Trazodone and mirtazapine: A possible opioid involvement in their use (at low dose) for sleep?
Introduction
Insomnia is a non-pathognomonic condition characterized by actual or perceived poor sleep quantity or quality. It may present in the forms of ‘initial insomnia’ (delayed sleep onset), ‘middle insomnia’ (nocturnal awakenings with difficulty returning to sleep), ‘early morning wakening’ (waking too early, and not feeling rested despite adequate sleep hours), or a combination of the above. Insomnia of any form may lead to distress and subjective impairment in the daytime [1], hence is important to address as it affects patients both psychologically and cognitively leading to poor quality of life and impediment on the way to recovery throughout recovery.
Hypno-sedative benzodiazepines such as triazolam and brotizolam substituted the unsafe (first generation) barbiturates, as the treatment of choice for short-term insomnia for many years [2]. But due to their own association with adverse effects such as rebound insomnia, withdrawal and dependency [3], a third-generation class of drugs has been developed: the non-benzodiazepine ‘Z compounds’. When introduced, these drugs were considered to have a reduced abuse potential and propensity to tolerance and withdrawal due to improved pharmacokinetics [4], [5], [6], [7] (for a review see [8]). However, despite such expectations, large levels of cases of misuse, abuse, dependence and death involving Z-drugs have been reported over the last two decades [9], [10], [11].
In a previous study (in mice) we have found zolpidem (one of the hypnotics ‘Z compounds’) to induce a weak, biphasic dose-dependent antinociceptive effect, antagonized primarily by the non-selective opioid antagonist naloxone and by the alpha-2 (noradrenergic) antagonist yohimbine. The weak antinociceptive effect of zolpidem was evident only at very high doses, far beyond those used clinically to induce sleep [12].
For decades, some antidepressants have been prescribed for long-term treatment of insomnia in chronic-insomnia patients, and in patients with addictive disorders, in order to prevent the possible development of tolerance, dependence and addiction to benzodiazepines or the ‘z-compounds’. This practice is widespread, even though none of these medications is licensed for insomnia and the evidence for their efficacy is unclear (for review, see [13]). Among the most frequently prescribed antidepressants (at a very low, non-therapeutic dose) for sleep is trazodone, found in the Cochrane Review [13] to have a moderate improvement in subjective sleep outcomes over placebo, and little or no difference in objective sleep efficiency measured with polysomnography [13]. Another “popular” antidepressant (also prescribed at subtherapeutic antidepressant dose) is mirtazapine (not evaluated in the Cochrane review).
Trazodone is a triazolopyridine derivative with antidepressant activity, in clinical use for more than 40 years now [14]. Its overall pharmacological profile differs from each of the other classes of psychotropic drugs, which it bears some resemblance to their action, i.e. benzodiazepines, antipsychotic phenothiazines and the tricyclic antidepressants [15], [16]. In vitro, trazodone is a weak, but specific, inhibitor of the synaptosomal uptake of serotonin, and it binds to alpha-1 and alpha-2 adrenoreceptor sites [17]. In a previous study (in mice), we found trazodone to induce a dose-dependent antinociceptive effect. This effect was antagonized both by naloxone (implying involvement of the opioid system) and by the nonselective serotonin antagonist metergoline (implying involvement of 5-HT mechanisms), but was unaffected by yohimbine, (the alpha-2 adrenergic antagonist) [18].
Mirtazapine is an antidepressant in use for more than 20 years now, one of a chemical series of compounds known as piperazinoazepines which is not related to any known class of psychotropic drugs. Mirtazapine enhances noraderenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central alpha-2-auto- and hetero-adrenoreceptors [19], [20]. Mirtazapine does not inhibit noradrenaline or serotonin uptake, but blocks specifically the 5-HT2 and 5-HT3 type receptors, while failing to modulate monoamine reuptake in animal models. In these models mirtazapine manifested a very low affinity for dopaminergic receptors and high affinity for histamine H1 receptors [20]. However, it seems that mirtazapine’s intrinsic noradrenergic activity counteracts its histaminergic effects [20]. Mirtazapine’s unique pharmacological profile, which in part resembles that of Mianserin [21], suggests a combined serotonin-noradrenaline mediated antinociception, with a possible involvement of the opioid system [22].
In the present paper we integrated the findings of trazodone’s and mirtazapine’s interaction with the opioid system previously described [18], [22], compared it to the interaction of the ‘Z drug’ zolpidem with the opioid system [12], and suggest a possible common pathway that may explain why trazodone and mirtazapine (of all so many different antidepressant medications) are the most (off-label) prescribed antidepressants for sleep (at much below their antidepressant dosage).
Section snippets
Subjects and surgery
Male ICR mice from Tel-Aviv University colony (Tel-Aviv, Israel), weight 25–35 gr. were used. The mice were maintained on a 12 h. light: 12 h. dark cycles with Purina rodent chow and water available ad libitum. Animals were housed five per cage in a room maintained at 22C° ± 0.5C until testing. Mice were used only once. Central injections in mice were made under light halothane anesthesia, using a Hamilton 10 μl syringe fitted to a 30-gauge needle with V1 tubing. Intrathecal (i.t.) injections
Trazodone mirtazapine and zolpidem antinociceptive effect and Naloxone effect
Screening of trazodone, mirtazapine or zolpidem in mice demonstrated its efficacy as an antinociceptive agent in the hotplate assay. Trazodone induced a dose-depend antinociceptive effect following i.p. injection (Fig. 1 A). The ED50 for mice in the hotplate assay for trazodone was 24.8 mg/kg (9.8; 67.4; 95% CL; i.p). At doses from 1 to 7.5 mg/kg, mirtazapine administered i.p. produced an antinociceptive effect in the hotplate test in a dose dependent manner (Fig. 1A). The antinociceptive
Discussion
This study was carried out in order to look for a possible common mechanism of action in mice, of the two most prescribed antidepressant medications for insomnia – trazodone and mirtazapine, and to compare them with one of the most prescribed hypnotic non-benzodiazepine ‘Z-compound’ medication zolpidem. Both trazodone and mirtazapine (as well as zolpidem), were found to induce an antinociceptive effect in the mouse hotplate assay, when administered at quasi-equipotent subtherapeutic
Funding
No financial support was offered (or needed) for this study.
Disclosures and acknowledgments
Both authors contributed equally to the development of the concept, data (PubMed) search and integration, conclusions reached and manuscript writing and reviewing. Both have read and approved the submitted version.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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