Interaction of Different Antidepressants with Acute and Chronic Methadone in Mice, and Possible Clinical Implications

Abstract

We studied the interaction of a single dose of different antidepressant medications with a single (acute) dose or implanted mini-pump (chronic) methadone administration in mice, using the hotplate assay. For the acute experiment, subthreshold doses of six antidepressant drugs were administered separately with a single dose of methadone. The addition of a subthreshold dose of desipramine or clomipramine to methadone produced significant augmentation of the methadone effect with each drug (p < 0.05). Fluvoxamine given at a fixed subthreshold dose induced a synergistic effect only with a low methadone dose. Escitalopram, reboxetine and venlafaxine given separately, each at a fixed subthreshold dose, induced no interaction. Possible clinical implications of these findings are that while escitalopram, reboxetine and venlafaxine do not affect methadone's antinociception in mice and are safe to be given together with methadone when indicated, fluvoxamine, clomipramine and desipramine considerably augment methadone-induced effects and should be avoided in this population due to the risk of inducing opiate overdose. For the chromic experiment, when a subthreshold dose of either escitalopram, desipramine or clomipramine was injected to mice following 2 weeks of methadone administration with the mini-pump, none of the antidepressant drugs strengthened methadone's analgesic effect. Further studies are needed before possible clinical implications can be drawn.

Pharmacological interaction between NSAIDS with clomipramine and risperidone in mice visceral pain

“…In this study, pretreatment of mice with either clomipramine or risperidone, increased the antinociceptive potency of ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol, this is reflected by a decrease in the values of antinociceptive ED 50 , in the tonic chemical inflammatory visceral pain (writhing test). This enhanced potency is in agreement with previous studies using other analgesics, such as opioids (Banks, Rice, & Negus, ; Schreiber et al, ).…”

Anti-Nociceptive Outcomes of Anticonvulsant/Antidepressant Medicines in the Management of Formalin Induced Pain in Group of Mice

“…However, fluvoxamine with subthreshold dose persuaded a synergistic effect with a dose of methadone. 19 It is proposed that antidepressant drugs mildly attenuating the action of pro-inflammatory cytokine and improved the symptoms of depression. 20 We found that Lamotrigine with a dose of 70mg/kg initially increase the response of protection in paw-licking (84%) whereas diminished effectiveness in lifting paw at time 15 -45 min (50%).…”

Magnesium Salt, a Simple Strategy to Improve Methadone Analgesia in Chronic Pain: An Isobolographic Preclinical Study in Neuropathic Mice

“…Consequently, the possibility of enhancing the analgesic effect of methadone (and therefore of reducing its dose) by combining it with other nonopioid antinociceptive drugs could significantly help to reduce the side effects and risks associated with the therapeutic use of this drug. Combination of methadone with tricyclic antidepressants (Banks et al, 2010;Schreiber et al, 2014), methylph enidate (Schreiber et a l., 2017), delta9tetrahydrocannabinol (Cichewicz et al, 1999) and ketamine (Pelissier et al, 2003) have already been reported, but almost in acute preclinical pain models. Methadone/ketamine (de Godoy et al, 2013) and methadone/ibuprofen (Ferrer-Brechner and Ganz, 1984) combinations have been used as antinociceptive agents in the clinic, but controlled studies reported that ketamine alone is more effective than the methadone/ketamine combination (Rigo et al, 2017) and that at the long-term nonsteroidal anti-inflammatory drugs (NSAIDs) can result in increased risk of gastrointestinal and cardiovascular side-effects (Wehling, 2014;Ho et al, 2018).…”