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, as well as 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 patient-related 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 has 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 (ie, 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 stablization (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 (30–32). 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, provides 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 six days of admission to achieve a timely equilibrium between analgesia and adverse effects. This intensive approach allowed for a relatively short time admission.
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.