Schedule H

Oral, Intravenous (IV), Intramuscular (IM), Rectal

• Tablets (Immediate-release): 50 mg, 100 mg

• Tablets (Sustained-release): 100 mg, 150 mg, 200 mg

• Capsules: 50 mg, 100 mg (includes SR formulations)

• Injection: 50 mg/mL (1 mL and 2 mL ampoules)

• Suppository: 100 mg (limited availability)

• Oral drops / Paediatric liquid formulations: NOT AVAILABLE in India

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Moderate to Moderately Severe Acute Pain (Post-operative, Trauma, Musculoskeletal)

Oral — Immediate-Release Formulation:

Parameter Dose

Starting dose 50–100 mg orally every 4–6 hours as needed

Titration Adjust based on pain response and tolerability; increase by 50 mg increments

Usual maintenance dose 200–300 mg/day in divided doses

Maximum dose 400 mg/day

Clinical Notes:

• For opioid-naive patients, start at lower end (50 mg)

• Use for shortest duration possible (typically ≤5–7 days for acute pain)

• Avoid concurrent use with other opioid analgesics

• Has serotonergic activity — avoid with SSRIs/SNRIs or use with caution

1. Chronic Non-Malignant Pain (Osteoarthritis, Chronic Back Pain, Neuropathic Component)

Oral — Sustained-Release Formulation:

Parameter Dose

Starting dose 100 mg orally once daily (or 50 mg twice daily if using IR initially)

Titration Increase by 50–100 mg/day every 3–5 days based on response and tolerability

Usual maintenance dose 150–300 mg/day (once daily or in two divided doses)

Maximum dose 400 mg/day

Clinical Notes:

• Reserve for patients who have not responded to or cannot tolerate non-opioid analgesics (paracetamol, NSAIDs)

• Consider tapering and discontinuation if used >2–4 weeks

• SR formulations should not be crushed or chewed

• Reassess need for continued therapy regularly; dependence risk with prolonged use

1. Postoperative Pain (Parenteral — Hospital/Monitored Setting Only)

Intravenous / Intramuscular:

Parameter Dose

Starting dose 50–100 mg IV or IM

Titration Repeat every 4–6 hours as needed based on pain control

Usual maintenance dose 200–400 mg/day in divided doses

Maximum dose 400 mg/day

Administration Notes:

• IV injection: Dilute in 10 mL of normal saline and administer slowly over 2–3 minutes to reduce dizziness, nausea, and hypotension

• IM injection: Administer deep into large muscle mass

• Switch to oral formulation as soon as clinically feasible

• Use only in monitored settings with access to resuscitation equipment

Secondary Indications – Adults (Off-label)

Indication Dose Duration Supervision Evidence Basis

Diabetic Peripheral Neuropathy (OFF-LABEL) Starting: 50 mg twice daily (IR) OR 100 mg SR once daily; Titration: increase to 100 mg twice daily or 200 mg SR daily; Maximum: 400 mg/day Evaluate efficacy after 4–6 weeks; discontinue if no benefit Specialist recommended (Neurology/Pain Medicine) Multiple RCTs; Indian pain clinic practice; reserve for cases refractory to gabapentin/pregabalin/duloxetine

Cancer Pain — Mild to Moderate (OFF-LABEL) 50–100 mg every 4–6 hours (IR) or 100–200 mg SR twice daily; Maximum: 400 mg/day As needed for pain control; transition to strong opioids if inadequate Specialist only (Palliative Care/Oncology) WHO Pain Ladder Step 2; Indian palliative care protocols

Premature Ejaculation (OFF-LABEL) 25–50 mg orally 1–2 hours before sexual activity; on-demand use only Intermittent; not for regular daily use Specialist only (Andrology/Urology) Limited RCTs show benefit; not approved indication; risk of dependence with repeated use

Restless Legs Syndrome — Refractory (OFF-LABEL) 50–100 mg at bedtime Long-term if effective Specialist only (Neurology) Case series; consider only when dopamine agonists and gabapentinoids have failed

PAEDIATRIC DOSING (Specialist Only)

⚠️ Tramadol is NOT recommended in children below 12 years of age due to risk of serious respiratory depression, particularly in CYP2D6 ultra-rapid metabolizers.

⚠️ Absolutely contraindicated in patients below 18 years undergoing tonsillectomy and/or adenoidectomy — fatalities reported.

Primary Indications

Moderate to Severe Pain (Children ≥12 years) — Short-term Use Only:

Parameter Dose

Starting dose 1–2 mg/kg/dose orally (maximum 50–100 mg per dose)

Titration Not applicable for short-term use

Usual maintenance dose 1–2 mg/kg/dose every 6 hours as needed

Maximum dose 8 mg/kg/day OR 400 mg/day (whichever is lower)

Clinical Notes:

• Use only under paediatric pain specialist or surgeon supervision

• Limit duration to <5 days

• Avoid in patients with history of sleep apnoea, neuromuscular disorders, or severe respiratory conditions

• Monitor closely for signs of respiratory depression, excessive sedation

Safety Monitoring:

• Respiratory rate and depth

• Sedation level (use validated sedation scale)

• Oxygen saturation (if available)

• GI symptoms (nausea, vomiting, constipation)

Secondary Indications – Paediatrics (Off-label)

Not recommended — insufficient safety data and significant risk of serious adverse events.

Age Restrictions:

• Not recommended below 12 years of age under any circumstances

• Contraindicated below 18 years for post-tonsillectomy/adenoidectomy pain

• Use in adolescents (12–18 years) should be limited to short-term, specialist-supervised settings only

Creatinine Clearance (CrCl) Recommendation

≥60 mL/min No adjustment required

30–59 mL/min Extend dosing interval to every 8 hours; maximum 300 mg/day

15–29 mL/min Extend dosing interval to every 12 hours; maximum 200 mg/day

<15 mL/min Avoid; if essential, maximum 100 mg/day with close monitoring

Haemodialysis Not efficiently removed; accumulation risk; avoid sustained-release formulations; if used, give IR formulation after dialysis session

Additional Notes:

• Active metabolite (O-desmethyltramadol) accumulates in renal impairment

• Avoid sustained-release formulations in moderate to severe renal impairment

• Increased risk of seizures and CNS toxicity with accumulation

• Known hypersensitivity to tramadol or other opioids

• Acute intoxication with alcohol, opioids, hypnotics, centrally-acting analgesics, or psychotropic drugs

• Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing MAOIs

• Uncontrolled epilepsy or history of seizure disorder

• Severe hepatic impairment

• Severe renal impairment (CrCl <15 mL/min)

• Children below 12 years of age

• Patients below 18 years undergoing tonsillectomy and/or adenoidectomy

• Severe respiratory depression or acute severe bronchial asthma (without monitoring/ventilatory support)

• Known or suspected gastrointestinal obstruction (including paralytic ileus)

• History of seizure disorder or conditions predisposing to seizures (head trauma, metabolic disorders, CNS infection, alcohol/drug withdrawal)

• Concurrent use with serotonergic drugs (SSRIs, SNRIs, triptans, TCAs, MAOIs) — risk of serotonin syndrome

• Elderly patients — increased sensitivity, slower metabolism, higher fall risk

• History of substance abuse or opioid dependence — potential for misuse and addiction

• Head injury or raised intracranial pressure — may mask neurological signs

• Respiratory conditions (COPD, sleep apnoea, cor pulmonale) — risk of respiratory depression

• Mild to moderate hepatic or renal impairment

• Concurrent CNS depressants (benzodiazepines, alcohol, antipsychotics)

• Patients who are CYP2D6 ultra-rapid metabolisers — increased risk of toxicity

• Biliary tract disorders

• Adrenal insufficiency

• Hypothyroidism

• Prostatic hypertrophy or urethral stricture

Parameter Information

Overall Safety Avoid unless clearly necessary; limited human data; animal studies show some risk

Risk Neonatal withdrawal syndrome if used chronically near term; potential for neonatal respiratory depression

Preferred Alternatives Paracetamol (first-line for mild-moderate pain); short-course NSAIDs (second trimester only under specialist guidance)

When Use May Be Justified Short-term use for moderate-severe pain when non-opioid alternatives inadequate; avoid near term; requires obstetric supervision

Monitoring Fetal movements; neonatal respiratory function and withdrawal symptoms after delivery if used in late pregnancy

Parameter Information

Compatibility Use with caution; avoid if possible, especially chronic use

Expected Drug Level in Milk Low (approximately 0.1% of maternal dose reaches infant); however, active metabolite also present

Risk to Infant Sedation, respiratory depression (particularly if mother is CYP2D6 ultra-rapid metaboliser), feeding difficulties

Preferred Alternatives Paracetamol; ibuprofen (if NSAID appropriate)

Infant Monitoring Sedation, alertness, feeding pattern, breathing, apnoea

Precautions Avoid high doses; limit duration; if single dose used, may breastfeed after 4 hours

Parameter Recommendation

Starting dose 25–50 mg orally every 6–8 hours (use IR formulation initially)

Titration Increase slowly every 4–5 days; use longer dosing intervals

Maximum recommended 300 mg/day (lower than general adult maximum)

Increased Risks Falls, confusion, excessive sedation, constipation, urinary retention, respiratory depression

Additional Precautions Assess renal and hepatic function before dosing; avoid sustained-release formulations in frail or cognitively impaired patients; monitor gait and cognition

Interacting Drug Mechanism Effect Management

MAOIs (phenelzine, tranylcypromine, moclobemide, linezolid) MAO inhibition + serotonergic effect of tramadol Severe serotonin syndrome, hypertensive crisis, hyperpyrexia Contraindicated — avoid combination; wait 14 days after stopping MAOI before starting tramadol

SSRIs (fluoxetine, sertraline, escitalopram) Additive serotonergic effect + CYP2D6 inhibition (fluoxetine, paroxetine) Serotonin syndrome; reduced conversion to active metabolite Avoid if possible; if essential, use lowest doses and monitor closely for serotonin syndrome

SNRIs (venlafaxine, duloxetine) Additive serotonergic effect Serotonin syndrome Avoid combination; if essential, monitor closely

Triptans (sumatriptan, rizatriptan) Additive serotonergic effect Serotonin syndrome Avoid concurrent use

Carbamazepine Strong CYP3A4 induction Markedly reduced tramadol efficacy (plasma levels reduced by up to 50%) Consider alternative analgesic; if used, significantly higher doses may be needed

Alcohol Additive CNS depression Profound sedation, respiratory depression, increased overdose risk Avoid concurrent use; patient counselling mandatory

Benzodiazepines / Other Opioids Additive CNS and respiratory depression Respiratory depression, sedation, coma, death Avoid combination if possible; if essential, reduce doses and monitor closely

Ondansetron 5-HT3 antagonism may reduce tramadol analgesia Reduced analgesic efficacy (some evidence) Consider alternative antiemetics (metoclopramide)

Interacting Drug Effect Management

Tricyclic Antidepressants (amitriptyline, nortriptyline) Additive serotonergic and anticholinergic effects; seizure threshold lowering Monitor for serotonin syndrome and seizures; use with caution

Antipsychotics (haloperidol, risperidone) Additive seizure threshold lowering Monitor for seizures; use with caution

Warfarin Rare reports of increased INR Monitor INR if chronic tramadol use; adjust warfarin dose as needed

Macrolides (clarithromycin, erythromycin) CYP3A4 inhibition; increased tramadol levels Monitor for toxicity; consider dose reduction

Ciprofloxacin CYP enzyme inhibition May elevate tramadol levels; monitor for adverse effects

Quinidine CYP2D6 inhibition Reduced formation of active metabolite; may reduce efficacy

Digoxin Rare reports of digoxin toxicity Monitor digoxin levels if concurrent use

Antiepileptics (phenytoin, phenobarbital) CYP enzyme induction Reduced tramadol efficacy

Rifampicin Strong CYP3A4 induction Significantly reduced tramadol efficacy

First-generation antihistamines Additive CNS depression Use with caution; monitor sedation

• Nausea (most common; dose-related)

• Vomiting

• Dizziness, vertigo

• Drowsiness, sedation

• Headache

• Constipation

• Dry mouth

• Sweating, diaphoresis

• Fatigue, asthenia

• Pruritus

Adverse Effect Clinical Action

Seizures (dose-related; risk increases >400 mg/day or with interacting drugs) Discontinue immediately; supportive care; avoid in patients with seizure history

Serotonin syndrome (when combined with serotonergic agents: hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes) Discontinue all serotonergic drugs immediately; supportive care; cyproheptadine may be used; hospitalisation often required

Respiratory depression (especially with overdose, renal impairment, CYP2D6 ultra-rapid metabolisers, or concurrent CNS depressants) Discontinue; supportive ventilation; naloxone may partially reverse (high doses may be needed)

Anaphylaxis / Severe allergic reactions Discontinue permanently; emergency management

Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis (rare) Discontinue immediately; hospitalisation; dermatology consultation

Physical dependence and withdrawal syndrome (with prolonged use: anxiety, insomnia, tremor, sweating, piloerection, GI symptoms, rarely seizures) Taper gradually; do not discontinue abruptly

Hypoglycaemia (rare; reported particularly in diabetics) Monitor blood glucose; manage hypoglycaemia appropriately

QT prolongation (rare; at high doses or overdose) Avoid in patients with known QT prolongation; ECG if suspected

After initiation (1–7 days) Pain control efficacy, sedation level, respiratory rate, nausea/vomiting, constipation, signs of serotonin syndrome

Long-term (if chronic use) Signs of tolerance, dependence, or misuse; bowel function (constipation management); cognitive effects (especially in elderly); reassess need for continued therapy every 2–4 weeks

On discontinuation Taper gradually (reduce by 25–50% every 2–4 days); monitor for withdrawal symptoms

Immediate-Release:

• Tramazac™ (Zydus) — 50 mg tablets

• Tramadol (Generic) — 50 mg, 100 mg tablets

• Contramal™ (Abbott) — 50 mg capsules

• Doltram™ — 50 mg tablets

Sustained-Release:

• Tramazac SR™ (Zydus) — 100 mg, 200 mg tablets

• Dolomed Retard™ — 100 mg, 150 mg tablets

• Contramal SR™ — 100 mg, 200 mg tablets

Injection:

• Tramadol Injection™ (Various) — 50 mg/mL ampoules

• Tramazac Injection™ — 50 mg/mL

Fixed-Dose Combinations (Tramadol + Paracetamol):

Note: FDCs with paracetamol are commonly used for short-term acute pain; do not exceed paracetamol 4 g/day from all sources.

Regulatory: Not listed under NLEM 2022; not under NPPA price control; prices vary by brand and region

1. Dual mechanism of action — Tramadol is not a pure opioid; it has weak mu-opioid agonism plus serotonin and norepinephrine reuptake inhibition — this accounts for both its efficacy in neuropathic pain and its serotonin syndrome risk

1. Seizure threshold — Risk of seizures is dose-dependent; do not exceed 400 mg/day; risk increases significantly with concurrent serotonergic drugs, antipsychotics, or in patients with epilepsy

1. Serotonin syndrome awareness — Do not combine with MAOIs (contraindicated); use extreme caution with SSRIs, SNRIs, triptans, TCAs — educate patients on symptoms (agitation, hyperthermia, tremor, rigidity)

1. Paediatric restriction — Absolutely avoid in children <12 years; contraindicated in any patient <18 years post-tonsillectomy/adenoidectomy — fatalities have been reported due to ultra-rapid CYP2D6 metabolism

1. Tramadol + Paracetamol FDCs — Useful for short-term acute pain (≤5 days); do not exceed paracetamol 4 g/day from all sources; superior analgesia with potentially lower tramadol doses

1. Dependence and tolerance — Physical dependence can develop within 2–4 weeks of regular use; always taper gradually when discontinuing; reassess need for ongoing therapy regularly

weak-opioid; analgesic; acute-pain; chronic-pain; neuropathic-pain; serotonin-syndrome; seizure-risk; paediatric-restricted; Schedule-H; not-NLEM; elderly-caution; renal-adjustment; hepatic-caution

RxIndia v1.0 — 01 May 2025

• CDSCO Product Information and Schedule H Listing

• Indian Pharmacopoeia (IP)

• NLEM 2022 (exclusion noted)

• API Textbook of Medicine

• AIIMS Drug Formulary and Pain Management Protocols

• Indian Association for Study of Pain — Guidelines

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• Harrison's Principles of Internal Medicine

• Indian Paediatric Association Position Statement on Tramadol in Children

• Indian Association of Palliative Care — Opioid Guidelines

• FDA Safety Communications on Tramadol in Paediatrics (supportive reference for age restrictions)

• RCTs on Tramadol in Neuropathic Pain (off-label evidence)