Generic Name
Tramadol hydrochloride
Brand Names
Ultram
Zydol
Tramal
Dromadol
Contramal
Tramake
Ralivia
Others: Tramacet (tramadol + acetaminophen), Dolotram
Drug Class
Opioid analgesic
Centrally acting analgesic
Dual-action agent (opioid agonist + monoamine reuptake inhibitor)
Schedule IV controlled substance (US), Schedule III in some countries, prescription-only globally
Mechanism of Action
Tramadol is a centrally acting analgesic with a dual mechanism
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Weak μ-opioid receptor agonist– Binds to μ-opioid receptors in the CNS– Inhibits ascending pain pathways– Produces analgesia and sedation– Affinity is 6,000 times less than morphine but contributes to analgesia– Active metabolite O-desmethyltramadol (M1) is more potent
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Inhibits reuptake of norepinephrine (NE) and serotonin (5-HT)– Enhances descending inhibitory pain pathways– Contributes to antidepressant-like and analgesic effects– Mechanism similar to SNRIs
No significant anti-inflammatory or antipyretic action
Onset: 1 hour
Peak effect: 2–3 hours
Duration: 4–6 hours
Indications
Approved Uses
Moderate to moderately severe pain
Acute or chronic pain
Postoperative pain
Musculoskeletal pain
Osteoarthritis
Neuropathic pain (second-line option)
Pain in cancer and palliative care settings
Fibromyalgia (off-label in some countries)
Fixed-dose combinations
Tramadol + acetaminophen (paracetamol) for short-term pain
Available under Tramacet, Zaldiar
Dosage and Administration
Immediate-Release (IR)
Adults:
– Start with 50–100 mg every 4–6 hours as needed
– Max single dose: 100 mg
– Max daily dose: 400 mg
– Elderly (>75 years): 50–100 mg every 6 hours; Max 300 mg/day
Extended-Release (ER)
– Initial: 100 mg once daily
– May increase every 5 days by 100 mg/day
– Max: 300–400 mg/day depending on formulation
Pediatrics
Not approved in children under 12 years
Contraindicated post-tonsillectomy/adenoidectomy in <18 years due to respiratory depression risk
Renal Impairment
CrCl <30 mL/min:
– Prolong dosing interval
– Avoid ER formulation
Hepatic Impairment
Use with caution
Avoid ER formulation
Dose reduction recommended
Route of Administration
Oral tablets or capsules (IR, ER)
Oral drops
Effervescent tablets
Rectal suppositories (in some markets)
Injectable tramadol (IM or slow IV) used in inpatient/emergency settings
Pharmacokinetics
Absorption
Well absorbed orally (bioavailability 70%)
Minimal first-pass effect
Peak plasma concentration in 1–2 hours (IR), 6 hours (ER)
Distribution
Volume of distribution ~3 L/kg
Crosses blood-brain barrier and placenta
Excreted in breast milk in small amounts
Metabolism
Primarily hepatic
– CYP2D6: Converts tramadol to active M1 metabolite (O-desmethyltramadol)
– CYP3A4 and CYP2B6: Secondary metabolism pathways
Elimination
Renal excretion (90%) as metabolites
Half-life:
– Tramadol: 6 hours
– M1 metabolite: 7–9 hours
Prolonged in renal or hepatic impairment
Contraindications
Hypersensitivity to tramadol or opioids
Acute intoxication with alcohol, hypnotics, narcotics, psychotropics
Concomitant use with or within 14 days of MAO inhibitors
Severe respiratory depression
Uncontrolled epilepsy
Pediatric patients <12 years or <18 years after tonsillectomy/adenoidectomy
Breastfeeding women
Warnings and Precautions
Seizures
– Risk increases with high doses, epilepsy, head trauma, CNS stimulants
– Avoid in uncontrolled epilepsy
Serotonin Syndrome
– Risk when used with SSRIs, SNRIs, MAOIs, triptans, or linezolid
– Symptoms: agitation, hallucination, tachycardia, hyperthermia, tremor
Respiratory Depression
– Risk increases with CNS depressants (e.g., benzodiazepines, alcohol)
– Monitor especially in elderly and debilitated
Addiction, Abuse, and Misuse
– Classified as a controlled drug in many countries
– Can cause physical dependence and withdrawal
Suicidality
– Use cautiously in patients with a history of depression or suicidal ideation
– Avoid in those at risk unless benefits outweigh risks
Impaired CYP2D6 Metabolizers
– Poor metabolizers may have reduced analgesia
– Ultra-rapid metabolizers may have higher risk of toxicity (esp. in children)
Liver and Kidney Disease
– Use lower doses
– Avoid ER forms
Driving and Machinery Use
– May impair cognitive and motor skills
– Advise patients not to operate machinery until effects are known
Adverse Effects
Very Common (>10%)
Dizziness
Nausea
Constipation
Dry mouth
Headache
Somnolence
Common (1–10%)
Vomiting
Sweating
Fatigue
Pruritus
Tremor
Insomnia
Anxiety
Dyspepsia
Uncommon (0.1–1%)
Palpitations
Orthostatic hypotension
Blurred vision
Mood swings
Confusion
Urinary retention
Rare (<0.1%)
Seizures
Serotonin syndrome
Anaphylaxis
Respiratory depression
Dependency
Hallucinations
Angioedema
Withdrawal Symptoms
Restlessness
Insomnia
Anxiety
Sweating
Chills
Nausea
Tremors
Overdose
Symptoms
CNS depression
Respiratory depression
Seizures
Coma
Miosis
Bradycardia
Hypotension
Management
Airway and breathing support
Naloxone can reverse opioid effects, but may precipitate seizures
Activated charcoal if early presentation
Cardiac and respiratory monitoring
Drug Interactions
Serotonergic Drugs
SSRIs, SNRIs, MAOIs, triptans → serotonin syndrome risk
CYP2D6 Inhibitors
Paroxetine, fluoxetine → reduced active metabolite → decreased efficacy
CYP3A4 Inhibitors
Ketoconazole, erythromycin → increased plasma levels
Benzodiazepines or Alcohol
Increased CNS and respiratory depression
MAOIs
Contraindicated → hypertensive crisis or serotonin syndrome
Carbamazepine
Reduces tramadol effect by enhancing metabolism
Warfarin
Rarely enhances anticoagulant effect → increased INR
Use in Special Populations
Pregnancy
Category C
Animal data suggest teratogenicity
Not recommended unless absolutely necessary
May cause neonatal withdrawal or respiratory depression
Lactation
Excreted in breast milk
Use discouraged due to potential for opioid toxicity in infant
Pediatrics
Contraindicated under 12 years
Contraindicated under 18 years post-tonsillectomy
Elderly
Increased risk of sedation, confusion, respiratory depression
Start at lower doses
Hepatic/Renal Impairment
Dose reduction needed
Avoid ER forms
Monitoring Parameters
Pain relief
Signs of sedation or respiratory depression
Signs of abuse or dependence
Mental status changes
Seizure activity in high-risk patients
Renal and hepatic function with prolonged use
Comparative Pharmacology
Less potent than morphine or oxycodone
Lower risk of respiratory depression compared to full opioids
Dual mechanism may help in neuropathic pain
More likely to cause serotonin syndrome compared to pure opioids
Less GI side effects than codeine
May be used when NSAIDs are contraindicated
Formulations Available
Immediate-release tablets/capsules (50 mg, 100 mg)
Extended-release tablets (100 mg, 200 mg, 300 mg)
Oral drops (in some countries)
Effervescent tablets
Injectable solution (IV/IM; hospital use)
Fixed combinations (e.g., tramadol 37.5 mg + acetaminophen 325 mg)
Regulatory and Legal Status
Controlled substance
– US: Schedule IV
– UK: Class C
– EU: Rx only; some countries restrict via narcotic laws
Included in WHO Model List of Essential Medicines
Requires prescription in most jurisdictions
Subject to monitoring for abuse potential
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