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Opioid

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

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

Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use disorder, reversing opioid overdose, and suppressing cough. Extremely potent opioids such as carfentanil are approved only for veterinary use. Opioids are also frequently used recreationally for their euphoric effects or to prevent withdrawal. Opioids can cause death and have been used for executions in the United States.

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

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

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

Terminology

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

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. Other opioids are usually reserved for the relief of moderate to severe pain.

Acute pain
Opioids are effective for the treatment of acute pain (such as pain following surgery). 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. 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.

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

In treating chronic pain, opioids are an option to be tried after other less risky pain relievers have been considered, including paracetamol/acetaminophen or NSAIDs like ibuprofen or naproxen. Some types of chronic pain, including the pain caused by fibromyalgia or migraine, are preferentially treated with drugs other than opioids.For information on the use and overuse of opioids to treat migraines, see, which cites
 * The efficacy of using opioids to lessen chronic neuropathic pain is uncertain.
 * The efficacy of using opioids to lessen chronic neuropathic pain is uncertain.
 * The efficacy of using opioids to lessen chronic neuropathic pain is uncertain.

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., which cites
 * Opioids can also cause heightened sensitivity to headache pain. When other treatments fail or are unavailable, opioids may be appropriate for treating headache if the patient can be monitored to prevent the development of chronic headache.
 * Opioids can also cause heightened sensitivity to headache pain. When other treatments fail or are unavailable, opioids may be appropriate for treating headache if the patient can be monitored to prevent the development of chronic headache.
 * Opioids can also cause heightened sensitivity to headache pain. When other treatments fail or are unavailable, opioids may be appropriate for treating headache if the patient can be monitored to prevent the development of chronic headache.
 * Opioids can also cause heightened sensitivity to headache pain. When other treatments fail or are unavailable, opioids may be appropriate for treating headache if the patient can be monitored to prevent the development of chronic headache.

Opioids are being used more frequently in the management of non-malignant chronic pain. This practice has now led to a new and growing problem with addiction and misuse of opioids. Because of various negative effects the use of opioids for long-term management of chronic pain is not indicated unless other less risky pain relievers have been found ineffective. Chronic pain which occurs only periodically, such as that from nerve pain, migraines, and fibromyalgia, frequently is better treated with medications other than opioids. Paracetamol/Tylenol/Acetaminophen and nonsteroidal anti-inflammatory drugs including ibuprofen and naproxen are considered safer alternatives. 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.

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

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

Diarrhea
In cases of diarrhea-predominate irritable bowel syndrome, opioids may be used to suppress diarrhea. 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. Naloxegol, a peripherally-selective opioid antagonist is now available to treat opioid induced constipation.

Shortness of breath
Opioids may help with shortness of breath particularly in advanced diseases such as cancer and COPD among others. 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.

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.

Hyperalgesia

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

Adverse effects
Each year 69,000 people worldwide die of opioid overdose, and 15 million people have an opioid addiction.

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

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

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

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. 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.

Tolerance to opioids is attenuated by a number of substances, including:
 * calcium channel blockers
 * intrathecal magnesium and zinc
 * NMDA antagonists, such as dextromethorphan, ketamine, and memantine.
 * cholecystokinin antagonists, such as proglumide
 * Newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.

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

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

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.

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.

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

Problems with opioids include the following:

 * 1) Some people find that opioids do not relieve all of their pain.
 * 2) Some people find that opioids side effects cause problems which outweigh the therapy's benefit.
 * 3) Some people build tolerance to opioids over time. This requires them to increase their drug dosage to maintain the benefit, and that in turn also increases the unwanted side effects.
 * 4) Long-term opioid use can cause opioid-induced hyperalgesia, which is a condition in which the patient has increased sensitivity to pain.

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

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 very commonly used, with the added advantages of not causing movement disorders, and also possessing analgesic-sparing properties. Δ9-tetrahydrocannabinol relieves nausea and vomiting; it also produces analgesia that may allow lower doses of opioids with reduced nausea and vomiting.
 * 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.

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

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, tilidine and meperidine (pethidine) 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.
 * 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. Since tolerance to this problem does not generally develop, most people on long-term opioids need to take a laxative or enemas.

Treatment of OIC is successional and dependent on severity. The first mode of treatment is non-pharmacological, and includes lifestyle modifications like increasing dietary fiber, fluid intake (around 1.5 L per day), and physical activity. If non-pharmacological measures are ineffective, laxatives, including stool softeners (e.g., polyethylene glycol), bulk-forming laxatives (e.g., fiber supplements), stimulant laxatives (e.g., bisacodyl, senna), and/or enemas, may be used. A common laxative regimen for OIC is the combination of docusate and bisacodyl. Osmotic laxatives, including lactulose, polyethylene glycol, and milk of magnesia (magnesium hydroxide), as well as mineral oil (a lubricant laxative), are also commonly used for OIC.

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

Opioid rotation is one method suggested to minimise the impact of constipation in long-term users. 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. Newer drugs such as BIMU-8 and CX-546 may be much more effective.
 * 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.

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

Increased pain sensitivity
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. If encountered, rotation between several different opioid pain medications may decrease the development of increased pain. Opioid induced hyperalgesia more commonly occurs with chronic use or brief high doses but some research suggests that it may also occur with very low doses.

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. 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.

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

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%. Conversely, opioid therapy did not significantly affect testosterone levels in women. However, opioids can also interfere with menstruation in women by limiting the production of luteinizing hormone (LH). Opioid-induced hypogonadism likely causes the strong association of opioid use with osteoporosis and bone fracture, due to deficiency in estradiol. It also may increase pain and thereby interfere with the intended clinical effect of opioid treatment. Opioid-induced hypogonadism is likely caused by their agonism of opioid receptors in the hypothalamus and the pituitary gland. 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. , the effect of low-dose or acute opioid use on the endocrine system is unclear. Long-term use of opioids can affect the other hormonal systems as well.

Disruption of work
Use of opioids may be a risk factor for failing to return to work.

Persons performing any safety-sensitive task should not use opioids. Health care providers should not recommend that workers who drive or use heavy equipment including cranes or forklifts treat chronic or acute pain with opioids. Workplaces which manage workers who perform safety-sensitive operations should assign workers to less sensitive duties for so long as those workers are treated by their physician with opioids.

People who take opioids long term have increased likelihood of being unemployed. 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.

Increased accident-proneness
Opioid use may increase accident-proneness. Opioids may increase risk of traffic accidents and accidental falls.

Reduced Attention

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

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). Both therapeutic and chronic use of opioids can compromise the function of the immune system. Opioids decrease the proliferation of macrophage progenitor cells and lymphocytes, and affect cell differentiation (Roy & Loh, 1996). Opioids may also inhibit leukocyte migration. However the relevance of this in the context of pain relief is not known.

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

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

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

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

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.

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.

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

Usage
Opioid prescriptions in the US increased from 76 million in 1991 to 207 million in 2013.

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

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

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

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

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.

Exactly when the world became aware of opium in India and China is uncertain, but opium was mentioned in the Chinese medical work K'ai-pao-pen-tsdo (973 AD) By 1590 AD, opium poppies were a staple spring crop in the Subahs of Agra region.

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

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

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

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

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.

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

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

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

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

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

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

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. The use of opioids was stigmatized, and it was seen as a dangerous substance, to be prescribed only as a last resort for dying patients. The Controlled Substances Act of 1970 eventually relaxed the harshness of the Harrison Act.

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.

In the 1980s the World Health Organization published guidelines for prescribing drugs, including opioids, for different levels of pain. In the U.S., Kathleen Foley and Russell Portenoy became leading advocates for the liberal use of opioids as painkillers for cases of "intractable non-malignant pain". 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.

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".

As a result, health care organizations and public health groups, such as Physicians for Responsible Opioid Prescribing, have called for decreases in the prescription of opioids. In 2016, the Centers for Disease Control and Prevention (CDC) issued a new set of guidelines for the prescription of opioids "for chronic pain outside of active cancer treatment, palliative care, and end-of-life care" and the increase of opioid tapering.

"Remove the Risk"
In April 2019 the U.S. Food and Drug Administration announced the launch of a new education campaign to help Americans understand the important role they play in removing and properly disposing of unused prescription opioids from their homes. This new initiative is part of the FDA's continued efforts to address the nationwide opioid crisis (see below) and aims to help decrease unnecessary exposure to opioids and prevent new addiction. The "Remove the Risk" campaign is targeting women ages 35–64, who are most likely to oversee household health care decisions and often serve as the gatekeepers to opioids and other prescription medications in the home.

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

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.

As of 2015, prescription drug monitoring programs exist in every state, except for Missouri. 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. The Centers for Disease Control and Prevention was tasked with establishing and publishing a new guideline, and was heavily lobbied. In 2016, the United States Centers for Disease Control and Prevention published its Guideline for Prescribing Opioids for Chronic Pain, recommending that opioids only be used when benefits for pain and function are expected to outweigh risks, and then used at the lowest effective dosage, with avoidance of concurrent opioid and benzodiazepine use whenever possible. Research suggests that the prescription of high doses of opioids related to chronic opioid therapy (COT) can at times be prevented through state legislative guidelines and efforts by health plans that devote resources and establish shared expectations for reducing higher doses.

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

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

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

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

Drug misuse and non-medical use include the use of drugs for reasons or at doses other than prescribed. Opioid misuse can also include providing medications to persons for whom it was not prescribed. Such diversion may be treated as crimes, punishable by imprisonment in many countries. In 2014, almost 2 million Americans abused or were dependent on prescription opioids.

Classification
There are a number of broad classes of opioids:
 * Natural opiates: alkaloids contained in the resin of the opium poppy, primarily morphine, codeine, and thebaine, but not papaverine and noscapine which have a different mechanism of action
 * Esters of morphine opiates: slightly chemically altered but more natural than the semi-synthetics, as most are morphine prodrugs, diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphine dipropionate), desomorphine, acetylpropionylmorphine, dibenzoylmorphine, diacetyldihydromorphine;
 * Semi-synthetic opioids: created from either the natural opiates or morphine esters, such as hydromorphone, hydrocodone, oxycodone, oxymorphone, ethylmorphine and buprenorphine;
 * Fully synthetic opioids: such as fentanyl, pethidine, levorphanol, methadone, tramadol, tapentadol, and dextropropoxyphene;
 * Endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins.
 * Endogenous opioids, non-peptide: Morphine, and some other opioids, which are produced in small amounts in the body, are included in this category.
 * Natural opioids, non-animal, non-opiate: the leaves from Mitragyna speciosa (kratom) contain a few naturally-occurring opioids, active via Mu- and Delta receptors. Salvinorin A, found naturally in the Salvia divinorum plant, is a kappa-opioid receptor agonist.

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

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

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

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. 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. Inflammatory pain is also blunted by endogenous opioid peptides activating peripheral opioid receptors.

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.

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
Phenanthrenes naturally occurring in (opium):

 * Codeine
 * Morphine
 * Thebaine
 * Oripavine

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

Anilidopiperidines

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

Benzimidazoles
Benzimidazoles opioids are also known as nitazenes.

 * Metodesnitazene (Metazene)
 * Etodesnitazene (Etazene)
 * Metonitazene
 * Etonitazene
 * Etonitazepyne
 * Etonitazepipne
 * 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
 * AP-237
 * 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.)

title: Opioid


text:
Baron Crawshaw

Baron Crawshaw, of Crawshaw in the County Palatine of Lancaster and of Whatton in the County of Leicester is a title in the Peerage of the United Kingdom. It was created on 25 August 1892 for Sir Thomas Brooks, 1st Baronet. He notably served as High Sheriff of Lancashire in 1884. Brooks had already been created a baronet in the Baronetage of the United Kingdom, of Crawshaw Hall and Whatton House, on 9 February 1891. the titles are held by his great-grandson, the fifth Baron, who succeeded his elder brother in 1997.

The family seat is Whatton House near Loughborough in Leicestershire.

Barons Crawshaw (1892)

 * Thomas Brooks, 1st Baron Crawshaw (15 May 1825 – 5 February 1908)
 * William Brooks, 2nd Baron Crawshaw (16 October 1853 – 19 January 1929)
 * Gerald Beach Brooks, 3rd Baron Crawshaw (1 April 1884 – 21 October 1946)
 * William Michael Clifton Brooks, 4th Baron Crawshaw (25 March 1933 – 7 November 1997)
 * David Gerald Brooks, 5th Baron Crawshaw (born 14 September 1934–)

The heir presumptive is the present holder's nephew, Edward Samuel Brooks (b. 1969). Next in line is the present holder's cousin Timothy Allan William Brooks (b. 1962), grandson of Hon. Herbert William Brooks (1890-1974), the younger son of the 2nd Baron. He has a daughter, Sophie (b. 2002) and a son, Rupert James (b. 2003).

Attribution

 * Kidd, Charles & Williamson, David (editors). Debrett's Peerage and Baronetage (1990 edition). New York: St Martin's Press, 1990,

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Baron Crawshaw


text:
Crystal City

Crystal City is the name of:

Canada

 * Crystal City, Manitoba, Canada

United States

 * Crystal, Colorado
 * Crystal City, Missouri
 * Corning (city), New York, nicknamed the Crystal City due to its glass industry
 * Crystal, North Dakota
 * Crystal City, Texas
 * Namesake of nearby Crystal City Internment Camp during World War II
 * Crystal City, Virginia

Stations

 * Crystal City station (VRE), a commuter rail station in Virginia
 * Crystal City station (Washington Metro), a Washington Metro station in Virginia

Other

 * The Crystal City, a 2003 novel by Orson Scott Card
 * Crystal City, an alternate name for the Crystal Heights development proposed for Washington DC by Frank Lloyd Wright

title: Crystal City


text:
Wink

A wink is a facial expression made by briefly closing one eye. A wink is an informal mode of non-verbal communication usually signaling shared hidden knowledge or intent. However, it is ambiguous by itself and highly dependent upon additional context, without which a wink could become misinterpreted or even nonsensical. For example, in some regions of the world, a wink may be considered rude or offensive. Depending on the relationship of the people involved, a wink could possibly constitute a sexual gesture.

General overview and meanings
Winking is one of the more subtle gestures, usually involving eye contact between those involved. In most cases it is only meant to be known by the sender and their intended receivers, but in some cases can be more widely intended.

Single wink
A single wink is usually a friendly gesture implying a degree of solidarity or intimacy.

A typical use of the wink is to quietly send a message that third parties are not aware of. For example, while person A is lying to person B or deliberately teasing them, they might wink at person C as a means of indicating the fact to C and incorporating them in the "conspiracy". Alternatively, if person A is joking or teasing person B in a friendly way, person A may wink directly at person B as a way to suggest to them that their own (A's) words are to be taken as a joke. It is also possible for person A to use winking in order to secretly imply to person B that the words or actions of some third party should not be taken seriously (for example, because the third party is joking or lying).

A wink could also be used as a somewhat humorous way to express sympathy, solidarity, and encouragement, especially when the winker is trying to put the receiver at ease in a situation where they might feel nervous or uncomfortable. In such cases a wink has a meaning very similar to that of a "thumbs up".

In some cultures it is often a sexual interest, or flirtatious manner, during momentary eye contact. This is often followed by a smile and usually a smile from the receiver if it is accepted or approved by them, sometimes combined with blushing if they are embarrassed. A smile from the receiver sometimes—but not always—indicates (sexual) interest in the winker. For example, in the Wodaabe tribe in the Niger area, someone who wants to engage in sexual activities can wink at a person. If the person continues to look at them, they will slightly move their lip corner, showing the way to the bush the person is expected to have sex with them in.

In particularly difficult or strenuous situations, Person A may wink at Person B to non-verbally communicate that Person B can trust Person C. An extreme example of this could be undercover cops when one does something otherwise questionable.

Double wink
Like a single wink but more emphatic, two winks in a row may be used by the sender as a subtle way to imply that something said by the sender, immediately beforehand, was "sneaky", "tricky", "misleading", or "untrue" to the receiver. In English-speaking countries, this has also given rise to the expression of vocally saying "wink wink" while winking—or sometimes while not even winking at all, in which case the sender is not communicating the "trickiness" of their words to a third party, but to the receiver, and is thus signalling that their words should not be taken literally but as a hint or euphemism.

Both eyes (bat/flutter)
To close and open, or "wink", both eyes is usually an involuntary action known as a "blink". Though if done intentionally, in a particular way (such as once slowly or a few times in a row quickly), while giving a sweet or suggestive look with the eyes, often with the head tilted or at an angle in combination with the shoulders, is known as to "bat an eyelash", "bat/batting eyelashes", or "flutter/fluttering eyelashes". This is done as a way of flirting, showing interest, or in an attempt to persuade the receiver. Depending on the context, it may also be used ironically. For instance, if person A says something outrageous, or obviously a lie. Person B will "bat their eyelash" at person C, letting person C know that they think what person A said was foolish, lazy, obvious, etc.

The Western world (including Eastern Europe and Latin America)
Winking in Western culture can be used as a way of letting someone else know that the winker or some other person is joking or lying (e.g., a parent tells their child a story about a fairy princess, and then winks at the child's older sibling, the sibling thus knows the parent is lying to the younger child). It may also be used to communicate sexual intentions, ranging from flirtation to an explicit invitation.

Asia
In China and reportedly to some extent in India, winking to anyone other than family or a friend who a person wishes to have sex with may be seen as an offensive or at least an impolite gesture. This is demonstrated in the commotion caused by Sarah Palin in a number of Asian countries during the 2008 vice presidential debate, where she winked several times while debating Joe Biden. When Frederick Spencer Chapman was training Chinese guerillas in Malaya to shoot rifles, he found that a large proportion of them were unable to close only one eye at a time.

However, winking in the Indian subcontinent often has similar connotations as in the West. It can be used to signal an "inside" joke, a sly gesture shared between two people privately, unbeknownst to those around them, as in a social gathering. It can also be a naughty "come on" towards the attractive sex.

Africa
West African parents may wink to signal children to leave the room, especially when there is a guest, or another adult coming in. It is considered rude for children to stay in a room where adults or elders want to have a conversation, and so winking is used as a more discreet way to tell the children to leave the room. Parents also try not to embarrass themselves in front of guests, because their children do not understand immediately when it is time to leave the room.

Noted examples

 * In the famous Monty Python sketch "Nudge Nudge", a younger man slyly asks an older gentleman about sex through innuendo, reiterating the phrase "nudge nudge wink wink" after his questions in an attempt to indicate that his innocent-sounding questions are intended to be double entendres, i.e., of a sexual nature.
 * During the 2008 United States vice-presidential debate, Republican candidate Sarah Palin winked at the audience several times. Her behaviour was considered to be highly unusual in the context of a formal political debate and received considerable media attention. While some conservative pundits defended Palin, other individuals were critical of and even offended by her conduct.
 * In online dating, a 'wink' is a way of communicating approval of another member (sometimes from a non-member) without sending email. It is used at sites such as Match.com.

Physiological aspects
Not all humans are able to wink voluntarily, and some can only wink one (usually the non-dominant) eye. Others are far better at winking one eye and find it awkward to wink the other.

Animal winks
Animal winks are thought to be just as meaningful as humans'. Dogs are said to wink as a sign of non-aggression due to the fact they see extended eye contact as a challenge for dominance. So, when dogs don’t want to fight, they will wink/blink in submission.

Although usually blinking slowly to show affection, cats are also more rarely known to wink to humans and other cats, communicating that it sees the other as trustworthy. This has led some people to refer to this action as a "cat kiss", since the cat is showing love, like human kisses do.

title: Wink


text:
Killeen

Killeen may refer to:

Places

 * Northern Ireland
 * Killean, County Armagh, a village in County Armagh
 * Killeen, County Down, a townland in County Down
 * Killeen, County Tyrone, a townland in County Tyrone

 * Ireland
 * Killeen, County Cork, a village in County Cork
 * Killeen, County Laois, a village in County Laois
 * Killeen, County Mayo, a village in County Mayo
 * Killeen, County Meath, a village in County Meath
 * Killeen, County Tipperary, a townland in County Tipperary
 * Killeen, County Westmeath, a townland in the civil parish of Castletownkindalen, barony of Moycashel

 * United States
 * Killeen, Texas, a city in Bell County, Texas
 * Killeen Air Force Station, Killeen, Texas

Other uses

 * Killeen (surname)
 * Killeen Castle (disambiguation)

title: Killeen


text:
Gonzales

Gonzales may refer to:

Places

 * Gonzales, California, U.S.
 * Gonzales, Louisiana, U.S.
 * Gonzales, Texas, U.S.
 * Gonzales County, Texas

Other uses

 * Battle of Gonzales, 1835
 * Gonzales (horse) (1977 – after 1996), an American-bred Thoroughbred racehorse
 * Gonzales (surname)
 * Gonzales v. Raich
 * Speedy Gonzales, animated cartoon character in the Warner Brothers Looney Tunes
 * Gonzales (musician), Chilly Gonzales

title: Gonzales


text:
New Brunswick Route 11

Route 11 is a provincial highway in northeastern New Brunswick, Canada. The 440 km road runs from Moncton to the Quebec border, near Campbellton, at the Matapédia Bridge, following the province's eastern and northern coastlines.

Between Shediac Bridge and Miramichi, and between Bathurst and Campbellton, it is a two-lane road with some sections designed as a super two expressway. The highway is twinned for 7 kilometres in the Shediac region near the Route 15 interchange.

Route description

The southern terminus of Route 11 is at an interchange with Route 2 in Moncton, where it begins a concurrency with Route 15 for 12 km to Shediac. At Shediac, Route 11 departs Route 15 and turns northward, where its exit numbers are reset. It runs northward, parallel to Route 134 as a four-lane divided highway for 7 km, then becomes a super two controlled-access highway. The route passes through the communities of Shediac Cape, intersecting Route 134, and crosses the Shediac River. The highway then enters Cocagne by crossing the Cocagne River. Intersecting with Route 535, the route continues through Ward Corner passing McKees Mills and Saint-François-de-Kent at the intersection of Route 115. The route crosses the Little Bouctouche River, then the Bouctouche River as it enters Bouctouche.

From Bouctouche, Route 11 continues north to Richibucto as well as Kouchibouguac National Park. The highway reverts to a 2-lane uncontrolled access highway between the national park and the city of Miramichi to the northwest. The highway crosses the Miramichi River in the Miramichi borough of Chatham on the Centennial Bridge with Route 8.

Immediately after crossing the Miramichi River, Route 11 exits the right of way, leaving Route 8 alone on the super two. Route 11 continues on a 2-lane uncontrolled access highway northeast along the coast of Miramichi Bay and the Gulf of St. Lawrence as it runs around the perimeter of the Acadian Peninsula. Through this region, Route 11 typically forms the main street through most of the coastal towns and settlements such as Neguac, Caraquet, Bertrand, Grande-Anse, and Stonehaven. The only exception is a Super 2 controlled access bypass of the town of Tracadie-Sheila.

Route 11 has another interchange with Route 8 at Bathurst, where the latter terminates. Route 11 becomes a super two controlled-access highway from Bathurst, running northwest several kilometres inland from the coast of Chaleur Bay to Glencoe, west of the city of Campbellton. Near Glencoe, Route 11 intersects Route 17 and turns north onto a 2-lane local road toward Tide Head. The highway turns west to follow the Restigouche River and terminates at the Matapédia Bridge, which crosses the river and connects to Quebec Route 132 in Matapédia, Quebec.

History
Since the late 1960s, Route 11 has received several upgrades and re-designations as it progresses towards becoming an expressway.

The most significant upgrade to the entire highway route along the east coast of New Brunswick was the opening of the Centennial Bridge which replaced a ferry service and bypassed the town of Chatham in 1967.

In 1973 a new 4-lane expressway opened between Moncton and Shediac, which was then referred to as the Shediac Four-Lane Highway or Shediac Expressway (it was subsequently numbered Route 15 and is known as the Veterans Memorial Highway). Prior to this new expressway, Route 11 followed the Shediac Road from Shediac to Moncton, terminating at Route 2, the Trans-Canada Highway in Lakeville. Route 11's southern terminus was then changed to the current interchange at Route 15 in Shediac.

Controlled access Super 2 expressway sections on Route 11 were completed during the 1970s in Bathurst and the Campbellton-Dalhousie area, as well as between Shediac and Bouctouche.

During the 1980s and into the early 1990s, two long stretches of Super 2 expressway were completed on Route 11; one running from Bouctouche to Kouchibouguac National Park (bypassing Richibucto), and another running between Bathurst and Charlo, where the existing Super 2 section running east from Campbellton ended. The Super 2 section in Bathurst was also extended eastward past Salmon Beach at the city's east end.

A bypass of Tracadie-Sheila opened to traffic in 2003. Also, an extension to that existing bypass was done in 2009, linking the northern end and Six-Roads, near Pokemouche. A bypass of Caraquet opened to traffic in 2016. Also going south from exiting Route 11 from Portage Road to Bertrand. The 13 km construction started in 2013, then finished in 2016.

In 2017, work was completed on a new interchange between Route 11 and 15 in Shediac, and 7 kilometres of twinned highway.

Currently, two other sections of highway are being twinned. The first is from the south side of the Shediac River to the Cocagne River, and the second from the north side of the Cocagne River to the Little Bouctouche River, meaning the highway will revert to two lanes across the Cocagne River on the current bridge.

title: New Brunswick Route 11


text:
13th Golden Raspberry Awards

The 13th Golden Raspberry Awards were held on March 28, 1993, at the Hollywood Roosevelt Hotel to recognize the worst the movie industry had to offer in 1992. Shining Through and Stop! Or My Mom Will Shoot each won three Razzies, though the latter wasn't nominated for Worst Picture. Tom Selleck did not attend the ceremony and later accepted his award on The Chevy Chase Show.

Alan Menken, who wrote the music for the Razzie-winning song "High Times, Hard Times" from Newsies, also received the Academy Award for Best Original Song for "A Whole New World" from Aladdin in 1993, making him the first person to receive a Razzie and Oscar in the same year, a feat not repeated until screenwriter Brian Helgeland in 1998.

Awards and nominations
{{Legend|#B0C4DE|Winner (in bold)}}

Films with multiple nominations
These films received multiple nominations:

Criticism
The awards was criticized for the nomination to Danny DeVito's well-received performance for Worst Supporting Actor in Batman Returns.

title: 13th Golden Raspberry Awards


text:
User:Jce~enwiki

Jens Egerer,

electronics engineer, with studies in Germany and the US. I will try to write some things on microelectronics (especially integrated circuit design), but also on other stuff I find interesting.

title: User:Jce~enwiki


text:
Sexed up

Sexed up refers to making something more sexually attractive. Since 2003 it has been used in the sense of making something more attractive than it really is by selective presentation; a modern update to the phrase "hyped up". One variant of "sexed up" is "sex it up". The implication is that no actual lying is taking place, but that spin is being placed on certain parts of the message.

History
The phrase gained currency in the United Kingdom on 29 May 2003, when BBC defence correspondent Andrew Gilligan filed a report for BBC Radio 4's Today programme in which he stated that an unnamed source, a senior British official, had told him that the September Dossier had been "sexed up", and that the intelligence agencies were concerned about some highly dubious information contained within it—specifically the claim that Saddam Hussein could deploy weapons of mass destruction within 45 minutes of an order. The dubious information was used to make a case for urgent action and to justify the war with Iraq.

Usage

 * "One event in particular sours many freshman orientations: sexed-up sex-ed."
 * "Some things remain the same, but critics all say that the show was 'sexed up' by the CW for today's audiences."
 * In The God Delusion, Richard Dawkins states that pantheism is "sexed up atheism" while "deism is watered-down theism".

In music

 * "Sexed Up" is a single released in 2003 by Robbie Williams.

title: Sexed up


text:
Tooker Gomberg

Tooker Gomberg (August 12, 1955 – March 4, 2004) was a Canadian politician and environmental activist. A native of Montreal, Quebec, a graduate of Herzliah High School and a liberal-arts graduate of Hampshire College (1980), Gomberg founded one of Canada's first curbside recycling programs in Montreal, and later moved to Edmonton, Alberta, where he created educational materials for Alberta's energy ministry and headed the EcoCity Society, an environmental agency.

Political career
In 1992, he was elected to Edmonton's city council. In 1995 he ran for re-election but was not elected. It is said his support for high-density development of the Little Brickyard in his home base of Riverdale lost him support among many of the people there. His stand was in line with his belief in built-up, not sprawling, urban centres.

He ran for the position of Mayor in the 1998 municipal election, placing fourth with 15 percent of the vote.

In 1997, he was the New Democratic Party candidate for the Montreal riding of Outremont.

Toronto mayoralty run
Gomberg then moved to Toronto, Ontario, where he ran for mayor in the 2000 municipal election. He received over 51,000 votes, but finished a distant second behind Mel Lastman who garnered over 80 per cent of the vote.

The campaign was nonetheless influential. Gomberg had been endorsed by urban guru Jane Jacobs, a longtime and influential resident of Toronto's Annex neighbourhood. Some of Gomberg's platform included advocacy of provincial powers for Toronto and tolls for downtown traffic, policies that re-emerged in the successful 2003 campaign of David Miller.

In the last days of the 2000 campaign, Lastman appeared with Canadian PM Jean Chrétien to promise nearly one billion dollars in social housing funding. After winning, one of Lastman's first acts was to appoint Jane Jacobs to the city's Charter Committee, which was seeking additional powers for the city (taking them from the province of Ontario). Both moves were generally attributed to the need to respond to Gomberg's insurgent campaign.

Media
While in Toronto, Gomberg also hosted Eco-Freako, a webcast TV show. It ran for ten episodes.

Activism and arrests
Gomberg was often controversial as an environmental activist, having been arrested numerous times.

In June 2000, he was arrested at the World Petroleum Congress protests in Calgary. A protest march had taken him by the Suncor building, which was a violation of terms from an arrest at a Suncor protest in Northern Alberta. He was held for a couple of hours, then released. His was one of only three arrests at the WPC protests - the others being a street youth with outstanding warrants, and a woman who, when leaving the convergence centre was followed by police for several kilometers, stopped, and arrested for traffic violations.

He locked himself in a safe in Alberta premier Ralph Klein's constituency office as a protest against the province's stance on Kyoto.

He was also arrested in the Netherlands after breaking into the Volkel NATO Air Force base with 9 other anti-nuclear activists working to expose the presence of nuclear weapons in that country.

Death
On Thursday, March 4, 2004, Gomberg was reported missing to police, who later stated that he appeared to have jumped off the middle of the Angus L. Macdonald Bridge, in Halifax, Nova Scotia, in the early hours of the morning. He had left his partner a suicide note stating that he had "lost his chutzpah" and his bicycle and helmet were found on the bridge. His body was never found.

His partner, Angela Bischoff, suspects that his use of the antidepressant Remeron may have led to his decision to commit suicide. Gomberg had become increasingly agitated in his final weeks and his Remeron dosage had been increased to the maximum amount two days before his death. Three weeks later, U.S. Food and Drug Administration issued stronger warnings about a link between antidepressants and the risk of suicide, particularly in the weeks after a patient starts treatment or their dosage is increased. Health Canada later followed suit, and as of 2005, Remeron was listed in Health Canada's adverse drug reaction database.

Toronto activists advocated the establishment of a major East-West Bike lane, to be called the "Tooker", on Bloor Street, to honour the life of Tooker Gomberg.

Tooker Gomberg's brother Ben is, as of summer 2009, the head of the Chicago Department of Transportation's Bike (bicycle) Program.

title: Tooker Gomberg


text:
Jackson County

Jackson County is the name of 24 counties in the United States, most of which are named after President Andrew Jackson:

 * Jackson County, Alabama
 * Jackson County, Arkansas
 * Jackson County, Colorado
 * Jackson County, Florida
 * Jackson County, Georgia
 * Jackson County, Illinois
 * Jackson County, Indiana
 * Jackson County, Iowa
 * Jackson County, Kansas
 * Jackson County, Kentucky
 * Jackson Parish, Louisiana
 * Jackson County, Michigan
 * Jackson County, Minnesota
 * Jackson County, Mississippi
 * Jackson County, Missouri
 * Jackson County, North Carolina
 * Jackson County, Ohio
 * Jackson County, Oklahoma
 * Jackson County, Oregon
 * Jackson County, South Dakota
 * Jackson County, Tennessee
 * Jackson County, Texas
 * Jackson County, West Virginia
 * Jackson County, Wisconsin

title: Jackson County


text:
Kemah

Kemah may refer to:

 * Kemah, Erzincan, a town and district of Erzincan Province, Turkey
 * Kemah, Texas, a city in Galveston County, Texas, United States
 * USS Kemah, a United States Navy patrol vessel in commission from 1918 to 1919
 * Kemah Bob, an American comedian

title: Kemah


text:
Eola

Eola may refer to:
 * Eola, Illinois
 * Eola, Oregon
 * Eola-Amity Hills AVA, Oregon wine region
 * Eola, Texas
 * Lake Eola, Orlando, Florida
 * Aeolian processes, the process of wind activity
 * End of Life Announcement is a milestone in Product Life Cycle

title: Eola


text:
College Station

College station or College Station may refer to:

Transportation

 * College station (MetroLink), a St. Louis light rail station in Saint Clair County, Illinois, United States
 * College station (PNR), a Philippine National Railways station in Los Baños, Laguna, Philippines
 * College railway station (Scotland), a former railway station in Glasgow, Scotland, United Kingdom
 * College station (Toronto), a subway station in Toronto, Ontario, Canada
 * Du Collège station, a metro station in Montreal, Quebec, Canada

United States

 * 17th Street/SMC station, a light rail station in Santa Monica, California
 * 68th Street–Hunter College station, a subway station in Manhattan, New York
 * 137th Street–City College station, a subway station in Manhattan, New York
 * Allen station, a light rail station in Los Angeles, California, also signed as Allen/College station
 * APU/Citrus College station, a light rail station in Azusa, California
 * Bedford Park Boulevard–Lehman College station, a subway station in Bronx, New York
 * Boston College station, a light rail station in Newton, Massachusetts
 * College Avenue station (Illinois), a commuter rail station in Wheaton, Illinois
 * College Bayside station, an automated people mover station in Miami, Florida
 * College Boulevard station, a light rail station in Oceanside, California
 * College Greens station, a light rail station in Sacramento, California
 * College Hill station, a former train station in Beaver Falls, Pennsylvania
 * College North station, an automated people mover station in Miami, Florida
 * Community College station, a rapid transit station in Boston, Massachusetts
 * Cosumnes River College station, a light rail station in Sacramento, California
 * Dallas College North Lake Campus station, a light rail station in Irving, Texas
 * Delavan/Canisius College station, a light rail station in Buffalo, New York
 * Flatbush Avenue–Brooklyn College station, a subway station in Brooklyn, New York
 * Franklin/Dean College station, a commuter rail station in Franklin, Massachusetts
 * Franklin Avenue–Medgar Evers College station, a subway station in Brooklyn, New York
 * GateWay Community College station, a light rail station in Phoenix, Arizona
 * Hālaulani station, a light metro station in Pearl City, Hawaii, also known as Leeward Community College station
 * Medford/Tufts station, an under-construction light rail station in Medford, Massachusetts, originally planned to be named College Avenue station
 * Palomar College station, a bus and train station in San Marcos, California
 * Pierce College station, a bus rapid transit station in Los Angeles, California
 * President Street–Medgar Evers College station, a subway station in Brooklyn, New York
 * Red Rocks College station, a light rail station in Lakewood, Colorado
 * Valley College station, a bus rapid transit station in Los Angeles, California
 * Vermont/Santa Monica station, a rapid transit station in Los Angeles, California, also known L.A. City College station
 * Veterans Way/College Avenue station, a regional transportation center in Tempe, Arizona

India

 * Arts College railway station, in Secunderabad, Telangana
 * Dharampeth College metro station, a rapid transit station in Maharashtra
 * Garware College metro station, a rapid transit station in Pune
 * Hindu College railway station, a commuter rail station in Chennai
 * JNTU College metro station, a rapid transit station in Hyderabad
 * Kilpauk Medical College metro station, a rapid transit station in Chennai
 * Maharaja's College metro station, a rapid transit station in Kochi
 * National College metro station, a rapid transit station in Bengaluru
 * Osmania Medical College metro station, a rapid transit station in Hyderabad
 * Pachaiyappa's College metro station, a rapid transit station in Chennai
 * Sir Theagaraya College metro station, a rapid transit station in Chennai

China

 * Arts College station (Hohhot Metro), a rapid transit station in Hohhot, Mongolia
 * Chengdu Medical College station, a rapid transit station in Kochi,
 * The Police College station, a rapid transit station in Chengdu,
 * Southeast University Chengxian College station, a rapid transit station in Nanjing,

Elsewhere

 * Dong-Pusan College station, a rapid transit station in Busan, South Korea, now named Witbansong station
 * Durham College Oshawa GO station a commuter rail station in Oshawa, Ontario, Canada
 * Gimhae College station, a light metro station in Busan, South Korea
 * Humber College station, an under construction light rail station in Toronto, Canada
 * Islamia College railway station, in Pakistan
 * Stadium–Songdam College station, an automated people mover station in Cheoin-gu, South Korea
 * Urdu College railway station, an abandoned railway station in Karachi, Pakistan
 * VCC–Clark station, a rapid transit station in Vancouver, Canada, named after nearby Vancouver Community College

Places

 * College Station, Arkansas, United States
 * College Station, Texas, United States

Institutions

 * Atlantic College Lifeboat Station, in Atlantic College, South Wales

title: College Station


text:
Littlefield

Littlefield may refer to:

Jurisdictions in the United States

 * Littlefield, Arizona
 * Littlefield, Texas
 * Littlefield Township, Michigan

Other

 * Littlefield (surname)
 * Institutions:
 * In Arizona (in or near town of Littlefield): Littlefield Unified School District
 * In Texas:
 * In or near city of Austin:
 * Littlefield Fountain
 * Littlefield House
 * In or near town of Littlefield in Lamb County:
 * Littlefield Municipal Airport
 * Littlefield Independent School District

title: Littlefield