How Does Tramadol Work?

Tramadol is a potent analgesic (or painkiller) that is classified under opioids. However, little is known about its mode of action since it works very differently from most narcotic analgesics like morphine. Compared to most NSAIDs (popular over-the-counter pain medications like ibuprofen and aspirin) that alter the production of inflammatory mediators, tramadol works primarily by acting directly on the brain. The primary mode of action is to decrease the brain's perception of pain.

NSAIDs are non-steroidal anti-inflammatory drugs that serve the same functions in the body as steroids (relieve pain, edema, fever and redness) whereas opioids are potent painkillers given as part of anesthesia or post-surgery pain remedy.

Overview of pain and pain remedies:

Pain is a feeling of discomfort or agony that results when the body sends signals to the brain. These pain signals are mediated by different receptors that act as relay stations for nerves. Generally, serotonin and epinephrine give a feeling of pleasure and relief. Any drug that increases the serotonin level improves the overall sense of well-being. Most painkillers (or anesthesia) function by temporarily increasing serotonin, dopamine, or epinephrine levels in the brain.

Nerves carry information regarding movement, sensation and vibration of different parts of the body to the brain. When the nerves get overly stimulated, the signaling speed greatly increases. This is perceived by the brain as discomfort or pain. Any process that can decrease the nerve signaling speed can also decrease the pain sensation.

Mechanism of action of tramadol:

Tramadol has several mechanisms of action:

Action on mu-opioid receptors:

Clinical studies on tramadol suggest that the active drug molecules also exert their action by decreasing the transmission of nerve signal carrying pain sensation. This effect is achieved by direct action of tramadol on mu-opioid receptors (receptors that accept information about moderate to severe intensity pain). However, unlike most narcotic agents, the tramadol effect is very mild (1/10 of that of morphine). This is responsible for its low addiction risk. According to MC Frank, the primary action of tramadol is mediated by increasing the dopamine turnover on mu-opioid receptors.

Norepinephrine uptake inhibition theory:

B. Driessen suggests that since the action of tramadol on mu-opioid receptors is very little, other mechanisms of action may be responsible for its potent analgesic effect. He carried out a series of experiments on rat brain models and identified that the active metabolic of tramadol is O-desmethyltramadol. This is responsible for primary actions of the parent drug by inhibiting the uptake of norepinephrine.

Opioid and non-opioid combined theory:

R. B. Raffa presented his research model on rat brains after subjecting it to tramadol exposure. He identified that the active chemicals of tramadol have modest affinity (attraction) for mu-opioid receptors but the analgesic (pain-relieving effect) is incomplete without neurochemicals like epinephrine and serotonin. R.B. Raffa identified that tramadol blocks the uptake of norepinephrine and serotonin to exert its analgesic actions. Alteration in serotonin levels is responsible for the pleasure and mood elevation effects noticed with tramadol. This can also be explained by the reversal of depression (that is caused by low serotonin levels in brain) upon tramadol intake, or the development of depressive symptoms upon its withdrawal.

Bottom Line

The partial effect of tramadol on mu-receptors is responsible for weak but significant addiction potential with prolonged use. The inhibition of norepinephrine uptake and serotonin is responsible for the potent side effects observed with MAO inhibitors (a class of drug) and other serotonin-elevating medications.