Dihydrocodeine

Dihydrocodeine is a semi-synthetic opioid analgesic derived from codeine, used primarily for the relief of moderate to moderately severe pain and, in some cases, for cough suppression or dyspnea management in palliative care. It is structurally related to codeine and morphine, but exhibits distinct pharmacokinetic and clinical properties. In the UK and other countries, it is available both alone and in combination with paracetamol or aspirin, and is regulated as a controlled drug in most jurisdictions due to its abuse potential.

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Pharmacological Classification

• Therapeutic class: Opioid analgesic

• Pharmacologic class: Semi-synthetic phenanthrene opioid

• ATC code: N02AA08

• Legal status:

  • Prescription-only in most countries

  • Schedule II / III / V depending on the formulation and jurisdiction (e.g., UK: Class B, Schedule 2; US: not FDA-approved as standalone)

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Mechanism of Action

Dihydrocodeine acts as an opioid receptor agonist, primarily binding to mu-opioid receptors (μ-receptors) in the central nervous system.

• It mimics endogenous endorphins by inhibiting ascending pain pathways, altering pain perception and emotional response to pain.

• Also exhibits mild kappa- (κ-) and delta-opioid receptor affinity.

• As a prodrug, it undergoes hepatic metabolism (mainly via CYP2D6) to form dihydromorphine, which is believed to be the active metabolite contributing to analgesia.

• Like other opioids, it reduces respiratory drive by acting on the brainstem, depresses the cough reflex, and slows gastrointestinal motility.

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Therapeutic Indications

Approved Uses

• Moderate to moderately severe pain (e.g., musculoskeletal pain, post-operative pain, trauma)

• Chronic pain conditions when non-opioid analgesics are insufficient

• Cough suppression (less commonly used for this indication today)

• Shortness of breath in advanced illness (palliative care)

• Neuralgic pain, in combination with adjuvants

Off-label or less common uses

• Restless leg syndrome (occasionally)

• Diarrhea (in certain compounded formulations)

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Dosage and Administration

Adults

Immediate-release tablets:

• 30 mg every 4 to 6 hours as needed

• Maximum daily dose: generally 240 mg/day, but may vary by national guidelines

Controlled-release (e.g., DHC Continus®):

• 60 mg every 12 hours (usual starting dose)

• Dose titration can occur depending on patient response and pain severity

• Maximum: Often not to exceed 120 mg per dose without specialist oversight

Combination products (e.g., Co-dydramol):

• 10–20 mg dihydrocodeine + 500 mg paracetamol

• One to two tablets every 4–6 hours (max 8 tablets/day due to paracetamol limits)

Elderly

• Lower starting doses recommended

• Monitor for increased risk of CNS depression and falls

Children

• Not routinely recommended

• Contraindicated in children under 12 years

• Use in adolescents (12–18 years) only when benefits outweigh risks, especially post-tonsillectomy or adenoidectomy due to risk of respiratory depression

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Contraindications

• Known hypersensitivity to dihydrocodeine or other opioids

• Severe respiratory depression, acute asthma, or respiratory obstruction

• Paralytic ileus

• Acute alcoholism or concurrent use of MAO inhibitors

• Comatose patients or those with raised intracranial pressure

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Warnings and Precautions

• Dependence and abuse: High potential with prolonged use

• CYP2D6 variability: Ultrarapid metabolizers may experience toxicity; poor metabolizers may have reduced efficacy

• Respiratory depression: Especially in elderly, children, or those with existing pulmonary disease

• Head injuries: May mask signs of increased intracranial pressure

• Hypotension and bradycardia: Especially when used with CNS depressants

• Constipation: Very common; laxatives are usually co-prescribed for chronic use

• Hepatic impairment: Use with caution; reduced metabolism and increased toxicity

• Renal impairment: Accumulation of active metabolites possible

• Withdrawal symptoms: Taper gradually after prolonged therapy

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Adverse Effects

Very Common (≥10%)

• Constipation

• Nausea, vomiting

• Drowsiness, dizziness

Common (1–10%)

• Dry mouth

• Sweating

• Itching, rash

• Miosis

• Confusion or euphoria

Rare (<1%)

• Respiratory depression

• Dependence and withdrawal symptoms

• Hallucinations, urinary retention

• Hypotension

• Seizures (in overdose)

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Drug Interactions

Pharmacodynamic Interactions

• Other CNS depressants: Increased risk of sedation and respiratory depression

  • e.g., benzodiazepines, alcohol, barbiturates, antipsychotics

• MAO inhibitors: Contraindicated due to potential for serotonin syndrome or hypertensive crisis

• Anticholinergic drugs: Additive risk of constipation, urinary retention

• Other opioids: Cumulative respiratory depression and risk of overdose

Pharmacokinetic Interactions

• CYP2D6 inhibitors: Reduce conversion to active metabolite (e.g., fluoxetine, paroxetine, quinidine)

• Enzyme inducers/inhibitors: May alter plasma levels

• Naltrexone or naloxone: Antagonize analgesic effects

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Use in Pregnancy and Lactation

Pregnancy

• Category C (UK), not recommended unless absolutely necessary

• Possible neonatal withdrawal syndrome if used in late pregnancy

• Animal studies have shown some teratogenicity at high doses

• Avoid during labour unless benefit outweighs risk

Lactation

• Excreted in breast milk in small amounts

• Use caution due to risk of respiratory depression or opioid toxicity in breastfed infants, especially if the mother is an ultrarapid CYP2D6 metabolizer

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Special Populations

Elderly

• Start with lower doses

• Monitor for confusion, falls, and constipation

• Increased sensitivity to sedative effects

Renal or Hepatic Impairment

• Use with caution

• Accumulation of active metabolites may occur

• Avoid in severe hepatic failure

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Overdose and Toxicity

Symptoms

• Pinpoint pupils

• Respiratory depression

• Cold/clammy skin

• Bradycardia

• Hypotension

• Seizures

• Coma and death in severe cases

Treatment

• Supportive care: Airway management, oxygenation

• Naloxone: Opioid antagonist administered IV, IM, or SC

• Activated charcoal if ingestion was recent

• Continuous monitoring of respiratory and cardiovascular status

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Comparison (Without Tables)

Dihydrocodeine vs. Codeine

• Both are prodrugs with similar analgesic profiles, but dihydrocodeine may produce stronger effects

• Dihydrocodeine has better oral bioavailability and slightly more potent analgesia

• Codeine is more commonly used as a cough suppressant

• Both metabolized via CYP2D6, with variable individual responses

Dihydrocodeine vs. Tramadol

• Tramadol has additional serotonin/norepinephrine reuptake inhibition

• Dihydrocodeine is pure opioid, while tramadol acts on multiple pain pathways

• Tramadol may cause more CNS effects (e.g., seizures, serotonin syndrome)

• Dihydrocodeine has less risk of serotonin toxicity, but greater risk of classic opioid side effects

Dihydrocodeine vs. Morphine

• Morphine is much more potent and used for severe pain

• Dihydrocodeine is a step 2 analgesic on the WHO ladder; morphine is step 3

• Dihydrocodeine preferred in outpatient or milder chronic pain settings

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Patient Counseling Points

• Take exactly as prescribed, and do not exceed recommended dose

• May cause drowsiness—avoid driving or operating machinery

• Avoid alcohol and other sedatives

• Take with food to reduce nausea

• Take laxatives concurrently for long-term use

• Store securely to prevent misuse or accidental ingestion

• Do not abruptly stop after long-term use—risk of withdrawal

• Report symptoms such as shortness of breath, confusion, or rash

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Abuse Potential and Regulatory Controls

• High risk of misuse and addiction

• Misuse may involve crushing or injecting modified-release tablets

• Subject to controlled drug prescribing regulations (e.g., UK Controlled Drugs Regulations, Schedule 2)

• Must be stored securely and prescribed with caution in known substance use disorder history