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) . 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) , 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 . 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) , and the pharmacology of individual opioids,including the advantages of different routes of administra-tion, has been reviewed elsewhere . This review focuseson opioid switching.The concept of interindividual variability in morphineanalgesic response is not a new one. In the 1950s, Lasagnaand Beecher  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 . 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 . 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.  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,
The World Health Organization analgesic ladder.