Opioid

A Venn diagram of several common psychoactive drugs

An opioid is a chemical that works by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract. The receptors in these organ systems mediate both the beneficial effects and the side effects of opioids.

The analgesic(painkiller) effects of opioids are due to decreased perception of pain, decreased reaction to pain as well as increased pain tolerance. The side effects of opioids include sedation, respiratory depression, and constipation. Opioids can cause cough suppression, which can be both an indication for opioid administration or an unintended side effect. Physical dependence can develop with ongoing administration of opioids, leading to a withdrawal syndrome with abrupt discontinuation. Opioids can produce a feeling of euphoria, motivating some to recreationally use opioids.

Although the term opiate is often used as a synonym for opioid, the term opiate is properly limited to only the natural alkaloids found in the resin of the opium poppy (Papaver somniferum).

Contents

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 and there are 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. The remainder of 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. 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.

It has been discovered in 1953, 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.

Pharmacology

Opioids bind to specific opioid receptors in the central 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.

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.

Drug Relative Potency[3] Nonionized Fraction Protein Binding Lipid Solubility[4]
Morphine 1 ++ ++ +
Meperidine 0.1 + +++ ++
Hydromorphone 10
Alfentanil 10-25 ++++ ++++ +++
Fentanyl 75-125 + +++ ++++
Remifentanil 250 +++ +++ ++
Sufentanil 500-1000 ++ ++++ ++++
Etorphine 1000-3000
+ very low, ++ low, +++ high, ++++ very high

Uses

Prescription use

Opioids have long been used to treat acute pain (such as post-operative pain). They have also been found to be invaluable in palliative care to alleviate the severe, chronic, disabling pain of terminal conditions such as cancer, and degenerative conditions such as rheumatoid arthritis. Contrary to popular belief, high doses are not necessarily required to control the pain of advanced or end-stage disease, so long as the effects of tolerance (which means a physical reaction which makes the body immune to analgesic as well as mental effects of opiates, narcotics, and others) allow patients to often require a median dose in such patients being only 15 mg oral morphine every four hours (90 mg/24 hours). This means that 50% of patients manage on lower doses, and requirements can level off for many months at a time, depending on severity of pain, which varies. This is despite the fact that opioids have some of the greatest potential for tolerance of any category of drugs, which essentially means in many cases, opioids are a successful long-term care strategy for those in chronic pain as well as acute pain.

In recent years there has been an increased use of opioids in the management of non-malignant chronic pain. This practice has grown from over 30 years experience in palliative care of long-term use of strong opioids which has shown that addiction is rare when the drug is being used for pain relief. The basis for the occurrence of iatrogenic addiction to opioids in this setting being several orders of magnitude lower than the general population is the result of a combination of factors. Open and voluminous communication and meticulous documentation amongst patient, caretakers, physicians, and pharmacists is one part of this; the aggressive and consistent use of opioid rotation, adjuvant analgesics, potentiators, and drugs which deal with other elements of the pain (NSAIDS) and opioid side effects both improve the prognosis for the patient and appear to contribute to the rarity of addiction in these cases. Unfortunately, in most countries the use of opioids is subject to complex legal regulations, which often impede proper medical use for pain control and thus result in unnecessary suffering for patients.

United States

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

In the U.S., doctors virtually never prescribe opioids for psychological relief (with the narrow exception of anxiety due to shortness of breath), despite their extensively reported psychological benefits, and the widespread use of opiates in depression and anxiety up until the mid 1950s. There are virtually no exceptions to this practice, even in circumstances where researchers have reported opioids to be especially effective and where the possibility of addiction or diversion is very low—for example, in the treatment of senile dementia, geriatric depression, and psychological distress due to chemotherapy or terminal diagnosis (see Abse; Berridge; Bodkin; Callaway; Emrich; Gold; Gutstein; Mongan; Portenoy; Reynolds; Takano; Verebey; Walsh; Way).

Use of opioids in palliative care

Indications for opioid administration in palliative care include:

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. morphine 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.

History

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.

Global shortage of poppy-based medicines

Morphine and other poppy-based medicines have been identified by The World Health Organization as essential in the treatment of severe pain. However, only six countries use 77% of the world's morphine supplies, leaving many emerging countries lacking in pain relief medication.[8] 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 different countries' national administrations to train healthworkers and to develop national regulations regarding drug prescription to facilitate a greater prescription of poppy-based medicines.[9]

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.

Adverse effects

Common adverse reactions in patients taking opioids for pain relief include: nausea and vomiting, drowsiness, itching, dry mouth, miosis, and constipation.[10]

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).[10]

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.[11][12] If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia.[13][14]

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.

Men who are taking moderate to high doses of an opioid analgesic long-term are likely to have subnormal testosterone levels, which can lead to osteoporosis and decreased muscle strength if left untreated. Therefore, total and free testosterone levels should be monitored in these patients; if levels are suboptimal, testosterone replacement therapy, preferably with patches or transdermal preparations, should be given. Also, prostate-specific antigen levels should be monitored.[15]

Treating opioid adverse effects

Nausea: tolerance occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol 1.5–3 mg once at night) are very effective. 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. Some antihistamines with anti-cholinergic properties (e.g. orphenadrine or diphenhydramine) may also be effective.

Vomiting: this is due to gastric stasis (large volume vomiting, brief nausea relieved by vomiting, oesophageal reflux, epigastric fullness, early satiation), besides direct action on 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 usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps. Certain opioids such as morphine and diamorphine (heroin) tend to be particularly sedating, while others such as oxycodone and meperidine (pethidine) tend to produce 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: 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: develops in 99% of patients on opioids and since tolerance to this problem does not develop, nearly all patients on opioids will need a laxative. Over 30 years experience in palliative care has shown that most opioid constipation can be successfully prevented: "Constipation ... is treated [with laxatives and stool-softeners]" (Burton 2004, 277). According to Abse, "It is very important to watch out for constipation, which can be severe" and "can be a very considerable complication" (Abse 1982, 129) if it is ignored. Peripherally acting opioid antagonists such as alvimopan (Entereg) and methylnaltrexone (Relistor) have been found to effectively relieve opioid induced constipation without affecting analgesia or triggering withdrawal symptoms.[16][17] For mild cases, a lot of water (around 1.5 L/day) and fiber might suffice (in addition to the laxative and stool-softeners).

Respiratory depression: although this is the most serious adverse reaction associated with opioid use it usually is seen with the use of a single, intravenous dose in an opioid-naive 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 block respiratory depression completely even from high doses of potent opioids, without affecting analgesia, although the only respiratory stimulant currently approved for this purpose is doxapram, which has only limited efficacy in this application.[18][19] Newer drugs such as BIMU-8 and CX-546 may however be much more effective.[20][21][22]

Finally, all opioid effects (adverse or otherwise) can readily be reversed with an opioid antagonist (more exactly, an inverse agonist) 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 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 (e.g. naloxone 400 μg) but giving this in small doses (e.g. naloxone 40 μg) until the respiratory rate has improved. An infusion is then started to keep the reversal at that level, while maintaining pain relief.

Safety

Studies over the past 20 years have repeatedly shown opioids to be safe when they are used correctly. In the UK two studies have shown that double doses of bedtime morphine did not increase overnight deaths,[23] and that sedative dose increases were not associated with shortened survival (n=237).[24] Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15).[25] In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival.[26] In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival.[27] The survival of Japanese patients on high dose opioids and sedatives in the last 48 hours was the same as those not on such drugs.[28] In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75).[29] Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial).[30] Injections of morphine given subcutaneously to Canadian patients with restrictive respiratory failure did not change their respiratory rate, respiratory effort, arterial oxygen level, or end-tidal carbon dioxide levels.[31] Even when opioids are given intravenously, respiratory depression is not seen.[32]

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 patients need low doses and which need high doses, so all have to be started on low doses, unless changing from another strong opioid.[33]

Opioid analgesics do not cause any specific organ toxicity, unlike many other drugs, such as aspirin and acetaminophen. They are not associated with upper gastrointestinal bleeding and renal toxicity.[15]

Tolerance

Tolerance is the process whereby neuroadaptation occurs (through receptor desensitization) resulting in reduced drug effects. Tolerance is more pronounced for some effects than for others; tolerance occurs quickly to the effects on mood, itching, urinary retention, and respiratory depression, but occurs more slowly to the analgesia and other physical side effects. However, tolerance does not develop to constipation or miosis.

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

Magnesium and zinc deficiency speed up the development of tolerance to opioids and relative deficiency of these minerals is quite common[43] due to low magnesium/zinc content in food and use of substances which deplete them including diuretics (such as alcohol, caffeine/theophylline) and smoking. Reducing intake of these substances and taking zinc/magnesium supplements may slow the development of tolerance to opiates.

Dependence

Dependence is characterised by extremely unpleasant withdrawal symptoms that occur if opioid use is abruptly discontinued after tolerance has developed. The withdrawal symptoms include severe dysphoria, sweating, nausea, rhinorrea, depression, severe fatigue, vomiting and pain. Slowly reducing the intake of opioids over days and weeks will reduce or eliminate the withdrawal symptoms.[33] 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, but methadone withdrawal takes longer. 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 also be treated with other medications, such as clonidine, antidepressants and benzodiazepines, but with a low efficacy.[44]

Addiction

Addiction is the process whereby physical and/or psychological dependence develops to a drug - including opioids. The withdrawal symptoms can reinforce the addiction, driving the user to continue taking the drug. Psychological addiction is more common in people taking opioids recreationally, it is rare in patients taking opioids for pain relief.[33]

Misuse

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.

Examples

Endogenous opioids

Opioid-peptides that are produced in the body include:

β-endorphin is expressed in Pro-opiomelanocortin (POMC) cells in the arcuate nucleus and in a small population of neurons in the brainstem, 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; [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.

Semisynthetic derivatives

Synthetic opioids

Anilidopiperidines

Phenylpiperidines

Diphenylpropylamine derivatives

Benzomorphan derivatives

Oripavine derivatives

Morphinan derivatives

Others

Opioid antagonists

See also

Notes

  1. ↑ "Ultram brand of TRAMADOL HYDROCHLORIDE" www.opiods.com
  2. ↑ "Tramadol induces antidepressant-type effects in mice" Copyright © 1998 Published by Elsevier Science Inc.
  3. ↑ Miller Anesthesia, 7ed, 2009
  4. ↑ Morgan GE, Mikhail MS, Clinical Anesthesiology, 4th ed, 2006
  5. ↑ Schneider JP. Opioids for the Treatment of Chronic Musculoskeletal Pain: Myths and Misunderstandings. Journal of Musculoskeletal Medicine. Podcast. March 24, 2010.
  6. ↑ Schneider JP. Rational use of opioid analgesics in chronic musculoskeletal pain. Journal of Musculoskeletal Medicine. 2010;27(4):142-148.
  7. ↑ Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle, D., Hanks, G., Cherney, I., and Calman, K., eds., Oxford University Press, 2004).
  8. ↑ http://www.senliscouncil.net/modules/publications/008_publication
  9. ↑ The World Health Organization "Assuring Availability of Opioid Analgesics" [www.euro.who.int/document/e76503.pdf]
  10. ↑ 10.0 10.1 Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
  11. ↑ Wilson GR, Reisfield GM. "Morphine hyperalgesia: a case report." Am J Hosp Palliat Care. 2003 Nov-Dec;20(6):459–61. PMID 14649563
  12. ↑ Vella-Brincat J, Macleod AD. "Adverse effects of opioids on the central nervous systems of palliative care patients." J Pain Palliat Care Pharmacother. 2007;21(1):15–25. PMID 17430825
  13. ↑ Mercadante S, Arcuri E. "Hyperalgesia and opioid switching." Am J Hosp Palliat Care. 2005 Jul-Aug;22(4):291–4. Review. PMID 16082916
  14. ↑ Fine PG. "Opioid insights:opioid-induced hyperalgesia and opioid rotation." J Pain Palliat Care Pharmacother. 2004;18(3):75–9. Review. PMID 15364634
  15. ↑ 15.0 15.1 Schneider JP. Rational use of opioid analgesics in chronic musculoskeletal pain. J Musculoskel Med. 2010;27:142-148.
  16. ↑ McNicol E, Boyce D, Schumann R, Carr D. Mu-opioid antagonists for opioid-induced bowel dysfunction. Cochrane Database of Systematic Reviews. 2008 Apr 16;(2):CD006332. PMID 18425947
  17. ↑ Portenoy RK, Thomas J, Moehl Boatwright ML, Tran D, Galasso FL, Stambler N, Von Gunten CF, Israel RJ. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study. Journal of Pain and Symptom Management. 2008 May;35(5):458–68. PMID 18440447
  18. ↑ Yost CS. A new look at the respiratory stimulant doxapram. CNS Drug Reviews. 2006 Fall-Winter;12(3–4):236–49. PMID 17227289
  19. ↑ Tan ZM, Liu JH, Dong T, Li JX. Clinical observation of target-controlled remifentanil infusion combined with propofol and doxapram in painless artificial abortion. (Chinese) Nan Fang Yi Ke Da Xue Xue Bao. 2006 Aug;26(8):1206–8. PMID 16939923
  20. ↑ Manzke T, Guenther U, Ponimaskin E, Haller M, Dutschmann M, Schwarzacher S, Richter D (2003). "5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia". Science 301 (5630): 226–9. doi:10.1126/science.1084674. PMID 12855812. 
  21. ↑ Wang X, Dergacheva O, Kamendi H, Gorini C, Mendelowitz D. 5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function. Hypertension. 2007 Aug;50(2):368–76. PMID 17576856
  22. ↑ Ren J, Poon BY, Tang Y, Funk GD, Greer JJ. Ampakines alleviate respiratory depression in rats. American Journal of Respiratory and Critical Care Medicine. 2006 Dec 15;174(12):1384–91. PMID 16973981
  23. ↑ Regnard C and Badger C. Opioids, sleep and the time of death. Palliative Medicine, 1987; 1(2): 107–110.
  24. ↑ Sykes N. Thorns A. Sedative use in the last week of life and the implications for end-of-life decision making. Arch Int Med 2003: 163(3): 341–4.
  25. ↑ Boyd KJ. Kelly M. Oral morphine as symptomatic treatment of dyspnoea in patients with advanced cancer. Palliative Medicine. 1997: 11(4): 277–81.
  26. ↑ Good PD, Ravenscroft PJ, Cavenagh J. Effects of opioids and sedatives on survival in an Australian inpatient palliative care population. Int Med J. 2005: 35(9): 512–7.
  27. ↑ Hu WY, Chiu TY, Cheng SY, Chen CY. Morphine for dyspnoea control in terminal cancer patients: is it appropriate in Taiwan? J Pain & Symp Manag. 2004: 28(4): 356–63.
  28. ↑ Morita T, Tsunoda J, Inoue S, Chihara S. Effects of high dose opioids and sedatives on survival in terminally ill cancer patients. J Pain & Symp Manag. 2001: 21(4): 282–9.
  29. ↑ Chan JD et al. Narcotic and benzodiazepines use after withdrawal of life support: association with time of death? Chest. 2004: 126(1): 286–93.
  30. ↑ Mazzocato C, Buclin T, Rapin CH. The effects of morphine on dyspnoea and ventilatory function in elderly patients with advanced cancer: a randomized double-blind control trial. Annals of Oncology. 1999: 10(12): 1511–4.
  31. ↑ Bruera E, Macmillan K, Pither J, MacDonald RN. Effects of morphine on the dyspnoea of terminal cancer patients. J Pain & Symp Manag, 1990: 5(6): 341–44.
  32. ↑ Bassam E, et al. Respiratory function during parenteral opioid titration for cancer pain. Palliative Medicine, 2007; 21: 81–86.
  33. ↑ 33.0 33.1 33.2 Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
  34. ↑ Santillán R, Maestre JM, Hurlé MA, Flórez J. "Enhancement of opiate analgesia by nimodipine in cancer patients chronically treated with morphine: a preliminary report." Pain. 1994 Jul;58(1):129–32. PMID 7970835
  35. ↑ Smith FL, Dombrowski DS, Dewey WL. "Involvement of intracellular calcium in morphine tolerance in mice." Pharmacology, Biochemistry, and Behavior. 1999 Feb;62(2):381–8. PMID 9972707
  36. ↑ McCarthy RJ, Kroin JS, Tuman KJ, Penn RD, Ivankovich AD. "Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats." Anesthesia and Analgesia. 1998 Apr;86(4):830–6. PMID 9539610
  37. ↑ Larson AA, Kovács KJ, Spartz AK. "Intrathecal Zn2+ attenuates morphine antinociception and the development of acute tolerance." European Journal of Pharmacology. 2000 Nov 3;407(3):267–72. PMID 11068022
  38. ↑ Wong CS, Cherng CH, Luk HN, Ho ST, Tung CS. "Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at mu-opioid receptors." Eur J Pharmacol. 1996 Feb 15;297(1–2):27–33. PMID 8851162
  39. ↑ McCleane GJ. The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine. Clinical Journal of Pain. 2003 May-Jun;19(3):200–1.
  40. ↑ Watkins LR, Kinscheck IB, Mayer DJ. Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide. Science. 1984 Apr 27;224(4647):395–6.
  41. ↑ Tang J, Chou J, Iadarola M, Yang HY, Costa E. Proglumide prevents and curtails acute tolerance to morphine in rats. Neuropharmacology. 1984 Jun;23(6):715–8.
  42. ↑ Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW. Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert Opinion on Investigational Drugs. 2007 Jul;16(7):935–50.
  43. ↑ WHC - Magnesium Deficiency
  44. ↑ Hermann D, Klages E, Welzel H, Mann K, Croissant B. Low efficacy of non-opioid drugs in opioid withdrawal symptoms. Addict Biol. 2005 Jun;10(2):165–9. PMID: 16191669
  45. ↑ Odell LR, Skopec J, McCluskey A. "Isolation and identification of unique marker compounds from the Tasmanian poppy Papaver somniferum N." Forensic Sci Int (2007). PMID 17765420

References

External links

Analgesics (N02A, N02B)
Opioids
See also: Opioids template
Opium & alkaloids thereof

Codeine · Morphine · Opium · Laudanum · Paregoric
Semi-synthetic opium
derivatives

Acetyldihydrocodeine · Benzylmorphine · Buprenorphine · Desomorphine · Dihydrocodeine · Dihydromorphine · Ethylmorphine · Diamorphine · Hydrocodone · Hydromorphinol · Hydromorphone · Nicocodeine · Nicodicodeine · Nicomorphine · Oxycodone · Oxymorphone
Synthetic opioids

Alphaprodine · Anileridine · Butorphanol · Dextromoramide · Dextropropoxyphene · Dezocine · Fentanyl · Ketobemidone · Levorphanol · Methadone · Meptazinol · Nalbuphine · Pentazocine · Propoxyphene · Propiram · Pethidine · Phenazocine · Piminodine · Piritramide · Tapentadol · Tilidine · Tramadol
Pyrazolones
Ampyrone/Aminophenazone · Metamizole · Phenazone · Propyphenazone
Cannabinoids
Ajulemic acid · AM404 · Cannabidiol · Cannabis · Nabilone · Nabiximols · Tetrahydrocannabinol
Anilides
Paracetamol (acetaminophen) · Phenacetin · Propacetamol
Non-steroidal
anti-inflammatories
See also: NSAIDs template
Propionic acid class

Fenoprofen · Flurbiprofen · Ibuprofen · Ketoprofen · Naproxen · Oxaprozin
Oxicam class

Meloxicam · Piroxicam
Acetic acid class

Diclofenac · Indometacin · Ketorolac · Nabumetone · Sulindac · Tolmetin
COX-2 inhibitors

Celecoxib · Rofecoxib · Valdecoxib · Parecoxib · Lumiracoxib
Anthranilic acid
(fenamate) class

Meclofenamate · Mefenamic acid

Aspirin (Acetylsalicylic acid) · Benorylate · Diflunisal · Ethenzamide · Magnesium salicylate · Salicin · Salicylamide · Salsalate · Trisalate · Wintergreen (Methyl salicylate)
Atypical, Adjuvant & Potentiators,
Metabolic agents and miscellaneous
Amitryptiline  · Befiradol · Bicifadine · Carisoprodol  · Camphor · Cimetidine · Clonidine · Chlorzoxazone · Cyclobenzaprine · Duloxetine · Esreboxetine · Flupirtine · Gabapentin · Glafenine · Hydroxyzine · Ketamine  · Menthol · Mephenoxalone · Methocarbamol · Nefopam · Orphenadrine · Pregabalin · Proglumide · Scopolamine · Tebanicline · Trazodone · XP-13512 (Gabapentin enacarbil) · Ziconotide

: CNS

anat(s,m,p,,e,b,d,c,,f,,g)/phys/devp/cell

noco(m,d,e,h,v,s)/cong/tumr,sysi/,injr

proc,drug(N1A/2AB/C/3/4/7A/B//)