Topical methadone and meperidine analgesic synergy in the mouse

Abstract

Topical analgesics have many potential advantages over systemic administration. Prior work has shown potent analgesic activity of a number of topical opioids in the radiant heat tailflick assay. The current study confirms the analgesic activity of morphine and extends it to two other mu opioids, methadone and meperidine. Combinations of topical morphine and lidocaine are synergistic. Similarly, the combination of methadone and lidocaine is synergistic. While there appeared to be some potentiation with the combination of meperidine and lidocaine, it did not achieve significance. Systemically, prior studies have shown that co-administration of morphine and methadone was synergistic. The combination of morphine and methadone was also synergistic when given topically. In contrast, the combination of morphine and meperidine was not synergistic systemically and it was not synergistic topically. Thus, the pharmacology of topical opioids mimics that seen with systemic administration. Their activity in the topical model supports their potential utility while the local limitation of their actions offers the possibility of a reduced side-effect profile.

Methadone is a local anaesthetic-like inhibitor of neuronal Na + channels and blocks excitability of mouse peripheral nerves

“…32 (iii) Methadone induces analgesia when applied topically on mouse skin. 9 Although none of these points really prove that the inhibition of Na + channels is of relevance for regional anaesthesia and LA in clinical practice, our finding that methadone acts as a quite potent LA on neuronal Na + channels identifies a very plausible opioid receptor-independent mechanism for analgesia and anaesthesia induced by methadone. We did not observe any substantial stereo-selectivity for tonic or use-dependent block of Nav1.7 by dextromethadone and levomethadone, that is, the interaction of methadone with Na + channels seems to differ from the interaction of methadone with several other membrane proteins.…”

Stabilization of morphine tolerance with long-term dosing: Association with selective upregulation of mu-opioid receptor splice variant mRNAs

“…Morphine ED 50 values were assessed at the indicated day using a cumulative dose-response paradigm (1, 2.5, 5, 10, 20, and 50 mg/kg) in the radiant heat tail-flick assay and were calculated using probit analysis. Analgesia was assessed quantally (doubling or greater of the baseline tailflick latency for the particular animal) with a maximal latency of 10 s to minimize any tissue damage, as previously described (26,46,47 Changes in mRNA levels of mMOR-1 splice variants after 6 wk of morphine administration in whole brain and brain regions. The levels of the fulllength variants following morphine administration were determined as described in Methods, and the changes were normalized to saline levels.…”

Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain

“…Combinations between different non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, have been evaluated either experimentally or clinically [ 4 ]-[ 8 ]. However, combinations of two opioid receptor agonists have been poorly explored experimentally [ 9 ],[ 10 ]. There is scarce information about clinical trials performed with opioid associations in patients affected by pain [ 11 ].…”