Tramadol

Tramadol is an Opioid agonist and SNRI (serotonin/norepinephrine reuptake inhibitor) belonging to the analgesic class.

Tramadol is a centrally acting opioid agonist and SNRI (serotonin/norepinephrine reuptake inhibitor) used for the management of moderate to severe pain in adults.

The bioavailability can be attributed to the 20-30%. Peak plasma concentrations of tramadol and the primary metabolite M1 occur at two and three hours, respectively. Following a single oral dose of 100mg of tramadol, the Cmax was found to be approximately 300μg/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55μg/L with a Tmax of 3 hours. Tramadol is rapidly and almost completely absorbed following intramuscular administration. Following injection of 50mg of tramadol, Cmax of 166μg/L was found with a Tmax of 0.75 hours. The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg. Tramadol undergoes extensive first-pass metabolism in the liver by N- and O- demethylation and conjugation. From the extensive metabolism, there have been identified at least 23 metabolites. Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.

Tramadol shows side effects like Sleepiness, headache, nervousness, uncontrollable shaking of a part of the body, changes in mood, heartburn or indigestion, dry mouth.

Tramadol is available in the form of Oral tablets and Oral Capsules.

Tramadol is available in India, US, UK, Germany, China, Italy, Spain and Canada.

Tramadol is an Analgesic belonging to the class Opioid agonist and SNRI (serotonin/norepinephrine reuptake inhibitor).

Tramadol and its active metabolite (M1) binds to μ-opiate receptors in the CNS causing inhibition of ascending pain pathways, altering the perception of and response to pain; also inhibits the reuptake of norepinephrine and serotonin, which are neurotransmitters involved in the descending inhibitory pain pathway responsible for pain relief.

Tramadol starts showing its effects (onset of action) within 1- 2 hours after taking oral forms.

The amount of time for which the Tramadol oral dosage forms (tablet, extended-release tablets and dispersible tablets) remain active is 6-7 hours.

The time to peak concentration of Tramadol is approximately 2-3 hours.

Tramadol is available in the form of an Oral Tablet and Oral Capsule.

Tramadol Tablet and Capsule are taken orally, usually in divided dose.

Tramadol is a painkiller medicine that belongs to a group of medicines known as opioid analgesics. It is used to provide effective relief from moderate to severe pain associated with various arthritic conditions, low back pain, neck pain, headache, etc. It is also used to relieve post-operative pain.

Tramadol is an Opioid agonist and SNRI (serotonin/norepinephrine reuptake inhibitor) belonging to the analgesic class.

Tramadol binds to mc-opiate receptors in the CNS resulting in inhibition of ascending pain pathways, thus altering the perception of and response to pain. Its inhibition of neuronal uptake of norepinephrine and enhancement of serotonin release may also contribute to its analgesic effect.

Tramadol is approved for use in the following clinical indications

• Pain management, moderate to severe

Tramadol is a centrally acting opioid agonist and SNRI (serotonin/norepinephrine reuptake inhibitor) used for the management of moderate to severe pain in adults.

• Premature ejaculation (off-label)

• Pain management, moderate to severe

Acute pain (eg, postoperative):

Immediate release: Oral: Initial: 50 mg every 4 to 6 hours as needed; if rapid onset of analgesic effect is required, may consider an initial dose of 50 to 100 mg every 4 to 6 hours; some experts suggest that 25 to 50 mg 3 times per day may be sufficient for patients with moderate acute pain. Increase dose as needed and tolerated to 50 to 100 mg every 4 to 6 hours; maximum daily dose: 400 mg/day.

Chronic pain (alternative agent):

Opioid-naive patients not currently on tramadol immediate release:

Immediate release: Oral: The ideal dosing regimen has not been established; consider restricting the initial dose to <300 mg tramadol per day (ie, <50 mg morphine equivalents daily). An example initial dose is 25 to 50 mg every 6 hours as needed. The dose may be increased as needed and tolerated to 50 to 100 mg every 4 to 6 hours (maximum: 400 mg/day).

Extended release: Initial: Oral: 100 mg once daily; titrate by 100 mg/day increments every 5 days as needed (maximum: 300 mg/day).

• Premature ejaculation (off-label)

Immediate release: Oral: The ideal dosing regimen has not been established; dosage range studied: 25 to 50 mg administered on demand 1 to 3 hours prior to intercourse.

Tramadol is available in various strengths as 50mg, 100mg and 150mg.

Tramadol is available in the form of Oral Tablet and Oral Capsule.

• Dosage Adjustment in Kidney Patient

CrCl ≥30 mL/minute: Immediate release, extended release: No dosage adjustment necessary.

CrCl <30 mL/minute: Immediate release: Increase dosing interval to every 12 hours; maximum: 200 mg/day. ER formulation should be avoided.

Tramadol is contraindicated in patients with

• Contraindications include hypersensitivity to tramadol or opioids.
• Known or suspected gastrointestinal obstruction, including paralytic ileus.
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days.

• Bronchial Asthma

Tramadol should be used with caution if you have acute or chronic asthma. Your doctor may monitor your lung functioning while you are using this medicine. Report any unusual symptoms to the doctor immediately.

• Fall in blood pressure

Tramadol can cause a temporary fall in blood pressure which can worsen based on posture (Orthostatic Hypotension). This can happen due to pre-existing medical conditions or the use of other medicines at the same time.

• Impaired brain function

Tramadol can increase the risk of side effects if you have a brain tumour or head injury. Your doctor will prescribe a suitable dose depending on your condition. He may monitor your condition while using this medicine. This medicine is not recommended for use in people who are in a coma.

• Other medicines

Tramadol has a high potential of interacting with a large number of medications. Report the use of all medications including supplements and herbs so that the side effects can be minimized.

• Reduced fertility

Prolonged use of Tramadol may reduce fertility in men and women. Therefore caution should be maintained while using this medicine.

• Seizures

Tramadol should be used with caution if you have a history of seizures as it can trigger a fresh attack of seizure and worsen your condition. Your doctor may adjust the dose of this medicine if required, based on your clinical condition.

• Suicidal Tendencies

Tramadol may cause suicidal thoughts. This risk is especially high upon the prolonged usage of the medicine. Any changes in behavior and mood should be reported to the doctor immediately.

Consumption of alcohol is not recommended while receiving Tramadol due to the increased risk of serious side effects such as severe stomach and intestinal bleeding, dizziness, fatigue, weakness, rashes, nausea, joint pain, fever, jaundice, etc.

Tramadol is not recommended for obstetrical preoperative medication or for postdelivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.

There are no adequate and well-controlled studies in pregnant women. Tramadol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing.

Common

Malaise, Vasodilation, Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder, Abdominal pain, Anorexia, Flatulence, Hypertonia, Rash, Visual disturbance, Menopausal symptoms, Urinary frequency, Urinary retention.

• Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation.
• Amphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed.
• Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined.
• Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin.
• Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used.
• Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended.
• Dextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined.
• Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available.
• Iopamidol: Agents with Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs.
• Linezolid: May enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes).
• Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression.
• Ondansetron: May enhance the serotonergic effect of Tramadol. This could result in serotonin syndrome. Ondansetron may diminish the therapeutic effect of Tramadol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and diminished tramadol efficacy when these agents are combined.
• Primidone: May enhance the CNS depressant effect of Tramadol. Primidone may decrease the serum concentration of Tramadol. Management: Avoid use of tramadol and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined.
• Selective Serotonin Reuptake Inhibitors: Tramadol may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and seizures when these agents are combined.
• Tricyclic Antidepressants: May enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression.

The common side effects of Tramadol include the following

• Common side effects

Sleepiness, headache, nervousness, uncontrollable shaking of a part of the body, changes in mood, heartburn or indigestion, dry mouth.

• Rare side effects

Rash, blisters, hoarseness, difficulty swallowing or breathing, chest pain.

• Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Tramadol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing.

• Nursing Mothers

Tramadol is not recommended for obstetrical preoperative medication or for postdelivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of Tramadol , the cumulative excretion in breast milk within 16 hours postdose was 100 μg of Tramadol (0.1% of the maternal dose) and 27 μg of M1.

• Pediatric Use

The safety and efficacy of Tramadol in patients under 16 years of age have not been established. The use of Tramadol in the pediatric population is not recommended.

• Geriatric Use

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. In patients over 75 years of age, daily doses in excess of 300 mg are not recommended.

Symptoms: Vomiting, sedation, miosis, seizures, skeletal muscle flaccidity, cold and clammy skin, pulmonary oedema, bradycardia, QT prolongation, hypotension, partial or complete airway obstruction, atypical snoring, CV collapse, respiratory depression, coma, serotonin syndrome, respiratory failure.

Management: Supportive treatment. Maintain patent airway and CV functions; initiate assisted or controlled ventilation as necessary. Employ oxygenation and administer vasopressors in case of circulatory shock and pulmonary oedema as clinically indicated. Administer naloxone for respiratory depression and IV diazepam to control seizures; other IV benzodiazepines may also be considered. Perform gastric lavage or administer activated charcoal within 2 hours of ingestion.

• Pharmacodynamic

Tramadol modulates the descending pain pathways within the central nervous system through the binding of parent and M1 metabolite to μ-opioid receptors and the weak inhibition of the reuptake of norepinephrine and serotonin. Apart from analgesia, Tramadol may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids.

• Pharmacokinetics

Absorption

Oral Administration

The bioavailability can be attributed to the 20-30%. Peak plasma concentrations of Tramadol and the primary metabolite M1 occur at two and three hours, respectively. Following a single oral dose of 100mg of Tramadol , the Cmax was found to be approximately 300μg/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55μg/L with a Tmax of 3 hours.

Intramuscular Administration

Tramadol is rapidly and almost completely absorbed following intramuscular administration. Following injection of 50mg of Tramadol , Cmax of 166μg/L was found with a Tmax of 0.75 hours.

Rectal Administration

Following rectal administration with suppositories containing 100mg of Tramadol , Cmax of 294μg/L was found with a Tmax of 3.3 hours. The absolute bioavailability was found to be higher than oral administration (77% vs 75%), likely due to reduced first-pass metabolism with rectal administration compared to oral administration.

Distribution

The volume of distribution of Tramadol is reported to be in the range of 2.6-2.9 L/kg. Tramadol has high tissue affinity; the total volume of distribution after oral administration was 306L and 203L after parenteral administration. Tramadol crosses the blood-brain barrier with peak brain concentrations occurring 10 minutes following oral administration. It also crosses the placental barrier with umbilical concentrations being found to be ~80% of maternal concentrations. About 20% of the administered dose is found to bind to plasma proteins. Protein binding appears to be independent of concentrations up to 10μg/mL.

Metabolism and Excretion

Tramadol undergoes extensive first-pass metabolism in the liver by N- and O- demethylation and conjugation. From the extensive metabolism, there have been identified at least 23 metabolites. There are two main metabolic pathways: the O-demethylation of Tramadol to produce O-desmethyl-Tramadol (M1) catalyzed by CYP2D6 and the N-demethylation to N-desmethyl-Tramadol (M2) catalyzed by CYP3A4 and CYP2B6. Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.

• https://www.uptodate.com/contents/tramadol-drug-information#F229583
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020281s032s033lbl.pdf
• https://www.rxlist.com/tramadol/generic-drug.htm#what_other_drugs_interact_with_tramadol_ultram
• https://medlineplus.gov/druginfo/meds/a695011.html#side-effects
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