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be especially exercised in those at an increased risk of seizures at baseline, including those with head trauma, a history of seizures, brain tumors, or traumatic brain injuries. Other notable adverse effects that may be prominent with chronic use include an increase in intracranial pressure, cardiovascular dilatation, myocardial infarction, postural hypotension, psychiatric effects, and suicidal ideation in those with emotional disturbances. Due to its receptor activity on serotoninergic receptors, there is
a risk of serotonin syndrome when combined with other serotonergic agents such as selective serotonin reuptake inhibitors. This is of particular concern inhibit cytochrome P450 2D6-mediated metabolism of tramadol, increasing its serum concentration in the body.8
COMPARISON OF TRAMADOL TO OTHER OPIOIDS
Tramadol has been promoted as a relatively safe and effective analgesic alternative in place of other short-acting opioids. It possesses the same relative potency as codeine and around 10% of
the potency associated with parenteral administration of morphine. Tramadol also possesses a higher oral bio- availability than morphine, which equates to a relative oral potency of around 20% as compared to that of oral morphine.4 Opioids as a class are known to carry a which may become life-threatening. It has activity of the M1 metabolite may lower the respiratory rate and potentially lead to severe respiratory depression. However, when compared to other opioids, the risk of respiratory depression associated with tramadol is lower at therapeutic doses.4
Over the years, tramadol has been suggested to carry a lower potential for
abuse and dependence, therefore making it a suitable alternative to other opioid options. However, this has been disputed. receptor agonist, it has been shown that chronic use over weeks to months can lead to the development of physical dependence.4 In fact, a recent study found that in surgical patients prescribed tramadol, there was a higher risk of prolonged use in comparison to those receiving other opioid medications.3 This is hypothesized to be due to tramadol’s large dependence on hepatic metabolism to its active opioid agonist metabolite, M1, which is more extensive after oral administration.4,9
CONTROVERSY SURROUNDING TRAMADOL
In addition to the risk of respiratory depression, physical dependence, and abuse, tramadol possesses a number of unattractive qualities that make it a less- than-ideal agent for the management of has reported that over 50,000 emergency department visits have been attributed to tramadol use, and more than half of these were due to side effects of the drug.1 As previously mentioned, tramadol is unique in that it possesses a dual mechanism of agonist, and secondly, as a serotonin
and norepinephrine reuptake inhibitor. While the dual mechanism of action of its drawbacks. Unrestrained serotonin
and norepinephrine reuptake inhibition can lead to a number of complications, which, if left untreated, are associated with high morbidity and mortality.9
The most serious complications are serotonin syndrome and seizures.10,11 Serotonin syndrome is a collection of symptoms characterized by altered mental status, autonomic dysfunction, and neuromuscular abnormalities that result
from uncontrollable serotonergic agonism of peripheral and central-nervous-system receptors.10 Mortality associated with serotonin syndrome varies depending on the level of severity, but has been shown to be as high as 12%.4 The incidence
of serotonin syndrome secondary to tramadol is believed to be underreported. The FDA’s Adverse Event Reporting tramadol cases between 1997 and 2017, and serotonin syndrome accounted for 3% of these cases.4 Lack of recognition and treatment of serotonin syndrome can lead to a number of complications, including rhabdomyolysis, myoglobinuria, acute renal failure, disseminated intravascular coagulation, metabolic acidosis, and acute respiratory-distress syndrome.
Seizures are another example of a concerning adverse event that can occur with excessive tramadol consumption, and are typically characterized in patients as a single, generalized tonic-clonic episode. Tramadol-induced seizures
minutes, and can occur in the setting of acute or chronic tramadol use.4,10 Between 1997 and 2017, there were 2,019 (7%) tramadol-related seizure cases reported
to the FDA AERS, of which 145 (0.5%) resulted in mortality.12 While tramadol possesses the capability of lowering seizure threshold alone, the risk appears to be much greater when combined with serotonergic psychotropic agents that inhibit cytochrome P-450 2D6, thereby increasing drug concentrations.7,11,14
The seizure threshold has been found
to decrease at a dosing range of 100 to 500mg, with a mean seizurogenic dose of 3,200mg.4,11 While it has been shown that higher doses of tramadol are associated with a greater risk of seizures, this relationship is not evidenced to be dose dependent.
Aside from the high degree of morbidity associated with the use of tramadol, it is
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