Opioid

From Wikipedia, the free encyclopedia

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 four broad classes of opioids:

• endogenous opioid peptides (opioids produced naturally in the body);
• opium alkaloids, such as morphine (the first alkaloid isolated from opium) and codeine;
• semi-synthetic opioids, such as heroin and oxycodone; and
• fully synthetic opioids, such as pethidine and methadone.

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.

Contents 1 Pharmacology 2 Uses 2.1 Clinical use 2.1.1 United States 2.1.2 Use of opioids in Palliative Care 2.1.3 History 3 Adverse effects 3.1 Treating opioid adverse effects 3.2 Dangerous opioids or dangerous prescribers? 3.3 Other concerns about opioids 4 Examples of opioids 4.1 Endogenous opioids 4.2 Opium alkaloids 4.3 Semisynthetic derivatives 4.4 Synthetic opioids 4.4.1 Anilidopiperidines 4.4.2 Phenylpiperidines 4.4.3 Diphenylpropylamine derivatives 4.4.4 Benzomorphane derivatives 4.4.5 Oripavine derivatives 4.4.6 Morphinan derivatives 4.4.7 Others 4.5 Opioid antagonists 5 See also 6 References 7 External links 8 Bibliography

[edit] Pharmacology

Main article: opioid receptor

Opioids bind to specific opioid receptors in the central nervous system and in other tissues. There are at least seventeen major classes of opioid receptors, although only four are generally spoken of: μ, κ, σ and possibly δ(mu, kappa, sigma, and delta). In addition, there are two subtypes of μ receptor: μ₁ and μ₂.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.

[edit] Uses

[edit] 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 4 hours (90mg/24 hours), ie. 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 longterm use of strong opioids which has shown that dependence is rare when the drug is being used for pain relief.

[edit] United States

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

• Analgesia and anesthesia
• Cough (codeine and hydrocodone only)
• Diarrhea (opium only)
• Anxiety due to shortness of breath (oxymorphone only)
• Detoxification (methadone and buprenorphine only)

In the US, 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).

[edit] 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.' (p327)
• Breathlessness shortness of breath: the largest evidence base exists for morphine. Several mechanisms are suggested for its action on breathlessness.(p605-7)
• 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.(p493)
• Painful wounds: topical morphine in an aqueous gel can be an effective agent.(p392) 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 (eg. morphine and oxycodone). Age (young or old) is not a contraindication to strong opioids.

[edit] History

Non-clinical use was criminalized in the USA 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 UK 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 US 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.

[edit] Adverse effects

Opioids are associated with a range of adverse drug reactions - mostly associated with their pharmacological actions at opioid receptors. See http://www.palliativedrugs.com for more information.

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, the existence of this has been disputed and it is not 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 relvance of this in the context of pain relief is not known.

[edit] Treating opioid adverse effects

Most adverse effects can be managed successfully:

Nausea: tolerance occurs within 7-10 days, during which antiemetics (eg. 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 (eg. domperidone or metoclopramide 10mg every 8 hours), but usually needs to be started by a non-oral route (eg. 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 for pain relief 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 (eg. naloxone 400 microg) but giving this in small doses (eg. 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.

[edit] 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. ^[1]
• UK doctors are particularly cautious about shortening life ^[2]
• Palliative care physicians are not faced with the dilemma of relieving symptoms at the risk of shortening life.
• The Dutch public equate high dose morphine and sedation with euthanasia. ^[3]
• Doctors are secretly killing patients.^[4]
• In the UK, a community doctor, Harold Shipman was convicted of giving 30 times an acceptable dose of diamorphine.
• Two other UK doctors have been acquitted of charges after using a starting dose of morphine or diamorphine up to 60 times higher than would be used in palliative care. Acquittal was on the basis of the defence of double effect.

How safe are opioids? A world view

• Morphine and sedatives do not hasten death

UK- Double doses of bedtime morphine did not increase overnight deaths. ^[5] UK- Sedative dose increases were not associated with shortened survival (n=237). ^[6]

Australia - No link between doses of opioids, benzodiazepines or haloperidol and survival. ^[7]

• Opioids & sedatives do not hasten death in dying patients

Taiwan - Giving morphine to treat breathlessness on admission and in last 48hrs did not affect survival. ^[8]

Japan - The survival of patients of high dose opioids and sedatives in last 48hrs was the same as those not on such drugs. ^[9]

USA - After ventilator withdrawal, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75). ^[10]

• Morphine does not hasten death in elderly, breathless patients or those with poor lung function

Switzerland - Morphine given to elderly patients for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial). ^[11]

UK - The respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15). ^[12]

Canada - Injections of morphine given subcutaneously to patients with restrictive respiratory failure did not change their respiratory rate, respiratory effort, arterial oxygen level, or end-tidal carbon dioxide levels. ^[13]

• Opioids are ineffective euthanasia agents

Netherlands - Opioids are not considered ‘standard’ drugs for euthanasia with reported use reducing by half from 1995 to 2001. ^[14]

Using opioids safely

In palliative care the aim is always to relieve symptoms while minimising mild to moderate adverse effects, and avoiding serious adverse effects. See http://www.palliativedrugs.com for more information.

Starting doses: a person who has never been on analgesics would be started on oral morphine 2.5 – 5mg 4-hourly (or morphine by injection 1 – 2.5mg 4-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 4 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.

The unsafe use of opioids

The UK doctor Harold Shipman gave 30mg diamorphine intravenously to patients who had no pain. Others have given 60mg diamorphine intravenously to patients who have never had an opioid before. Such doses are 30-60 times higher than would be used in palliative care. The result is to breakthrough the safety margin and cause dangerously high levels of drug in the blood. The high levels will be reached more rapidly, and to higher levels, if the drug is given intravenously – the route chosen by Shipman. Even if death does not occur, agitation and distress can occur.

If a doctor was to give or prescribe insulin at 30 times the correct starting dose, his or her medical defence organisation would be unlikely to defend such negligence. If a doctor gave a patient 30 times a dose of paracetamol (a lethal dose), malice would be the presumed intention. Excessive doses of morphine or diamorphine are equally unacceptable.

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.

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. 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 modern cars which are inherently safe unless they are driven by negligent or malicious drivers: If bad drivers rather than cars are responsible for most road deaths, why blame morphine and ignore bad prescribers?

[edit] Other concerns about opioids

Tolerance, dependence, addiction and abuse

These issues cause doctors and patients many concerns, and are the commonest reason 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 phenomenon to any chemical, including coffee. Tolerance is more pronounced for some effects than for others so that opioids demonstrate selective tolerance:

• rapid tolerance to euphoria, dysphoria, itch, urinary retention, and respiratory depression
• gradual tolerance 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 wthout precipitating a physical withdrawal syndrome.

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.

Abuse is the misuse of opioids in the context of addiction.

Drug abuse issues

In opioid addiction (not 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 minimised 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, such as clonidine for sympathetic hyperactivity and a benzodiazepine for anxiety and insomnia.

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.

[edit] Examples of opioids

[edit] 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

[edit] Opium alkaloids

Phenanthrenes naturally occurring in opium:

• Morphine
• Codeine
• Thebaine

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

[edit] Semisynthetic derivatives

• Diacetylmorphine (heroin)
• Oxycodone
• Hydrocodone
• Dihydrocodeine
• Hydromorphone
• Oxymorphone
• Nicomorphine

[edit] Synthetic opioids

[edit] Anilidopiperidines

• Fentanyl
• Alfentanil
• Sufentanil
• Remifentanil
• Carfentanyl
• Ohmefentanyl

[edit] Phenylpiperidines

• Pethidine (meperidine)
• Ketobemidone
• MPPP
• Allylprodine
• Prodine
• PEPAP

[edit] Diphenylpropylamine derivatives

• Propoxyphene
• Dextropropoxyphene
• Dextromoramide
• Bezitramide
• Piritramide
• Methadone
• 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)

[edit] Benzomorphane derivatives

• Pentazocine
• Phenazocine

[edit] Oripavine derivatives

• Buprenorphine
• Etorphine

[edit] Morphinan derivatives

• Butorphanol
• Nalbufine
• Levorphanol
• Levomethorphan

[edit] Others

• Dezocine
• Lefetamine
• Tilidine
• Tramadol

[edit] Opioid antagonists

• Naloxone
• Naltrexone

[edit] See also

• Psychoactive drug

[edit] References

1. ^ Seale C. National survey of end-of-life decisions made by UK medical practitioners. Palliative Medicine 2006; 20(1): 3-10
2. ^ Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. Palliative Medicine 2006; 20(7): 653-9
3. ^ 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.
4. ^ Dignity in Dying. The Problem with the Current Law. http://www.dignityindying.org.uk/information/factsheets.asp?id=84
5. ^ Regnard C and Badger C. Opioids, sleep and the time of death. Palliative Medicine, 1987; 1(2): 107-110.
6. ^ 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.
7. ^ 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
8. ^ 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.
9. ^ 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.
10. ^ Chan JD et al. Narcotic and benzodiazepines use after withdrawal of life support: association with time of death? Chest. 2004: 126(1): 286-93.
11. ^ 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.
12. ^ Boyd KJ. Kelly M. Oral morphine as symptomatic treatment of dyspnoea in patients with advanced cancer. Palliative Medicine. 1997: 11(4): 277-81.
13. ^ 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.
14. ^ Rurup ML. Et al. Nederlands Tijdschrift voor Geneeskunde. 2006: 150(11): 618-24.

[edit] 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
• 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

[edit] 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.