Codeine Phosphate Chronicles - Transforming Pain Into Comfort

Overview

Codeine phosphate is an opioid analgesic commonly prescribed for pain management. It belongs to the opiate class of medications and is derived from the opium poppy plant. Codeine phosphate is used to alleviate moderate to moderately severe pain and may also be employed as an antitussive to suppress coughing in certain formulations. The United States Food and Drug Administration (FDA) has approved various formulations of Codeine phosphate, including tablets, capsules, and liquid preparations, with different strengths catering to individual patient needs. Its mechanism of action involves binding to mu-opioid receptors in the central nervous system, modulating pain perception. While effective in pain relief, Codeine phosphate is not without risks, including the potential for dependence and side effects such as drowsiness and constipation. FDA approval underscores the drug's recognized benefits when used judiciously under medical supervision. The healthcare professionals closely monitor its use to ensure patient safety and optimal therapeutic outcomes.

Drug Group:

Opioid analgesics, commonly referred to as narcotics, constitute a class of potent pain-relieving medications derived from or mimicking the effects of opium. These drugs exert their analgesic effects by binding to specific receptors in the brain and spinal cord known as opioid receptors. By doing so, they modulate the transmission of pain signals and alter the perception of pain. Opioid analgesics are often prescribed for managing moderate to severe pain, such as post-surgical discomfort or pain associated with certain medical conditions. While these medications are effective in providing relief, they come with potential side effects, including drowsiness, constipation, and the risk of respiratory depression. Moreover, there is a significant concern regarding the potential for dependence and addiction with prolonged or misuse of these substances. Healthcare providers carefully weigh the benefits of pain relief against the risks when prescribing opioid analgesics and close monitoring is essential to ensure their appropriate and safe use. Patient education, regular follow-ups, and a comprehensive approach to pain management are integral components of navigating the complexities associated with opioid analgesics.

Available Doses and Dosage Forms:

Codeine phosphate is available in various dosage forms and strengths, and specific formulations may vary by region and pharmaceutical manufacturer. Common dose forms and strengths include:

Tablets:

Codeine phosphate is often available in tablet form with different strengths, such as 15 milligrams, 30 milligrams, or 60 milligrams per tablet.

Capsules:

Capsule formulations of Codeine phosphate may also be available, typically with similar strength variations.

Liquid Formulations:

Syrups or oral solutions containing Codeine phosphate are common, providing a liquid option for administration. These may have concentrations such as 15 milligrams/5 mL or 30 milligrams/5 mL.

Combination Products:

Codeine phosphate is sometimes combined with other medications, such as Acetaminophen (paracetamol) or Ibuprofen, in various strengths for enhanced pain relief.

For Patients

How Does Codeine Phosphate Work?

Codeine phosphate is used for the relief and management of mild to moderate degrees of pain. It is sometimes used, in conjunction with other medicines, for the treatment of cough. Codeine phosphate is well-known to aid in the relief of symptoms but fails to treat the primary cause of the conditions. Codeine phosphate belongs to a group of medications called opioid or narcotic analgesics and another class of medicines called antitussives. Codeine medication functions by altering the way the brain and central nervous system (CNS) respond to any pain in the system. This is for pain relief. On the contrary, when Codeine is used for coughing, it works by reducing the mechanism or activity associated with the coughing in the part of the brain. Codeine phosphate is also accessible as an active ingredient for many cold and cough medications with the combination of other medications, including Aspirin, Acetaminophen, Carisoprodol, Promethazine, and others.

What Is the Dosage of Codeine Phosphate?

The recommended dosage of Codeine phosphate for pain management in adults is 15 milligrams to 60 milligrams orally for up to every four hours as required. The maximum dosage is considered to be 360 milligrams in 24 hours.

How Effective Is Codeine Phosphate?

Codeine phosphate is an opioid analgesic commonly used for pain relief. It functions by binding to specific receptors in the brain and spinal cord, altering the perception of pain. Its effectiveness lies in its ability to diminish the transmission of pain signals and reduce the brain's awareness of discomfort. Codeine is often prescribed for moderate to moderately severe pain, such as post-surgical pain or injury-related discomfort. However, its efficacy can vary among individuals, and it carries potential side effects and risks, including drowsiness, constipation, and the risk of dependence. Healthcare professionals carefully assess patients' medical histories and consider the balance between pain relief and potential adverse effects when prescribing codeine phosphate, ensuring its appropriate use for managing specific types and levels of pain.

What Are the Things to Inform the Doctor Before Taking Codeine Phosphate?

• It is important to inform the doctor in the case of allergy or hypersensitivity to Codeine, other ingredients, or other medications in general.

• It is also critical to disclose to the healthcare providers the prescription and nonprescription medication one takes. This includes prescription medication, over-the-counter medicines, vitamins, nutritional supplements, and herbal products.

• Inform the doctor if anyone is taking the monoamine oxidase inhibitors (MAOIs) or if one has just stopped taking them within the last 14 days. The drugs include Linezolid, Isocarboxazid, Phenelzine, Methylene blue, Selegiline, and Tranylcypromine. The doctors will mostly advise not to take the Codeine if one is under MAOIs or has been under therapy in the last two weeks.

• Inform the doctors about the herbal products one ingest, especially Tryptophan and St. John’s wort.

• It is pivotal to inform healthcare professionals about the medical problems one is experiencing or experienced in the past. Reveal to the doctor if one has or ever had a narrowing or blockage in the stomach or intestine, or paralytic ileus. Paralytic ileus is a condition where the digested food items cannot be moved along the intestines.

• Inform the doctor if one takes alcohol, or had any recent abdominal or urinary tract surgeries.

• Addedly, one must inform the doctor if one has or ever had mental illness or seizures (involuntary body jerking or movements). Urinary problems, prostatitis (enlargement or inflammation of the male reproductive organ called prostate), hypotension (low blood pressure), Addison’s disease (a condition where the system does not make an adequate amount of certain natural substances), or any pancreatic, intestinal, thyroid, liver, kidney, or gallbladder disease.

• Inform the doctor if one is pregnant or about to be in the future.

• Tell the doctor if one is breastfeeding. One must not breastfeed while on Codeine treatment. Codeine is known to induce shallow breathing, noisy breathing, extreme drowsiness, confusion, difficulty sleeping, and lumpiness in infants.

Important Considerations:

• Do not abruptly stop taking Codeine phosphate without consulting the healthcare provider. Abrupt cessation of Codeine phosphate or any opioids could lead to certain withdrawal symptoms.

• Codeine phosphate might decrease fertility in both men and women. Discuss with the doctor about the potential risks of this medication.

• Inform the dentist about Codeine therapy if one is about to have any dental surgeries.

• This medication might make one extremely drowsy. Hence, one should not drive a car or operate high machinery until one knows the exact mechanism of this medication.

• Codeine phosphate might cause constipation. Talk to the doctor regarding the diet plan or usage of other medication to prevent and manage constipation.

• One must know that Codeine phosphate might cause lightheadedness, dizziness, fainting, and sleepiness when one gets up abruptly from the lying position. These symptoms are more common during the initial stage of therapy. One can consider getting out of bed slowly and resting the feet on the floor for several minutes prior to standing.

How Is Codeine Phosphate Administered?

• Doctors pivotally advise to adhere to the prescribed dosing and frequency.

• Avoid self-adjusting or exceeding recommended limits to prevent adverse effects and overdose.

• Codeine phosphate medication could be taken with or without food intake. However, adapt to the instructions provided by the healthcare provider on food intake.

• Swallow the Codeine phosphate tablets whole with a full glass of water. One must not crush, break, or chew the tablets unless directed otherwise.

• Take this medication with milk or food if this causes any distress, or upsetting the stomach.

• Take Codeine phosphate as soon as onset of pain is felt, or as prescribed. There is no need to wait until the pain becomes intense or severe.

Side Effects of Codeine Phosphate

One should seek an emergency helpline in case of any signs of allergic reactions to Codeine phosphate. The signs include the following.

• Hives.

• Rashes.

• Difficult breathing.

• Swelling of the face and throat.

Common Side Effects

The common side effects of Codeine phosphate are as follows.

• Dizziness or drowsiness.

• Constipation.

• Sweating.

• Nausea.

• Vomiting.

• Stomach pain.

• Mild itching.

• Rashes.

Serious Side Effects

Serious side effects are more common in geriatric populations and individuals who are malnourished, obese and debilitated. Call the doctor and get the appropriate treatment measures at the earliest if one encounters any one of the following serious side effects.

• Noisy breathing interrupted breathing during sleep, and shallow breathing.

• Weak pulse.

• Low heart rate.

• Lightheadedness.

• Confusion.

• Agitation.

• Seizures or convulsions.

• Urination problems.

• Hallucinations.

• Distorted thoughts and behaviors.

• Feelings of intense sadness or happiness.

• Symptoms of low cortisol levels include nausea, loss of appetite, vomiting, dizziness, weakness, and distressing tiredness.

Serotonin Syndrome:

One must seek medical attention and care straight away if they have any symptoms associated with serotonin syndrome. The symptoms are as follows.

• Hallucinations.

• Fever.

• Agitation.

• Sweating.

• Rapid heart rate.

• Shivering.

• Twitching.

• Muscle stiffness.

• Loss of coordination.

• Nausea.

• Vomiting.

• Diarrhea.

Fertility: Prolonged use of opioid medications, including Codeine phosphate might affect fertility in both men and women. However, it is undetermined whether the effects of opioids on fertility are significant and permanent.

Fatal: Similar to other narcotic drugs, Codeine phosphate could slow the breathing. Hence, Codeine intake can turn out to be fatal when the breathing becomes too slow and weak. One must seek prompt medical attention in the case of laggy breathing with long breaks, bluish discoloration of lips, or other significant changes.

Dietary Considerations: Healthcare providers generally recommend following the routine classic diet while on Codeine phosphate treatment. Hence, one can stick to a healthy and nutritious diet unless the doctor utters any dietary restrictions. Refrain from consuming alcohol while taking Codeine phosphate, as it can enhance drowsiness and other side effects.

Missed Dose: Codeine phosphate is generally taken as required. However, the doctors might prescribe the Codeine phosphate regularly for certain treatments. In such cases, one can ingest the missed dosage as soon as one has the thought. Nevertheless, skip the missed dosage and proceed with the routine dosing schedule, if it is nearly the time for the subsequent dose. It is crucial to know that individuals should not take double doses of Codeine phosphate for the compensation of the missed one.

Overdose: Discuss with the healthcare providers about the rescue medication for Codeine overdose. This medication is called Naloxone. Naloxone is typically used for reversing the potentially life-threatening effects associated with Codeine. Naloxone works by inhibiting the effects of opiates, relieving the hazardous symptoms attributable to the increased levels of opiates in the bloodstream. The family members and caregivers of the patient must be aware of the drug Naloxone. The second dosage of Naloxone is usually given within two to three minutes after the first dosage, assessing the improvement.

One must reach out to poison control care or emergency medical services in case of an overdose of Codeine phosphate medication.

Symptoms of Overdose:

• Difficulty breathing.

• Excessive drowsiness.

• Gradual or shallow breathing.

• Inability to wake up.

• Inability to respond.

• Fainting.

• Dizziness.

• Loss of muscle tone.

• Cold and clammy skin.

• Slow heartbeat.

Storage

Store the Codeine medication at room temperature while away from excess moisture and heat. It is crucial to keep Codeine phosphate in a firmly closed container. Keep the Codeine phosphate and any other medications out of the sight and reach of children.

For Doctors:

Indication:

Codeine phosphate is prescribed for various indications, primarily as a pain-relieving medication. Some common indications include:

Pain Management: Codeine phosphate is often used to alleviate moderate to moderately severe pain, such as pain following surgery, injury, or certain medical conditions.

Cough Suppression: In some cases, Codeine phosphate is prescribed as an antitussive to suppress coughing, particularly when other cough medications have proven ineffective.

Dose:

Adults:

The dosing strengths are 15 milligrams, 30 milligrams, and 60 milligrams.

1. Pain:

• The recommended dosage of Codeine is 15 to 60 milligrams orally every four to six hours.

• Not to exceed 360 milligrams per day in the case of naive patients.

Dosing Considerations:

• Individuals with a history of opioid exposure might require higher doses of Codeine during the initial phase of treatment.

• Consider titration of the dose for pain relief. Hence, prescribe the lowest effective dosage for a brief period.

2. Cough (Off-Label)

• The recommended dosage for cough is 7.5 to 30 milligrams of Codeine orally every four to six hours Pro pre-nata (in the circumstances).

Dosing Considerations:

• Access is required for Naloxone on initiation and renewal of therapy.

• Hence, consider prescribing Naloxone based on the individual’s risk factors for overdose (history of opioid dependence or opioid use disorder, concomitant use of central nervous system (CNS) depressants, and prior opioid overdose), any presence of risk factors circumventing the appropriate pain management, household people including little ones, and another close contact at danger of overdose or accidental ingestion.

Hence, consult the patients and their caregivers with the following measures.

• Availability of the drug Naloxone for emergency care of overdosage of opioids.

• Measures to obtain Naloxone as authorized by the individual state of prescribing and dispensing guidelines.

Pharmacological Aspects of Codeine Phosphate

Mechanism of Action

Codeine phosphate exerts its analgesic effects through a complex mechanism of action involving the central nervous system. As an opioid analgesic, codeine is a prodrug, meaning it undergoes conversion into its active form, morphine, within the body. Once metabolized, morphine primarily binds to mu-opioid receptors in the brain and spinal cord. These receptors are part of the endogenous opioid system, which modulates pain perception. By binding to these receptors, codeine and its active metabolite morphine inhibit the transmission of pain signals and alter the brain’s response to pain stimuli. This modulation results in a reduction of the perception of pain and an overall analgesic effect. Additionally, opioids like codeine can have central nervous system depressant effects, contributing to side effects such as sedation.

Pharmacodynamics

The pharmacodynamics of codeine phosphate involves its interaction with opioid receptors in the central nervous system. Codeine is a prodrug, meaning it undergoes metabolism in the body to its active form, morphine. Morphine, in turn, acts as an agonist primarily at the mu-opioid receptors. These receptors are primarily located in the brain and spinal cord. Activation of mu-opioid receptors produces analgesia (pain relief) by modulating pain perception. Opioid receptor activation by codeine results in central nervous system depression. This can cause sedation, drowsiness, and a general calming effect. It also contributes to the analgesic properties of the drug.

Pharmacokinetics

Absorption:

• Codeine is well absorbed from the gastrointestinal (GI) tract.

• The maximum plasma concentration of Codeine phosphate is attained 60 minutes after the oral administration.

• It is determined that high-calorie food intake prior to 30 minutes of Codeine ingestion does not have any significant effect on the absorption of the drug.

Distribution:

• The presumed volume of distribution of Codeine is about three to six liters per kilogram.

• This value shows an extensive and substantial distribution of the Codeine into the tissues.

• The plasma binding capacity of Codeine is nearly seven to 25 percent.

Metabolism:

• About 70 to 80 percent of the administered dosage of Codeine undergoes well metabolization in the liver.

• This is achieved by the conjugation process with glucuronic acid to form codeine-6 glucuronide (C6G) and by means of the o-demethylation process forming morphine and N-demethylation forming nor-codeine.

• The major metabolite enzymes responsible for the glucuronidation of the Codeine to its corresponding metabolite codeine 6 glucuronide are UDP- glucuronosyltransferase (UGT) 2B4 and 2B7.

• Cytochrome P450 2D6 is the chief enzyme mediating the conversion of Codeine to morphine while P450 3A4 is the enzyme for transforming Codeine to nor-codeine.

• Therefore, the glucuronide metabolites of morphine are known to be morphine-3-glucuronide and morphine-6-glucuronide.

• Morphine and its metabolite morphine-6-glucuronide are determined to possess analgesic properties, especially in humans.

• Nevertheless, the analgesic activity of conjugated product CG6 in humans is not determined at this period.

• Morphine-3-glucuronide and nor-codeine are not regarded to have any analgesic effect.

Elimination:

• About 90 percent of the complete dosage of Codeine gets excreted by means of kidneys.

• Nearly ten percent of the drug Codeine gets excreted by the kidney in an unchanged form.

• Significant excretory products are generally found in the urine within six hours of administration.

• About 40 to 60 percent of the Codeine is excreted in conjugated or free form while five to 15 percent is free and conjugated morphine and 10 to 20 percent as free and conjugated nor-codeine.

Half-Life and Clearance:

• The plasma half-life period of Codeine and its respective metabolites is determined to be comparatively three hours.

• The renal clearance of Codeine is 183 ml min-1, according to a clinical study.

• It is known that renal impairment might relatively decrease the Codeine clearance.

Adverse Effects: Codeine can induce adverse effects in certain groups of people. The potential adverse effects of the drug Codeine are listed below.

Common (Greater Than 10 Percent):

• Drowsiness.

• Constipation.

Less Common (One to Ten Percent):

• Hypotension.

• Tachycardia or bradycardia.

• Dizziness.

• Confusion.

• Headache.

• Malaise.

• Lightheadedness.

• False perception of well-being.

• Malaise.

• Restlessness.

• Paradoxical central nervous system stimulation.

• Anorexia.

• Rashes.

• Urticaria.

• Xerostomia.

• Blurred vision.

• Weakness.

• Urethral spasm.

• Decreased urination.

• Increased values of liver function tests.

• Histamine release.

• Burning sensation at the injection site.

Rare (Less Than One Percent)

• Hypotension (decreased blood pressure) with intravenous use of Codeine.

• Seizures with substantial dosage.

• Respiratory depression.

• Anaphylactoid reactions in rare instances.

Post Marketing Reports:

• Severe hypotension.

• Neonatal opioid withdrawal syndrome.

• Potentially life-threatening respiratory depression.

• Adrenal insufficiency.

• A fatal condition associated with the ultra-rapid metabolizers of Codeine.

• Seizures.

• Euphoria.

• Dysphoria.

• Abdominal pain.

• Sweating.

• Pruritus.

• Anaphylaxis.

• Serotonin syndrome.

• Androgen insufficiency.

What Are the Contraindications of Codeine Phosphate?

The Codeine medication possesses several benefits attributing to pain and cold relief. Nevertheless, this drug is contraindicated in several conditions including the following.

• Hypersensitivity to Codeine and other drugs belonging to the same group.

• Presence of significant respiratory depression.

• Children less than 12 years of age.

• Acute or severe bronchial asthmatic disease in unmonitored settings or devoid of resuscitative equipment.

• For postoperative pain management in the case of children less than 18 years of age, especially those who had undergone surgical interventions like adenoidectomy and tonsillectomy.

• Concurrent usage of Codeine and monoamine oxidase inhibitors (MAOIs).

• Use of Monoamine oxidase inhibitors (MAOIs) within the last two weeks.

• In case of diagnosed or suspected gastrointestinal obstruction, such as paralytic ileus.

Warnings and Precautions:

Risk Evaluation and Mitigation Strategy (REMS) of Opioid Analgesics:

Any opioid or narcotic drug exposes individuals to the risk of opioid addiction, misuse, and abuse. This could eventually lead to opioid overdose and even death. Hence, assess the risk of individuals prior to the prescription and monitor for the development of distorted behaviors and conditions at regular intervals.

The Food and Drug Administration (FDA) has published a risk evaluation and mitigation strategy (REMS) to ensure the potential benefits of opioids outweigh the risks of abuse, misuse, and addiction.

Hence, healthcare providers are strictly encouraged to consider the following strategies.

• Complete the education program of REMS-compliant.

• Counsel both the patients and their caregivers with the prescription, safety profile, storage, serious complications, and disposal of the medication.

• Accentuate to the patients and their family members the significance of reading and understanding the medication guideline every time it is issued.

• Consider other potential equipment and precautions to improve the safety of patients, households, and the community.

Life-Threatening Respiratory Depression:

• Severe, lethal, or fatal respiratory depression might occur with Codeine therapy.

• Hence, evaluate for respiratory distress, specifically during the initial phase of treatment and following any dosage modification.

• Respiratory depression and death have been resourced after surgical procedures like tonsillectomy or adenoidectomy in individuals that manifested to be ultra-rapid metabolizers attributable to CYP2D6 polymorphism.

Rapid Metabolism of Codeine and the Risk Factors for Respiratory Depression in Children:

• Life-threatening lethal respiratory depression and death have occurred in the pediatric population who received Codeine.

• However, most of the reported cases resulted following adenoidectomy or tonsillectomy.

• Many of the children manifested the evidence of being rapid metabolizers of Codeine because of cytochrome CYP P450 2D6 polymorphism.

• It is recommended to avoid Codeine use in adolescents of 12 to 18 years of age who possess other risk factors that could increase the sensitivity to Codeine effects of respiratory depression.

Drug Interactions With Those Affecting Cytochrome P450 Isoenzymes:

• The effects associated with the concomitant use of the discontinuation of CYP3A4 inhibitors, CYP3A4 inducers, and CYP2D6 inhibitors with Codeine phosphate are intricate.

• Hence, those combinations require conscientious monitoring and consideration.

Neonatal Opioid Withdrawal Syndrome:

• Prolonged Codeine treatment during pregnancy could lead to neonatal opioid withdrawal syndrome.

• This condition can turn out to be life-threatening if not addressed and treated.

• Advise the women about the risk of neonatal opioid withdrawal syndrome and ensure the utilization of appropriate treatment if opioid use is required for the long term in pregnancy.

Concomitant Use With CNS Depressants and Benzodiazepines:

• Concomitant use of opioids with central nervous system (CNS) depressants and benzodiazepines, including alcohol, might lead to critical sedation, respiratory distress, coma, and even death.

• Reverse the concomitant prescription of opioids with these drugs in individuals for whom the alternative or adjunct treatment options are inadequate.

• It is also critical to limit the frequency and dosage to the minimum required.

• Consider monitoring the patients for any signs and symptoms of sedation, coma, and respiratory depression.

Drug Interactions of Codeine Phosphate

The following drug interactions and their corresponding effects have been determined.

• Monoamine Oxidase Inhibitors (MAOI): Concomitant use of Codeine phosphate and MAOIs are usually avoided due to the potential risk of depression and excitation.

• Benzodiazepines and Other CNS Depressants: Concomitant use might result in respiratory depression, sedation, coma, and even death.

• Anticholinergics: There can be an increased risk of severe constipation, resulting in paralytic ileus and urinary retention.

• Hypnotics and Anxiolytics: This gives an enhanced sedative effect with a greater risk of respiratory depression.

• Anti-Diarrheal Drugs: There can be an increased risk of severe constipation.

• Metoclopramide and Domperidone: This influences the gastrointestinal tract, manifesting an antagonist effect of GI activity.

• Anesthetics: This shows a significant sedative and hypotensive effect.

• Antipsychotics: The concomitant use of antipsychotics, including Phenothiazine, shows an enhanced hypotensive and sedative effect.

• Tricyclic Antidepressants: This gives an enhanced sedative effect.

• Quinidine: Concomitant use of Codeine with Quinidines typically results in reduced analgesic effect.

• Opioid Antagonists: This might precipitate the withdrawal symptoms associated with the drug Codeine phosphate.

• Antihypertensive Drugs: This group of drugs manifests a substantial hypotensive effect.

• Ritonavir: This might increase the plasma concentration of opioid analgesics.

• Cimetidine: Use of Cimetidine with Codeine potentially inhibits the metabolism process of opioid analgesics, resulting in increased plasma concentration of Codeine.

• Mexiletine: A combination of Codeine and Mexiletine delays the overall absorption of Mexiletine.

• Ciprofloxacin: It is recommended to avoid opioids as premedication since they decrease the plasma concentration of Ciprofloxacin.