Dual opioid therapy using methadone as a coanalgesic

Keywords:

• coanalgesic
• dual opioid therapy
• methadone
• neuropathic pain
• opioid induced hyperalgesia
• opioid tolerance

We greatly appreciate Dr. Mercadante’s recent report on the efficacy and safety of dual opioid therapy [1]. The role of opioid combinations although controversial is a very exciting and new concept. Combination opioid therapy may improve the analgesic response due to the action of different mu opioid receptor subtypes and may confer reduced dose-related adverse effects. Keeping that in mind, we would like to discuss the addition of methadone as a coanalgesic or dual opioid not only to take advantage of its mu receptor agonist activity but also its potentially non-opioid receptor activity.

In advanced cancer patients chronic opioid use may result in dose escalation which may be due to disease progression, development of tolerance and increased pain sensitization due to opioid induced hyperalgesia (OIH). Activation of the pro-nociceptive glutaminergic system wherein the NMDA receptor plays a key role is implicated in development of opioid tolerance, OIH and opioid-resistant neuropathic pain syndromes [2]. Opioid rotation and addition of an NMDA receptor antagonist have been suggested as remedies in such cases.² NMDA receptor antagonists were effective in treating neuropathic pain and potentiate the analgesic response when administered in conjunction with opioids in animal models.

Methadone, a potent mu opioid receptor agonist also is an NMDA receptor antagonist. The addition of methadone as a coanalgesic may thereby prevent opioid dose escalation and OIH. Moreover, methadone has been shown to be effective in treating non-cancer neuropathic pain syndromes. Addition of a small dose of methadone as a coanalgesic to an existing opioid regimen was well tolerated and resulted in improvement of pain in patients with moderate to severe cancer related pain 3, 4. In another study, low dose methadone used along with other opioids in 93 palliative care patients provided adequate pain control without any opioid dose escalation or OIH [5]. Frequent dose escalation, development of tolerance and OIH are common in opioid therapy of both chronic and cancer related pain. Methadone which is inexpensive, available in multiple routes, has no active metabolites, and has a fecal route of excretion, could be a very valuable tool when used as a coanalgesic. Therefore, well designed and adequately powered prospective studies are needed in both cancer and chronic pain patients to evaluate the use of methadone as a coanalgesic or an adjuvant in optimizing analgesia, reducing the frequency of OIH, and minimizing dose escalation.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

The marvelous carousel of opioids

I appreciated the comments of Reddy and colleagues [1] which underlined an extremely interesting aspect of opioid therapy. We have recognized that the future of opioid therapy in cancer patients more likely lies in a better physicians’ knowledge and growing experience with existent opioids, rather than new molecules that at the moment do not offer significant advantages [2]. This means that clinicians need to bridge the gap between experimental studies and their relative suggestions, and the real world where applying new ideas. Reddy and colleagues raised the relevant problem with escalating doses of an opioid. Poor pain relief with increasing doses of an opioid may be translated in a sort of adverse effect, in this case opioid-induced hyperalgesia (OIH). A recognition of this phenomenon by expert physicians who used to strictly monitor the large number of components influencing the opioid response may suggest an early switching to reverse or limit OIH. Removing the offending drug and substituting for another one may be of benefit. The rationale of opioid switching relies on many pharmacokinetic and pharmacodynamic variables, including asymmetric tolerance, opioid specificity and genetic enzymatic and receptor profiles, all of them having a dynamic and transformist behavior, so that the opioid response may change in time. However, opioid switching requires meticulous monitoring, with individual dose titration based on the specific clinical condition, particularly in patients receiving high doses of opioids, as many problems related to dose conversion and modality of switching still remain controversial particularly in conditions of OIH where any approximate conversion ratio is difficult to predict. As pointed out by Reddy et al., methadone has been demonstrated to exert an inhibition of NMDA receptor activity, other than offering other non-opioid properties; for example, a noradrenergic component, and could revert states of hypersensitization observed with OIH, independently from the opioid effects [3]). This observation could give support to opioid combination, adding a low dose of methadone to globally improve the opioid performance. The potential benefit of a combination of opioids with different receptor characteristics has been poorly explored. The complexity of opioid receptor systems, in terms of opioid heterogeneity, activities of distinct receptor types and opioid ligands, colocalization of receptor types, and the potential for ligand- and receptor-receptor interactions, specific clinical situations, as well individual heterogeneity, may make difficult the application of a fascinating hypothesis which requires more experimental and clinical data. About ten years ago we have shown preliminary data regarding this approach, a sort of semiswitching, adding a second opioid to a previous opioid regimen. Low doses of the second opioid were effective in breaking the opioid escalation index, particularly when adding methadone. This beneficial effect, however, was not reported in all patients and was weaker with other opioid combinations [4].

Of concern, palliative care clinicians fear the use of methadone, due to its unpredictable pharmacokinetics, and even more an opioid combination, that adds complexities to the treatment. I could say that it would be as a cardiologist would use an antihypertensive agent alone. However, it is well known that a combination of drugs with different mechanisms have changed the prognosis of many patients with cardiovascular diseases. We believe that palliative care physicians should be third level specialists able to treat difficult clinical situations and drugs interactions. Therefore, the challenge for researchers is double: first, to demonstrate the efficacy of opioid combination in a large number of patients. Second, to counteract a conservative behavior and resistance to innovation, often due to suboptimal knowledge of opioid pharmacology.

While there are plausible reasons to semiswitch to another opioid when the opioid response is suboptimal, according to personal experiences, both in Palermo and Houston 4, 5, robust clinical trials are needed to both evaluate the practice of opioid combination. Unfortunately, randomized trials in a cancer setting are difficult to perform and justify. The lack of evidence, however, should not deter physicians to use alternative approaches to find the best opioid individual response in critical situations, like OIH, which requires great flexibility and experience, hardly to replay in a strict protocol design.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.