Optimal use of Opioid Analgesics
This article is one section of the book "How Cancer Pain is Treated: A non-technical guide for patients and their carers". You will find links to the other articles in the series at the bottom of this page. Alternatively, you may download the whole book in various formats HERE. (All downloads are free.)
This article, written by a senior medical practitioner with considerable experience in palliative medicine and hospice care, is offered purely for educational purposes. Nothing in it should be taken as therapeutic advice for any particular patient. Mention of any trade (brand) name should not be taken as an endorsement of the brand or its manufacturer.
If you read the articles in this series carefully, and think about the information in them, in relation to a particular pain management problem affecting you or someone you love, you may sometimes be able to think of modifications to the current treatment which might be expected to improve the situation.
However, it is very dangerous to make changes to a patient's medication without first discussing them with the prescribing doctor. The doctor must always know exactly what the patient is taking, as virtually all medications can cause unwanted side effects and interact in various ways with other medications.
Importantly, this also applies to "natural", "alternative" or "complementary" therapies, many of which have significant interactions with prescribed medications. Therefore, even if you feel that the current pain management is not optimal, never make any changes without first discussing them with the doctor.
The optimal use of opioid analgesics is more complex than that of simple analgesics or co-analgesics (analgesic adjuvants), so I have devoted this whole article to it. Importantly, this article does NOT describe the various opioid analgesics which can be used in the management of cancer pain, NOR does it discuss the simple analgesics and co-analgesics which must frequently be used in combination with any opioid analgesic. Those topics were covered in the previous article in this series, Medications used to Relieve Cancer Pain.
In other words, this article will concentrate on the method by which an opioid analgesic can most effectively be used in the management of cancer pain, while assuming that the many other aspects of cancer pain management are also being employed appropriately. With that proviso, when prescribing an opioid for the relief of cancer pain, a patient's doctor has to do the following things:
1. Choose the most suitable opioid
2. Give it regularly and at the right intervals
3. Find the right dosage by "dose titration"
4. Administer it by the most suitable route
5. Control any side effects which occur
6. Reassess every aspect of the regimen frequently
It is often very helpful if patients and their carers have a clear and fairly comprehensive understanding of what is being done and why, so I will go into some detail about each point.
1. The Right Opioid
This is very often morphine. However, when treating any given patient, substituting other opioids such as oxycodone, hydromorphone, fentanyl or methadone sometimes results in equivalent analgesia with fewer side effects. A similar effect can sometimes be achieved by using the same opioid in a different dose form, especially where this also involves a different route of administration. In recent years, this process of trying different opioids, though not in itself new, has been referred to by a new name, "opioid rotation".
When opioid rotation is thought to be necessary, the prescribing doctor has to remember that "equianalgesic tables" (which list approximately equivalent doses for different analgesics and different routes of administration) can only provide very approximate information. Conversion to a different dose form or a different opioid is simply not an exact science. It is therefore necessary for the doctor to reassess the patient frequently after such a change has been made.
2. The Right Regimen
Whatever opioid is used, and regardless of its dosage and the route by which it is administered, regular timing of doses is of crucial importance. Because acute pain, which was discussed earlier under the general classification of pain, is more common than chronic pain, most people (including many doctors) have become used to thinking in terms of occasional, short term pain relief, on an "as required" basis.
This simply does not work for most cases of cancer pain. Whether it is labelled subacute pain or chronic pain, the fact remains that most of the pain caused by advanced cancer is present most or all of the time. Therefore, the ONLY way to relieve it with analgesic medication is to make sure that the medication is present in the bloodstream, at sufficient concentration, all the time.
For this reason, the prescribing of "p.r.n." analgesia, which is often appropriate for patients who might experience an episode of acute pain from time to time, is never appropriate as a means of controlling chronic or subacute cancer pain. Instead, analgesic medication(s) used to control subacute or chronic cancer pain must be given at regular intervals around the clock., 
For many analgesic agents, including morphine, the right interval for immediate release dose forms, whether used for dose titration or for continuing baseline analgesia, is about four hours. At high dosages, smoother control may be achieved if the doses are given each three hours. But vague instructions such as "four times a day" are simply disastrous, because the interval between doses is just as important as the number of doses.
In practice, it is often necessary to adjust doses within a range prescribed by the doctor when the patient was last reviewed. These adjustments should be made by someone who is on the spot. In hospitals, that usually means a member of the nursing staff. For patients living at home, the patient or a relative could make the adjustments, following the doctor's advice carefully.
In my experience, whether it is done in a hospital or at home, this approach to dose titration requires a medication chart specifically designed for the purpose, such as the morphine chart shown in Figure 1 at the bottom of this page. However, when the dosage is stable, and especially if a sustained release dose form of the opioid is then used, this type of chart is no longer necessary.
3. The Right Dosage
The first and most important point to make about opioid dosage is that there is really no such thing as a "maximum dose" in the case of most strong opioids. While simple analgesics, weak opioids and adjuvants almost always have a maximum dose, which is not usually very much greater than the starting dose, the doses of most strong opioids can simply be increased according to need, with no absolute ceiling.
Some degree of physiological tolerance develops to any opioid with continuing use. Either an increase in physiological tolerance, or an increase in the severity of pain, may therefore necessitate an increase in opioid dosage. It is also true that misuse of any opioid, where the aim is to produce pleasure rather than control pain, can lead to psychological addiction. However, neither physiological tolerance nor psychological addiction pose significant problems when strong opioids are used properly in the management of cancer pain., 
In my own palliative care practice, I prescribed doses of oral morphine as low as one milligram each six hours, and as high as 1,000 milligram (one gram) each four hours. The low end of this range was sometimes sufficient to relieve breathlessness in a frail patient with no prior exposure to opioid medication, and the high end was sometimes needed to control severe pain in a patient with considerable physiological tolerance.
Interestingly, some patients receiving very low doses reported drowsiness, while some patients receiving very high doses remained quite alert and fully ambulant. The lesson to be learned from such observations is that the right dose of a strong opioid is simply the dose that provides the desired effect.
That dose can only be determined by careful titration of the dosage against the effects it causes, starting with a dose which can be expected, from past experience, to be well tolerated in all the particular circumstances involved. In the case of oral medication, it has been traditional to prescribe an immediate release dose form for this purpose, so that the effect of each dose can be assessed with a minimum of delay. However, dose titration can also be done (a little more slowly) with extended release medications, and this is sometimes more convenient.
Once the dosage required to provide effective baseline analgesia has been determined by titration using an immediate release dose form, that dosage can be expressed in terms of an amount per twenty-four hours. The doctor will then usually prescribe this amount in the form of extended (sustained) release tablets or capsules. These are more convenient for most patients, especially as they allow unbroken sleep without loss of analgesic effect. Of course, in patients who are unable to swallow, both dose titration and continuing treatment will be provided by one of the non-oral routes discussed below.
4. The Right Route
In most cases, the oral route of administration is the most convenient and comfortable, as long as the patient can swallow, retain and absorb the medication satisfactorily. When oral administration is not satisfactory, another route must, of course, be used. The general principle which guides the doctor is simply to find the most satisfactory route for each patient.
As discussed in the previous article in this series, Medications used to Relieve Cancer Pain, some opioids can be given rectally, usually as suppositories, but occasionally in liquid or tablet form. This is often useful as a short term measure, but it is not usually a comfortable and convenient long term solution.
Subcutaneous injections given at regular intervals can also be useful as a short term measure, but blood levels fluctuate more than they do with oral doses, making it more difficult to achieve good pain control around the clock while minimising unwanted side effects. Doctors also try to avoid prescribing frequent injections because doing so can give the impression of a difficult situation, and may also cause some psychological and/or physical discomfort when they are administered.
The long term use of intravenous opioids is usually avoided whenever possible, partly because of the inevitable complications associated with venous cannulae, and partly because there is anecdotal evidence of excessive dose escalation when extra doses are frequently given intravenously.
In many cases, the most effective method of administration, when oral medication is not satisfactory, is for the doctor or nurse to place a fine needle in the subcutaneous fat under the surface of the skin, somewhere convenient, and fix it in position with a sterile adhesive dressing. One or more medications can then be administered through this needle as a slow continuous infusion. (The "syringe drivers" used for this purpose are discussed in Appendix 3, along with some less common types of administration used in special circumstances.)
As also discussed in the previous article in this series, Medications used to Relieve Cancer Pain, the strong opioid fentanyl can provide continuous baseline analgesia via transdermal patches, often with very good results. On the other hand, the currently available buprenorphine patches are rarely useful for cancer pain. Patches for the administration of various other analgesic or co-analgesic medications, as well as "active patches" from which drugs could be delivered at more precisely controlled rates, will probably be very useful when they become available.
Very occasionally, an opioid is best administered by the "neuraxial" route, so that it acts directly on the spinal cord (or sometimes the brain). Other pain medications are also occasionally administered by this route. The neuraxial delivery of analgesia is briefly discussed in Appendix 3.
5. Control of Opioid Side-effects
The main side-effects of opioids are nausea, constipation and drowsiness. Respiratory depression is a potential risk, but is rarely a problem in practice if opioids are used correctly in the management of cancer pain. (Depression of mood is, however, not uncommon after some weeks or months of regular opioid therapy, and should always be watched for.)
Other side effects which may require attention in some cases include mental confusion; emotional distress; unsteadiness; dizziness; fainting; headache; dry mouth; slow, fast or irregular pulse; palpitations; itch; rash; excessive sweating; and wheeze. (The latter is more often a reaction to preservatives than to the opioid itself, and is rare in the absence of a history of asthma.)
Although very rare, other acute allergic reactions are also possible. In addition, like all medications, opioids may interact with other medications or with pre-existing medical conditions, and such interactions may cause unwanted effects in some cases. (Problems specifically associated with kidney or liver failure are discussed in Appendix 1 and Appendix 2.)
Whenever it proves difficult to control opioid side effects, a change of opioid or dose form, as discussed under The Right Opioid, above, is then considered. The concurrent use of co-analgesic agents, and of methods of pain management other than the use of analgesic medication, also helps in many cases, by enabling a lower dose of the opioid in question to be used.
Although it is not feasible in this series of articles to go into detail about all of the possible opioid side effects which may occasionally occur, I will include a certain amount of information about the most common ones, under the subheadings which follow.
Nausea and Vomiting
Firstly, it must be remembered that nausea or vomiting (or indeed any other symptom) experienced by a cancer patient taking an opioid is not necessarily due either to the cancer or the opioid. Nausea and/or vomiting may be due to almost any abdominal, cerebral or inner ear condition, almost any infection, or a wide range of pharmaceutical, metabolic, endocrine, biochemical or psychological causes. However, as my topic is the treatment of nausea or vomiting as a side effect of an opioid, all I will say about alternative causes is that, as always, the doctor will need to make a diagnosis of the cause.
Nausea or vomiting within five minutes of a dose of morphine mixture is sometimes due to irritation of the stomach by additives such as alcohol, chloroform water or other preservatives. In this case, morphine mixture containing only morphine hydrochloride and purified water should be used. (This will usually keep for about a month at room temperature, and three or more months if refrigerated.)
However, opioids themselves can cause nausea and vomiting in a number of ways. Most often, they do so by stimulating a part of the brain called the "chemoreceptor trigger zone" (CTZ), which in turn stimulates the adjacent "true vomiting centre" (TVC). Sometimes, they stimulate the latter centre directly.
They can also affect the vestibule of the inner ear (thus imitating motion sickness) or slow down the emptying of the stomach, or the movement of food through the small intestine. Finally, as discussed below, they have a powerful constipating effect on the large intestine. All of these effects can sometimes either cause, or worsen, nausea or vomiting.
Having determined that a patient's nausea and/or vomiting is partly or wholly due to opioid medication, an antiemetic which suppresses the CTZ is usually the first thing the doctor tries, and this is quite often all that is needed. A small regular dose of haloperidol is often used for this purpose. Alternatives include metoclopramide and domperidone, which have a "prokinetic" effect as well as suppressing the CTZ.
Sometimes, one of the above medications is started at the same time as the opioid, so that nausea or vomiting will be less likely to occur in the first place. This has the advantage of preventing an unpleasant symptom, but also the disadvantage of using a drug which may not be needed at all. In either case, the antiemetic can often be stopped quite soon, as opioid nausea quite often resolves spontaneously after some days.
When suppressing the CTZ is not effective (and especially when the opioid is not the only factor causing the symptom) a wide range of other medications may be prescribed to relieve the various causes of nausea and/or vomiting mentioned above.
Examples include antihistamines, such as promethazine or cyclizine, antiserotonin drugs (5-HT3 antagonists), such as ondansetron or tropisetron, anticholinergics, such as hyoscine or atropine, benzodiazepines, such as diazepam or oxazepam, and corticosteroids, such as dexamethasone or prednisone. The prokinetic effects of medications such as metoclopramide and domperidone, as mentioned above, may also be helpful in some cases, though counterproductive, or even dangerous, in others.
In refractory cases, the atypical neuroleptic drug olanzapine and the antidepressant medication mirtazapine have both been reported to help some patients. In addition, in some jurisdictions, the cannabinoid tetrahydrocannabinol, which is the main active ingredient of marijuana, may be used for refractory nausea or vomiting, as well as for neuropathic pain.
There are various definitions of constipation, but its main features are infrequent and/or uncomfortable bowel motions, with a firm or hard stool consistency. There may also be a feeling of fullness in the lower bowel, or a sense of incomplete evacuation after moving the bowels. (In the case of faecal impaction, which is discussed below, some or all of these features are replaced by loose or liquid bowel motions, which have leaked past the impacted stool, often adding insult to injury by causing faecal incontinence.)
If preventive measures are neglected, constipation is almost invariable when an opioid is given regularly, regardless of the particular opioid used or the route of administration (although the latter factors can certainly influence its severity). However, opioid constipation can always be prevented by starting laxatives early and monitoring bowel function closely.
There are many, many causes of constipation apart from opioid analgesia, but only the latter cause is my current topic. It is also very important to distinguish between constipation and bowel obstruction, but that is not my topic either. I will therefore restrict myself to a reminder that, if constipation is not responding to the treatment prescribed, the doctor must always be informed, so that other possible causes can be considered.
In the general population, the likelihood of constipation is greatly reduced by a diet high in fibre and not deficient in fat, a high fluid intake, and regular vigorous exercise. While these general principles should not be forgotten, some of them will not be practicable for some patients, and they are rarely sufficient to prevent or treat opioid constipation completely.
Incidentally, although the frequency and size of bowel motions is reduced somewhat in patients who are eating very little, low intake cannot be considered to be the cause of significant constipation, as food residues account for only a small proportion of the total stool volume. The rest is largely made up of dead epithelial cells shed by the mucosal lining layer of the intestine, dead and living bacteria, and water.
Principles of laxative therapy
Although a method of preventing opioid constipation by directly inhibiting its cause is currently being evaluated (see later), laxative therapy is still the mainstay for most patients at the time of writing. To prevent opioid constipation, laxative therapy should always be started on the same day as the opioid analgesia. It must then be titrated against bowel function, just as the opioid dosage itself is titrated against pain.
Laxatives can be broadly classified as stool softeners, intestinal lubricants, peristaltic stimulants, osmotic laxatives and bulking agents. (These terms are explained below.) However, many laxatives work in more than one of these ways. The best results are usually obtained by combining laxatives with different modes of action. Importantly, some types of laxative are unsuitable for some patients, as will be discussed.
At the time of writing, the only common laxative which is usually classified as a stool softener (though sometimes as a lubricant) is dioctyl sodium sulfosuccinate (sometimes spelt sulphosuccinate). This laxative is often referred to by the simpler name docusate sodium, and was originally marketed in many countries under the brand name Coloxyl.
The commonest intestinal lubricant is liquid paraffin, which also softens stools and possibly promotes peristalsis to some extent. While liquid paraffin can be very helpful in some cases, it is very dangerous if it gets into the lungs, so it is never recommended for patients who have swallowing problems.
Peristaltic stimulants, as their name suggests, act by stimulating peristalsis. If used to excess, they can therefore cause intestinal colic. They must not be used at all if there is a mechanical bowel obstruction or a weakened or inflamed area in the bowel, because powerful contractions might then cause a perforation. Common peristaltic stimulants include senna, bisacodyl and glycerol (also called glycerin or glycerine).
Osmotic laxatives, as their name implies, hold water in the bowel by osmosis. This both softens the stool and increases its bulk, thus also tending to stimulate peristalsis. If given in a solution which has the same osmotic pressure as human blood, an osmotic laxative will not draw any more water from the bloodstream into the bowel, and it is then referred to as an "iso-osmotic" laxative. However, as the amount of water involved is much less than the normal daily water requirement, this is usually a relatively minor advantage.
In the past, mineral salts such as sodium phosphate and magnesium sulphate have been used to create the osmotic effect, but their use can easily give rise to electrolyte imbalances. At the time of writing, the most suitable osmotic laxative for prevention or treatment of opioid constipation (among other uses) appears to be macrogol (polyethylene glycol) 3350. A somewhat less effective alternative is lactulose. One popular macrogol 3350 based laxative is Movicol, which also contains some sodium and potassium salts. When dissolved according to the manufacturer's directions, it is iso-osmotic, and it is also claimed to cause no net gain or loss of sodium or potassium.
Bulking agents may consist of soluble or insoluble plant fibre, or sometimes synthetic compounds with similar properties. Dietary fibre has quite complex effects on bowel function. Whether soluble or insoluble, the fibre naturally adds its own bulk to the stool. Insoluble fibre (also called roughage) also stimulates peristalsis. Soluble fibre also absorbs water, thus increasing its bulk further, forming a soft gelatinous substance.
Many dietary fibres are also excellent food for bacteria, which actually make up the largest single component of stool bulk in many cases. In addition, the soluble substances produced by the fermentation of undigested fibre in the colon attract water by osmosis, and the increase in bulk itself tends to stimulate peristalsis. Bulking agents are therefore very good examples of laxatives which act in more than one way.
Importantly, because bulking agents absorb water, leading to transfer of water from the bloodstream to the bowel if insufficient water is present in the bowel, they should only be used if the fluid intake is fairly good. Otherwise, they may not provide a laxative effect, but may instead worsen dehydration, and could cause a faecal impaction (which is discussed below).
Laxative therapy in practice
A simple practical approach to the prevention of opioid constipation, which is recommended by many doctors, is to start taking a small dose of dioctyl sodium sulfosuccinate, often combined with a peristaltic stimulant such as senna, when regular opioid analgesia is first introduced. The dosage is then increased as necessary, and one or more other laxative agents are added if needed. In order to know when it is necessary to increase the dose or add another laxative, the frequency and consistency of the patient's bowel motions must be monitored.
Whether the patient is at home or in hospital, the best way to monitor bowel motions is to maintain a "bowel chart" on which the date, approximate size and consistency of every bowel motion is recorded. This is hardly rocket science, but it is remarkable how often this basic essential of safe and effective opioid analgesia is carelessly completed, or even neglected altogether. The result of such neglect is almost always considerable unnecessary suffering for the patient.
A Possible Alternative
Although the laxatives mentioned above can always control opioid constipation if they are used properly, they do not directly prevent its cause. However, an opioid antagonist which prevented the effect of opioids on bowel motility, without significantly interfering with their analgesic effect, would attack the problem at its source. At the time of writing, two opioid antagonists are being evaluated for this purpose.
The more promising of the two is a peripherally acting opioid antagonist called methylnaltrexone. This drug is poorly absorbed when taken by mouth, so most of it remains in the intestine. If it is given by injection, it does not cross the "blood-brain barrier". This is very important, because even a small amount of methylnaltrexone could interfere with the vitally important analgesic effects of opioids on the central nervous system if it were able to gain access to the brain and spinal cord.
Methylnaltrexone can be given orally or by injection for the treatment of opioid constipation when the response to laxatives is insufficient, and it appears to be very well tolerated. Its exact place in the management of opioid constipation is still being evaluated at the time of writing, but there seems little doubt that it can be very useful in some situations, and it is likely that its use will increase considerably over the next few years.
The less promising of the two is a peripherally and centrally acting opioid antagonist called naloxone. Naloxone reverses opioid effects in the brain as well as elsewhere, because, unlike methylnaltrexone, it does cross the "blood-brain barrier". An injection of naloxone can therefore be used to treat opioid overdoses, and it is very effective for that purpose.
However, naloxone is poorly absorbed when taken by mouth, and at low dosage the inhibitory effect of oral naloxone on opioid constipation can be much greater than its inhibitory effect on opioid analgesia. A tablet containing naloxone and an opioid in a fixed ratio is available in some countries, but for best results the two drugs should really be given separately, so that their dosage can be adjusted independently.
Unfortunately, even oral naloxone can precipitate severe opioid withdrawal in some circumstances, and that is not only painful but potentially life threatening. At the time of writing, it therefore seems likely that methylnaltrexone will prove far more useful than naloxone as a direct inhibitor of opioid constipation.
If constipation develops in spite of the precautions taken to prevent it (or because they were neglected) it may be possible to treat it with the same laxatives which can be used for its prevention. However, if there is associated rectal discomfort, or if there has been no bowel motion for three or more days, a gentle rectal examination should be performed by the doctor or nurse, in case a large stool is obstructing the rectum.
If the rectum is packed with stool, one or more evacuant suppositories or "microenemas" may help, especially if combined with an osmotic or lubricant laxative. If this approach is not effective, either a potable tap water enema or a disposable phosphate enema can be administered. (The latter must only be given by a very experienced person, as the phosphate solution can cause fatal rectal necrosis if the nozzle penetrates the lining of the anal canal or rectum.)
Giving a water enema suitable for the treatment of rectal impaction involves gradually instilling 250 to 500 millilitres of tap water into the rectum via a flexible enema tube. The enema should then be retained for some time if possible, to allow it to soften the stool. The procedure may need to be repeated one or more times before the problem is resolved.
In some cases, "manual removal" of stool from the rectum may be necessary. Using plenty of a lubricant, such as K-Y jelly or Vaseline, a well gloved index finger can be used to indent the stool and, with the finger slightly hooked, draw it out a little at a time. This will be more comfortable for the patient if extra analgesia is provided in advance of the procedure. Of course, it will be even more comfortable if it never becomes necessary.
Sometimes a faecal impaction in the rectum is suspected, but examination shows the rectum to be empty. This does not necessarily exclude impaction, as the retained stool may be higher up in the colon. In some cases, a high impaction can be felt through the abdominal wall, feeling rather like a large sausage, which can be indented by gentle sustained pressure from the examining fingers. A plain X-ray of the abdomen may also demonstrate the presence of a faecal impaction.
A high faecal impaction sometimes responds to laxative therapy, especially if osmotic and/or lubricant laxatives are used, but more often it needs to be treated by giving a very slow enema of two litres of potable tap water. (Such a large enema can only be given very slowly, otherwise it will be returned as quickly as it is given.) This procedure is usually carried out in a hospital, hospice or emergency room, but there is no reason that it could not be done by a nurse in the patient's home.
The best way to give a large enema is via an intravenous infusion set, or something similar, attached to a soft catheter which is inserted rectally so that its tip lies near the junction between the rectum and the sigmoid colon. The rate of infusion is then adjusted so that about two litres of water will be very gradually administered over two or more hours. In some cases, this may need to be repeated on one or more successive days.
Drowsiness and Confusion
Some degree of drowsiness should be expected during the first three or four days of regular opioid analgesia, and it is important for the patient and relatives to know this in advance. Drowsiness may also recur at times of significant increase in dosage, but in most cases it is only a temporary inconvenience.
Occasionally, stimulants such as methylphenidate appear to be helpful if opioid drowsiness is severe and persistent, though side effects (including confusion and other abnormal mental states) are quite common, and these could easily be mistaken for complications of the underlying cancer or side effects of other medications currently being used.
A newer stimulant, modafinil, has been suggested as an alternative to methylphenidate for the relief of opioid drowsiness, but its effectiveness for this purpose is still being evaluated. The use of stimulants to counteract fatigue or memory impairment, when these occur in association with opioid analgesia, has also been suggested, but at the time of writing their value in these roles has not been confirmed.
In a small proportion of cases, opioid drowsiness progresses to a confusional state. This is more common in elderly patients. Mild or moderate confusion may improve spontaneously over a day or so, just as drowsiness often does. Otherwise, strategies such as a change of opioid, optimisation of co-analgesic medication, review of other medications or conditions which may be contributing to the problem, or increased reliance on other methods of pain management, may become necessary.
Of course, confusion (which is sometimes called delirium or acute brain syndrome) is yet another condition which may occur as a feature or a complication of almost any illness, or as a side effect of many medications. Therefore, as always, it cannot be assumed to be due to the opioid medication. Careful assessment by the doctor, usually followed by various investigations to aid in making a diagnosis, is an essential first step whenever any patient becomes confused.
All analgesic regimens need frequent reassessment by the doctors and nurses caring for the patient. Doses must be "titrated" upwards or downwards according to the patient's response. Residual pain, breakthrough pain, side effects of medications, and co-existing symptoms must be specifically enquired about. The suitability of any opioid in use, and the need for adjuvant medication(s) to improve the overall results, must be considered and reconsidered at frequent intervals.
Declaration of Interest
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Footnotes: (Click the number of a footnote to return to its reference in the text)
 Dose titration means gradually increasing (or, if necessary, decreasing) the dose until the desired effect is obtained.
 Mercadante S. Opioid rotation for cancer pain: rationale and clinical aspects. Cancer. 1999 Nov 1;86(9):1856-66.
 P.r.n. is an abbreviation often used on prescriptions and medication charts. It stands for pro re nata, a Latin phrase which translates literally as "for an occasion that has arisen", but is used by doctors to mean "if needed". However, in the case of cancer pain, it usually stands for "pain relief never"!
 Tempest SM, Clarke IMC. The control of pain. I. By drugs; II. By non-drug methods. In: Wilkes E, ed. The dying patient. Lancaster: MTP Press Limited, 1982.
 Twycross RG. Relief of pain. In: Saunders C, ed. The management of terminal disease. London: Edward Arnold, 1978: 65-92.
 Twycross RG. Clinical experience with diamorphine in advanced malignant disease. Int J Clin Pharmacol 1974; 9: 184.
 Twycross RG, Wald SJ. The long-term use of diamorphine in advanced cancer. In: Bonica JJ, Albe-Faescard D, eds. Advances in pain research and therapy. Vol. 1. New York: Raven Press, 1976: 653.
 As mentioned earlier, dose titration means gradually increasing (or, if necessary, decreasing) the dose until the desired effect is obtained.
 Twycross RG. Relief of pain. In: Saunders C, ed. The management of terminal disease. London: Edward Arnold, 1978: 65-92.
 Haloperidol is a major tranquilliser, and can cause a number of side effects, but it is usually well tolerated at low dosage. It also has a useful co-analgesic effect, often allowing the opioid dosage to be reduced.
 Prokinetics are drugs which promote the wavelike contractions called peristalsis, which move the contents of the gastro-intestinal tract onwards. Importantly, these drugs must be avoided in the presence of gastric outlet obstruction by tumour, when they can cause very severe vomiting. They must also be avoided if there is a bowel obstruction, when they can cause severe colic and also increase the risk of intestinal perforation.
 Peristalsis is the process of co-ordinated muscular contractions which effectively squeezes the contents of the intestine towards its lower end.
 Osmosis is the tendency for a solvent such as water to move through a semi-permeable membrane towards the side which has the more concentrated solution, thus gradually equalising the concentrations.
 An electrolyte can be any solution that conducts electricity, but in the physiological context it refers to the various salts of sodium, potassium, calcium, magnesium, zinc etc which are present in solution in body fluids.
 Lactulose, a synthetic sugar, is sometimes referred to as soluble fibre. As discussed, soluble fibre has a variety of laxative effects, including osmosis. However, the laxative effect of lactulose is almost entirely osmotic.
 Examples are glycerol, Durolax and Coloxyl suppositories.
 An example is the 5ml Microlax enema.
 Trade (brand) names for methylphenidate include Concerta, Metadate, Methylin and Ritalin.
 Trade (brand) names for modafinil include Alertec, Modafinilo, Modalert, Modavigil, Modiodal and Provigil.
Articles in the Cancer Pain Series
4. Optimal Use of Opioid Analgesics (this page)
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Figure 1: A morphine titration chart
Chart reproduced from Coates, G.T. 1987. The FIVD Regimen [fixed interval, variable dose morphine] 1987 Edition. Published by author.
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