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

8/3/2019 Joy R. Ross et al- Clinical Pharmacology and Pharmacotherapy of Opioid Switching in Cancer Patients

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The Oncologist 2006;11:765773 www.TheOncologist.com

Clinical Pharmacology and Pharmacotherapyof Opioid Switching in Cancer Patients

Joy R. Ross, , Julia Riley, Columba Quigley, Ken I. Welsh

aDepartment of Palliative Medicine, Royal Marsden Hospital, London, United Kingdom;bDepartment of Clinical Genomics, Imperial College, London, United Kingdom;

cCancer 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: [email protected] Received March 15, 2006; accepted for publi-cation May 26, 2006. AlphaMed Press 1083-7159/2006/$20.00/0

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IntroductionPain is one of the most common and often most fearedsymptoms in patients with cancer. Ongoing or progressive

pain 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 ObjectivesAfter 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 onl ine and receive 1 AMA PRA Category 1 Credit at CME.TheOncologist.comCMECME


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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 prescr ibing 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, controlled

clinical tr ials (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 switchedto 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 morphine

analgesic 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 alternative

opioid [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, part icularly 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 TrialsIf 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 demonstratesuperior ity of one opioid over another [1419]. Therefore,F 1.The World Health Organization analgesic ladder.


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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 clinical

experience 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 par t 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, 0.2512.

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 tr i-als have not been done to directly compare opioids, andsmaller individual trials are underpowered to demonstratesuperiority of one opioid over another [1419]. 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 therapeut ic 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 tr ials (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 variablessuch as a change in route aswell as drug, grouping neuropathic and nociceptive paintogether, and failure to exclude other potential causes of adverse effectsmade it impossible to draw defin itiveconclusions in the review.

A more recent study, published since the systematicreview, prospect ively 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. Thir ty-sevenof these (79%) had a successful outcome with a second-lineopioid, oxycodone.

Scientific Rationale for Switching:Genetic Variation in Candidate GenesA patients response to a drug depends on multiple factors.Pharmacokinetic determinants include drug absorption,distribution, metabolism, and elimination. Pharmacody-namic factorsfor 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 (0.2412).


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target site, number and morphology of target receptors, andvariation in downstream events after receptorligand bind-ingall combine to influence overall response. Pharmaco-dynamic and pharmacokinetic variation in drug handlingmay be further in fluenced by age, concomitant medica-

tions, underlying disease, and various environmental fac-tors, including diet. When comparing different opioids, it isuseful to consider both their routes of metabolism and theirreceptor profiles [7].

Little of the interindividual variation in response tomorphine can be attributed to age, gender, cancer diagnosis,or renal or liver function [23], and a number of authors havehighlighted the potential importance of a genetic influ-ence on morphine responsiveness [2427]. It would appearthat, although some of the differences among individuals interms of opioid sensitivity can be related to differences inenvironmental factors, age, pain severity, emotional state,

and prior pain experience, much of this variation could be aresult of genetic factors [28].

The genetic code, DNA, carr ies the complete geneticinformation of a cell and consists of thousands of genes.Each gene serves as a code or template for building a pro-tein molecule, such as a receptor or an enzyme. Variation inthe genetic code can alter protein expression and function.Given the broad spectrum of proteins involved in determin-ing response to a drug, genetic variation in multiple genescould inf luence an individuals response to different opi-oids [29]. In addition, given the pharmacokinetic and phar-macodynamic differences among the opioids, such varia-tion may favor treatment with one opioid versus another fora given individual. The evidence for genetic variation in aselection of candidate genes, influencing response to dif-ferent opioids, is outlined below.

D T p : P-G pThe membrane-bound drug transporter P-glycoproteininfluences drug absorption and drug excretion [30, 31]. Itregulates transfer of opioids across the bloodbrain bar-rier and can act ively pump opioids out of the central ner-vous system (CNS) [32]. P-glycoprotein knockout mice,which are completely devoid of P-glycoprotein activity,have enhanced absorption and high CNS concentrationsof P-glycoprotein substrates (e.g. morphine, fentanyl, andmethadone) with associated prolongation of analgesia [33].Administration of cyclosporin, a P-glycoprotein inhibitor,results in increased fentanyl- and morphine-induced anal-gesia [33, 34]. Inter individual variability in P-glycoproteinactivity is well recognized, and genetic variation in themultidrug resistance gene MDR-1 , which encodes for P-glycoprotein, has been associated with resultant alterationsin P-glycoprotein activity [32, 35]. Because P-glycopro-

tein modulation of opioid CNS levels varies substantiallyamong different opioids, the effects of genetic variationaltering P-glycoprotein activity are different, depending onthe opioid in question [34]. MDR-1 , the gene that codes forP-glycoprotein, is therefore a good candidate gene for inf lu-

encing analgesic response to opioids and the prevalence of opioid-induced CNS side effects.Whereas multiple single nucleotide polymorphisms

(SNPs) have been identified in the MDR-1 gene, two muta-tions ( C3435T and G2677T/A ) have been associated withdifferences in P-glycoprotein expression or function [36,37]. Variation in the G2677T/A genotype has also beenshown to alter drug levels [38] and drug-induced side effects[39]. There are no studies to date reporting on analgesicresponse or opioid side-effect profiles in relation to varia-tion in the MDR-1 genotype.

Op R pDuring the past 20 years, three opioid receptors p, , , andhave been identified, and the genes coding for thesereceptors have now been cloned [40]. Morphine and othercommonly used opioids, including oxycodone, hydromor-phone, methadone, and fentanyl, act primarily at the sametarget receptor, the -opioid receptor [41]. In addition, oxy-codone [42], methadone [20], and buprenorphine [43] mayhave clinically important activity at other opioid receptors.In -opioid receptor knockout mice, in which the gene codingfor the receptor has been disrupted, analgesic models showcomplete loss of analgesic and other morphine activities,reinforcing the critical importance of the -opioid receptor inmorphine-mediated effects [44]. Changes in -opioid recep-tor densities, potentially contributed to by allelic variants, canproduce changes in nociceptive responses and affect opioidresponse [44]. Binding studies to postmortem brain samplesand in vivo positron-emission tomography radio-ligand anal-yses suggest 30%50% or even larger ranges of individualhuman differences in -opioid receptor densities [45].

More than 100 polymorphisms have been identifiedin the human -opioid receptor gene, and some of thesevariants have been shown to alter the binding affinities of different opioids [4649]. The most widely studied poly-morphism in the -opioid receptor gene is the A118G nucle-otide substitution, which codes for the amino-acid changeasparagine to aspartic acid. It has been reported in associa-tion with both addiction and pain studies. Addiction stud-ies have published conflicting results. While some studieshave reported a protective effect of the mutant allele againstdrug [50] and a lcohol [51] abuse, other studies found nosuch association [5254]. In pain studies, there have beensuggestions that the mutant allele may decrease the potencyof morphine or morphine-6-glucuronide (M6G) in cancer


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patients [5256]. A study of 99 patients with controlled can-cer pain reported that patients homozygous for the variantallele ( n = 4) needed more morphine to control pain thanheterozygous ( n = 17) and homozygous wild-type ( n = 78)individuals [57]. In a recent, prospective study in cancer

patients, we evaluated genetic variation in a number of candidate genes, including the -opioid receptor gene, inpatients with cancer pain who responded to morphine ver-sus those who were switched to an alternative opioid [26].No differences were seen in genotype or allelic frequenciesfor polymorphisms in the -opioid receptor gene.

The -opioid receptor is a G-protein-coupled receptor(GPCR) [58]. Opioid receptor signaling results in inhibitionof neuronal transmission of painful stimuli by a complexsequence of events [59]. GPCR signaling is regulated byreceptor desensitization, endocytosis, and downregulation[60]. -arrestin-2 is an intracellular protein that is involved

at multiple points in regulating receptor phosphorylation,desensitization, and internalization [61, 62]. In animalstudies, the analgesic effect of morphine is both increasedand prolonged in -arrestin-2 knockout mice [63]. Becauserates of -opioid receptor internalization and desensitiza-tion differ according to which ligand binds [64], polymor-phic variation affecting -arrestin-2 may have a greater orlesser effect depending on the opioid given.

Whereas the study by Ross et al. [26] above showed nodifferences between controls and switchers for polymor-phisms in the -opioid receptor gene, a significant differ-ence was seen in genotype and a llelic frequency for theT8622C polymorphism in the -arrestin-2 gene. This SNPin exon 11 does not result in an amino-acid change but isat a wobble position and may therefore influence mRNAtranslation [65].

Op MThere is no single common metabolic pathway for themetabolism of opioids. Codeine [66] and oxycodone [67]are metabolized by the cytochrome P450 (CYP)2D6enzyme. Oral morphine and hydromorphone are primar-ily metabolized in the liver through the uridine-diphos-phoglucuronosyltransferase (UGT) system [68]. Fentanyl[69] and methadone [70] are metabolized by the CYP3A4enzyme, which is responsible for the complete or partia lmetabolism of 50% of all known drugs. Genetic varia-tion in CYP2D6 results in poor metabolism of the opioidcodeine to its active metabolite morphine [66, 71]. Otherstudies have shown important pharmacogenetic influencesin oxycodone [67] and morphine [72] metabolism.

Oral morphine is primarily metabolized in the liverby the UGT system [68]. The pharmacology of morphineand these two main metabolites in humans has been well

documented [73]. Both morphine and its metabolite lev-els vary greatly among individuals, not only because of differences in dosing, but also because of interindividualvariability in pharmacokinetics. Faura et al. [73] showeda high correlation, independent of clinical variables,

between M3G and M6G, confirming that a single enzymeis responsible for metabolism of morphine, na melyUGT2B7 [74].

A number of SNPs in the promoter region of UGT2B7have been reported, but their impact on enzyme functionis debated [75]. In vitro studies have demonstrated alteredtranscription factor binding to polymorphic regions, butthese do not translate into altered promoter activity [76].Whereas one clinical study showed that genetic variationin the promoter region correlated with serum morphineand M6G concentrations [77], this was not confirmed ina subsequent larger study [78]. One SNP in exon 2 results

in an amino-acid substitution, histidine to tyrosine, at theproposed location of the substrate-binding site [76]. How-ever, no relationship has been shown between this vari-ant and morphine metabolism in patients with cancer [26,79]. Although research continues in this area, it appears atthe moment that polymorphisms in genes controlling themetabolism of morphine do not, in isolation, explain inter-individual variability in morphine response.

The CYP enzymes CYP3A4, CYP3A5, and CYP2D6are important in the metabolism of a number of strong opi-oids, including oxycodone, fentanyl, and methadone. Multi-ple SNPs have been validated in the CYP3A4 gene, but


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Genetic variation may affect both the funct ion of a givenprotein (e.g., an enzyme or receptor) and also the amount of protein that is transcribed. Such differences in gene expres-sion can result from alterations in the cis-acting DNA pro-moter and enhancer sequences that are typically found in

the 5 ends of genes and are often recognition sites for regu-latory DNA-binding proteins [91]. These proteins includetranscription factors whose primary function is to bind tospecific sequences within the gene regulatory region and tointeract with RNA polymerase in order to regulate the rateof transcription.

Transcription of UGT2B7 is regulated by the transcrip-tion factor hepatic nuclear factor 1 alpha (HNF-1 ) [90,92]. Another transcription factor, octamer transcriptionfactor 1, acts as a coregulatory protein by binding to HNF-1 to increase the rate of UGT2B7 transcription [92]. Othercoregulatory proteins, such as dimerization cofactor of

HNF-1 (DCoH), stabilize the proteinDNA complex priorto recruitment of RNA polymerase [93]. As such, geneticvariation in these genes may also be important in inf luenc-ing response to morphine.

A number of transcr iption factor recognition siteshave been postulated in the human -opioid receptor gene[91, 94]. One of these, signal tr anducer and activator of transcr iption 6 (STAT-6) has been shown to be function-ally relevant [95]. Whereas the stat-6 gene is known tobe highly polymorphic, most of the validated SNPs liein intronic, noncoding regions. Our study, comparingswitchers who did not tolerate morphine with controlswho responded to morphine, showed significant di ffer-ences in the genotype of the stat-6 gene between switchersand controls [26]. Research continues to examine othertranscription factors that may be important in inf luencingresponse to different opioids.

C p x P : O P IResponse to a painful stimulus is regulated by interactionsbetween multiple regions within the brain v ia differentneurochemical pathways [96]. There is evidence to supportinteraction between dopaminergic and adrenergic pathways

and opioid signaling pathways in the CNS [97]. Catechol-O-methyltransferase (COMT) is one of the enzymes thatmetabolizes catecholamines and is an important modula-tor of neurotransmitters in the brain. Polymorphic variationin the COMT gene has been shown to affect -opioid neu-rotransmitter responses to a pain stressor [97] and to influ-ence interindividual var iation in pain sensitivity [98]. Inaddition, Rakvag et al. [99] have demonstrated a correlationbetween COMT genotype and morphine dose requirementsin cancer patients.

Conclusion

There is evidence to support the therapeutic maneuver of opioid switching in clinical practice, but further evidenceis needed to elucidate the underlying mechanisms for inter-individual differences in response to different opioids.Large, robust clinical trials will be needed if clinical differ-ences among side-effect profiles of different opioids are tobe clearly demonstrated. In addition to the candidate genesdescribed above, review of the current literature shows thatapproximately 500 genes have now been implicated in painfrom animal or human studies. In order to continue to evalu-ate the genetic contributions to both pain susceptibility andanalgesic response, further candidate genes need to be con-sidered. Good pain control remains a high priority for clini-cians and patients, and there is much work to be done to fur-ther individualize analgesic therapy for patients with cancer.

Disclosure of Potential Conflictsof InterestThe authors indicate no potential conf licts of interest.

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DOI: 10.1634/theoncologist.11-7-7652006;11;765-773Oncologist

Joy R. Ross, Julia Riley, Columba Quigley and Ken I. WelshClinical Pharmacology and Pharmacotherapy of Opioid Switching in Cancer Patients

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

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