What is tramadol?
Tramadol is a pain-relieving medicine. It belongs to the group of medicines which are called opioid analgesics.
Forms of tramadol
Tramadol is present in the following forms:
Tramadol is used to treat moderate to severe pain. It acts on the central nervous system to relieve pain.
This medicine is available under a restricted distribution program. This program is called Opioid Analgesic REMS (Risk Evaluation and Mitigation Strategy) program.
How tramadol affects the body?
Tramadol is an analgesic medicine. It is structurally related to morphine and codeine.
Enantiomers of tramadol
Tramadol consists of following two enantiomers:
- (+)-O-desmethyl-tramadol (M1)
How tramadol enantiomers perform analgesic activity?
Both enantiomers perform analgesic activity via different mechanisms.
(+)-Tramadol inhibits the reuptake of serotonin and the (-)-tramadol inhibits the reuptake of norepinephrine. Both enantiomers work together. The complementary actions of both enantiomers improve its effectivity against pain.
Tramadol is present in various forms. During oral use, tramadol is rapidly absorbed by the body. During a period of 12 hours, active ingredients are released, and tramadol is actively distributed throughout the body. After distribution, tramadol is metabolized. Its metabolization occurs through O- and N-demethylation. During metabolization, glucuronides and sulfates are formed which are released via kidneys. O-demethylation of tramadol occurs through cytochrome P450 (CYP) 2D6 while the N-demethylation occurs through CYP2B6 and CYP3A4. The O- and N-demethylation of tramadol occur through stereo selection.
In this way, tramadol performs its analgesic activity. Its activity can be enhanced by combining it with non-opioid analgesic drugs. Tramadol can be used after surgery of thorax or upper abdomen. It can also be used for patients with poor cardiopulmonary function. Tramadol is also helpful in reducing pain from trauma or malignant treatment. It causes less constipation and dependency as compared to other drugs
What are the Side effects of tramadol?
Tramadol is commonly prescribed because of its low risk of addiction in comparison to other opiates. However, Long time use of this medicine can cause mental or physical dependence on it.
Misuse or overdose of this medication can cause many side effects. Side effects associated with it are the following:
It has been reported that tramadol monotherapy causes Seizures in animal and human. Seizures can occur at both recommended and high doses of tramadol. Gardner studied the effects of tramadol. In his study, less than 80 patients out of 9,000 had seizures after their first prescription of tramadol. An Australian study on tramadol was conducted by Labate. His study presented 8.2% new onset of seizures in patients after the exposure of tramadol. His study also stated that “In our First Seizure Clinic, tramadol [was] the most frequently suspected cause of provoked seizures.”
However, some other studies found no potential risk associated with tramadol. Tramadol was found less likely to cause risk of seizures as compared to other analgesic monotherapies.
To understand the effects of overdose or misuse of tramadol many studies are performed. In a study, Jovanovic-Cupic reported the effects of overdosing tramadol. He examined that 54.4% of the patients had at least one seizure during the study period of three years.
In 2003, Thundiyil also examined and confirmed the effects of tramadol overdosing. He found that out of 386 seizures cases, 29 was because of the drug overdose. In another research Spiller examined 126 cases of tramadol overdoing. He reported that eight percent of victims had experienced seizures. All these studies also suggest that overdosing can cause adverse effects on patients with an existing seizure disorder
Tramadol monotherapy can also cause serotonin syndrome. serotonin syndrome is also called as “serotonin toxicity”. It is a potentially lethal condition and is caused by excessive serotonin in the body.
It can occur because of the following reasons:
- Excessive serotonin synthesis
- slow serotonin metabolism
- serotonin reuptake inhibition
Effect of tramadol
In most cases, it is caused by overdosing of drugs or complex interaction between various drugs. Like, it can occur because of the following:
- Tramadol overdosing
- Use of tramadol along with other medications, particularly antidepressants.
The combinations of tramadol with venlafaxine, sertraline, fluvoxamine, fluoxetine, and TCAs has been reported to cause serotonin syndrome. The study of Gnanadesigan has also reported four cases of serotonin syndrome. These four cases happened because of the prescribed use of tramadol in combination with mirtazapine.
No laboratory study is present for the diagnosis of serotonin syndrome.
Clinical features of serotonin syndrome
This syndrome shows many clinical features which are the following:
- Autonomic hyperactivity
- Neuromuscular hyperactivity
- Agitation or confusion
In most cases of serotonin syndrome, the clinical symptoms resolve within 24 hours after the discontinuation of the causative drug.
Hypoglycemia is a critical condition and is associated with increased death rates in patients suffering from diabetes
Effect of tramadol
Recent studies have shown that the use of tramadol might cause hypoglycemia. The pharmacovigilance study had shown that tramadol-induced hypoglycemia occurred in patients within ten days of tramadol use. However, no risk of diabetes mellitus was not found in more than 40% reports.
In 2015, an epidemiological study was performed to investigate the link between the use of tramadol and hospitalization for hypoglycemia. The study found that tramadol use increases the risk of hospitalization for hypoglycemia. During the study, an intentional overdose of tramadol was reported to cause hypoglycemia in women. This study showed that hypoglycemia was caused soon after the initiation of tramadol therapy.
Tramadol mode of action
Tramadol mainly acts through the following mechanisms:
- Activation of µ opioid receptors
- Inhibition of central serotonin and norepinephrine reuptake
Many studies report the Serotonin pathways to have complex effects on glucose regulation. Serotonin causes a reduction in glucose levels in diabetic rats. Tramadol is known to cause inhibition of norepinephrine and serotonin reuptake. Then, the increased level of serotonin induces low glucose level in the body. In this way tramadol induces hypoglycemia.
Tramadol causes an increase in the activation of µ opioid receptors which increases the risk of hypoglycemia. µ pathways have a strong role in causing hypoglycemia but it requires more investigations.
Reports have suggested that tramadol causes hypoglycemia. The use of tramadol caused a 2- fold increase in the risk of hypoglycemia in comparison to the use of codeine. Tramadol-induced hypoglycemia can be potentially fatal in only rare cases.
Reports suggest that tramadol induced hypoglycemia can occur in the first few weeks after tramadol therapy.
In a case study in Uk, 1105 hospitalizations of hypoglycemia were studies. In 30 days of study, incidences of tramadol induced hypoglycemia were 2.5-fold higher than codeine induced hypoglycemia. The risk of hypoglycemia was associated with the first 30 days of tramadol therapy.