Codeine: Opioid Analgesic and Antitussive with Controlled-Substance Status

Codeine is a naturally occurring opium alkaloid belonging to the class of opioids. It is derived from morphine and is a prodrug: in the body, codeine is partially converted to morphine by the enzyme CYP2D6, which mediates the principal analgesic effect. Codeine itself also has weak opioid receptor activity. As an antitussive it suppresses the cough reflex and is used in both pain preparations and cough medicines.

Codeine is available as a pure substance as well as in fixed combinations with paracetamol or ibuprofen. Well-known combination products include Talvosilen and Novalgin with codeine. An important distinction is based on codeine content: preparations containing up to 2.5% codeine are not subject to controlled-substance prescribing requirements; higher concentrations fall under narcotics legislation.

Controlled-Substance Status

Codeine is listed as a controlled substance in many countries. Preparations with a codeine content exceeding defined thresholds may only be prescribed on a special controlled-substance prescription. These prescriptions are subject to particular record-keeping and storage obligations for physicians and pharmacists. Patients and healthcare professionals must be familiar with and observe the applicable regulations.

Mechanism of Action

Codeine binds as a weak agonist to mu, delta and kappa opioid receptors in the central and peripheral nervous system. The analgesic effect is attributable primarily to the hepatic conversion of codeine to morphine by CYP2D6. Morphine activates mu opioid receptors in the spinal cord, brainstem and supraspinal structures, leading to pain modulation.

The antitussive effect is mediated via opioid receptors in the cough centre of the medulla oblongata. Codeine raises the threshold for the cough reflex and reduces cough frequency. This effect is largely independent of morphine conversion, which explains why individuals with CYP2D6 deficiency may still experience an antitussive effect.

The individual efficacy of codeine varies considerably according to CYP2D6 genotype. Ultra-rapid metabolisers convert codeine to morphine particularly quickly and are at risk of reaching toxic morphine levels. Poor metabolisers, on the other hand, experience little or no analgesic effect.

Indications

• Pain management: Mild to moderate pain, particularly in combination with paracetamol or ibuprofen
• Irritant cough: Dry, distressing cough without therapeutic benefit from coughing (e.g. in viral respiratory infections)
• Postoperative analgesia: Short-term use after procedures when weaker analgesics are insufficient
• Chronic pain therapy: Only in exceptional cases and under strict medical supervision when pain cannot be controlled by other means

Codeine is not approved for use in children under 12 years of age (since the EMA decision of 2013). In children and adolescents under 18 years following tonsillectomy or adenotomy, codeine is contraindicated.

Dosage and Administration

The recommended single dose in adults is 15 to 60 mg codeine every 4 to 6 hours. The maximum daily dose should not exceed 240 mg. When used as an antitussive, lower doses (10 to 20 mg every 4 to 6 hours) are employed. Codeine may be taken with or without food; administration with food may reduce gastrointestinal discomfort.

In patients with renal or hepatic insufficiency, in elderly patients and in patients with known CYP2D6 polymorphisms, dosage must be adjusted individually and tolerability monitored closely. The duration of treatment should be kept as short as possible.

Side Effects

As an opioid, codeine shares the typical side-effect profile of this drug class: constipation (very common), nausea and vomiting, sedation and drowsiness, and dizziness occur regularly. Respiratory depression is the most serious adverse effect, which can occur particularly with excessive dosing, concomitant use of other centrally depressant agents, or in CYP2D6 ultra-rapid metabolisers.

Other possible adverse effects include dry mouth, urinary retention, miosis (pupil constriction), pruritus and mood changes. With long-term use, physical and psychological dependence may develop. The dependence potential is lower than for pure morphine but remains clinically significant.

Drug Interactions

Centrally depressant substances such as benzodiazepines, barbiturates, other opioids, alcohol and antihistamines substantially enhance the respiratory-depressant and sedating effects of codeine. This combination can be life-threatening. MAO inhibitors must not be used concurrently and not within 14 days after discontinuation.

CYP2D6 inhibitors (e.g. fluoxetine, paroxetine, bupropion, quinidine) inhibit the conversion of codeine to morphine and can markedly reduce the analgesic effect. CYP3A4 inducers (e.g. rifampicin, carbamazepine) accelerate the breakdown of codeine. Naloxone and naltrexone reverse the opioid effects of codeine.

Special Notes

Codeine is contraindicated during pregnancy, particularly in the third trimester, as it can cause respiratory depression and withdrawal symptoms in the neonate. Codeine is contraindicated during breastfeeding because it passes into breast milk and can cause potentially life-threatening respiratory depression in the infant, especially if the mother is an ultra-rapid metaboliser.

Patients with bronchial asthma, COPD, sleep apnoea, prostatic enlargement or raised intracranial pressure should use codeine only under strict medical supervision. Driving and operating machinery are restricted during treatment.

Frequently Asked Questions

Why is codeine subject to controlled-substance regulations?

As an opioid, codeine has a potential for misuse and dependence. Controlled-substance legislation governs the handling of addictive substances and ensures that codeine is used only under medical supervision and in controlled quantities.

Why does codeine not work in some people?

The analgesic effect of codeine depends on its conversion to morphine by the enzyme CYP2D6. Approximately 5 to 10 percent of the Caucasian population are poor metabolisers in whom this conversion barely takes place. These individuals experience little or no pain-relieving effect.

Can codeine cause dependence?

Yes, codeine has a dependence potential. With short-term use as intended, the risk is low. With prolonged use or misuse, physical and psychological dependence can develop. Self-initiated dose increases or extension of treatment without medical consultation are not permissible.

What should be noted when taking codeine with sedatives?

Concomitant use of codeine and benzodiazepines or other sedating agents substantially increases the risk of life-threatening respiratory depression. This combination should only be employed in exceptional circumstances under the closest possible medical supervision.

References and Further Information

• Relevant national narcotics legislation and prescribing regulations
• EMA: Codeine-containing medicines and use in children (2013)
• Summaries of Product Characteristics for codeine-containing preparations (current versions)
• S3 Guideline on the Treatment of Chronic Non-Cancer Pain (AWMF)
• Federal Institute for Drugs and Medical Devices (BfArM)