Tramadol

Tramadol is often considered a “non-traditional” opioid due to its weaker opioid receptor activity—only about one-tenth the strength of morphine (39). But what makes it unusual is its additional pharmacological effects: it increases levels of serotonin and noradrenaline in the brain, while reducing the activity of GABA (gamma-aminobutyric acid), the brain’s primary inhibitory neurotransmitter (39, 40).

This complex action contributes to its central pain-relieving effects, but also introduces a fine line between therapeutic benefits and serious side effects, especially with long-term use. These include:

• Serotonin Syndrome – A potentially life-threatening reaction caused by tramadol’s serotonergic activity, especially when combined with antidepressants or supplements like tryptophan (41).

• Respiratory Depression – Though less common than with classical opioids, it remains a risk, particularly in fast metabolisers.

• Neuropsychiatric Effects – Tramadol is associated with anxiety, agitation, mania, depression, increased suicide risk, and seizures (39, 40, 43).

• Addiction Potential – Previously thought to be low, addiction rates are rising, particularly in Europe and North Africa (43, 44).

While tramadol was designed to be safer than traditional opioids, its unique pharmacology carries its own risks. It should not be viewed as a universally “safe” alternative without caution.

Specificity of Tramadol and Other Opioids

Tramadol has several distinct pharmacological actions, each with different consequences for pain relief, side effects, and potential drug interactions.

By inhibiting enzymes that break down neurotransmitters such as serotonin, dopamine, noradrenaline, and adrenaline, tramadol can interact with antidepressants and supplements like tryptophan, potentially triggering serotonin syndrome (41). Additionally, by reducing GABA activity—the brain’s main “brake”—tramadol may contribute to neuropsychiatric symptoms like anxiety, agitation, and even seizures (39, 40).

Like all opioids, long-term tramadol use can lead to opioid use disorder (OUD)—commonly referred to as addiction. Importantly, addiction risk is now understood to involve the immune system, which plays a broader regulatory role in brain and body health than previously thought (2, 3, 4, 8). This same mechanism also contributes to pain chronification, where pain becomes more persistent and harder to treat, and reduces opioid effectiveness over time (2, 5, 8).

Certain life experiences—such as childhood trauma, psychological stress, or brain injuries—can “prime” this immune system response, increasing the risk of developing addiction (6, 7).

Emerging evidence also suggests that tramadol may cause inflammation and oxidative stress at the cellular level, even at normal doses if used over long periods?(45, 46).

Tramadol Compared to Classical Opioids

It’s true that tramadol is generally considered to carry lower risk of addiction and respiratory depression than stronger opioids like morphine or oxycodone (39, 40). However, its unusual pharmacology—including effects on serotonin, noradrenaline, and seizure thresholds—creates a different risk profile. These unique risks mean tramadol should not be dismissed as a safer opioid by default.

The so-called “dark side” of tramadol is becoming more recognised, especially as its own toxicity profile comes under closer scrutiny. We'll explore that further in the next sections.

Patient Advice: Managing Pain Safely

If you have a history of early life stress, psychological trauma, or brain injury, it’s especially important to follow the guidance below when using tramadol or other opioids:

• Stay in close contact with your GP or pain specialist. Always follow the prescribed dose.

• Don’t extend the course of treatment without medical advice. Shorter treatment is usually safer.

• If your pain remains uncontrolled, speak to your doctor rather than adjusting the dose yourself.

• Watch for warning signs such as low mood, irritability, or flu-like symptoms when skipping a dose—these may indicate physical dependence.

• If you experience any emotional changes or unusual physical symptoms, contact your clinician promptly.

Important Note on Other Medications

If you’re taking antidepressants (especially SSRIs) or supplements like tryptophan, it’s crucial to speak with a doctor or pharmacist before starting tramadol. These combinations can significantly raise the risk of serotonin syndrome, a potentially serious drug interaction (41).

Tramadol Side Effects

Like classical opioids, tramadol can be safe when used correctly — with appropriate dosing, duration, and clinical oversight (39, 40). But its broader mechanism of action introduces added risks.

Tramadol inhibits monoamine reuptake and MAO activity, raising serotonin levels. When combined with certain antidepressants or tryptophan supplements, this can trigger serotonin syndrome.

Serotonin Syndrome

Serotonin syndrome (41) can begin rapidly—within 1 hour in 30% of cases, and within 6 hours in 60%. Symptoms affect:

• Brain: agitation, anxiety, confusion, seizures, coma.

• Muscle control: tremor, poor coordination, rhythmic jerks (myoclonus).

• Autonomic function: sweating, diarrhoea, fast heart rate, fever, or hyperthermia (>40°C).

It may range from mild to life-threatening and needs urgent attention.

Seizures & CNS Effects

Tramadol lowers seizure threshold by inhibiting GABA, the brain’s main “brake” (40). It causes seizures more often than classical opioids. Seizures may:

• Occur 6 hours post-ingestion.

• Be tonic-clonic (loss of consciousness, convulsions).

• Happen even at normal doses (50–100mg), especially with risk factors.

• Appear during withdrawal—up to 84% in high-dose users (50).

Cognitive issues are also reported (46, 45, 47, 39, 40, 43, 48), including:

• Mood swings, irritability, mania, depression.

• Memory loss, poor focus.

• Dementia risk in long-term users.

Cardiovascular Effects

Tramadol’s noradrenaline-related activity and metabolism can cause (40, 42):

• Palpitations, hypertension.

• Bradycardia or tachycardia on ECG.

• Life-threatening pulmonary hypertension in overdose.

Respiratory Depression & Addiction

Tramadol is less potent than morphine but still addictive (43, 44). Its metabolite (via CYP2D6) can cause respiratory depression, especially in ultrarapid metabolisers (42).

Addiction Risk & Withdrawal

Addiction is more likely with (2, 3, 6, 8, 9, 13, 50):

• Trauma, stress, brain injury.

• Long-term use (>3 months).

• Polypharmacy or poor clinical supervision.

Warning signs (15):

• Social withdrawal, persistent low mood.

• Needing higher doses.

• Deteriorating relationships or performance.

Withdrawal symptoms are both physical and psychological (50):

• Nausea, vomiting, drowsiness, coordination issues.

• Anxiety, cravings, mood swings.

• Seizures in 84% of high-dose users.

• Anxiety similar to SSRI withdrawal due to serotonin effects.

Other Common Side Effects (50)

• Nausea

• Dizziness

• Itching (pruritus)

• Constipation

• Vomiting

As discussed, tramadol’s clinical effects stem from a complex interplay between the parent drug and its active and inactive metabolites. Understanding how it is processed in the body—and how genetic variants affect that processing—is key to both safety and efficacy.

Tramadol Drug Interactions

Tramadol's wide-ranging pharmacological effects make it prone to significant drug interactions, particularly due to the way it is metabolised. To understand these risks, it’s important to distinguish between tramadol itself and its two main metabolites (39, 40, 42, 50):

• The parent drug (tramadol) has weak opioid activity and is mainly responsible for serotonin-related side effects, including lowered seizure threshold.

• The M1 metabolite (O-desmethyl tramadol) is produced via CYP2D6 and contributes most of the opioid-like analgesia—and also the risks of respiratory depression and dependence.

• The M2 metabolite (N-desmethyl tramadol) is produced via CYP3A4 and has little to no pharmacological effect.

The Role of CYP2D6 and CYP3A4 in Tramadol Safety

The clinical relevance of this metabolic pathway becomes clearer when considering drug–gene and drug–drug interactions (50):

• CYP2D6 inhibitors (e.g. amiodarone, quinidine, fluoxetine, paroxetine, bupropion) raise blood levels of the parent drug. This increases the risk of serotonin syndrome and seizures, particularly when SSRIs (like fluoxetine or paroxetine) are also involved.

• When a CYP2D6 inhibitor is suddenly stopped, patients may experience a surge in M1 metabolite levels—potentially leading to respiratory depression.

• CYP3A4 inhibitors (e.g. erythromycin, ketoconazole, ritonavir) can cause an overall rise in tramadol levels, with a knock-on effect of more M1 via the CYP2D6 route. This raises the risk of opioid side effects, seizures, and fatal respiratory depression.

• Stopping a CYP3A4 inhibitor can cause tramadol levels to fall quickly, potentially triggering withdrawal symptoms in dependent patients.

• Conversely, CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine) lower tramadol levels and can reduce its effectiveness. Stopping an inducer can increase levels unexpectedly, increasing the risk of serious side effects.

Clinical advice: If co-prescribing is unavoidable, consider reducing the tramadol dose and monitor closely for signs of toxicity or withdrawal.

Related Medications:

Tramadol is not the only opioid affected by genetic variation. Other opioids where pharmacogenomic testing may offer clinical value include:

• Codeine – a classic CYP2D6-dependent prodrug with high variability in pain relief and side effect risk.

• Hydrocodone – also partially reliant on CYP2D6 for activation.

• Morphine – not a prodrug, but subject to variability in metabolism and CNS effects via UGT enzymes and possibly OPRM1 variants.

• Fentanyl and Alfentanil – primarily metabolised by CYP3A4, meaning drug–drug interactions play a major role in patient response and risk.