A comprehensive evaluation of the titration phase during first-line methadone treatment of cancer pain is provided. A growing number of studies report the successful use of methadone as a first line opioid . Moreover, it has been proposed that methadone titration might be easier and safer in strong opioid naïve patients than in patients rotated from other strong opioid to methadone [11, 21]. However, a recent revision of these studies concluded that information about the modalities of dose titration is still insufficient , with only few studies that partially analyze this phase. For example, Ventafridda and colleagues showed that during the first days, methadone average dose remained unchanged while that of morphine had to be consistently increased . In contrast, another comparative study showed that methadone initially required more up and down changes until dose stabilization than morphine . On the other hand, Bruera and colleagues found a higher rate of dropouts due to opioid-induced side effects (mainly sedation) during titration with methadone than with morphine .
The latest reviews in methadone [5, 7] advise a strategy of slow titration without dose increase in the first 5 to 7 days, along with the use of shorter-acting opioid medication for breakthrough pain. Such scheme is based on methadone´s pharmacokinetics where the steady state is supposed to be achieved after 5–7 days and it is mainly supported by studies in drug dependence and methadone maintenance therapy [23, 24]. Palat and colleagues have recently described their method for methadone titration in the outpatient setting which allowed dose increases of no more than 5 mg every 5–7 days, according to the patient's response .
Our modality for titration allowed early dose increases from Day 1, in accordance with previous reports where the steady state was achieved in less than 5 days , together with the use of rescue methadone for breakthrough pain. The feasibility of this more aggressive titration method is based on our previous positive experience  and the possibility for a close daily supervision of patients. Using this scheme, we found minimal need for titration and for breakthrough doses, and no evidence of accumulation or sedation by the end of the week. The time to achieve dose stabilization (3 days) was comparable to previous reports . The highest median methadone daily dose administered (7.5 mg/day) was lower than the initial doses used in most of the preceding studies [11, 15, 21, 22, 28–30], and the OEI was similar or lower [11, 30–32]. These findings suggest that the methadone dose remained low and stable over the analyzed period.
In the present study, multiple complementary and strict pain reduction and pain control criteria were used. Pain control was determined through the combination of both numerical and categorical scales. The tolerability scale, on the other hand, relies on the patients’ subjective experience of pain alleviation. Sometimes, the patient’s tolerance to pain, and not the numerical score, guided the physician’s decision to increase the opioid dose. We observed a drastic decrease of the median intensity of pain from 8 to 4 after the first day on methadone, which was paralleled by the other scales. At the individual level, 50 patients (81%) reached pain control, most of them in the first 48 hours, and 36 (58%) reached an intensity of pain they considered still comfortable +/- 1 point. It is worth to say that a substantial percentage of patients (35%) expressed high expectations, with desired values of 0 or 1.
There were two cases of limiting delirium, one of them seemed to be secondary to hypercalcemia. In a previous study, methadone as compared to morphine produced more adverse effects and dropout rate, particularly during the first 8 days . Authors raised the possibility that the relative higher starting doses of methadone (median of 15 mg/day) or the utilization of methadone as a breakthrough opioid may have accounted for the higher toxicity. In this sense, the low methadone doses used in the present study could justify the low toxicity despite the use of methadone rescues. There were also few cases of severe nausea and constipation. In addition to methadone´s lower induction of nausea and constipation in comparison to other opioids [11, 15, 21, 32], there was a substantial prescription of adjuvant laxatives and antiemetics at admission. Other symptoms accounting for the moderate to high initial symptom burden, namely asthenia, wellbeing, and anxiety, also significantly decreased from Day 1.
A considerable percentage of patients (6%) withdrew from the study at their own decision, none of them due to uncontrolled pain. The underlying reasons were the patient’s ability or willingness to continue. In addition to the progression of the disease, aversion to opioids for presumed side effects (opiophobia, bad press), reluctance to participating in research protocols, and lack of confidence with a team they were meeting for the first time, may have accounted for this result, and would probably have affected continuity in protocols with other opioids as well.
The major weaknesses of this study include the relatively small sample size and the high rate of patient discontinuation. A high attrition rate is intrinsic to PC trials , so being able to access a larger initial sample would be essential. In addition, further studies are necessary to evaluate the OEI and adverse effects beyond the first week with this modality of treatment.
It can be concluded that the first week of treatment with low dose methadone, including the use of methadone for breakthrough pain, and mainly in the outpatient setting resulted in a rapid pain control with no need for significant titration in most patients. Methadone is a desirable alternative for LMIC due to extremely high prize of extended-release opioid alternatives. Despite the need for precaution, methadone is frequently the only opioid that can be administered 2- times a day and it is therefore among the most used opioids in our population. Present evidence for a convenient and safe titration can significantly improve its accessibility and help to overcome existing challenges in pain alleviation in these countries.