Alternative Opioids to Morphine in Palliative Care: Postgrad Med J: First Published As 10.1136/Pmj.77.908.371 on 1 June 2001

Postgrad Med J 2001;77:371–378 371

Alternative opioids to morphine in palliative care: Postgrad Med J: first published as 10.1136/pmj.77.908.371 on 1 June 2001. Downloaded from a review of current practice and evidence

M Barnett

This is a review of current practice of opioid x Nausea/vomiting use in palliative care, conducted from the per- x Urinary retention spective of a practising clinician working in the x Myoclonus increasingly complex area of symptom control. x Paradoxical pain In examining alternative opioids to morphine, x Respiratory depression choice and availability of diVerent drugs reﬂect For practical purposes, the most important the UK perspective. Some drugs or formula- side eVects are sedation, nausea, and constipa- tions may not be available elsewhere, but the tion. principles discussed may hopefully still be Sedation and nausea occur particularly when applied. starting the drug, usually temporarily, but may The aims of this paper are several-fold: recur with dose increases. Nausea can be (1) To present an overview of available opio- pre-empted by using a centrally acting an- ids. tiemetic. This is not always necessary but (2) To consider factors aVecting possible advisable if the patient is already nauseated or choice of opioid—with particular reference fearful about it. Sedation is usually unavoidable to the palliative care setting. but short lived (48–72 hours) among patients (3) To consider availability and limitations of starting oV on low doses. It may become more current data which may aVect evidence intractable at high dose, and there is some work based decisions. on counteracting this eVect with stimulants,1 (4) To comment on areas of interest for future although not widely practised. clinical trials. Constipation, in contrast, occurs in almost every patient taking opioids and does not lessen Terms of reference with continued use, but can be ameliorated by OPIOID RECEPTORS AND EFFECTS aperients. There are three main classes of opioid receptor: Respiratory depression, while potentially mu, kappa, and delta (table 1), responsible for serious, is rarely clinically signiﬁcant when diVering opioid eVects. Opioid drugs vary in treating pain (even among patients with their receptor aYnity, thus aVecting their prin- respiratory impairment), as this antagonises Walsgrave Hospital, cipal actions (table 2). The main site of action the depressant eVect. In practice respiratory

Coventry and is the mu receptor, but some opioids have more http://pmj.bmj.com/ University of Warwick depression usually occurs in opioid naïve complex activity. patients after acute administration (for exam- Correspondence to: ple, bolus intravenous dose). Tolerance devel- Dr M Barnett, Centre for ops rapidly with repeat doses, so does not pose Primary Health Care SIDE EFFECTS OF OPIOIDS Studies, University of Side eVects are common to all opioids, signiﬁcant problems for long term pain man- Warwick, Coventry although to diVering degrees. agement. CV4 7AL, UK x Sedation

Submitted 8 May 2000 x Hallucinations Cancer pain and choice of opioid on September 30, 2021 by guest. Protected copyright. Accepted 31 October 2000 x Constipation “Cancer pain” can be complex. Causes include: direct tumour inﬁltration of pain sensi- Table 1 Classes of opioid receptor and response mediated tive structures, injuries resulting from cancer treatment (radiation, chemotherapy, or sur- Receptor Response on activation gery) and vascular occlusion due to tumour or Mu Analgesia, respiratory depression, miosis, euphoria, reduced gastrointestinal mobility treatment eVects. Physiologically, there are Kappa Analgesia, dysphoria, psychotomimetic eVects, miosis, respiratory depression three types of pain: Delta Analgesia (1) Somatic or nociceptive pain (arising from Source: Oxford Textbook of Palliative Medicine. receptors in cutaneous or deep tissues such as bone).

Table 2 DiVerences in opioid receptor action

Opioid Receptor action Comments Morphine Mu agonist Metabolised in liver to morphine-3 and morphine-6 glucuronides (M3G and M6G). M6G metabolite more potent than morphine Hydromorphone Mu agonist Morphine analogue Fentanyl Mu agonist Oxycodone Mu agonist Pentazocine Kappa agonist; weak mu antagonist Multiple receptor activity: kappa eVects analgesic but also increased psychotomimetic eVects cf mu agonists. Mu receptor antagonism can precipitate withdrawal if given alongside mu agonist Methadone Mixed mu/delta agonist; N-methyl-D-aspartate Multiple receptor activity—may act on complex pain (NMDA) receptor antagonist Buprenorphine Partial mu agonist; kappa antagonist; delta agonist Complex receptor action—has dose ceiling for analgesic eVect and antagonises other opioids Tramadol Opioid plus serotonergic eVects For moderate pain. Tricyclic-like action—may act on neuropathic pain

www.postgradmedj.com 372 Barnett Postgrad Med J: first published as 10.1136/pmj.77.908.371 on 1 June 2001. Downloaded from Opioid for moderate to Table 4 Relative potency of commonly used opioids severe pain + non Potency ratio with Duration of opioid +/– adjuvant Analgesic oral morphine action (hours) Codeine 1/10 3–5 Opioid for mild to Pethidine 1/8 2–3 moderate pain + non- Tramadol 1/5 5–6 opioid +/– adjuvant Dipipanone 1⁄2 3–5 Oxycodone 1.5–2 5–6 Dextromoramide 2 2–3 Phenazocine 5 6–8 Methadone 5–10 8–12 Non-opioid Pain persists Hydromorphone 7.5 3–5 +/– adjuvant Buprenorphine 60 6–8 or Fentanyl 150 72 Pain increases persists or Choosing an appropriate opioid increases Several factors influence choice of an appropriate opioid. Figure 1 WHO analgesic ladder (adapted from WHO2). x Availability x Drug profile (2) Visceral pain (arising from internal organ x Individual patient factors involvement). x Possible/desirable routes of administration (3) Neuropathic pain (arising from peripheral x Comparative analgesic eVects or central nervous systems). x Comparative adverse eVects Most pain can be controlled by pharmaco- x Other potential therapeutic eVects logical means, but it is essential to choose the right drugs for the individual. To help simplify AVAILABILITY approaches to pain control, the World Health In the UK, there is a wide range of opioids Organisation (WHO) developed a three step available (table 3). The initial choice of weak, analgesic ladder (fig 1). The fundamental prin- moderate, or strong opioid is determined after ciples are that: careful assessment of the individual patient. It (1) Inadequate pain control at one level cannot be emphasised enough that pain is requires a move to the next level, not to an multifactorial and that successful treatment alternative drug of the same eYcacy. depends on comprehensive evaluation. (2) Continuous pain requires continuous anal- For the purposes of this review, I will focus gesia. discussion on strong opioids. The steps are simple: DRUG PROFILE (1) Treatment of mild pain is initiated with In palliation, the aim is to administer eVective non-opioid analgesics (for example, para- analgesics with a half life of several hours so that cetamol). pain can be quickly controlled. Once dose http://pmj.bmj.com/ (2) Moderate pain that is not controlled requirements have stabilised, modified release by non-opioids should be treated by a formulations are extremely helpful, allowing weak opioid (alone or in combination longer dose intervals but maintaining flexibility with a non-opioid, for example, co- to make dose alterations without risk of proxamol: paracetamol and dextropo- accumulation. Thus potency and duration of poxyphene). action are major determining factors. Morphine (3) Severe pain should be treated by strong provides the gold standard: in unmodified form opioids. its four hour clinical duration of action allows on September 30, 2021 by guest. Protected copyright. At all levels adjuvant drugs can be added for regular review of pain control. Once stable, sus- specific indications: non-steroidal anti- tained release formulations reduce dose fre- inflammatory drugs (NSAIDs) for bone pain; quency to once or twice daily. Breakthrough anticonvulsants or tricyclics for neuropathic pain is controlled with extra doses of the pain. This is, however, a large subject in its unmodified drug (calculated as 1/6 of the total own right, and will not be dealt with further 24 hour opioid dose requirement). Drugs with a here. very short half life (for example, pethidine) are unsuitable, because of the need for more frequent repeat dosing, which is both inconven- Table 3 A selection of opioids in common use in the UK (from the British National Formulary) ient and can cause build-up of toxic metabolites. Drugs with inherently long half lives (for exam- (1) Weak opioids (2) Moderate and strong opioids ple, methadone), are useful for long term main- Dextropopoxyphene Buprenorphine (Temgesic) tenance, but can be diYcult to titrate safely in Codeine Dextromoramide (Palfium) unstable pain. Table 4 illustrates the relative Dihydrocodeine Diamorphine potency of various opioids compared with oral Dipipanone (Diconal) Fentanyl morphine, and also their duration of action. Hydromorphone (Palladone) Methadone PATIENT FACTORS Morphine Oxycodone Biomedical Pentazocine (Fortral) These include age related changes in metabolism Pethidine and concurrent medical conditions. In palliative Phenazocine (Narphen) care, many patients are both elderly and have Tramadol concurrent medical conditions, both of which

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Table 5 Important clinical drug interactions with opioids Postgrad Med J: first published as 10.1136/pmj.77.908.371 on 1 June 2001. Downloaded from

Class of drug Clinical eVects of interaction Alcohol Enhanced sedative and hypotensive eVects (all opioids) Antiarrhythmics Delayed absorption of mexiletine (all opioids) Antibacterials Rifampicin accelerates metabolism of methadone (reduced eVect of opioid); ciproﬂoxacin plasma concentration reduced by opioids (reduced eVect of antibiotic) Antidepressants Possible central nervous system excitation or depression if opioids given alongside monoamine oxidase inhibitors; increased riskof convulsions with selective serotonin reuptake inhibitors and tricyclics if tramadol coadministered Antiepileptics EVect of tramadol reduced by carbamazepine; phenytoin accelerates methadone metabolism Antipsychotics Enhanced sedative and hypotensive eVects (all opioids) Anxiolytics and hypnotics Enhanced sedative eVect (all opioids) Dopaminergics Metaclopramide and domperidone antagonise gastrointestinal eVects of opioids Ulcer healing drugs Cimetidine inhibits metabolism of opioids (increased plasma concentration)

may influence the pharmacokinetics of opioids. Many older patients in particular view the For example cirrhosis aVects bioavailability due introduction of strong opioids as “the end of to reduction of the first-pass eVect. However, the road”. They may be frightened of taking renal impairment is most important, as it aVects strong painkillers “too soon”, believing they clearance of many opioids. Reduced renal clear- will no longer work when their illness ance is also the most important age related progresses; this may lead them to downplay change, occurring in the elderly independently their symptoms. They may also have fears of specific disease conditions. either of addiction or overdose. Recent high Therefore this group is particularly prone to profile murder trials may have exacerbated accumulation of drugs at conventional dose confusion over the diVerence between deliber- intervals (the British National Formulary ate fatal overdosage and the side eVects of suggests by upwards of 50%3). However, therapeutic opioid levels.5 While hopefully caution should not lead to inadequate analge- most people still trust their doctors’ motives, sia, as all patients should have their pain there may yet be a knock-on eVect.6 requirements titrated individually. In practice, Many patients also have concerns about their starting doses in uncontrolled pain usually ability to function normally when taking opio- remain the same, but patients with stable pain ids. It is worthwhile negotiating and planning requirements and reduced renal clearance may the introduction of an opioid to minimise any require longer dose intervals or smaller doses. negative impact on the patient’s life. Concurrent drug therapy can also alter opioid Patient safety—Other factors to consider are pharmacokinetics, for example, morphine and physical limitations (such as poor sight) or amitriptyline interact to produce increased cognitive impairment, especially among pa- bioavailability of the opioid, whereas coadmin- tients living alone, where safety as well as com- istration of methadone and phenytoin leads to pliance may be an issue. faster elimination of methadone (see table 5 for further examples). It is perhaps the uncommon interactions which should be remembered; ROUTES OF ADMINISTRATION http://pmj.bmj.com/ Opioids can be given by a variety of routes others, while commonly warned against are (table 6). While most opioids can be given often less relevant in clinical practice in pallia- orally, a di erent route requirement may a ect tive care, for example, alcohol in moderate V V choice of drug. It should be noted that the doses rarely causes problems and enhances intramuscular route has not been included. In psychosocial well being. the palliative care setting, this is rarely Genetic factors predisposing to diVerences in 4 necessary or appropriate: it can be painful, par-

opioid receptor response may be important, on September 30, 2021 by guest. Protected copyright. ticularly for debilitated patients with wasted although these yet remain to be categorised. muscles. In comparison, the subcutaneous route is more comfortable yet equally eVective. Psychosocial Patient acceptability—Acceptability is para- mount to ensure compliance and ultimately Oral eVectiveness. At one end of the scale acceptabil- The most commonly used route is oral. As ity may be determined by simple factors such as most opioids are available in oral form, choice taste or ease of swallowing; at the other end are is determined by the comparative efﬁcacy, bio- complex issues such as the patient’s previous availability, and side eVect proﬁle of diVerent analgesic experience or individual health be- drugs. A comparison of morphine with two liefs. This needs to be explored sensitively to other commonly available strong opioids is encourage doubts or concerns to be voiced. given in table 7.

Table 7 Comparative drug portraits Table 6 Routes of administration of opioids in the Morphine Hydromorphone Methadone palliative care setting Origin Main opium constituent Semisynthetic opioid Synthetic opioid Oral absorption 20 mins (10–30) 30 mins 3 hours (1–5 hours) Oral Oral bioavailability About 40% About 50% About 80% Sublingual Liver metabolites M6G active HM3G probably inactive N-Demethylation: M1 and M2 both inactive Subcutaneous M3G inactive Intravenous Excretion Kidney Kidney Kidney (increased by acid urine) and faeces Epidural/intrathecal Half life Oral 2–2.5 hours 3–4 hours Acute 8–20 hours Transdermal Chronic 16–29 hours Rectal Useful analgesia 3–6 hours 4 hours Variable

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Hydromorphone—Hydromorphone is rela- of irritant eVects, although recent work has Postgrad Med J: first published as 10.1136/pmj.77.908.371 on 1 June 2001. Downloaded from tively new on the market, aimed as an alterna- suggested options to alleviate irritation and tive to oral morphine.7 It has a similar pharma- allow continued use of methadone.14 cology to morphine but has inactive Perhaps because it has been neglected in the metabolites, which may explain its being better past and because of its variable half life, there tolerated in selected patients. It is formulated has been a lack of consensus on appropriate in four hourly unmodified and 12 hourly protocols, although this has improved with modified release tablets, simplifying the transi- wider usage.15 Methadone is perhaps best tion from morphine, although the conversion viewed as a useful second line drug in the spe- ratio can be oV-putting (7.5:1, that is, 7.5 mg cialist palliative care setting. morphine is equipotent to 1 mg of hydromor- Tramadol and oxycodone are two other drugs phone). For opioid responsive pain, it is that have recently been strongly marketed. comparable with morphine, and anecdotally, Tramadol is a relatively recent arrival, which has less severe side eVects; however, its similar inhibits serotonin reuptake in addition to its receptor aYnity does not allow this to be weak mu receptor agonist action; this makes it predicted for individual patients, and clinical potentially useful for opioid responsive pain trials to date have failed to demonstrate a clear with neuropathic elements. This has been superiority over morphine. It therefore tends to demonstrated in the management of polyneu- be used as a second-line alternative, or in ropathy.16 It also has less eVect on gastric stasis. “opioid rotation”. However, although it provides a useful alterna- “Opioid rotation” means switching from one tive at high dose in moderate pain,17 it is less strong opioid to another where pain manage- potent than morphine and less eVective for ment is requiring increasing dose escalation, as managing severe pain.18 Its current place in patients may achieve better analgesia and/or palliative care is therefore unclear. reduced toxicity with an alternative drug.8 Oxycodone is a long established drug A baseline figure for this is where the dose of recently relaunched in new sustained release oral morphine has reached >1 g/24 hours. In oral formulations. It is reputed to be less likely some centres this is taken a step further with to cause hallucinations and delirium.19 It has patients switched between opioids at regular been used successfully in patients with ad- intervals to minimise the development of anal- vanced cancer,20 but may not be totally gesic tolerance.9 Opioid rotation is an area of equivalent in analgesic eYcacy to morphine,21 increasing research interest in palliative care.10 although comparison of controlled release Methadone—Methadone is an interesting preparations in stable pain showed no diVer- drug that has recently come back into vogue in ence.22 palliative care.11 Previously it was considered pharmacologically “dirty”: its broad based Sublingual receptor activity, combined with a complex This could be useful in theory, particularly for biodistribution led to diYculties in dose patients with swallowing diYculties. However,

titration. While these considerations remain, it only buprenorphine is so formulated. As a par- http://pmj.bmj.com/ may have a particular place in treating complex tial analgesic agonist which antagonises other pains. Indications include nociceptive pain and opioids, it is diYcult to use in the palliative care opioid responsive pain with neuropathic ele- setting and is not recommended. ments, such as intractable facial pain. It is slowly eliminated, reducing the inci- Rectal dence of breakthrough pain, yet does not accu- This route was much favoured in the past, par- mulate in renal impairment, and shows no ticularly in nursing homes, because it provided cross tolerance with other opioids. Thus it can a reliable route for non-specialist nurses treat- on September 30, 2021 by guest. Protected copyright. be used in cases of true morphine allergy ing semiconscious patients who were unable to (although relatively uncommon) and is useful swallow. With the development of syringe driv- for opioid rotation.12 ers and transdermal formulations it is now less Its disadvantages represent the flip side to its commonly used. advantages. While the half life of the free drug Although a variant on the gastrointestinal is measured in hours, only a small fraction is route, rectal administration may aVect bioavail- present in the circulation, the greater part ability due to partial bypassing of hepatic passing into a much larger tissue reservoir. metabolism. In the opioid naïve patient, there Reliable dosing is only achieved when these is some evidence of both more rapid and fractions have reached equilibrium. This makes sustained pain control when comparing rectal initial dose titration diYcult, particularly the with oral administration of morphine.23 There risk of overdose. There are also conversion dif- is however little published on long term use for ficulties (if opioid rotating) because of the cancer pain.24 absence of cross tolerance. Breakthrough pain Prepared rectal formulations (that is, sup- can also be diYcult to treat because of the positories) include morphine, hydromorphone, drug’s slow onset of action. Specialist supervi- and oxycodone. Opioids have also been admin- sion is therefore advisable for the first two istered rectally in non-standard preparations, weeks or so, usually as an inpatient, although it usually liquid for fast absorption. has been reported in the outpatient setting, with careful monitoring.13 Subcutaneous The other disadvantage is that if patients This route has increased in popularity over the cannot take the oral form, subcutaneous last 15 years, as clinicians have come to appre- administration is generally not advised because ciate its flexibility, safety, and practicality. It is

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now the first choice in most instances where Postgrad Med J: first published as 10.1136/pmj.77.908.371 on 1 June 2001. Downloaded from the parenteral route is required. Summary of factors influencing choice In the community setting it has revolution- of opioid x Opioid sensitivity of pain—although obvi- ised patient care, both in the terminal stages ous, there is a fundamental requirement and for those with dysphagia, vomiting, to assess the nature of the presenting pain impaired absorption, or obstruction. The before prescribing an opioid at all. crucial development has been the syringe 25 x Stability of pain control—relevant in driver. This simple device utilises normal determining the formulation to be used. plastic syringes, the rate of flow being preset x Presence of coexisting symptoms. (usually to run over 24 hours). Being battery x Presence of concurrent factors aVecting driven, it is relatively unobtrusive and does not metabolism and drug elimination. aVect mobility. It oVers a reliable constant x Necessary or preferred route of adminis- route of administration; at the same time tration. subcutaneous absorption is partially rate lim- x Patient psychosocial factors. ited (compared with intravenous route), so reducing the risk of inadvertent overdose, mak- ing it safer for use in unsupervised settings. gastrointestinal obstruction where severe spas- Setting up and recharging the driver are modic pain may exacerbate lower levels of straightforward procedures for trained district background pain. nurses. More recently the Edmonton Injector26 has The opioids most commonly employed are been developed to allow subcutaneous bolus diamorphine (UK), morphine (US), or more injection, leading to more widescale use in the recently hydromorphone. The avoidance of community setting in North America, although first-pass metabolism increases bioavailability, this has not yet found favour in the UK. although there is some variation in practice as to actual dosage regimens. The majority of Epidural/intrathecal centres in the UK use a 3:1 ratio (that is, 300 Spinal routes of administration are used commonly for inpatients. Community use is mg oral morphine over 24 hours converts to possible but more problematic because of lack 100 mg subcutaneous diamorphine). of trained back-up. Problems with subcutaneous administration The main applications of this route are two- usually relate to skin sites, most commonly fold: when using high concentrations of opioid, or (1) Providing longer duration of analgesia at a when combining opioid with other drugs lower overall dose, because of greatly (compatibility guidelines are available). Irrita- increased bioavailability, and hence re- tion can often be overcome by reducing the duced unwanted peripheral side eVects. concentration of drugs (using a larger volume) (2) Useful for controlling severe localised or by adding hydrocortisone to the infusion. lower body pain, for example, pelvic

Similarly problems with absorption can be disease. http://pmj.bmj.com/ ameliorated by adding hyaluronidase (an en- Disadvantages are: zyme that breaks down connective tissue and (1) Risk of infection, minimised by tunnelling increases local diVusion). Other occasional the catheter. problems include localised needle reactions (an (2) Risk of overdose if breakthrough doses are alternative Teﬂon cannula is available), while in given by inexperienced staV; this can be severely cachectic patients, siting may be diY- avoided as long as pain control is stable cult due to lack of subcutaneous tissue. Very before discharge, as oral administration occasionally, shutdown of the patient’s periph- can still be used for occasional break- on September 30, 2021 by guest. Protected copyright. eral circulation in the terminal phase may cause through requirements. unreliable absorption, requiring more frequent In Britain diamorphine remains the drug of review and appropriate dose adjustments to choice, because of its high solubility, with mor- prevent distress. phine used elsewhere. More controlled trials are required to establish the place of other opioids. Intravenous This route is not commonly used now: bolus Transdermal administration provides rapid onset (10–15 The transdermal route (that is, skin patch) is mins for morphine) but short duration of another relatively recent development in pain action of analgesia and is therefore only used control: only fentanyl is currently available in for emergency symptom control. Continuous this formulation. intravenous infusion is useful for control of Fentanyl is a highly potent mu receptor severe pain where the subcutaneous route is opioid with good comparative clinical analgesic not tolerated, particularly for dose titration eYcacy to morphine.27 Main indications for its over a relatively short period. Most intravenous use are where oral administration is not possi- pumps are unwieldy and intrusive, requiring ble for reasons such as dysphagia, vomiting, or mains attachment, so constraining mobility impaired gastrointestinal absorption, that is, and longer term acceptability. similar to indications for the subcutaneous Patient controlled analgesia—This has been route. Fentanyl is reported to have less gastro- widely used intravenously in the acute setting intestinal side eVects than other opioids. It may for control of postoperative pain, pain associ- therefore be helpful when nausea and vomiting ated with bone marrow transplants, and in is drug related, or in severe constipation.28

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It should only be used after titration with Postgrad Med J: first published as 10.1136/pmj.77.908.371 on 1 June 2001. Downloaded from short acting opioids to stabilise pain, as the Questions (see p 377 for answers) slow equilibration of blood levels transdermally (1) What are the principal opioid receptor makes it unsuitable for short term review. sites, and which physiological eVects The advantages of transdermal administra- are mediated by each? tion are: it is generally highly acceptable to patients; patches can be applied by patients or (2) How does methadone diVer from other relatives themselves; the long duration of action opioids in its receptor activation, and requires infrequent patch changes, minimising what is the clinical significance of this? non-compliance in the community and reduc- (3) Why is methadone diYcult to titrate? ing the time spent by ward staV administering controlled drugs. (4) Name two routes of administration Fentanyl may also be more acceptable both other than oral which are important in to patients and physicians because of its lack of palliative care. association with morphine, enhanced by per- (5) What potential advantages does fenta- ception of the transdermal route as less “medi- nyl appear to demonstrate in terms of cal”. This may encourage individual patients to side eVects? accept more eVective pain control, but should not be a substitute for education among (6) Are opioids useful for the treatment of clinicians anxious about prescribing appropri- dyspnoea? ate doses of opioids. The downside of viewing fentanyl as “in- nocuous” is that patients may be prescribed a patch de novo after weak opioids only, without x Studies comparing eVects of diVerent routes assessment of opioid requirement. This can of administration of the same opioid are lacking. cause problems of overdosage and side eVects, Systematic comparison and quantification of particularly because the morphine equivalent x adverse eVects between opioids is lacking, dose eVect of the patches demonstrates consid- for example, there are reports of reduced erable and unpredictable interpatient adverse gastrointestinal side eVects with fen- variability—the 25 µg/hour patch being equiv- tanyl and hydromorphone in comparison alent to between 30 and 135 mg of oral with oral morphine, but this needs more sys- morphine over 24 hours! The other problem tematic exploration. with using patches de novo in unstable pain is x Studies comparing analgesic eVects of opio- the slow titration to analgesic requirements, ids in treating complex pain. This is particu- with patients still requiring breakthrough doses larly relevant to methadone, whose of another strong opioid, as fentanyl is not cur- N-methyl-D-aspartate (NMDA) receptor rently available for this. antagonist action may make it more eVective Other disadvantages are its long half life pro- for neuropathic-type pain. However, no http://pmj.bmj.com/ longing the duration of action after patch clinical studies have been carried out to removal, and so eVects in overdose, and examine this systematically.30 complicating opioid rotation. Its duration of Finally, an area which is almost completely 29 action also makes it less flexible for circadian unexplored: or other individual variations in analgesic x Studies comparing potentially beneficial side requirement. Finally, it is relatively expensive. eVects between opioids, for example, impact While cost considerations should never prevent on dyspnoea. appropriate use, overenthusiastic prescribing In this example, initial experience using on September 30, 2021 by guest. Protected copyright. for inappropriate reasons (such as avoidance of inhaled morphine has suggested that dyspnoea a discussion about morphine) is not to be con- could be improved independent of any analge- doned. sic requirement,31 32 while a small randomised controlled trial failed to reach significance, but Limitations of existing evidence did report strong treatment eVects in indi- While the above can be a guide, it may be more vidual patients.33 Studies of inhaled morphine diYcult to make systematic choices in practice, have demonstrated rapid systemic absorption because reviews of published evidence reveal yet a lack of eVect on dyspnoea,34 while a small several limitations: study of patients receiving oral morphine dem- x Most studies have focused on morphine onstrated symptomatic improvement in itself. breathlessness alongside systemic side eVects.35 x Most studies of other opioids focus on Thus it is not clear whether the response is due “new” drugs or new product licences. to morphine acting at local receptor level in the x Single drug studies have considered only lungs or through central inhibition combined analgesic eYcacy and acceptability. with reduction of anxiety. If that is the picture x Comparative studies have focused on estab- regarding morphine, it is not surprising that to lishing eYcacy/potency of analgesic action. date no comparison studies have emerged. So what’s missing? There are few large scale Clearly, more work needs to be done on comparative trials, and most have focused on dyspnoea and opioids. analgesia. However, to use diVerent opioids in a more sophisticated way it is the other opioid Questions we might like to ask eVects which may swing the balance, and it is in At present, we cannot eVectively predict the this area that least work has been done: response to an individual opioid for an

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summary of their initial conclusions (October 1998); and the Postgrad Med J: first published as 10.1136/pmj.77.908.371 on 1 June 2001. Downloaded from Answers Napp Information Service for additional searches and supply of monographs on hydromorphone. (1) Mu, kappa and delta—analgesia is Literature search: Netscape search of Medline using search terms “palliative care and opiates”; “opiates and cancer”; “opi- mediated by all three, while nausea, ates and dyspnoea”. sedation, and constipation are prima- Further reading: Oxford Textbook of Palliative Medicine. Doyle D, Hanks GWC, MacDonald N, eds. 1st Ed (reprint in paper- rily through mu receptor activity, and back; 3rd edition in press), Oxford University Press, 1996; dysphoria and psychotomimetic eVects Symptom management in advanced cancer. Twycross R. 2nd Ed, RadcliVe Medical Press, 1997; Handbook of Palliative Care. Faull through the kappa receptor. C, Carter Y, Woof R, eds, Blackwell Science, 1998. (2) Methadone has an additional action as 1 Bruera E, Fainsinger R, MacEachern T, et al. The use of an NMDA receptor antagonist—the methylphenidate in patients with incident cancer pain clinical significance of this is that it receiving regular opiates. A preliminary report. Pain 1992;50:75–7. may confer improved analgesic eVects 2 Report of a WHO Expert Committee. Cancer pain relief and when treating complex pains with a palliative care. Geneva: World Health Organisation, 1990 (WHO Technical Report Series, No 804). neuropathic element. 3 British Medical Association and Royal Pharmaceutical Society of Great Britain. Prescribing for the elderly. British (3) Methadone is diYcult to titrate because National Formulary. London: BMA, March 2000;39:16–17. it has a complex biodistribution, with a 4 Galer BS, Coyle N, Pasternak GW, et al. 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J Palliat Care efits exist, but larger randomised trials 1996;12:6–9. have yet to be conducted. 10 Mercadante S. Opioid rotation for cancer pain: rationale and clinical aspects. Cancer 1999;86:1856–66. 11 Gannon C. The use of methadone in the care of the dying. European Journal of Palliative Care 1997;4:152–7. 12 Crews JC, Sweeney NJ, Denson DD. Clinical eYcacy of methadone in patients refractory to other mu-opioid recep- individual patient. These gaps in our knowl- tor agonist analgesics for management of terminal cancer edge lead to a number of specific questions for pain. Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics. Cancer further research: 1993;72:2266–72. x What are the comparative eVects of diVerent 13 Hagen NA, Wasylenko E. Methadone: outpatient titration and monitoring strategies in cancer patients. J Pain opioids in alleviating breathlessness? 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