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Joy R. Ross et al- Clinical Pharmacology and Pharmacotherapy of Opioid Switching in Cancer Patients

Joy R. Ross et al- Clinical Pharmacology and Pharmacotherapy of Opioid Switching in Cancer Patients

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The Oncologist
2006;11:765–773 www.TheOncologist.com
Clinical Pharmacology and Pharmacotherapyof Opioid Switching in Cancer Patients
Joy R. Ross,
Julia Riley,
Columba Quigley,
Ken I. Welsh
Department of Palliative Medicine, Royal Marsden Hospital, London, United Kingdom;
Department of Clinical Genomics, Imperial College, London, United Kingdom;
Cancer Centre, Hammersmith Hospital, London, United Kingdom
K W.
Cancer • Opioid • Switching • Polymorphism
Correspondence: Joy R. Ross, M.D., Department of Palliative Medicine, Horder Ward, Royal Marsden Hospital, London SW3 6JJ, UnitedKingdom. Telephone: 0207-808-2761; Fax: 0207-808-2478; e-mail: joy.ross@rmh.nhs.uk Received March 15, 2006; accepted for publi-cation May 26, 2006. ©AlphaMed Press 1083-7159/2006/$20.00/0
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The Oncologist
Pain is one of the most common and often most fearedsymptoms in patients with cancer. Ongoing or progressivepain is physically debilitating and has a marked impact onquality of life. Since a third of the population will die fromcancer, and of these, 80% will experience severe pain in
Learning Objectives
After completing this course, the reader will be able to:1. Describe some of the underlying mechanisms that contribute to why patients show differential responses todifferent opioids.2. Identify some of the individual genes that may influence response to different opioids.3. Critically evaluate the evidence for the therapeutic maneuver of switching.
Access and take the CME test online and receive 1
 AMA PRA Category 1 Credit 
at CME.TheOncologist.com
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Opioid Switching in Cancer
their final year of life, effective treatment of cancer-relatedpain remains both a high priority and an ongoing challengein clinical practice. Individuals with moderate to severecancer-related pain require treatment with strong analge-sics, namely opioids.An important advance in promoting the principles of good pain control for cancer patients worldwide was thepublication of the World Health Organization (WHO)analgesic ladder (Fig. 1) [1]. This sought to simplify painmanagement strategies and promote a universal step-wiseincrease in potency of analgesics prescribed. In addition,emphasis was placed on tailoring prescribing to each indi-vidual and encouraging the use of regular analgesia, bythe oral route, with regular review and dose escalation toachieve and maintain good pain control. Whereas the rec-ommendations for each step of the analgesic ladder havenot been individually evaluated in randomized, controlledclinical trials (RCTs), the use of the analgesic ladder as atreatment strategy has been validated in the clinical setting,with up to 88% of patients obtaining satisfactory relief frompain [2, 3]. It is now widely accepted in clinical practice.Whereas morphine is the opioid of choice for the treat-ment of moderate to severe cancer pain (step 3 on the lad-der) [1], a significant proportion of patients treated with oralmorphine do not have successful outcomes either because of intolerable adverse effects, inadequate analgesia, or a com-bination of both [4]. These patients are often “switched”to alternative strong opioids. Opioid switching, or chang-ing from morphine to an alternative opioid, is a therapeuticmaneuver that is gaining popularity in pain management asa method of improving analgesic response and/or reducingadverse side effects [5, 6]. This strategy should not be con-fused with opioid rotation, which also includes the practiceof simply switching to an alternative drug either to changethe route of administration or because of either patient orclinician preference. Studies of both opioid switchingand/or rotation have been extensively reviewed by one of us (CQ) [6], and the pharmacology of individual opioids,including the advantages of different routes of administra-tion, has been reviewed elsewhere [7]. This review focuseson opioid switching.The concept of interindividual variability in morphineanalgesic response is not a new one. In the 1950s, Lasagnaand Beecher [8] reported a 65% “success” rate with mor-phine in an experimental pain model. Similarly, a bimodalresponse to morphine analgesia has been described in den-tal extraction pain [9]. Whereas mild sedation and nauseaand vomiting occur relatively frequently on initiation of opioids, with cautious dose titration these problems usu-ally disappear within days. However, for a minority, thesesymptoms persist, preventing further dose titration and ade-quate analgesia. Persistent confusion, drowsiness, nausea,and nightmares are the most commonly reported adverseeffects, which result in the need to switch to an alternativeopioid [10]. Less common side effects and reasons reportedfor switching include neuromuscular disturbances such asmuscle spasm, myoclonus, and pruritus.Clinically, it can be difficult to identify true opioid intol-erance, particularly in patients with cancer, where symp-toms such as drowsiness, nausea, and vomiting can havemany causes. De Stoutz et al. [11] identified adverse effects,primarily cognitive impairment, in 41% of patients with can-cer on regular opioids. However, not all symptoms resolvedon switching opioids, suggesting that nonopioid causes wereimportant. In general, a pragmatic approach is usually taken,in which, if there is a clinical suspicion that symptoms areopioid related, a trial of an alternative opioid is instigated.Two questions need to be asked: first, what is the evidencethat patients who are intolerant of morphine can be correctlyidentified, and second, is there evidence to support the useof opioid switching to improve clinical outcome?
Evidence-Based Rationale for Switching:Clinical Trials
If one accepts opioid switching as a recommended thera-peutic maneuver, the underlying implication is that there isa true clinical difference among different opioids. However,at present, there is little evidence to support the use of onestrong opioid over another in the treatment of cancer-relatedpain. Drug company trials have focused on acute and/ornonmalignant pain [12, 13], such as chronic back pain, andcare should be taken when extrapolating data from thosetrials to support use in patients with cancer who, by nature,are less well and often taking multiple concomitant medi-cations. To date, large RCTs have not been undertaken todirectly compare opioids for cancer-related pain, andsmaller individual trials are underpowered to demonstratesuperiority of one opioid over another [14–19]. Therefore,
F 1.
The World Health Organization analgesic ladder.
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Ross, Riley, Quigley et al.
the decision by both the WHO and the European Associa-tion for Palliative Care (EAPC) to recommend morphineas the opioid of choice is based largely on clinical expertiseand pragmatic reasons, such as the general availability of morphine sulphate worldwide and the considerable clinicalexperience in using this drug.In terms of analgesia, all opioids should be equipotent,provided appropriate equianalgesic doses are used. How-ever, there is variability in published dose-conversion tablesand wide interindividual variability in response. In clinicalpractice, a dose ratio of oral morphine:oxycodone of 2 isoften used. Figure 2 shows the preswitch dose of morphineand subsequent stable dose of oxycodone postswitchingfor 44 patients who were recruited as part of a prospectiveclinical trial to evaluate opioid switching [10]. Whereasthe median dose ratio of morphine:oxycodone was 1.7, therange from the individual patient data was large, 0.25–12.This illustrates the need to use conversion tables as a guidebut to titrate doses for individual patients. Such problemsare accentuated with opioids such as methadone, which isstored in adipose tissue and has a rapid distribution phasefollowing oral administration followed by a slow elimi-nation phase with slow transfer between tissue stores andplasma [20, 21].Is there a difference among opioids in relation to theadverse-effect profile? Large, randomized, controlled tri-als have not been done to directly compare opioids, andsmaller individual trials are underpowered to demonstratesuperiority of one opioid over another [14–19]. In addition,studies involving more recently available opioids have beenundertaken in mainly noncancer populations. One cannotassume side-effect profiles will be the same in patients witha diagnosis of advanced cancer, often with comorbiditiesand taking multiple concomitant medications. This doesnot exclude the possibility that real differences exist clini-cally between morphine and other opioids. However, we donot currently have sufficient evidence to prove this point.Is there any evidence that patients who are switchedachieve a better clinical outcome? A recent systematicreview looked at the evidence for opioid switching as auseful therapeutic maneuver in patients (adults and chil-dren, cancer and noncancer) with pain [6]. The reviewhighlights the lack of robust data available: no RCTs werelocated. Published data on opioid switching included casereports (52 studies), retrospective studies/audits (15 stud-ies), and prospective controlled trials (14 studies). Notsurprisingly, published reports tended to report positiveresults, improvement in pain and/or adverse effects, onswitching opioids. In general, morphine tended to be theopioid of first choice, with most initial switches involv-ing methadone. Infrequently, there have been reports of anopioid switch failing to improve symptoms [22]. A varietyof confounding variables—such as a change in route aswell as drug, grouping neuropathic and nociceptive paintogether, and failure to exclude other potential causes of adverse effects—made it impossible to draw definitiveconclusions in the review.A more recent study, published since the systematicreview, prospectively evaluated the clinical benefits of switching from morphine to an alternative opioid [10]. Onehundred eighty-six palliative care patients were recruited.Responders were treated with morphine for more than 4weeks with good analgesia and minimal side effects. Non-responders (switchers) either had uncontrolled pain orunacceptable morphine-related side effects. Forty-seven(of 186) patients were in the switchers group. Thirty-sevenof these (79%) had a successful outcome with a second-lineopioid, oxycodone.
Scientific Rationale for Switching:Genetic Variation in Candidate Genes
A patient’s response to a drug depends on multiple factors.Pharmacokinetic determinants include drug absorption,distribution, metabolism, and elimination. Pharmacody-namic factors—for example, drug concentration at the
F 2.
Comparison of opioid dose before and after switch-ing. Morphine dose (mg/24 hours) versus final oxycodonedose (mg/24 hours) in 44 switchers who responded to oxyco-done as a second-line opioid. The median (range) dose ratio of morphine:oxycodone was 1.7 (0.24–12).
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