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. Its main indication is for pain and cough.

FDA-Approved Indication

Pain

Codeine plays a role in the treatment of mild to moderate pain. Its use is recognized in chronic pain due to ongoing cancer and 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 standard tissue healing time, which is three months.[1] The 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 is necessary on an ongoing basis with the therapy.

Non-FDA Approved Indications

Cough

Codeine is useful in the treatment of various etiologies producing chronic cough. Also, 46% of patients with 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 15 mg to 120 mg a day. It is, however, indicated in the management of prolonged cough (in specific populations 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 medications.[5]

Persistent Diarrhea (Palliative)

Codeine and loperamide are equally effective, and the choice between them has its basis in the assessment of the physician evaluating the small but undoubted addictive potential of codeine versus the higher cost of loperamide, and an individual difference in patient's vulnerability to adverse effects.[6]

Classically, there are three 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 neuronal cells, decreased neurotransmitter release. Within the nervous system, activation of mu receptors in the midbrain is the dominant mechanism of opioid-induced analgesia. The cough reflex primarily gets 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: 50 mg, 100 mg, 150 mg and 200 mg
• As an immediate-release tablet, 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 an option.[8]

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] The clinician should advise stool softeners along with codeine.

Nausea or vomiting is another commonly seen adverse effect that is expected to diminish the 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 receive counsel about considering precautions at work and restrictions with driving. They should also understand 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 higher 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