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Tramadol is a centrally acting synthetic opioid analgesic and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine and morphine. Due to its good tolerability profile and multimodal mechanism of action tramadol is generally considered a lower-risk opioid option for the treatment of moderate to severe pain. It is considered a Step 2 option on the World Health Organization's pain ladder and has about 1/10th of the potency of morphine.
Tramadol differs from other traditional opioid medications in that it doesn't just act as a μ-opioid agonist but also affects monoamines by modulating the effects of neurotransmitters involved in the modulation of pain such as serotonin and norepinpehrine which activate descending pain inhibitory pathways.13 Tramadol's effects on serotonin and norepinephrine mimic the effects of other SNRI antidepressants such as duloxetine and venlafaxine.
Tramadol exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms and are also themselves metabolized into active metabolites: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These pathways are complementary and synergistic improving tramadol's ability to modulate the perception of and response to pain.1225
Tramadol has also been shown to affect a number of other pain modulators within the central nervous system as well as non-neuronal inflammatory markers and immune mediators.1718202616 Due to the broad spectrum of targets involved in pain and inflammation it's not surprising that the evidence has shown that tramadol is effective for a number of pain types including neuropathic pain post-operative pain lower back pain as well as pain associated with labour osteoarthritis fibromyalgia and cancer. Due to its SNRI activity tramadol also has anxiolytic antidepressant and anti-shivering effects which are all frequently found as comorbidities with pain.16
Similar to other opioid medications tramadol poses a risk for development of tolerance dependence and abuse. If used in higher doses or with other opioids there is a dose-related risk of overdose respiratory depression and death.2230 However unlike other opioid medications tramadol use also carries a risk of seizure and serotonin syndrome particularly if used with other serotonergic medications.