Alternative opioids to morphine in palliative care: a review of current practice and evidence

This is a review of current practice of opioid use in palliative care, conducted from the perspective of a practising clinician working in the increasingly complex area of symptom control. In examining alternative opioids to morphine, choice and availability of different drugs reflect the UK perspective. Some drugs or formulations may not be available elsewhere, but the principles discussed may hopefully still be applied. The aims of this paper are several-fold: To present an overview of available opioids. To consider factors affecting possible choice of opioid—with particular reference to the palliative care setting. To consider availability and limitations of current data which may affect evidence based decisions. To comment on areas of interest for future clinical trials. There are three main classes of opioid receptor: mu, kappa, and delta (table 1), responsible for differing opioid effects. Opioid drugs vary in their receptor affinity, thus affecting their principal actions (table 2). The main site of action is the mu receptor, but some opioids have more complex activity. Classes of opioid receptor and response mediated Classes of opioid receptor and response mediated Differences in opioid receptor action Differences in opioid receptor action Side effects are common to all opioids, although to differing degrees. Sedation Hallucinations Constipation Nausea/vomiting Urinary retention Myoclonus Paradoxical pain Respiratory depression For practical purposes, the most important side effects are sedation, nausea, and constipation. Sedation and nausea occur particularly when starting the drug, usually temporarily, but may recur with dose increases. Nausea can be pre-empted by using a centrally acting antiemetic. This is not always necessary but advisable if the patient is already nauseated or fearful about it. Sedation is usually unavoidable but short lived (48–72 hours) among patients starting off on low doses. It may become more intractable at high dose, and there is some work on counteracting this effect with stimulants,1 although not widely practised. Constipation, in contrast, occurs in almost every patient taking opioids and does not lessen with continued use, but can be ameliorated by aperients. Respiratory depression, while potentially serious, is rarely clinically significant when treating pain (even among patients with respiratory impairment), as this antagonises the depressant effect. In practice respiratory depression usually occurs in opioid naïve patients after acute administration (for example, bolus intravenous dose). Tolerance develops rapidly with repeat doses, so does not pose significant problems for long term pain management. “Cancer pain” can be complex. Causes include: direct tumour infiltration of pain sensitive structures, injuries resulting from cancer treatment (radiation, chemotherapy, or surgery) and vascular occlusion due to tumour or treatment effects. Physiologically, there are three types of pain: Somatic or nociceptive pain (arising from receptors in cutaneous or deep tissues such as bone). Visceral pain (arising from internal organ involvement). Neuropathic pain (arising from peripheral or central nervous systems). Most pain can be controlled by pharmacological means, but it is essential to choose the right drugs for the individual. To help simplify approaches to pain control, the World Health Organisation (WHO) developed a three step analgesic ladder ?fig 1). The fundamental principles are that: WHO analgesic ladder (adapted from WHO2). Inadequate pain control at one level requires a move to the next level, not to an alternative drug of the same efficacy. Continuous pain requires continuous analgesia. The steps are simple: Treatment of mild pain is initiated with non-opioid analgesics (for example, paracetamol). Moderate pain that is not controlled by non-opioids should be treated by a weak opioid (alone or in combination with a non-opioid, for example, co-proxamol: paracetamol and dextropopoxyphene). Severe pain should be treated by strong opioids. At all levels adjuvant drugs can be added for specific indications: non-steroidal anti-inflammatory drugs (NSAIDs) for bone pain; anticonvulsants or tricyclics for neuropathic pain. This is, however, a large subject in its own right, and will not be dealt with further here. Several factors influence choice of an appropriate opioid. Availability Drug profile Individual patient factors Possible/desirable routes of administration Comparative analgesic effects Comparative adverse effects Other potential therapeutic effects In the UK, there is a wide range of opioids available (table 3). The initial choice of weak, moderate, or strong opioid is determined after careful assessment of the individual patient. It cannot be emphasised enough that pain is multifactorial and that successful treatment depends on comprehensive evaluation. A selection of opioids in common use in the UK (from the British National Formulary) A selection of opioids in common use in the UK (from the British National Formulary) For the purposes of this review, I will focus discussion on strong opioids. In palliation, the aim is to administer effective analgesics with a half life of several hours so that pain can be quickly controlled. Once dose requirements have stabilised, modified release formulations are extremely helpful, allowing longer dose intervals but maintaining flexibility to make dose alterations without risk of accumulation. Thus potency and duration of action are major determining factors. Morphine provides the gold standard: in unmodified form its four hour clinical duration of action allows regular review of pain control. Once stable, sustained release formulations reduce dose frequency to once or twice daily. Breakthrough pain is controlled with extra doses of the unmodified drug (calculated as 1/6 of the total 24 hour opioid dose requirement). Drugs with a very short half life (for example, pethidine) are unsuitable, because of the need for more frequent repeat dosing, which is both inconvenient and can cause build-up of toxic metabolites. Drugs with inherently long half lives (for example, methadone), are useful for long term maintenance, but can be difficult to titrate safely in unstable pain. Table 4 illustrates the relative potency of various opioids compared with oral morphine, and also their duration of action. Relative potency of commonly used opioids Relative potency of commonly used opioids These include age related changes in metabolism and concurrent medical conditions. In palliative care, many patients are both elderly and have concurrent medical conditions, both of which may influence the pharmacokinetics of opioids. For example cirrhosis affects bioavailability due to reduction of the first-pass effect. However, renal impairment is most important, as it affects clearance of many opioids. Reduced renal clearance is also the most important age related change, occurring in the elderly independently of specific disease conditions. Therefore this group is particularly prone to accumulation of drugs at conventional dose intervals (the British National Formulary suggests by upwards of 50%3). However, caution should not lead to inadequate analgesia, as all patients should have their pain requirements titrated individually. In practice, starting doses in uncontrolled pain usually remain the same, but patients with stable pain requirements and reduced renal clearance may require longer dose intervals or smaller doses. Concurrent drug therapy can also alter opioid pharmacokinetics, for example, morphine and amitriptyline interact to produce increased bioavailability of the opioid, whereas coadministration of methadone and phenytoin leads to faster elimination of methadone (see table 5 for further examples). It is perhaps the uncommon interactions which should be remembered; others, while commonly warned against are often less relevant in clinical practice in palliative care, for example, alcohol in moderate doses rarely causes problems and enhances psychosocial well being. Important clinical drug interactions with opioids Important clinical drug interactions with opioids Genetic factors predisposing to differences in opioid receptor response may be important,4 although these yet remain to be categorised. Patient acceptability—Acceptability is paramount to ensure compliance and ultimately effectiveness. At one end of the scale acceptability may be determined by simple factors such as taste or ease of swallowing; at the other end are complex issues such as the patient's previous analgesic experience or individual health beliefs. This needs to be explored sensitively to encourage doubts or concerns to be voiced. Many older patients in particular view the introduction of strong opioids as “the end of the road”. They may be frightened of taking strong painkillers “too soon”, believing they will no longer work when their illness progresses; this may lead them to downplay their symptoms. They may also have fears either of addiction or overdose. Recent high profile murder trials may have exacerbated confusion over the difference between deliberate fatal overdosage and the side effects of therapeutic opioid levels.5 While hopefully most people still trust their doctors' motives, there may yet be a knock-on effect.6 Many patients also have concerns about their ability to function normally when taking opioids. It is worthwhile negotiating and planning the introduction of an opioid to minimise any negative impact on the patient's life. Patient safety—Other factors to consider are physical limitations (such as poor sight) or cognitive impairment, especially among patients living alone, where safety as well as compliance may be an issue. Opioids can be given by a variety of routes (table 6). While most opioids can be given orally, a different route requirement may affect choice of drug. It should be noted that the intramuscular route has not been included. In the palliative care setting, this is rarely necessary or appropriate: it can be painful, particularly for debilitated patients with wasted muscles. In comparison, the subcutaneous route is more comfortable yet equally effective. Routes of administration of opioids in the palliative care setting Routes of administration of opioids in the palliative care setting The most commonly used route is oral. As most opioids are available in oral form, choice is determined by the comparative efficacy, bioavailability, and side effect profile of different drugs. A comparison of morphine with two other commonly available strong opioids is given in table 7. Comparative drug portraits Comparative drug portraits Hydromorphone—Hydromorphone is relatively new on the market, aimed as an alternative to oral morphine.7 It has a similar pharmacology to morphine but has inactive metabolites, which may explain its being better tolerated in selected patients. It is formulated in four hourly unmodified and 12 hourly modified release tablets, simplifying the transition from morphine, although the conversion ratio can be off-putting (7.5:1, that is, 7.5 mg morphine is equipotent to 1 mg of hydromorphone). For opioid responsive pain, it is comparable with morphine, and anecdotally, has less severe side effects; however, its similar receptor affinity does not allow this to be predicted for individual patients, and clinical trials to date have failed to demonstrate a clear superiority over morphine. It therefore tends to be used as a second-line alternative, or in “opioid rotation”. “Opioid rotation” means switching from one strong opioid to another where pain management is requiring increasing dose escalation, as patients may achieve better analgesia and/or reduced toxicity with an alternative drug.8 A baseline figure for this is where the dose of oral morphine has reached >1 g/24 hours. In some centres this is taken a step further with patients switched between opioids at regular intervals to minimise the development of analgesic tolerance.9 Opioid rotation is an area of increasing research interest in palliative care.10 Methadone—Methadone is an interesting drug that has recently come back into vogue in palliative care.11 Previously it was considered pharmacologically “dirty”: its broad based receptor activity, combined with a complex biodistribution led to difficulties in dose titration. While these considerations remain, it may have a particular place in treating complex pains. Indications include nociceptive pain and opioid responsive pain with neuropathic elements, such as intractable facial pain. It is slowly eliminated, reducing the incidence of breakthrough pain, yet does not accumulate in renal impairment, and shows no cross tolerance with other opioids. Thus it can be used in cases of true morphine allergy (although relatively uncommon) and is useful for opioid rotation.12 Its disadvantages represent the flip side to its advantages. While the half life of the free drug is measured in hours, only a small fraction is present in the circulation, the greater part passing into a much larger tissue reservoir. Reliable dosing is only achieved when these fractions have reached equilibrium. This makes initial dose titration difficult, particularly the risk of overdose. There are also conversion difficulties (if opioid rotating) because of the absence of cross tolerance. Breakthrough pain can also be difficult to treat because of the drug's slow onset of action. 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Continuous intravenous is useful for control of severe pain where the subcutaneous route is not particularly for dose titration over a relatively short Most intravenous are and requiring so and longer term Patient controlled has been widely used in the acute setting for control of pain, pain with bone and in where severe pain may levels of pain. recently the has been developed to allow subcutaneous bolus to more use in the setting in although this has not yet in the Opioid of there is a fundamental requirement to the of the pain an opioid at of pain in determining the to be of symptoms. of concurrent factors affecting metabolism and drug or route of Patient psychosocial factors. routes of administration are used commonly for use is possible but more because of of The main of this route are longer duration of analgesia at a dose, because of increased bioavailability, and reduced peripheral side effects. for severe pain, for example, of by the of if breakthrough doses are given by this can be as long as pain control is stable as oral administration can still be used for breakthrough In the drug of because of its high with morphine used controlled trials are to the place of other opioids. The route is, is another relatively development in pain only is available in this is a mu receptor opioid with comparative clinical analgesic to for its use are where oral administration is not possible for such as or that is, similar to for the subcutaneous is reported to have less side effects other opioids. It may therefore be when nausea and is drug or in severe It should only be used after titration with short acting opioids to pain, as the slow of levels makes it for short term The of administration it is to can be by patients or the long duration of action requires in the and reducing the by controlled drugs. may also be more both to patients and because of its of with morphine, by of the route as less This may encourage individual patients to more effective pain control, but should not be a for among about appropriate doses of opioids. The of as is that patients may be a after weak opioids without assessment of opioid This can cause problems of overdosage and side particularly because the morphine dose effect of the and being to between and mg of oral morphine over 24 The other with using in unstable pain is the slow titration to analgesic with patients still requiring breakthrough doses of another strong opioid, as is not available for Other disadvantages are its long half life the duration of action after and so effects in and opioid Its duration of action also makes it less for or other individual in analgesic it is relatively While considerations should appropriate use, for (such as of a discussion about is not to be While the can be a it may be more difficult to make in practice, because of evidence several Most have on morphine Most of other opioids focus on drugs or new drug have considered only analgesic and Comparative have on of analgesic action. There are large scale comparative and most have on analgesia. However, to use different opioids in a more it is the other opioid effects which may the and it is in this area that work has been effects of different routes of administration of the same opioid are comparison and of adverse effects between opioids is for example, there are of reduced adverse side effects with and in comparison with oral morphine, but this needs more analgesic effects of opioids in treating complex pain. This is particularly relevant to receptor action may make it more effective for pain. However, no clinical have been to this an area which is almost potentially side effects between opioids, for example, impact on are the principal opioid receptor and which effects are mediated by does methadone from other opioids in its receptor and is the clinical of is methadone difficult to two routes of administration other oral which are important in palliative potential does to demonstrate in of side opioids useful for the treatment of In this example, initial experience using morphine has that be of any analgesic while a small controlled failed to but strong treatment effects in individual of morphine have yet a of effect on while a small of patients oral morphine in side Thus it is not clear the response is due to morphine acting at receptor level in the or central combined with reduction of that is the morphine, it is not that to date no comparison have more work needs to be on and opioids. At cannot the response to an individual opioid for an individual patient. These in lead to a of specific for further are the comparative effects of different opioids in For example, morphine methadone is the most choice of short acting opioid to use for breakthrough pain when there significant differences between opioids with to methadone have a specific place in cancer pain At present of these can be trials in palliative care have been slow to There are practical issues of and trials among a large of small and difficulties in that the needs of patients both clinically and tends to be and assessment of effects by patients problems and requiring different treatment However, comparative work needs to be if are to patients choice and symptom control. In end disease there is no to in and patients or with pain, will care and and of life. and is mediated by all while nausea, sedation, and are mu receptor activity, and and effects the has an action as an receptor clinical of this is that it may analgesic effects when treating complex with a neuropathic is difficult to titrate because it has a complex with a small free fraction and large tissue reservoir. and to have less effects other opioids. The still on this scale trials have clinical but larger trials have yet to be The in for a on in for discussion of review by on of on Opioid and for of their initial and the for and of on of using care and and and of in in management in of