Chronic Methadone Treatment Shows a Better Cost/Benefit Ratio than Chronic Morphine in Mice

Abstract

Chronic treatment of pain with opiate drugs can lead to analgesic tolerance and drug dependence. Although all opiate drugs can promote tolerance and dependence in practice, the severity of those unwanted side effects differs depending on the drug used. Although each opiate drug has its own unique set of pharmacological profiles, methadone is the only clinically used opioid drug that produces substantial receptor endocytosis at analgesic doses. Here, we examined whether moderate doses of methadone carry any benefits over chronic use of equianalgesic morphine, the prototypical opioid. Our data show that chronic administration of methadone produces significantly less analgesic tolerance than morphine. Furthermore, we found significantly reduced precipitated withdrawal symptoms after chronic methadone treatment than after chronic morphine treatment. Finally, using a novel animal model with a degrading -opioid receptor we showed that, although endocytosis seems to protect against tolerance development, endocytosis followed by receptor degradation produces a rapid onset of analgesic tolerance to methadone. Together, these data indicated that opioid drugs that promote receptor endocytosis and recycling, such as methadone, may be a better choice for chronic pain treatment than morphine and its derivatives that do not.

Opioid–galanin receptor heteromers mediate the dopaminergic effects of opioids

“…This difference may explain the reduced tolerance of methadone relative to morphine (morphine characteristically induces little MOR internalization; refs. 25,26). But this difference would predict weaker dopaminergic activation by morphine, which is the opposite of what we observed in the present study.…”

“…Methadone is also pharmacodynamically different from morphine in that it has a greater ability to promote MOR internalization and the consequent recycling of nondesensitized MOR (25,26). This difference may explain the reduced tolerance of methadone relative to morphine (morphine characteristically induces little MOR internalization; refs.…”

“…Also taking into account the higher brain penetrability of methadone (30), it could be predicted that methadone is a more efficacious analgesic than morphine. In fact, in experimental animals, methadone has been reported to be a more potent analgesic and to produce significantly less antinociceptive tolerance than does morphine (25,34). The reduced tolerance of methadone has been attributed to its superior ability to induce MOR internalization and the consequent recycling of nondesensitized MORs (25,26).…”

“…In fact, in experimental animals, methadone has been reported to be a more potent analgesic and to produce significantly less antinociceptive tolerance than does morphine (25,34). The reduced tolerance of methadone has been attributed to its superior ability to induce MOR internalization and the consequent recycling of nondesensitized MORs (25,26). Yet, methadone is almost never given as a first-line analgesic in human clinical settings.…”

Drug discovery to counteract antinociceptive tolerance with mu-opioid receptor endocytosis

“…Furthermore, opioid combinations of morphine with low-dose DAMGO (He et al, 2002) or methadone (He and Whistler, 2005), which are MOR agonists with substantial MOR internalization ability, diminished both morphine tolerance and dependence in rats. However, when using a mixture of agonists, it is difficult to strongly conclude that MOR endocytosis contributes to morphine tolerance/dependence because numerous sets of MOR signaling pathways are modified by each agonist (Alvarez et al, 2002;Blanchet et al, 2003;Enquist et al, 2012;He et al, 2009;Milan-Lobo and Whistler, 2011) according to the so-called agonistselective theory (Zheng et al, 2010). A previous study indicated that morphine induces MOR endocytosis in mutant L83I (mouse orthologue of human L85I) without altering binding affinity or cAMP signaling.…”