Medications used to Relieve Cancer Pain

by Dr Gordon Coates

Series Context

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.)

Disclaimers

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.

Cautions

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.

Introduction

The optimal use of medications is almost always pivotal in the effective control of cancer pain, and the basic principles governing their use can and should be understood by all cancer patients and all those who care about their welfare. I will therefore say a great deal more about this method of pain management than I said about the other methods (which were discussed in the previous article, available via the series links near the bottom of this page).

In this article, I will discuss the main medications which are used, and then I will provide more detail about the optimal use of opioid analgesics in the next article. I will mention many medications, and say quite a bit about how they can best be used. Do not be deterred by their strange, and sometimes lengthy, names. Everything needs a name, just as everybody needs a name. The names of some medications may seem very weird at first, but they are just names, and you will soon get used to them.

The WHO Analgesic Ladder

A simple introduction to the effective use of medications for the relief of cancer pain is provided by the so-called "analgesic ladder"[12] recommended by the World Health Organisation (WHO). Here are the "steps" on the WHO analgesic ladder:

Step 1

• Non-opioid analgesia (e.g. paracetamol, aspirin etc)
• Plus adjuvant[13] medication(s) if necessary

Step 2

• A mild opioid (such as codeine)
• Plus non-opioid analgesia if necessary
• Plus adjuvant medication(s) if necessary

Step 3

• A strong opioid (such as morphine)
• Plus non-opioid analgesia if necessary
• Plus adjuvant medication(s) if necessary

On the WHO website, the following explanation accompanies the three-step "ladder" shown above:

'If pain occurs, there should be prompt oral administration of drugs in the following order: non-opioids (aspirin and paracetamol); then, as necessary, mild opioids (codeine); then strong opioids such as morphine, until the patient is free of pain. To calm fears and anxiety, additional drugs – “adjuvants” – should be used. To maintain freedom from pain, drugs should be given “by the clock”, that is every 3-6 hours, rather than “on demand”. This three-step approach of administering the right drug in the right dose at the right time is inexpensive and 80-90% effective. Surgical intervention on appropriate nerves may provide further pain relief if drugs are not wholly effective.'

Despite its brevity, that summary provides a very useful overview. I will flesh it out by describing the medications it refers to, and after that, I will discuss some very important aspects of the correct use of opioid analgesics. Even though it is the doctor who prescribes the medications, it can be very helpful if the patient and carers understand the principles involved well enough to facilitate discussion, and to request referral if pain is not well controlled.

The various medications which can be used to relieve pain fall into three main groups:

• Simple (non-opioid) analgesics
• Opioid analgesics (sometimes called narcotic analgesics)
• Co-analgesics (also called analgesic adjuvants)

Although the second group contains more powerful analgesics than the first group, and the members of the third group are not primarily analgesics at all, any of the three groups may be the most important in a particular case, depending on the cause of the pain. In quite a few cases, one or more drugs from each group must be used simultaneously for best results. I will now discuss each of these three main groups of medications in some detail, before going on to discuss some very important aspects of the use of opioid analgesics in the management of cancer pain.

Simple analgesics

Simple analgesics often play an important role in the management of cancer pain, regardless of the severity or complexity of the pain in question. They are particularly useful for pain of "connective tissue" origin. Two important examples of connective tissue are bone, and the outer (capsular) layer of any organ in the abdomen or chest. When simple analgesics do not relieve cancer pain, it is very often best to add an opioid analgesic, rather than stopping the simple analgesic when the opioid analgesic is commenced.

Most simple analgesics are quite well known to many people because they are used to relieve common pains such as headache, backache, or sore throat. Many of them can be purchased without prescription in most countries. However, they should not be thought of as weak or insignificant, as they play a very valuable role in many cases of cancer pain. Sometimes, they are the only analgesics needed, but in most cases they need to be used in combination with an opioid, or sometimes with an opioid plus one or more adjuvant drugs.

All simple analgesics exert their effect by interfering with the synthesis of substances called prostaglandins, which are chemical "messengers" that are involved in many physiological processes, including pain, fever, blood coagulation and inflammation. To distinguish them from another group of drugs (glucocorticosteroids) which also reduce inflammation, they are called non-steroidal anti-inflammatory drugs (NSAIDs). However, NSAIDs are not all identical in their actions, and the differences are sometimes important, as discussed below.

Paracetamol (acetaminophen)

Paracetamol (acetaminophen)[14] differs considerably from other NSAIDs in that its antiprostaglandin effect is almost entirely limited to the central nervous system. For this reason, although it reduces pain and fever, it has very little effect on blood coagulation or inflammation. For practical purposes, it is therefore an "NSAID" in name only, and in fact it is not very often called one at all, except by pharmacologists.

The great advantage of paracetamol (acetaminophen) is that, because its peripheral effects are so slight, it almost never causes gastric or duodenal ulcers, or a generalised bleeding tendency – things which all other NSAIDs sometimes do. Indeed, although adverse reactions to paracetamol (at correct dosage) can occur, they are extremely uncommon.

Another advantage of paracetamol (acetaminophen) is that it can be given in combination with another NSAID, often resulting in significantly better analgesia without adding any appreciable side effects. This is most likely to be effective when the other NSAID is needed to reduce local inflammation.

It is usually recommended that not more than four grams of paracetamol (acetaminophen) be given to an adult patient in any twenty-four hour period. This is sometimes increased to six grams per twenty-four hours in the management of cancer pain in adults with good liver function (which should then be monitored). On the other hand, when liver function is very poor, which is quite often the case in patients with advanced cancer, paracetamol dosage may need to be reduced to less than two grams per twenty-four hours, or even avoided altogether.

Aspirin (acetylsalicylic acid)

Aspirin (acetylsalicylic acid)[15] has been used for a very long time, both as an analgesic and as an anti-inflammatory drug. It differs from other NSAIDs in the opposite direction to paracetamol, by interfering much more strongly with blood coagulation than most NSAIDs do, while sharing their tendency to cause gastric or duodenal ulceration.

Depending on the individual patient, reducing the tendency of the blood to coagulate can be an advantage or a disadvantage. However, in patients with advanced cancer, it is more often a disadvantage, and for this reason aspirin is not used as much in cancer pain management as other simple analgesics are.

Other NSAIDs

Other NSAIDs, such as naproxen[16] and many others[17], are the third type of simple analgesic. They also have some inhibitory effect on blood coagulation, but not usually enough to cause significant problems. Their main advantage is that they can directly reduce inflammation in peripheral tissues, as well as having an analgesic effect within the central nervous system.

A major disadvantage of these other NSAIDs is that, like aspirin, they quite often cause gastric or duodenal ulceration. Although this can often be prevented, by adding one or more medications to protect the mucosal lining of the stomach and duodenum, it considerably reduces their overall value, and indeed makes them completely unsuitable for some patients.

These other NSAIDs also have various other side effects, especially when used in combination with common treatments for high blood pressure, so they must be used with care. As some of them are available without prescription in many countries, it is very important to tell your doctor if you are taking one of them. (Of course, this also applies to all other medications, including "natural", "complementary" or "alternative" remedies, as harmful interactions are common.)

Opioid Analgesics

Opioid analgesics are named after the opium poppy, from which the oldest (and in most ways still the best) example, morphine, is extracted. They relieve pain mainly by interfering with its transmission and perception in the central nervous system (spinal cord and brain). They also have a variety of other effects, some of which affect other parts of the body. They are particularly useful for pain arising from organs in the abdomen or chest, or from skeletal muscle tissue, but may also be needed as part of the treatment of severe pain of any origin.

Opioid analgesics are often classified as either weak or strong, according to the degree of analgesia they can provide without causing excessive side effects. This is a fairly loose classification, and in some cases the same opioid might be considered weak or strong depending on the route by which it is administered. When an opioid is needed in an analgesic regimen, it is common practice to start with a weak opioid, and then replace it with a strong opioid if and when necessary. However, this two step approach is entirely optional.

The main reason that starting with a weak opioid is common practice is the reluctance of both patients and their doctors to accept the need for a strong opioid – even if the low dosage employed means that its effect is actually quite weak. The reason that it is entirely optional is simply that a smaller dose of a strong opioid can provide exactly the same effect as a larger dose of a weak opioid. In fact, it usually does this with fewer unwanted side effects or undesirable interactions with other medications, thus giving a better end result.

Weak Opioids

Weak opioids include codeine, dihydrocodeine, pentazocine, dextropropoxyphene, butorphanol, nalbuphine and tramadol. (The last one mentioned, tramadol, is not a typical opioid at all, as it has many other actions in addition to its weak opioid effect. As discussed below, it should never be used for its weak opioid effect alone. However, because of its other effects, it can be a useful drug in some circumstances.)

Codeine and Dihydrocodeine

Codeine[18] is found naturally, along with morphine and many other alkaloids[19], in the crude opium harvested from the opium poppy, and it can also be easily and cheaply synthesised. It has a weak opioid analgesic effect on most people.

Dihydrocodeine, as its name suggests, is very similar in chemical structure to codeine. Its actions are also similar. However, both the metabolism and mechanism of action of codeine and dihydrocodeine are very incompletely understood.

These two weak opioids both undergo metabolism in the liver, and some of their metabolic products also have opioid analgesic actions. Especially in the case of codeine, one of these metabolites is morphine. It is probable that the morphine produced by metabolism provides a considerable proportion of the analgesic effect of codeine.

Variations in the ability of different people to perform this metabolic transformation may account for the fact that codeine has an unexpectedly strong effect (including side effects) on some people, but produces only its usual side effects, with almost no analgesic effect, in some other people. Further research is needed to clarify this matter, and also to determine whether dihydrocodeine behaves in the same way.

The main reason that these drugs continue to be used at all is that, because they were introduced into clinical practice before regulatory mechanisms were well established, there is less "red tape" associated with their prescribing than with that of the strong opioids discussed later. Nevertheless, they are both capable of providing useful, though not very powerful, analgesic effects in a reasonable proportion of patients.

Tramadol

Tramadol[20] has quite a number of actions, and its pharmacology is very complex. As a weak opioid with many side effects, it is completely unsuitable for the management of nociceptive pain. Indeed, it has a particularly poor side effect profile (including induction of seizures at therapeutic dosage) and can cause many serious drug interactions (including the potentially fatal serotonin syndrome[21]).

Because escalation of its dosage is limited by severe toxicity, tramadol has a low addiction potential, and is therefore subject to fewer prescribing restrictions, in most jurisdictions, than are strong opioids. This fact, combined with very skilful marketing, often results in it being prescribed inappropriately for nociceptive pain, sometimes with disastrous results.

However, tramadol also has a variety of non-opioid actions, some of which can be of value for some patients with neuropathic pain. Therefore, although considerable expertise is needed to use it safely, it is a useful drug in some situations.

Other weak opioids

Most of the other weak opioids named above may very occasionally be helpful to a particular patient, but the combination of their weak analgesic effect and their numerous side effects usually severely limits (or in some cases completely precludes) their practical usefulness. Even codeine and dihydrocodeine, which are often thought of as being pretty harmless, usually cause significantly more unwanted side effects than an equivalent dose of morphine.

Strong Opioids

There are many opioids which possess a strong analgesic effect. The main examples used in the management of cancer pain are morphine, oxycodone, hydromorphone and fentanyl. Methadone and buprenorphine can also be useful in a few unusual circumstances, but are not suitable for most patients.

Dextromoramide, pethidine and diacetylmorphine (heroin) have been used in the past, and occasionally still are, but they possess no useful advantages over the previously mentioned drugs. Dextromoramide and pethidine also have very significant disadvantages, as discussed below, and diacetylmorphine is no longer available in most countries.

Morphine

Morphine[22] is a purified extract of the sap released when shallow cuts are made in the unripe seedpods of the common poppy Papaver somniferum (the same poppy which yields the poppy seeds used in various foods). Morphine has been commercially available for nearly two hundred years, and despite all the advances of modern pharmacology, it is still the most useful of all the available opioids.

The main reason that alternative opioids are sometimes needed is that not all patients can tolerate morphine. This might occur because of renal failure[23], hepatic failure[24], increased susceptibility to morphine side effects or allergy to morphine. Another reason, at the time of writing, is that morphine cannot be administered via an adhesive patch applied to the skin.[25]

Preparations of morphine for oral administration which have not been modified to produce extended (sustained) release are sometimes referred to as "immediate release" (IR) morphine; or, in the case of morphine sulphate, as "morphine sulphate immediate release" (MSIR). As discussed later, IR morphine is essential in some circumstances, but the longer acting formulations are more convenient in other circumstances.

Extended (sustained) release oral formulations sometimes include the syllable "dur" or "cont" in their trade names, or else use the suffix ER or SR to denote extended release or sustained release. However, most morphine trade names do not specify whether the morphine preparation has been formulated for immediate or sustained release, so this information has to be found elsewhere on the label, or in the Product Information.

As discussed later, the difference is extremely important, as immediate release and sustained release formulations of morphine (or any other medication) behave differently and can therefore not be directly substituted for each other. When changing from one to the other, the prescribing doctor has to change the size of each dose, and also the interval between doses, in order to achieve a safe and effective result.

Immediate release oral morphine is often provided in liquid form, which increases the flexibility of dosage, but also reduces accuracy somewhat, especially if the doses are measured with a spoon or medicine glass rather than a syringe. The use of liquid oral dose forms, such as "morphine mixture", makes it easier to adjust the dosage frequently until the correct dosage for "baseline analgesia"[26] has been established by "dose titration"[27]. After that, extended (sustained) release preparations are usually more convenient. This will all be discussed further in the next article, "Optimal Use of Opioid Analgesics".

It is very important to remember that liquid oral morphine preparations are available in many different concentrations. This means that the actual dose of morphine depends on the concentration, as well as the volume, of liquid administered. For this reason, doses of morphine mixture given in hospitals are usually prescribed (and recorded) in milligrams, rather than millilitres, even though the dose itself then has to be calculated, and measured, in millilitres. For the same reason, patients living at home who are prescribed morphine mixture must make sure they understand exactly how to measure their doses.

Similarly, sustained release oral morphine is available in tablets and capsules of many different strengths. This means that the actual dose of morphine depends on the amount of morphine in each tablet or capsule as well as the number of tablets or capsules taken. This has the potential to cause confusion when the strength of tablets or capsules is changed, so patients and their carers must make absolutely sure that the new instructions are clearly understood.

As mentioned above, extended (sustained) release oral formulations of morphine (or in some cases oxycodone or hydromorphone, as discussed later) usually provide the most convenient way of maintaining baseline analgesia in patients who are able to swallow their medication, once the correct dosage for this purpose has been established. Even if tablets or capsules are too difficult to swallow, preparations which consist of small granules encased in a capsule, such as Kapanol, can still be taken by sprinkling the contents of the capsule over some soft or pureed food.

Some sustained release morphine tablets can also be inserted rectally[28], though this would constitute "off-label use"[29] in most jurisdictions. However, if morphine is to be used rectally, the doctor first needs to adjust the dosage[30]. An approximate starting dose might be somewhere between half and two thirds of the oral dose, but the dosage then usually needs to be adjusted further according to the patient's response.

Morphine is, of course, also available in ampoules for administration by injection or infusion. The ampoules usually contain morphine sulphate, but morphine tartrate, which is more soluble in water and therefore allows a larger dose to be given in the same volume of fluid, is sometimes convenient.

A subcutaneous injection of morphine is often used for rapid control of new pain, breakthrough pain or incident pain[31], as it reaches the bloodstream more quickly than morphine taken by mouth. (Intravenous injections work even more quickly, but they are also more likely to cause side effects, and may possibly result in excessive tolerance if given frequently.)

A continuous morphine infusion can be used to provide baseline analgesia when other methods of administration are not suitable. Continuous subcutaneous infusion is the most convenient, safe and well tolerated type of continuous infusion, but continuous intravenous infusion is preferred in some circumstances. (Sometimes, as discussed in Appendix 3, morphine is infused "epidurally" or "intrathecally", so that it affects the spinal cord directly. Very rarely, it is infused into a "cerebral ventricle", so that it affects the brain directly.)

Fentanyl

Fentanyl[32] is a strong synthetic opioid which was first synthesised in 1959. It has high potency[33], a rapid onset of action and a short duration of action. It was originally used intravenously in anaesthesia, where it still plays an important role. However, it is poorly and inconsistently absorbed when swallowed, so tablets, capsules and mixtures are not available.

Despite this disadvantage, other dose forms of fentanyl, developed over the last fifteen years, have made fentanyl very useful for some patients, both for baseline analgesia and for the relief of new, incident or breakthrough pain. Because its side effect profile is different to that of morphine, it can often be used successfully in patients who are intolerant of morphine.

One important advantage of fentanyl (in common with its less well known analogues, such as alfentanil, sufentanil and remifentanil) is that it causes less sedation, confusion and constipation than most other opioids. Another is that it can be used in the presence of renal or hepatic failure, as discussed in Appendix 1 and Appendix 2 respectively. However, morphine is still the most useful opioid for the majority of patients.

Short term fentanyl analgesia, which is useful for new pain, breakthrough pain or incident pain, can be given by injection, or alternatively by "transmucosal" absorption across the epithelial lining of the mouth. Available formulations of fentanyl for transmucosal delivery include lozenges (sometimes referred to as fentanyl lollipops), effervescent tablets, discs of buccal soluble film and buccal sprays. Various other short acting dose forms of fentanyl, including buccal tablets, buccal patches, nasal sprays and pulmonary inhalers, are also being evaluated.

Baseline fentanyl analgesia for the management of chronic pain can be provided by continuous subcutaneous infusion (or occasionally intravenous or epidural infusion) but transdermal absorption of fentanyl from an adhesive patch applied to the skin is usually the most convenient method for this purpose.

Fentanyl transdermal patches[34] work by gradually releasing fentanyl through the skin into the subcutaneous fat, and thence into the bloodstream, over about 72 hours, after which the patch is replaced with a new one. Patches of different sizes result in different blood levels, these remaining fairly stable after rising gradually for about 24 hours after applying the first patch and rising a little further with the second patch.

The rate of absorption of fentanyl from currently available fentanyl patches is dependent on a number of factors, including body temperature, skin type, amount of body fat, the anatomical site of placement of the patch and the brand of patch used. This means that estimation of the necessary initial dosage, when a doctor first prescribes fentanyl patches for a patient, is even more approximate than it is with most other methods of analgesia.[35]

An inevitable delay in the onset of analgesia, until the level of fentanyl in the bloodstream has stabilised after the application of the first two patches, is another factor which the doctor needs to take into account. However, as long as the patient is closely observed for signs of undertreatment or overdosage, excellent results can be achieved with fentanyl patches.

When switching to fentanyl patches from another opioid, or even from another route of fentanyl administration, the doctor's estimate of the equivalent dosage is also very approximate, due to variability in dosage equivalence in different patients.

When switching in the opposite direction, continuing release of fentanyl into the bloodstream after removal of the last patch (from a reservoir of fentanyl which always collects in the subcutaneous fat while a patch is on) is yet another factor which the doctor must consider. Therefore, whenever fentanyl patches are started or stopped, very frequent review of the patient by the medical and nursing staff members is absolutely essential until stable analgesia is achieved.

In practice, although morphine is still generally considered to be the best opioid analgesic to try first, for most cancer patients in most situations, the various available dose forms of fentanyl can often provide a better overall result for the following types of patients:

• patients who cannot swallow
• patients who are intolerant of other opioids
• patients with moderate or severe renal failure
• patients with severe hepatic failure

Oxycodone

Oxycodone[36] is a semisynthetic opioid derived from thebaine[37]. Its chemical structure is very similar to that of codeine, but it lacks the main disadvantages of that drug, its effects being almost identical to those of morphine. It has been used for nearly a hundred years and is sometimes the strong opioid which is best tolerated by a particular patient. (It is probably slightly better tolerated than morphine in the presence of renal failure, but it is rarely the best opioid to use in that situation.)

Although oxycodone is in fact a strong opioid, it was previously considered to be of medium strength, simply because its usual routes of administration (oral and rectal) made it relatively unsuitable for use at high dosage, due to the inconveniently large number of tablets or suppositories which would be required.[38] In addition, because of its non-threatening name, which sounds more like codeine than morphine, it is frequently employed at low dosage in the guise of a "weak" opioid (a role it plays much better than the weak opioids discussed earlier).

Immediate release dose forms of oxycodone can provide reasonably smooth baseline analgesia when taken at intervals of four to six hours. As in the case of morphine, extended (sustained) release oral dose forms of oxycodone can allow conveniently increased dosing intervals to be employed once the correct daily dosage has been established by titration.

Some sustained release oxycodone tablets can also be administered rectally, again usually at somewhat decreased dosage, if the patient is unable to swallow them, though there is less reported experience of this "off-label use" than is the case with rectal administration of extended (sustained) release morphine tablets.

Importantly, all of the precautions mentioned earlier in relation to different formulations and strengths of morphine also apply to oxycodone, and to all the other medications discussed in this series of articles – as indeed they do to every medication in existence which is available in more than one formulation.

Hydromorphone

Hydromorphone[39], another chemically modified derivative of morphine, has also been used for nearly a hundred years, and is commercially available in most countries. It can be given orally, rectally or by injection or infusion, and it is occasionally the best alternative analgesic for patients who are unusually susceptible to the side effects of morphine. (Like oxycodone, it is probably somewhat better tolerated than morphine in the presence of renal failure. However, as discussed in Appendix 1, other opioids are usually preferable in that situation.)

Hydromorphone has a somewhat shorter duration of action than morphine, but reasonably smooth baseline analgesia can be achieved when immediate release dose forms are given each four hours. These dose forms can also be used for the treatment of new pain, incident pain and breakthrough pain.

Extended (sustained) release forms of oral hydromorphone with a 12 hour, or in at least one case a 24 hour, duration are available in some countries, and these can conveniently be used for baseline analgesia once the correct daily dosage has been established. I have not seen any reports of "off-label" rectal administration of sustained release hydromorphone tablets, but hydromorphone suppositories are available in some countries.

Methadone

Methadone[40] is a synthetic opioid with effects similar to those of morphine, but with a very long, and inconsistently variable, duration of action. In addition to strong opioid analgesia, methadone has other actions which are sometimes helpful in cases of neuropathic, inflammatory or ischaemic pain[41]. It also has the advantage of not causing toxic metabolites to accumulate in the presence of renal failure.

However, due to unpredictable changes in its duration of action when it is given regularly, safe and effective methadone analgesia requires considerable experience and expertise. Even in expert hands, it should usually be reserved for neuropathic, inflammatory or ischaemic pain, or only tried when other opioids have not been successful.

Buprenorphine

Buprenorphine[42] is a strong opioid, with a short duration of action, which has been available for injection since the 1980s. More recently, it has become available in the form of adhesive patches for transdermal drug delivery, as discussed above in relation to fentanyl. However, the patches available in most countries, at the time of writing, can only provide weak baseline opioid analgesia, due to the relatively low doses of buprenorphine which they deliver.

Weak opioid analgesia is, of course, appropriate for some patients. However, in the case of the currently available patches, the blood levels can take from three to seven days to reach steady state levels, so finding the right dose is an impracticably slow process. Therefore, the buprenorphine patches available at the time of writing are rarely, if ever, used in the management of cancer pain.

Another important disadvantage of buprenorphine, regardless of the route of administration, is that it is a "mixed agonist and antagonist" at opioid receptors (meaning that it can block opioid effects, as well as stimulate them). It therefore has the potential to precipitate sudden opioid withdrawal in patients who have been receiving another opioid analgesic. In addition to the pain, which then of course returns, opioid withdrawal can be dangerous, or occasionally even fatal.

The disadvantages described above mean that, at the time of writing, buprenorphine has very little place in the management of cancer pain. In patients who are not already receiving another opioid, it could be given by injection for new, breakthrough or incident pain, or by continuous infusion for baseline analgesia. However, doctors with experience in pain management rarely prescribe buprenorphine for cancer pain.

Dextromoramide

Dextromoramide[43] is a synthetic opioid which is structurally related to methadone, but has a very short duration of action. It is only available in a small (and decreasing) number of countries.[44] It has a rapid onset when given orally or sublingually, and as its effect lasts for little more than an hour, it can sometimes be useful for breakthrough or incident pain.

Even in those countries where it is available, variations in its absorption can be problematic, especially when switching between oral and sublingual dose forms. Importantly, it is quite impracticable for baseline analgesia, as it would need to be given approximately every single hour around the clock (day and night) to provide reasonably smooth blood levels. (Doctors sometimes forget this, and the results are uniformly disastrous.)

Pethidine (Meperidine)

Pethidine[45], which is known in some countries as meperidine (and also frequently referred to as demerol, after its best known trade name) was developed in 1932 as a potential anti-spasmodic agent, but was found to have analgesic, rather than antispasmodic, properties. It has a short duration of action, and a very poor side effect profile, and it therefore has virtually no place whatsoever in the management of cancer pain.

It certainly cannot be used to provide baseline analgesia for chronic pain, as it has toxic metabolites which accumulate even in the absence of renal impairment. If treatment was continued at a dosage and frequency sufficient to control moderate or severe pain, these metabolites would soon cause confusion, then delirium, convulsions and ultimately death.

However, some clinicians still use pethidine for the treatment of new pain, incident pain or breakthrough pain, and it is usually fairly well tolerated when used in that way. (It was once thought that pethidine was superior to morphine in the treatment of spasmodic pains, such as renal, biliary or intestinal colic, but that alleged advantage has since been disproved.)

Diacetylmorphine (Heroin)

Diacetylmorphine[46], also known as diamorphine (but more often referred to as heroin, after its original trade name) is simply the diacetyl derivative of morphine. It is slightly more potent than morphine, so the equivalent dosage is a little lower. It is also more soluble in water than morphine, so subcutaneous injections can be given in a smaller volume of fluid. However, its beneficial effects, side effects and interactions with other medications are identical to those of morphine.

Because it is no more effective as an analgesic than morphine, the fact that heroin is a prohibited substance in most countries has no deleterious effects whatsoever on the management of pain, whether due to cancer or any other cause. On the other hand, heroin purchased illegally would almost invariably have very deleterious effects, as it is always of unknown concentration, and often contains poisonous adulterants.

Co-analgesics (Adjuvants)

In the context of analgesia, the terms "co-analgesic" and "adjuvant" are very often used interchangeably, to refer to medications which are combined with an opioid to achieve a better result, as judged by the achievement of effective analgesia with minimal side effects. However, I have noticed that they sometimes seem to be used slightly differently, in that simple (non-opioid) analgesics are sometimes included under the umbrella of "co-analgesics", but are sometimes omitted under the umbrella of "adjuvants".

Co-analgesics are useful in most cases of cancer pain management, and are almost always essential when treating neuropathic pain, which was discussed in Myths and Facts about Cancer Pain, the first article in this series (available via the series links near the bottom of this page). Indeed, they are sometimes more important than an opioid for this type of pain. In future, it may become possible to treat neuropathic cancer pain entirely with non-opioid medication. However, at the time of writing, neuropathic pain occurring in patients with advanced cancer usually requires a strong opioid as well as one or more adjuvant medications.

Adjuvants used for Neuropathic Pain

As discussed previously, neuropathic pain is much more resistant to standard analgesic approaches than is the more common nociceptive pain. Understanding of the mechanisms responsible for neuropathic pain is increasing each year, and important developments (such as the introduction of the "gabapentinoids" mentioned below) occur from time to time.

At the time of writing, it is often necessary for the doctor to try a number of different agents before the best treatment for a particular patient is discovered. Under the next few subheadings, I will say a little about various medications which are sometimes used in the management of neuropathic pain. As usual, the medications mentioned in this context are marketed under quite a number of different trade (brand) names, but here I will only refer to them by their approved (generic) names.

Anticonvulsants

The members of a new class of anticonvulsant drugs called gabapentinoids (such as pregabalin and gabapentin) are being used increasingly for neuropathic pain, with very good results in many cases. Other fairly new anticonvulsants, such as lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam and zonisamide, have also been used. Older anticonvulsants, such as sodium valproate, carbamazepine and clonazepam, still remain useful for some patients.

Antidepressants

Low doses of early tricyclic antidepressants such as amitriptyline and imipramine may be effective in reducing neuropathic pain. However, the "secondary amine tricyclic drugs", such as nortriptyline and desipramine, are better tolerated by some patients. Newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs) paroxetine and citalopram, or the serotonin-noradrenaline reuptake inhibitors (SNRIs) venlafaxine and duloxetine, may also be effective, and are often better tolerated than tricyclic antidepressants.

Opioids with extra actions

A number of opioids have extra pharmacological actions which can be useful in the management of neuropathic pain. Methadone and Tramadol are probably the most important examples. Both of these opioids are difficult to use safely, but either may be helpful in some situations. These two opioids are particularly dangerous if a SSRI or SNRI (see above) is also being taken, or was recently ceased. In my opinion, their use should always be supervised by a clinician with considerable experience and expertise in pain management.

Other Drugs

Although not specific to neuropathic pain, glucocorticosteroids and NSAIDs, which have been mentioned previously, may be very effective when compression or inflammation of nervous tissue is the mechanism causing the neuropathic pain. They are also sometimes tried when the mechanism is unclear. Major or minor tranquillisers may also be helpful in some cases, and agents such as lidocaine and capsaicin, applied to the skin over the region where pain is felt, also appear to help some patients.

Many other drugs have been tried for neuropathic pain, with variable success. Examples include mexiletine, tocainide, baclofen, clonidine, ziconotide and ketamine. (Some of these drugs are administered, either optionally or exclusively, by the "neuraxial" route, which is discussed briefly in Appendix 3.)

In some jurisdictions the cannabinoid tetrahydrocannabinol, which is the main active ingredient of marijuana, may legally be used for neuropathic pain, as well as for refractory nausea or vomiting, and this appears to be effective for some patients.

Adjuvants used for Bone Pain

Bone pain due to cancer is a very complex phenomenon. In addition to the expected nociception arising from local inflammation, tissue disruption, and interference with the local blood supply, damage to nerve fibres within trabeculated (spongy) bone can create a major neuropathic component. Consequently, the use of three or more medications is frequently necessary in order to control bone pain effectively.

Almost any of the analgesics and co-analgesics mentioned previously might be prescribed in some cases. In addition, interventions directed at the size and local effects of the tumour deposits might include any or all of radiotherapy, radioisotope therapy, chemotherapy, hormone therapy and immunotherapy. Various types of immobilisation, ranging from gentle nursing through to specific orthopaedic procedures for pathological fractures, are also very important in relieving bone pain.

Especially in the case of breast cancer, prostate cancer and multiple myeloma, all of which frequently cause bone pain, medications which interfere with the normal reabsorption of bone can relieve the pain and reduce the risk of pathological fractures. These medications are called "osteoclast inhibitors", and are also used in other conditions, especially osteoporosis.

Adjuvants used for Nociceptive Pain

If simple analgesics are included under the "adjuvant" umbrella, as they often are, then a simple analgesic is usually the first adjuvant to consider for nociceptive pain, and may sometimes be the only one required. Simple analgesics were discussed above, so I will not say any more about them now.

The antidepressant medications discussed in connection with neuropathic pain may also be useful as "opioid-sparing" agents when treating nociceptive pain, allowing a lower dose of opioid to be used than would otherwise be necessary. Other strategies usually reserved for the treatment of neuropathic pain may also be needed occasionally when standard treatments are either contraindicated for some reason or are incompletely effective.

Various major tranquillisers, such as haloperidol, and various minor tranquillisers, such as diazepam, can also be used as adjuvants when treating nociceptive pain. Their value is greater when anxiety is a significant factor in lowering the pain threshold, but their use is not limited to that situation.

Finally, some medications chosen for more specific effects might sometimes be thought of as "adjuvants", though their action is really "reducing a local tumour effect", as discussed earlier. Examples include the use of an antispasmodic to relax the "smooth muscle" spasm which causes intestinal or other colic, or a glucocorticosteroid such as dexamethasone to reduce raised intracranial pressure (which causes a severe headache).

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Footnotes: (Click the number of a footnote to return to its reference in the text)

[12] WHO online, "WHO's Pain Relief Ladder", © 2010. Accessed on 30 September 2010 at http://www.who.int/cancer/palliative/painladder/en/

[13] "Adjuvant" (or "co-analgesic") medications are discussed later.

[14] The trade (brand) names of paracetamol (acetaminophen) include Acamol, Apiretal, Benuron, Calpol, Dafalgan, Datril, Depon, Dexamol, Doliprane, Dolo, Dolprone, Dymadon, Efferalgan, Febridol, Pacimol, Pamol, Panado, Panadol, Panamax, Paralgin, Perfalgan and Tylenol.

[15] The trade (brand) names of aspirin (acetylsalicylic acid, sometimes provided as an acetylsalicylate) include Acenterine, Acetophen, Acetylin, Adiro, Albyl, Aquapin, Asatard, Aspegic, Aspisol, Aspro, Astrin, Bamyl, Colfarit, Coryphen, Delgesic, Dispril, Disprin, Ecotrin, Empirin, Magnecyl, Novasen, Premaspin, Rhonal, Rhusal, Solprin and Soluspril.

[16] The trade (brand) names of naproxen include Aleve, Anaprox, Bonyl, Equiproxen, Flanax, Floginax, Inza, Laraflex, Laser, Naixan, Naprelan, Napren, Naprium, Naprius, Naprogesic, Naprosine, Naprosyn, Naprosyne, Narocin, Proxen and Xenobid.

[17] Many other NSAIDs, including celecoxib, etodolac, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, piroxicam, sulindac and tenoxicam, are available, under brand names too numerous to include here.

[18] Codeine is usually marketed simply as codeine, though dihydrocodeine is often sold under various trade (brand) names.

[19] The term alkaloids refers to a large group of related chemicals, mainly found in plants, many of which have toxic or medicinal effects on animals.

[20] The trade (brand) names of tramadol include Contramal, Dromadol, Mabron, Nobligan, Ralivia, Ryzolt, Siverol, Topalgic, Tradol, Tradolan, Tradonal, Tralodie, Tramadex, Tramadin, Tramadolor, Tramahexal, Tramake, Tramal, Tramed, Tramedo, Trexol, Tridural, Ultram, Zamadol, Zamudol, Zydol and Zytram.

[21] Serotonin syndrome is a medical emergency which can occur as a result of various drug interactions. The details of this very complex, very dangerous and potentially fatal condition are outside the scope of this series of articles.

[22] Morphine, as morphine hydrochloride, morphine sulphate or occasionally morphine tartrate, is marketed under many trade (brand) names, some of which will be listed later.

[23] The use of opioids in renal failure is discussed in Appendix 1 (see the series links near the bottom of this page).

[24] The use of opioids in hepatic failure is discussed in Appendix 2 (see the series links near the bottom of this page).

[25] Transdermal drug delivery from adhesive patches applied to the skin will be discussed later when describing fentanyl.

[26] In the context of cancer pain management, baseline analgesia means the continuous analgesia which controls a patient's chronic pain most of the time, but which may not prevent new pain, breakthrough pain or incident pain.

[27] Dose titration means gradually increasing (or, if necessary, decreasing) the dose until the desired effect is obtained. This is analogous, though not identical, to the meaning of titration in chemistry. Dose titration has traditionally been done using immediate release medications, but it can also be done (a little more slowly) with extended (sustained) release medications.

[28] In some countries, sustained release suppositories are available for this purpose.

[29] Off-label prescribing is the prescribing of a pharmaceutical substance in a way which does not constitute an officially approved indication at the time.

[30] The main reason that this dosage adjustment is necessary is that when a drug is given by mouth it is absorbed from the small intestine, and venous blood from the small intestine passes through the liver before reaching the rest of the body. This allows some inactivation to occur even before the drug has a chance to start working. However, the veins which collect blood from the rectum join the general circulation without this "first pass effect".

[31] See the General Classification of types of pain in "Myths and Facts about Cancer Pain", available via the series links near the bottom of this page.

[32] Trade (brand) names for various dose forms of fentanyl (which is sometimes spelt fentanil) include Actiq, Durogesic, Duragesic, Fentora, Instanyl, Matrifen, Onsolis and Sublimaze.

[33] The term potency simply refers to the amount required for a given effect. Although fentanyl is very much more "potent" than morphine, this has nothing whatsoever to do with its effectiveness. It simply means that its equivalent dosage, by weight, is smaller than that of morphine.

[34] Trade (brand) names for fentanyl transdermal patches include Durogesic, Duragesic and Matrifen.

[35] "Active" transdermal patches, controlled by heat or electrical signals, may provide better control of absorption rates in the fairly near future.

[36] Trade (brand) names for various dose forms of oxycodone include Endocodone, Endone, Oxycontin, Oxydose, Oxynorm, Percolone, Proladone, Roxicodone and Supeudol.

[37] Thebaine, like morphine, can be extracted from crude opium.

[38] This is rarely a problem with the extended (sustained) release oral dose forms of oxycodone, which are available in a wide range of strengths. It is also possible to give oxycodone by injection (marketed in some countries as Eukodol, Eucodol or Oxynorm injection) or as a nasal spray, but these dose forms are not widely available at the time of writing.

[39] Trade (brand) names for various dose forms of hydromorphone (which is sometimes called dihydromorphinone or dimorphone) include Dilaudid, Hydal Retard, Hydromorph Contin, Hymorphan, Jurnista, Laudicon, Opidol, Palladone, Palladone SR and Sophidone.

[40] Trade (brand) names for various dose forms of methadone (or sometimes its isomer polamidon) include Amidone, Dolophine, Heptadon, Heptadone, Levo-Polamidone, Methadose, Physeptone, Polamidone and Symoron.

[41] See the Physiological Classification of types of pain in "Myths and Facts about Cancer Pain", available via the series links near the bottom of this page.

[42] Trade (brand) names for various dose forms of buprenorphine include Bupregesic, Buprenex, Buprigesic, Butrans, Morgesic, Norspan, Subutex, Temgesic and Transtec.

[43] When it was more widely available, trade (brand) names for dextromoramide included Alcoid, Dimorlin, Errecalma, Jetrium, Linfadol, Palfadonna, Palfium, Palphium and Troxilan.

[44] Like diacetyl morphine (heroin), dextromoramide became very popular with opioid abusers, which led to its prohibition in many jurisdictions.

[45] Trade (brand) names for pethidine (meperidine) include Aldolan, Alodan, Centralgin, Cluyer, Demerol, Dispadol, Dolantin, Dolantina, Dolantine, Dolargan, Dolcontral, Dolestine, Dolosal, Dolsin, Isonipecaine, Lydol, Meperol, Mialgin, Opystan, Pethadol, Pethanol, Petidin and Piridosal.

[46] Trade (brand) names for diacetylmorphine (diamorphine) include or have included Diacephin, Diagesil, Diamorfina and various slight modifications of its first trade name, Heroin.

Articles in the Cancer Pain Series

1. Myths and Facts about Cancer Pain

2. How Cancer Pain can be Relieved

3. Medications used to Relieve Cancer Pain (this page)

4. Optimal Use of Opioid Analgesics

5. Appendices:

Appendix 1: Use of Opioids in Renal Failure

Appendix 2: Use of Opioids in Hepatic Failure

Appendix 3: Special Medication Delivery Systems

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