Part 1: Codeine Phosphate

This article is part of the Substance Use Education India series. It is designed strictly for educational, clinical, and harm-reduction purposes. All data verified as of May 12, 2026.

If you or someone you know is struggling with substance dependence, contact the National Drug De-Addiction Helpline: 14446

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1. Generic Name and Drug Class

Property	Detail
Generic Name	Codeine Phosphate (Codeine Phosphate Sesquihydrate)
Chemical Name	3-Methylmorphine
Drug Class	Opioid Analgesic; Antitussive
Origin	Naturally occurring phenanthrene alkaloid from the opium poppy (Papaver somniferum)
WHO Status	Listed on the WHO Model List of Essential Medicines

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2. History of the Drug

Codeine was first isolated in 1832 by the French chemist and pharmacist Pierre Jean Robiquet while researching refined methods for extracting morphine from opium. Its name derives from the Ancient Greek word kṓdeia (κώδεια), meaning “poppy head.”

Key Timeline:

• 1832: Pierre Robiquet isolates codeine in France.
• 1830s: Early clinical adoption as an antitussive (cough suppressant) begins.
• Late 1800s: Codeine is marketed as a “safer” alternative to morphine. It was even used to treat morphine withdrawal.
• 1905: First detailed reports of codeine addiction surface, challenging earlier safety claims.
• 20th Century: Codeine becomes one of the most widely used opioids globally, particularly in cough syrups and combination analgesics.
• 2016 (India): Government bans several codeine-containing Fixed Dose Combinations (FDCs) including specific formulations of Phensedyl and Corex.
• 2025-2026 (India): Intensified crackdowns under “Operation Prahaar” and state-level SITs. In August 2025, Odisha STF seized 26,658 bottles of Wincerex cough syrup worth ₹52 lakhs. In December 2025, a Special Investigation Team (SIT) was formed in Nagaland specifically to probe codeine syrup trafficking.

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3. Mechanism of Action and Pharmacodynamics

Codeine is a prodrug — it has minimal direct pharmacological activity. Its therapeutic and psychoactive effects depend almost entirely on its metabolic conversion to Morphine in the liver.

How It Works:

1. Analgesia: Once converted to morphine via CYP2D6, it binds to mu-opioid receptors (MOR) in the CNS. This inhibits ascending pain pathways, altering the perception of pain.
2. Antitussive Effect: Acts directly on the cough center in the medulla oblongata of the brainstem, elevating the cough reflex threshold.
3. GI Effect: Binds to opioid receptors in the enteric nervous system, slowing gut motility (hence used for severe diarrhea).
4. Euphoria: The morphine produced triggers dopamine release in the nucleus accumbens (reward center), creating a “warm, dreamy, and sedated” euphoric state. This euphoria is moderate compared to stronger opioids like morphine or heroin, but is the primary driver of misuse.

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4. Pharmacokinetics (ADME)

Parameter	Detail
Absorption	Rapidly absorbed orally. Peak plasma concentration in ~1 hour.
Bioavailability	~53% (oral)
Volume of Distribution	3–6 L/kg
Protein Binding	~7–25%
Half-life	3–4 hours
Excretion	~90% renal (urine), ~10% as unchanged codeine

Metabolism (The CYP2D6 Gateway):

This is the single most important pharmacological concept for codeine:

• CYP2D6 → Converts codeine to Morphine (~5–10% of the dose). This is the pathway responsible for all analgesic and euphoric effects.
• CYP3A4 → Converts codeine to Norcodeine (~10%). Inactive metabolite.
• UGT2B7 → Converts codeine to Codeine-6-glucuronide (~70–80%). Primarily inactive.

Why CYP2D6 Polymorphism Is Life-or-Death:

• Poor Metabolizers (~5–10% of population): Produce almost no morphine. Codeine provides virtually zero pain relief. They are essentially immune to codeine’s effects.
• Extensive Metabolizers (Normal): Standard conversion. Expected therapeutic effect.
• Ultra-Rapid Metabolizers (~1–7% of population): Convert codeine to morphine at vastly accelerated rates. Even a standard 30mg dose can produce dangerously high morphine levels, leading to fatal respiratory depression. This is the basis of the FDA’s Black Box Warning.

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5. Approved Medical Uses and Therapeutic Dosages

Approved Uses:

1. Antitussive: Dry, non-productive cough that fails non-opioid treatment.
2. Analgesic: Mild to moderate pain (often combined with Paracetamol).
3. Antidiarrheal: Short-term acute diarrhea management.

Therapeutic Dosages (Adults):

Indication	Dose	Frequency	Max Daily Dose
Cough	10–20 mg	Every 4–6 hours	120 mg/day
Pain	15–60 mg	Every 4–6 hours	360 mg/day
Diarrhea	15–30 mg	Every 6 hours	As directed

Why Codeine Requires Higher Doses Than Fentanyl:

Codeine requires milligram dosing (30mg+) while Fentanyl is dosed in micrograms (50–100mcg) because:

1. Prodrug dependency: Only 5–10% converts to active morphine.
2. Low lipophilicity: Codeine crosses the blood-brain barrier slowly.
3. Low receptor affinity: Codeine itself has negligible mu-opioid binding. Fentanyl binds directly and instantly with extreme affinity.

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6. Side Effects, Serious Adverse Effects & Black Box Warnings

Common Side Effects:

• Constipation (extremely common, near-universal)
• Drowsiness and sedation
• Nausea and vomiting
• Dry mouth (Xerostomia)
• Lightheadedness, dizziness
• Pruritus (itching, due to histamine release)

Serious Adverse Effects:

• Respiratory Depression (life-threatening)
• Severe hypotension
• Anaphylaxis / severe allergic reactions
• Adrenal insufficiency (chronic use)
• Biliary spasm

FDA Black Box Warnings:

1. Ultra-Rapid CYP2D6 Metabolism: Fatal respiratory depression even at standard doses.
2. Pediatric Deaths: Contraindicated in children under 12. Contraindicated under 18 after tonsillectomy/adenoidectomy.
3. Addiction, Abuse, and Misuse: High risk of opioid use disorder.
4. Neonatal Opioid Withdrawal Syndrome: Use in pregnancy can cause life-threatening withdrawal in newborns.
5. Breastfeeding Risk: Ultra-rapid metabolizer mothers can pass lethal morphine levels through breast milk.

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7. Drug Interactions

Critical Interactions:

Interaction	Risk	Mechanism
Alcohol	Fatal respiratory depression	Additive CNS depression
Benzodiazepines	Fatal respiratory depression	Additive CNS depression
CYP2D6 Inhibitors (Fluoxetine, Paroxetine, Quinidine)	Loss of analgesic effect	Blocks conversion to morphine
MAOIs	Contraindicated — Hypertensive crisis, serotonin syndrome	Requires 14-day washout
Serotonergic drugs (SSRIs, SNRIs)	Risk of serotonin syndrome	Serotonin accumulation
Other opioids	Profound respiratory depression	Additive MOR agonism

Contraindications:

• Children under 12 years
• Post-tonsillectomy/adenoidectomy (under 18)
• Acute respiratory depression / severe asthma / COPD
• Known CYP2D6 ultra-rapid metabolizer status
• Concurrent MAOI use (or within 14 days)
• Severe hepatic/renal impairment
• Head injuries (masks clinical signs)
• Breastfeeding

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8. Toxicity, Overdose & Lethal Doses

Toxicity Thresholds:

• Toxic effects begin: ≥240 mg in opioid-naive adults.
• Estimated lethal dose: 500–1,000 mg (0.5–1 gram) in non-tolerant adults. However, due to CYP2D6 polymorphism, fatalities have occurred at standard doses in ultra-rapid metabolizers.
• Combination danger: When codeine is taken in Paracetamol combination products (e.g., Codimol), consuming large quantities for the opioid effect leads to massive paracetamol toxicity → acute liver necrosis (often fatal within 72 hours).

Overdose Warning Signs (The Opioid Triad):

1. Pinpoint pupils (miosis)
2. Unconsciousness / extreme lethargy
3. Respiratory depression (breathing < 8 breaths/min, shallow, stopped)

Additional Signs:

• Blue/gray lips and fingernails (cyanosis)
• Cold, clammy skin
• Weak/slow pulse
• Gurgling or choking sounds

Emergency Treatment:

• Call emergency services immediately.
• Naloxone (Narcan): Opioid antagonist that reverses respiratory depression. Available in Indian government hospitals.
• Recovery position: Place person on their side to prevent choking.

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9. Pricing and Availability in India (May 2026)

The market for Codeine-based products in India has become highly bifurcated in 2026 between strictly regulated clinical supply and a volatile, high-priced retail sector.

A. PMBJP (Jan Aushadhi Kendra) Availability

❌ Codeine is NOT available in Jan Aushadhi Kendras. The PMBJP program has intentionally excluded narcotic-based cough syrups to prevent public-sector diversion and prioritize non-addictive antitussives.

B. Branded Market Prices (Commercial Sector)

Legitimate pharmaceutical brands now include specialized “anti-diversion” markings and 2D barcodes for tracking.

Brand Name	Manufacturer	Strength (per 5ml)	Approx. Market Price (INR)
Phensedyl New	Abbott India	10mg Codeine + 4mg CPM	₹168.00 (per 100ml)
Codistar	Mankind Pharma	10mg Codeine + 4mg CPM	₹145.00 (per 100ml)
T-Rex	Cipla Ltd.	10mg Codeine + 4mg CPM	₹155.00 (per 100ml)
Ascoril-C	Glenmark	10mg Codeine + 4mg CPM	₹192.00 (per 100ml)
Corex-T	Pfizer India	10mg Codeine + 4mg CPM	₹175.00 (per 100ml)
Grilinctus CD	Franco-Indian	10mg Codeine + 4mg CPM	₹138.00 (per 100ml)

C. Tablet Formulations (Schedule H1)

Combined with Paracetamol or Ibuprofen for severe pain management.

Brand Name	Manufacturer	Strength	Approx. Price (INR)
Codimol	Cipla Ltd.	30mg Codeine + 500mg Para	₹85.00 (10 Tabs)
Acitiz-P	Abbott	30mg Codeine + 500mg Para	₹92.00 (10 Tabs)

[!CAUTION] Black Market Inflation: Due to the 2026 “Operation Prahaar,” the illicit price of a single 100ml bottle can reach ₹1,200 to ₹2,500 in high-demand zones. These products are frequently adulterated and pose a severe risk of sudden poisoning.

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10. Legal Status in India

NDPS Act, 1985:

Codeine is classified as a “Manufactured Drug” (opium derivative).

Key Legal Points:

• Notification S.O. 826(E) (14.11.1985): Codeine preparations containing ≤100mg per dosage unit and ≤2.5% concentration are exempt from the strictest NDPS provisions when handled through legitimate pharmaceutical channels.
• However: Courts have increasingly ruled that this exemption does not apply when the preparations are diverted for illicit use, smuggling, or unauthorized sale.
• Small Quantity: 10 grams of codeine (pure base).
• Commercial Quantity: 1,000 grams (1 kg).
• The Mixture Rule (Hira Singh v. UOI): The entire weight of the seized mixture (syrup + solvent + codeine) is considered, not just the codeine content. This means seizing a few hundred bottles of cough syrup can easily cross the “commercial quantity” threshold, triggering severe penalties.

Drugs and Cosmetics Act (Schedule H1):

• Prescription mandatory: Sale only against a valid, dated prescription.
• Record-keeping: Pharmacist must maintain a separate register (patient name, doctor details, quantity) for 3 years.
• Red-bordered label: “Rx” and “Schedule H1” warning required.

Recent Enforcement (2025-2026):

• August 2025: Odisha STF seized 26,658 bottles of Wincerex cough syrup (mfg: Wings Pharmaceuticals, Baddi, HP) worth ₹52 lakhs from courier hubs.
• December 2025: SIT formed in Nagaland to probe codeine syrup trafficking.
• January 2026: Multi-state raids in Bihar, Haryana, and Punjab targeting codeine diversion.

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11. Misuse Trends in India

The Euphoria Profile:

Codeine produces a moderate euphoria — a warm, heavy, dream-like sedation. It is far milder than heroin or fentanyl but more accessible. Users typically consume entire bottles of cough syrup (200mg+ codeine) to achieve the desired effect.

Key Misuse Trends:

• “Purple Drank” / “Lean” Culture: Influenced by American hip-hop, mixing codeine syrup with soda and candy. This trend has permeated Indian urban youth.
• Northeast India: States like Nagaland, Manipur, and Mizoram face acute crises due to proximity to manufacturing hubs and porous borders.
• Punjab Opioid Crisis: Codeine syrups serve as a cheaper substitute when heroin supply is disrupted.
• Cross-Border Smuggling: Historically, Indian-manufactured Phensedyl was massively smuggled into Bangladesh, where it became the most widely abused opioid.

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12. Dependence, Withdrawal & Recovery

Withdrawal Timeline:

Phase	Time After Last Dose	Symptoms
Onset	6–12 hours	Anxiety, yawning, sweating, runny nose
Peak	24–72 hours	Severe muscle/bone pain, vomiting, diarrhea, cold flashes, “goosebumps,” insomnia
Subsiding	3–5 days	Physical symptoms gradually improve
Protracted	Weeks to months	Anxiety, depression, insomnia, cravings

Recovery Resources in India:

• National Drug De-Addiction Helpline: 14446 (Toll-free, 24/7)
• NIMHANS, Bengaluru: Centre for Addiction Medicine — world-class outpatient de-addiction services (Mon/Thu/Sat OPD). Website: nimhans.ac.in
• Government OST Centers: Over 300 Opioid Substitution Therapy centers across India providing Buprenorphine-based maintenance treatment.
• Drug Treatment Clinics (DTCs): Available at district-level government hospitals.
• Vandrevala Foundation Helpline: 1860-2662-345

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13. Safe Storage

• Store in a cool, dry place below 30°C.
• Keep strictly out of reach of children — codeine poisoning in children is often fatal.
• Do not transfer to unmarked containers.
• Dispose of unused medication through a pharmacy take-back program or mix with coffee grounds/cat litter before discarding.

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Disclaimer: This documentation is strictly for public health education. It does not provide instructional guidance for the non-medical use of any substance. Always follow the guidance of a qualified medical professional and adhere to Indian law.

Next: Part 2: Tramadol Hydrochloride