Opioid

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 a number of broad classes of narcotics:

• natural opiates, alkaloids contained in the resin of the opium poppy including morphine, codeine, thebaine, and oripavine;
• semi-synthetic opiates, created from the natural opioids, such as hydromorphone, hydrocodone, oxycodone, and heroin;
• fully synthetic opioids, such as fentanyl, pethidine, methadone, and propoxyphene;
• endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins.

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.

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.

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.

Finally, some opioids such as diphenoxylate do not possess analgesic action, narcotic or otherwise.

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Pharmacology

Main article: 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. Another receptor of clinical importance is the opioid-receptor-like receptor 1 (ORL1), which is involved in pain responses as well as having a major role in the development of tolerance to μ-opioid agonists used as analgesics. These are all G-protein coupled receptors acting on GABAergic neurotransmission. The pharmacodynamic response to an opioid depends 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 addiction 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 many emerging countries lacking in pain relief medication.^[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 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.^[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 to 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:

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. ^{[4] [5]} If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia. ^{[6] [7]}

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 ^[8] 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.

How safe are opioids? A world view

There are a number of paradoxical beliefs about opioids:

• 33% of UK doctors believe they had possibly shortened life during alleviation of symptoms,^[9] and yet a follow-up study showed that UK doctors are particularly cautious about shortening life.^[10]
• 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.^[11]
• The Dutch public equate high dose morphine and sedation with euthanasia,^[12] and yet it is the least used class of drug used for euthanasia in the Netherlands.

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,^[13] and that sedative dose increases were not associated with shortened survival (n=237).^[14] Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15).^[15] In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival.^[16] In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival.^[17] 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.^[18] In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75).^[19] Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial).^[20] 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.^[21] Even when opioids are given intravenously, respiratory depression is not seen.^[22]

Using opioids safely

• 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.

• 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.

• 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.^[23]

Double effect

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.^[24]

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.^[25] 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.

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.

Tolerance to opioids is attenuated by a number of substances, including calcium channel blockers^[26][27], intrathecal magnesium^[28] and zinc^[29], and NMDA antagonists such as ketamine.^[30]

Magnesium and zinc deficiency speed up the development of tolerance to opioids^{[citation needed]} and relative deficiency of these minerals is quite common^[31] 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.^{[citation needed]}

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.^[32] 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. ^[33] Dependence also occurs for most other drugs, including caffeine and alcohol.

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.^[34]

Abuse

Drug abuse is the misuse of drugs producing negative consequences.

Examples of opioids

Endogenous opioids

Opioid-peptides that are produced in the body include:

• Endorphins
• Enkephalins
• Dynorphins
• Endomorphins

β-endorphin is expressed in Pro-opiomelanocortin (POMC) cells in the arcuate nucleus and in a small population of neurons in the brainstem, and acts through μ-opioid receptors. β-endorphin has many effects, including on sexual behavior and appetite. β-endorphin is also secreted into the circulation from pituitary corticotropes and melanotropes. α-neoendorphin is also expressed in POMC cells in the arcuate nucleus.

[met]-enkephalin is widely distributed in the CNS; [met]-enkephalin is a product of the proenkephalin gene, and acts through μ and δ-opioid receptors. [leu]-enkephalin, also a product of the proenkephalin gene, acts through δ-opioid receptors.

Dynorphin acts through κ-opioid receptors, and is widely distributed in the CNS, including in the spinal cord and hypothalamus, including in particular the arcuate nucleus and in both oxytocin and vasopressin neurons in the supraoptic nucleus.

Endomorphin acts through μ-opioid receptors, and is more potent than other endogenous opioids at these receptors.

Opium alkaloids

Phenanthrenes naturally occurring in opium:

• Codeine
• Morphine
• Thebaine
• Oripavine^[35]

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

• 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)

Benzomorphan derivatives

• Pentazocine
• Phenazocine

Oripavine derivatives

• Buprenorphine
• Etorphine

Morphinan derivatives

• Butorphanol
• Nalbuphine
• Levorphanol
• Levomethorphan

Others

• Dezocine
• Lefetamine
• Meptazinol
• Tilidine
• Tramadol
• Tapentadol

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. ^ Wilson GR, Reisfield GM. "Morphine hyperalgesia: a case report." Am J Hosp Palliat Care. 2003 Nov-Dec;20(6):459-61. PMID 14649563
5. ^ 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
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10. ^ Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. Palliative Medicine 2006; 20(7): 653–9.
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21. ^ 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.
22. ^ Bassam E, et al Respiratory function during parenteral opioid titration for cancer pain. Palliative Medicine, 2007; 21: 81-86.
23. ^ Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
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25. ^ Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. Palliative Medicine 2006; 20(7): 653–9
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28. ^ McCarthy RJ, Kroin JS, Tuman KJ, Penn RD, Ivankovich AD. "Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats." Anesthesia and Analgesia. 1998 Apr;86(4):830-6. PMID 9539610
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