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Tramadol Pharmacology

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Although the Tramadol series of articles tend to provide information on Tramadol that almost anyone can understand. This Tramadol Pharmacology section will contain medical jargon so bear with us.


Tramadol is a unique analgesic that is available in various formulations. It is being prescribed increasingly as an alternative to opioid pain relievers. Tramadol is a synthetic form of opioid-like medication.

It is an opioid receptor agonist and can be used to treat moderate to severe pain both acute and chronic. It also has a wide age range and can treat children to adults to animals.

Tramadol is considered a prodrug that gets metabolized by Cytochrome P450 (CYP) enzymes, CYP2D6, and CYP3A4, especially the O-demethylation product M1. The analgesic effects of Tramadol are, therefore, determined by a particular patient’s CYP genetics.

Someone with poor CYP metabolizing ability will have little production of M1 while another with high mobilizer may experience the full opioid analgesic effects.

While Tramadol is an opioid agonist, it also acts as Serotonin and Norepinephrine reuptake inhibitor simultaneously. This may cause some side effects that should be considered before prescribing Tramadol.

Interactions with other drugs should also be taken into account. We will discuss Tramadol drug interaction in a different article.

What can Tramadol Treat?

Studies show that Tramadol (Ultram) can be prescribed to treat multiple types of chronic and acute pains. It has been observed to do well with neuropathic pain, osteoarthritis, rheumatic arthritis, and back pain.

There is also significant proof that Tramadol works for post-surgical pains. However, it cannot be used immediately after. For the first 2-3 days an actual opioid is recommended as Tramadol doesn’t metabolize like morphine. Tramadol may keep the patient awake while a real opioid puts the patient to sleep, which is recommended after surgery.

Tramadol can, however, be used after 2-3 days as a step-down medication. If the patient still feels pain due to a low rate of metabolism to M1, a non-opioid like Ibuprofen can be added to increase effectiveness.

Off-label use of Tramadol as a treatment for premature ejaculation has also been recorded, but US FDA does not recognize this treatment.

Tramadol Prescription Trends

Due to its in-between (Opioid and Non-opioid) nature, there has been a significant increase in the number of Tramadol prescriptions on the analgesic market. The USA has seen a 65% increase in 2013. While the use of Tramadol increases the use of Oxycodone and Hydrocodone has fallen by 24% and 13%.

This attitude towards Tramadol is the direct result of the fact that Tramadol is a lot less addictive than regular opioids.

Tramadol Pharmacology

Tramadol is entirely new in its class. It was first developed in Germany as they were looking for an opioid alternative that has the same type of potency.

Tramadol has a dual pain relief effects. It works as an opioid agonist. At the same time, it is a monoaminergic Serotonin and Norepinephrine reuptake inhibitor. It acts simultaneously on the μ-opioid receptor and acts on serotonergic and noradrenergic nociception.

Tramadol has 2 chiral focuses and is utilized as a 1:1 racemic combination of 2 enantiomeric diastereomers, the R, R-enantiomer ([+]-Tramadol) and S, S-enantiomer ([−]-tramadol).

The (+)- Tramadol enantiomer is the most intense serotonin reuptake inhibitor, though the (−)- Tramadol enantiomer is the most strong norepinephrine and serotonin reuptake inhibitor.14 By freely upgrading noradrenergic and serotonergic movement, they cooperate to deliver results of the absence of pain in the focal sensory system (CNS).

Tramadol is changed over by CYP450 catalysts 3A4 and 2D6 into 3 significant metabolites, 2 of which are dynamic. (+)- Tramadol and (+)- M1 metabolites both tie to the µ-narcotic receptor to deliver a large portion of its narcotic pain-relieving effects.

However, (+)- M1 is a high-fondness ligand and creates more powerful pain-relieving results than the parent compound, which is a low-proclivity narcotic agonist. There are some enantiomeric contrasts in the pain-relieving power of the 2 enantiomers of M1, with the (+)- O-desmethyl Tramadol arrangement multiple times more noteworthy than that of the (−) configuration.

The subsequent metabolite, N, O-desmethyl tramadol metabolite (M5), is additionally dynamic and adds to the pain-relieving effects. Because of the great partiality of (+)- M1 for the µ-narcotic receptor, its fixation, in blend with that of the M5 metabolite, is essentially liable for the pain-relieving impacts of Tramadol.

Tramadol Pharmacokinetics

As CYP450-interceded stage I metabolic responses are slower than stage II formation responses, they become rate restricting in the, generally speaking, the metabolic attitude of CYP substrate drugs.

The stage I digestion of Tramadol is catalyzed by CYP2D6 and CYP3A4, with the O-demethylation response to the dynamic M1 metabolite catalyzed by CYP2D6. Roughly 80% of Tramadol is processed by CYP2D6, an effectively immersed, low-limit, high-proclivity catalyst that addresses simply 1% to 5% of the liver CYP content.

Since the use limit of patients with a hepatic disability might be essentially diminished, harmfulness at the suggested portion might happen, yet this has not yet been concentrated in patients with liver disease.

Although processed in the liver, unaltered Tramadol and its metabolites are for the most part discharged in urine. In renal weakness, there are reports of diminished leeway and a 2-overlap expansion in the half-existence of Tramadol and the M1 metabolite. Because just 7% of a regulated portion is taken out by dialysis, patients might accept their ordinary portion of Tramadol.

That ends our Tramadol Pharmacology.


We’d like to thank the following doctors and researchers for their contributions have made this article possible.

  • Dr. Karen Miotto, MD.
  • Dr. Arthur K. Cho, PhD.
  • Dr. Jun D. Sasaki, MD.
  • Dr. Richard Rawson, PhD.
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