Quigley C - Opioid Switching To Improve Pain Relief and Drug Tolerability

Opioid switching to improve pain relief and drug tolerability (Review)
Quigley C
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2005, Issue 2 http://www.thecochranelibrary.com
Opioid switching to improve pain relief and drug tolerability (Review) Copyright 2005 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
TABLE OF CONTENTS ABSTRACT . . . . . . . . . . . . . . . . . . . . SYNOPSIS . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW SEARCH STRATEGY FOR IDENTIFICATION OF STUDIES . . METHODS OF THE REVIEW . . . . . . . . . . . . . DESCRIPTION OF STUDIES . . . . . . . . . . . . . METHODOLOGICAL QUALITY . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . POTENTIAL CONFLICT OF INTEREST . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . TABLES . . . . . . . . . . . . . . . . . . . . . Characteristics of excluded studies . . . . . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . Table 01 Characteristics of prospective studies . . . . . . . Table 02 Characteristics of retrospective surveys . . . . . . Table 03 Characteristics of case reports . . . . . . . . . COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 2 2 2 2 3 4 5 5 5 5 6 6 6 6 9 9 10 10 16 24 27
Opioid switching to improve pain relief and drug tolerability (Review)

Quigley C
This record should be cited as: Quigley C. Opioid switching to improve pain relief and drug tolerability. The Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD004847. DOI: 10.1002/14651858.CD004847. This version rst published online: 19 July 2004 in Issue 3, 2004. Date of most recent substantive amendment: 21 May 2004
ABSTRACT Background Patients with cancer, and increasingly chronic non-cancer pain frequently require strong opioids for pain relief. Morphine is the rstline strong opioid of choice for these patients. While most achieve adequate analgesia with morphine, a signicant minority either suffer intolerable side-effects, inadequate pain relief, or both. For these patients switching to an alternative opioid is becoming established clinical practice. However, the evidence for the effectiveness of opioid switching does not appear to be established. Objectives The aim of this review was to investigate the usefulness of opioid switching for patients with pain. Search strategy Randomised trials that assessed opioid rotation, switching, or substitution in adults or children with acute or chronic pain were sought through electronic databases and by handsearching relevant journals. Date of the most recent search: January 2003. Selection criteria The search strategy retrieved no randomised controlled trials, and therefore no studies were available to enable a quantitative synthesis that would assess the effectiveness of the strategy of opioid switching. Data collection and analysis Given the lack of RCTs, the review examined all case reports, uncontrolled, and retrospective studies in an attempt to determine the current level of evidence. Main results Fifty-two reports were identied, comprising 23 case reports, 15 retrospective studies/audits and 14 prospective uncontrolled studies. The majority of the reports used morphine as rst-line opioid and the most frequently used second-line opioid was methadone. All reports, apart from one, concluded that opioid switching is a useful clinical manoeuvre for improving pain control and/or reducing opioid-related side-effects. Authors conclusions For patients with inadequate pain relief and intolerable opioid-related toxicity/adverse effects, a switch to an alternative opioid may be the only option for symptomatic relief. However, the evidence to support the practice of opioid switching is largely anecdotal or based on observational and uncontrolled studies. Randomised trials, including N of 1 studies, where a patient acts as their own control, are needed: rstly, to establish the true effectiveness of this clinical practice; secondly, to determine which opioid should be used rst-line or second-line; and thirdly, to standardise conversion ratios when switching from one opioid to another.
Opioid switching to improve pain relief and drug tolerability (Review) Copyright 2005 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 1
SYNOPSIS The effectiveness of opioid switching to manage pain relief inadequacies and intolerable side effects could not be assessed because of a lack of randomised controlled trials. Opioid switching is the term given to the clinical practice of substituting one strong opioid with another, in an attempt to achieve a better balance between pain relief and side effects. This is an established clinical practice for patients with cancer pain, but the evidence is based on case reports and uncontrolled studies, and no randomised trials met the inclusion criteria for this review. In addition, the case reports and uncontrolled studies are inconsistent in their reporting of the reasons for opioid switching (whether the change was made because of intolerable side effects, inadequate pain relief, or both). It is also unclear whether the initial opioid was being given at a high enough, but tolerable, dose to achieve maximum pain relief. Opioids are increasingly used for non-cancer pain, but the practice of opioid switching does not yet appear to be established in this group of patients.
CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW BACKGROUND Most patients with cancer develop pain requiring strong opioids (Foley 1985). In addition, the use of strong opioids in the management of chronic non-cancer pain is increasing (Allan 2001). Morphine is the drug of choice, as recommended by the World Health Organisation, for the management of moderate to severe cancer-related pain (WHO 1996). However, a signicant minority do not achieve adequate analgesia with morphine. In this group of patients, intolerable side-effects such as vomiting, delirium and myoclonus preclude dose escalation. It has been observed clinically that switching from one opioid, which has failed to control pain or caused intolerable side-effects, to an alternative opioid can result in improved tolerability, or pain control, or both (Daeninck 1999b). Opioid rotation, or more accurately opioid switching, is the term given to the clinical practice of substituting one strong opioid with another in an attempt to achieve a better balance between analgesia and side effects. Some clinicians claim that most patients need to change the type of strong opioid at least once to achieve optimal pain control with acceptable side effects (Bruera 1996). However, the evidence for opioid switching as a useful therapeutic manoeuvre appears to be largely based on uncontrolled surveys and clinical reports. Despite this, opioid switching has become an established practice for the management of cancer-related pain,and sequential trials of opioid analgesics are now recommended in clinical guidelines (Jacox 1994). Types of studies All randomised trials controlled trials, published and unpublished, that assess opioid rotation/switching/substitution as a strategy for pain relief and/or side-effect management were sought. Types of participants Subjects included adults and children, both male and female, of any age. Patients suffering from any illness, with either acute or chronic pain, including cancer pain and post-operative pain, were eligible for inclusion in the review. Studies of healthy volunteers, who received opioids for experimental pain, were not included. Types of intervention All studies which involved switching from one opioid to another because of inadequate analgesia and/or intolerable side-effects were considered, regardless of duration of treatment (single or multiple doses) or mode of administration (oral/parenteral/epidural). Types of outcome measures Pain and adverse effects, measured by visual analogue scale and verbal rating scale, were assessed. When extracting pain data, patientreported assessments of analgesic effect were preferred. Where available, data on the following were also extracted: analgesic requirements for the relief of breakthrough pain patient preference quality of life global improvement
OBJECTIVES This review aims to determine the effectiveness of opioid switching as an effective therapeutic strategy for patients with pain.
SEARCH STRATEGY FOR IDENTIFICATION OF STUDIES See: Pain, Palliative Care and Supportive Care Group search strategy
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Electronic databases The following electronic databases were searched for trials for inclusion in this review: The Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library , Issues 2 and 3 MEDLINE (1966 to January 2003) EMBASE (1980 to January 2003) A search strategy was devised for use in MEDLINE, and adapted appropriately for the other databases. The strategy combines free text and MeSH (ME) terms: #1 MORPHINE:ME #2 METHADONE:ME #3 LEVORPHANOL:ME #4 DIACETYLMORPHINE:ME #5 FENTANYL:ME #6 ALFENTANIL:ME #7 SUFENTANIL:ME #8 OXYCODONE:ME #9 MEPERIDINE:ME #10 NARCOTICS:ME #11 OPIOID* #12 MORPHINE* #13 METHADONE #14 LEVORPHANOL #15 FENTANYL #16 SUFENTANIL #17 OXYCODONE #18 HYDROMORPHONE #19 DIAMORPHINE #20 KETOBEMIDONE #21 PETHIDINE #22 DIACETYLMORPHINE #23 ALFENTANIL #24 MEPERIDINE #25 OPIATE* #26 (((((((((((((((((((((((#1 or #2) or #3) or #4) or #5) or #6) or #7) or #8) OR (#9 and OR#10)) OR #11) OR #12) OR #13) OR #14) OR #15) OR #16) OR #17) OR #18) OR #19) OR #20) OR #21) OR #22) OR #23) OR #24) OR #25) #27 ((((OPIOID or OPIATE) NEAR ROTATION) OR ((OPIOID OR OPIATE) NEAR SWITCH*)) OR ((OPIOID OR OPIATE) NEAR SUBSTITUT*)) #28 ((SWITCH* or ROTAT*) or SUBSTITUT*) #29 (#27 or #28) #30 (#26 and #29) Language Relevant studies were sought irrespective of language of publication. Hand searching
The following journals were hand searched (up to January 2003) Pain Journal of Pain and Symptom Management Anesthesia and Analgesia European Journal of Oncology Nursing European Journal of Pain European Journal of Palliative Care International Journal of Palliative Nursing Journal of Cancer Education Journal of Palliative Care Pain Reviews Palliative Medicine Progress in Palliative Care The Hospice Journal In addition, the reference lists of all identied studies or reports were searched for additional trial reports.
METHODS OF THE REVIEW Selection of studies The abstracts of references retrieved by the search strategy were assessed against the inclusion criteria. If insufcient information was provided in the abstract to determine if a trial was eligible for inclusion, or the abstract was not available, a full paper copy was obtained. Reasons for excluding trials from the review are reported in the Characteristics of Excluded Studies Table. Data extraction A data extraction form was designed for the purpose of the review. For each study it was planned to extract the following information: study design number of patients in the trial patient characteristics (gender, age, weight, condition: acute pain, chronic pain, cancer pain) interventions (type of opioid(s) administered, comparisons, dosing regimens, route of administration) outcome measures used (patient-reported pain relief/intensity change scores; global improvement; patient satisfaction/ preference; quality of life scores) analgesic outcomes (number of patients remedicating and time to remedication) study duration
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adverse effects outcomes reasons for patient withdrawal and number of withdrawals Data analysis Data analysis using the standardized mean difference method for continuous data was planned. If appropriate, converting the data to dichotomous outcomes using the number of patients obtaining at least 50% maximum total pain relief would have been undertaken, and a summary statistic for treatment effect using RevMan Analyses 1.02 (in Review Manager software 4.2.6) would have been derived. A subgroup analysis of patients with cancer pain was planned. In addition, the review planned to perform an analysis of individual opioids in relation to opioid switching, both in terms of frequency and efcacy. Quality assessment The validity of each trial that met the inclusion criteria was to be assessed rstly, using the method described in the Cochrane Handbook where a grade is allocated to each study on the basis of allocation concealment (A = adequate; B = unclear; C = clearly inadequate; D = allocation concealment not used), and secondly, using the Oxford scale derived by Jadad 1996, a three-item, 1-5 score, that assesses methodological quality. In the event, the lack of included studies meant that these assessments were not undertaken.
sufentanil for postoperative pain control in patients with cancer already receiving morphine pre-operatively (de Leon 1994). Few reports described the pain diagnosis, and whether a neuropathic component was present. Seven of the prospective studies were open, uncontrolled studies, the remaining seven were audits/prospective data collection of current practice. Thirteen of the 14 articles reported that switching of opioid improved pain control, or reduced opioid adverse effects, or both. One paper which collected prospective data on 13 rotations from methadone to an alternative opioid, reported pain escalation and/or dysphoria with the second opioid (Moryl 2002). The authors of this study conclude that the lack of a uniformly accepted conversion ratio for substituting methadone with another opioid can created difculties with opioid switching. Four studies involved a specic switch to methadone; the morphine:methadone conversion ratio varied from 4:1 to 12:1. Eight studies involved a change of route of drug administration as well as a change of opioid. Retrospective studies (Table 02) Fifteen retrospective studies/surveys are described in Table 02 (Bruera 1995b; Bruera 1996; De Conno 1996; de Stoutz 1995; Gagnon 1999b; Kloke 2000; Lawlor 1997b; Lawlor 1998; Lee 2001; Morley 1993; Paix 1995; Quang-Cantagrel 2000; Rimmer 1996; Ripamonti 1998b; Thomsen 1999). One paper described the effects of opioid rotation in patients with chronic nonmalignant pain (Thomsen 1999). The remaining 14 reports involved patients requiring opioids for cancer-related pain. Overall, opioid switching appeared to be instigated for relief of opioid-related toxicity and/or inadequate analgesia. All 15 papers reported a favourable outcome with opioid switching. Six surveys looked specically at switching to oral methadone (Bruera 1996; De Conno 1996; Lawlor 1998; Morley 1993; Rimmer 1996; Ripamonti 1998b). While methadone appeared well tolerated and effective, it was suggested that the potency of methadone is underestimated and therefore a switch from less potent opioids such as morphine to methadone should be undertaken with caution. Case reports (Table 03) Twenty-three published papers were found that described case studies, all involved cancer patients (Bruera 1992a; Crews 1993; Daeninck 1999a; del Rosario 2001; Fainsinger 1995; Fitzgibbon 1997; Galer 1992; Hagen 1997; Jellema 1987; Kalso 1988; Katcher 1999; Lawlor 1997a; Leng 1994; Loitman 2002; MacDonald 1993; Manfredi 1997; Parkinson 1990; Sabatowski 2002; Shaiova 2002; Sjogren 1994; Steinberg 1992; Thomas 1995; Vigano 1996). The number of cases ranged from one to six in each reported series, with a median of two case reports per paper. The reasons for switching opioid were refractory pain, intolerable adverse effects (hallucinations, drowsiness, delirium, myoclonus, vomiting, constipation, itching), or both. The most frequently
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DESCRIPTION OF STUDIES Included studies Despite an extensive search of the literature, no randomised controlled trials were identied that met the inclusion criteria. However, 52 uncontrolled studies were identied by the search strategy for electronic trials described above, and these are described in three Additional tables (Table 01, Table 02, Table 03). Other studies Of the 52 uncontrolled studies retrieved by the search strategy, 14 were prospective studies, 15 were retrospective surveys, and 23 were case reports. All 52 reports assessed patients with chronic pain: two reports focused on non-cancer pain and the remaining 50 reported on opioid switching in the cancer pain setting exclusively. More than half of the papers were based on research conducted at centres in Canada or North America. Prospective studies (Table 01) Fourteen prospective reports were retrieved: Ashby 1999; Bruera 1995a; Cherny 1995; de Leon 1994; Gagnon 1999a; Maddocks 1996; Mercadante 1999a; Mercadante 2001; Moryl 2002; Santiago-Palma 2001; Sawe 1981; Slover 1992; Walsh 2002; Tse 2003. All patients assessed in these reports had cancer pain. In 13 reports the opioid switch was indicated for cancer-related pain. One study described switching from epidural morphine to epidural
used initial opioid was morphine, and the most frequently used second-line opioid was methadone.
(excluding reviews) on opioid switching. The papers retrieved fell into three main groups: case reports, retrospective surveys and prospective uncontrolled studies. These are described above in the Description of Studies section. Case reports The purpose of case reports is to generate hypotheses, in this case that switching from one opioid to another can be a useful therapeutic manoeuvre for a sub-group of patients with uncontrolled chronic pain. No further signicance can be attached to case reports as evidence for guiding clinical practice. Retrospective studies Similarly, while retrospective studies can support hypotheses generated by case reports and guide research, from a methodological point of view retrospective data are too open to bias and confounding variables to allow evidence-based conclusions to be drawn. Prospective studies Fourteen prospective studies were identied. Seven of these were open, uncontrolled studies involving between ve and 63 patients with cancer pain. While these studies varied signicantly in their methodology, the ndings of these seven papers can be broadly summarised as follows: Opioid switching appeared to be effective, both in terms of improving pain relief and reducing opioid related adverse effects. Issues of equianalgesic dose ratios between different opioids remain unresolved.
METHODOLOGICAL QUALITY The search strategy did not retrieve any randomised trials that met the inclusion criteria. Therefore no studies were assessed for methodological quality.
RESULTS No studies with appropriate methods were identied for inclusion in this review, and therefore no data were available for analysis. However, a summary of the best information available is provided in Table 01, Table 02 and Table 03.
DISCUSSION Most patients with moderate to severe cancer pain require strong opioids. In addition, the use of strong opioids in those with chronic non-cancer pain is increasing. While morphine remains the gold standard strong opioid, in 10-30% of patients with cancer pain adequate analgesia is not achieved (Cherny 2001). This is generally because intolerable opioid-related adverse effects preclude dose escalation to the point of maximum analgesia. It is a widely held belief that, for these patients, a switch to an alternative opioid is generally better tolerated, giving decreased toxicity and increased pain relief. While the term opioid rotation is frequently seen in the literature, opioid switching more accurately reects clinical practice, as few reports indicated rotation back to the original opioid. From a neurophysiological stand-point, the scientic rationale behind the inter-individual variability in opioid response is poorly understood. Notwithstanding, the practice of opioid switching to improve analgesia and tolerability is an established and recommended practice in palliative medicine (Jacox 1994; Daeninck 1999b). This review attempted to establish the evidence base for switching opioid for patients who have inadequate analgesia and/or intolerable opioid-related adverse-effects. However, an extensive search failed to identify any randomised controlled trials that attempted to establish the benets of this strategy for the relief of chronic pain, reduction of opioid adverse effects, or to establish dose conversion ratios. The absence of data appropriate for analysis means that there is currently limited evidence available to guide clinical practice. However, in order to assess current experience and to guide future research, it was decided to look more closely at all published reports
AUTHORS CONCLUSIONS Implications for practice In all the identied reports of opioid switching, it is unclear whether the improved outcome post-switch is a true drug effect, or merely improved tolerability as a result of dose reduction. Inconsistencies in the reporting of conversion ratios makes it difcult to interpret results. In addition, other confounding variables such as pain syndrome, use of adjuvant analgesics, other causes of toxicity, were not addressed in the majority of the reports. Publication bias, where there is a bias towards reporting only positive ndings, is especially obvious here, with only one paper highlighting potential problems with opioid switching (Moryl 2002). A robust evidence base for the practice of opioid switching does not exist. Uncontrolled data available suggest that for some patients a switch in opioid may improve pain and/or opioid related adverse effects. However, these hypotheses have not been tested in a controlled trial. In addition, few reports involve true rotations, that is, rotation back to the original opioid to see whether the positive benet is a true drug effect. In addition, many reported opioid switches also involved a switch of route, which may have a specic and additional effect of its own.
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However, it needs to be acknowledged that, despite the lack of an evidence base for this therapeutic strategy, for patients suffering chronic cancer pain opioid switching may be the only option for enhancing pain relief and minimising opioid toxicity. Opioid switching is not yet an established practice for the management of chronic, non-cancer pain. However, with the increasing use of strong opioids for the management of all types of chronic pain, opioid switching may be seen more frequently in the clinical management of those patients with non-cancer pain and poor opioid response. Implications for research Due to differences in opioid formulation (for example, transdermal fentanyl) and kinetics (for example, long acting methadone), it is difcult to test opioid switching in a randomised blinded trial, although blinding of outcome assessors and patients should be possible in most instances. Application of the N of 1 trial design, with each patient acting as their own control, would, with sufcient numbers, provide some useful evidence. Opioids with similar pharmacokinetic proles, such as morphine, hydromorphone and oxycodone, could be compared in terms of toxicity and analgesia in a randomised controlled trial. In addition, the fate of opioids such as hydromorphone, oxycodone and fentanyl, both the parent drug and active metabolites, in renal dysfunction is not clear. An understanding of which opioids are safe to use in patients with renal impairment would signicantly improve management in this group of patients.
While most clinicians believe that opioid switching benets a small group of patients, there are still wide gaps in our understanding of inter-individual variability in opioid response. Translational research, to bridge the gap between what is practised in the clinical setting, and basic scientic research into the neurophysiology, is needed to test the hypothesis that opioid switch is a useful manoeuvre for some patients with uncontrolled pain and/or intolerable opioid related adverse effects.
ACKNOWLEDGEMENTS The author wishes to acknowledge the assistance of Sylvia Bickley, Trials Search Co-ordinator for the Pain, Palliative and Supportive Care Group, in the development of the search strategy for this review.
POTENTIAL CONFLICT OF INTEREST None known.
SOURCES OF SUPPORT External sources of support No sources of support supplied Internal sources of support No sources of support supplied
REFERENCES
References to studies excluded from this review

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Allan 2001 Allan L, Hays H, Jensen NHJ, et al. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ 2001;322:11548. Ashby 1999 Ashby MA, Martin P, Jackson KA. Opioid substitution to reduce adverse effects in cancer pain management. Medical Journal of Australia 1999;170:6871. Bruera 1992a Bruera E, Schoeller T, Montejo G. Organic hallucinosis in patients receiving high doses of opiates for cancer pain. Pain 1992;48:3979. Bruera 1995a Bruera E, Watanabe S, Fainsinger RL, et al. Custom-made capsules and suppositories of methadone for patients on high-dose opioids for cancer pain. Pain 1995;62:1416. Bruera 1995b Bruera E, Franco JJ, Maltoni M, et al. Changing pattern of agitated impaired mental status in patients with advanced cancer: association with cognitive monitoring, hydration, and opioid rotation. Journal of Pain and Symptom Management 1995;10:28791. Bruera 1996 Bruera E, Pereira J, Watanabe S, et al. Opioid rotation in patients with cancer pain: a retrospective comparison of dose ratios between methadone, hydromorphone and morphine. Cancer 1996;78:8527. Cherny 1995 Cherny NJ, Chang V, Frager G, et al. Opioid pharmacotherapy in the management of cancer pain. Cancer 1995;76:128893. Cherny 2001 Cherny N, Ripamonti C, Pereira J, Davis C, Fallon M, McQuay H, et al. Strategies to manage the adverse effects of oral morphine: an
Hagen 1997 Hagen N, Swanson R. Strychnine-like multifocal myoclonus and seizures in extremely high-dose opioid administration: treatment strategies. Journal of Pain and Symptom Management 1997;14:51 8. Jacox 1994 Jacox A, Carr DB, Payne R. Management of cancer pain. Clinical Practice Guideline No. 9 (AHCPR Publication no. 94-0592). Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1994. Jadad 1996 Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clinical Trials 1996;17:112. Jellema 1987 Jellema JG. Hallucination during sustained-release morphine and methadone. Lancet 1987;ii:392. Kalso 1988 Kalso E, Vainio A. Hallucinations during morphine but not oxycodone treatment. Lancet 1988;56:912. Katcher 1999 Katcher J, Walsh D. Opioid-induced itching: morphine sulfate and hydromorphone hydrochloride. Journal of Pain and Symptom Management 1999;17:702. Kloke 2000 Kloke M, Rapp M, Bosse B, Kloke O. Toxicity and/or insufcient analgesia by opioid therapy: risk factors and the impact of changing the opioid. A retrospective analysis of 273 patients observed at a single center. Support Care Cancer 2000;8:47986. Lawlor 1997a Lawlor P, Walker P, Bruera E, Mitchell S. Severe opioid toxicity and somatization of psychosocial distress in a cancer patient with a background of chemical dependence. Journal of Pain and Symptom Management 1997;13:35661. Lawlor 1997b Lawlor PG, Turner KS, Hanson J, et al. Dose ratio between morphine and methadone in patients with cancer pain: a retrospective study. Pain 1997;72:7985. Lawlor 1998 Lawlor P, Turner K, Hanson J, et al. Dose ratio between morphine and methadone in patients with cancer pain: a retrospective study. Cancer 1998;82:116773. Lee 2001 Lee MA, Leng MEF, Tiernan EJJ. Retrospective study of the use of hydromorphone in palliative care patients with normal and abnormal urea and creatinine. Palliative Medicine 2001;15:2634. Leng 1994 Leng G, Finnegan MJ. Successful use of methadone in nociceptive cancer pain unresponsive to morphine. Palliative Medicine 1994;8: 1535. Loitman 2002 Loitman JE. Transmucosal fentanyl in ovarian cancer. Journal of Pain and Symptom Management 2002;23:56.
MacDonald 1993 MacDonald N, Der L, Allan S, Champion P. Opioid hyperexcitability: the application of alternate opioid therapy. Pain 1993;53:3535. Maddocks 1996 Maddocks I, Somogyi A, Abbott F, et al. Attenuation of morphineinduced delirium in palliative care by substitution with infusion of oxycodone. Journal of Pain and Symptom Management 1996;12:182 9. Manfredi 1997 Manfredi PL, Borsook D, Chandler SW, et al. Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations. Pain 1997;70:99101. Mercadante 1999a Mercadante S, Casuccio A, Calderone L. Rapid switching from morphine to methadone in cancer patients with poor response to morphine. Journal of Clinical Oncology 1999;17:330712. Mercadante 2001 Mercadante S, Casuccio A, Fulfaro F, et al. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. Journal of Clinical Oncology 2001;19:2898904. Morley 1993 Morley JS, Watt JWG, Wells JC, et al. Methadone in pain uncontrolled by morphine. Lancet 1993;342:1243. Moryl 2002 Moryl N, Santiago-Palma J, Kornick C, et al. Pitfalls of opioid rotation:substituting another opioid for methadone in patients with cancer pain. Pain 2002;96:3258. Paix 1995 Paix A, Coleman A, Lees J, et al. Subcutaneous fentanyl and sufentanil infusion substitution for morphine intolerance in cancer pain management. Pain 1995;63:2639. Parkinson 1990 Parkinson SK, Bailey SL, Little WL, Mueller JB. Myoclonic seizure activity with chronic high-dose spinal opioid administration. Anesthesiology 1990;72:7435. Quang-Cantagrel 2000 Quang-Cantagrel ND, Wallace MS, Magnuson SK. Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review. Anesthesia and Analgesia 2000;90:9337. Rimmer 1996 Rimmer T, Trotman I. Methadone restores opioid sensitivity in cancer pain (abstract). Palliative Medicine 1996;10:58. Ripamonti 1998b Ripamonti C, De Conno F, Groff L, et al. Equianalgesic dose/ratio between methadone and other opioid agonists in cancer pain: comparison of two clinical experiences. Annals of Oncology 1998;9:7983. Sabatowski 2002 Sabatowski R, Kasper SM, Radbruch L. Patient-controlled analgesia with intravenous L-methadone in a child with cancer pain refractory to high-dose morphine. Journal of Pain and Symptom Management 2002;23:35.
8
Santiago-Palma 2001 Santiago-Palma J, Khojainova N, Kornick C, et al. Intravenous methadone in the management of chronic cancer pain. Cancer 2001; 92:191925. Sawe 1981 Sawe J, Hansen J, Ginman C, et al. Patient-controlled dose regimen of methadone for chronic cancer pain. BMJ 1981;282:7713. Shaiova 2002 Shaiova L, Sperber KT, Hord ED. Methadone for refractory cancer pain. Journal of Pain and Symptom Management 2002;23:1789. Sjogren 1994 Sjogren P, Jensen N, Jensen TS. Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists. Pain 1994;59:3136. Slover 1992 Slover R. Transdermal Fentanyl: Clinical Trial at the University of Colorado Health Sciences Center. Journal of Pain and Symptom Management 1992;7(3S):S4547. Steinberg 1992 Steinberg RB, Gilman DE, Johnson III F. Acute toxic delirium in a patient using transdermal fentanyl. Anesthesia and Analgesia 1992; 75:10146.
Thomas 1995 Thomas Z, Bruera E. Use of methadone in a highly tolerant patient receiving parenteral hydromorphone. Journal of Pain and Symptom Management 1995;10:3157. Thomsen 1999 Thomsen AB, Becker N, Eriksen J. Opioid rotation in chronic nonmalignant pain patients. Acta Anaesthesiol Scand 1999;43:91823. Tse 2003 Tse DMW, Sham MKM, Ng DKH, Ma HM. An ad libitum schedule for conversion of morphine to methadone in advanced cancer patients: an open uncontrolled prospective study in a Chinese population. Palliative Medicine 2003;17:20611. Vigano 1996 Vigano A, Fan D, Bruera E. Individualized use of methadone and opioid rotation in the comprehensive management of cancer pain associated with poor prognostic indicators. Pain 1996;67:1159. Walsh 2002 Walsh D, Mahmoud FA, Sarhill N, et al. Parenteral opioid rotation in advanced cancer: a prospective study. Proceedings of ASCO. 2002; 21:Abstract 1429. WHO 1996 World Health Organization. Cancer Pain Relief. 2nd Edition. Geneva: World Health Organization, 1996.
Indicates the major publication for the study
TABLES
Characteristics of excluded studies

Bruera 1992b Eisele 1992 Graham 1999 Hunt 1999 Kaiko 1983 McDonald 1991 Mercadante 1996 Murray 1998 Radbruch 2000 Ripamonti 1998a Sjogren 1993 Waller 1987 Wong 1997 Wood 1998 Study did not involve opioid switching Did not involve an opioid switch Letter/comment - not a clinical study/report Comparison of different opioid - not a switch for intolerable side-effects, inadequate analgesia Meridine toxicity - no opioid switch described Comparison of route only, not opioid Patients did not have inadequate analgesia/toxicity pre-switch Letter/comment - not a clinical study/report Comparison of opioid induced constipation; pain and side-effects not problematic pre-switch Patients did not have inadequate analgesia/toxicity pre-switch Morphine-induced toxicity - no opioid switch reported Letter/comment - not a clinical study/report Pain control/toxicity not a problem pre-switch Pain control/toxicity not a problem pre-switch
ADDITIONAL TABLES
Table 01 Characteristics of prospective studies Study ID Objective Design Patients 49 palliative care patients with cancer pain a/es and pain control pre and post sustitution Total of 49/55 substitutions for a/es. 44 substitutions involved a switch from M to F (31), to O (10), to S (2), to Me (1). Conversion ratios: 1:1 for oral M to oral/rectal O, 66:1 for parenteral M to F, 10:1 for F to S. Switches involved route as well as drug change. Partial/complete relief of confusion in 18/25, nausea/vomiting in 13/19, drowsiness in 8/15. Equivalent dose for responders was higher. Pain control reported as good post substitution in 42/44. Pain intensity, extra doses of breakthrough analgesia, toxicity, cost Outcome measures Results To assess effects of opioid substitution on opioid-related adverse effects (a/es) Audit
Authors conclusions Recommend substitution for patients with intractable a/es as opioid related a/es differ between opioids for same patient
Ashby 1999
Bruera 1995a
To assess effectiveness, safety and cost of high dose oral and rectal Me in patients with poor pain control receiving high doses of conventional opioids
37 advanced cancer patients with poor pain control
Slow switch-over to Me safe, effective and cheap in selected patients with poor prognostic pain syndromes
10
Open uncontrolled study switching from SC HM to PR/PO Me. Criteria for switch: 1. On opioids for at least 4 weeks 2. Daily equivalent opioid dose > 500 mg parenteral morphine. 3. need for dose increase at least every 3 days 4. Moderate or severe pain
Switch from SC HM to PO Me, n=21, PR Me, n=16. Ratio M:HM of 5:7. Mean SC HM dose pre-switch 276 +/- 163mg/day. Pain intensity (VAS) and extra doses signicantly less with Me (p<0.001); toxicity with Me limited to mild sedation and
Table 01 Characteristics of prospective studies (Continued ) Objective

proctitis; no signicant difference in cognitive function post switch. Me signicantly cheaper. 14 pts had neuropathic pain, 17 incident pain. To review opioid switching strategies Survey of current practice 100 consecutive patients with cancer pain Frequency of, and indications for switching opioid, route of administration, or both. 80/100 referrals underwent total of 182 changes in route, drug, or both. Reasons for change: convenience (adequate analgesia) 31.4%, a/es (adequate analgesia) 25%, inadequate analgesia and a/es 17.7%, reduce invasiveness of therapy 19.3%. Overall, changes resulted in improved pain control and reduced a/es. Pain intensity, morphine PCA dose All patients switched as VAS <5/10 not achieved with epidural M; post switch all patients received adequate analgesia with sufentanil; lower PCA requirements with sufentanil 20 cancer patients requiring postoperative pain control (preop all patients on chronic doses of oral morphine, >250 mg/day) Sufentanil useful in opioid-tolerant patients who do not achieve adequate analgesia with high dose epidural morphine
Study ID
Design
Patients
Outcome measures
Results
Authors conclusions
Cherny 1995
de Leon 1994
To test hypothesis that epidural sufentanil provides adequate analgesia when epidural morphine fails
Open uncontrolled study
Gagnon 1999a
11
To investigate the effects of intermittent SC injections of
Prospective data collection of patients rotated from a strong
63 cancer patients with advanced cancer and uncontrolled
Reversal of delirium, pain control, other opioid a/es
All patients had received at least 2 strong opioids (M,
Oxycodone safe, effective and inexpensive

oxycodone in patients requiring opioid rotation opioid to oxycodone because of intolerable a/es symptoms Me, HM) pre-switch to O. 38/63 switches because of delirium successfully reversed in 13 patients; 13 patients switched route only (ie PO to SC oxycodone); no difference in pain intensity or MMSE post switch (using conversion ratio of median MSED/oxycodone ratio of 1.4 Pain intensity, breakthrough analgesia, cognitive impairment, drowsiness, nausea/ vomiting 13 pts completed study. M:O potency ratio - 0.7:1. No signicant improvement in pain control; signicant improvements in mental state and nausea/vomiting; delirium persisted in 11/13 patients 19 cancer patients with pain on PO/SC morphine 24 cancer patients with pain poorly responsive to morphine Methadone dose, pain intensity, a/es SC Oxycodone provides effective analgesia without signicant a/es in patients with morphine-induced delirium.
Study ID
Design
Patients
Outcome measures
Results
Authors conclusions
Maddocks 1996
To test hypothesis that oxycodone produces less delirium than morphine
Mercadante 1999a
To investigate clinical effects of abrupt switch from morphine to methadone using xed 1:5 ratio in patients for whom a/es preclude morphine dose escalation
Rapid substitution, 5:1 ratio, safe and effective for improving pain/a/es balance in patients with poor morphine response.
12
Switch effective (balance between pain and a/es) in 19/24 within 3 days. Signicant reduction in symptom intensity post switch; Methadone dose higher in those with

lower preswitching doses of morphine. To evaluate benets of switching from morphine to PO methadone in patients with poor analgesia or opioid a/es Open uncontrolled study 52 cancer patients with pain Pain intensity, opioidrelated a/es, symptom distress score Data available for 50 pts; 10 switched due to uncontrolled pain, 8 due to a/es, 32 due to both. Switching successful (pain VAS <4, decreased a/es) in 80%. Signicant improvement in drowsiness, n/v, constipation, post switch. 7/13 switched due to inadequate analgesia and dose-limiting s/es, 2/13 due to sedation with Me, 4/13 at patients request (Me associations with drug addicts). Average pain score increased signicantly post switch. Effect of switch on sedation variable. Only 1/13 satied with switch. 13 cancer patients Data collection: reason for switch, patient satisfaction post switch 18 cancer patients Data collection: reason for switch; conversion ratio In most pts with poor pain control and/or a/es switch to PO Methadone valid therapeutic option. Higher doses of Methadone than predicted may be necessary in setting of poor pain control.
Study ID
Design
Patients
Outcome measures
Results
Authors conclusions
Mercadante 2001
Moryl 2002
To present prospective data on rotations from Me to laternative opioids
Prospective data collection
Opioid rotation from Me to other opioids complicated by worsening pain and dysphoria. Uniformly accepted conversion ratio for substituting Me with another opioid not currently available.
Santiago-Palma 2001
To describe effects of rotation from IV PCA F to IV PVA Me
Propective data collection
Conversion ratio of 25mcg/hour IV F to 0.1mg/hr IV Me safe and effective. Reasons for switch ; uncontrolled pain plus sedation or confusion. Decrease in pain scores and sedation post switch; 5/6 cases of
13

confusion improved. Investigate effectiveness of xed dose oral Methadone (10 mg), dose frequency determined by patients, in patients on strong opioids but with uncontrolled pain To investigate effects of switch to transdermal fentanyl for uncontrolled pain Open uncontrolled study 5 patients on opioids (HM, M, O) for cancer pain Pain intensity, pain relief, mood, Functional Living Index 3/5 completed study. Signicant improvement in pain relief in these 3 pts. 4 pts reported less constipation with TDF; no difference in other opioid a/es. Open uncontrolled study 14 patients on various opioids (oral an parenteral oxycodone, pentazocine, dextropropoxyphene) for severe cancer pain Pain intensity, a/es, global effects 11/14 achieved complete/almost complete analgesia; all reported positive global effects, no signicant difference in a/es Patient-controlled dosage regime of oral Methadone safe and effective alternative to parenteral opioids
Study ID
Design
Patients
Outcome measures
Results
Authors conclusions
Sawe 1981
Slover 1992
TDF effective and well tolerated: decreased s/es with better analgesia; signicant functional improvement.
Walsh 2002
To determine frequency and indications fo opioid rotation
Prospective consecutive data collection study
Admissions to an acute Palliative Care Unit
Frequency of rotation and indications
Frequency of switching 15% in this population (lower than suggested by previous reports), all opioid toxicity and poor analgesia improved with switch; pain control improved at opioid equivalents lower than predicted to be analgesic.
14
275 admissions on parenteral opioids 40 underwent opioid rotation: 19 from M to F, 12 from M to Me, 2 from M to O, 2 from Me to F, 2 from Me to intrathecal M, 1 from F to O, 1 from F to Me, 1 from M to HM. Reasons for switch: 20 had neurotoxicity, 14 had opioid unresponsive pain, 6 had nausea and vomiting. Pain and side-effects improved

post switch. To evaluate effectiveness of rotation from oral M to oral Me in patients with intolerable a/es or poor pain control Open uncontrolled study 37 Hospice inpatients with advanced cancer Pain intensity (VRS), a/es 27 completed. All pts reported good pain relief by day 11 post switch. Median time to achieve pain control was 3 days. 88.6% of M-related a/es improved post rotation Ad libitum schedule effective in conversion from M to Me
Study ID
Design
Patients
Outcome measures
Results
Authors conclusions
Tse 2003
Abbreviations
HM=hydromorphone; M=morphine; DM=diamorphine; Me=methadone; F=fentanyl; S=sufentanil; TDF=transdermal fentanyl; PCA=patient controlled analgesia; IV=intravenous; SC=subcutaneous; PR= rectal route; PO= by mouth ; pts=patients; a/es=adverse effects; VAS=visual analogue scale
15
Table 02 Characteristics of retrospective surveys Study ID Objective Participants Method Retrospective chart review of 117 and 162 patients admitted in 1988-1989 and 1991-1992, respectively. All pts in 1991 had cognitive assessment Agitated IMS, rehydration, opioid rotation, use of neuroletics Decrease incidence of agitated IMS (determined by use of haloperidol and neuroleptics) in 1991. Frequency of opioid rotation and hydration signicantly greater in 1991 (p<0.001 and <0.01, respectively). Outcome measures Results Authors conclusions Routine cognitive monitoring, opioid rotation, and hydration reduces incidence of agitated IMS in terminal cancer patients To compare prevalence Patients with advanced cancer of agitated impaired mental status (IMS) following implementation of specic diagnostic and therapeutic measures, including practice of opioid rotation
Bruera 1995b
Bruera 1996
To review analgesic dose ratios for methadone compared with hydromorphone
Patients with advanced cancer and severe symptom complexes
Retrospective chart review involving rotations from morphine to hydromorphone, hydromorphone to morphine, or hydromorphone to methadone
Reason for switching, dose of M or HM pre switch; stabilisation dose of new alternate opioid; sedation or respiratory depression
Only partial tolerance develops between Me and HM. Me is more potent than previously described and switch should start at lower equivalent dose.
16
113 pts evaluable: Group 1 (n=65) changed from SC HM to PO or PR Me; Group 2 (n=36) changed from PO or SC M to PO or SC HM; Group 3 (n=12) changed from PO or SC HM to PO or SC M. Reason for switch mainly escalating opioid dose in Group 1, opioid toxicity in Groups 2 and 3. Median total equivalent morphine dose preswitch 1185mg/day Group 1, 145mg/day Group 2, 165mg/day Group 3. Dose ratio Group 1 (HM-Me) 1.14, Group 2 (MHM) 5.33, Group 3 (HM-M) 0.28. Severe
Table 02 Characteristics of retrospective surveys Objective

sedation/respiratory depression only in those rotated to Me (12%). To describe analgesia, side-effects, dosage and causes of treatment suspension after oral Me administration Patients with advanced cancer pain Retrospective data collection from 196 outpatients treated with 8 hourly PO Me. Pts analysed at baseline (pre Me), and at 7, 15, 30, 45, 60, 90 days: pain intensity, side-effects, Palliation Index (period when pain reduced by >35% compared to baseline) Majority of patients (53.6%) on other opioids pre Me, and all of these switched to Me because of poor pain control. Reduction in pain intensity compared to baseline occurred at all time-points; in 55% of patients reduction was >35% according to Palliation Index. Overall worsening of other symptoms. 11% wtihdrew due to analgesic efcacy; 6.6% withdrew due to side-effects. Reasons for opioid use, change in dose and opioid rotation; pain and side-effect assessment Oral Me is an appropriate analgesic for advanced cancer pain; worsening of other symptoms may be due to progressive disease.
(Continued ) Method Outcome measures Results Authors conclusions
Study ID
Participants
De Conno 1996
de Stoutz 1995
To determine the effectiveness of opioid rotation (OR) in relieving opioid toxicity
191 patients with terminal cancer
Retrospective chart review
Symptoms of opioid toxicity can be relieved by OR, and that a choice of different opioids is necessary to obtain adequate longterm analgesia
17
80/191 underwent rotation; total of 111 episodes of OR. Those with opioid toxicity had chronic and more difcult pain syndromes, and longer admissions. Most patients (75%) initially on morphine. In 90% of rotations

opioids used were M, Me and F. Most frequently observed opioid toxicity was cognitive failure. Post rotation improvement was noted in 29/42 with cognitive failure, 10/15 with hallucinations, 9/9 with myoclonus, 7/10 with uncontrolled pain, 2/4 with nausea. To explore the hypothesis that the equianalgesic dose ratio of hydromorphone or morphine to methadone is different for patients with neuropathic and nonneuropathic pain Patients with cancer pain Review of computerised patient records to determine ratio of M and HM (expressed as M subcutaneous equivalent dose) to Me post rotation from M or HM to Me Pain VAS, opioid ratios 131 rotations in 120 patients: 40 rotations in 34 patients evaluable; 22 rotations in patients with neuropathic pain, 18 in patients with noneuropathic pain. Ratio of M SC equivalent dose to Me between 5 to 7, higher than previous reports. No difference in ratios for patients with neuropathic compared with nonneuropathic pain Study failed to demonstrate different dose ratios for neuropathic versus non-neuropathic pain syndromes. However, Me was a potent and effective opioid for all pain types. There is no need to adjust dose of Me in neuropathic pain. Close clinical supervision during rotation to Me necessary due to wide variability of ratios from patient to patient
Study ID
Participants
Gagnon 1999b
Lawlor 1997b
Patients with cancer pain
18
To determine equianalgesic dose ratios for rotations involving M and HM
Review of computerised records of rotations involving M and HM
Pain VAS, cognitive impairment (MMSE), M and HM doses and rations
253 rotations over a 3 year period: 91 rotations in 74 patients evaluable.
Two different dose ratios suggests that in one direction (MHM) HM is 5 times

44 pts had M-HM rotations, 34 with SC route, 10 PO route. 47 pts had HM-M rotations, 35 SC, 12 PO. No signicant differences in pain VAS pre and post rotation for any of the groups. Unied median dose ratio (n=91): 4.29. MHM (n=44) median dose ratio: 5, HMM (n=47): 3.7, p=0.0001. To determine the equianalgesic dose ratio between morphine and methadone in patients with cancer pain, and to establish whether ratios cahnages as a function of previous opioid dose Patients with cancer pain Retrospective analysis Opioid doses, pain intensity (VAS) 20 rotations: 14 from M to Me, 6 from Me to M. M route was mixed: PO, SC, IV. 14/20 rotations resulted from inadequate analgesia. No signicant difference in pain intensity post rotation. Strong correlation between M dose and conversion ratio: dose ratio 3 times higher in patients receiving >1165mg M/day. Overall median dose ratio of 11.2:1 between M and Me.

more potent than M, while in the other direction (HM-M) HM is only 3.7 times more potent. No correlation observed between dose ratios and level of previous opioid dose.
Study ID
Participants
Lawlor 1998
Potency of Me grossly underestimated. Ratio of M:Me is not xed and depends on previous opioid dose.
19

To dene efcacy and role of HM in opioid switching Palliative care patients Retrospective data collection Pain control, sideeffects, renal function (serum urea and creatinine) 55 patients: 53 with cancer, 1 with nonmalignant disease, 2 with renal failure on dialysis. 46 had received M preswitch, 3 coproxamol, 2 fentanyl, 1 diamorphine. Main reason for switch: opioid side-effects. Side-effect prole improved in 80% of switches. Pain relief achieved in 4/5

HM is a exible morphine alternative, appeared safe in patients with renal failure (n=2)
Study ID
Participants
Lee 2001
Morley 1993
To show benet of switching from morphine to methadone for uncontrolled pain To evaluate SC fentanyl as a secondline opioid 11 patients with cancer pain and unacceptable morphine-related s/es Retrospective case notes survey
5 hospice inpatients with pain uncontrolled on oral morphine
Retrospective data collection
Pain relief
Me can be used safely and successfully
Paix 1995
Quality of analgesia; adverse effects
SC F is a useful second-line opioid for patients with intractable adverse effects on morphine
20
11 patients switched from morphine (CSCI - 9, epidural - 1, PO - 1) to SC F as a result of s/es (nausea/ vomiting - 6, delirium - 5, drowsiness/ respiratory depression - 1). 4 pts reported better analgesia, 6 similar analgesia, 1 pain remained uncontrolled. A/es improved for all patients. Mean F/M potency: 68:1 (range:

15-100). To evaluate safety and tolerability of opioids in the longterm management of chronic noncancer pain 86 outpatients with chronic noncancer pain Retrospective chart review Number of different opioids used; efcacy and tolerability of each opioid Number of opioid used by each patient was 2.3 + 1.4; rst opioid effective in 36%, stopped due to a/es in 30%, ineffectiveness in 34%. Second opioid wwas effective in 31%, third in 40%, fourth in 56%, fth in 14%. 3 pts were on M, 6 on DM pre-switch. Switched to Me, 3 hourly, initial dose 1/10th previous total daily M equivalent dose. Pain improved in 6 (full relief in 3, marked improvement in 2, moderate in 1). 2 died during titration period. 1 pt did not achieve any pain relief. A/es - mild drowsiness in 1 patient only. Retrospective study and comparison of 2 separate units Opioids doses, reason for switching, analgesia VAS and integrated pain score (IPS) Failure of one opioid cannot predict response to another. Changing to a different opioid may result in lessening of a/es and/or improved analgesia
Study ID
Participants
Quang-Cantagrel 2000
Rimmer 1996
To review use of methadone in patients whose pain is uncontrolled on morphine or diamorphine
9 patients with advanced cancer and severe pain
Retrospective review
Pain verbal score
If properly titrated, Me can be introduced safely and effectively. Me requirements cannot be calculated from previous opioid dose.
Ripamonti 1998b
88 patients with advanced cancer (51 Milan, 37 - Canada) who switched to Me
21
1. To determine equianalgesic dose ratio between oral Me and other opioid agonists. 2. To compare different cohorts of patients
All pts in Canada on parenteral HM preswitch; pts in Italy on different opioids. Dose ratio HM/Me for Canada group was 5-15 times higher than
Me is more potent than previously described; HM:Me ratio higher than expected; ratio correlates with total opioid dose pre-

with different opioid exposure preswitching to Me that for Italian group. Dose ratio tended to be higher when patients were receiving higher dose preswitch. No pt suffered s/es which necessitated Me discontinuation. 393 chronic nonmalignant pain patients Retrospective analysis of clinical charts Pain control, opioid doses, side-effects switch.
Study ID
Participants
Thomsen 1999
To investigate the effects of opioid rotation in chronic non-malignant pain patients
Opioid rotations between different LAO resulted in better pain control and fewer s/es at doses predicted to be equianalgesic; majority rotating from SAO to LAO improved analgesia, but at cost of almost doubling opioid dose
22
Opioid rotation performed in 88 (32%) patients. 37 rotations between different long-acting opioids (LAO) and 59 rotations from short acting opioids (SAO) to LAO. Reason for switching inadequate analgesia; s/es a contributing factor in 24%. Rotation resulted in better pain control in 59% of pts rotated between different LAO, and 73% of pts rotated from SAO to LAO. Symptoms of withdrawal and overdosing frequent for both groups. No signicant dose changes in rotations between different LAO; rotations form

SAO to LAO resulted in 74% increase in opioid dose. To evaluate frequency of, and risk factore for opioid switiching Cancer patients who required an opioid change due to inadequate pain relief, opioid adverse effects or both Retrospective chart review Pain relief and adverse effects Of 273 chart reviews 103 required an opioid change. Opioid switch was successful in 65%. Opioid change can be a useful therapeutic option for some patients
Study ID
Participants
Kloke 2000
Abbreviations
HM=hydromorphone; M=morphine; DM=diamorphine; Me=methadone; F=fentanyl; S=sufentanil; TDF=transdermal fentanyl; PCA=patient controlled analgesia; IV=intravenous; SC=subcutaneous; PR= rectal route; PO= by mouth; pts=patients; a/es=adverse effects; VAS=visual analogue scale
23
Table 03 Characteristics of case reports Study ID Participants Indication Bruera 1992a 4 cancer patients Organic hallucinosis on high doses of opiates Pain refractory to opioids other than methadone
Switch HM to M (ratio of 1:5) All switched to Me (from various opioids; some pts had unsuccessfully tried 3 other opioids (M, HM, F) pre switch). 5 pts switched using IV Me
Outcome Hallucinations resolved All reported adequate analgesia post switch. Me well tolerated.
Comments Haloperidol also prescribed
Crews 1993
6 cancer patients
Daeninck 1999a
4 cancer patients
To investigate effects All switched to Me of switching to Me on opioid-related constipation
Improved constipation and decreased laxative requirements post switch. MMSE improved in 2 pts and hallucinosis and myoclonis resolved in 1 pt. Delirium commenced on day 2 post switch, resolved spontaneously on day 11, Me continued and pain controlled Improved pain and decreased drowsiness post switch Individual variability in opioid response. In all cases dose escalation resulted in successful treatment with one opioid and intolerable side-effects with analgesia with others. Data insufcient; analgesia appeared better controlled on Doses of parenteral M, HM pre switch extremely high
24
del Rosario 2001
1 cancer patient
Uncontrolled bone pain
Switch from TDF to Me
Me conversion ratio equivalent to 1:10 oral M ratio
Fitzgibbon 1997
1 cancer patient
Pain refractory to high dose M
Switch from PCA M to IV Me
Galer 1992
4 cancer patients; 1 non-cancer patient
Inadequate pain control and intolerable opioid side-effects
1. M to HM. 2. M to HM to levorphanol to Me. 3. M to levorphanol. 4. M to levorphanol to Me. 5. Oxycodone to M to Me
Hagen 1997
5 cancer patients
Myoclonus with very high doses of opioids
Switch from M or HM to alternative opioids, at <1% of
Table 03 Characteristics of case reports (Continued ) Study ID Participants Indication
Switch
equianalgesic dose of prior opioid
Outcome
much lower doses of second line opioids. Transient hallucinations on day 20 post switch - resolved spontaneously (liver function tests 10 fold higher on day 20) Hallucinations resolved and pain controlled Itching resolved and pain controlled Toxicity resolved
Comments
Jellema 1987
1 cancer patient
Hallucinations, restlessness, vomiting with M
Switch to Me
Kalso 1988
Cancer patients - number not specied 1 cancer patient
Morphine related hallucinations opioid-induced itching opioid toxicity (delirium, myoclonus, hallucinations) and poor pain control Inadequate analgesia
Switch to oxycodone
Katcher 1999
M (incomplete analgesia and itching) to HM M to Me
Lawlor 1997a
1 cancer patient
Patient had a history of chemical dependence
Leng 1994
3 cancer patients
M to Me
Analgesia improved on Me; Me well tolerated Fentanyl effective and well tolerated Toxicity resolved; M requirements 20-25% of predicted equipotent dose Excellent analgesia, no signicant sideeffects; Me dose 3% of predicted equianalgesic dose 1. Myoclonus with HM resolved on IV M. 2. Myoclonus resolved on sufentanil (also given midazolam). Side-effects resolved; good pain
1 patient morphine toxic pre-switch Breakthrough pain only
Loitman 2002
4 patients with ovarian cancer 3 cancer patients
Inadequate analgesia and opioid sideeffects Opioid related neurotoxicity
Various opioids to transmucosal fentanyl HM to M
MacDonald 1993
Manfredi 1997
4 cancer patients
Persistent pain and opioid side effects
M/HM to Me
Parkinson 1990
2 cancer patients
Myoclonus with high dose spinal opioids
1.Epidural M to intrathecal HM to IV M. Epidural M to epidural bupivicaine plus sufentanil to IV HM M to PCA Me, ratio 20:1
1. Patient died 36 hours later. 2. Patient remained heavily sedated and died 38 hours later
Sabatowski 2002
1 child (8 year old) with cancer pain
Pain refractory to high-dose morphine
25
Switch
Outcome
control achieved
Comments
Shaiova 2002
1 patient with cancer pain 4 cancer patients
Refractory pain
Oral Me plus HM to IV Fentanyl to IV HM to IV Me M to Me, ketobemidone, sufentanil, Me TDF to IV M
Achieved pain control on IV Me Hyperalgesia resolved Delirium resolved and pain controlled on M Pain controlled 1. Nausea improved with initial switch to HM. 2. Developed myoclonus with increasing doses of HM. Pain improved (and ? myoclonus) on switch to Me. 3. 4 mths later increasing doses of Me again caused myoclonus and sedation. 4. Agitated delirium resolved, and pain improved, on switching back to HM. 5. 4 wks later problems with nausea, so switched back to Me - improved and pain control good. Each switch involved dose escalation, which caused increasing agitation. Final dose of Me, which successfully controlled pain without toxicity, was a lower equivalent opioid dose than original combination of TDF plus M
Me dose 10% of predicted
Sjogren 1994
morphine-induced hyperalgesia Acute toxic delirium
Steinberg 1992
1 cancer patient
Thomas 1995 Vigano 1996
1 cancer patient 1 cancer patient
Uncontrolled pain Uncontrolled pain, nausea, sedation, myoclonus
SC HM to Me M to HM to Me to HM to Me
Mixed nociceptive/ neuropathic pain
Fainsinger 1995
1 cancer patient
Uncontrolled (neuropathic) pain
TDF plus PO M to PO HM to SC HM to SC DM to SC HM to PO Me
26

Abbreviations: HM=hydromorphone; M=morphine; DM=diamorphine; Me=methadone; F=fentanyl; S=sufentanil; TDF=transdermal fentanyl; PCA=patient controlled analgesia; IV=intravenous; SC=subcutaneous; PR= rectal route; PO= by mouth; pts=patients; a/es=adverse effects; VAS=visual analogue scale
Switch
Outcome
Comments
This review has no graphs.
COVER SHEET Title Authors Contribution of author(s) Issue protocol rst published Review rst published Date of most recent amendment Date of most recent SUBSTANTIVE amendment Whats New Date new studies sought but none found Date new studies found but not yet included/excluded Date new studies found and included/excluded Date authors conclusions section amended Contact address Opioid switching to improve pain relief and drug tolerability Quigley C Information not supplied by author 2004/3 2004/3 21 October 2004 21 May 2004 Information not supplied by author Information not supplied by author Information not supplied by author Information not supplied by author Information not supplied by author Dr Columba Quigley MD MRCP Consultant/Honorary Senior Lecturer in Palliative Medicine Medical Oncology Hammersmith Hospitals Trust
27
Du Cane Road London W12 0NN UK Telephone: +44 208 8461 412 E-mail: cquigley@hhnt.org Cochrane Library number Editorial group Editorial group code CD004847 Cochrane Pain, Palliative Care and Supportive Care Group HM-SYMPT
28

Quigley C - Opioid Switching To Improve Pain Relief and Drug Tolerability

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Opioid switching to improve pain relief and drug tolerability (Review)

Opioid switching to improve pain relief and drug tolerability (Review)

POTENTIAL CONFLICT OF INTEREST None known.

References to studies excluded from this review

Indicates the major publication for the study

Characteristics of excluded studies

37 advanced cancer patients with poor pain control

Table 01 Characteristics of prospective studies (Continued ) Objective

Open uncontrolled study

To investigate the effects of intermittent SC injections of

Prospective data collection of patients rotated from a strong

63 cancer patients with advanced cancer and uncontrolled

Reversal of delirium, pain control, other opioid a/es

All patients had received at least 2 strong opioids (M,

Oxycodone safe, effective and inexpensive

Table 01 Characteristics of prospective studies (Continued ) Objective

To test hypothesis that oxycodone produces less delirium than morphine

Open uncontrolled study

Open uncontrolled study

Table 01 Characteristics of prospective studies (Continued ) Objective

To present prospective data on rotations from Me to laternative opioids

Prospective data collection

To describe effects of rotation from IV PCA F to IV PVA Me

Propective data collection

Table 01 Characteristics of prospective studies (Continued ) Objective

To determine frequency and indications fo opioid rotation

Prospective consecutive data collection study

Admissions to an acute Palliative Care Unit

Frequency of rotation and indications

Table 01 Characteristics of prospective studies (Continued ) Objective

To review analgesic dose ratios for methadone compared with hydromorphone

Patients with advanced cancer and severe symptom complexes

Table 02 Characteristics of retrospective surveys Objective

(Continued ) Method Outcome measures Results Authors conclusions

To determine the effectiveness of opioid rotation (OR) in relieving opioid toxicity

191 patients with terminal cancer

Retrospective chart review

Table 02 Characteristics of retrospective surveys Objective

(Continued ) Method Outcome measures Results Authors conclusions

Patients with cancer pain

To determine equianalgesic dose ratios for rotations involving M and HM

Review of computerised records of rotations involving M and HM

Pain VAS, cognitive impairment (MMSE), M and HM doses and rations

253 rotations over a 3 year period: 91 rotations in 74 patients evaluable.

Table 02 Characteristics of retrospective surveys Objective

(Continued ) Method Outcome measures Results Authors conclusions

Table 02 Characteristics of retrospective surveys Objective

(Continued ) Method Outcome measures Results Authors conclusions

5 hospice inpatients with pain uncontrolled on oral morphine

Retrospective data collection

Me can be used safely and successfully

Quality of analgesia; adverse effects

Table 02 Characteristics of retrospective surveys Objective

(Continued ) Method Outcome measures Results Authors conclusions

To review use of methadone in patients whose pain is uncontrolled on morphine or diamorphine

9 patients with advanced cancer and severe pain

Pain verbal score

88 patients with advanced cancer (51 Milan, 37 - Canada) who switched to Me

Table 02 Characteristics of retrospective surveys Objective

(Continued ) Method Outcome measures Results Authors conclusions

To investigate the effects of opioid rotation in chronic non-malignant pain patients

Table 02 Characteristics of retrospective surveys Objective