Tramadol


Generic Medicine Info
Indications and Dosage
Oral
Moderate to severe pain
Adult: As conventional tab/cap/orodispersible or dispersible tab: 50-100 mg 4-6 hourly. Max: 400 mg daily. As modified release (12-hourly) cap: Initially, 50-100 mg bid, may be titrated to 150 mg or 200 mg bid if necessary. Max: 400 mg daily. As modified release (24-hourly) tab/cap: Initially, 100 mg or 150 mg once daily. Max: 300 mg or 400 mg daily. Use the lowest effective dose for the shortest possible treatment duration. Adjust dose based on the severity of pain and individual sensitivity. Dosage recommendations may vary among countries and individual product (refer to detailed product guideline).
Child: ≥12 years Same as adult dose.
Elderly: >75 years Dosage interval may be prolonged according to individual requirements. Treatment recommendations may vary among countries and individual products (refer to detailed product guideline).

Parenteral
Postoperative pain
Adult: Initially, 100 mg via slow IV, IM, or SC inj, followed by 50 mg every 10-20 minutes up to a total of 250 mg (including the initial dose) in the 1st hour. Subsequent doses of 50 mg or 100 mg 4-6 hourly may be given. Max: 600 mg daily.
Child: ≥12 years Same as adult dose.
Elderly: >75 years Dosage interval may be prolonged according to individual requirements.

Parenteral
Moderate to severe pain
Adult: 50-100 mg 4-6 hourly via slow IV over 2-3 minutes, IM, or SC inj. Max: 600 mg daily.
Child: ≥12 years Same as adult dose.
Elderly: >75 years Dosage interval may be prolonged according to individual requirements.
Special Patient Group
Patient taking benzodiazepine: Use the lowest effective dose for the shortest possible duration.

Pharmacogenomics:

Tramadol is metabolised in the liver by the CY2D6 isoenzyme to form the active metabolite, O-desmethyltramadol (M1), which has a significantly higher affinity for opioid receptors. CYP2D6 is a highly polymorphic gene which may be associated with the clinical effect and safety of tramadol. Genetic testing may be considered prior to therapy.

According to studies, CYP2D6 ultrarapid metabolisers have 1.1 to 5.9-fold higher M1 concentrations than normal metabolisers. An approximate of 2-4-fold higher nonresponse rate to tramadol were reported among CYP2D6 poor metabolisers than normal metabolisers or intermediate metabolisers. Variations in CYP2D6 polymorphism occur at different frequencies among subpopulations of different ethnic or racial origin. Some individuals may be ultrarapid metabolisers of CYP2D6. The prevalence of CYP2D6 ultrarapid metabolisers varies widely and has been estimated to be 29% in African/Ethiopian, 3.4-6.5% in African American, 1.2-2% in Asian, 3.6-6.5% in Caucasian, 6% in Greek, 1.9% in Hungarian, and 1-2% in Northern European population. Meanwhile, up to 7% of the Caucasian population has a deficiency or is completely lacking functional CYP2D6 activity.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of December 2020:
Phenotype Implications Recommendations 
CYP2D6 ultrarapid metabolisers
Increased formation of the active metabolite, O-desmethyltramadol, resulting in an increased risk of toxicity.
Avoid tramadol use due to the potential for toxicity. If opioid use is needed, may consider a non-codeine opioid as an alternative.
CYP2D6 intermediate metabolisers Decreased O-desmethyltramadol formation. No dose adjustments needed, however, if there is no response and opioid use is warranted, it is recommended to consider the use of a non-codeine opioid.
CYP2D6 poor metabolisers Greatly reduced O-desmethyltramadol formation resulting in diminished therapeutic effect. Avoid tramadol use due to the possibility of diminished analgesic effect. If opioid use is needed, may consider a non-codeine opioid.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of November 2018:
Phenotype Implications Recommendations
CYP2D6 ultrarapid metabolisers Increased conversion of tramadol into the active metabolite which may result in increased risk of potentially life-threatening adverse effects. Choose an alternative agent that is not metabolised by CYP2D6 (e.g. morphine). If an alternative is not possible, may use 40% of the usual dose and advise patient to report adverse effects (e.g. drowsiness, confusion, respiratory depression).
CYP2D6 intermediate metabolisers Reduced conversion of tramadol into the active metabolite which may result in reduced analgesic effect. Be vigilant of the reduced effect. In case of inadequate response, a dose increase may be considered and if there is no response, an alternative agent that is not metabolised by CYP2D6 (e.g. morphine) may be given. If no alternative agent is selected, advise patient to report for inadequate analgesic effect.
CYP2D6 poor metabolisers Reduced conversion of tramadol into the active metabolite which may result in reduced analgesic effect. Be vigilant of the reduced effect. In case of inadequate response, a dose increase may be considered and if there is no response, an alternative agent that is not metabolised by CYP2D6 (e.g. morphine) may be given. If no alternative agent is selected, advise patient to report for inadequate analgesic effect.

Additionally, the annotation of FDA label for tramadol recommends that CYP2D6 ultrarapid metabolisers must not use tramadol due to the risk of life-threatening respiratory depression even at labelled dosage regimens.

Treatment recommendations may vary among local treatment guidelines. Refer to country-specific guidelines.
Renal Impairment
Oral:
CrCl (mL/min) Dosage
<10
Not recommended.
<30 As conventional tab/cap: Increase dosage intervals to 12 hourly. Max: 200 mg daily.

Parenteral:
CrCl (mL/min) Dosage
<10 Not recommended.
<30 Increase dosage intervals to 12 hourly.
Hepatic Impairment
Oral:
As conventional tab/cap: Dosage interval may be prolonged according to individual requirements. Treatment recommendations may vary among countries and individual products (refer to detailed product guideline).
Parenteral:
Dosage interval may be prolonged according to individual requirements (refer to detailed product guideline).
Administration
May be taken with or without food.
Incompatibility
IV/IM/SC: May form precipitates when mixed in the same syringe with diazepam, diclofenac Na, flunitrazepam, glyceryl trinitrate, indometacin, midazolam, piroxicam, and phenylbutazone.
Contraindications
Acute intoxication with centrally acting analgesics, hypnotics, psychotropic drugs, alcohol, or other opioids; uncontrolled epilepsy, significant respiratory depression, acute or severe bronchial asthma (in unmonitored setting or lack of resuscitative equipment), known or suspected gastrointestinal obstruction (including paralytic ileus). Children <12 years and in children <18 years who have undergone tonsillectomy and/or adenoidectomy. CYP2D6 ultrarapid and poor metabolisers. Concomitant use or within 14 days after MAOI therapy. Use for narcotic withdrawal treatment or during light planes of anaesthesia.
Special Precautions
Patient with history of epilepsy or those with susceptibility to seizures (e.g. alcohol or drug withdrawal, metabolic disorders, CNS infection, malignancy), head injury, intracranial lesions, increased intracranial pressure, mental health conditions (e.g. anxiety disorders, depression, post-traumatic stress disorder), hypovolaemia, CV disease (e.g. acute MI), acute abdominal conditions, adrenal insufficiency (e.g. Addison's disease), delirium tremens, toxic psychosis, prostatic hyperplasia and/or urinary stricture, significant COPD or cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression, thyroid dysfunction, biliary tract disease (including acute pancreatitis), history of drug abuse or acute alcoholism. Morbidly obese, cachectic, or debilitated patients. Avoid use in suicidal patients and in patients with circulatory shock, impaired consciousness or coma. Not recommended in children in whom respiratory function may be compromised (e.g. neuromuscular disorders, upper respiratory or lung infections, multiple trauma or extensive surgical procedures). Not recommended in patients with severe renal impairment (CrCl <10 mL/min). Avoid abrupt withdrawal following prolonged use. Renal and hepatic impairment. Children ≥12 years (particularly when used for post-operative pain relief) and elderly. Pregnancy and lactation. Concomitant use with other serotonergic agents, CNS depressant drugs; CYP3A4 inducers and CYP3A4 or CYP2D6 inhibitors.
Adverse Reactions
Significant: Sleep-related breathing disorders (e.g. sleep-related hypoxaemia, central sleep apnoea), withdrawal symptoms, convulsions, reversible adrenal insufficiency, severe hypotension (including syncope and orthostatic hypotension), hyponatraemia (including severe cases), CNS depression, spasm of the sphincter of Oddi. Rarely, drug dependence (prolonged use) and abuse; hypoglycaemia (including severe cases).
Cardiac disorders: Palpitations, tachycardia.
Gastrointestinal disorders: Nausea, vomiting, dry mouth, constipation, abdominal discomfort, dyspepsia.
General disorders and administration site conditions: Fatigue, asthenia.
Musculoskeletal and connective tissue disorders: Muscle spasticity.
Nervous system disorders: Dizziness, drowsiness, headache, tremor.
Psychiatric disorders: Anxiety, agitation, emotional lability, euphoria, hallucinations, nervousness.
Reproductive system and breast disorders: Menopausal symptoms.
Skin and subcutaneous tissue disorders: Pruritus, urticaria, rash, hyperhidrosis, toxic epidermal necrolysis, Stevens-Johnson syndrome.
Potentially Fatal: Serotonin syndrome, respiratory depression (particularly in children), neonatal withdrawal syndrome (long-term use during pregnancy). Rarely, serious anaphylactoid reactions; hypoglycaemia (including severe cases).
Patient Counseling Information
This drug may cause dizziness and drowsiness, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor renal function, LFTs, pain relief, respiratory status (particularly within the 1st 24-72 hours of initial therapy and dose increases), mental status or alertness, blood pressure, heart rate, blood glucose (if hypoglycaemia is suspected), bowel function. Evaluate patient's alcohol use, history of alcoholism, risk for addiction, misuse, or abuse before initiating and regularly during therapy. Monitor for signs and symptoms of serotonin syndrome (e.g. mental status changes, autonomic instability, neuromuscular changes, gastrointestinal symptoms), hyponatraemia (particularly during initial treatment), tolerance, addiction, abuse, misuse, or suicidal ideation. Observe for withdrawal symptoms, mood changes, pain control, and use of other substances upon discontinuation.
Overdosage
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.
Drug Interactions
Increased risk of INR elevation and ecchymoses with coumarin derivatives (e.g. warfarin). Increased risk of convulsions with SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), anorectics, TCAs, antipsychotics, and other seizure-threshold lowering agents (e.g. bupropion, mirtazapine). Concomitant use with mixed agonist/antagonist analgesics (e.g. buprenorphine, butorphanol, nalbuphine, pentazocine) may precipitate withdrawal symptoms and/or diminish analgesic effect in patients after prolonged therapy with tramadol. Concomitant use with CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, bupropion) may increase plasma levels of tramadol and decrease plasma concentration of M1 (active metabolite). Concomitant use with CYP3A4 inhibitors (e.g. erythromycin, ketoconazole, ritonavir) may increase tramadol plasma concentration which may result in greater amount of metabolism by CYP2D6 isoenzyme and increased levels of M1. May decrease plasma levels with CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin).
Potentially Fatal: May result in serotonin syndrome when used concomitantly or within 14 days after MAOI therapy. May result in sedation, respiratory depression, and coma with benzodiazepines or other CNS depressants. May increase the risk of serotonin syndrome with SSRIs, SNRIs, TCAs, lithium, triptans, 5-HT3 receptor antagonists, certain muscle relaxants (e.g. metaxalone, cyclobenzaprine), and drugs that affect serotonergic neurotransmitter system (e.g. mirtazapine).
Food Interaction
May potentiate the CNS depressant effects of alcohol. May increase the risk of serotonin syndrome with St. John's wort.
Lab Interference
May give false-positive result in urine detection of phencyclidine.
Action
Description: Tramadol is a centrally acting analgesic that has opioid agonist properties. It binds to μ-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.
Onset: Analgesia: Oral (immediate release): Within 1 hour (peak effect: 2-3 hours).
Duration: Analgesia: Oral: 3-6 hours (peak effect: 1-4 hours post-dosing).
Pharmacokinetics:
Absorption: Rapidly and completely absorbed following oral administration. Bioavailability: Oral: Approx 75% (immediate release); approx 85-90% (modified release; as compared to immediate release); IM: 100%. Time to peak plasma concentration: Tramadol: Approx 2 hours (immediate release); approx 4-12 hours (modified release).
Distribution: Widely distributed in the body. Crosses the placenta; enters breast milk (small amounts). Volume of distribution: IV: 2.9 L/kg (females); 2.6 L/kg (males). Plasma protein binding: Approx 20%.
Metabolism: Extensively metabolised in the liver mainly via N- and O-demethylation by CYP2D6 and CYP3A4 isoenzyme, glucuronidation, and sulfation into several metabolites; O-desmethyltramadol (M1) is the only active metabolite.
Excretion: Via urine (60% as metabolites, approx 30% as unchanged drug). Elimination half-life: Oral: Immediate release: 6.3 ± 1.4 hours (tramadol); 7.4 ± 1.4 hours (M1). Modified release: Cap: Approx 10 hours (tramadol); approx 11 hours (M1); Tab: Approx 7.9 hours (tramadol); 8.8 hours (M1).
Chemical Structure

Chemical Structure Image
Tramadol

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 33741, Tramadol. https://pubchem.ncbi.nlm.nih.gov/compound/33741. Accessed Sept. 28, 2021.

Storage
Store between 15-30°C.
MIMS Class
Analgesics (Opioid)
ATC Classification
N02AX02 - tramadol ; Belongs to the class of other opioids. Used to relieve pain.
References
Crews KR, Monte AA, Huddart R et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Clinical Pharmacology & Therapeutics. 2021 Sep. doi: 10.1002/cpt.2149. Accessed 05/10/2021

Annotation of DPWG Guideline for Tramadol and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 05/10/2021.

Annotation of FDA Label for Tramadol and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 05/10/2021.

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Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org. Accessed 05/10/2021.

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Tramadol 100 mg/mL Oral Drops, Solution (Mercury Pharmaceuticals Ltd). MHRA. https://products.mhra.gov.uk. Accessed 05/10/2021.

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Disclaimer: This information is independently developed by MIMS based on Tramadol from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2022 MIMS. All rights reserved. Powered by MIMS.com
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