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 treating chronic pain and off-label use in cough, persistent diarrhea, and restless leg syndrome. In addition, this activity will highlight the mechanism of action, adverse event profile, off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, toxicity, and relevant interactions pertinent for interprofessional team members in treating 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 care delivery 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. Codeine's main indications are pain and dry 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 of 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 assessing the risk of substance addiction, misuse, or abuse. 
• Clinicians must consider codeine as an option if the pain has a deleterious effect on the quality of life and the benefits of the therapy outweigh potential risks.
• Initial treatment with codeine must be discussed by the health care providers and the patients as a therapeutic trial to determine whether the therapy is appropriate.
• A risk-benefit 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 treating refractory restless leg syndrome when given at night. However, the dose prescribed should be low, and patients should be non-responders to all other standard treatment protocols for RLS.[5]

Persistent Diarrhea (Palliative)

Codeine and loperamide are equally effective, and the choice between them has its basis in assessing 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 occur, resulting in a decreased intracellular cAMP, hyperpolarization of the cell and neuronal cells, and 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 is primarily mediated through the opioid receptors in the medulla.[7]

Pharmacokinetics (according to manufacturer's product labeling)

Absorption: Codeine sulfate is absorbed from the gastrointestinal tract and maximum plasma concentration (Cmax) after one hour. Administration of codeine every four hours for five days resulted in steady-state concentrations in 48 hours. Food does not significantly affect the absorption of codeine.

Distribution: Codeine has an apparent volume of distribution of 3 to 6 L/kg, suggesting extensive tissue distribution.

Metabolism: Codeine is metabolized by conjugation to morphine (5% to 10%) and N-demethylation to norcodeine (~10%). Cytochrome P450 2D6 is the principal enzyme responsible for the transformation of codeine to morphine, and P450 3A4 is the major enzyme for converting codeine to norcodeine.[8]

Excretion: Approximately 90% of codeine is excreted by the kidney, of which approximately 10% is unchanged codeine. The t½ of codeine and its metabolites are 3 hours.

Administration

It is available in four 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

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.[9]

Use in Specific Patient Populations

Patients with Hepatic Impairment: According to manufacturer labeling, no studies have been conducted on patients with hepatic impairment. Hence clinicians should prescribe codeine at a lower dose in these patients.

Patients with Renal Impairment: The kidney is the major route of elimination, so pharmacokinetics is altered in the patients with renal impairment. Consequently, clinicians should prescribe codeine at a lower than normal dose or with longer dosing intervals.

Pregnancy Considerations: 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. If codeine use is required for a long time in a pregnant woman, counsel the patient on the risk of neonatal opioid withdrawal syndrome (Boxed Warning) and ensure adequate management.[10] 

Breastfeeding Considerations: Maternal use of codeine during breastfeeding can cause infant drowsiness, central nervous system depression, and death. If the newborn shows sedation, problems in breastfeeding, or breathing difficulties, the mother should contact the clinician immediately. Neonates seem especially susceptible to the effects of even small dosages of codeine. Hence, professional organizations and regulatory agencies advise against using codeine completely during breastfeeding. Hence, it is reasonable to provide analgesia to the mother with non-narcotic agents.[11]

Pharmacogenomic Considerations (Boxed Warning): Patients who are ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism gene (ultrarapid metabolizers) can metabolize codeine to morphine rapidly. Consequently, even with standard doses of codeine, these patients may experience the symptoms of opioid overdose. Hence the FDA drug label for codeine reports that individuals who are ultrarapid metabolizers may have life-threatening or fatal respiratory depression at a therapeutic dose.[12]

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.[13] The clinician should advise stool softeners along with codeine. Nausea or vomiting is another commonly seen adverse effect that is expected to diminish within 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. However, 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 of concomitant exposure to other substances and drugs with sedating effects.

Chronic use of controlled release codeine was associated with hypogonadism and lower dehydroepiandrosterone sulfate levels.[14] 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.[15]

Patients with 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.[10]

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
• Paralytic ileus
• Intestinal obstruction
• Monoamine oxidase inhibitor use
• Asthma in an unmonitored setting
• Boxed Warning: Pediatric patients with a history of tonsillectomy or adenoidectomy[16]
• Boxed Warning: Concomitant use of opioids with benzodiazepines or other (CNS) depressants, including alcohol, may result in respiratory depression, profound sedation, coma, and death. FDA boxed warning has been associated with a decline in the number of patients with co-prescriptions of opioids and benzodiazepines; however, prescribers must be cautious.[17]

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.[18] Urine drug screening, pill counts, caregiver or family member encounters, and prescription monitoring program data can be useful monitoring tools for 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.[19]

Monitoring with tools such as the Opioid Risk Tool (ORT) for Narcotic abuse helps identify patients with an increased risk for misuse and who might benefit more from other pain control modalities besides narcotics (for patients with chronic pain). Clinicians can use the Revised Opioid Risk Tool for patients with chronic nonmalignant pain (CNMP).[20]

Toxicity

Deaths related to toxicity have increased recently, and a major proportion of the increase derives from an accidental overdose. The patient population is presumed 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 on codeine. Therefore, there is a need for specialist intervention for a complex patient population.[21]

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 opioid antagonist naloxone. If the patient is physically dependent on opioids, administration of opioid antagonists may precipitate acute withdrawal syndrome. Consequently, clinicians should prescribe opioid antagonists with care to patients with physical dependence and smaller than usual doses of the antagonist. (according to manufacturer's labeling).

Enhancing Healthcare Team Outcomes

Managing drug overdose requires an interprofessional team of healthcare professionals, including a nurse, laboratory technologists, a pharmacist, and several clinicians in different specialties. Without proper management, the morbidity and mortality from codeine overdose are high. Therefore, 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 the blood and or urine
• Monitor the patient for signs and/or symptoms of respiratory depression, cardiac arrhythmias, and narcotic bowel syndrome
• Performing various maneuvers to help limit the absorption of the drug in the body
• Consult with the pharmacist about the use of activated charcoal and naloxone.[22]
• 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 the 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 decrease. Initial short-term data reveal that the use of naloxone can be life-saving.[23] The long-term outcomes for detoxification and drug rehabilitation remain guarded.[24]

Opioid Risk Evaluation and Mitigation Strategy (REMS): The FDA has required a REMS for opioids so that the benefits of opioids outweigh the risks of addiction, misuse, and abuse. All the healthcare providers are strongly recommended to complete the REMS education program and advise patients and their caregivers on safe use and serious risks associated with opioids.[25] Similarly, the efficient use of the Prescription Drug Monitoring Program (PDMP) can identify the patients who are likely to develop long-term use of opioids.[19] Emergency Department-Initiated Buprenorphine for Opioid Use Disorder is associated with increased engagement in addiction treatment and reduced illicit opioid use.[26]

Given the potential for misuse, clinicians and ancillary staff (nurses, pharmacists, and mental health professionals) must be alert to a patient exhibiting adverse effects of codeine use. Nursing can monitor the effectiveness of treatment and watch for signs of adverse events or misuse. The pharmacist should counsel the patient on proper medication use, watch for signs of misuse like early refills or "doctor shopping," and report such behavior to the clinicians involved. This communication also applies to any mental health professionals or social workers who may interact 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 5]