Article Author:
Basil Peechakara
Article Editor:
Mohit Gupta
12/28/2018 6:53:01 PM
PubMed Link:


Codeine is the most commonly taken opioid medication. It is at the center of the opioid addiction problem in the United States and thus is highly regulated. It is mainly prescribed for pain and cough.

FDA-Approved Indication


Codeine is used in the treatment of mild to moderate pain. Its use is recognized in chronic pain due to ongoing cancer and in palliative care. However, the use of codeine to treat other types of chronic pain remains controversial. Chronic pain, defined by the International Association for the Study of Pain, is pain persisting beyond the normal tissue healing time, which is 3 months.[1] Most prevalent causes of non-cancer chronic pain include back pain, fibromyalgia, osteoarthritis, and headache.

Care must be taken with the prescription of codeine as follows:[2]

  • Before initiating codeine therapy, clinicians must perform a history, physical examination and essential testing, including an assessment of the risk of substance addiction, misuse or abuse. 
  • Clinicians must consider codeine as an option if the pain is having a deleterious effect on the quality of life, and benefits of the therapy outweigh potential risks.
  • Initial treatment with codeine must be regarded both by the patient and the care provider as a therapeutic trial to determine whether the therapy is appropriate.
  • A benefit to harm evaluation must be performed on an ongoing basis with the therapy.

Non-FDA Approved Indications


Codeine is used in the treatment of various etiologies producing chronic cough. In addition, 46% of patients with a chronic cough do not have a distinct etiology despite a proper diagnostic evaluation.[3] Codeine produces a decrease in cough frequency and severity in these patients. However, there is limited literature demonstrating the efficacy of codeine in chronic cough.[4] The dose can vary from 15mg- 120mg a day. It is, however, indicated in the management of prolonged cough(in certain population like lung cancer) usually as 30 mg every 4 to 6 hours as needed.

Restless Leg Syndrome

Codeine is effective in the treatment of restless leg syndrome when given at night time, especially for those whose symptoms are not relieved by other treatments.[5]

Persistent Diarrhea (Palliative)

Codeine and loperamide are equally effective, and the choice among them is decided by the assessment of the physician of the meager but undoubted addictive potential of codeine versus the higher cost of loperamide, and an individual difference in patient's vulnerability to adverse effects.[6]

Mechanism of Action

Classically, there are 3 main opioid receptors, although there are other subtypes. These are all G-protein coupled and originally named mu, delta, and kappa. When opioids bind to these receptors, a series of intracellular events take place resulting in a decreased intracellular cAMP, hyperpolarization of the cell, and for neuronal cells, decreased neurotransmitter release. Within the nervous system, activation of mu receptors in the midbrain is considered as the major mechanism of opioid-induced analgesia. Cough reflex is primarily mediated through the opioid receptors present in the medulla. [7]


It is available in 4 formulations: 

  • As a solution for injection, as Phosphate: 30 mg/ml
  • As an oral solution, as Phosphate: 25 mg/ml
  • As a controlled release tablet, Codeine Contin: 50 mg, 100 mg, 150 mg and 200 mg
  • As a immediate release table, Codeine Sulfate: 15mg, 30mg, 60 mg

Codeine has a half-life of 3 hours. Initial dosing and titration can be individualized depending on the patient's health status, previous opioid exposure, attainment of therapeutic outcomes, and predicted or observed adverse events. In patients who are on around-the-clock continuous codeine with breakthrough pain, short-acting opioids may be tried. [8]

Adverse Effects

Constipation is one of the most common adverse effects of codeine. Most patients report some constipation following the initiation of therapy or increases in dose. With continued exposure, the resolution of constipation does not occur. [9]Stool softeners should be advised along with Codeine.

Nausea or vomiting is another commonly seen adverse effect that is expected to diminish following days to weeks of continued codeine exposure. Anti-emetic therapies, in oral and rectal formulations, are available for the treatment of nausea or vomiting.

Clouded mentation or sedation following codeine initiation tends to fade over time. During initiation or increasing doses, patients should be counseled about considering precautions at work and restrictions with driving. They should also be educated about the effects and risks with concomitant exposure to other substances and drugs with sedating effects.

Chronic use of controlled release codeine was associated with hypogonadism and lower levels of dehydroepiandrosterone sulfate.[10] The patients reported symptoms consistent with their presence, for example, decreased libido, fatigue or sexual dysfunction.

Other common adverse effects include pruritis, urinary retention, hypersensitivity, blurred vision, bronchospasm, tremor, weakness, abdominal cramps, and pancreatitis.

Clinicians must consider opioid rotation when patients chronically on a particular opioid experience intolerable adverse effects or inadequate relief despite dose increments.[11]

Patients who have sleep apnea or other coexisting pulmonary disorders may be at a greater risk for respiratory depression, and doses must be initiated and titrated with caution.

When used in pregnancy, unfavorable newborn outcomes such as premature birth, low birth weight, hypoxic-ischemic brain injury, and neonatal death may occur. Newborns may also develop neonatal abstinence syndrome. [12]


  • Hypersensitivity reaction to codeine or any component of the formulation
  • Respiratory depression due to comorbid respiratory disorder
  • Children less than 12 years of age
  • Pediatric patients with a history of tonsillectomy or adenoidectomy
  • Paralytic ileus
  • Intestinal obstruction
  • Monoamine oxidase inhibitor use
  • Asthma in an unmonitored setting


Monitoring should include subjective as well as objective assessment via laboratory testing. There must be documentation of pain intensity, level of functioning, progress toward therapeutic goals, the presence of adverse effects, and adherence to the therapy.[13] Urine drug screening, pill counts, caregiver or family member encounters, and prescription monitoring program data can be useful monitoring tools. In patients whom are on stable doses and have a low risk for adverse outcomes, monitoring once every 3 to 6 months is adequate. For patients with high risk, weekly monitoring is a reasonable strategy.


Deaths related to toxicity have increased recently, and a major proportion of the increase is attributed to accidental overdose. The patient population is more likely to have a history of substance abuse problem, injecting drug use and chronic pain. These patterns indicate that, in accidental deaths, there could be evidence of codeine used for supplementing prescribed pain medication; codeine dose escalation; and the development of dependence of codeine. Therefore, there is a need for specialist intervention for a complex patient population. [14]

Maximum Tolerated Dose

  • Immediate-release preparation: 360 mg per day
  • Controlled-release preparation: 600 mg per day

Treatment of toxicity depends on the symptoms and degree of intoxication and involves symptomatic therapy like enema and definitive therapy with an opioid antagonist.

Enhancing Healthcare Team Outcomes

Managing drug overdose requires an interprofessional team of healthcare professionals that includes a nurse, laboratory technologists, pharmacist, and a number of physicians in different specialties. Without proper management the morbidity and mortality from codeine overdose are high. The moment the triage nurse has admitted a codeine overdose, the emergency department clinician is responsible for coordinating the care which includes the following:

  • Ordering drug levels in blood and or urine
  • Monitor the patient for signs and symptoms of respiratory depression, cardiac arrhythmias, and narcotic bowel syndrome
  • Performing various maneuvers to help limit absorption of the drug in the body
  • Consult with the pharmacist about the use of activated charcoal and naloxone.[15] (Level A)
  • Consult with a toxicologist and nephrologist on further management, which may include dialysis
  • Consult with the radiologist about imaging tests to ensure that the patient has not swallowed any drug packages
  • Consult with the intensivist about intensive care unit (ICU) care and monitoring while in hospital

The management of codeine overdose does not stop in the emergency department. Once the patient is stabilized, healthcare practitioners must determine how and why the patient overdosed. Consult with a mental health counselor if this was an intentional act and determine risk factors for-self harm. Further, the possibility of addiction and withdrawal symptoms have to be considered. Only by working as an interprofessional team can the morbidity of codeine overdose be decreased. Initial short-term data reveal that the use of naloxone can be life-saving.[16] (Level A) The long-term outcomes for detoxification and drug rehabilitation remain guarded.[16],[17] (Level B)