Continuing Education Activity

Codeine is a medication used in the management and treatment of chronic pain. It is in the opioid class of medications. This activity outlines the indications, action, and contraindications for codeine as a valuable agent in the treatment of chronic pain and off label use in cough and restless leg syndrome. This activity will highlight the mechanism of action, adverse event profile, off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions pertinent for members of the interprofessional team in the treatment of patients with chronic pain and related conditions.

Objectives:

• Describe the indications for codeine.
• Review the adverse effects of codeine.
• Outline the mechanism of action of codeine.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients with codeine use.

Indications

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]

Mechanism of Action

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]

Administration

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]

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] 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]

Contraindications

• 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

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 who 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.

Toxicity

Deaths related to toxicity have increased recently, and a major proportion of the increase derives from accidental overdose. The patient population is more likely to have a history of substance misuse problems, 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]
• 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] The long-term outcomes for detoxification and drug rehabilitation remain guarded.[16],[17]

Given the potential for misuse, clinicians, and ancillary staff (nurses, pharmacists, mental health professionals) must be alert to a patient exhibiting adverse effects with codeine use. Nursing can monitor both the effectiveness of treatment as well as watch for signs of adverse events or misuse. The pharmacist should counsel the patient on the proper use of their medication, and watch for signs of misuse like early refills or "doctor shopping," reporting such behavior to the clinicians involved. This communication also applies to any mental health professionals or social workers who may have involvement with the patient. Only with a collaborative healthcare team approach to therapeutic codeine can the drug attain its intended purpose without causing adverse outcomes. [Level V]