Codeine Pharmacology: A Detailed Examination of Opioid Receptor Interactions
Codeine is a naturally occurring opiate synthesised from the opium poppy and used as an analgesic, antitussive and antidiarrheal. While it relieves mild to moderate pain, it comes with potential side effects, addiction and overdose risks, as its analgesic effect occurs as a result of its metabolism into morphine. This article will go into detail about codeine, covering its pharmacology, uses, effects, addiction profile and management.

Opioid receptors are a group of G-protein-coupled receptors that mediate the effects of opioid drugs in the body. The 3 main subtypes—mu (μ), delta (δ), and kappa (κ) opioid receptors—are found throughout the central and peripheral nervous systems and have distinct roles in pain modulation, mood regulation and other physiological processes. The mu-opioid receptor (MOR) is the main target for most opioid analgesics including codeine producing pain relief and euphoria but also contributing to respiratory depression and addiction potential.
Codeine works by binding to opioid receptors in the central nervous system (CNS) mainly the MOR. Since codeine is metabolised by the CYP2D6 enzyme, its effects vary between individuals depending on their level of enzyme expression and activity which is largely genetically determined. CYP2D6 genetic polymorphisms can significantly affect the rate and extent of morphine formation and codeine’s efficacy and side effects. Some individuals metabolise codeine rapidly and experience more intense effects while others metabolise it more slowly and experience reduced analgesia.
Genotyping for CYP2D6 can help identify individuals who may experience adverse effects or treatment failure with codeine and allow for personalised pain management. Codeine also binds to delta-opioid receptors (DOR) and kappa-opioid receptors (KOR) to a lesser extent than morphine. These interactions contribute to codeine’s overall pharmacological profile including its antitussive (cough-suppressing) and antidiarrheal effects.
Codeine’s Role in Pain Management: Efficacy, Limitations, and Alternative Analgesics

Codeine is used for mild to moderate pain such as headaches, dental pain and musculoskeletal pain. It’s often combined with other pain relief such as paracetamol or ibuprofen to boost its effectiveness. While codeine can work for pain relief its limitations need to be considered. Because it’s metabolised into morphine its effects are variable and unpredictable. Codeine is not effective for severe pain and not recommended for long term use due to the risk of dependence and tolerance. Other pain relief such as NSAIDs or other opioids may be more suitable for some individuals or pain conditions. A thorough assessment of the patient’s pain level, medical history and risk factors is essential in choosing the right pain relief.
Neurophysiological Effects and Symptomology on Central Nervous System
Codeine, like all opioids, works on the CNS by binding to opioid receptors, primarily the μ-opioid receptors (MORs). Activation of MORs leads to a cascade of neurophysiological effects including analgesia, sedation, respiratory depression, euphoria and constipation. In the brain codeine affects areas involved in pain perception, mood regulation and reward processing. It inhibits the transmission of pain signals by reducing the release of neurotransmitters such as substance P and glutamate.
Codeine also affects the brainstem by acting on μ-opioid receptors in the medulla, leading to respiratory depression and cough suppression. The subjective effects of codeine such as euphoria and relaxation are mediated by its effects on the mesolimbic dopamine system. Prolonged codeine use can lead to neuroadaptive changes in the brain resulting in tolerance, dependence and addiction.
Codeine’s Side Effect Profile: Incidence, Severity, and Mitigation Strategies
Codeine has a range of side effects which can vary in incidence and severity. Common side effects are constipation, nausea, vomiting, dizziness, drowsiness and dry mouth. These side effects are generally mild and transient but can be bothersome to some individuals. More serious side effects such as respiratory depression, hypotension and allergic reactions are less common but can be life threatening. Risk factors for serious side effects include high doses of codeine, concomitant use of CNS depressants such as benzodiazepines and alcohol, as well as medical conditions such as respiratory diseases (COPD), and liver dysfunction which can impair codeine metabolism .
Mitigation strategies for codeine side effects are dose reduction, use of laxatives for constipation, antiemetics for nausea and vomiting and avoidance of alcohol and other CNS depressants. Patients should be educated about the side effects of codeine and told to seek medical attention if they experience any worrying symptoms.
Mechanisms, Risk Factors, and Management

Long term use of codeine can lead to tolerance and dependence. Tolerance occurs when prolonged codeine use leads to diminished effects, requiring higher doses to achieve the same pain relief. Dependence is when the body gets physically and psychologically hooked on codeine and experiences withdrawal symptoms when it is stopped. The mechanisms of tolerance and dependence are neuroadaptive changes in the brain including changes in opioid receptor expression, neurotransmitter release and intracellular signalling pathways. Risk factors for codeine dependence are a history of substance use disorders, mental health conditions and chronic pain. Management of codeine dependence is gradual dose reduction (tapering) and supportive care for withdrawal symptoms.
Overdose: Recognition, Immediate Management and Long Term Consequences
Codeine overdose is a life threatening condition that can cause respiratory depression, coma and death. Signs of codeine overdose are slow or shallow breathing, pinpoint pupils, confusion, loss of consciousness and blue skin. Immediate management of codeine overdose includes the administration of naloxone, an opioid antagonist that counteracts respiratory depression. Naloxone should be given as soon as possible to get breathing and consciousness back, however due to codeines profile as a prodrug, delayed toxicity can occur.
As such, codeine overdose requires ongoing monitoring and supportive care including oxygen therapy and mechanical ventilation if necessary. Long term consequences of codeine overdose are brain damage from hypoxia, aspiration pneumonia and death. Prevention of codeine overdose is educating patients about the risks of codeine, prescribing the lowest effective dose and avoiding concomitant use of other CNS depressants.
Codeine Withdrawal Syndrome: Symptom Presentation, Timeline, and Supportive Care
Stopping codeine after long term use can cause withdrawal symptoms including anxiety, irritability, insomnia, increased heart rate, muscle aches, sweating, yawning, runny nose, diarrhea and abdominal cramps. The severity and duration of withdrawal symptoms depend on the dose and length of codeine use as well as individual factors. The timeline of codeine withdrawal is usually onset of symptoms within 6-12 hours of the last dose, peak at 1-3 days and resolves within 5-7 days. Supportive care for codeine withdrawal is providing a safe and comfortable environment, managing symptoms with medications such as antiemetics and antidiarrheals and providing psychological support and counselling.
Aftercare: Individual Therapy and Integration Strategies for Longterm Management

Aftercare is a critical part of overall codeine management, focusing on long-term recovery and preventing relapse. Individual therapy plays a big role in addressing the underlying psychological and behavioural factors that contribute to codeine use. This may include cognitive-behavioural approaches to identify and change maladaptive thoughts and behaviours as well as strategies to manage cravings and triggers. Integration strategies help individuals transition back into their home and work environment by applying relapse prevention techniques, stress management skills, and coping mechanisms to navigate situations and triggers.
The team at Highlands Recovery, located near Sydney in Australia, recognises that recovery from codeine dependence and its associated behavioural challenges is a lifelong process. As an Institute of Behavioural Medicine, Highlands Recovery applies a comprehensive clinical model designed to support sustainable recovery. Their four-phase recovery program begins with intensive residential care in the first two phases, offering a structured and supportive environment to address the biological, psychological, and social dimensions of codeine dependence.
Reviewed by: Dr. Emma Bardsley

Dr Emma Bardsley is a neuroscientist with a PhD from Oxford and a post doctorate from Auckland University, along with an undergraduate degree in Pharmacology from King’s College London. She has lectured extensively on neuroscience, physiology, and pharmacological interventions, bridging foundational research and its clinical applications. With a strong record of publications in high-impact journals and extensive experience in scientific writing, editing, and peer review, she excels at translating complex research into practical insights. Based in New Zealand and collaborating internationally, Emma is dedicated to advancing understanding and treatment in the fields of trauma, addiction, and recovery.
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