Conversion ratios for opioid switching: a pragmatic study

The final conversion ratios among opioids used for successful switching are unknown. The aim of this study was to determine the initial and final conversion ratios used for a successful opioid switching in cancer patients, and eventual associated factors. Ninety-five patients who were successfully switched were evaluated. The following data were collected: age, gender, Karnofsky performance score, primary cancer, cognitive function, the presence of neuropathic, and incident pain. Opioids, route of administration, and their doses expressed in oral morphine equivalents used before OS were recorded as well as opioids use for starting opioid switching, and at time of stabilization. Physical and psychological symptoms were routinely evaluated by Edmonton Symptom Assessment Scale. No statistical changes were observed between the initial conversion ratios and those achieved at time of stabilization for all the sequences of opioid switching. When considering patients switched to methadone, there was no association between factors taken into considerations. Opioid switching is a highly effective and safe technique, improving analgesia and reducing the opioid-related symptom burden. The final conversion ratios were not different from those used for starting opioid switching. Patients receiving higher doses of opioids should be carefully monitored for individual and unexpected responses in an experienced palliative care unit, particularly those switched to methadone. Future studies should provide data regarding the profile of patients with difficult pain to be hospitalized.


Introduction
Pain is a common symptom experienced by patients with advanced cancer [1]. Opioids are the most important drugs to treat cancer pain [2]. When pain is not controlled, an increase in opioid doses will be necessary. Such increasing doses may produce adverse effects. When the balance between analgesia and adverse effects is unfavorable, a substitution with another opioid is recommended [3]. The rationale of opioid switching (OS) has been previously reported [4]. OS may improve the level of analgesia and/ or reduce the intensity of opioid-induced adverse effects in a large amount of patients [5]. OS involves calculating the oral morphine equivalent (OME) of the previous opioid, and then converting to another opioid. To perform OS efficiently and minimize adverse effects, it is essential to establish appropriate conversion ratios, particularly when using methadone as second opioid [6][7][8]. This drug, in fact, has peculiar characteristics that make it difficult to use for the risk of accumulation. The substitution of methadone for another opioid is not simple. Clinical experience shows a dose ratio when switching from morphine that varies widely. This variability has been associated with the extent of previous exposure to opioids, total opioid dose before OS, and drug interactions [9]. Regardless of the conversion ratios reported in the past decade, many clinicians use different methods in their clinical practices [10].
Understanding opioid ratios used in clinical practice by skilled palliative care professionals could help for future large-scale efforts to provide conversion ratios to be used for OS in the daily activity. We aimed to determine the initial and final conversion ratios used for successful OS. The second aim was to assess eventual factors that could interfere with the final effective ratio, that is, the definitive and successful ratio obtained after OS.

Methods
Ninety-five patients who were admitted to an acute supportive/palliative care unit (ASPCU) and had a successful OS were selected from a sample of a concomitant study assessing a tool for monitoring the outcomes of OS [11] from January 1, 2020, to June 30th, 2021.
Inclusion criteria included a diagnosis of cancer, age ≥ 18 years, use of opioids for cancer pain management with poor pain control and/or prevalence of adverse effects, or both. Exclusion criteria were an expected short survival (less than 2 weeks), the use of less than 60 mg of oral morphine equivalents (OME), or an OS performed for other reasons. Written informed consent was obtained from all patients or proxies, when patients were unable to do that. The ethical committee of the University of Palermo approved the study.

Procedures
OS was considered as a switch from one opioid to another one in patients with an unfavorable response to opioids, due to poor pain control, the development of adverse effects, or both. OS was pragmatically performed according to local department policies, already described, substantially based on targeted individual characteristics [12]. Accordingly, no changes of clinical practice of skilled clinicians were done. The initial conversion ratios used among opioids and routes of administration, previously reported, could be changed according to the clinical conditions and laboratory data regarding renal and hepatic function. A "stop and go" strategy was performed (discontinuing the previous opioid and starting with the opioid used for substitution concomitantly) [13]. Subsequently, opioid doses were timely changed to optimize the balance between pain and opioid-related symptoms intensity, according a comprehensive pain and symptom management. No patient received anticancer treatments during the admission. Patients were strictly monitored by a team consisting of doctors and nurses well experienced in palliative care.

Measurements
The following data were collected: age, gender, Karnofsky performance score, primary cancer, and pain mechanism. T0 was considered the day when OS was started. Tx was considered the day of dose stabilization for two consecutive days with ≤ 3 breakthrough episodes (successful OS). Opioids, route of administration, and their doses expressed in oral morphine equivalents (OME) [12], used before OS, were recorded as well as opioids use for starting OS (T0) and at Tx. DN4 was used for assessing the presence of neuropathic pain [14]. This is a validated system for diagnosing the presence of a neuropathic component. Scores of 4 or above are considered as indicative of the presence of neuropathic pain [15]. The presence of incident pain on movement was also recorded [16]. A screening test for history of alcohol dependence (CAGE; cut down, annoy, guilt, eye-opener) was also administered [17].
Physical and psychological symptoms were routinely evaluated by Edmonton Symptom Assessment Scale (ESAS) at admission (T0) and at time of stabilization, that is, the time when OS was considered clinically successful (Tx). ESAS is a self-reported tool assessing the intensity of most common psychological and physical symptoms on a 0 to 10 numerical scale, rated on the average score in the previous 24-hperiod. ESAS is a valid and reliable tool for assessing the overall symptom burden, sensible to changes produced by a treatment [18]. At the same time intervals, the Memorial Delirium Assessment Scale (MDAS) was used to assess the cognitive status of patients. MDAS is a validated tool to quantify the intensity of delirium [19].

Statistical analysis
Qualitative data have been summarized by frequency and relative frequencies (%), whereas quantitative variables have been shown as mean (standard deviation-SD) and median (interquartile range-IQR). The paired Wilcoxon signedrank test was used to compare opioid ratios at T0 and at time of stabilization (Tx) for different opioid switching groups, and the Spearman rank correlation test was performed to assess the relation between the final conversion ratio in patients switched to methadone, and the clinical patients' characteristics. The data were analyzed by the SPSS software, version 22 (SPSS Inc, Chicago, IL, USA). All statistical tests were two-tailed, and statistical significance was defined as P ≤ 0 0.05.

Results
The characteristics of 95 patients who were successfully switched are reported in Table 1. Most patients were switched to methadone (n.67). Eleven, 17, 28, 4, and 7 patients were switched to morphine, oxycodone, fentanyl, buprenorphine, and hydromorphone, respectively. The mean period for a successful OS (Tx) was 6 days (range 5-8). The sequences of OS are listed in Table 2. No statistical changes were observed between the initial conversion ratios (T0) and those achieved at time of stabilization (Tx) for all the sequences of OS ( Table 2).
The Spearman rank correlation analysis was performed in the 67 patients who were switched to methadone (Table 3). There was no correlation between factors taken into considerations (age, gender, Karnofsky, primary tumor, incident pain, neuropathic pain, reason to switch, previous opioid dose in OME, MDAS at T0and MDAS at Tx) and the final conversion ratio. In only eight patients, methadone dose was reduced at Tx, while in the majority of cases, doses were stable or increased.

Discussion
This pragmatic study provided interesting information gathered from daily practice in an ASPCU with skilled personnel. Once a conversion ratio was chosen according to local policy, eventually with some variations based on clinical    and laboratory variables, the final conversion ratio recorded at time of stabilization did not change significantly. We also examined some factors which could potentially influence the successful final conversion ratio. However, age, gender, Karnofsky, primary rumor, incident pain, neuropathic pain, reasons to switch, and previous opioid doses were not influent. The conversion ratio to be used is a complex issue that has been debated in literature, particularly when switching to methadone. The term "equianalgesic dose ratio" refers to the ratio of the dose of two opioids required to produce the same analgesic effect [20]. Indeed, this concept may confound clinicians, as it is impossible to reproduce the same level of analgesia in clinical practice. Thus, the term conversion ratio used in this study refers to a meaningful ratio used for starting OS, according to local policy, and the ratio found at the end of a successful OS that means a condition where pain control is improved and/or adverse effects minimized at an acceptable level for patients. Of interest, we reported data of complete successful OS in patients who were then discharged home, avoiding confounding terms such as partial success [21]. In fact, patients who were reported to be successfully switched also reported a positive patient's global impression [11].
In a recent survey, a wide variation in conversion ratios used across various disciplines and geographic locations was found [10,22]. Many opioid equianalgesic tables are based on single-dose studies in acute pain settings, in opioid-naïve patients or in patients receiving low opioid doses. These ratios often do not apply to patients receiving higher doses of opioids for cancer pain management [7,23,24]. Moreover, such tables do not take into account some patient-related factors, such as age, gender, co-morbidities, liver and renal function, eventual drug-drug interactions, the level of opioid tolerance, and the reason for OS. These factors may be crucial in determining the successful dose for OS. A stepwise approach to OS and conversion ratio has been proposed, and included pain assessment, total opioid dose calculation, use of equianalgesic tables, adjusting the dose based on patientrelated factors, and monitoring [8].
In this study, none of these factors influenced the final conversion ratio of a successful OS, including the level of tolerance, that is, the doses, expressed as OME, of the previous opioid. Indeed, the majority of patients required some dose increases to obtain an appropriate analgesia, even in patients switched to methadone. Conversion ratios for switching to methadone have been largely debated in literature. This finding confirms data from previous larger studies. In patients undergoing a rapid OS by using a morphine-methadone ratio of 5:1, no differences in methadone doses were reported between the starting and final doses of methadone [25]. No significant differences between initial conversion ratios and ratios were achieved after stabilization and no significant correlation between the previous opioid dose and the final conversion ratio were found [26]. No relationship was identified between unsuccessful switching and the opioid dose, opioid sequence, pain mechanism, or use of adjuvant [12,21]. Of interest, with a careful monitoring during the adjustment phase before reaching the dose stabilization, no dangerous overdosing was observed. This occurred despite a relatively strong ratio used for starting methadone (5:1).
In patients who were switched from fentanyl to methadone, the conversion ratio was relatively stable at time of stabilization, although it required frequent therapeutic interventions during a mean of 4 to 5 days of admission to achieve a timely equilibrium between analgesia and adverse effects. This intensive approach was safe in an intensive setting and allowed for a relatively short-time admission [27]. In patients receiving a mean OME of 220 mg/day who were successfully switched to methadone, the stable median conversion ratio was found to be 5:1. In contrast with the findings of the present study, however, both the reasons for OS and previous OME were predictive factors for the final ratio. Specifically, the highest conversion ratio (9.1:1) was associated to opioid-related adverse effects as the reason for OS, and to previous OME of more than 300 mg/day [9]. The different findings could be attributed to the low number of patients presenting different indications (i.e., both poor pain control and adverse effects (47.2%), poor pain control (50%), or adverse effects (2.8%), and the different times necessary to achieve dose stabilization [27].
Caution in the use of methadone is recommended, particularly in outpatient setting [24,28,29]. Prospective and retrospective studies have shown that patients can be safely and effectively switched to methadone even in the outpatient setting, despite the need of a long period to reach pain stability [30][31][32]. In an outpatient setting, methadone doses were relatively low and did not significantly change at the follow-up that was performed at long and different time intervals [33]. Age and gender, although potentially could have an influence in the process of OS and opioid conversion ratios, were not associated with different conversion ratios, as reported in most studies of OS [34].
The presence of a neuropathic component did not influenced opioid doses and conversion ratios during OS, as previously reported [25]. This finding was also reported in a preliminary study that failed to show a difference in the ratios of patients with neuropathic or non-neuropathic pain syndromes [35].
The single-center experience is the principal limitation of this study. Data were recorded in an ASCPU with large experience in OS and the use of methadone. This approach could be not easily replicable in other settings. Patients are carefully monitored on an individual basis for possible unexpected responses until they achieve a clinical stabilization. This approach, which is possible in an intensive setting where patients are frequently seen and monitored, may provide a short time to achieve stabilization and avoid prolonged suffering in patients with high levels of distress for their pain or symptom burden. With other modalities and different settings, stabilization is achieved within prolonged periods of time [9]. On the other hand, this study reflects a pragmatic approach showing data resulting from daily practice, without using restrictive protocols that could infer in some way the results. The flexibility in timely modifying the opioid regimen for each individual may allow better outcomes. However, the approach to these kinds of patients with relevant clinical problems requires high-level facilities. Such patients cannot be followed in an outpatient or home care setting, where opioid doses are generally lower. Of interest, a pragmatic multidimensional intervention has been reported to be effective in improving pain control in many opioid-tolerant patients without the need to increase the opioid dose [36]. The rationale of the approach used in the present study was based on previous experiences, in which a priming dose of methadone was considered necessary to achieve a rapid outcome in an acute clinical setting. The approach used in this study requires expertise and strict surveillance in an acute setting, where symptom monitoring and continuous evaluation is the basis to maintain a high level of safety while providing timely pain and symptom control. It also requires frequent therapeutic interventions during a mean of 6 days of admission to achieve a timely equilibrium between analgesia and adverse effects. This intensive approach allowed for a relatively short time admission. The other limitation is the low number of patients who were switched to other opioids other than methadone, which is the favorite drug for OS in our unit in daily practice, probably for the large experience in the use of this drug [37,38] In conclusion, OS is a highly effective and safe technique, improving analgesia and reducing the opioid-related symptom burden. Although conversion ratios in general will be maintained, the possible variability in response should be monitored and managed accordingly. Patients receiving high doses of opioids should be protected in an inpatient unit with large experience in OS and the use of methadone. Less problematic patients receiving lower doses of opioids could be switched in outpatient clinic or at home. Future studies should provide data regarding the profile of patients with difficult pain to be hospitalized.
Author contribution SM: protocol, writing.
Data availability Data are available on request.