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An 'opioid' is a chemical substance that has a morphine-like action in the body. The main use is for pain relief. These agents work by binding to opioid receptors, 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 five broad classes of narcotics:
★ endogenous opioid peptides (opioids produced naturally in the body);
★ 'opiates', such as the naturally occurring alkaloids, morphine, codeine, thebaine, and papaverine, and also the non-alkaloid, heroin (processed morphine);
★ 'semi-synthetic opioids', created from the natural opioids, such as hydromorphone, hydrocodone, and oxycodone;
★ 'fully synthetic opioids', such as fentanyl, pethidine , methadone, and propoxyphene;
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.
Main articles: opioid receptor
Opioids bind to specific opioid receptors in the central nervous system and in 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, 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: μ1 and μ2. Of clinical importance is also the opioid-receptor-like receptor 1 (ORL1), which is also involved in pain responses. These are all G-protein coupled receptors acting on GABAergic 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 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 (dependency) by the μ2 receptor, and sedation and spinal analgesia by the κ receptor.
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.
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 dependence is rare when the drug is being used for pain relief.
The sole clinical indications for opioids in the United States, according to ''Drug Facts and Comparisons,'' 2005, are
★ Analgesia and anesthesia
★ Cough (codeine and hydrocodone only)
★ Diarrhoea (generally loperamide or diphenoxylate, but laudanum or morphine may be used in some cases of severe diarrheal diseases)
★ Anxiety due to shortness of breath (oxymorphone only)
★ Detoxification (methadone and buprenorphine only)
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).
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
★ "Any pain of moderate or greater severity, irrespective of the underlying pathophysiological mechanism." (p.327)
★ Breathlessness shortness of breath: the largest evidence base exists for morphine. Several mechanisms are suggested for its action on breathlessness (p.605–7).
★ 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).
★ 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.
'Not just opioids...'
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.
'Contraindications for opioids'
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.
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.
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 emerging countries in particular, lacking in pain relief medicine.[1]. 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 presciption 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 presciption of poppy-based medicines.[2]
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 access poppy-based drugs under the current system.
For more information see[3] and the online palliative care formulary (available on Palliativedrugs.com).
'Common adverse reactions in patients taking opioids for pain relief:'
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).
'Infrequent adverse reactions in patient taking opioids for pain relief:'
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).
'Other adverse effects:'
A phenomenon of opioid-induced hyperalgesia has been proposed, whereby individuals using opioids to relieve pain may paradoxically have more pain as a result of their medication. However, it has not been reported to have been seen in palliative care where there is the greatest experience of the use of strong opioids over months or years.
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.
Most adverse effects can be managed successfully. (For more complete information see [4] and the online palliative care formulary available on Palliativedrugs.com.)
''Nausea:'' tolerance occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol 1.5–3mg once at night) are very effective.
''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).
''Drowsiness:'' tolerance usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps.
''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.
''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.
''Reversing the effect of opioids:'' Opioid effects can be rapidly reversed with an opioid antagonist such as naloxone or naltrexone. These competitive antagonists bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This displaces the agonist, attenuating 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.
There are a number of paradoxical beliefs about opioids:
★ 33% of UK doctors believe they had possibly shortened life during alleviation of symptoms.[5] and yet UK doctors are particularly cautious about shortening life.[6]
★ 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.[7]
★ The Dutch public equate high dose morphine and sedation with euthanasia,[8] and yet it is the least used class of drug used for euthanasia in the Netherlands.
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,[9] and that sedative dose increases were not associated with shortened survival (n=237).[10] Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15).[11] In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival.[12] In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival.[13] 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.[14] In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75).[15]
Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial).[16] 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.[17] Even when opioids are given intravenously, respiratory depression is not seen.[18]
★ Starting doses: a person who has never been on analgesics would be started on oral morphine 2.5–5mg four-hourly (or morphine by injection 1–2.5mg four-hourly). Higher doses can be used if the patient was already on weaker analgesics.
★ Titration: this describes the adjustment of a drug dose to an individual 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.
★ Safety margin of opioids: morphine and diamorphine have a wide safety margin or "therapeutic range".
★ 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.[4]
Opioids have a well defined acute toxicity for respiratory depression, so a single but large enough dose of an opioid can casue life-threatening respiratory depression. Fortunately, the safety margin for most opioids is very wide. Usually respiratory depression is not a problem in pain or palliative care medicine. The reason for this is not the level of dose, but the speed of titration. Good practice is to titrate the dose to the individual in 25-50% steps at 2-3 day intervals, until pain control is achieved with the minimal of adverse effects. In contrast, giving a large dose to a person who has previously taken no opioids is likely to casue problems.
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.[7]
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.
With exceptions such as Shipman, UK doctors are very cautious about shortening life.[21] 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.
Strong opioids such as morphine are inherently safe when used correctly, but they are powerful drugs with the potential for harm. There is a parallel here with power tools which are inherently safe unless they are used in a negligent or malicious way. Why blame the tool—morphine—and ignore bad prescribers?
These issues cause doctors and patients many concerns, and are the most common reasons for inadequate use of analgesia in patients with severe pain. Putting these issues into the context of analgesia is important.
''Tolerance'' is the tendency of the body to adapt to the presence of opioids and is a common reaction to any chemical, including caffeine. Tolerance is more pronounced for some effects than for others; thus, opioids demonstrate ''selective tolerance:''
★ rapid tolerance to euphoria, dysphoria, itch, urinary retention, and respiratory depression;
★ gradual tolerance to nausea, drowsiness;
★ no tolerance to constipation, pain relief, sexual side effects.
''Dependence'' is the tendency of the body to manifest a characteristic and unpleasant ''withdrawal syndrome'' if regular doses of opioids are abruptly discontinued after tolerance has developed. This is also common for many chemicals, including coffee. For opioids the withdrawal syndrome generally consists of severe dysphoria, anxiety, eye tearing, a runny nose, goose bumps, sweating, nausea, vomiting, cramps and deep pains are common. For patients taking opioids for pain relief, this can occur in some (but not all), but it is not a clinical problem, since most can rapidly reduce their opioids over 1–2 weeks without precipitating a physical withdrawal syndrome.[22]
''Addiction'' is a psychological craving for certain effects of opioids (such as the euphoria that many people experience when the drugs are taken in sufficiently large doses) that drives the user to take the drug despite adverse and maladaptive consequences. Dependency and the unpleasantness of withdrawal can work to maintain addiction, although they do not cause it. This occurs only in specific social circumstances for an individual. Consequently, addiction is common in people taking opioids recreationally, but it is very rare in patients taking opioids for pain relief.[4]
''Abuse'' is the misuse of opioids in the context of addiction.
There is evidence that the mechanism by which opioid tolerance develops is different than the mechanism by which opioids inhibit pain. The significance of this is that the effects of opioids could, potentially, be realized while, at the same time, addiction and tolerance could be delayed or prevented and (possibly) even reversed.[1][2]
In opioid addiction (rarely seen in patients taking opioids for pain relief), the speed and severity of withdrawal depends on the half-life of the opioid—heroin withdrawal occurs more quickly and is 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. Withdrawal symptoms can be minimized by slowly tapering the dose over days or weeks, sometimes after switching to a long-acting opioid such as methadone. The symptoms of opioid withdrawal can also be treated with other medications, but with low efficacy. [24]
Occasionally, people who are addicted to opioids on the street develop a painful condition which requires strong opioids. Carers are often very reluctant to give these patients analgesia, fearing it will make their addiction worse. Paradoxically, increasing experience of caring for such patients in palliative care has shown that they can be managed in the same way as any other patient with regular administration of opioids, plus extra doses for breakthrough medication. It seems that, because the social context is fundamentally different to the one when they were abusing their drugs, they do not run the risk of addiction. Indeed, if the cause of the pain settles, they can reduce their opioids without problem.
Opioid-peptides that are produced in the body:
★ Endorphins
★ Dynorphins
★ Enkephalins
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.
[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.
Nociceptin, formerly known as orphanin FQ, is an opioid-related peptide, but it does not act at the classic opioid receptors and actions are not antagonised by the opioid antagonist naloxone. Nociceptin is a potent anti-analgesic. Noiceptin is widely distributed in the CNS; it is found in many regions of the hypothalamus, brainstem, forebrain, as well as in the ventral and dorsal horns of the spinal cord. Nociceptin acts at the NOP1 receptor, formerly known as ORL-1. The receptor is also widely distributed in the brain, including in the cortex, anterior olfactory nucleus, lateral septum, hypothalamus, hippocampus, amygdala, central gray, pontine nuclei, interpeduncular nucleus, substantia nigra, raphe complex, locus coeruleus, and spinal cord.
Endomorphin acts through μ-opioid receptors, and is more potent than other endogenous opioids at these receptors.
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
Phenanthrenes naturally occurring in opium:
★ Codeine
★ Morphine
★ Thebaine
Preparations of mixed opium alkaloids, including papaveretum, are still occasionally used.
★ Diacetylmorphine (heroin)
★ Dihydrocodeine
★ Hydrocodone
★ Hydromorphone
★ Nicomorphine
★ Oxycodone
★ Oxymorphone
Anilidopiperidines
★ Fentanyl
★ Alphamethylfentanyl
★ Alfentanil
★ Sufentanil
★ Remifentanil
★ Carfentanyl
★ Ohmefentanyl
Phenylpiperidines
★ Nocaine
★ Pethidine (meperidine)
★ Ketobemidone
★ MPPP
★ Allylprodine
★ Prodine
★ PEPAP
Diphenylpropylamine derivatives
★ Propoxyphene
★ Dextropropoxyphene
★ Dextromoramide
★ Bezitramide
★ Piritramide
★ Methadone
★ Dipipanone
★ Levo-alphacetylmethadol (LAAM)
★ Loperamide (used for diarrhoea, does not cross the blood-brain barrier)
★ Diphenoxylate (used for diarrhoea, does not appreciably cross the blood-brain barrier)
Benzomorphane derivatives
★ Pentazocine
★ Phenazocine
Oripavine derivatives
★ Buprenorphine
★ Etorphine
Morphinan derivatives
★ Butorphanol
★ Nalbuphine
★ Levorphanol
★ Levomethorphan
★ Dezocine
★ Lefetamine
★ Tilidine
★ Tramadol
★ Nalmefene
★ Naloxone
★ Naltrexone
★ Psychoactive drug
1. http://www.senliscouncil.net/modules/publications/008_publication
2. The World Health Organisation "Assuring Availability of Opioid Analgesics" [www.euro.who.int/document/e76503.pdf]
3. Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
4. ''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
5. Seale C. National survey of end-of-life decisions made by UK medical practitioners, ''Palliative Medicine'' 2006; 20(1): 3–10.
6. Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. ''Palliative Medicine'' 2006; 20(7): 653–9.
7. George R, Regnard C. Lethal opioids or dangerous prescribers? ''Palliative Medicine'', 2007; 21: 77-80.
8. 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.
9. Regnard C and Badger C. Opioids, sleep and the time of death. ''Palliative Medicine'', 1987; 1(2): 107–110.
10. 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.
11. Boyd KJ. Kelly M. Oral morphine as symptomatic treatment of dyspnoea in patients with advanced cancer. ''Palliative Medicine''. 1997: 11(4): 277–81.
12. 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.
13. 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.
14. 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.
15. Chan JD et al. Narcotic and benzodiazepines use after withdrawal of life support: association with time of death? ''Chest.'' 2004: 126(1): 286–93.
16. 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.
17. 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.
18. Bassam E, ''et al'' Respiratory function during parenteral opioid titration for cancer pain. ''Palliative Medicine'', 2007; 21: 81-86.
19. ''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
20. George R, Regnard C. Lethal opioids or dangerous prescribers? ''Palliative Medicine'', 2007; 21: 77-80.
21. Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. Palliative Medicine 2006; 20(7): 653–9
22. Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004)
23. ''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
24. 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
★ American Pain Foundation
★ American Pain Society
★ American Academy of Pain Management
★ American Academy of Addiction Psychiatry, professional association of psychiatrists expert in addiction treatment
★ CLiP- Current Learning in Palliative Care Fifty-six workshops on palliative care which can be used online or dounloaded. Free access, no restrictions.
★ International Association for Hospice and Palliative Care
★ Opioids FAQ
★ Palliativedrugs.com. Online palliative care formulary. Also has bulletin board with over 22,000 international professionals registered. Free access after registration.
★ Palliative Care Matters Palliative Care information.
★ Palliative Care Handbook Online palliative care textbook
★ The use of opioids for chronic pain @ The APS
★ Merck Entry on Opioids
★ Pain
★ Palliativedrugs.com Palliative Care Formulary and bulletin board with over 22,000 worldwide registered. Free to register.
★ Wall and Melzack’s textbook of pain, 5th ed. Stephen B. McMahon and Martin Koltzenburg, eds. Edinburgh : Elsevier Churchill Livingstone, 2006.
★ 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.
★ Rossi S (Ed.) (2005). ''Australian Medicines Handbook 2005''. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-9-3.
★ 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.
★ Symptom Management in Advanced Cancer, 3rd edition. 2001. Twycross RG, Wilcock A. Abingdon: Radcliffe Medical Press.
★ Hanks GW. Forbes K. Opioid responsiveness. Acta Anaesthesiologica Scandinavica. 1997; 41: 154-8.
★ Cancer Pain Relief and Palliative Care. Geneva : WHO, 1990.
★ Oral Morphine, Information for Patients, Families and Friends. Twycross R., Lack S.A. Beaconsfield Publishers. 1988.
★ endogenous opioid peptides (opioids produced naturally in the body);
★ 'opiates', such as the naturally occurring alkaloids, morphine, codeine, thebaine, and papaverine, and also the non-alkaloid, heroin (processed morphine);
★ 'semi-synthetic opioids', created from the natural opioids, such as hydromorphone, hydrocodone, and oxycodone;
★ 'fully synthetic opioids', such as fentanyl, pethidine , methadone, and propoxyphene;
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.
Pharmacology
Main articles: opioid receptor
Opioids bind to specific opioid receptors in the central nervous system and in 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, 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: μ1 and μ2. Of clinical importance is also the opioid-receptor-like receptor 1 (ORL1), which is also involved in pain responses. These are all G-protein coupled receptors acting on GABAergic 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 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 (dependency) by the μ2 receptor, and sedation and spinal analgesia by the κ receptor.
Uses
Clinical use
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.
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 dependence is rare when the drug is being used for pain relief.
United States
The sole clinical indications for opioids in the United States, according to ''Drug Facts and Comparisons,'' 2005, are
★ Analgesia and anesthesia
★ Cough (codeine and hydrocodone only)
★ Diarrhoea (generally loperamide or diphenoxylate, but laudanum or morphine may be used in some cases of severe diarrheal diseases)
★ Anxiety due to shortness of breath (oxymorphone only)
★ Detoxification (methadone and buprenorphine only)
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).
Use of opioids in palliative care
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
★ "Any pain of moderate or greater severity, irrespective of the underlying pathophysiological mechanism." (p.327)
★ Breathlessness shortness of breath: the largest evidence base exists for morphine. Several mechanisms are suggested for its action on breathlessness (p.605–7).
★ 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).
★ 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.
'Not just opioids...'
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.
'Contraindications for opioids'
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.
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 Organisation as essential in the treatment of severe pain. However, only six countries use 77% of the world's morphine supplies, leaving emerging countries in particular, lacking in pain relief medicine.[1]. 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 presciption 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 presciption of poppy-based medicines.[2]
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 access poppy-based drugs under the current system.
Adverse effects
For more information see[3] and the online palliative care formulary (available on Palliativedrugs.com).
'Common adverse reactions in patients taking opioids for pain relief:'
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).
'Infrequent adverse reactions in patient taking opioids for pain relief:'
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).
'Other adverse effects:'
A phenomenon of opioid-induced hyperalgesia has been proposed, whereby individuals using opioids to relieve pain may paradoxically have more pain as a result of their medication. However, it has not been reported to have been seen in palliative care where there is the greatest experience of the use of strong opioids over months or years.
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.
Treating opioid adverse effects
Most adverse effects can be managed successfully. (For more complete information see [4] and the online palliative care formulary available on Palliativedrugs.com.)
''Nausea:'' tolerance occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol 1.5–3mg once at night) are very effective.
''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).
''Drowsiness:'' tolerance usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps.
''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.
''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.
''Reversing the effect of opioids:'' Opioid effects can be rapidly reversed with an opioid antagonist such as naloxone or naltrexone. These competitive antagonists bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This displaces the agonist, attenuating 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.
Dangerous opioids or dangerous prescribers?
There are a number of paradoxical beliefs about opioids:
★ 33% of UK doctors believe they had possibly shortened life during alleviation of symptoms.[5] and yet UK doctors are particularly cautious about shortening life.[6]
★ 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.[7]
★ The Dutch public equate high dose morphine and sedation with euthanasia,[8] and yet it is the least used class of drug used for euthanasia in the Netherlands.
How safe are opioids? A world view
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,[9] and that sedative dose increases were not associated with shortened survival (n=237).[10] Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15).[11] In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival.[12] In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival.[13] 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.[14] In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75).[15]
Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial).[16] 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.[17] Even when opioids are given intravenously, respiratory depression is not seen.[18]
Using opioids safely
★ Starting doses: a person who has never been on analgesics would be started on oral morphine 2.5–5mg four-hourly (or morphine by injection 1–2.5mg four-hourly). Higher doses can be used if the patient was already on weaker analgesics.
★ Titration: this describes the adjustment of a drug dose to an individual 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.
★ Safety margin of opioids: morphine and diamorphine have a wide safety margin or "therapeutic range".
★ 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.[4]
The unsafe use of opioids: the overdose
Opioids have a well defined acute toxicity for respiratory depression, so a single but large enough dose of an opioid can casue life-threatening respiratory depression. Fortunately, the safety margin for most opioids is very wide. Usually respiratory depression is not a problem in pain or palliative care medicine. The reason for this is not the level of dose, but the speed of titration. Good practice is to titrate the dose to the individual in 25-50% steps at 2-3 day intervals, until pain control is achieved with the minimal of adverse effects. In contrast, giving a large dose to a person who has previously taken no opioids is likely to casue problems.
Double effect—a myth with a double life?
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.[7]
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.
With exceptions such as Shipman, UK doctors are very cautious about shortening life.[21] 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.
Strong opioids such as morphine are inherently safe when used correctly, but they are powerful drugs with the potential for harm. There is a parallel here with power tools which are inherently safe unless they are used in a negligent or malicious way. Why blame the tool—morphine—and ignore bad prescribers?
Other concerns about opioids
Tolerance, dependence, addiction and abuse
These issues cause doctors and patients many concerns, and are the most common reasons for inadequate use of analgesia in patients with severe pain. Putting these issues into the context of analgesia is important.
''Tolerance'' is the tendency of the body to adapt to the presence of opioids and is a common reaction to any chemical, including caffeine. Tolerance is more pronounced for some effects than for others; thus, opioids demonstrate ''selective tolerance:''
★ rapid tolerance to euphoria, dysphoria, itch, urinary retention, and respiratory depression;
★ gradual tolerance to nausea, drowsiness;
★ no tolerance to constipation, pain relief, sexual side effects.
''Dependence'' is the tendency of the body to manifest a characteristic and unpleasant ''withdrawal syndrome'' if regular doses of opioids are abruptly discontinued after tolerance has developed. This is also common for many chemicals, including coffee. For opioids the withdrawal syndrome generally consists of severe dysphoria, anxiety, eye tearing, a runny nose, goose bumps, sweating, nausea, vomiting, cramps and deep pains are common. For patients taking opioids for pain relief, this can occur in some (but not all), but it is not a clinical problem, since most can rapidly reduce their opioids over 1–2 weeks without precipitating a physical withdrawal syndrome.[22]
''Addiction'' is a psychological craving for certain effects of opioids (such as the euphoria that many people experience when the drugs are taken in sufficiently large doses) that drives the user to take the drug despite adverse and maladaptive consequences. Dependency and the unpleasantness of withdrawal can work to maintain addiction, although they do not cause it. This occurs only in specific social circumstances for an individual. Consequently, addiction is common in people taking opioids recreationally, but it is very rare in patients taking opioids for pain relief.[4]
''Abuse'' is the misuse of opioids in the context of addiction.
Prevention of tolerance
There is evidence that the mechanism by which opioid tolerance develops is different than the mechanism by which opioids inhibit pain. The significance of this is that the effects of opioids could, potentially, be realized while, at the same time, addiction and tolerance could be delayed or prevented and (possibly) even reversed.[1][2]
Drug abuse issues
In opioid addiction (rarely seen in patients taking opioids for pain relief), the speed and severity of withdrawal depends on the half-life of the opioid—heroin withdrawal occurs more quickly and is 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. Withdrawal symptoms can be minimized by slowly tapering the dose over days or weeks, sometimes after switching to a long-acting opioid such as methadone. The symptoms of opioid withdrawal can also be treated with other medications, but with low efficacy. [24]
Occasionally, people who are addicted to opioids on the street develop a painful condition which requires strong opioids. Carers are often very reluctant to give these patients analgesia, fearing it will make their addiction worse. Paradoxically, increasing experience of caring for such patients in palliative care has shown that they can be managed in the same way as any other patient with regular administration of opioids, plus extra doses for breakthrough medication. It seems that, because the social context is fundamentally different to the one when they were abusing their drugs, they do not run the risk of addiction. Indeed, if the cause of the pain settles, they can reduce their opioids without problem.
Examples of opioids
Endogenous opioids
Opioid-peptides that are produced in the body:
★ Endorphins
★ Dynorphins
★ Enkephalins
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.
[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.
Nociceptin, formerly known as orphanin FQ, is an opioid-related peptide, but it does not act at the classic opioid receptors and actions are not antagonised by the opioid antagonist naloxone. Nociceptin is a potent anti-analgesic. Noiceptin is widely distributed in the CNS; it is found in many regions of the hypothalamus, brainstem, forebrain, as well as in the ventral and dorsal horns of the spinal cord. Nociceptin acts at the NOP1 receptor, formerly known as ORL-1. The receptor is also widely distributed in the brain, including in the cortex, anterior olfactory nucleus, lateral septum, hypothalamus, hippocampus, amygdala, central gray, pontine nuclei, interpeduncular nucleus, substantia nigra, raphe complex, locus coeruleus, and spinal cord.
Endomorphin acts through μ-opioid receptors, and is more potent than other endogenous opioids at these receptors.
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
Opium alkaloids
Phenanthrenes naturally occurring in opium:
★ Codeine
★ Morphine
★ Thebaine
Preparations of mixed opium alkaloids, including papaveretum, are still occasionally used.
Semisynthetic derivatives
★ Diacetylmorphine (heroin)
★ Dihydrocodeine
★ Hydrocodone
★ Hydromorphone
★ Nicomorphine
★ Oxycodone
★ Oxymorphone
Synthetic opioids
Anilidopiperidines
★ Fentanyl
★ Alphamethylfentanyl
★ Alfentanil
★ Sufentanil
★ Remifentanil
★ Carfentanyl
★ Ohmefentanyl
Phenylpiperidines
★ Nocaine
★ Pethidine (meperidine)
★ Ketobemidone
★ MPPP
★ Allylprodine
★ Prodine
★ PEPAP
Diphenylpropylamine derivatives
★ Propoxyphene
★ Dextropropoxyphene
★ Dextromoramide
★ Bezitramide
★ Piritramide
★ Methadone
★ Dipipanone
★ Levo-alphacetylmethadol (LAAM)
★ Loperamide (used for diarrhoea, does not cross the blood-brain barrier)
★ Diphenoxylate (used for diarrhoea, does not appreciably cross the blood-brain barrier)
Benzomorphane derivatives
★ Pentazocine
★ Phenazocine
Oripavine derivatives
★ Buprenorphine
★ Etorphine
Morphinan derivatives
★ Butorphanol
★ Nalbuphine
★ Levorphanol
★ Levomethorphan
Others
★ Dezocine
★ Lefetamine
★ Tilidine
★ Tramadol
Opioid antagonists
★ Nalmefene
★ Naloxone
★ Naltrexone
See also
★ Psychoactive drug
References
1. http://www.senliscouncil.net/modules/publications/008_publication
2. The World Health Organisation "Assuring Availability of Opioid Analgesics" [www.euro.who.int/document/e76503.pdf]
3. Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
4. ''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
5. Seale C. National survey of end-of-life decisions made by UK medical practitioners, ''Palliative Medicine'' 2006; 20(1): 3–10.
6. Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. ''Palliative Medicine'' 2006; 20(7): 653–9.
7. George R, Regnard C. Lethal opioids or dangerous prescribers? ''Palliative Medicine'', 2007; 21: 77-80.
8. 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.
9. Regnard C and Badger C. Opioids, sleep and the time of death. ''Palliative Medicine'', 1987; 1(2): 107–110.
10. 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.
11. Boyd KJ. Kelly M. Oral morphine as symptomatic treatment of dyspnoea in patients with advanced cancer. ''Palliative Medicine''. 1997: 11(4): 277–81.
12. 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.
13. 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.
14. 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.
15. Chan JD et al. Narcotic and benzodiazepines use after withdrawal of life support: association with time of death? ''Chest.'' 2004: 126(1): 286–93.
16. 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.
17. 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.
18. Bassam E, ''et al'' Respiratory function during parenteral opioid titration for cancer pain. ''Palliative Medicine'', 2007; 21: 81-86.
19. ''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
20. George R, Regnard C. Lethal opioids or dangerous prescribers? ''Palliative Medicine'', 2007; 21: 77-80.
21. Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. Palliative Medicine 2006; 20(7): 653–9
22. Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004)
23. ''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
24. 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
External links
★ American Pain Foundation
★ American Pain Society
★ American Academy of Pain Management
★ American Academy of Addiction Psychiatry, professional association of psychiatrists expert in addiction treatment
★ CLiP- Current Learning in Palliative Care Fifty-six workshops on palliative care which can be used online or dounloaded. Free access, no restrictions.
★ International Association for Hospice and Palliative Care
★ Opioids FAQ
★ Palliativedrugs.com. Online palliative care formulary. Also has bulletin board with over 22,000 international professionals registered. Free access after registration.
★ Palliative Care Matters Palliative Care information.
★ Palliative Care Handbook Online palliative care textbook
★ The use of opioids for chronic pain @ The APS
★ Merck Entry on Opioids
★ Pain
Bibliography
★ Palliativedrugs.com Palliative Care Formulary and bulletin board with over 22,000 worldwide registered. Free to register.
★ Wall and Melzack’s textbook of pain, 5th ed. Stephen B. McMahon and Martin Koltzenburg, eds. Edinburgh : Elsevier Churchill Livingstone, 2006.
★ 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.
★ Rossi S (Ed.) (2005). ''Australian Medicines Handbook 2005''. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-9-3.
★ 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.
★ Symptom Management in Advanced Cancer, 3rd edition. 2001. Twycross RG, Wilcock A. Abingdon: Radcliffe Medical Press.
★ Hanks GW. Forbes K. Opioid responsiveness. Acta Anaesthesiologica Scandinavica. 1997; 41: 154-8.
★ Cancer Pain Relief and Palliative Care. Geneva : WHO, 1990.
★ Oral Morphine, Information for Patients, Families and Friends. Twycross R., Lack S.A. Beaconsfield Publishers. 1988.
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