "Nimodipine-enhanced opiate analgesia in cancer patients requiring morphine dose escalation: a double-blind, placebo-controlled study". Pain 76 (1–2): 17–26. May 1998. doi:10.1016/S0304-3959(98)00019-0. PMID 9696455.
83. ↑ "Involvement of intracellular calcium in morphine tolerance in mice". Pharmacology, Biochemistry, and Behavior 62 (2): 381–8. February 1999. doi:10.1016/S0091-3057(98)00168-3. PMID 9972707.
84. ↑ "Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats". Anesthesia and Analgesia 86 (4): 830–6. April 1998. doi:10.1097/00000539-199804000-00028. PMID 9539610. http://www.anesthesia-analgesia.org/cgi/reprint/86/4/830. Retrieved 12 November 2007.
85. ↑ "Effect of intrathecal magnesium in the presence or absence of local anaesthetic with and without lipophilic opioids: a systematic review and meta-analysis". British Journal of Anaesthesia 110 (5): 702–12. May 2013. doi:10.1093/bja/aet064. PMID 23533255.
86. ↑ "Intrathecal Zn2+ attenuates morphine antinociception and the development of acute tolerance". European Journal of Pharmacology 407 (3): 267–72. November 2000. doi:10.1016/S0014-2999(00)00715-9. PMID 11068022.
87. ↑ "Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at mu-opioid receptors". European Journal of Pharmacology 297 (1–2): 27–33. February 1996. doi:10.1016/0014-2999(95)00728-8. PMID 8851162.
88. ↑ "Interaction of memantine and ketamine in morphine- and pentazocine-induced antinociception in mice". Pharmacological Reports 60 (2): 149–55. Mar–Apr 2008. PMID 18443375. http://www.if-pan.krakow.pl/pjp/pdf/2008/2_149.pdf. Retrieved 17 September 2011.
89. ↑ "The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine". The Clinical Journal of Pain 19 (3): 200–1. 2003. doi:10.1097/00002508-200305000-00008. PMID 12792559.
90. ↑ "Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide". Science 224 (4647): 395–6. April 1984. doi:10.1126/science.6546809. PMID 6546809. Bibcode: 1984Sci...224..395W.
91. ↑ "Proglumide prevents and curtails acute tolerance to morphine in rats". Neuropharmacology 23 (6): 715–8. June 1984. doi:10.1016/0028-3908(84)90171-0. PMID 6462377.
92. ↑ "Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes". Expert Opinion on Investigational Drugs 16 (7): 935–50. July 2007. doi:10.1517/13543784.16.7.935. PMID 17594181.
93. ↑ 93.0 93.1 93.2 93.3 Oxford Textbook of Palliative Medicine (3rd ed.). Oxford University Press. 2004. ISBN 978-0-19-856698-4.
94. ↑ "Low efficacy of non-opioid drugs in opioid withdrawal symptoms". Addiction Biology 10 (2): 165–9. June 2005. doi:10.1080/13556210500123514. PMID 16191669.
95. ↑ "Ibogaine in the treatment of substance dependence". Current Drug Abuse Reviews 6 (1): 3–16. March 2013. doi:10.2174/15672050113109990001. PMID 23627782.
96. ↑ Duceppe, Marc-Alexandre; Perreault, Marc M.; Frenette, Anne Julie; Burry, Lisa D.; Rico, Philippe; Lavoie, Annie; Gélinas, Céline; Mehta, Sangeeta et al. (April 2019). "Frequency, risk factors and symptomatology of iatrogenic withdrawal from opioids and benzodiazepines in critically Ill neonates, children and adults: A systematic review of clinical studies". Journal of Clinical Pharmacy and Therapeutics 44 (2): 148–156. doi:10.1111/jcpt.12787. ISSN 1365-2710. PMID 30569508.
97. ↑ "Will abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose?". Drugs 72 (13): 1713–23. September 2012. doi:10.2165/11635860-000000000-00000. PMID 22931520.
98. ↑ "Abuse-deterrent and tamper-resistant opioid formulations: what is their role in addressing prescription opioid abuse?". CNS Drugs 24 (10): 805–10. October 2010. doi:10.2165/11584260-000000000-00000. PMID 20839893.
99. ↑ "Opioid therapy pharmacogenomics for noncancer pain: efficacy, adverse events, and costs". Pain Research and Treatment 2013. 2013. doi:10.1155/2013/943014. PMID 24167729.
100. ↑ "Complications of long-term opioid therapy for management of chronic pain: the paradox of opioid-induced hyperalgesia". Journal of Medical Toxicology 8 (4): 387–92. December 2012. doi:10.1007/s13181-012-0260-0. PMID 22983894.
101. ↑ "The role of cannabinoids in regulation of nausea and vomiting, and visceral pain". Current Gastroenterology Reports 17 (2): 429. February 2015. doi:10.1007/s11894-015-0429-1. PMID 25715910.
102. ↑ "Cannabis in cancer care". Clinical Pharmacology and Therapeutics 97 (6): 575–86. June 2015. doi:10.1002/cpt.108. PMID 25777363.
103. ↑ "UCSF Study Finds Medical Marijuana Could Help Patients Reduce Pain with Opiates". 6 December 2011. https://www.ucsf.edu/news/2011/12/11077/ucsf-study-finds-medical-marijuana-could-help-patients-reduce-pain-opiates.
104. ↑ "Cannabinoid-opioid interaction in chronic pain". Clinical Pharmacology and Therapeutics 90 (6): 844–51. December 2011. doi:10.1038/clpt.2011.188. PMID 22048225.
105. ↑ "Analgesic impact of intra-operative opioids vs. opioid-free anaesthesia: a systematic review and meta-analysis". Anaesthesia 74 (5): 651–662. May 2019. doi:10.1111/anae.14582. PMID 30802933. https://serval.unil.ch/notice/serval:BIB_6A01A1CDCF6A. Retrieved 15 September 2022.
106. ↑ Busse, Jason W.; Wang, Li; Kamaleldin, Mostafa; Craigie, Samantha; Riva, John J.; Montoya, Luis; Mulla, Sohail M.; Lopes, Luciane C. et al. (2018-12-18). "Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis" (in en). JAMA 320 (23): 2448–2460. doi:10.1001/jama.2018.18472. ISSN 0098-7484. PMID 30561481.
107. ↑ "Pharmacologic treatment of opioid-induced sedation in chronic pain". The Annals of Pharmacotherapy 39 (4): 727–31. April 2005. doi:10.1345/aph.1E309. PMID 15755795.
108. ↑ "Amphetamines to counteract opioid-induced sedation". The Annals of Pharmacotherapy 33 (12): 1362–6. December 1999. doi:10.1345/aph.19024. PMID 10630837.
109. ↑ Canadian Agency for Drugs and Technologies in Health (26 June 2014). "Dioctyl Sulfosuccinate or Docusate (Calcium or Sodium) for the Prevention or Management of Constipation: A Review of the Clinical Effectiveness". PMID 25520993.
110. ↑ "Overview and treatment of opioid-induced constipation". Postgraduate Medicine 125 (4): 7–17. July 2013. doi:10.3810/pgm.2013.07.2651. PMID 23782897.
111. ↑ 111.0 111.1 111.2 111.3 111.4 "Opioid-induced constipation: pathophysiology, clinical consequences, and management". Gastroenterology Research and Practice 2014. 2014. doi:10.1155/2014/141737. PMID 24883055.
112. ↑ 112.0 112.1 Alguire, Patrick Craig; American College of Physicians; Clerkship Directors in Internal Medicine (2009). Internal Medicine Essentials for Clerkship Students 2. ACP Press. pp. 272–. ISBN 978-1-934465-13-4. https://books.google.com/books?id=_oNOMxckD4QC&pg=PA272.
113. ↑ 113.0 113.1 113.2 Elliott, Jennifer A.; Smith, Howard S. (19 April 2016). Handbook of Acute Pain Management. CRC Press. pp. 89–. ISBN 978-1-4665-9635-1. https://books.google.com/books?id=Em7OBQAAQBAJ&pg=PA89.
114. ↑ "Evolving paradigms in the treatment of opioid-induced bowel dysfunction". Therapeutic Advances in Gastroenterology 8 (6): 360–72. November 2015. doi:10.1177/1756283X15589526. PMID 26557892.
115. ↑ "Oxycodone with an opioid receptor antagonist: A review". Journal of Opioid Management 12 (1): 67–85. 2016. doi:10.5055/jom.2016.0313. PMID 26908305.
116. ↑ Candy, Bridget; Jones, Louise; Vickerstaff, Victoria; Larkin, Philip J.; Stone, Patrick (2022-09-15). "Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care". The Cochrane Database of Systematic Reviews 2022 (9). doi:10.1002/14651858.CD006332.pub4. ISSN 1469-493X. PMID 36106667.
117. ↑ "Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and network meta-analysis". Gut 68 (3): 434–444. May 2018. doi:10.1136/gutjnl-2018-316001. PMID 29730600. https://eprints.whiterose.ac.uk/132159/2/gutjnl-2018-316001R2 Clean copy.pdf. Retrieved 23 September 2019.
118. ↑ "Efficacy of naldemedine for the treatment of opioid-induced constipation: A meta-analysis". Journal of Gastrointestinal and Liver Diseases 28 (1): 41–46. March 2019. doi:10.15403/jgld.2014.1121.281.any. PMID 30851171.
119. ↑ "Opioid-induced bowel dysfunction: epidemiology, pathophysiology, diagnosis, and initial therapeutic approach". The American Journal of Gastroenterology Supplements 2 (1): 31–7. September 2014. doi:10.1038/ajgsup.2014.7. PMID 25207610.
120. ↑ "A new look at the respiratory stimulant doxapram". CNS Drug Reviews 12 (3–4): 236–49. 2006. doi:10.1111/j.1527-3458.2006.00236.x. PMID 17227289.
121. ↑ "[Clinical observation of target-controlled remifentanil infusion combined with propofol and doxapram in painless artificial abortion]". Nan Fang Yi Ke da Xue Xue Bao = Journal of Southern Medical University 26 (8): 1206–8. August 2006. PMID 16939923.
122. ↑ "5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia". Science 301 (5630): 226–9. July 2003. doi:10.1126/science.1084674. PMID 12855812. Bibcode: 2003Sci...301..226M.
123. ↑ "5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function". Hypertension 50 (2): 368–76. August 2007. doi:10.1161/HYPERTENSIONAHA.107.091033. PMID 17576856.
124. ↑ "Ampakines alleviate respiratory depression in rats". American Journal of Respiratory and Critical Care Medicine 174 (12): 1384–91. December 2006. doi:10.1164/rccm.200606-778OC. PMID 16973981.
125. ↑ Cozowicz, Crispiana; Chung, Frances; Doufas, Anthony G.; Nagappa, Mahesh; Memtsoudis, Stavros G. (October 2018). "Opioids for Acute Pain Management in Patients With Obstructive Sleep Apnea: A Systematic Review". Anesthesia and Analgesia 127 (4): 988–1001. doi:10.1213/ANE.0000000000003549. ISSN 1526-7598. PMID 29958218.
126. ↑ Gupta, Kapil; Nagappa, Mahesh; Prasad, Arun; Abrahamyan, Lusine; Wong, Jean; Weingarten, Toby N.; Chung, Frances (14 December 2018). "Risk factors for opioid-induced respiratory depression in surgical patients: a systematic review and meta-analyses". BMJ Open 8 (12). doi:10.1136/bmjopen-2018-024086. ISSN 2044-6055. PMID 30552274.
127. ↑ "Morphine hyperalgesia: a case report". The American Journal of Hospice & Palliative Care 20 (6): 459–61. 2003. doi:10.1177/104990910302000608. PMID 14649563.
128. ↑ "Adverse effects of opioids on the central nervous systems of palliative care patients". Journal of Pain & Palliative Care Pharmacotherapy 21 (1): 15–25. 2007. doi:10.1080/J354v21n01_05. PMID 17430825.
129. ↑ "Hyperalgesia and opioid switching". The American Journal of Hospice & Palliative Care 22 (4): 291–4. 2005. doi:10.1177/104990910502200411. PMID 16082916.
130. ↑ "Opioid insights:opioid-induced hyperalgesia and opioid rotation". Journal of Pain & Palliative Care Pharmacotherapy 18 (3): 75–9. 2004. doi:10.1080/J354v18n03_08. PMID 15364634.
131. ↑ "A comprehensive review of opioid-induced hyperalgesia". Pain Physician 14 (2): 145–61. 2011. doi:10.36076/ppj.2011/14/145. PMID 21412369. http://www.painphysicianjournal.com/current/pdf?article=MTQ0Ng==&journal=60. Retrieved 11 November 2016.
132. ↑ "Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon?". Current Pain and Headache Reports 15 (2): 129–36. April 2011. doi:10.1007/s11916-010-0171-1. PMID 21225380.
133. ↑ "Selective sigma-1 (sigma1) receptor antagonists: emerging target for the treatment of neuropathic pain". Central Nervous System Agents in Medicinal Chemistry 9 (3): 172–83. September 2009. doi:10.2174/1871524910909030172. PMID 20021351.
134. ↑ "Opioid-induced hyperalgesia: pathophysiology and clinical implications". Journal of Opioid Management 4 (3): 123–30. 2018. doi:10.5055/jom.2008.0017. PMID 18717507.
135. ↑ "Neuropathic Pain: A Clinical Perspective". Sensory Nerves. Handbook of Experimental Pharmacology. 194. 2009. pp. 3–30. doi:10.1007/978-3-540-79090-7_1. ISBN 978-3-540-79089-1.
136. ↑ "Review of the effect of opioid-related side effects on the undertreatment of moderate to severe chronic non-cancer pain: tapentadol, a step toward a solution?". Current Medical Research and Opinion 26 (7): 1677–84. July 2010. doi:10.1185/03007995.2010.483941. PMID 20465361.
137. ↑ 137.0 137.1 "Testosterone suppression in opioid users: a systematic review and meta-analysis". Drug Alcohol Depend 149: 1–9. April 2015. doi:10.1016/j.drugalcdep.2015.01.038. PMID 25702934.
138. ↑ "Testosterone deficiency in non-cancer opioid-treated patients". Journal of Endocrinological Investigation 41 (12): 1377–1388. December 2018. doi:10.1007/s40618-018-0964-3. PMID 30343356.
139. ↑ 139.0 139.1 "MECHANISMS OF ENDOCRINOLOGY: Endocrinology of opioids". European Journal of Endocrinology 179 (4): R183–R196. October 2018. doi:10.1530/EJE-18-0270. PMID 30299887.
140. ↑ "The effect of opioid therapy on endocrine function". The American Journal of Medicine 126 (3 Suppl 1): S12-8. March 2013. doi:10.1016/j.amjmed.2012.12.001. PMID 23414717.
141. ↑ "Opioid-induced endocrinopathy". The Journal of the American Osteopathic Association 109 (1): 20–5. January 2009. PMID 19193821.
142. ↑ "Opioid-induced androgen deficiency (OPIAD)". Pain Physician 15 (3 Suppl): ES145-56. July 2012. PMID 22786453.
143. ↑ "Prediction of failure to retain work 1 year after interdisciplinary functional restoration in occupational injuries". Archives of Physical Medicine and Rehabilitation 93 (2): 268–74. February 2012. doi:10.1016/j.apmr.2011.08.029. PMID 22289236.
144. ↑ "Opioid therapy for nonspecific low back pain and the outcome of chronic work loss". Pain 142 (3): 194–201. April 2009. doi:10.1016/j.pain.2008.12.017. PMID 19181448.
145. ↑ 145.0 145.1 145.2 American College of Occupational and Environmental Medicine (February 2014), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation (American College of Occupational and Environmental Medicine), http://www.choosingwisely.org/doctor-patient-lists/american-college-of-occupational-and-environmental-medicine/, retrieved 24 February 2014 , which cites
* "Opioids Guideline". Occupational medicine practice guidelines: evaluation and management of common health problems and functional recovery in workers (online March 2014) (3rd ed.). Elk Grove Village, IL: American College of Occupational and Environmental Medicine. 2011. p. 11. ISBN 978-0-615-45227-2.
146. ↑ "The management of chronic pain in important patient subgroups". Clinical Drug Investigation 32 (Suppl 1): 35–44. February 2012. doi:10.2165/11630060-000000000-00000. PMID 23389874.
147. ↑ "Opiates for chronic nonmalignant pain syndromes: can appropriate candidates be identified for outpatient clinic management?". American Journal of Physical Medicine & Rehabilitation 88 (12): 995–1001. December 2009. doi:10.1097/PHM.0b013e3181bc006e. PMID 19789432.
148. ↑ "Basic concepts in opioid prescribing and current concepts of opioid-mediated effects on driving". The Ochsner Journal 13 (4): 525–32. 2013. PMID 24358001.
149. ↑ "Prescription medicines and the risk of road traffic crashes: a French registry-based study". PLOS Medicine 7 (11). November 2010. doi:10.1371/journal.pmed.1000366. PMID 21125020.
150. ↑ "Opioid analgesics and the risk of fractures in older adults with arthritis". Journal of the American Geriatrics Society 59 (3): 430–8. March 2011. doi:10.1111/j.1532-5415.2011.03318.x. PMID 21391934.
151. ↑ "Systematic Review and Meta-Analysis on Neuropsychological Effects of Long-Term Use of Opioids in Patients With Chronic Noncancer Pain". Pain Practice 19 (3): 328–343. March 2019. doi:10.1111/papr.12741. PMID 30354006.
152. ↑ 152.0 152.1 152.2 "Risks, management, and monitoring of combination opioid, benzodiazepines, and/or alcohol use". Postgraduate Medicine 125 (4): 115–30. July 2013. doi:10.3810/pgm.2013.07.2684. PMID 23933900.
153. ↑ "A comparison of opioids and benzodiazepines dispensing in Australia". PLOS ONE 14 (8). 2019. doi:10.1371/journal.pone.0221438. PMID 31425552. Bibcode: 2019PLoSO..1421438I.
154. ↑ "Trends and Variations in Concurrent Dispensing of Prescription Opioids and Benzodiazepines in Australia: A Retrospective Analysis". Contemporary Drug Problems 47 (2): 136–148. 2020. doi:10.1177/0091450920919443.
155. ↑ "Effects of anesthetics, sedatives, and opioids on ventilatory control". Comprehensive Physiology 2 (4): 2281–2367. 2012. doi:10.1002/cphy.c100061. ISBN 978-0-470-65071-4. PMID 23720250.
156. ↑ "Opioid antagonists with minimal sedation for opioid withdrawal". The Cochrane Database of Systematic Reviews 2017 (5). May 2017. doi:10.1002/14651858.CD002021.pub4. PMID 28553701.
157. ↑ Bolton, Monica; Hodkinson, Alex; Boda, Shivani; Mould, Alan; Panagioti, Maria; Rhodes, Sarah; Riste, Lisa; van Marwijk, Harm (15 January 2019). "Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis". BMC Medicine 17 (1): 10. doi:10.1186/s12916-018-1242-0. ISSN 1741-7015. PMID 30642329.
158. ↑ Greene, Jennifer Anne; Deveau, Brent J.; Dol, Justine S.; Butler, Michael B. (April 2019). "Incidence of mortality due to rebound toxicity after 'treat and release' practices in prehospital opioid overdose care: a systematic review". Emergency Medicine Journal 36 (4): 219–224. doi:10.1136/emermed-2018-207534. ISSN 1472-0213. PMID 30580317.
159. ↑ Miller, Ronald D. (2010). Miller's Anesthesia (7th ed.). Elsevier Health Sciences. ISBN 978-0-443-06959-8. https://books.google.com/books?id=HPpgOjIGYtAC.
160. ↑ Morgan, G. Edward; Mikhail, Maged S.; Murray, Michael J. (2006). Clinical Anesthesiology (4th ed.). McGraw Hill. ISBN 978-0-07-110515-6.
161. ↑ Chestnut, David H.; Wong, Cynthia A.; Tsen, Lawrence C.; Kee, Warwick D. Ngan; Beilin, Yaakov; Mhyre, Jill (2014). Chestnut's Obstetric Anesthesia: Principles and Practice. Elsevier Health Sciences. p. 468. ISBN 978-0-323-11374-8. https://books.google.com/books?id=FMU0AwAAQBAJ&pg=PA468. "The lipid solubility of hydromorphone lies between morphine and fentanyl, but is closer to that of morphine."
162. ↑ "On the selection of an opioid for local skin analgesia: Structure-skin permeability relationships". International Journal of Pharmaceutics 489 (1–2): 177–85. July 2015. doi:10.1016/j.ijpharm.2015.04.071. PMID 25934430.
163. ↑ Comer, Sandra D.; Cahill, Catherine M. (November 2019). "Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment". Neuroscience and Biobehavioral Reviews 106: 49–57. doi:10.1016/j.neubiorev.2018.12.005. ISSN 1873-7528. PMID 30528374.
164. ↑ Volpe, Donna A.; McMahon Tobin, Grainne A.; Mellon, R. Daniel; Katki, Aspandiar G.; Parker, Robert J.; Colatsky, Thomas; Kropp, Timothy J.; Verbois, S. Leigh (April 2011). "Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs". Regulatory Toxicology and Pharmacology 59 (3): 385–390. doi:10.1016/j.yrtph.2010.12.007. ISSN 1096-0295. PMID 21215785.
165. ↑ Higashikawa, Yoshiyasu; Suzuki, Shinichi (2008-06-01). "Studies on 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fentanyl) and its related compounds. VI. Structure-analgesic activity relationship for fentanyl, methyl-substituted fentanyls and other analogues" (in en). Forensic Toxicology 26 (1): 1–5. doi:10.1007/s11419-007-0039-1. ISSN 1860-8973.
166. ↑ "Putative kappa opioid heteromers as targets for developing analgesics free of adverse effects". Journal of Medicinal Chemistry 57 (15): 6383–92. August 2014. doi:10.1021/jm500159d. PMID 24978316.
167. ↑ "A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine". The Journal of Pharmacology and Experimental Therapeutics 344 (3): 708–17. March 2013. doi:10.1124/jpet.112.201616. PMID 23300227.
168. ↑ "Interaction of two phencyclidine opiate-like derivatives with 3H-opioid binding sites". European Journal of Pharmacology 101 (3–4): 281–284. June 1984. doi:10.1016/0014-2999(84)90171-7. PMID 6088255.
169. ↑ 169.0 169.1 169.2 "Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands". Journal of Medicinal Chemistry 45 (9): 1949–56. April 2002. doi:10.1021/jm010576e. PMID 11960505.
170. ↑ 170.00 170.01 170.02 170.03 170.04 170.05 170.06 170.07 170.08 170.09 170.10 170.11 170.12 170.13 170.14 170.15 170.16 170.17 170.18 170.19 170.20 170.21 170.22 170.23 170.24 170.25 170.26 170.27 170.28 170.29 170.30 170.31 170.32 170.33 170.34 170.35 170.36 170.37 170.38 170.39 "Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors". Molecular Pharmacology 45 (2): 330–4. February 1994. PMID 8114680.
171. ↑ Alburges, ME (1992). "Utilization of a radioreceptor assay for the analysis of fentanyl analogs in urine". J Anal Toxicol 16 (1): 36–41. doi:10.1093/jat/16.1.36. PMID 1322477. https://academic.oup.com/jat/article-abstract/16/1/36/775908?redirectedFrom=fulltext&login=false. Retrieved 21 November 2023.
172. ↑ 172.0 172.1 172.2 172.3 172.4 172.5 172.6 "Molecular determinants of non-specific recognition of delta, mu, and kappa opioid receptors". Bioorganic & Medicinal Chemistry 9 (1): 69–76. January 2001. doi:10.1016/S0968-0896(00)00223-6. PMID 11197347.
173. ↑ 173.0 173.1 173.2 173.3 173.4 173.5 173.6 173.7 "(+)-[3H]SKF 10,047, (+)-[3H]ethylketocyclazocine, mu, kappa, delta and phencyclidine binding sites in guinea pig brain membranes". European Journal of Pharmacology 109 (1): 33–41. February 1985. doi:10.1016/0014-2999(85)90536-9. PMID 2986989.
174. ↑ 174.0 174.1 174.2 174.3 174.4 174.5 174.6 174.7 174.8 "Selectivity of Ligands for Opioid Receptors". Opioids. Handbook of Experimental Pharmacology. 104 / 1. 1993. pp. 645–679. doi:10.1007/978-3-642-77460-7_26. ISBN 978-3-642-77462-1.
175. ↑ 175.00 175.01 175.02 175.03 175.04 175.05 175.06 175.07 175.08 175.09 175.10 175.11 175.12 175.13 175.14 175.15 175.16 175.17 175.18 "Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception". The Journal of Pharmacology and Experimental Therapeutics 274 (3): 1263–70. September 1995. PMID 7562497.
176. ↑ "Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist". The Journal of Pharmacology and Experimental Therapeutics 349 (3): 535–548. June 2014. doi:10.1124/jpet.114.213694. PMID 24713140.
177. ↑ "Influence of tramadol on neurotransmitter systems of the rat brain". Arzneimittel-Forschung 46 (11): 1029–36. November 1996. PMID 8955860.
178. ↑ "Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy". British Journal of Pharmacology 131 (2): 203–12. September 2000. doi:10.1038/sj.bjp.0703562. PMID 10991912.
179. ↑ "Pharmacological study of dihydroetorphine in cloned mu-, delta- and kappa-opioid receptors". European Journal of Pharmacology 291 (3): 367–73. November 1995. doi:10.1016/0922-4106(95)90078-0. PMID 8719422.
180. ↑ "3H-dihydromorphine binding sites in subcellular fractions of rat striatum.". Pol J Pharmacol Pharm 34 (1–3): 73–78. 1982. PMID 6300816.
181. ↑ "Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity?". Neuropsychopharmacology 30 (12): 2254–62. December 2005. doi:10.1038/sj.npp.1300811. PMID 15988468.
182. ↑ "Syntheses and opioid receptor binding properties of carboxamido-substituted opioids". Bioorganic & Medicinal Chemistry Letters 19 (1): 203–8. January 2009. doi:10.1016/j.bmcl.2008.10.134. PMID 19027293.
183. ↑ 183.0 183.1 "Activity of opioid ligands in cells expressing cloned mu opioid receptors". BMC Pharmacology 3. January 2003. doi:10.1186/1471-2210-3-1. PMID 12513698. "Activation profiles of opioid ligands in HEK cells expressing delta opioid receptors". BMC Neuroscience 3. November 2002. doi:10.1186/1471-2202-3-19. PMID 12437765. "Pharmacological profiles of opioid ligands at kappa opioid receptors". BMC Pharmacology 6. January 2006. doi:10.1186/1471-2210-6-3. PMID 16433932.
184. ↑ "Syntheses of novel high affinity ligands for opioid receptors". Bioorganic & Medicinal Chemistry Letters 19 (8): 2289–94. April 2009. doi:10.1016/j.bmcl.2009.02.078. PMID 19282177.
185. ↑ "The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist". Translational Psychiatry 4 (7): e411. July 2014. doi:10.1038/tp.2014.30. PMID 25026323.
186. ↑ Truver, M. T.; Smith, C. R.; Garibay, N.; Kopajtic, T. A.; Swortwood, M. J.; Baumann, M. H. (2020). "Pharmacodynamics and pharmacokinetics of the novel synthetic opioid, U-47700, in male rats". Neuropharmacology 177. doi:10.1016/j.neuropharm.2020.108195. PMID 32533977.
187. ↑ "Synthesis, opioid receptor binding profile, and antinociceptive activity of 1-azaspiro[4.5]decan-10-yl amides". Journal of Medicinal Chemistry 32 (6): 1259–65. June 1989. doi:10.1021/jm00126a019. PMID 2542556.
188. ↑ "Annual prevalence of use of drugs, by region and globally, 2016". World Drug Report 2018. United Nations Office on Drugs and Crime. 2018. https://dataunodc.un.org/drugs/prevalence_regional. Retrieved 7 July 2018.
189. ↑ Volkow, Nora D.. "America's Addiction to Opioids: Heroin and Prescription Drug Abuse". National Institute on Drug Abuse. https://www.drugabuse.gov/about-nida/legislative-activities/testimony-to-congress/2016/americas-addiction-to-opioids-heroin-prescription-drug-abuse#_ftn5.
190. ↑ "Narcotic Drugs Stupéfiants Estupefacientes". INTERNATIONAL NARCOTICS CONTROL BOARD. 2012. http://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2012/Narcotic_Drugs_Report_2012.pdf.
191. ↑ "Opioid Consumption Data | Pain & Policy Studies Group". Painpolicy.wisc.edu. http://www.painpolicy.wisc.edu/opioid-consumption-data.
192. ↑ "Researching Prescription Drug Misuse among First Nations in Canada: Starting from a Health Promotion Framework". Substance Abuse 6: 23–31. 2012. doi:10.4137/SART.S9247. PMID 22879752.
193. ↑ "Socially disadvantaged Ontarians being prescribed opioids on an ongoing basis and at doses that far exceed Canadian guidelines". Ices.on.ca. 25 January 2011. http://www.ices.on.ca/Newsroom/News-Releases/2011/Socially-disadvantaged-Ontarians-being-prescribed-opiods.
194. ↑ 194.0 194.1 "Avoiding Abuse, Achieving a Balance: Tackling the Opioid Public Health Crisis". College of Physicians and Surgeons of Ontario. 8 September 2010. http://www.cpso.on.ca/CPSO/media/uploadedfiles/policies/policies/Opioid_report_final.pdf.
195. ↑ "A Systematic Review of Economic Evaluation Studies of Drug-Based Non-Malignant Chronic Pain Treatment". Current Pharmaceutical Biotechnology 20 (11): 910–919. 2019. doi:10.2174/1389201020666190717095443. PMID 31322067.
196. ↑ "National trends in long-term use of prescription opioids". Pharmacoepidemiology and Drug Safety 27 (5): 526–534. May 2018. doi:10.1002/pds.4278. PMID 28879660.
197. ↑ "Crystal structure of the µ-opioid receptor bound to a morphinan antagonist". Nature 485 (7398): 321–6. March 2012. doi:10.1038/nature10954. PMID 22437502. Bibcode: 2012Natur.485..321M. "Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain.".
198. ↑ Colledge, Sue; Conolly, James (10 August 2007). The Origins and Spread of Domestic Plants in Southwest Asia and Europe. Walnut Creek, CA: Left Coast Press. pp. 179–181. ISBN 978-1-59874-988-5. https://books.google.com/books?id=D2nym35k_EcC&pg=PA179. Retrieved 28 August 2018.
199. ↑ Kunzig, Robert; Tzar, Jennifer (1 November 2002). "La Marmotta". Discover. http://discovermagazine.com/2002/nov/cover.
200. ↑ Chevalier, Alexandre; Marinova, Elena; Pena-Chocarro, Leonor (1 April 2014). Plants and People: Choices and Diversity through Time. Oxbow Books. pp. 97–99. ISBN 978-1-84217-514-9. https://books.google.com/books?id=R5f9AwAAQBAJ&pg=PA97. Retrieved 28 August 2018.
201. ↑ "The history of the poppy and of opium and their expansion in antiquity in the eastern Mediterranean area". Bulletin on Narcotics XIX (4). 1967. https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1967-01-01_3_page004.html. Retrieved 23 August 2018.
202. ↑ Sonnedecker, Glenn (1962). "Emergence of the Concept of Opiate Addiction". Journal Mondial de Pharmacie 3: 275–290.
203. ↑ 203.0 203.1 203.2 203.3 203.4 203.5 "A brief history of opiates, opioid peptides, and opioid receptors". Proceedings of the National Academy of Sciences of the United States of America 90 (12): 5391–3. June 1993. doi:10.1073/pnas.90.12.5391. PMID 8390660. Bibcode: 1993PNAS...90.5391B.
204. ↑ 204.0 204.1 204.2 204.3 Duarte, Danilo Freire (February 2005). "Uma breve história do ópio e dos opióides". Revista Brasileira de Anestesiologia 55 (1). doi:10.1590/S0034-70942005000100015. http://www.scielo.br/pdf/rba/v55n1/en_v55n1a15.pdf. Retrieved 13 September 2019.
205. ↑ "Poppy and Opium in Ancient Times: Remedy or Narcotic?". Biomedicine International 1: 81–87. 2010.
206. ↑ "References to anesthesia, pain, and analgesia in the Hippocratic Collection". Anesthesia and Analgesia 110 (1): 188–94. January 2010. doi:10.1213/ane.0b013e3181b188c2. PMID 19861359.
207. ↑ "987 The Art of Alleviating Pain in Greek Mythology". European Journal of Pain 10 (S1): S255b–S255. September 2006. doi:10.1016/S1090-3801(06)60990-7. "Sedare dolorem opus divinum est – an old Latin inscription – means "alleviating pain is the work of the divine". This inscription is often attributed to either Hippocrates of Kos or Galen of Pergamum, but it is most likely an anonymous proverb".
208. ↑ Osbaldeston, Tess Anne (2000). Dioscorides (translation). Johannesburg, South Africa: Ibidis Press. pp. 607–611. ISBN 978-0-620-23435-1.
209. ↑ "Medicinal aspects of opium as described in Avicenna's Canon of Medicine". Acta medico-historica Adriatica 11 (1): 101–12. 2013. PMID 23883087. https://www.researchgate.net/publication/251877190. Retrieved 28 August 2018.
210. ↑ 210.0 210.1 210.2 "The Cultivation of the Opium Poppy in India". Bulletin on Narcotics (3). 1954. https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1954-01-01_3_page002.html#s020. Retrieved 5 September 2018.
211. ↑ 211.0 211.1 211.2 "Laudanum in the Works of Paracelsus". Bull. Hist. Med. 9: 530–544. 1941. http://www.samorini.it/doc1/alt_aut/sz/sigerist-laudanum-in-the-work-of-paracelsus.pdf. Retrieved 5 September 2018.
212. ↑ 212.0 212.1 212.2 212.3 212.4 "In the arms of Morpheus the development of morphine for postoperative pain relief". Canadian Journal of Anaesthesia 47 (4): 367–74. April 2000. doi:10.1007/BF03020955. PMID 10764185.
213. ↑ 213.0 213.1 Farooqui, Amar (December 2016). "The Global Career of Indian Opium and Local Destinies". Almanack (14): 52–73. doi:10.1590/2236-463320161404. http://www.scielo.br/pdf/alm/n14/2236-4633-alm-14-00052.pdf. Retrieved 5 September 2018.
214. ↑ 214.0 214.1 Deming, Sarah (2011). "The Economic Importance of Indian Opium and Trade with China on Britain's Economy, 1843–1890". Economic Working Papers 25 (Spring). https://www.whitman.edu/Documents/Academics/Economics/Working Paper Contents/WP_25.pdf. Retrieved 5 September 2018.
215. ↑ 215.00 215.01 215.02 215.03 215.04 215.05 215.06 215.07 215.08 215.09 215.10 Rinde, Meir (2018). "Opioids' Devastating Return". Distillations 4 (2): 12–23. https://www.sciencehistory.org/distillations/magazine/opioids-devastating-return. Retrieved 23 August 2018.
216. ↑ Mills, James H. (2016). "Review of 'Opium and Empire in Southeast Asia: Regulating Consumption in British Burma'". Reviews in History. Cambridge imperial and post-colonial studies series (Palgrave Macmillan). doi:10.14296/RiH/2014/2010. ISBN 978-0-230-29646-6. https://www.recensio.net/rezensionen/zeitschriften/reviews-in-history/2016/october/opium-and-empire-in-southeast-asia. Retrieved 5 September 2018.
217. ↑ "The isolation of morphine by Serturner". Indian Journal of Anaesthesia 60 (11): 861–862. November 2016. doi:10.4103/0019-5049.193696. PMID 27942064.
218. ↑ Courtwright, David T. (2009). Forces of habit drugs and the making of the modern world (1 ed.). Cambridge, Mass.: Harvard University Press. pp. 36–37. ISBN 978-0-674-02990-3. https://books.google.com/books?id=GHqV3elHYvMC&pg=PA36.
219. ↑ "Discovery and resupply of pharmacologically active plant-derived natural products: A review". Biotechnology Advances 33 (8): 1582–1614. December 2015. doi:10.1016/j.biotechadv.2015.08.001. PMID 26281720.
220. ↑ "Innovation, diffusion and safety of a medical technology: a review of the literature on injection practices". Social Science & Medicine 60 (5): 1133–47. March 2005. doi:10.1016/j.socscimed.2004.06.044. PMID 15589680.
221. ↑ Mosher, Clayton J. (2013). Drugs and Drug Policy: The Control of Consciousness Alteration. SAGE Publications. p. 123. ISBN 978-1-4833-2188-2. https://books.google.com/books?id=2UQXBAAAQBAJ&pg=PA123.
222. ↑ Fisher, Gary L. (2009). Encyclopedia of substance abuse prevention, treatment, & recovery. Los Angeles: SAGE. p. 564. ISBN 978-1-4522-6601-5. https://books.google.com/books?id=DFR2AwAAQBAJ&pg=PT598.
223. ↑ 223.0 223.1 Trickey, Erick (4 January 2018). "Inside the Story of America's 19th-Century Opiate Addiction". Smithsonian. https://www.smithsonianmag.com/history/inside-story-americas-19th-century-opiate-addiction-180967673/.
224. ↑ Schechter, Neil L. (1993). Pain in Infants, Children, and Adolescents. Williams & Wilkins. ISBN 978-0-683-07588-5. https://books.google.com/books?id=Qh19Z6WLsqUC&pg=PA189. Retrieved 6 September 2018.
225. ↑ Hicks, Robert D. (2011). "Frontline Pharmacies". Chemical Heritage Magazine (Chemical Heritage Foundation). https://www.sciencehistory.org/distillations/magazine/frontline-pharmacies. Retrieved 29 October 2018.
226. ↑ 226.0 226.1 Booth, Martin (12 June 1999). Opium: a history (1st U.S. ed.). St. Martin's Press. ISBN 978-0-312-20667-3. https://archive.org/details/opiumhistory00boot.
227. ↑ Wisniak, Jaime (March 2013). "Pierre-Jean Robiquet". Educación Química 24: 139–149. doi:10.1016/S0187-893X(13)72507-2.
228. ↑ Filan, Kenaz (2011). The power of the poppy: harnessing nature's most dangerous plant ally. Park Street Press. p. 69. ISBN 978-1-59477-399-0. https://books.google.com/books?id=JV4oDwAAQBAJ&pg=PT69. Retrieved 30 October 2018.
229. ↑ "Felix Hoffmann". June 2016. https://www.sciencehistory.org/historical-profile/felix-hoffmann.
230. ↑ Cooper, Raymond; Deakin, Jeffrey John (22 February 2016). Botanical miracles: chemistry of plants that changed the world. CRC Press. p. 137. ISBN 978-1-4987-0428-1. https://books.google.com/books?id=aXGmCwAAQBAJ&pg=PA137. Retrieved 30 October 2018.
231. ↑ "The discovery of heroin". Lancet 352 (9141): 1697–9. November 1998. doi:10.1016/S0140-6736(98)07115-3. PMID 9853457. https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(98)07115-3.pdf. Retrieved 30 October 2018. "Bayer registered the name heroin in June, 1898.".
232. ↑ 232.0 232.1 232.2 232.3 232.4 Newton, David E. (2016). Youth substance abuse: a reference handbook. Santa Barbara, CA: ABC-CLIO. pp. 41–60. ISBN 978-1-4408-3983-2. https://books.google.com/books?id=NNGuDAAAQBAJ&pg=PA41. Retrieved 30 October 2018.
233. ↑ Crow, James Mitchell (3 January 2017). "Addicted to the cure". Chemistry World. https://www.chemistryworld.com/features/new-opioid-drugs/2500163.article.
234. ↑ Methadone Matters: Evolving Community Methadone Treatment of Opiate Addiction. CRC Press. 2003. p. 13. ISBN 978-0-203-63309-0. https://books.google.com/books?id=A8ObB64ZKWoC&pg=PA13.
235. ↑ "Fact Sheet: Fentanyl and Synthetic Opioids". September 2016. http://www.drugpolicy.org/sites/default/files/Synthetic-Opioids-Fact-Sheet.pdf.
236. ↑ "Laws Learn about the laws concerning opioids from the 1800s until today". https://www.naabt.org/laws.cfm.
237. ↑ White, William L.. "The Early Criminalization of Narcotic Addiction". http://www.williamwhitepapers.com/pr/dlm_uploads/2014-The-Early-Criminalization-of-Narcotic-Addiction.pdf.
238. ↑ "Peer pressure and imposed consensus: the making of the 1984 Guidelines of Good Clinical Practice in the Treatment of Drug Misuse". Making Health Policy. Clio Medica. 75. 2003. pp. 149–83. doi:10.1163/9789004333109_009. ISBN 978-90-04-33310-9.
239. ↑ 239.0 239.1 Jacobs, Harrison (26 May 2016). "This one-paragraph letter may have launched the opioid epidemic". Business Insider. https://www.businessinsider.com/porter-and-jick-letter-launched-the-opioid-epidemic-2016-5.
240. ↑ "Chronic use of opioid analgesics in non-malignant pain: report of 38 cases". Pain 25 (2): 171–86. May 1986. doi:10.1016/0304-3959(86)90091-6. PMID 2873550.
241. ↑ 241.0 241.1 241.2 "The Ongoing Opioid Prescription Epidemic: Historical Context". American Journal of Public Health 106 (8): 1365–6. August 2016. doi:10.2105/AJPH.2016.303297. PMID 27400351.
242. ↑ Quinones, Sam (2015). Dreamland: the true tale of America's opiate epidemic. Bloomsbury Press. ISBN 978-1-62040-251-1.
243. ↑ "CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016". MMWR. Recommendations and Reports 65 (1): 1–49. March 2016. doi:10.15585/mmwr.rr6501e1. PMID 26987082.
244. ↑ "opioid: definition of opioid in Oxford dictionary (American English) (US)". http://www.oxforddictionaries.com/us/definition/american_english/opioid. "Opioid: 1950s: from opium + -oid."
245. ↑ "Factors regulating oral consumption of an opioid (Etonitazene) by morphine-addicted rats". Psychopharmacologia 5: 55–76. October 1963. doi:10.1007/bf00405575. PMID 14082382. "In this paper, the term, 'opioid', is used in the sense originally proposed by DR. GEORGE H. ACHESON (personal communication) to refer to any chemical compound with morphine-like activities.".
246. ↑ "Opioid antagonists". Pharmacological Reviews 19 (4): 463–521. December 1967. PMID 4867058.
247. ↑ "Opioid analgesics and antagonists". Textbook of Pharmacology. Elsevier India. 2008. p. III.137. ISBN 978-81-312-1158-8.
248. ↑ "Epidemic: Responding to America's Prescription Drug Abuse Crisis". The White House. 2011. http://www.whitehouse.gov/sites/default/files/ondcp/issues-content/prescription-drugs/rx_abuse_plan.pdf.
249. ↑ "First Do No Harm: Responding to Canada's Prescription Drug Crisis". March 2013. http://www.ccsa.ca/resource library/canada-strategy-prescription-drug-misuse-report-en.pdf.
250. ↑ "UK: Task Force offers ideas for opioid addiction solutions". Delhidailynews.com. 11 June 2014. http://www.delhidailynews.com/news/UK--Task-Force-offers-ideas-for-opioid-addiction-solutions-1402491160/.
251. ↑ Kite, Allison (29 April 2018). "Every state but Missouri has opioid drug tracking. Why are senators against it?". The Kansas City Star. https://www.kansascity.com/news/politics-government/article209982404.html.
252. ↑ "Most primary care physicians are aware of prescription drug monitoring programs, but many find the data difficult to access". Health Affairs 34 (3): 484–92. March 2015. doi:10.1377/hlthaff.2014.1085. PMID 25732500.
253. ↑ Perrone, Matthew (20 December 2015). "Painkiller politics: Effort to curb prescribing under fire". Philly.com. http://www.philly.com/philly/news/nation_world/20151220_Painkiller_politics__Effort_to_curb_prescribing_under_fire.html.
254. ↑ "The Impact of Opioid Risk Reduction Initiatives on High-Dose Opioid Prescribing for Patients on Chronic Opioid Therapy". The Journal of Pain 17 (1): 101–10. January 2016. doi:10.1016/j.jpain.2015.10.002. PMID 26476264.
255. ↑ Achenbach, Joel; Wagner, John; Bernstein, Lenny. "Trump says opioid crisis is a national emergency, pledges more money and attention". Washington Post. https://www.washingtonpost.com/politics/trump-declares-opioid-crisis-is-a-national-emergency-pledges-more-money-and-attention/2017/08/10/5aaaae32-7dfe-11e7-83c7-5bd5460f0d7e_story.html.
256. ↑ "Feasibility Study on Opium Licensing in Afghanistan for the Production of Morphine and Other Essential Medicines". ICoS. September 2005. http://www.isn.ethz.ch/Digital-Library/Publications/Detail/?id=13751&lng=en.
257. ↑ "Assuring Availability of Opioid Analgesics". World Health Organization. http://www.euro.who.int/document/e76503.pdf.
258. ↑ "The pharmacological basis of opioids". Clinical Cases in Mineral and Bone Metabolism 12 (3): 219–21. 2015. doi:10.11138/ccmbm/2015.12.3.219. PMID 26811699. "The opioid effects transcending analgesia include sedation, respiratory depression, constipation and a strong sense of euphoria.".
259. ↑ "What constitutes prescription drug misuse? Problems and pitfalls of current conceptualizations". Current Drug Abuse Reviews 1 (3): 255–62. November 2008. doi:10.2174/1874473710801030255. PMID 19630724. http://www.bentham.org/cdar/openaccsesarticle/cdar 1-3/0002CDAR.pdf.
260. ↑ "Subtypes of nonmedical prescription drug misuse". Drug and Alcohol Dependence 102 (1–3): 63–70. June 2009. doi:10.1016/j.drugalcdep.2009.01.007. PMID 19278795.
261. ↑ "Prescription Opioid Overdose Data | Drug Overdose | CDC Injury Center". 31 August 2018. https://www.cdc.gov/drugoverdose/data/overdose.html.
262. ↑ "Chronic Pain Management and Opioid Misuse: A Public Health Concern (Position Paper)" (in en-US). https://www.aafp.org/about/policies/all/chronic-pain-management-opiod-misuse.html.
263. ↑ Simon, Bradley T.; Lizarraga, Ignacio. "Opioids". Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones. Wiley Blackwell. pp. 355–356, 376–377. ISBN 978-1-119-83027-6.
264. ↑ "Opioid drug". https://www.sciencedaily.com/terms/opioid.htm.
265. ↑ "Esters of Morphine". United Nations Office on Drugs and Crime. 1953. http://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1953-01-01_2_page009.html.
266. ↑ "Esters of Morphine Opioids". 28 May 2014. http://www.eopiates.com/opioids/classification/esters-of-morphine-opioids.html.
267. ↑ Roth, Bryan L.; Baner, Karen; Westkaemper, Richard; Siebert, Daniel; Rice, Kenner C.; Steinberg, SeAnna; Ernsberger, Paul; Rothman, Richard B. (2002-09-03). "Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist". Proceedings of the National Academy of Sciences of the United States of America 99 (18): 11934–11939. doi:10.1073/pnas.182234399. ISSN 0027-8424. PMID 12192085. Bibcode: 2002PNAS...9911934R.
268. ↑ "Mechanistic and functional differentiation of tapentadol and tramadol". Expert Opinion on Pharmacotherapy 13 (10): 1437–49. July 2012. doi:10.1517/14656566.2012.696097. PMID 22698264.
269. ↑ "Tramadol induces antidepressant-type effects in mice". Life Sciences 63 (12): PL175-80. 1998. doi:10.1016/S0024-3205(98)00369-5. PMID 9749830.
270. ↑ "Attacking pain at its source: new perspectives on opioids". Nature Medicine 9 (8): 1003–8. August 2003. doi:10.1038/nm908. PMID 12894165.
271. ↑ "Peripheral mechanisms of opioid analgesia". Current Opinion in Pharmacology 9 (1): 3–8. February 2009. doi:10.1016/j.coph.2008.12.009. PMID 19157985.
272. ↑ "Opioid receptors and opioid peptide-producing leukocytes in inflammatory pain--basic and therapeutic aspects". Brain, Behavior, and Immunity 24 (5): 683–94. July 2010. doi:10.1016/j.bbi.2009.10.013. PMID 19879349.
273. ↑ "Isolation and identification of unique marker compounds from the Tasmanian poppy Papaver somniferum N. Implications for the identification of illicit heroin of Tasmanian origin". Forensic Science International 175 (2–3): 202–8. March 2008. doi:10.1016/j.forsciint.2007.07.002. PMID 17765420.

## 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

Articles Related to Opioid

* v
* t
* e

Treatment of drug dependence (N07B)

Nicotine dependence|

* Bupropion
* Cytisine
* Lobeline
* Mecamylamine
* Varenicline
* AA (Clonidine)

Alcohol dependence|

* AD inhibitor (Disulfiram
* Calcium carbimide
* Hydrogen cyanamide)
* Acamprosate
* Opioid antagonists
* Naltrexone
* Nalmefene)
* κ-Opioid receptor antagonists
* Aticaprant
* Topiramate
* AA (Clonidine)
* Baclofen
* Metadoxine
* Phenibut

Opioid dependence|

* AA (Clonidine
* Lofexidine)
* Ibogaine
* Opioids
* Buprenorphine (+naloxone)
* Levacetylmethadol
* Methadone
* Dihydrocodeine
* Dihydroetorphine
* Hydromorphone (extended-release)
* Morphine (extended-release)
* Opioid antagonists (Naltrexone
* Nalmefene)

Benzodiazepine dependence|

* AA (Clonidine)
* Benzodiazepines (Diazepam
* Lorazepam
* Chlordiazepoxide
* Oxazepam)
* Barbiturates (Phenobarbital)

Research|

Salvia divinorum

* v
* t
* e

Analgesics (N02A, N02B)

Opioids|

| Opiates/opium|

* Codeine# (+paracetamol, +aspirin)
* Morphine# (+naltrexone)
* Opium
* Laudanum
* Paregoric

|

Semisynthetic|

* Acetyldihydrocodeine
* Benzylmorphine
* Buprenorphine (+naloxone)
* Desomorphine
* Diamorphine (heroin)
* Dihydrocodeine (+paracetamol)
* Dihydromorphine
* Ethylmorphine
* Hydrocodone (+paracetamol, +ibuprofen, +aspirin)
* Hydromorphinol
* Hydromorphone
* Nicocodeine
* Nicodicodine
* Nicomorphine
* Oxycodone (+paracetamol, +aspirin, oxycodone/ibuprofen

Synthetic|

* Alfentanil
* Alphaprodine
* Anileridine
* Butorphanol
* Carfentanil
* Dextromoramide
* Dextropropoxyphene
* Dezocine
* Fentanyl# (+fluanisone)
* Ketobemidone
* Levorphanol
* Lofentanil
* Meptazinol
* Methadone#
* Nalbuphine
* NFEPP
* Pentazocine
* Pethidine (meperidine)
* Phenadoxone
* Phenazocine
* Piminodine
* Piritramide
* Propiram
* Remifentanil
* Sufentanil
* Tapentadol
* Tilidine
* Tramadol

Paracetamol-type|

* Acetanilide‡
* Bucetin‡
* Butacetin‡
* Paracetamol (acetaminophen)#
* Parapropamol‡
* Phenacetin‡
* Propacetamol‡

NSAIDs|

| Propionates|

* Fenoprofen
* Flurbiprofen
* Ibuprofen#
* Ketoprofen
* Naproxen
* Oxaprozin

|

Oxicams|

* Meloxicam
* Piroxicam

Acetates|

* Diclofenac
* Indometacin
* Ketorolac
* Nabumetone
* Sulindac
* Tolmetin

COX-2 inhibitors|

* Celecoxib
* Etoricoxib
* Lumiracoxib
* Parecoxib
* Rofecoxib ‡
* Valdecoxib ‡

Fenamates|

* Meclofenamic acid
* Mefenamic acid

Salicylates|

* Aspirin (acetylsalicylic acid)# (+paracetamol/caffeine)
* Benorylate
* Diflunisal
* Ethenzamide
* Magnesium salicylate
* Salicin
* Salicylamide
* Salsalate
* Wintergreen (methyl salicylate)

Pyrazolones|

* Aminophenazone‡
* Ampyrone
* Metamizole (dipyrone)
* Nifenazone
* Phenazone
* Propyphenazone (+paracetamol/caffeine)

Others|

* Glafenine

Cannabinoids|

* Cannabidiol
* Cannabis
* Nabilone
* Nabiximols
* Tetrahydrocannabinol (dronabinol)

Ion channel
modulators|

| Calcium blockers|

* Gabapentin
* Gabapentin enacarbil
* Mirogabalin
* Pregabalin
* Ziconotide

|

Sodium blockers|

* Carbamazepine
* Lacosamide
* Local anesthetics (e.g., cocaine, lidocaine)
* Mexiletine
* Nefopam
* Tricyclic antidepressants (e.g., amitriptyline#)

* Nav1.7/1.8-selective: DSP-2230§
* Funapide§
* PF-05089771§

Potassium openers|

* Flupirtine

Myorelaxants|

* Carisoprodol
* Chlorzoxazone
* Cyclobenzaprine
* Mephenoxalone
* Methocarbamol
* Orphenadrine

Others|

* Analgesic adjuvant
* Analgecine
* Camphor
* Capsaicin
* Clonidine
* Ketamine
* Menthol
* Methoxyflurane
* Nefopam
* Proglumide
* Tricyclic antidepressants (e.g., amitriptyline#)

* #WHO-EM
* ‡Withdrawn from market
* Clinical trials:
* †Phase III
* §Never to phase III

* v
* t
* e

Recreational drug use

Major
recreational
drugs|

| Depressants|

* Barbiturates
* Benzodiazepines
* Carbamates
* Ethanol (alcohol)
* Alcoholic drinks
* Beer
* Wine
* Gabapentinoids
* GHB
* Inhalants
* Medical
* Nitrous oxide
* Hazardous solvents
* contact adhesives
* Gasoline
* nail polish remover
* Paint thinner
* Other
* Freon
* Kava
* Nonbenzodiazepines
* Quinazolinones

|

Opioids|

* Buprenorphine
* Suboxone
* Subutex
* Codeine
* Desomorphine
* Krokodil
* Dextropropoxyphene
* Darvocet
* Darvon
* Fentanyl
* Diamorphine
* Heroin
* Hydrocodone
* Hydromorphone
* Dilaudid
* Methadone
* Mitragyna speciosa
* Kratom
* Morphine
* Opium
* Oxycodone
* /paracetamol
* Tramadol

Stimulants|

* Amphetamine
* Arecoline
* Areca
* Betel
* Caffeine
* Coffee
* Energy drinks
* Tea
* Cathinone
* Khat
* Cocaine
* Coca
* Crack
* Ephedrine
* Ephedra
* MDPV
* Mephedrone
* Methamphetamine
* Methylone
* Methylphenidate
* Modafinil
* Nicotine
* Tobacco
* Theobromine
* Cocoa
* Chocolate

Entactogens|

* 2C series
* 6-APB
* Benzofury
* AMT
* MDA
* MDMA
* Ecstasy

Hallucinogens|

| Psychedelics|

* Bufotenin
* Psychoactive toads
* Vilca
* Yopo
* DMT
* Ayahuasca
* LSA
* LSD-25
* Mescaline
* Peruvian torch
* Peyote
* San Pedro
* Psilocybin / Psilocin
* Psilocybin mushrooms

|

Dissociatives|

* DXM
* Glaucine
* Inhalants
* Nitrous oxide
* alkyl nitrites
* poppers
* amyl nitrite
* Ketamine
* MXE
* Muscimol
* Amanita muscaria
* PCP
* Salvinorin A
* Salvia divinorum

Deliriants|

* Atropine and Scopolamine
* Atropa belladonna
* Datura
* Hyoscyamus niger
* Mandragora officinarum
* Dimenhydrinate
* Diphenhydramine

Cannabinoids|

* JWH-018
* THC
* Cannabis
* Hashish
* Hash oil
* Marijuana

Oneirogens|

* Calea zacatechichi
* Silene capensis

Club drugs|

* Cocaine
* Quaaludes
* MDMA (Ecstasy)
* Nitrous oxide
* Poppers

Drug culture|

| Cannabis culture|

* 420
* Cannabis cultivation
* Cannabis smoking
* Head shop
* Legal history of cannabis in the United States
* Legality of cannabis
* Marijuana Policy Project
* Medical cannabis
* NORML
* Cannabis and religion
* Stoner film

|

Coffee culture|

* Coffee break
* Coffeehouse
* Latte art
* Tea house

Drinking culture|

* Bartending
* Beer culture
* Beer festival
* Binge drinking
* Diethyl ether
* Drinking games
* Drinking song
* Happy hour
* Hip flask
* Nightclub
* Pub
* Pub crawl
* Sommelier
* Sports bar
* Tailgate party
* Wine bar
* Wine tasting

Psychedelia|

* Psychonautics
* Art
* Drug
* Era
* Experience
* Literature
* Music
* Microdosing
* Therapy

Smoking culture|

* Cigarette card
* Fashion cigarettes
* Cloud-chasing
* Loosie
* Smokeasy
* Smoking fetishism
* Tobacco smoking

Other|

* Club drug
* Counterculture of the 1960s
* Dance party
* Drug paraphernalia
* Drug tourism
* Entheogen
* Hippie
* Needle sharing
* Nootropic
* Party and play
* Poly drug use
* Rave
* Religion and drugs
* Self-medication
* Sex and drugs
* Whoonga

Drug
production
and trade|

| Drug
production|

* Coca production in Colombia
* Drug precursors
* Opium production in Afghanistan
* Rolling meth lab

|

Drug trade|

* Illegal drug trade
* Colombia
* Darknet market
* Drug distribution
* Beer shop
* Cannabis shop
* Liquor store
* Liquor license

Issues with
drug use|

* Abuse
* Date rape drug
* Impaired driving
* Drug harmfulness
* Effects of cannabis
* Addiction
* Dependence
* Prevention
* Opioid replacement therapy
* Rehabilitation
* Responsible use
* Drug-related crime
* Fetal alcohol spectrum disorder
* Long-term effects of cannabis
* Neurotoxicity
* Overdose
* Passive smoking
* of tobacco or other substances

Legality of
drug use|

| International|

* 1961 Narcotic Drugs
* 1971 Psychotropic Substances
* 1988 Drug Trafficking
* Council of the European Union decisions on designer drugs

|

State level|

* Drug policy
* Decriminalization
* Prohibition
* Supply reduction
* Policy reform
* Demand reduction
* Drug Policy Alliance
* Harm reduction
* Law Enforcement Action Partnership
* Liberalization
* Latin America
* Students for Sensible Drug Policy
* Transform Drug Policy Foundation

Drug policy
by country|

* Australia
* Canada
* Germany
* India
* Netherlands
* Portugal
* Slovakia
* Soviet Union
* Sweden
* Switzerland
* United States
* Just Say No
* Office of National Drug Control Policy
* School district drug policies
* California
* Colorado
* Maryland
* Virginia

Other|

* Arguments for and against drug prohibition
* Capital punishment for drug trafficking
* Cognitive liberty
* Designer drug
* Drug court
* Drug possession
* Drug test
* Narc
* Politics of drug abuse
* War on Drugs
* Mexican Drug War
* Plan Colombia
* Philippine Drug War
* Zero tolerance

Lists of
countries by...|

* Alcohol legality
* Alcohol consumption
* Anabolic steroid legality
* Cannabis legality
* Annual use
* Lifetime use
* Cigarette consumption
* Cocaine legality
* Cocaine use
* Methamphetamine legality
* Opiates use
* Psilocybin mushrooms legality
* Salvia legality

* v
* t
* e

Euphoriants

* μ-Opioid receptor agonists (opioids) (e.g., morphine]], heroin, hydrocodone, oxycodone, opium, kratom)
* α2δ subunit-containing voltage-dependent calcium channels blockers (gabapentinoids) (e.g., gabapentin, pregabalin, phenibut)
* AMPA receptor antagonists (e.g., perampanel)
* CB1 receptor agonists (cannabinoids) (e.g., THC]], cannabis)
* Dopamine receptor agonists (e.g., levodopa)
* Dopamine releasing agents (e.g., amphetamine, methamphetamine]], MDMA, Chemistry:Mephedrone

See also: Recreational drug use

* v
* t
* e

Neuropathic pain and fibromyalgia pharmacotherapies

Monoaminergics|

* SNRIs (e.g., duloxetine, milnacipran)
* TCAs (e.g., amitriptyline, nortriptyline, dosulepin)
* Opioid MRIs (e.g., tapentadol, tramadol)

Ion channel blockers|

* Anticonvulsants (e.g., gabapentin, Chemistry:Pregabalin

Others|

* Alpha lipoic acid
* Benfotiamine
* Botulinum toxin A
* Bupropion
* Cannabinoids (e.g., cannabis, dronabinol, nabilone)
* NMDA receptor antagonists (e.g., ketamine, dextromethorphan, methadone)
* Opioids (e.g., hydrocodone, morphine, oxycodone, methadone, buprenorphine, tramadol, tapentadol)
* Sodium oxybate (GHB)

* v
* t
* e

Opioid receptor modulators

MOR|

* Agonists (abridged; see here for a full list): 3-HO-PCP
* 7-Acetoxymitragynine
* 7-Hydroxymitragynine
* ψ-Akuammigine
* α-Chlornaltrexamine
* α-Narcotine
* Acetyldihydrocodeine
* Acetylfentanyl
* Acrylfentanyl
* Adrenorphin (metorphamide)
* AH-7921
* Akuammicine
* Akuammidine
* Alfentanil
* Anileridine
* Apparicine
* β-Endorphin
* BAM-12P
* BAM-18P
* BAM-22P
* Benzhydrocodone
* Benzylmorphine
* Bezitramide
* Biphalin
* BU08070
* Buprenorphine
* Butorphan
* Butorphanol
* Butyrfentanyl
* BW373U86
* Carfentanil
* Casokefamide
* Cebranopadol
* Chloroxymorphamine
* Codeine
* DADLE
* DAMGO (DAGO)
* Dermorphin
* Desmetramadol (desmethyltramadol)
* Desomorphine
* Dextromoramide
* Dextropropoxyphene (propoxyphene)
* Dezocine
* Dimenoxadol
* Dimethylaminopivalophenone
* Eluxadoline
* Diamorphine (heroin)
* Dihydrocodeine
* Dihydroetorphine
* Dihydromorphine
* Dinalbuphine sebacate
* Diphenoxylate
* Dipipanone
* Dynorphin A
* Embutramide
* Endomorphin-1
* Endomorphin-2
* Eseroline
* Ethylmorphine
* Etorphine
* Fentanyl
* Fluorophen
* Frakefamide
* Furanylfentanyl
* Hemorphin-4
* Herkinorin
* Hodgkinsine
* Hydrocodone
* Hydromorphinol
* Hydromorphone
* IBNtxA
* Ketamine
* Ketobemidone
* Kratom
* Laudanosine
* Lefetamine
* Leu-enkephalin
* Levacetylmethadol
* Levomethorphan
* Levorphanol
* Lexanopadol
* Loperamide
* Loxicodegol
* Matrine
* Meptazinol
* Met-enkephalin (metenkefalin)
* Methadone
* Metkefamide
* Metopon
* Mitragynine
* Mitragynine pseudoindoxyl
* Morphiceptin
* Morphine
* Nalbuphine
* NalBzOH
* Nalmexone
* Naltalimide
* Neopine
* NFEPP
* Nicocodeine
* Nicodicodine
* Nicomorphine
* NKTR-181
* Norketamine
* Octreotide
* Oliceridine
* OM-3-MNZ
* Oripavine
* Oxycodone
* Oxymorphazone
* Oxymorphonazine
* Oxymorphone
* Oxymorphone phenylhydrazone
* OxyPNPH
* Papaver somniferum (opium)
* Pentazocine
* Pericine
* Pethidine (meperidine)
* Phenazocine
* Phencyclidine
* Piminodine
* Piritramide
* PL-017
* Prodine
* Propiram
* PZM21
* Racemethorphan
* Racemorphan
* Remifentanil
* Salsolinol
* SC-17599
* Sinomenine
* Sufentanil
* Tapentadol
* Tetrahydropapaveroline
* TH-030418
* Thebaine
* Thienorphine
* Tianeptine
* Tilidine
* Tramadol
* Trimebutine
* TRIMU 5
* TRV734
* Tubotaiwine
* U-47700
* Valorphin
* Viminol
* Xorphanol

* PAMs: BMS-986121
* BMS-986122

* Antagonists: (3S,4S)-Picenadol
* 2-(S)-N,N-(R)-Viminol
* 3CS-nalmefene
* 4-Caffeoyl-1,5-quinide
* 4′-Hydroxyflavanone
* 4',7-Dihydroxyflavone
* 6β-Naltrexol
* 6β-Naltrexol-d4
* 18-MC
* α-Gliadin
* β-Chlornaltrexamine
* β-Funaltrexamine
* Akuammine
* Alvimopan
* AM-251
* Apigenin
* AT-076
* Axelopran
* Bevenopran
* Catechin
* Catechin gallate
* Clocinnamox
* CTAP
* CTOP
* Cyclofoxy
* Cyprodime
* Diacetylnalorphine
* Diprenorphine
* ECG
* EGC
* Epicatechin
* Eptazocine
* Gemazocine
* Ginsenoside R
* Hyperoside
* Ibogaine
* Levallorphan
* Lobeline
* LY-255582
* LY-2196044
* Methocinnamox
* Methylnaltrexone
* Methylsamidorphan chloride
* Naldemedine
* Nalmefene
* Nalodeine (N-allylnorcodeine)
* Nalorphine
* Nalorphine dinicotinate
* Naloxazone
* Naloxegol
* Naloxol
* Naloxonazine
* Naloxone
* Naltrexazone
* Naltrexonazine
* Naltrexone
* Naltrindole
* Naringenin
* Noribogaine
* Oxilorphan
* Pawhuskin A
* Rimonabant
* Quadazocine
* Samidorphan
* Taxifolin

* Unknown/unsorted: Cannabidiol
* Coronaridine
* Cyproterone acetate
* Dihydroakuuamine
* Tabernanthine
* Tetrahydrocannabinol

DOR|

* Agonists: 3CS-nalmefene
* 6'-GNTI
* 7-SIOM
* ADL-5747 (PF-04856881)
* ADL-5859
* Alazocine (SKF-10047)
* Amoxapine
* AR-M100390 (ARM390)
* AZD2327
* β-Endorphin
* BAM-18P
* Biphalin
* BU-48
* Butorphan
* Butorphanol
* BW373U86
* Casokefamide
* Cebranopadol
* Codeine
* Cyclazocine
* DADLE
* Deltorphin A
* Deltorphin I
* Deltorphin II
* Desmethylclozapine
* Desmetramadol (desmethyltramadol)
* Dezocine
* Diamorphine (heroin)
* Dihydroetorphine
* Dihydromorphine
* DPDPE
* DPI-221
* DPI-3290
* DSLET
* Ethylketazocine
* Etorphine
* Fentanyl
* FIT
* Fluorophen
* Hemorphin-4
* Hydrocodone
* Hydromorphone
* Ibogaine
* Isomethadone
* JNJ-20788560
* KNT-127
* Kratom
* Laudanosine
* Leu-enkephalin
* Levomethorphan
* Levorphanol
* Lexanopadol
* Lofentanil
* Met-enkephalin (metenkefalin)
* Metazocine
* Metkefamide
* Mitragynine
* Mitragynine pseudoindoxyl
* Morphine
* N-Phenethyl-14-ethoxymetopon
* Norbuprenorphine
* NalBzOH
* Oripavine
* Oxycodone
* Oxymorphone
* Pethidine (meperidine)
* Proglumide
* Racemethorphan
* Racemorphan
* RWJ-394674
* Samidorphan
* SB-235863
* SNC-80
* SNC-162
* TAN-67 (SB-205,607)
* TH-030418
* Thebaine
* Thiobromadol (C-8813)
* Tonazocine
* Tramadol
* TRV250
* Xorphanol
* Zenazocine

* Antagonists: 4',7-Dihydroxyflavone
* 5'-NTII
* 6β-Naltrexol
* 6β-Naltrexol-d4
* α-Santolol
* β-Chlornaltrexamine
* Apigenin
* AT-076
* Axelopran
* Bevenopran
* BNTX
* Catechin
* Catechin gallate
* Clocinnamox
* Diacetylnalorphine
* Diprenorphine
* ECG
* EGC
* Eluxadoline
* Epicatechin
* ICI-154129
* ICI-174864
* LY-255582
* LY-2196044
* Methylnaltrexone
* Methylnaltrindole
* N-Benzylnaltrindole
* Nalmefene
* Nalorphine
* Naltrexone
* Naltriben
* Naltrindole
* Naloxone
* Naringenin
* Noribogaine
* Pawhuskin A
* Quadazocine
* SDM25N
* SoRI-9409
* Taxifolin
* Thienorphine

* Unknown/unsorted: 18-MC
* Cannabidiol
* Coronaridine
* Cyproterone acetate
* Tabernanthine
* Tetrahydrocannabinol

KOR|

* Agonists: 3CS-nalmefene
* 6'-GNTI
* 8-CAC
* 18-MC
* 14-Methoxymetopon
* β-Chlornaltrexamine
* β-Funaltrexamine
* Adrenorphin (metorphamide)
* Akuuamicine
* Alazocine (SKF-10047)
* Allomatrine
* Apadoline
* Asimadoline
* BAM-12P
* BAM-18P
* BAM-22P
* Big dynorphin
* Bremazocine
* BRL-52537
* Butorphan
* Butorphanol
* BW373U86
* Cebranopadol
* Ciprefadol
* CR665
* Cyclazocine
* Cyclorphan
* Cyprenorphine
* Desmetramadol (desmethyltramadol)
* Diamorphine (heroin)
* Diacetylnalorphine
* Difelikefalin
* Dihydroetorphine
* Dihydromorphine
* Dinalbuphine sebacate
* Diprenorphine
* Dynorphin A
* Dynorphin B (rimorphin)
* Eluxadoline
* Enadoline
* Eptazocine
* Erinacine E
* Ethylketazocine
* Etorphine
* Fedotozine
* Fentanyl
* Gemazocine
* GR-89696
* GR-103545
* Hemorphin-4
* Herkinorin
* HS665
* Hydromorphone
* HZ-2
* Ibogaine
* ICI-199,441
* ICI-204,448
* Ketamine
* Ketazocine
* Laudanosine
* Leumorphin (dynorphin B-29)
* Levallorphan
* Levomethorphan
* Levorphanol
* Lexanopadol
* Lofentanil
* LPK-26
* Lufuradom
* Matrine
* MB-1C-OH
* Menthol
* Metazocine
* Metkefamide
* Mianserin
* Mirtazapine
* Morphine
* Moxazocine
* MR-2034
* N-MPPP
* Nalbuphine
* NalBzOH
* Nalfurafine
* Nalmefene
* Nalodeine (N-allylnorcodeine)
* Nalorphine
* Naltriben
* Niravoline
* Norbuprenorphine
* Norbuprenorphine-3-glucuronide
* Noribogaine
* Norketamine
* Oripavine
* Oxilorphan
* Oxycodone
* Pentazocine
* Pethidine (meperidine)
* Phenazocine
* Proxorphan
* Racemethorphan
* Racemorphan
* RB-64
* Salvinorin A (salvia)
* Salvinorin B ethoxymethyl ether
* Salvinorin B methoxymethyl ether
* Samidorphan
* Spiradoline (U-62,066)
* TH-030418
* Thienorphine
* Tifluadom
* Tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline)
* U-50488
* U-54,494A
* U-69,593
* Xorphanol

* Antagonists: 4′-Hydroxyflavanone
* 4',7-Dihydroxyflavone
* 5'-GNTI
* 6'-GNTI
* 6β-Naltrexol
* 6β-Naltrexol-d4
* β-Chlornaltrexamine
* Buprenorphine/samidorphan
* Amentoflavone
* ANTI
* Apigenin
* Arodyne
* AT-076
* Aticaprant
* Axelopran
* AZ-MTAB
* Binaltorphimine
* BU09059
* Buprenorphine
* Catechin
* Catechin gallate
* CERC-501 (LY-2456302)
* Clocinnamox
* Cyclofoxy
* Dezocine
* DIPPA
* EGC
* ECG
* Epicatechin
* Hyperoside
* JDTic
* LY-255582
* LY-2196044
* LY-2444296
* LY-2459989
* LY-2795050
* MeJDTic
* Methylnaltrexone
* ML190
* ML350
* MR-2266
* N-Fluoropropyl-JDTic
* Naloxone
* Naltrexone
* Naltrindole
* Naringenin
* Norbinaltorphimine
* Noribogaine
* Pawhuskin A
* PF-4455242
* RB-64
* Quadazocine
* Taxifolin
* UPHIT
* Zyklophin

* Unknown/unsorted: Akuammicine
* Akuammine
* Coronaridine
* Cyproterone acetate
* Dihydroakuuamine
* Ibogamine
* Tabernanthine

NOP|

* Agonists: (Arg14,Lys15)Nociceptin
* ((pF)Phe4)Nociceptin(1-13)NH2
* (Phe1Ψ(CH2-NH)Gly2)Nociceptin(1-13)NH2
* Ac-RYYRWK-NH2
* Ac-RYYRIK-NH2
* BU08070
* Buprenorphine
* Cebranopadol
* Dihydroetorphine
* Etorphine
* JNJ-19385899
* Levomethorphan
* Levorphanol
* Levorphanol
* Lexanopadol
* MCOPPB
* MT-7716
* NNC 63-0532
* Nociceptin (orphanin FQ)
* Nociceptin (1-11)
* Nociceptin (1-13)NH2
* Norbuprenorphine
* Racemethorphan
* Racemorphan
* Ro64-6198
* Ro65-6570
* SCH-221510
* SCH-486757
* SR-8993
* SR-16435
* TH-030418

* Antagonists: (Nphe1)Nociceptin(1-13)NH2
* AT-076
* BAN-ORL-24
* BTRX-246040 (LY-2940094)
* J-113,397
* JTC-801
* NalBzOH
* Nociceptin (1-7)
* Nocistatin
* SB-612,111
* SR-16430
* Thienorphine
* Trap-101
* UFP-101

Unsorted|

* β-Casomorphins
* Amidorphin
* BAM-20P
* Cytochrophin-4
* Deprolorphin
* Gliadorphin (gluteomorphin)
* Gluten exorphins
* Hemorphins
* Kava constituents
* MEAGL
* MEAP
* NEM
* Neoendorphins
* Nepetalactone (catnip)
* Peptide B
* Peptide E
* Peptide F
* Peptide I
* Rubiscolins
* Soymorphins

Others|

* Enkephalinase inhibitors: Amastatin
* BL-2401
* Candoxatril
* D -Phenylalanine
* Dexecadotril (retorphan)
* Ecadotril (sinorphan)
* Kelatorphan
* Racecadotril (acetorphan)
* RB-101
* RB-120
* RB-3007
* Opiorphan
* Selank
* Semax
* Spinorphin
* Thiorphan
* Tynorphin
* Ubenimex (bestatin)

* Propeptides: β-Lipotropin (proendorphin)
* Prodynorphin
* Proenkephalin
* Pronociceptin
* Proopiomelanocortin (POMC)

* Others: Kyotorphin (met-enkephalin releaser/degradation stabilizer)

See also: Receptor/signaling modulators • Signaling peptide/protein receptor modulators

* v
* t
* e

Chemical classes of psychoactive drugs

Stimulants|

* Amphetamine-type/dopamine releasing agents: Alkylamines
* Cycloalkylaminopropanes
* Arylpiperazines
* Benzylpiperazines
* Phenylpiperazines
* Phenethylamines
* Aminorexes/phenyloxazolamines
* Amphetamines/α-methylphenethylamines
* Cathinones/β-ketoamphetamines
* β-Hydroxyamphetamines/cathinols
* Naphthylaminopropanes
* Phentermines
* Phenylisobutylamines/α-ethylphenethylamines
* α-Propylphenethylamines
* Phenylmorpholines/phenmetrazines
* Thiopropamines/thienylaminopropanes

* Cocaine-type/typical dopamine reuptake inhibitors: Phenethylamines
* Phenidates/benzylpiperidines
* Phenylethylpyrrolidines
* Pyrrolidinophenones
* Phenyltropanes/cocaine analogues

* Modafinil-type/atypical dopamine reuptake inhibitors: Modafinil analogues
* Phenylpiracetams

* Caffeine-type/adenosine receptor antagonists: Xanthines/methylxanthines

* Nicotine-type/nicotinic acetylcholine receptor agonists: Nicotine analogues

Depressants|

* GABAA receptor positive allosteric modulators: Alcohols/ethanol analogues
* Barbiturates
* Benzodiazepines
* Pyrrolobenzodiazepines
* Thienobenzodiazepines
* Thienodiazepines
* Thienotriazolodiazepines
* Triazolobenzodiazepines
* Carbamates
* Ethers
* Neuroactive steroids
* Nonbenzodiazepines
* β-Carbolines
* Cyclopyrrolones
* Imidazopyridines
* Pyrazolopyrimidines
* Phenols
* Piperidinediones
* Quinazolinones

* GABAA receptor agonists: Isoxazoles

* GHB receptor agonists: 1,4-Butanediols

* α2δ subunit-containing voltage-gated calcium channel blockers: Gabapentinoids

* Opioids/μ-opioid receptor agonists: Benzimidazoles
* Nitazenes
* Fentanyl analogues/phenylpiperidines
* Mitragyna alkaloids
* Morphinans/phenanthrenes
* Opiates/opium alkaloids
* Utopioids

* Antihistamines/H1 receptor antagonists: Benzimidazoles
* Diarylmethanes
* Ethylenediamines
* Tricyclics
* Dibenzocycloheptenes

Hallucinogens|

* Serotonergic psychedelics/serotonin 5-HT2A receptor agonists: Arylpiperazines
* Phenylpiperazines
* Quinolinylpiperazines
* Cyclized phenethylamines
* 3-Benzazepines
* Cyclized tryptamines
* Azepinoindoles
* Ibogalogs
* Iboga alkaloids
* β-Carbolines
* Harmala alkaloids
* Ergolines
* Lysergamides
* Simplified/partial lysergamides
* Phenethylamines (methoxyphenethylamines)
* 2Cs
* 25-NB/NBOMes
* 2C-Os
* 2C-Ts
* HOT-x
* TWEETIOs
* Amphetamines/α-methylphenethylamines
* 3Cs
* Dimethoxyamphetamines/DMAs
* DOx
* Alephs
* Ethylenedioxyamphetamines/EDxx
* Methylenedioxyamphetamines/MDxx
* Trimethoxyamphetamines/TMAs
* BOx
* FLYs/benzofurans
* Phenylisobutylamines/α-ethylphenethylamines
* 4Cs
* Scalines
* Ψ-PEAs
* Tryptamines
* α-Alkyltryptamines
* α-Alkyl-β-ketotryptamines
* 4-Hydroxytryptamines
* 5-Hydroxytryptamines
* 5-Methoxytryptamines
* Miscellaneous

* Dissociatives/NMDA receptor antagonists: Adamantanes
* Arylcyclohexylamines
* Diarylethylamines
* Morphinans

* κ-Opioid receptor agonists: Benzomorphans
* Salvinorins

* GABAA receptor agonists: Isoxazoles

* Deliriants/anticholinergics/muscarinic acetylcholine receptor antagonists: Diarylmethanes
* Tropanes

* Others: Cyclized tryptamines
* Azepinoindoles
* Iboga alkaloids
* (Phyto)cannabinoids

Entactogens|

* Serotonin releasing agents: Phenethylamines
* 2-Aminoindanes
* 2-Aminotetralins
* Amphetamines
* Benzofuranylaminopropanes
* Benzothiophenylaminopropanes
* Ethylenedioxyamphetamines/EDxx
* Indanylaminopropanes
* Indolylaminopropanes
* Methylenedioxyamphetamines/MDxx
* Tetralinylaminopropanes
* Tryptamines
* α-Alkyltryptamines
* Miscellaneous

Psychiatric drugs|

* Anxiolytics: Azapirones
* Benzodiazepines
* Pyrrolobenzodiazepines
* Thienobenzodiazepines
* Thienodiazepines
* Thienotriazolodiazepines
* Triazolobenzodiazepines

* Antidepressants: Tricyclic antidepressants
* Dibenzazepines
* Dibenzocycloheptenes
* Dibenzothiepins
* Dibenzoxazepines
* Dibenzoxepins
* Tetracyclic antidepressants

* Antipsychotics/dopamine D2 receptor antagonists or partial agonists: Benzamides
* Benzimidazoles
* Benzisothiazoles
* Benzisoxazoles
* Butyrophenones
* Diphenylbutylpiperidines
* Phenylpiperazines
* Tricyclics
* Dibenzazepines
* Dibenzodiazepines
* Dibenzothiazepines
* Dibenzothiepins
* Dibenzoxazepines
* Phenothiazines
* Thienobenzodiazepines

* Mood stabilizers/anticonvulsants: Gabapentinoids
* Tricyclics
* Dibenzazepines
* Valproates

Others|

* Nootropics: Racetams
* Phenylpiracetams

* Miscellaneous: 3-Benzazepines
* Adamantanes
* Catecholamines
* Tetrahydroisoquinolines
* Yohimbans

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Original source: https://en.wikipedia.org/wiki/Opioid. Read more

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Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Opioid&oldid=4358093"
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[ND]: No data
*[BNTX]: 7-Benzylidenenaltrexone
*[SIOM]: 7-Spiroindinooxymorphone
*[c.]: circa
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitor
*[TCAs]: Tricyclic antidepressants
*[MRIs]: monoamine reuptake inhibitors
*[GHB]: γ-hydroxybutyric acid
*[NOP]: Nociceptin receptor