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.
Some minor opium alkaloids and various substances with opioid action are also found elsewhere in nature, including alkaloids present in the Kratom, Corydalis, and Salvia plants and some species of poppy aside from Papaver somniferum, and there are strains which produce copious amounts of thebaine, an important raw material for making many semi-synthetic and synthetic opioids. Of all of the more than 120 poppy species, only two produce morphine.
It has been discovered that the human body, as well as those of some other animals, naturally produce small amounts of morphine and codeine and possibly some of their simpler derivatives like heroin and dihydromorphine, in addition to the well known endogenous opioids. Some bacteria are capable of producing some semi-synthetic opioids such as hydromorphone and hydrocodone when living in a solution containing morphine or codeine respectively.
Amongst analgesics are a small number of agents which act on the central nervous system but not on the opioid receptor system and therefore have none of the other (narcotic) qualities of opioids although they may produce euphoria by relieving pain -- a euphoria that, because of the way it is produced, does not form the basis of habituation, physical dependence, or addiction. Foremost amongst these are nefopam, orphenadrine, and perhaps phenyltoloxamine and/or some other antihistamines. 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, ibuprofen and the like. Paracetamol is predominantly a centrally acting analgesic (non-narcotic) which mediates its effect by action on descending serotonergic (5-hydroxy triptaminergic) pathways, to increase 5-HT release (which inhibits release of pain mediators). It also decreases cyclo-oxygenase activity.
Many of the alkaloids and other derivatives of the opium poppy are not opioids or narcotics; the best example is the smooth-muscle relaxant papaverine. Noscapine is a marginal case as it does have CNS effects but not necessarily similar to morphine, and it is probably in a category all its own. Dextromethorphan (the stereoisomer of levomethorphan, a semi-synthetic opioid agonist) and its metabolite dextrorphan have no opioid agonist effects at all despite their structure similarity to other opioids, instead they are potent NMDA antagonists and sigma 1 and 2 agonists and are used in many over-the-counter cough suppressants.
Opioids have long been used to treat acute pain (such as post-operative pain). They have also been found to be invaluable in palliative care to alleviate the severe, chronic, disabling pain of terminal conditions such as cancer. 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, and requirements can level off for many months at a time despite the fact that opioids have some of the greatest potential for tolerance of any category of drugs.
In recent years there has been an increased use of opioids in the management of non-malignant chronic pain. This practice has grown from over 30 years experience in palliative care of long-term use of strong opioids which has shown that addiction is rare when the drug is being used for pain relief. The basis for the occurrence of iatrogenic addiction to opioids in this setting being several orders of magnitude lower than the general population is the result of a combination of factors. Open and voluminous communication and meticulous documentation amongst patient, any caretakers, physicians, and chemists (pharmacists) is one part of this; the aggressive and consistent use of opioid rotation, adjuvant analgesics, potentiators, and drugs which deal with other elements of the pain (NSAIDS) and opioid side effects (stimulants in some cases, antihistamines) both improve the prognosis for the patient and appear to contribute to the rarity of addiction in these cases.
The use of some opioids against depression, especially as a short-term or one-time treatment in cases of severe point-source temporary exacerbation depression or the failure of coping mechanisms in non-depressed people has been "rediscovered" in the English-speaking world in the last eight years or so although this was a common indication for some of the milder narcotic preparations prior to the Harrison Narcotic Act of 1914. A quick Google search on any day shows the following:
The sole clinical indications for opioids in the United States, according to Drug Facts and Comparisons, 2005, are:
In the U.S., doctors virtually never prescribe opioids for psychological relief (with the narrow exception of anxiety due to shortness of breath), despite their extensively reported psychological benefits, and the widespread use of opiates in depression and anxiety up until the mid 1950s. There are virtually no exceptions to this practice, even in circumstances where researchers have reported opioids to be especially effective and where the possibility of addiction or diversion is very low—for example, in the treatment of senile dementia, geriatric depression, and psychological distress due to chemotherapy or terminal diagnosis (see Abse; Berridge; Bodkin; Callaway; Emrich; Gold; Gutstein; Mongan; Portenoy; Reynolds; Takano; Verebey; Walsh; Way).
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:
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 of the accumulation of the parent drug or their active metabolites (e.g. morphine and oxycodone). Age (young or old) is not a contraindication to strong opioids. Some synthetic opioids such as pethidine have metabolites which are actually neurotoxic and should therefore be used only in acute situations.
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.
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.
For more information see 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, itching, 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. If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia.
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 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. Stronger antiemetics such as ondansetron or tropisetron may be indicated if nausea is severe or continues for an extended period, although these tend to be avoided due to their high cost unless nausea is really problematic.
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. Certain opioids such as diamorphine tend to be particularly sedating, while others such as oxycodone and meperidine (pethidine) tend to produce less sedation, but individual patients responses can vary markedly and some degree of trial and error may be needed to find the most suitable drug for a particular patient.
Itching: tends not to be a severe problem when opioids are used for pain relief, but if required then antihistamines are useful for counteracting itching. Non-sedating antihistamines such as fexofenadine are preferable so as to avoid increasing opioid induced drowsiness, although some sedating antihistamines such as orphenadrine may be helpful as they produce a synergistic analgesic effect which allows smaller doses of opioids to be used while still producing effective analgesia. For this reason some opioid/antihistamine combination products have been marketed, such as Meprozine (meperidine/promethazine) and Diconal (dipipanone/cyclizine), which may also have the added advantage of reducing nausea as well.
Constipation: 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. Peripherally acting opioid antagonists such as alvimopan and methylnaltrexone (Relistor) are currently under development which have been found to effectively relieve opioid induced constipation without affecting analgesia or triggering withdrawal symptoms.
Respiratory depression: Although this is the most serious adverse reaction associated with opioid use it usually is seen with the use of a single, intravenous dose in an opioid-naive patient. In patients taking opioids regularly for pain relief, tolerance to respiratory depression occurs rapidly, so that it is not a clinical problem. Several drugs have been developed which can block respiratory depression completely even from high doses of potent opioids, without affecting analgesia, although the only respiratory stimulant currently approved for this purpose is doxapram, which has only limited efficacy in this application. Newer drugs such as BIMU-8 and CX-546 may however be much more effective.
Reversing the effect of opioids: Opioid effects can be rapidly reversed with an opioid antagonist (literally an inverse agonist) such as naloxone or naltrexone. These competitive antagonists bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This displaces the agonist, attenuating and/or reversing the agonist effects. However, the elimination half-life of naloxone can be shorter than that of the opioid itself, so repeat dosing or continuous infusion may be required, or a longer acting antagonist such as nalmefene may be used. In patients taking opioids regularly it is essential that the opioid is only partially reversed to avoid a severe and distressing reaction of waking in excruciating pain. This is achieved by not giving a full dose (e.g. naloxone 400 μg) but giving this in small doses (e.g. naloxone 40 μg) until the respiratory rate has improved. An infusion is then started to keep the reversal at that level, while maintaining pain relief.
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, and that sedative dose increases were not associated with shortened survival (n=237). Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15). In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival. In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival. The survival of Japanese patients on high dose opioids and sedatives in the last 48 hours was the same as those not on such drugs. In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75). Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial). 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. Even when opioids are given intravenously, respiratory depression is not seen.
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.
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, intrathecal magnesium and zinc, and NMDA antagonists such as ketamine. The cholecystokinin antagonist proglumide is also used to reduce tolerance to opioid drugs, and newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.
Magnesium and zinc deficiency speed up the development of tolerance to opioids and relative deficiency of these minerals is quite common 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.
Dunniod-peptides that are produced in the body include:
β-endorphin is expressed in Pro-opiomelanocortin (POMC) cells in the arcuate nucleus and in a small population of neurons in the brainstem, and acts through μ-opioid receptors. β-endorphin has many effects, including on sexual behavior and appetite. β-endorphin is also secreted into the circulation from pituitary corticotropes and melanotropes. α-neoendorphin is also expressed in POMC cells in the arcuate nucleus.
[met]-enkephalin is widely distributed in the CNS; [met]-enkephalin is a product of the proenkephalin gene, and acts through μ and δ-opioid receptors. [leu]-enkephalin, also a product of the proenkephalin gene, acts through δ-opioid receptors.
Dynorphin acts through κ-opioid receptors, and is widely distributed in the CNS, including in the spinal cord and hypothalamus, including in particular the arcuate nucleus and in both oxytocin and vasopressin neurons in the supraoptic nucleus.
Endomorphin acts through μ-opioid receptors, and is more potent than other endogenous opioids at these receptors.
Preparations of mixed opium alkaloids, including papaveretum, are still occasionally used.
Investigators at University of Calgary, Hotchkiss Brain Institute Publish New Data on Opioid Receptors.(Report)
Jan 24, 2011; A report, 'Heterodimerization of ORL1 and opioid receptors and its consequences for N-type calcium channel regulation,' is newly...