Opioid

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Opioids are substances that act on the nervous system in a similar way to opiates such as morphine and codeine.[1] In a medical context the term usually indicates medications that are artificially made rather than extracted from opium.[2] Common examples include oxycodone, hydrocodone, and hydromorphone.[3] Opioids are primarily used in medicine for the treatment of pain.

The side effects of opioids include sedation, respiratory depression, constipation, and a strong sense of euphoria. Opioid dependence can develop with ongoing administration, leading to a withdrawal syndrome with abrupt discontinuation. Morphine-like opioids are well known for their addictive properties, and for their ability to produce euphoria, motivating some to use opioids recreationally. They can cause death in overdose from respiratory depression. A number of substances occurring naturally in the body that can decrease the sensation of pain are also classified as opioids. Opioid like compounds found in natural opium latex are classified as opiates, but are also opioids.

In 2013 between 28 and 38 million people used opioids recreationally (0.6% to 0.8% of the global population between the ages of 15 and 65).[4] Opioids work 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.

Opioids are among the world's oldest known drugs; the medical use of the opium poppy predates recorded history. Although the term opiate is often used as a synonym for opioid, the term opiate is properly limited to the natural alkaloids found in the resin of the Papaver somniferum (opium poppy), while opioid refers to both natural and synthetic compounds with an opium-like effect (by being agonists at the opioid receptor). i.e. all opiates are opioids, but not all opioids are opiates.[2]

Definition

The term "opioid" was first used in the early 1960s.[5] Its basic meaning is "opiate-like" ("opiates" being a set of narcotic drugs derived from opium), and many sources do not define it more explicitly than that. 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 DR. GEORGE H. ACHESON (personal communication) to refer to any chemical compound with morphine-like activities".[5] By the late 1960s, it came to be understood that opiate effects are mediated by activation of specific molecular receptors in the nervous system, which were termed "opioid receptors".[6] 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".[1] Some sources use the term "opioid" to exclude opiates, but the majority use it inclusively.

Medical uses

Acute pain

Opioids are effective for the treatment of acute pain (such as pain following surgery).[7] 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.

Chronic non cancer pain

Guidelines have concluded that the risk of opioids are likely greater than their benefits when used for most non-cancer chronic conditions including headaches, back pain and fibromyalgia.[8] Thus they should be used cautiously in chronic non-cancer pain.[9]

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.[10] Some types of chronic pain, including the pain caused by fibromyalgia or migraine, are preferentially treated with drugs other than opioids.[11][12] The efficacy of using opioids to lessen chronic neuropathic pain is uncertain.[13]

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.[14] Opioids also can cause heightened sensitivity to headache pain.[14] 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.[14]

Opioids are being used more frequently in the management of non-malignant chronic pain.[15][16][17] This practice has now led to a new and growing problem with addiction and misuse of opioids.[9][18] 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 drugs other than opioids.[11] Paracetamol and non-steroidal anti-inflammatory drugs including ibuprofen and naproxen are both safer alternatives[citation needed] and used as a complement to opioids, i.e. Percocet (Paracetamol/Oxycodone) and Vicoprofen (Ibuprofen/Hydrocodone).

Shortness of breath

Opioids may help with shortness of breath particularly in advanced diseases such as cancer and COPD among others.[19][20]

Diarrhea

Sometimes in cases of diarrhea-predominate irritable bowel syndrome, opiates are used to prevent diarrhea when other treatments are ineffective.

Adverse effects

Adverse effects of opioids
Common and short term
Other

Studies have shown opioids to be safe when they are used correctly and in the ways that are well understood.[22]

Carefully titrating the dose of opioids can provide for effective pain relief while minimizing adverse effects. Morphine and diamorphine have been shown to have a wider therapeutic range or "safety margin" than some other opioids. It is impossible to tell which people need low doses and which need high doses, so all have to be started on low doses, unless changing from another strong opioid.[23]

Opioid analgesics 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 renal toxicity.[24]

In older adults, opioid use is associated with increased adverse effects such as "sedation, nausea, vomiting, constipation, urinary retention, and falls".[25] As a result, older adults taking opioids are at greater risk for injury.[26]

Research suggests that when methadone is used long-term it can build up unpredictably in the body and lead to potentially deadly slowed breathing.[27][28] Regular physician monitoring reduces the likelihood of problems.[27]

According to a cohort study, the rate of opioid related death was 0.017% per year amongst patients prescribed opioids for non-cancer pain from 1997-2005 in Washington State. Increasing dose and age were found to correlate with increased risk of overdose.[29] While a cohort study is a higher level of evidence than case-control, a case-control study done in Canada correlates well as it had an opioid related death rate of 0.024% per year amongst patients prescribed opioids for non-cancer pain over a 10-year period.[30]

Tolerance

Tolerance is a process characterized by neuroadaptations that result in reduced drug effects. While receptor downregulation may often play an important role other mechanisms are also known.[31] 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.[32]

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

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.[23] The speed and severity of withdrawal depends on the half-life of the opioid; heroin and morphine withdrawal occur more quickly and are more severe 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.[45] 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.[46]

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 sufferer 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.[23]

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. In other European countries including the UK, this is also legally used for OST although on a varying scale of acceptance.

Tamper-release formulations of time-controlled preparations of medications are intended to curb abuse and 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.[47][48]

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 dependence or substance abuse can give long-term pain relief with little risk of developing addiction, abuse, or other serious side effects.[22]

Problems with opioids include the following:

  1. Some people find that opioids do not relieve all of their pain.[49]
  2. Some people find that opioids side effects cause problems which outweigh the therapy's benefit[22]
  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.[22]
  4. Long-term opioid use can cause opioid-induced hyperalgesia, which is a condition in which the patient has increased sensitivity to pain.[50]

All of the opioids can cause side effects.[21] Common adverse reactions in patients taking opioids for pain relief include nausea and vomiting, drowsiness, itching, dry mouth, dizziness, and constipation.[21][23]

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.[citation needed] Due to severe side effects such as tardive dyskinesia, haloperidol is currently rarely used. A related drug, Compazine (prochlorperazine) is more often used, although it has similar risks. Stronger antiemetics such as ondansetron or tropisetron may be indicated if nausea is severe or continues for an extended period, although these tend to be avoided due to their high cost unless nausea is really problematic. A cheaper alternative is dopamine antagonists, e.g. domperidone and metoclopramide. Domperidone does not cross the blood–brain barrier, so blocks opioid emetic action in the chemoreceptor trigger zone without adverse central anti-dopaminergic effects (not available in the U.S.) Some antihistamines with anti-cholinergic properties (e.g. orphenadrine or diphenhydramine) may also be effective. The first-generation anti-histamine hydroxyzine is very commonly used, with the added advantages of not causing movement disorders, and also possessing analgesic-sparing properties.

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 10 mg every eight hours). If vomiting has already started, these drugs need to be administered by a non-oral route (e.g. subcutaneous for metoclopramide, rectally for domperidone).

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. Treatment is at any rate possible—CNS stimulants are generally effective.

Itching

Itching tends not to be a severe problem when opioids are used for pain relief, but if required then antihistamines are useful for counteracting itching. Non-sedating antihistamines such as fexofenadine are preferable so as to avoid increasing opioid induced drowsiness, although some sedating antihistamines such as orphenadrine may be helpful as they produce a synergistic analgesic effect which allows smaller doses of opioids to be used while still producing effective analgesia. For this reason some opioid/antihistamine combination products have been marketed, such as Meprozine (meperidine/promethazine) and Diconal (dipipanone/cyclizine), which may also have the added advantage of reducing nausea as well.

Constipation

Constipation develops in 90 to 95% of people taking opioids long term.[51] Since tolerance to this problem does not develop readily, most people on long-term opioids will need a laxative.[52]

For mild cases, a lot of water (around 1.5 L/day) and fibre might suffice (in addition to the laxative and stool-softeners). Caution: one dose of Opioid + one dose of stool softener up to maximum dose of four stool softener per day. One dose + one dose tends to balance the effects of constipation using an Opioid.

  • Stool-softening and peristalsis-promoting laxatives (e.g. docusate in combination with bisacodyl or senna).
  • Peripherally-acting opioid antagonists (e.g. methylnaltrexone) effectively prevent constipation while not affecting centrally mediated analgesia or provoking withdrawal syndrome; however, these can still potentially reduce the efficacy of opioid analgesics in the treatment of conditions where much of the pain relief comes from action at peripherally situated opioid receptors, such as in inflammatory conditions like arthritis or post-surgical pain.
  • High water intake and dietary fiber

For more severe and/or chronic cases, the drugs that are used work by not increasing peristalsis, but by preventing water uptake in the intestine, leading to a softer stool with a larger component of water, and, additionally, by acidifying the environment inside the intestine, which both decreases water uptake and enhances peristalsis (e.g. lactulose, which is controversially noted as a possible probiotic). The following drugs are generally efficacious:

There is tentative evidence that alvimopan or methylnaltrexone help.[53]

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.[54][55] Newer drugs such as BIMU-8 and CX-546 may however be much more effective.[56][57][58]

  • 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)

Opioid-induced hyperalgesia

Opioid-induced hyperalgesia has been observed in some patients, whereby individuals using opioids to relieve pain may paradoxically experience more pain as a result of their medication. This phenomenon, although uncommon, is seen in some palliative care patients, most often when dose is escalated rapidly.[59][60] If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia.[61][62]

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.[63] 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 addition of a supplemental non-opioid analgesic), rotating between different opioid drugs, or by switching to a milder opioid with mixed mode of action that also counteracts neuropathic pain, particularly tramadol or tapentadol.[64][65][66]

Hormone imbalance

Clinical studies have consistently associated medical and recreational opioid use with hypogonadism and hormone imbalance in both genders. The effect is dose-dependent. Most studies suggest that the majority (perhaps as much as 90%) of chronic opioid users suffer hormone imbalances. Opioids can also interfere with menstruation in women by limiting the production of luteinizing hormone (LH). Opioid-induced endocrinopathy likely causes the strong association of opioid use with osteoporosis and bone fracture. It also may increase pain and thereby interfere with the intended clinical effect of opioid treatment. Opioid-induced endocrinopathy is likely caused their agonism of opioid receptors in the hypothalamus and the pituitary gland. A study conducted on heroin addicts found that their testosterone levels returned to normal within one month of abstinence, suggesting that the effect is temporary. As of 2013, the effect of low-dose or acute opiate use on the endocrine system is unclear.[67][68][69]

Disruption of work

Use of opioids may be a risk factor for failing to return to work.[70][71]

Persons performing any safety-sensitive task should not use opioids.[72] 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.[72] 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.[72]

People who take opioids long term have increased likelihood of being unemployed.[73] Taking opioids further disrupts 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.[74]

Increased accident-proneness

Opioid use may increase accident-proneness. Opioids may increase risk of traffic accidents[75][76] and accidental falls.[77]

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).[23] 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.[78]

With benzodiazepines or alcohol

The concurrent use of opioids with benzodiazepines or ethanol increases the rates of adverse events, overdose, and death in patients.[78] These risks are lessened with close monitoring by a physician, who may conduct ongoing screening for changes in patient behavior and treatment compliance.[78] When opioids are combined with sedatives then the patient has increased risk of breathing problems.[79]

Opioid antagonist

Finally, opioid effects (adverse or otherwise) can be reversed with an opioid antagonist such as naloxone or naltrexone.[80] These competitive antagonists bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This displaces the agonist, attenuating and/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.

Pharmacology

Opioid comparison
Drug Relative Potency[81] Nonionized Fraction Protein Binding Lipid Solubility[82]
Morphine 1 ++ ++ ++
Meperidine 0.1 + +++ ++
Hydromorphone 10
Alfentanil 10–25 ++++ ++++ +++
Fentanyl 75–125 + +++ ++++
Remifentanil 250 +++ +++ ++
Sufentanil 500–1000 ++ ++++ ++++
Etorphine 1000–3000

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 laevo-rotatory isomers. In addition, there are three subtypes of μ-receptor: μ1 and μ2, and the newly discovered μ3. Another receptor of clinical importance is the opioid-receptor-like receptor 1 (ORL1), which is involved in pain responses as well as having a major role in the development of tolerance to μ-opioid agonists used as analgesics. These are all G-protein coupled receptors acting on GABAergic neurotransmission.

Locants of the morphine molecule

The pharmacodynamic response to an opioid depends upon the receptor to which it binds, its affinity for that receptor, and whether the opioid is an agonist or an antagonist. For example, the supraspinal analgesic properties of the opioid agonist morphine are mediated by activation of the μ1 receptor; respiratory depression and physical dependence by the μ2 receptor; and sedation and spinal analgesia by the κ receptor[citation needed]. Each group of opioid receptors elicits a distinct set of neurological responses, with the receptor subtypes (such as μ1 and μ2 for example) providing even more [measurably] specific responses. Unique to each opioid is its distinct binding affinity to the various classes of opioid receptors (e.g. the μ, κ, and δ opioid receptors are activated at different magnitudes according to the specific receptor binding affinities of the opioid). For example, the opiate alkaloid morphine exhibits high-affinity binding to the μ-opioid receptor, while ketazocine exhibits high affinity to ĸ receptors. It is this combinatorial mechanism that allows for such a wide class of opioids and molecular designs to exist, each with its own unique effect profile. Their individual molecular structure is also responsible for their different duration of action, whereby metabolic breakdown (such as N-dealkylation) is responsible for opioid metabolism.

INTA: selective agonist of KOR-DOR and KOR-MOR heteromers. Does not recruit β-arrestin II. Antinociceptive devoid of aversion, tolerance, and dependence in mice.[83]

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 a chemical compound with the code number TRV130. It displays analgesic activity and reduced adverse effects.[84]

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 chart is used to find the equivalent dosage of another.

Usage

Global estimates of illegal drug users in 2013
(in millions of users)[85]
Substance Best
estimate
Low
estimate
High
estimate
Amphetamine-
type stimulants
33.90 13.87 53.81
Cannabis 181.79 128.48 232.07
Cocaine 17.04 13.80 20.73
Ecstasy 18.79 9.34 28.39
Opiates 16.53 12.92 20.46
Opioids 32.42 27.99 37.56

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 patients 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.[86] The number of opioid prescriptions in the United States and Canada is double the consumption in the European Union, Australia, and New Zealand.[87] Certain populations have been affected by the opioid addiction crisis more than others, including First World communities[88] and low-income populations.[89] Public health specialists say that this may result from unavailability or high cost of alternative methods for addressing chronic pain.[90]

History

A sample of raw opium

Non-clinical use was criminalized in the U.S by the Harrison Narcotics Tax Act of 1914, and by other laws worldwide. Since then, nearly all non-clinical use of opioids has been rated zero on the scale of approval of nearly every social institution. However, in 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 U.S. the Controlled Substances Act of 1970 markedly relaxed the harshness of the Harrison Act.

Before the twentieth century, institutional approval was often higher, even in Europe and America. In some cultures, approval of opioids was significantly higher than approval of alcohol. Opiates were used to treat depression and anxiety until the mid-1950s.[91]

Society and culture

Efforts to reduce abuse

In 2011, the Obama administration released a white paper describing the administration's plan to deal with what it referred to as an epidemic of prescription drug abuse. The administration's concerns about addiction and accidental overdosing have been echoed by numerous other medical and government advisory groups around the world.[90][92][93][94] The Centers for Disease Control and Prevention was set to release new guidelines for prescribing opioid painkillers in January 2016. But after months of lobbying by groups linked to the pharmaceutical industry, the CDC is allowing for public comment and changes.[95]

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.[96] 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.[97]

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 suffering from severe pain and unable to access poppy-based drugs under the current system.

United States approval

The sole clinical indications for opioids in the United States, according to Drug Facts and Comparisons, 2005, are:

Evidence supports the use of low dose, regular oral opioids for the safe relief of breathlessness that is not responsive to disease-modifying treatments. This action appears to be a result of the effect on opioid receptors in the limbic system.

Opioids are not used for psychological relief.

Opioids are often used in combination with adjuvant analgesics (drugs which have an indirect effect on the pain). In palliative care, opioids are not recommended for sedation or anxiety because experience has found them to be ineffective agents in these roles. Some opioids are relatively contraindicated in renal failure because of the accumulation of the parent drug or their active metabolites (e.g. codeine and oxycodone). Age (young or old) is not a contraindication to strong opioids. Some synthetic opioids such as pethidine have metabolites which are actually neurotoxic and should therefore be used only in acute situations.

Recreational use

Drug misuse is the use of drugs for reasons other than what the drug was prescribed for. Opioids are primarily misused due to their ability to produce euphoria. Misuse can also include giving drugs to people for whom it was not prescribed or selling the medication, both of which are crimes punishable by imprisonment in some, if not most, countries.[98][99]

Classification

There are a number of broad classes of opioids:

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 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 and/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, making paracetamol a prodrug) which enhances the release of serotonin and also interacts as with the cannabinoid receptors by inhibiting the uptake of anandamide.[citation needed]

Other analgesics work peripherally (i.e., not on the brain or spinal cord). Research is starting to show that morphine and related drugs may indeed have peripheral effects as well, such as morphine gel working on burns. Recent investigations discovered opioid receptors on peripheral sensory neurons.[103] 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.[104] Inflammatory pain is also blunted by endogenous opioid peptides activating peripheral opioid receptors.[105]

It has been discovered in 1953,[citation needed] that the human body, as well as those of some other animals, naturally produce minute amounts of morphine and codeine and possibly some of their simpler derivatives like heroin and dihydromorphine, in addition to the well known endogenous opioid peptides. Some bacteria are capable of producing some semi-synthetic opioids such as hydromorphone and hydrocodone when living in a solution containing morphine or codeine respectively.

Many of the alkaloids and other derivatives of the opium poppy are not opioids or narcotics; the best example is the smooth-muscle relaxant papaverine. Noscapine is a marginal case as it does have CNS effects but not necessarily similar to morphine, and it is probably in a category all its own.
Dextromethorphan (the stereoisomer of levomethorphan, a semi-synthetic opioid agonist) and its metabolite dextrorphan have no opioid analgesic effect at all despite their structural similarity to other opioids; instead they are potent NMDA antagonists and sigma 1 and 2-receptor agonists and are used in many over-the-counter cough suppressants.
Salvinorin A is a unique selective, powerful ĸ-opioid receptor agonist. It is not properly considered an opioid nevertheless, because:

  1. chemically, it is not an alkaloid; and
  2. it has no typical opioid properties: absolutely no anxiolytic or cough-suppressant effects. It is instead a powerful hallucinogen.
Opioid peptides Skeletal molecular images
Adrenorphin Chemical structure of Adrenorphin
Amidorphin Chemical structure of Amidorphin.
Casomorphin Chemical structure of Bovine β-casomorphin.
DADLE Chemical structure of DADLE.
DAMGO Chemical structure of DAMGO.
Dermorphin Chemical structure of Dermorphin.
Endomorphin Chemical structure of Endomorphin 1.
Morphiceptin Chemical structure of Morphiceptin.
Nociceptin Chemical structure of Nociceptin.
Octreotide Chemical structure of Octreotide.
Opiorphin Chemical structure of Opiorphin.
TRIMU 5 Chemical structure of TRIMU 5.

Endogenous opioids

Opioid-peptides that are produced in the body include:

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-neo-endorphin 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):

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

Esters of morphine

Ethers of morphine

Semi-synthetic alkaloid derivatives

Synthetic opioids

Anilidopiperidines

Phenylpiperidines

Diphenylpropylamine derivatives

Benzomorphan derivatives

Oripavine derivatives

Morphinan derivatives

Others

Allosteric modulators

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

Opioid antagonists

Table of morphinan opioids

Table of non-morphinan opioids

See also

References

  1. 1.0 1.1 Mehdi B (2008). "Opioid analgesics and antagonists". In Seth SD, Seth V. Textbook Of Pharmacology. Elsevier India. p. III.137. ISBN 9788131211588. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  2. 2.0 2.1 D'Arcy, Pamela Stitzlein Davies, Yvonne (2012). Compact clinical guide to cancer pain management an evidence-based approach for nurses. New York: Springer. p. 55. ISBN 9780826109743.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  3. "opioid". Taber's Online Medical Dictionary. Unbound Medicine, Inc. Retrieved 2 September 2015.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  4. "Status and Trend Analysis of Illict [sic] Drug Markets". World Drug Report 2015 (PDF). Retrieved 26 June 2015.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  5. 5.0 5.1 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  6. Martin WR (1967). "Opioid antagonists". Pharmacol. Rev. 19 (4): 463–521. PMID 4867058.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  7. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  8. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  9. 9.0 9.1 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
    Responses to Okie's perspective: Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  10. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  11. 11.0 11.1 Regarding using opioids to treat migraine, see American Academy of Neurology (February 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, American Academy of Neurology, retrieved 1 August 2013<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>, which cites
      • Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
      • Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
      • Institute for Clinical Systems Improvement (2011), Headache, Diagnosis and Treatment of, Institute for Clinical Systems Improvement<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles> Cite error: Invalid <ref> tag; name "AANfive" defined multiple times with different content
  12. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  13. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  14. 14.0 14.1 14.2 American Headache Society (September 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, American Headache Society, retrieved 10 December 2013<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>, which cites
    • Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
    • Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
    • Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
    • Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  15. "Opioid epidemic in the United States". Pain Physician. 15 (3 Suppl): ES9–38. Jul 2012. PMID 22786464.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  16. http://www.jpain.org/article/S1526-5900(08)00830-4/abstract
  17. "PAIN". Painjournalonline.com. 2015-09-01. Retrieved 2016-01-07.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  18. USA (2015-09-28). "Long-term opioid treatment of chronic nonmalignant pain: unproven efficacy and neglected safety?". Ncbi.nlm.nih.gov. Retrieved 2016-01-07.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  19. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  20. Wiseman, R; Rowett, D; Allcroft, P; Abernethy, A; Currow, DC (Mar 2013). "Chronic refractory dyspnoea--evidence based management". Australian family physician. 42 (3): 137–40. PMID 23529525.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  21. 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  22. 22.0 22.1 22.2 22.3 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  23. 23.0 23.1 23.2 23.3 23.4 Doyle, D.; Hanks, G.; Cherney, I.; et al., eds. (2004). Oxford Textbook of Palliative Medicine (3rd ed.). Oxford University Press. ISBN 0198566980.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  24. Schneider JP. Rational use of opioid analgesics in chronic musculoskeletal pain. J Musculoskel Med. 2010;27:142-148.
  25. Baumann S (2009). "A nursing approach to pain in older adults". Medsurg Nurs. 18 (2): 77–82, quiz 83. PMID 19489204.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  26. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  27. 27.0 27.1 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  28. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  29. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  30. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  31. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  32. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  33. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  34. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  35. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  36. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  37. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  38. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  39. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  40. Malec D, Mandryk M, Fidecka S (Mar–Apr 2008). "Interaction of memantine and ketamine in morphine- and pentazocine-induced antinociception in mice" (PDF). Pharmacological Reports. 60 (2): 149–55. PMID 18443375. Retrieved 17 September 2011. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  41. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  42. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  43. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  44. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  45. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  46. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  47. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  48. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  49. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  50. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  51. Canadian Agency for Drugs and Technologies in Health (Jun 26, 2014). "Dioctyl Sulfosuccinate or Docusate (Calcium or Sodium) for the Prevention or Management of Constipation: A Review of the Clinical Effectiveness". PMID 25520993.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  52. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  53. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  54. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  55. Tan ZM, Liu JH, Dong T, Li JX (August 2006). "[Clinical observation of target-controlled remifentanil infusion combined with propofol and doxapram in painless artificial abortion]". Nan Fang Yi Ke Da Xue Xue Bao. 26 (8): 1206–8. PMID 16939923. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  56. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  57. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  58. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  59. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  60. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  61. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  62. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  63. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  64. Mitra S (2008). "Opioid-induced hyperalgesia: pathophysiology and clinical implications". Journal of Opioid Management. 4 (3): 123–30. PMID 18717507.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  65. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  66. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  67. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  68. Colameco S, Coren JS (January 2009). "Opioid-induced endocrinopathy". J Am Osteopath Assoc. 109 (1): 20–5. PMID 19193821.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  69. Smith HS, Elliott JA (July 2012). "Opioid-induced androgen deficiency (OPIAD)". Pain Physician. 15 (3 Suppl): ES145–56. PMID 22786453.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  70. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  71. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  72. 72.0 72.1 72.2 American College of Occupational and Environmental Medicine (February 2014), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, American College of Occupational and Environmental Medicine, retrieved 24 February 2014<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>, which cites
    • Weiss, MS; Bowden, K; Branco, F; et al. (2011). "Opioids Guideline". In Kurt T. Hegmann. Occupational medicine practice guidelines : evaluation and management of common health problems and functional recovery in workers (online March 2014) (3rd ed.). Elk Grove Village, IL: American College of Occupational and Environmental Medicine. p. 11. ISBN 978-0615452272.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  73. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  74. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  75. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  76. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  77. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  78. 78.0 78.1 78.2 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  79. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  80. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  81. Miller, Ronald D. (2010). Miller's Anesthesia (7th ed.). Elsevier Health Sciences. ISBN 978-0-443-06959-8.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  82. Morgan, G. Edward; Mikhail, Maged S.; Murray, Michael J. (2006). Clinical Anesthesiology (4th ed.). McGraw Hill. ISBN 978-0-07-110515-6.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  83. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  84. DeWire SM et al. (2013): J Pharmacol Exp Ther, 344(3):708-17. doi:10.1124/jpet.112.201616 PMID 23300227
  85. "Annual prevalence of drug use by regions and globally by drug types". United Nations Office on Drugs and Crime. June 2015. Retrieved 27 August 2015.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  86. http://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2012/Narcotic_Drugs_Report_2012.pdf
  87. "Opioid Consumption Data | Pain & Policy Studies Group". Painpolicy.wisc.edu. Retrieved 2016-01-07.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  88. USA. "Researching Prescription Drug Misuse among First Nations in Canada: Starting from a Health Promotion Framework". Ncbi.nlm.nih.gov. Retrieved 2016-01-07.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  89. MENU (2011-01-25). "Socially disadvantaged Ontarians being prescribed opioids on an ongoing basis and at doses that far exceed Canadian guidelines". Ices.on.ca. Retrieved 2016-01-07.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  90. 90.0 90.1 http://www.cpso.on.ca/CPSO/media/uploadedfiles/policies/policies/Opioid_report_final.pdf
  91. see Abse; Berridge; Bodkin; Callaway; Emrich; Gold; Gutstein; Mongan; Portenoy; Reynolds; Takano; Verebey; Walsh; Way.
  92. http://www.whitehouse.gov/sites/default/files/ondcp/issues-content/prescription-drugs/rx_abuse_plan.pdf
  93. http://www.ccsa.ca/resource%20library/canada-strategy-prescription-drug-misuse-report-en.pdf
  94. "UK: Task Force offers ideas for opioid addiction solutions". Delhidailynews.com. 2014-06-11. Retrieved 2016-01-07.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  95. Matthew Perrone, Associated Press. "Painkiller politics: Effort to curb prescribing under fire". Philly.com. Retrieved 2016-01-07.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  96. "Feasibility Study on Opium Licensing in Afghanistan for the Production of Morphine and Other Essential Medicines". ICoS. September 2005.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  97. "Assuring Availability of Opioid Analgesics" (PDF). World Health Organization.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  98. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  99. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  100. "Esters of Morphine". United Nations Office on Drugs and Crime. http://www.unodc.org. Retrieved 10 March 2012. External link in |publisher= (help)<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  101. "Ultram brand of TRAMADOL HYDROCHLORIDE" www.opiods.com
  102. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  103. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
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  106. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).

External links