Part 1: Opioids (Mild) — Codeine, Tramadol, and Tapentadol

Clinical Reference for Healthcare Professionals. Not intended as a guide for recreational use.

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1. Codeine Phosphate

Field	Detail
INN / Salt	Codeine Phosphate
Drug Class	Opioid Analgesic / Antitussive
Schedule	Schedule H1; also regulated under NDPS Act
Indian Brands	Corex (banned formulation), Phensedyl, Tossex, Codimol
Legitimate Uses	Mild to moderate pain relief; cough suppression

Mechanism of Action

Codeine is a prodrug. It is metabolized by the liver enzyme CYP2D6 into Morphine, which then binds to mu-opioid receptors in the CNS, producing analgesia and cough suppression. Approximately 5-10% of the dose is converted to Morphine.

CYP2D6 Polymorphism Warning: Approximately 1-7% of the Indian population are “ultra-rapid metabolizers” of CYP2D6, meaning they convert far more Codeine to Morphine than average. For these individuals, even a therapeutic dose can cause fatal respiratory depression. Conversely, ~5-10% are “poor metabolizers” who get no analgesic effect at all.

Pharmacokinetics

Parameter	Value
Bioavailability	~53% (oral)
Onset of Action	30-45 minutes
Peak Plasma	1-2 hours
Half-Life	2.5-3.5 hours
Duration	4-6 hours
Metabolism	Hepatic (CYP2D6 → Morphine, CYP3A4 → Norcodeine)
Excretion	Renal (90%)

Why It Is Abused

Codeine-containing cough syrups (especially those combined with Promethazine) are consumed in large quantities. The combination produces a sedated, euphoric, dissociated state. This practice, known as “Lean” or “Purple Drank,” has spread from the US hip-hop culture into Indian urban youth.

India-Specific Data: Regional studies have reported that 12-26% of individuals seeking treatment at de-addiction centers identified codeine cough syrups as their primary substance of abuse. Typical users are young (18-30), educated, and urban. The low cost (₹80-150 per bottle) and OTC availability at many pharmacies despite Schedule H1 restrictions fuel the crisis.

Side Effects & Dangers of Abuse

• Respiratory Depression: The primary cause of opioid overdose death. Risk multiplied 3-5x when combined with alcohol or benzodiazepines.
• Severe Constipation: Chronic use leads to opioid-induced constipation requiring laxatives.
• Physical Dependence & Withdrawal: Flu-like symptoms, severe anxiety, diarrhea, muscle aches, lacrimation, rhinorrhea.
• Promethazine Toxicity: In combination products, the antihistamine component causes seizures, QT prolongation, and neuroleptic malignant syndrome at high doses.
• Liver Damage: Many formulations contain Paracetamol (Acetaminophen). At the doses consumed for a “high” (5-10x therapeutic), Paracetamol causes acute hepatic necrosis — potentially fatal liver failure.
• Histamine Release: Codeine causes significant histamine release, leading to itching, flushing, bronchospasm, and hypotension.

Clinician Red Flags

• Patient requesting specific codeine-containing brands by name.
• Frequent “lost prescription” claims or “losing” the medication.
• Multiple prescriptions from different doctors (“doctor shopping”).
• Visiting multiple pharmacies in different areas.
• Young, healthy patient with a persistent “cough” that doesn’t respond to non-opioid antitussives.

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2. Tramadol Hydrochloride

Field	Detail
INN / Salt	Tramadol Hydrochloride
Drug Class	Opioid Analgesic (Atypical)
Schedule	Schedule H1 + NDPS Act (since 2018)
Indian Brands	Ultracet, Contramal, Tramadol, Domadol
Legitimate Uses	Moderate to moderately severe pain

Mechanism of Action

Tramadol has a dual mechanism: (1) Weak mu-opioid receptor agonism (binding affinity ~6,000x weaker than Morphine), and (2) Inhibition of serotonin and norepinephrine reuptake (similar to an SNRI antidepressant). Its active metabolite, O-desmethyltramadol (M1), is 2-4x more potent at the mu receptor than the parent drug and is responsible for most of the opioid effect. This dual action produces both opioid-like euphoria and a mood-elevating effect.

Pharmacokinetics

Parameter	Value
Bioavailability	68-72% (oral); ~100% (IM)
Onset of Action	30-60 minutes (oral)
Peak Plasma	1.5-2 hours
Half-Life	6-8 hours (parent); 7-9 hours (M1 metabolite)
Time to Full Elimination	~35-40 hours (5 half-lives)
Metabolism	Hepatic (CYP2D6 → M1; CYP3A4 → M2)
Excretion	Renal (90%)

Why It Is Abused

Tramadol is massively abused across India, particularly in North-East India (Manipur, Nagaland) and Punjab. It was historically cheap (₹2-5 per tablet), easy to obtain without a prescription, and produces a combined opioid-antidepressant high. The Indian government reclassified it as a psychotropic substance under the NDPS Act on April 26, 2018, in response to the epidemic.

India-Specific Data: Before the NDPS reclassification, Tramadol was frequently abused by individuals dependent on other opioids as a cheaper, more accessible substitute. It was also used as a “fighter drug” — soldiers and militants in conflict zones used it to stay awake and suppress pain. Cross-border trafficking to Bangladesh and Myanmar was a major enforcement challenge. Punjab’s opioid crisis reports consistently identify Tramadol as one of the top 3 pharmaceutical substances of abuse alongside heroin and Buprenorphine.

Side Effects & Dangers of Abuse

• Seizures: Tramadol lowers the seizure threshold even at therapeutic doses. Risk is dramatically increased at doses >400mg/day, in patients with epilepsy, or when combined with SSRIs, TCAs, or antipsychotics.
• Serotonin Syndrome: Fatal if combined with other serotonergic drugs (SSRIs, MAOIs, St. John’s Wort, Triptans). Symptoms: hyperthermia (>41°C), clonus, agitation, diaphoresis.
• Respiratory Depression: Less severe than strong opioids but still dangerous, especially with alcohol or benzodiazepines.
• Severe Withdrawal: Unique among opioids — includes BOTH classic opioid withdrawal (body aches, diarrhea, goosebumps) AND SSRI discontinuation syndrome (“brain zaps,” electric shock sensations, severe anxiety, insomnia).
• Hepatotoxicity: Chronic high-dose use causes liver enzyme elevation and, rarely, acute liver failure.
• Hyponatremia: Tramadol can cause dangerously low sodium levels (SIADH), especially in the elderly.

Clinician Red Flags

• Requests for Tramadol specifically over other NSAIDs for minor pain.
• Escalating dose requirements beyond 400mg/day.
• Combining Tramadol prescriptions from multiple providers.
• History of opioid use disorder with “new” pain complaints.
• Patient with a seizure history being prescribed Tramadol (contraindicated).

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3. Tapentadol Hydrochloride

Field	Detail
INN / Salt	Tapentadol Hydrochloride
Drug Class	Opioid Analgesic (Atypical, Centrally Acting)
Schedule	Schedule H1
Indian Brands	Tapal, Nucynta, Tydol, Tapenta
Legitimate Uses	Moderate to severe acute pain; diabetic neuropathic pain

Mechanism of Action

Similar to Tramadol but more potent. It acts as a mu-opioid receptor agonist (18x stronger than Tramadol at the mu receptor) AND a norepinephrine reuptake inhibitor (NRI). Critically, it has minimal serotonergic activity compared to Tramadol, giving it a significantly lower risk of both seizures and serotonin syndrome.

Pharmacokinetics

Parameter	Value
Bioavailability	~32% (oral, due to first-pass metabolism)
Onset of Action	30-60 minutes
Peak Plasma	1.25-1.5 hours
Half-Life	4-5 hours (shorter than Tramadol)
Metabolism	Hepatic (glucuronidation → inactive metabolites; NO CYP2D6 dependency)
Excretion	Renal (99%)

Why It Is Abused

Tapentadol is the “next generation” Tramadol. As Tramadol has become harder to obtain due to NDPS controls (post-April 2018), abusers are shifting to Tapentadol, which produces a stronger opioid high with less nausea and lower seizure risk. Since Tapentadol is NOT metabolized by CYP2D6, it avoids the pharmacogenomic variability that makes Tramadol’s effects unpredictable in different individuals. It is currently under increased regulatory scrutiny for potential NDPS scheduling.

Clinical Significance: The shift from Tramadol to Tapentadol represents a classic “substitution pattern” — when regulators tighten controls on one drug, abusers migrate to the closest pharmacological alternative that remains more accessible.

Side Effects & Dangers of Abuse

• Respiratory Depression: More significant than Tramadol due to stronger mu-receptor agonism.
• Physical Dependence: Develops rapidly with daily use. Withdrawal onset is faster (within 12-24 hours of last dose) due to shorter half-life.
• Gastrointestinal Effects: Nausea, vomiting, severe constipation.
• CNS Depression: Dizziness, somnolence, confusion, hallucinations.
• Adrenal Insufficiency: Long-term opioid use can suppress cortisol production.

Clinician Red Flags

• Requests for Tapentadol by patients who previously used Tramadol.
• Claims of Tramadol “not working anymore” (tolerance, seeking escalation).
• Patients presenting with knowledge of Tapentadol’s lower seizure risk compared to Tramadol (suggests informed recreational use).
• Requests for IR (Immediate Release) formulations specifically over ER (Extended Release).

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Next: Part 2: Strong Opioids — Morphine, Fentanyl, Pethidine, Buprenorphine