Abstract
Analgesic efficacy of methadone in cancer and chronic non-cancer pains is greater than that of other opioids, probably because of its unique pharmacokinetics properties and also because it targets glutamatergic receptors in addition to µ-opioid receptors. However, methadone has drawbacks which are clearly related to dosing and treatment duration. The authors hypothesized that the antinociceptive efficacy of methadone could be synergistically potentiated by magnesium and copper salts in a preclinical mouse model of chronic pain, using the intraplantar formalin test as algesimetric tool. The spared nerve injury mice model was used to generate mononeuropathy. A low dose (0.25%) formalin was injected in the neuropathic limb in order to give rise only to Phase I response, resulting from direct activation by formalin of nociceptive primary afferents. Licking/biting of the formalin-injected limb was evaluated as nociceptive behavior during a 35-min observation period. Dose-response curves for intraperitoneal magnesium sulfate (10, 30, 100, and 300 mg/kg i.p.), copper sulfate (0.1, 0.3, 1, and 3 mg/kg i.p.) and methadone (0.1, 0.3, 1, and 3 mg/kg i.p.) allowed to combine them in equieffective doses and to determine their interaction by isobolographic analysis. Magnesium sulfate, copper sulfate and methadone dose-dependently decreased the nociceptive response evoked by formalin injection, the respective ED50 being 76.38, 1.18, and 0.50 mg/kg i.p. Isobolographic analysis showed a superadditive interaction for magnesium and methadone. Indeed, despite that both ED50 are obviously equieffective, the ED50 for the MgSO4/methadone combination contained less than one third of the methadone having the ED50 for methadone alone. For the CuSO4/methadone combination, the interaction was only additive. Extrapolated to clinical settings, the results suggest that magnesium salts might be used to improve synergistically the efficacy of methadone in neuropathy, which would allow to reduce the dose of methadone and its associated side effects.
Highlights
The present results showed that both magnesium sulfate and copper sulfate produced dose-dependent antinociceptive effects in the intraplantar formalin test
The antinociceptive effects showed by magnesium and copper ions coincide with those obtained in other studies using formalininduced pain, where systemic magnesium improved the antinociceptive effect of ketamine (Vujović et al, 2017) and copper-nonsteroidal anti-inflammatory drugs (NSAIDs) complexes exhibited higher antinociceptive effect than NSAIDs alone (Gumilar et al, 2012)
The foregoing results showed that the MgSO4/methadone and CuSO4/ methadone combinations produced higher antinociception than methadone alone, an opiate agonist that has proven to be effective in thermal and mechanical pain models (Lemberg et al, 2006), as well as in chemonociception (Miranda et al, 2014) and different models of neuropathic pain (Erichsen et al, 2005)
Summary
Among the variety of opioid drugs currently used to manage cancer and chronic non-cancer pains, methadone is well positioned because: (i) methadone has no known active metabolites, it is well absorbed by oral and rectal routes, suffers less first pass metabolization and has a lesser interindividual variation in bioavailability than oral morphine (Gourlay et al, 1986); (ii) analgesic efficacy during chronic dosing is greater (Davis and Walsh, 2001) and opioid escalation is lesser (Mercadante et al, 1998) in patients treated with methadone than those treated with morphine; (iii) methadone displays antagonistic properties at the N-methyl-D-aspartate (NMDA) receptor (Ebert et al, 1995; Gorman et al, 1997), which is known to be involved in chronic pain; and (iv) methadone acts as an inhibitor of 5-hydroxytryptamine and norepinephrine uptake (Codd et al, 1995), a mechanism classically associated to pain control by tricyclic antidepressants, important in the case of neuropathic pain Besides to those adverse effects that are common for all opioids (i.e., addiction, sedation, nausea, and respiratory depression), methadone has some drawbacks. 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)
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