Tramadol Side Effects: How to Use Tramadol Safely

Introduction to Tramadol Side Effects:

Tramadol is a prescription medication used for pain relief. As an opioid analgesic, it is approved for managing severe pain in adults and children older than 12 years when other medicines are inadequate. (1)

Unlike morphine, tramadol does not show many serious adverse effects in therapeutic doses, yet, life-threatening reactions may occur when tramadol is used as recommended. (1-2) Respiratory depression, serotonin syndrome, or overdose can end fatally. Moreover, the long use of tramadol may lead to addiction development, while getting relaxed is a reason for tramadol abuse. (1)

This article is about tramadol side effects, warnings, and precautions. Recognizing signs of life-threatening side effects may save your or your loved one’s life. Keep reading to learn the possible side effects and when to ask for medical care.

How Does Tramadol Work?

To better understand the possible side effects, let’s get closer to tramadol’s two mechanisms of action, opioid and non-opioid. Tramadol inhibits serotonin and norepinephrine reuptake, so their amount in the brain decreases. Tramadol’s M1 metabolite binds with the opioid receptors in the brain and interrupts the pain signal that the brain sends to the body. By that, it reduces the feeling of pain. (2-3)

Half of the tramadol can actively stay in the body for about 7 hours before its elimination. To achieve a daily effect against the pain, the doctor will prescribe tramadol four times a day or decide to prescribe an extended-release formulation once daily. (1, 2, 4)

Common Tramadol Side Effects

The most common side effects of tramadol with an incidence ≥15.0% in patients from clinical trials were dizziness/vertigo, nausea, constipation, headache, somnolence, vomiting, and pruritus. (1) In clinical studies of tramadol extended-release, flushing, vomiting, insomnia, and dry mouth have been reported additionally in the tramadol group by ≥10% of patients. (4)

The risk of these side effects is higher if tramadol is used longer (2-3 months compared with seven days) (1) and the daily dose is higher (e.g., 400 mg vs. 100mg) (4).

Warning and Precautions

Addiction, Abuse, and Misuse

Tramadol has a high potential for abuse, similar to other opioids, and can develop an addiction. The risk is higher if the patient has a personal or family history of substance abuse, including drug (antidepressants) or alcohol abuse or addiction, or mental illness such as depression. (1, 4)

Early recognition of tramadol abuse signs, listed below, can prevent addiction development:

  • Nausea or vomiting;
  • Changes in appetite;
  • Drowsiness;
  • Headaches;
  • Slurred speech;
  • Impaired coordination. (5)

Tramadol addiction can be developed if used for long-term treatment. It can occur, but not necessarily, after the body becomes tolerant and dependent on the drug, so higher doses are needed to achieve the same effect. You can recognize addiction by behavioral and cognitive changes such as:

  • A strong desire to take the drug.
  • Difficulties in controlling its use.
  • Persisting in its use despite its harmful effect and consequences.
  • Using tramadol as of high priority than other activities and obligations.
  • Increased tolerance.
  • Physical withdrawal. (1, 4)

Persons that have developed an addiction to tramadol or other drugs have “drug-seeking” behavior using different tactics to get immediate prescriptions and “doctor shopping” when they aim to visit more prescribers to obtain the drug. (1, 4)

Tramadol abuse increases the risk of overdose and death (1, 4). Symptoms of overdose may include the following:

  • Decreased size of the pupil;
  • Difficulty breathing;
  • Slow or shallowing breathing;
  • Extreme drowsiness or sleepiness;
  • Unable to respond or wake up;
  • Slowed heartbeat;
  • Muscle weakness;
  • Cold, clammy skin. (6)

Call your doctor if the prescribed dose does not relieve you from the pain.

Life-Threatening Respiratory Depression

Opioid usage, including tramadol in recommended doses, can result in serious, life-threatening respiratory depression, also known as hypoventilation. (1, 4)

In respiratory depression, the breathing is too slow or shallow, so the body is not sufficiently supplied with oxygen, and the carbon dioxide levels rise and increase acids in the body. The person with respiratory depression feels sleepy. (7)

The mortality risk of opioid-induced respiratory depression is, on average, dose-dependent; however, any dose brings a risk. A recent study published in the Journal of Neurophysiology suggests that even small opioid doses, under certain metabolic conditions, can lead to an overdose. (7)

Respiratory depression must be treated immediately, otherwise can lead to respiratory arrest and end up fatal. The risk is greater when initiating tramadol treatment and increasing the dose. For this reason, increase the dose slowly, as recommended. Never increase the dose by yourself. Your doctor will monitor your condition in the first days of the treatment and when the dose increases. (1, 4)

Tramadol Risks when used in children

Tramadol is approved for use in children older than 12. However, tramadol is contraindicated in children younger than 18 for pain treatment after the surgery of the ear, nose, and throat (tonsillectomy and/or adenoidectomy). This limitation in usage is due to reported cases of life-threatening respiratory depression, death, and ultra-rapid metabolizer of tramadol. (1, 4)

After oral administration, tramadol has rapid absorption, and 75% of the drug becomes available in the body. It is metabolized in the liver, into two metabolites, M1 and M2, by two enzymes, CYP2D6 and CYP3A4. (3, 8)

In 7% of children, the CYP2D6 enzyme has reduced activity; the outcome is 20% higher tramadol levels in plasma and 40% lower M1 metabolite. In the other 5% ultra-rapid metabolizers, the M1 metabolite levels are higher. (8)

CYP2D6 activity is genetically predefined, and certain drugs can also impact it. The changing levels of tramadol and its M1 metabolite affect the safety and efficacy of tramadol, especially in children. (8)

The doctor will avoid tramadol use in children with postoperative status, obesity, severe lung disease, obstructive sleep apnea, neuromuscular disease, and the use of other medications that cause respiratory depression.

If tramadol is the best treatment option for your child, the doctor will prescribe the lowest dose and closely monitor how the child reacts to the treatment beginning and dose increases.

Keep tramadol away from children. Even one dose of tramadol extended-release tablet taken by accident can result in respiratory depression and death in children. (1)

Serotonin Syndrome

Serotonin Syndrome is a serious drug reaction when serotonin levels in the body are high. (9) This syndrome can occur during tramadol treatment in recommended dosage alone or when used together with:

  • Selective serotonin reuptake inhibitors (SSRIs);
  • Serotonin and norepinephrine reuptake inhibitors (SNRIs);
  • Tricyclic antidepressants (TCAs);
  • Triptans;
  • 5-HT3 receptor antagonists;
  • Mirtazapine, trazodone, tramadol;
  • Drugs that impair serotonin metabolism, including MAO inhibitors. (1, 4)

Symptoms of serotonin syndrome can occur as early as several hours of concomitant use; however, it can also occur a few days after. (1, 4) While some symptoms are mild, others, such as muscle rigidity or seizures, can be severe and need treatment. Untreated serotonin syndrome can lead to unconsciousness and cause death. (9)

If you recognize any of the following symptoms, call your doctor for treatment discontinuation:

  • Agitation;
  • Hallucinations;
  • Tachycardia;
  • Hyperthermia;
  • Incoordination;
  • Rigidity;
  • Nausea;
  • Vomiting;
  • Diarrhea. (1, 4)

Increased risk of seizures

Seizures can occur when tramadol is used in the recommended dose, but the risk increases with doses higher than recommended. Patients with epilepsy, those who had seizures, and those with head trauma, metabolic disorder, alcohol withdrawal, or CNS infection are at higher risk. (1, 4)

If the patient is using any of the following drugs, concomitant use of tramadol increases the risk for seizures:

  • SSRI antidepressants or anorectics;
  • TCAs;
  • Opioids;
  • MAO inhibitors;
  • Neuroleptics;
  • Drugs that reduce the seizure threshold.

Even naloxone, a medication given for tramadol overdose, may increase the risk of seizures. (1, 4)


Tramadol is not recommended for suicidal or addiction-prone patients. If the patient has a history of misuse, currently use antidepressant or tranquilizer, drink alcohol, or is depressed, tramadol should be prescribed with caution. It is important to use tramadol at the recommended dose and to limit alcohol. (1, 4)

Warnings and precautions measures should be also taken due to the following:

Neonatal Opioid Withdrawal Syndrome – when tramadol is used in pregnancy for a longer time, it can result in the withdrawal of the neonate. This syndrome may be life-threatening in newborns and requires medical treatment after early signs appear.

Interactions with other medications – amiodarone, quinidine, ketoconazole, erythromycin, and ritonavir may increase tramadol plasma levels and decrease M1 metabolite levels. Other drugs, such as cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor, when used with tramadol, may lower tramadol levels.

If tramadol is used with benzodiazepines or other CNS depressants, this may result in profound sedation, respiratory depression, coma, and death.

Tell your doctor all the medications you take before start using tramadol.

Adrenal Insufficiency – after diagnosis, the treatment is initiated after the patient is weaned off the opioid.

Severe Hypotension – the doctor will monitor the patient during tramadol initiation and titration.

Gastrointestinal Adverse Reactions – tramadol may cause spasms of the sphincter of Oddi and is not for use in patients with known or suspected gastrointestinal obstruction.

Hypersensitivity Reactions – swelling of your face, tongue, or throat are some of the symptoms of an allergic reaction. An allergic reaction happens after the first dose, and serious and rarely fatal anaphylactic reactions have been reported in clinical studies.

In case of hypersensitive signs occur, stop the treatment and ask immediately for medical help.

Withdrawal – if the patient using tramadol is physically dependent on opioids, rapid discontinuation of the therapy may lead to a withdrawal syndrome and return the pain.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness – the doctor will monitor the patient due to possible sedation and respiratory depression. (1, 4)

Available formulation and tramadol dosage recommendation

Tramadol is available as tablets, capsules, and syrup. Tablets and capsules can have immediate or extended-release. Tramadol is available as a combination product with gamma-aminobutyric acid, acetaminophen, diclofenac, celecoxib, and dexketoprofen. (10)

Since long tramadol usage may develop resistance and addiction, the FDA approved the use of the lowest effective dose for the shortest duration to achieve individual treatment goals. (1, 4)

The recommended starting dose is 25 mg/day. The dose can be increased slowly and with titration according to the following recommendations:

–        every 3 days by 25 mg until 100 mg/day is achieved;

–        every 3 days by 50 mg until 200 mg/day is achieved.

After titration, the single dose can be 50 to 100 mg, making a total of a maximum of 400 mg/daily. (1)

If you have severe kidney or liver impairment, your doctor will recommend a lower dose of tramadol and take it every 12 hours. (1)

If your doctor prescribes tramadol extended-release formulation, the usual initial dose is 100 mg/day, which can be increased by 100 mg every five days. The maximal daily dose is limited to 300 mg. (4)


Tramadol is an effective painkiller and should be used in the smallest dose and shorter period. However, its usage in recommended doses can cause side effects; therefore, identification of early signs can help you take this medication safely.

Don’t underestimate the signs of possible side effects. Instead, call your doctor and report it to the Food and Drug Administration’s (FDA) MedWatch Adverse Event Reporting program online ( or by phone (1-800-332-1088).

Using tramadol without following doctors’ recommendations can be dangerous and develop an addiction. Overdose is life-threatening and can be fatal.

Take this strong painkiller in recommended doses and stay safe throughout the treatment.

See Also

Metformin Side Effects

Prednisolone Side Effects

Side Effects of Paxlovid

Gabapentin Side Effects

Cephalexin Side Effects

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  1. J.Ramirez, N.J.Burgraff et al., Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding, JPN Journal of Neurophysiology, 2021 May,
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  1. Mayo Clinic, Serotonin syndrome, 2022 Jan,

  1. Drugbank, Tramadol, 2023 Jan,


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