The Effect of Age on Opioid Switching to Methadone: A Systematic Review

Introduction

Opioids are the mainstay of moderate to severe cancer pain management, and most patients favorably respond to opioid therapy. Patients with cancer often require escalating doses of opioids to control their pain. This can results in untoward adverse effects and development of tolerance to opioids. Several studies have shown that a failure to respond to one opioid does not mean failure to respond to all opioids, and opioid switching (also known as opioid rotation) may allow a better pain control also decreasing the intensity of adverse disabling effects.^1–5

The keystone to the rationale behind opioid substitution is incomplete cross-tolerance, although the exact reason why opioid substitution is successful remains unclear. ⁶ In some patients poorly responsive pain may arise because of the development of analgesic tolerance to an opioid, while tolerance to adverse effects does not develop to the same extent. As a consequence the escalating dose of any opioid may reach a level at which the adverse effects become predominant. Thus, the benefits of switching from one opioid to another opioid could depend on cross-tolerance to the analgesic effects being less than cross-tolerance to the adverse effects.

The most controversial drug for opioid switching is methadone and the vast majority of studies focused on switching from different opioids to methadone. Most reports of methadone for refractory pain or adverse effects with other opioids have been favorable. Initial reports of switching to methadone found a dramatic dose reduction as well as frequent improvement in pain intensity and opioid toxicity. ⁵ The absence of know metabolites allowing a safe use with renal failure, extraopioid activity on N-methyl-d-aspartic acid (NMDA) receptor system, and low cost are the positive characteristics of this agent. However, methadone has major pharmacokinetic and pharmacodynamic differences capable of making the switching more complex. The dose of methadone cannot be easily predicted, as it will depend on a series of factors, including individual response, pharmacodynamics, pain mechanism, pharmacogenetics, and degree of cross-tolerance. ⁶ Specifically, lack of reliable equianalgesic conversion ratios, increased potency associated with methadone in patients previously exposed to high-dose opioids, large interindividual variability in methadone pharmacokinetics, and the potential for pharmacologic interaction with other drugs, have made the clinical use of methadone difficult. ⁴ Systematic reviews on switching to methadone have shown a large heterogeneity in terms of opioid ratios and modality of switching utilized.^5,7,8–12

In the elderly patient, changes in drug metabolism, protein binding, distribution, and clearance associated with aging may result in a diminished rate of elimination, thus amplifying the drug effects. ¹³ The relationship between progression of disease, changes in neuroplasticity, and opioid receptor activity is quite complex,^2,10–12 and this network of factors involved in the opioid response make the evaluation of a single element, such as age, more difficult. In studies of opioid switching the role of age has been variably reported, and has never been the primary outcome. The aim of this review was to assess from the existing literature the effect of age on the outcome of opioid switching to methadone, and the possible influence on conversions ratios.

Methods

MEDLINE, Pubmed, EMBASE text words, and MeSH/EMTREE terms have been used for electronic databases search, including “opioid switching,” “opioid substitution,” “opioid conversion ratio,” “opioid rotation,” and “methadone.” Hand search of main international conference proceedings of the last 3 years was also performed for gray literature. Study inclusion criteria were: studies performed in humans, adult patients with chronic cancer pain, the use of methadone as second opioid in the sequence of switching, English language, studies containing data pertinent to the review, particularly calculation on conversion ratios in aged population. Both authors assessed the included studies. Comparative-parallel or crossover studies, and studies of chronic pain non-cancer patients were excluded. Finally, series of less than 10 patients were excluded.

Results

Twenty-two studies were selected.^14–35 Seven hundred seventy-six opioid substitutions to methadone were retrieved (Table 1). Age was mentioned as a possible factor influencing conversion ratios and/or outcome in only 2 studies, for a global number of patients of 154.^32,35

In the first prospective study, several factors influencing morphine-methadone ratio, including age, were analyzed in a cohort of patients with advanced cancer who were switched from morphine to methadone. ³² The initial ratio was 5:1. The ratio was 10:1 in patients receiving morphine doses of more than 600 mg/d. The modality of switching was performed, regardless of the patient's age. Of 74 patients who underwent opioid switching from morphine to methadone, 54 patients (72.9%) achieved adequate control of pain and adverse effects with stable doses at day 10 after switching. From the previous median morphine doses of 220 mg/d, patients achieved pain and symptom stabilization with final median methadone doses of 45 mg/d. The final conversion ratio was 5. Apart from reasons for switching and previous morphine dose, age was the only variable associated with the morphine-methadone conversion ratio (p=0.04). Age, however, lost significance as an independent predictor of morphine-methadone conversion ratio when it was introduced in the multiple regression analysis (p=0.97).

Similar observations were reported in a recent retrospective chart review of patients switched from different opioids to methadone in an outpatient setting. Median morphine equivalent daily dose before methadone initiation was 100 mg/d. The median methadone dose was 15 mg/d and 18 mg/d, at first follow-up visit and at second follow-up visit, respectively. The final conversion ratio was 5.5. A significant correlation between previous opioid dose and opioid/methadone ratio was found. The conversion ratio was 6 for patients 65 years of age or younger and 9 for patients 65 years of age or older. While in the univariate analysis older patients had a higher conversion ratio (p<0.03), in the multivariate analysis age was not significantly associated with conversion ratios. ³⁵

Discussion

Despite the favorable effects reported with opioid switching, data are based on open studies, most of them being retrospective or small case series. The reason for switching may influence the doses to be chosen. Patients switched due to convenience are different from patients switched due to uncontrolled pain, who are different from patients with adverse effects and controlled pain, who are different from patients with uncontrolled pain and adverse effects. ³⁴ Previous opioid doses of hydrophilic drugs, such as morphine or hydromorphone, and reasons for switching have been found to be predictive factors of conversions ratios to methadone.^32,34 Patients with adverse effects required higher conversions ratios (lower doses of methadone) in comparison with patients switched for uncontrolled pain. ³² However, emerging evidence regarding opioid-induced hyperalgesia in patients who had received rapid escalating doses of opioids, has shown that just discontinuing the offending drug may improve analgesia and opioid requirement may become surprisingly low. ¹⁴ Moreover, renal insufficiency, liver dysfunction, or particular drug interactions may change the potency and effects of the previous as well as the second opioid of the sequence. These effects have not been clarified in the context of opioid switching. ¹⁰

The influence of age has been the primary subject of investigation. An inverse association between age group and doses of opioids, like fentanyl, morphine, and oxycodone, was highly significant. ³⁶ While it seems that in general opioid requirements are inversely related to age, ³⁷ the therapeutic response to opioid titration^38,39 and to methadone ⁴⁰ appears to not be as simple as it would appear.

The two studies reporting the influence of age suggested that age may be of importance, although the correlation with conversion ratios was not high.^32,35 However, despite the obvious limitation represented by the retrospective nature of data, the conversion ratio found between morphine equivalents and methadone in a relative large sample of patients ³⁵ was one third higher in comparison with the subgroup of adults (6:1 versus 9:1), suggesting further caution when switching to methadone in such a population.

The few studies of switching from fentanyl to methadone showed a relative linear correlation between the doses of the two drugs, independently on the previous dose of fentanyl.^28,29 The reasons could also be attributed by the fact that these drugs undergo to similar metabolic pathways. This similarity could potentially produce more predictable response in elderly, at least in terms of pharmacokinetics. It might also be possible to hypothesize that older patients with advanced cancer are more likely to have impaired renal function and renal function is of great importance for the clearance of most other opioids but not for methadone. This might be a potential reason why age might be a less defining factor for methadone. While these implications are intuitive, no data have ever been reported, so that this hypothesis should be confirmed in appropriate studies.

In particular situations such as states of hyperalgesia induced by increasing doses of opioids, no calculation is predictable, and only careful clinical judgment and strict monitoring may serve as a guide to appropriately adjust the doses of the second opioid.^41,42 This is even more important in aged population. As a consequence, opioid conversion should not be a mere mathematical calculation, but just a part of a more comprehensive patient's assessment of the actual opioid therapy, evaluating the underlying clinical situation, pain and adverse effect intensity, comorbidity, concomitant drugs, and excluding any possible pharmacokinetic factor limiting the effectiveness of a certain drug.

Conclusion

There are limited data on opioid switching to methadone in elderly patients. In general the findings indicate that the conversion ratio from opioids to methadone may vary widely and change as a function of the previous dose exposure and recent opioid escalation, as well as the presence of major organ dysfunction.^5,8–11,32 Other reasons to switch, for example uncontrolled pain, could influence the final conversion ratio, while the role of age remains to be clarified.^24,32,34

In this context, older patients represent a challenge for physicians, as a further factor may play a role in dosing methadone and possibly on successful switching. Although existing data are not conclusive, because this aspect did not receive particular attention in most studies, at the present time age has not been found to be independently associated with the dose ratio. Further prospective studies in a large sample of patients, subgrouped for classes of age, opioid doses, and reasons to switch should be designed to provide more information.