Opioid Rotation in Cancer Pain Treatment
A systematic review
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Background: Rotating several different WHO level III opioid drugs is a therapeutic option for patients with chronic cancer-related pain who suffer from inadequate analgesia and/or intolerable side effects. The evidence favoring opioid rotation is controversial, and the current guidelines in Germany and other countries contain only weak recommendations for it.
Methods: This review is based on pertinent publications retrieved by a systematic review of the literature on opioid rotation for adult patients with chronic cancer-related pain who are regularly taking WHO level III opioids by the oral or transdermal route.
Results: 9 individual studies involving a total of 725 patients were included in the analysis, and 3 previous systematic reviews of studies involving a total of 2296 patients were also analyzed. Morphine, oxycodone, fentanyl, hydromorphone, and buprenorphine were used as first-line opioid drugs, and hydromorphone, buprenorphine, tapentadol, fentanyl, morphine, oxymorphone, and methadone were used as second-line opioid drugs. In all of the studies, pain control was achieved for 14 days after each rotation. In most of them, the dose of the new drug introduced in each rotation needed to be increased above the dose initially calculated from a rotation ratio, with the exception of rotations to methadone. The frequency of side effects was only rarely lessened, but patients largely considered the result of opioid rotation to be positive. No particular opioid drug was found to be best.
Conclusion: Opioid rotation can improve analgesia and patient satisfaction. The success of opioid rotation appears to depend on the magnitude of the initial dose, among other factors. Tables of equianalgesic doses should be considered no more than a rough guide for determining the dose of the new drug. Rotations to methadone should be carried out under clinical supervision in experienced hands.
Pain is experienced by 50 to 90% of cancer patients (1). It is estimated that adequate pain relief can be achieved in 71 to 100% of cases if the “WHO analgesic ladder” for cancer pain is used (2). Nevertheless, around 30% of patients treated with powerful opioids still have pain, opioid-associated adverse drug reactions, or both (3). The term opioid rotation describes the change from one drug (“first-line opioid”) to another (“second-line opioid”) owing to intolerable adverse events accompanying adequate analgesia or to increasing side effects when the opioid dose is increased because of inadequate pain relief (4, 5). There are limited opportunities for dose escalation, because the risk of opioid-associated mortality increases sharply at morphine equivalent daily doses over 100 mg (6).
The terms opioid rotation and opioid switch are largely used synonymously in the literature. It should be noted that authors do not always distinguish rotation for the reasons outlined above from rotation on grounds of “convenience.” The latter is more correctly referred to as opioid conversion and may take place, for example, because the patient prefers a particular preparation although stable analgesia without side effects has already been achieved.
In principle opioid rotation can also be used to alleviate non-cancer pain, but in practice it plays a much smaller part, particularly since the publication of the LONTS guideline in Germany (7). According to the literature opioid rotation is necessary in 20 to 44% of cancer pain patients and can lead to clinical improvement in 40 to 80% of cases (8, e1).
Following a Cochrane review in 2004, only two further systematic reviews of the efficacy of opioid rotation specifically in cancer pain patients appeared up to 2010 (9, 10). The authors of all three publications came to the conclusion that although opioid rotation is widely practiced, robust evidence is lacking due to the mainly methodological limitations of the studies concerned. The dose equivalents listed in Table 1 are commonly used in clinical practice and form the basis of various guideline recommendations.
The mostly cautious nature of the recommendations in guidelines (Box) makes it clear that considerable uncertainty prevails in the practice of opioid rotation for the management of cancer pain.
The aim of this review is therefore to provide an update on opioid rotation in cancer-related chronic pain by means of a systematic survey of publications with a high level of evidence.
The systematic literature search was oriented on the recommendations of the PRISMA Statement (11) and the rules of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) for the formulation of guidelines (e6).
A Cochrane review by Quigley (8), published in 2004, systematically examined the primary literature on opioid rotation for treatment of pain from 1960 to January 2003. We carried out a systematic search for aggregated evidence published thereafter (January 2003 to January 2017) in DARE (Database of Abstracts of Reviews of Effects) and MEDLINE (PubMed). Inspection and evaluation of the aggregated evidence revealed one high-quality systematic review published by Dale et al. in 2011 (10) (search period for primary literature 2003 to 2010). Based on the search strategy in that review, we defined a sensitive strategy for searching the databases MEDLINE (via PubMed) and CENTRAL (Central Register of Controlled Trials). Furthermore, we carried out a hand search of the major German and international journals. The detailed search strategy for all databases is presented in eTable 1.
Abstracts of the publications found in all sources were initially screened for relevant content. The research question was formulated in PICO format (Table 2).
Study selection: inclusion/exclusion criteria
Two reviewers (MS and FH) read the full text of all articles identified as potentially relevant on abstract screening for a priori defined inclusion and exclusion criteria regarding content and methods (eTable 2). With regard to study design, we included systematic reviews (SRs) with or without meta-analysis, randomized controlled trials (RCTs), and prospective observational studies (with or without a control group). Narrative/nonsystematic reviews, retrospective observational studies, case series, and individual case reports were excluded.
Data extraction and evaluation
The central clinical and methodological data of all included studies are reported in evidence tables stratified by study design (SRs: eTable 3, RCTs and prospective observational studies: eTable 5).
Quality assessment of the included systematic reviews and studies
The risk of bias (RoB) in the included RCTs was assessed by two independent reviewers using the validated Cochrane Risk of Bias Tool (14).
The study quality of the prospective observational studies was judged with the aid of the validated MINORS assessment instrument (Methodological Index for Non-randomized Studies) (15).
Classification of the evidence
In addition to quality assessment of the included publications, the SRs and individual studies were classified according to the Oxford Centre for Evidence-Based Medicine (CEBM) levels of evidence LoE 1a to LoE 5 (16).
Altogether, the database survey and hand search identified 502 publications, 12 of which satisfied our inclusion criteria: three SRs (9, 10, 17), four RCTs (18–21), and five prospective observational studies without a control group (22–26). For the sake of completeness, the results of two SRs identified during the search for aggregated evidence in the years 2003 to 2010 were tabulated (8, 27). None of the reviews had performed a meta-analysis of the individual studies’ results. Three of the five identified SRs had explicitly followed the PRISMA Statement. On the basis of the AMSTAR criteria, the methods of all reviews except one were classed as high quality and together with the primary literature represent evidence level 3a.
Results of the systematic reviews
The 2011 review by Dale (10), conceived as a follow-up to Quigley’s Cochrane review (8), included 11 uncontrolled prospective studies (n = 280) of various opioids with low numbers of cases (n = 10 to 32). With regard to pain, seven studies reported a reduction of >3/10 points on the numeric rating scale (NRS). Three studies expressed the amelioration of pain as a success rate of 50 to 80%; however, the measurement criteria were inconsistent. No advantage could be discerned for any individual substance, but the success of rotation was associated with the dose intensity of the first-line opioid. The authors concluded that higher dosage tended to lead to lower success of rotation. Most studies did not report whether there had been adequate titration of the primary opioid or whether the follow-up period after rotation had been sufficiently long. The authors reasoned that observation for at least 14 days after rotation is necessary to obtain meaningful data.
The SR of 10 prospective studies (including one RCT, n = 42) and 15 retrospective studies (n = 1229) by McLean (17) examined rotation to methadone and took a look at various rotation regimens (Table 4). However, only in 17 of these studies were the endpoints ascertained by means of validated instruments; in the remaining eight studies they were established by clinical assessment alone. While pointing out methodological limitations, the authors stated that the result of rotation was rated positive in almost all studies. Both the ad libitum approach and the 3-day switch method were judged successful in over 90% of patients, but this was the case for only 78% of patients in whom the rapid conversion technique was used.
Mercadante and Caraceni (9) conducted an SR of 5 RCTs and 26 prospective case series (n = 1887) with the aim of verifying the evidence level of equianalgesic dose recommendations. This SR formed the basis for the recommendations in Table 1, but also found clear-cut dependence on the dose intensity of the first-line opioid: the higher the dose, the less likely was successful rotation without dose adjustment, while the data in Table 1 for oxycodone, hydromorphone, fentanyl, and buprenorphine in lower dosage proved reliable. The authors did not specify a cut-off value for a first-line opioid dose below which the recommendations in the table should be followed. They explicitly gave no equianalgesic recommendation for rotation to methadone due to the large variance of results.
Results of the individual studies
In six of the nine individual studies included (total n = 725), opioid rotation had been carried out because of pain or intolerable side effects, while in the other three studies analgesia was stable and the reason for rotation was purely for convenience (eTable 5).
With regard to the primary endpoint, all of the studies showed amelioration of pain (if that was the reason for rotation) or continuation of stable pain relief (if the intervention was performed on grounds of convenience).
All of the studies featured dose titration phases to achieve stable analgesia, and in all of them one or more dose adjustments were made in the follow-up period to attain the endpoint. The first-line opioid dose differed considerably between studies with patients who were switching for convenience (MEDD 33 to 92 mg) and those in which the patients had inadequate analgesia and/or intolerable side effects (MEDD 124 to 1330 mg). In the majority of studies the dose of the second-line opioid was increased in the course of the follow-up period after rotation (Table 3). Only Moksnes (19), who rotated to methadone using the stop-and-go method (SAG) or the 3-day switch (3DS), found a reduction in the equivalent dose of methadone at the end of the 14-day observation phase. In the study by Poulain (20) the methadone dose remained stable with no great variation during the observation period.
Opioid-related side effects were described in all studies, although the criteria and the instruments used for measurement were heterogeneous. The stated proportions of patients with adverse effects varied from 25% and 33% for Poulain (20) to >90% in the studies by Slatkin (21), Imanaka (18), and Lee (22). Two studies found no difference in the rate of side effects before and after rotation (20, 24). In their convenience study, Imanaka et al. (18) described superiority of tapentadol over morphine (38 % versus 54 %) with regard to the occurrence of gastrointestinal adverse effects. The remaining side effects were comparable in the two groups. In another convenience population, Minami et al. (25) found an amelioration of oxycodone-associated fatigue after rotation to fentanyl while other adverse effects were comparable. None of the studies of patients with pain or intolerable side effects revealed any advantage for a specific substance.
Three studies investigated the patients’ subjective satisfaction. The highest rate (96%) was reported by Slatkin; at the same time, 93% of the patients stated they had experienced at least one new undesired effect following rotation (21). In two other studies (22, 25) with rotation from oxycodone to hydromorphone (n = 114, rotation due to pain) and from oxycodone to fentanyl (n = 49, rotation for convenience), around 60% of patients were satisfied with the results 14 days after rotation.
Applicability of equianalgesic conversion charts
Once the decision to switch opioids has been made, the dose of the second-line opioid must be selected for safety as well as efficacy. If the change is being made because of insufficient analgesia, intolerable side effects, or both, guidelines recommend that the new dose should be lower than calculated at first, then titrated upward after rotation (8). In the studies investigated here, however—with the exception of those on methadone—the initially calculated dose of opioid had to be increased to achieve adequate analgesia, regardless of the indication for rotation (Table 3). In this regard, McLean et al. (17) point out that precisely in patients who are clinically unstable or experiencing exacerbated pain, one should consider giving a higher dosage of the second-line opioid from the very beginning, to avoid the risk of persisting undertreatment. High dosage of the first-line opioid may reflect a complex pain situation and have an important effect on the success of rotation (24).
Special features of the clinical deployment of methadone
A variety of methods are used for rotation to methadone (Table 4). The 3-day switch and ad libitum methods seem effective, despite weak evidence, while models that attempt swift rotation (stop and go, rapid conversion) appear to yield no advantage (17). Owing to the long half-life, the time required to achieve dose stability varies from 35 to 325 h (13.5 days). The higher the dosage of the first-line opioid, the greater is the effect of the methadone. Therefore, a comparably low dosage of methadone is used in rotations from high-dose first-line opioids (Table 4). Moreover, high initial doses (≥ 40 mg/day) and rapid increases (>25 mg/day) are classed as risky (28). Therefore, regardless of the method selected one should follow the EAPC guideline recommendation (e1) and monitor the patient during the opioid rotation.
Opioid-associated adverse drug reactions
Gastrointestinal side effects are among the most frequently occurring adverse drug reactions associated with opioid intake. In particular, obstipation affects 41 to 73% of cancer patients treated with opioids (37). In cases of refractory obstipation, guidelines (16) recommend, among other options, rotation to fentanyl or methadone. Combination of opioids with naloxone is also thought to be beneficial by decreasing the effect on µ-receptors (38), and studies of patients with non-cancer pain have shown that administration of tapentadol is helpful in the presence of gastrointestinal side effects (39, 40). This was confirmed in a comparative study in which 100 patients rotated to either tapentadol or morphine (18): the rate of gastrointestinal adverse effects was much lower in the tapentadol group than in those who switched to morphine.
The systematic reviews included in this study displayed considerable heterogeneity with regard to their methods, the nature of the studies they covered, their choice of endpoints, and their assessment of the individual studies analyzed. Despite a sensitive, systematic search for primary literature we identified only a small number of randomized controlled trials. One general problem in the conduct of clinical studies on patients with pain is that for ethical reasons it is difficult or impossible to include those suffering from uncontrolled pain or adverse drug reactions in studies of that nature (27), and this restricts the data available. Furthermore, our hand search and database survey principally brought up studies that demonstrated the efficacy of opioid rotation while simultaneously having high drop-out rates. Publication bias is likely.
A further limitation of the individual studies included in our analysis is the high potential for bias in documentation of the endpoints. Although pain and side effects are often measured with standardized instruments (numerical/verbal rating scales), they are reported by the patients and are thus subjective endpoints vulnerable to bias. Just as vulnerable are the treating physicians’ estimations of the endpoints in the absence of blinding. There was particularly pronounced variation in the interpretations placed on the commonly used terms “effective” and “successful.” The real “success” of opioid rotation is therefore difficult to assess, very hard to compare, and above all should not be evaluated too early. According to Dale (10) the observation period should not be less than 14 days.
The conversion ratios for the attainment of effective analgesia described in the publications investigated here differ, in some cases considerably, from the prevailing recommendations and in all studies—with the exception of rotation to methadone—they were higher than the calculated equianalgesic doses. In this light it seems advisable to ascertain whether the current guidelines, which recommend initial dose reduction on opioid rotation precisely in patients with insufficient analgesia, should be reevaluated to avoid long-term analgesic undertreatment.
From the methodological viewpoint, further high-quality RCTs with low risk of bias are required to increase the strength of evidence for the guideline recommendations, which at the moment are based largely on consensus. Overall, opioid rotation should not be withheld from properly selected patients with cancer pain, as amelioration of analgesia, reduction of side effects, and improvement in quality of life can be achieved.
Conflict of interest statement
Dr. Laufenberg-Feldmann has received lecture fees from Grünenthal.
The remaining authors declare that no conflict of interest exists.
Manuscript submitted on 11 July 2016, revised version accepted on 14 November 2017
Translated from the original German by David Roseveare
Dr. med. Michael Schuster
Klinik für Anästhesiologie, Universitätsmedizin Mainz
Langenbeckstr. 1, 55131 Mainz, Germany
For eReferences please refer to:
Dr. Schuster, PD Dr. Heid, Dr. Laufenberg-Feldmann
Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI),
University Hospital Mainz: Bayer
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