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| {{CMG}} | | __NOTOC__ |
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| | | [[File:Siren.gif|30px|link=Opioid withdrawal resident survival guide]]|| <br> || <br> |
| | | [[Opioid withdrawal resident survival guide|'''Resident'''<br>'''Survival'''<br>'''Guide''']] |
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| | {{Opioid}} |
| | {{CMG}}; {{AE}} {{VB}} |
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| | ==[[Opioid overview|Overview]]== |
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| | ==[[Opioid historical perspective|Historical Perspective]]== |
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| {{SI}}
| | ==[[Opioid classification|Classification]]== |
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| ==Overview== | | ==[[Opioid pharmacology|Pharmacology]]== |
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| An '''opioid''' is a chemical [[substance]] that has a [[morphine]]-like action in the body. The main use is for [[analgesia|pain relief]]. These agents work by binding to [[opioid receptor]]s, which are found principally in the [[central nervous system]] and the [[gastrointestinal tract]]. The receptors in these two organ systems mediate both the beneficial effects, and the undesirable [[side effects]]. There are a number of broad classes of narcotics:
| | ==[[Opioid indications|Indications]]== |
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| *'''natural''' opiates, [[alkaloids]] contained in the resin of the [[opium poppy]] including [[morphine]], [[codeine]], [[thebaine]], and [[oripavine]];
| | [[Opioid in benign chronic pain]] | [[Opioid in palliative care]] |
| *'''semi-synthetic''' opiates, created from the natural opioids, such as [[hydromorphone]], [[hydrocodone]], [[oxycodone]], and [[heroin]];
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| *'''fully synthetic''' opioids, such as [[fentanyl]], [[pethidine]], [[methadone]], and [[propoxyphene]];
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| *'''[[endogenous]]''' opioid [[peptide]]s, produced naturally in the body, such as [[endorphin]]s, [[enkephalin]]s, [[dynorphin]]s, and [[endomorphin]]s.
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| Although the term '''''[[opiate]]''''' is often used as a synonym for ''opioid'', it is more properly limited to the natural opium alkaloids and the semi-synthetics derived from them.
| | ==[[Opioid contraindications|Contraindications]]== |
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| 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 morbid seek orientation, habituation, physical dependence, or addiction. Foremost amongst these are [[nefopam]], [[orphenadrine]], and perhaps [[phenyltoloxamine]] and/or some other [[antihistamines]]. The remainder of analgesics work peripherally. Research is starting to show that morphine and related drugs may indeed have peripheral effects as well, such as morphine gel working on burns, but peripherally-acting analgesics include aspirin, paracetamol, ibuprofen and the like.
| | ==[[Opioid adverse reactions|Adverse Reactions]]== |
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| 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.
| | ==[[Opioid abuse and dependence|Abuse and Dependence]]== |
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| Finally, some opioids such as [[diphenoxylate]] do not possess analgesic action, narcotic or otherwise.
| | ==[[Opioid intoxication|Opioid Intoxication]]== |
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| == Pharmacology == | | ==[[Opioid withdrawal|Opioid Withdrawal]]== |
| {{main|opioid receptor}}
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| Opioids bind to specific opioid receptors in the central nervous system and in other tissues. There are three principal classes of [[opioid receptor]]s, μ, κ, δ (mu, kappa, and delta), although up to seventeen have been reported, and include the ε, ι, λ, and ζ (epsilon, iota, lamda and zeta) receptors. σ (sigma) receptors are no longer considered to be opioid receptors as they are not reversed by naloxone, exhibit high-affinity binding for ketamine and phencyclidine and are stereoselective for dextro-rotatory isomers while the other opioid receptors are stereo-selective for laevo-rotatory isomers. In addition, there are two subtypes of μ receptor: μ<sub>1</sub> and μ<sub>2</sub>. 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 receptor]]s acting on [[GABA]]ergic [[neurotransmission]]. The [[pharmacodynamic]] response to an opioid depends on which receptor it binds, its affinity for that receptor, and whether the opioid is an [[agonist]] or an [[receptor antagonist|antagonist]]. For example, the [[supraspinal]] analgesic properties of the opioid agonist [[morphine]] are mediated by activation of the μ<sub>1</sub> receptor, respiratory depression and [[drug dependence|physical dependence]] (dependency) by the μ<sub>2</sub> receptor, and sedation and spinal analgesia by the κ receptor.
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| == Uses == | | ==[[Opioid shortage status|Shortage Status]]== |
| === Clinical use ===
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| Opioids have long been used to treat acute pain (such as post-operative pain). They have also found to be invaluable in [[palliative care]] to alleviate the severe, chronic, disabling pain of terminal conditions such as [[cancer]]. Contrary to popular belief, high doses are ''not'' required to control the pain of advanced or end-stage disease, with the median dose in such patients being only 15mg oral morphine every four hours (90mg/24 hours), i.e. 50% of patients manage on lower doses.
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| 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.
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| ====United States====
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| The sole clinical indications for opioids in the United States, according to ''Drug Facts and Comparisons,'' 2005, are
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| * [[Analgesia]] and [[anesthesia]]
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| * Cough ([[codeine]] and [[hydrocodone]] only)
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| * Diarrhoea (generally [[loperamide]] or [[diphenoxylate]], but [[laudanum]] or [[morphine]] may be used in some cases of severe diarrheal diseases)
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| * Anxiety due to [[dyspnoea|shortness of breath]] ([[oxymorphone]] only)
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| * Detoxification ([[methadone]] and [[buprenorphine]] only)
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| <!--Note 37 detailed citations on Talk page.-->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. 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).
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| <!--Note 37 detailed citations on Talk page.-->
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| ====Use of opioids in palliative care====
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| The current key text for palliative care is the ''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle, D., Hanks, G., Cherney, I., and Calman, K., eds., Oxford University Press, 2004). This states that the indications for opioid administration in palliative care are:
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| * "Any pain of moderate or greater severity, irrespective of the underlying pathophysiological mechanism." (p.327)
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| * [[dyspnoea|Breathlessness / shortness of breath]]: the largest evidence base exists for morphine. Several mechanisms are suggested for its action on breathlessness (p.605–7).
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| * Diarrhoea: codeine and loperamide are the most widely used opioid for this problem. Loperamide has the advantage of acting only on the gut, since very little is absorbed (p.493).
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| * Painful wounds: topical morphine in an aqueous gel can be an effective agent (p.392). Their use is based on the discovery of activated opioid receptors in damaged tissue.
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| '''Not just opioids...'''
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| In palliative care opioids are always used in combination with adjuvant analgesics (drugs which have an indirect effect on the pain), and as an integral part of care of the whole person.
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| '''Contraindications for opioids'''
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| 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 the of 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.
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| ==== History ====
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| 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.
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| 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.
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| ===Global shortage of poppy-based medicines===
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| Morphine and other poppy-based medicines have been identified by the World Health Organisation 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.<ref>http://www.senliscouncil.net/modules/publications/008_publication</ref>. The current system of supply of raw poppy materials to make poppy-based medicines is regulated by the [[International Narcotics Control Board]] under the provision of the 1961 [[Single Convention on Narcotic Drugs]]. The amount of raw poppy materials that each country can demand annually based on these provisions must correspond to an estimate of the country's needs taken from the national consumption within the preceding two years. In many countries, underprescription of morphine is rampant because of the high prices and the lack of training in the prescription of poppy-based drugs. The [[World Health Organisation]] is now working with different countries' national administrations to train healthworkers and to develop national regulations regarding drug prescription in order to facilitate a greater prescription of poppy-based medicines.<ref>The World Health Organisation "Assuring Availability of Opioid Analgesics" [www.euro.who.int/document/e76503.pdf]</ref>
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| 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.
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| == Adverse effects ==
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| For more information see<ref>Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).</ref> and the online palliative care formulary (available on [http://www.palliativedrugs.com Palliativedrugs.com]).
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| Opioid analgesics may cause more [[drug toxicity]], at least in [[geriatrics]], than non-selective inhibitors of [[cyclooxygenase]] ([[non-steroidal anti-inflammatory agent]]s) or [[cyclooxygenase 2 inhibitor]]s.<ref name="pmid21149752">{{cite journal| author=Solomon DH, Rassen JA, Glynn RJ, Lee J, Levin R, Schneeweiss S| title=The comparative safety of analgesics in older adults with arthritis. | journal=Arch Intern Med | year= 2010 | volume= 170 | issue= 22 | pages= 1968-76 | pmid=21149752 | doi=10.1001/archinternmed.2010.391 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21149752 }} </ref>
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| [[Oxycodone]] and [[codeine]] may increase mortality relative to codeine and hydrocodone<ref name="pmid21149754">{{cite journal| author=Solomon DH, Rassen JA, Glynn RJ, Garneau K, Levin R, Lee J et al.| title=The comparative safety of opioids for nonmalignant pain in older adults. | journal=Arch Intern Med | year= 2010 | volume= 170 | issue= 22 | pages= 1979-86 | pmid=21149754 | doi=10.1001/archinternmed.2010.450 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21149754 }} </ref> and may cause more drug toxicity in [[geriatrics]] than codeine or hydrocodone.<ref name="pmid21149754">{{cite journal| author=Solomon DH, Rassen JA, Glynn RJ, Garneau K, Levin R, Lee J et al.| title=The comparative safety of opioids for nonmalignant pain in older adults. | journal=Arch Intern Med | year= 2010 | volume= 170 | issue= 22 | pages= 1979-86 | pmid=21149754 | doi=10.1001/archinternmed.2010.450 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21149754 }} </ref> In contrast to [[hydrocodone]], [[oxycodone]] and [[codeine]] and metabolized by [[cytochrome P-450 CYP2D6]] which may lead to variable [[pharmacokinetics]] due to [[single-nucleotide polymorphism]]s and [[drug interaction]]s.<ref name="pmid20590588">{{cite journal| author=Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC et al.| title=Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. | journal=Br J Pharmacol | year= 2010 | volume= 160 | issue= 4 | pages= 919-30 | pmid=20590588 | doi=10.1111/j.1476-5381.2010.00709.x | pmc=PMC2935998 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20590588 }} </ref>
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| Opioid analgesics, with long-term use, 80% of patients may have [[drug toxicity]], most commonly gastrointestinal. In addition, substance abuse and "aberrant medication-taking behaviors" may occur.<ref name="pmid17227935">{{cite journal |author=Martell BA, O'Connor PG, Kerns RD, ''et al'' |title=Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction |journal=Ann. Intern. Med. |volume=146 |issue=2 |pages=116–27 |year=2007 |pmid=17227935 |doi= |url=http://www.annals.org/cgi/content/full/146/2/116 |issn=}}</ref>
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| Serious drug toxicity from long-term use may be low according to one [[systematic review]].<ref name="pmid20091598">{{cite journal| author=Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C et al.| title=Long-term opioid management for chronic noncancer pain. | journal=Cochrane Database Syst Rev | year= 2010 | volume= | issue= 1 | pages= CD006605 | pmid=20091598 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=20091598 | doi=10.1002/14651858.CD006605.pub2 }}</ref>
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| ===Common adverse reactions in patients taking opioids for pain relief:===
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| These include: nausea and vomiting, drowsiness, dry mouth, [[miosis]], and constipation. Fortunately, most of these are not a problem (see Treating Opioid Adverse Effects below).
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| ===Infrequent adverse reactions in patient taking opioids for pain relief:===
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| These include: dose-related respiratory depression (see below), 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).
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| ===Male hypogonadism===
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| Chronic opioids may cause male hypogonadism.<ref name="pmid11014399">{{cite journal| author=Finch PM, Roberts LJ, Price L, Hadlow NC, Pullan PT| title=Hypogonadism in patients treated with intrathecal morphine. | journal=Clin J Pain | year= 2000 | volume= 16 | issue= 3 | pages= 251-4 | pmid=11014399 | doi= | pmc= | url= }} </ref><ref name="pmid15483091">{{cite journal| author=Bliesener N, Albrecht S, Schwager A, Weckbecker K, Lichtermann D, Klingmüller D| title=Plasma testosterone and sexual function in men receiving buprenorphine maintenance for opioid dependence. | journal=J Clin Endocrinol Metab | year= 2005 | volume= 90 | issue= 1 | pages= 203-6 | pmid=15483091 | doi=10.1210/jc.2004-0929 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15483091 }} </ref>
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| ===Employability===
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| Use of opioids may be a risk factor for failing to return to work.<ref name="pmid22289236">{{cite journal| author=Brede E, Mayer TG, Gatchel RJ| title=Prediction of failure to retain work 1 year after interdisciplinary functional restoration in occupational injuries. | journal=Arch Phys Med Rehabil | year= 2012 | volume= 93 | issue= 2 | pages= 268-74 | pmid=22289236 | doi=10.1016/j.apmr.2011.08.029 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22289236 }} </ref><ref name="pmid19181448">{{cite journal| author=Volinn E, Fargo JD, Fine PG| title=Opioid therapy for nonspecific low back pain and the outcome of chronic work loss. | journal=Pain | year= 2009 | volume= 142 | issue= 3 | pages= 194-201 | pmid=19181448 | doi=10.1016/j.pain.2008.12.017 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19181448 }} </ref>
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| In addition, lack of employment may be a predictor of aberrant use of prescription opioids.<ref name="pmid19789432">{{cite journal| author=White KT, Dillingham TR, González-Fernández M, Rothfield L| title=Opiates for chronic nonmalignant pain syndromes: can appropriate candidates be identified for outpatient clinic management? | journal=Am J Phys Med Rehabil | year= 2009 | volume= 88 | issue= 12 | pages= 995-1001 | pmid=19789432 | doi=10.1097/PHM.0b013e3181bc006e | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19789432 }} </ref>
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| ===Impaired judgment===
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| Opioids may increase risk of [[traffic accident]]s<ref>Orriols L, Delorme B, Gadegbeku B, Tricotel A, Contrand B, et al. 2010 Prescription Medicines and the Risk of Road Traffic Crashes: A French Registry-Based Study. PLoS Med 7(11): e1000366. {{doi|10.1371/journal.pmed.1000366}} </ref> and [[accidental fall]]s<ref name="pmid21391934">{{cite journal| author=Miller M, Stürmer T, Azrael D, Levin R, Solomon DH| title=Opioid analgesics and the risk of fractures in older adults with arthritis. | journal=J Am Geriatr Soc | year= 2011 | volume= 59 | issue= 3 | pages= 430-8 | pmid=21391934 | doi=10.1111/j.1532-5415.2011.03318.x | pmc= | url= }} </ref>.
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| ===Dependency===
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| Opioid agonist therapy includes [[buprenorphine]] and [[methadone]]. Although [[buprenorphine]]–[[naloxone]] may be less effective than [[methadone]]<ref name="pmid15677600">{{cite journal| author=Schottenfeld RS, Chawarski MC, Pakes JR, Pantalon MV, Carroll KM, Kosten TR| title=Methadone versus buprenorphine with contingency management or performance feedback for cocaine and opioid dependence. | journal=Am J Psychiatry | year= 2005 | volume= 162 | issue= 2 | pages= 340-9 | pmid=15677600
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| | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15677600 | doi=10.1176/appi.ajp.162.2.340 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16246888 Review in: Evid Based Ment Health. 2005 Nov;8(4):112]></ref>, it has more predictable dosing<ref name="pmid15720937">{{cite journal| author=Simoens S, Matheson C, Bond C, Inkster K, Ludbrook A| title=The effectiveness of community maintenance with methadone or buprenorphine for treating opiate dependence. | journal=Br J Gen Pract | year= 2005 | volume= 55 | issue= 511 | pages= 139-46 | pmid=15720937
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| | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15720937 | pmc=PMC1463190 }}</ref>, and can be prescribed by qualifying office-based physicians.<ref name="pmid18458279">{{cite journal| author=Sullivan LE, Fiellin DA| title=Narrative review: buprenorphine for opioid-dependent patients in office practice. | journal=Ann Intern Med | year= 2008 | volume= 148 | issue= 9 | pages= 662-70 | pmid=18458279
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| | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18458279 }}</ref>
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| ====Mortality and Overdose====
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| Death from overdose on opioids may be more common than traffic accidents in the United States.<ref>{{cite news |url= http://www.latimes.com/news/local/la-me-drugs-epidemic-20110918,0,2557221,full.story |title=Drug deaths now outnumber traffic fatalities in U.S., Times analysis shows - latimes.com |first= |last={{err|{{AUTHOR MISSING}}}} |work=[[Los Angeles Times]] |date={{err|{{DATE MISSING}}}} |publisher=[[Tribune Co]] |location=[[Los Angeles, CA|Los Angeles]] |issn=0458-3035 |accessdate=September 23, 2011}}</ref> The rate of overdose is increasing faster among women and men according to the [[Centers for Disease Controll]].<ref name="pmid23820967">{{cite journal| author=Centers for Disease Control and Prevention (CDC)| title=Vital signs: overdoses of prescription opioid pain relievers and other drugs among women - United States, 1999-2010. | journal=MMWR Morb Mortal Wkly Rep | year= 2013 | volume= 62 | issue= 26 | pages= 537-42 | pmid=23820967 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23820967 }} </ref>
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| Chronic use of the equivalent of more than 20 mg/day of morphine may lead to unintentional or intentional overdose.<ref name="pmid20083827">{{cite journal| author=Dunn KM, Saunders KW, Rutter CM, Banta-Green CJ, Merrill JO, Sullivan MD et al.| title=Opioid prescriptions for chronic pain and overdose: a cohort study. | journal=Ann Intern Med | year= 2010 | volume= 152 | issue= 2 | pages= 85-92 | pmid=20083827 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=20083827 | doi=10.1059/0003-4819-152-2-201001190-00006 }}</ref>
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| Overdose may be more common with with doses equivalent to more than 100 mg/day of [[morphine]].<ref name="pmid21467284">{{cite journal| author=Bohnert AS, Valenstein M, Bair MJ, Ganoczy D, McCarthy JF, Ilgen MA et al.| title=Association between opioid prescribing patterns and opioid overdose-related deaths. | journal=JAMA | year= 2011 | volume= 305 | issue= 13 | pages= 1315-21 | pmid=21467284 | doi=10.1001/jama.2011.370 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21467284 }} </ref> Overdose may<ref name="pmid20837827">{{cite journal| author=Braden JB, Russo J, Fan MY, Edlund MJ, Martin BC, DeVries A et al.| title=Emergency department visits among recipients of chronic opioid therapy. | journal=Arch Intern Med | year= 2010 | volume= 170 | issue= 16 | pages= 1425-32 | pmid=20837827 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20837827 | doi=10.1001/archinternmed.2010.273 }} </ref> or may not<ref name="pmid21467284">{{cite journal| author=Bohnert AS, Valenstein M, Bair MJ, Ganoczy D, McCarthy JF, Ilgen MA et al.| title=Association between opioid prescribing patterns and opioid overdose-related deaths. | journal=JAMA | year= 2011 | volume= 305 | issue= 13 | pages= 1315-21 | pmid=21467284 | doi=10.1001/jama.2011.370 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21467284 }} </ref> be increased with long acting opioids.
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| In veterinary medicine, there is a maximum effective analgesic dose of buprenorphine, although the frequency of administration may usefully be increased.<ref>''need to dig up the Cornell handbook''</ref>
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| ====Substance abuse====
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| With chronic use for treatment of [[pain]], [[dependency]] may lead to substance abuse and "aberrant medication-taking behaviors" may occur.<ref name="pmid17227935">{{cite journal |author=Martell BA, O'Connor PG, Kerns RD, ''et al'' |title=Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction |journal=Ann. Intern. Med. |volume=146 |issue=2 |pages=116–27 |year=2007 |pmid=17227935 |doi= |url=http://www.annals.org/cgi/content/full/146/2/116 |issn=}}</ref> From 2000-2005, the abuse of prescribed opiods, especially [[oxycodone|oxycodone extended release (OxyContin)]] and [[hydrocodone]], has increased.<ref name="pmid16202959">{{cite journal| author=Cicero TJ, Inciardi JA, Muñoz A| title=Trends in abuse of Oxycontin and other opioid analgesics in the United States: 2002-2004. | journal=J Pain | year= 2005 | volume= 6 | issue= 10 | pages= 662-72 | pmid=16202959 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16202959 | doi=10.1016/j.jpain.2005.05.004 }} </ref> From Contracts may reduce abuse, but comparative studies provide conflicting results.<ref>{{Cite journal | doi = 10.1059/0003-4819-152-11-201006010-00004 | volume = 152 | issue = 11 pages = 712-720 | last = Starrels | first = Joanna L. | coauthors = William C. Becker, Daniel P. Alford, Alok Kapoor, Arthur Robinson Williams, Barbara J. Turner | title = Systematic Review: Treatment Agreements and Urine Drug Testing to Reduce Opioid Misuse in Patients With Chronic Pain | journal = Annals of Internal Medicine | accessdate = 2010-06-01 | date = 2010-06-01 | url = http://www.annals.org/content/152/11/712.abstract }}</ref> Most agreements stated, "patients agreed not to abuse illicit drugs or alcohol, obtain opioids from more than 1 provider or pharmacy, or request a refill before the previous prescription should have been completed."
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| ==='''Other adverse effects:===
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| [[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. <ref>Wilson GR, Reisfield GM. "Morphine hyperalgesia: a case report." ''Am J Hosp Palliat Care''. 2003 Nov-Dec;20(6):459-61. PMID 14649563</ref> <ref>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</ref> If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia. <ref>Mercadante S, Arcuri E. "Hyperalgesia and opioid switching." ''Am J Hosp Palliat Care''. 2005 Jul-Aug;22(4):291-4. Review. PMID 16082916 </ref> <ref>Fine PG. "Opioid insights:opioid-induced hyperalgesia and opioid rotation." ''J Pain Palliat Care Pharmacother''. 2004;18(3):75-9. Review. PMID 15364634 </ref>
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| Both therapeutic and chronic use of opioids can compromise the function of the [[immune system]]. Opioids decrease the proliferation of [[macrophage]] progenitor cells and [[lymphocyte]]s, 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.
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| ===Treating opioid adverse effects===
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| Most adverse effects can be managed successfully. (For more complete information see <ref>''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).</ref> and the online palliative care formulary available on [http://www.palliativedrugs.com Palliativedrugs.com].)
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| ''Nausea:'' tolerance occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol 1.5–3mg once at night) are very effective.
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| ''Vomiting:'' if this is due to gastric stasis (large volume vomiting, brief nausea relieved by vomiting, oesophageal reflux, epigastric fullness, early satiation) then this can be managed with a prokinetic (e.g. domperidone or metoclopramide 10mg every eight hours), but usually needs to be started by a non-oral route (e.g. subcutaneous for metoclopramide, rectally for domperidone).
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| ''Drowsiness:'' tolerance usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps.
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| ''Constipation:'' this 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.
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| ''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.
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| ''Reversing the effect of opioids:'' Opioid effects can be rapidly reversed with an opioid antagonist such as [[naloxone]] or [[naltrexone]]. These [[competitive antagonist]]s 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. 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 microg) but giving this in small doses (e.g. naloxone 40 microg) until the respiratory rate has improved. An infusion is then started to keep the reversal at that level, while maintaining pain relief.
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| ===How safe are opioids? A world view===
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| There are a number of paradoxical beliefs about opioids:
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| * 33% of UK doctors believe they had possibly shortened life during alleviation of symptoms,<ref> Seale C. National survey of end-of-life decisions made by UK medical practitioners, ''Palliative Medicine'' 2006; 20(1): 3–10.</ref> and yet a follow-up study showed that UK doctors are particularly cautious about shortening life.<ref> Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. ''Palliative Medicine'' 2006; 20(7): 653–9.</ref>
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| * There is a belief that the use of opioids in pain is a fine balance between relief and hastening death, and yet palliative care physicians do not find themselves faced with the dilemma of relieving symptoms at the risk of shortening life.<ref>George R, Regnard C. Lethal opioids or dangerous prescribers? ''Palliative Medicine'', 2007; 21: 77-80.</ref>
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| * The Dutch public equate high dose morphine and sedation with euthanasia,<ref>Rietjens JAC et al Preferences of the Dutch general public for a good death and associations with attitudes towards end-of-life decision-making. ''Palliative Medicine'' 2006; 20(7): 685–92.</ref> and yet it is the least used class of drug used for euthanasia in the Netherlands.
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| However, studies around the globe 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,<ref>Regnard C and Badger C. Opioids, sleep and the time of death. ''Palliative Medicine'', 1987; 1(2): 107–110.</ref> and that sedative dose increases were not associated with shortened survival (n=237).<ref>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.</ref> Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15).<ref>Boyd KJ. Kelly M. Oral morphine as symptomatic treatment of dyspnoea in patients with advanced cancer. ''Palliative Medicine''. 1997: 11(4): 277–81.</ref> In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival.<ref>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.</ref> In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival.<ref>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.</ref> The survival of Japanse patients on high dose opioids and sedatives in the last 48 hours was the same as those not on such drugs.<ref>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.</ref> In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75).<ref>Chan JD et al. Narcotic and benzodiazepines use after withdrawal of life support: association with time of death? ''Chest.'' 2004: 126(1): 286–93.</ref>
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| Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial).<ref>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.</ref> 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.<ref>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.</ref> Even when opioids are given intravenously, respiratory depression is not seen.<ref>Bassam E, ''et al'' Respiratory function during parenteral opioid titration for cancer pain. ''Palliative Medicine'', 2007; 21: 81-86.</ref>
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| ===Using opioids safely===
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| * Starting doses: a person who has never been on analgesics would be started on oral morphine 2.5–5mg every four hours (or morphine by injection 1–2.5mg every four hours). Higher doses can be used if the patient was already on weaker analgesics.
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| * Titration: this describes the adjustment of a drug dose to a patient, while allowing the patient’s body time to adjust to the drug to minimise adverse effects. Titration is done in 25–50% steps every 1–2 days.
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| * Safety margin of opioids: morphine and diamorphine have a wide safety margin or "therapeutic range".
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| * Dose range: this is very wide but usually lies between 30–500mg per 24 hours of oral morphine, but with a median of 90mg (or 15mg every four hours). 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.<ref>''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).</ref>
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| ===Double effect===
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| The principle of [[double effect]] is not used in palliative care. Doctors are not faced with the dilemma of giving a potentially lethal drug dose to a distressed patient.<ref>George R, Regnard C. Lethal opioids or dangerous prescribers? ''Palliative Medicine'', 2007; 21: 77-80.</ref>
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| A palliative care doctor gives repeated, small doses of one or more drugs, each titrated to an individual until the symptoms are eased, while doing everything possible to avoid toxicity. Doctors who give 30–60 times the required dose of morphine or diamorphine, usually as a single intravenous dose, are acting either negligently or maliciously. Since drug records should exist for opioids, there is a clear audit trail to follow if a subsequent investigation is required.
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| With exceptions such as Shipman, UK doctors are very cautious about shortening life.<ref>Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. Palliative Medicine 2006; 20(7): 653–9</ref> The persistent belief that opioids and sedatives shorten life or hasten death stems from the experiences of bad practice in the use of the drugs. Evidence in the last 20 years has shown that opioids and sedatives are safe when following palliative care protocols. Clinicians who believe otherwise should be challenged to provide robust clinical evidence to support their view.
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| ===Tolerance===
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| ''[[Drug 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.
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| Tolerance to opioids is attenuated by a number of substances, including calcium channel blockers<ref>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</ref><ref>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</ref>, [[intrathecal]] [[magnesium]]<ref>McCarthy RJ, Kroin JS, Tuman KJ, Penn RD, Ivankovich AD. "[http://www.anesthesia-analgesia.org/cgi/reprint/86/4/830 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</ref> and [[zinc]]<ref>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</ref>, and [[NMDA antagonist]]s such as [[ketamine]].<ref>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</ref>
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| Magnesium and zinc deficiency speed up the development of tolerance to opioids and relative deficiency of these minerals is quite common<ref>http://www.worldwidehealthcenter.net/articles-360.html</ref> 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.
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| ===Dependence===
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| ''[[Drug 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.<ref>''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).</ref> 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, but with a low efficacy. <ref>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 </ref> Dependence also occurs for most other drugs, including [[caffeine]] and [[alcohol]].
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| ===Addiction===
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| ''[[Drug addiction|Addiction]]'' is the process whereby physical and/or psychological addiction 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.<ref>''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).</ref>
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| ===Abuse===
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| ''[[Drug abuse]]'' is the misuse of drugs producing negative consequences.
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| == Examples of opioids ==
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| === Endogenous opioids ===
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| Opioid-[[peptide]]s that are produced in the body include:
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| * [[Endorphin]]s
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| * [[Enkephalin]]s
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| * [[Dynorphin]]s
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| * [[Endomorphin]]s
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| [[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.
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| [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.
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| [[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]].
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| [[Endomorphin]] acts through μ-opioid receptors, and is more potent than other endogenous opioids at these receptors.
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| === Opium alkaloids ===
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| [[Phenanthrene]]s naturally occurring in [[opium]]:
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| * [[Codeine]]
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| * [[Morphine]]
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| * [[Thebaine]]
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| * [[Oripavine]]<ref name="Odell 2007">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</ref>
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| Preparations of mixed opium alkaloids, including [[papaveretum]], are still occasionally used.
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| === Semisynthetic derivatives ===
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| * [[Diacetylmorphine]] (heroin)
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| * [[Dihydrocodeine]]
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| * [[Hydrocodone]]
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| * [[Hydromorphone]]
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| * [[Nicomorphine]]
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| * [[Oxycodone]]
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| * [[Oxymorphone]]
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| === Synthetic opioids ===
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| ==== [[Anilidopiperidine]]s ====
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| * [[Fentanyl]]
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| * [[Alphamethylfentanyl]]
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| * [[Alfentanil]]
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| * [[Sufentanil]]
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| * [[Remifentanil]]
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| * [[Carfentanyl]]
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| * [[Ohmefentanyl]]
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| ==== [[Phenylpiperidine]]s ====
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| * [[Pethidine]] (meperidine)
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| * [[Ketobemidone]]
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| * [[MPPP]]
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| * [[Allylprodine]]
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| * [[Prodine]]
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| * [[PEPAP]]
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| ==== [[Diphenylpropylamine]] derivatives ====
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| * [[Propoxyphene]]
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| * [[Dextropropoxyphene]]
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| * [[Dextromoramide]]
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| * [[Bezitramide]]
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| * [[Piritramide]]
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| * [[Methadone]]
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| * [[Dipipanone]]
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| * [[Levo-alphacetylmethadol]] (LAAM)
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| * [[Loperamide]] (used for diarrhoea, does not cross the [[blood-brain barrier]])
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| * [[Diphenoxylate]] (used for diarrhoea, does not appreciably cross the [[blood-brain barrier]])
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| ==== [[Benzomorphan]] derivatives ====
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| * [[Pentazocine]]
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| * [[Phenazocine]]
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| ==== [[Oripavine]] derivatives ====
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| * [[Buprenorphine]]
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| * [[Etorphine]]
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| ==== [[Morphinan]] derivatives ====
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| * [[Butorphanol]]
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| * [[Nalbuphine]]
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| * [[Levorphanol]]
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| * [[Levomethorphan]]
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| ==== Others ====
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| * [[Dezocine]]
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| * [[Lefetamine]]
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| * [[Meptazinol]]
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| * [[Tilidine]]
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| * [[Tramadol]]
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| * [[Tapentadol]]
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| === Opioid antagonists ===
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| * [[Nalmefene]]
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| * [[Naloxone]]
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| * [[Naltrexone]]
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| == See also ==
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| * [[Psychoactive drug]]
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| ==References==
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| {{Reflist|2}}
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| == External links ==
| |
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| * [http://www.painfoundation.org American Pain Foundation]
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| * [http://www.ampainsoc.org American Pain Society]
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| * [http://www.aapainmanage.org American Academy of Pain Management]
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| * [http://www.aaap.org American Academy of Addiction Psychiatry], professional association of psychiatrists expert in addiction treatment
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| * [http://www.helpthehospices.org.uk/elearning/index.htm CLiP- Current Learning in Palliative Care] Fifty-six workshops on palliative care which can be used online or downloaded. Free access, no restrictions.
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| * [http://www.hospicecare.com/ International Association for Hospice and Palliative Care]
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| * [http://www.opiateinfo.com/library/opiate_basics.htm Opioids FAQ]
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| * [http://www.palliativedrugs.com Palliativedrugs.com]. Online palliative care formulary. Also has bulletin board with over 22,000 international professionals registered. Free access after registration.
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| * [http://www.pallcare.info/ Palliative Care Matters] Palliative Care information.
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| * [http://book.pallcare.info/ Palliative Care Handbook] Online palliative care textbook
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| * [http://www.ampainsoc.org/advocacy/opioids.htm The use of opioids for chronic pain @ The APS]
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| * [http://www.merck.com/mmhe/sec07/ch108/ch108c.html Merck Entry on Opioids]
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| * [http://www.new-health-articles.com/category/pain/ Pain]
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| == Bibliography ==
| |
| | |
| * [http://www.palliativedrugs.com Palliativedrugs.com] Palliative Care Formulary and bulletin board with over 22,000 worldwide registered. Free to register.
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| * Wall and Melzack’s textbook of pain, 5th ed. Stephen B. McMahon and Martin Koltzenburg, eds. Edinburgh : Elsevier Churchill Livingstone, 2006.
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| * Gutstein, Howard B. and Huda Akil, “Opioid Analgesics”, in ''Goodman and Gilman’s The Pharmacological Basis of Therapeutics'', 11th Edition, 2006, edited by Brunton, Laurence L., John S. Lazo, Keith L. Parker, Iain L. O. Buxton, and Donald Blumenthal.
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| * Rossi S (Ed.) (2005). ''[[Australian Medicines Handbook]] 2005''. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-9-3.
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| * A Guide to Symptom Relief in Palliative Care, 5th ed. Regnard C, Hockley J. Abingdon: Radcliffe Medical Press, 2004
| |
| * PCF2- Palliative Care Formulary, 2nd ed. Twycross RG, Wilcock A, Charlesworth S. Abingdon: Radcliffe Medical Press, 2003.
| |
| * Oxford Textbook of Palliative Medicine 3rd ed. Doyle D, Hanks G, Cherny NI, Calman K eds. Oxford : Oxford University Press, 2003.
| |
| * Hanks GW. Conno F. Cherny N. Hanna M. Kalso E. McQuay HJ. Mercadante S. Meynadier J. Poulain P. Ripamonti C. Radbruch L. Casas JR. Sawe J. Twycross RG. Ventafridda V. Expert Working Group of the Research Network of the European Association for Palliative Care. Morphine and alternative opioids in cancer pain: the EAPC recommendations. British Journal of Cancer. 2001; 84(5): 587-93.
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| * Symptom Management in Advanced Cancer, 3rd edition. 2001. Twycross RG, Wilcock A. Abingdon: Radcliffe Medical Press.
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| * Hanks GW. Forbes K. Opioid responsiveness. Acta Anaesthesiologica Scandinavica. 1997; 41: 154-8.
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| * Cancer Pain Relief and Palliative Care. Geneva : WHO, 1990.
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| * Oral Morphine, Information for Patients, Families and Friends. Twycross R., Lack S.A. Beaconsfield Publishers. 1988.
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| {{Opioids}}
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