Abstract
Tramadol is a widely used, centrally acting, opioid analgesic compound, with additional inhibitory effects on the synaptic reuptake of serotonin and noradrenaline, as well as on the 5-HT2 and NMDA receptors. Preclinical and clinical evidence also suggests its therapeutic potential in the treatment of depression and anxiety. The effects of most widely used antidepressants on sleep and quantitative electroencephalogram (qEEG) are well characterized; however, such studies of tramadol are scarce. Our aim was to characterize the effects of tramadol on sleep architecture and qEEG in different sleep–wake stages. EEG-equipped Wistar rats were treated with tramadol (0, 5, 15 and 45 mg/kg) at the beginning of the passive phase, and EEG, electromyogram and motor activity were recorded. Tramadol dose-dependently reduced the time spent in rapid eye movement (REM) sleep and increased the REM onset latency. Lower doses of tramadol had wake-promoting effects in the first hours, while 45 mg/kg of tramadol promoted sleep first, but induced wakefulness thereafter. During non-REM sleep, tramadol (15 and 45 mg/kg) increased delta and decreased alpha power, while all doses increased gamma power. In conclusion, the sleep-related and qEEG effects of tramadol suggest antidepressant-like properties, including specific beneficial effects in selected patient groups, and raise the possibility of a faster acting antidepressant action.
Highlights
Tramadol (1RS,2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol]hydrochloride is a widely used, centrally acting opioid analgesic in the treatment of acute and chronic pain [1]
Tramadol dose-dependently affected time spent in wakefulness and this effect changed during the 6 h, post-injection (treatment: F(3, 21) = 21.95, p < 0.0001, treatment × time interaction: F(27, 189) = 22.36, p < 0.0001, Figure 1a)
In parallel with its effects on wakefulness, tramadol dose-dependently affected the time spent in non-rapid eye movement (NREM) sleep (treatment: F(3, 21) = 11.03, p = 0.0001, treatment × time interaction: F(27, 189) = 21.73, p < 0.0001, Figure 1b)
Summary
Tramadol (1RS,2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol]hydrochloride is a widely used, centrally acting opioid analgesic in the treatment of acute and chronic pain [1]. Tramadol acts as a weak agonist on μ-opioid receptors and inhibits serotonin (5-HT) and noradrenaline (NA) reuptake. It shows antagonist properties on 5-HT2 , muscarinic acetylcholine, as well as NMDA receptors [2]. Given the monoaminergic effects of tramadol, which is characteristic of most antidepressants, and its structural similarities to venlafaxine (a reuptake inhibitor antidepressant), several preclinical studies have investigated the potential antidepressant effects of tramadol [5,6,7]. Preclinical studies have reported the antidepressant effects of tramadol in rodents [8,9]. Using a novel network-based drug repositioning method, Zhang et al have proposed the antidepressant-like effects of tramadol [10]. Machine learning analysis applied on patient drug reviews on WebMD predicted the repurposing
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