About all

What is acetaminophen with codeine. Acetaminophen with Codeine: Understanding the Risks and Symptoms of Overdose

What are the signs of acetaminophen with codeine overdose. How to respond to a suspected overdose. What treatment options are available for acetaminophen with codeine poisoning. Why is prompt medical attention crucial in cases of overdose.

Содержание

What is Acetaminophen with Codeine and Its Uses?

Acetaminophen with codeine, commonly known as Tylenol #3, is a powerful prescription pain medication. This combination drug contains acetaminophen (Tylenol), an over-the-counter pain reliever and fever reducer, along with codeine, an opioid analgesic. It’s primarily used to treat severe pain that doesn’t respond well to other painkillers.

The addition of codeine to acetaminophen enhances the pain-relieving effects, making it more potent than acetaminophen alone. However, this increased potency also comes with a higher risk of side effects and potential for abuse.

When is Acetaminophen with Codeine Prescribed?

  • Severe acute pain (e.g., post-surgical pain)
  • Chronic pain conditions unresponsive to other treatments
  • Cancer-related pain
  • Severe dental pain

Healthcare providers carefully consider the risks and benefits before prescribing this medication, as it carries a risk of dependence and other serious side effects.

Recognizing the Symptoms of Acetaminophen with Codeine Overdose

An overdose of acetaminophen with codeine can be life-threatening. Recognizing the signs early is crucial for timely intervention. Symptoms can affect various body systems:

Respiratory System Effects

  • Shallow breathing
  • Slow and labored breathing
  • Respiratory arrest (stopped breathing)

Codeine, being an opioid, can significantly depress respiratory function, leading to potentially fatal outcomes if not addressed promptly.

Cardiovascular and Neurological Impacts

  • Low blood pressure
  • Coma or lack of responsiveness
  • Seizures
  • Extreme drowsiness or stupor

These symptoms indicate severe central nervous system depression, a hallmark of opioid overdose.

Gastrointestinal and Hepatic Symptoms

  • Nausea and vomiting
  • Stomach and intestinal spasms
  • Liver failure (due to acetaminophen toxicity)

Acetaminophen overdose can cause severe liver damage, which may not be immediately apparent but can be life-threatening.

Immediate Response to Suspected Overdose

If you suspect an acetaminophen with codeine overdose, taking immediate action is critical:

  1. Call emergency services (911 in the US) immediately.
  2. Contact the Poison Help hotline (1-800-222-1222 in the US) for expert guidance.
  3. Do not induce vomiting unless specifically instructed by medical professionals.
  4. Gather essential information: patient’s age, weight, medication details, time and amount of ingestion.
  5. If possible, bring the medication container to the hospital.

Time is of the essence in overdose situations. Prompt medical intervention can significantly improve outcomes and prevent long-term complications or fatality.

Medical Treatment for Acetaminophen with Codeine Overdose

Upon arrival at a medical facility, healthcare providers will initiate a comprehensive treatment plan:

Initial Assessment and Stabilization

  • Vital sign monitoring (temperature, pulse, breathing rate, blood pressure)
  • Oxygen administration and respiratory support if needed
  • Intravenous fluid administration

Diagnostic Procedures

  • Blood and urine tests to assess drug levels and organ function
  • Chest X-rays and ECG to evaluate cardiopulmonary status
  • CT scan of the brain if neurological symptoms are present

Specific Treatments

Treatment focuses on counteracting the effects of both acetaminophen and codeine:

  • Administration of activated charcoal to absorb remaining drugs in the stomach
  • N-acetyl cysteine (NAC) as an antidote for acetaminophen toxicity
  • Naloxone to reverse opioid effects if severe respiratory depression is present
  • Supportive care, including IV fluids and electrolyte management

The timely administration of NAC is crucial in preventing or minimizing liver damage from acetaminophen toxicity.

Long-term Prognosis and Recovery

The outcome of an acetaminophen with codeine overdose largely depends on several factors:

  • The amount of medication ingested
  • Time elapsed between ingestion and treatment
  • Presence and severity of organ damage, particularly to the liver
  • Overall health status of the patient

With prompt and appropriate treatment, many patients recover fully within 24 to 48 hours. However, cases involving significant liver damage may require more extended recovery periods and potentially long-term management.

Potential Long-term Complications

  • Chronic liver dysfunction
  • Kidney damage
  • Neurological deficits (in cases of prolonged oxygen deprivation)

Follow-up care and monitoring are essential to assess for any lingering effects and manage potential complications.

Preventing Acetaminophen with Codeine Overdose

Prevention is key in avoiding the potentially devastating consequences of overdose. Here are some crucial steps to minimize risks:

Proper Medication Management

  • Always follow prescribed dosages and schedules
  • Never combine with alcohol or other central nervous system depressants
  • Be aware of all medications containing acetaminophen to avoid unintentional overdose
  • Store medications securely, out of reach of children and others

Education and Awareness

Understanding the risks associated with acetaminophen and codeine is crucial. Patients should be educated about:

  • Signs of potential overdose or adverse reactions
  • The importance of not sharing prescription medications
  • The risks of developing tolerance and dependence with prolonged use

Regular Medical Follow-up

Maintaining open communication with healthcare providers is essential. Regular check-ups allow for:

  • Monitoring of medication effectiveness and side effects
  • Adjusting treatment plans as needed
  • Addressing any concerns or questions about medication use

Alternative Pain Management Strategies

Given the risks associated with acetaminophen and codeine, exploring alternative pain management strategies can be beneficial:

Non-Opioid Medications

  • NSAIDs (e.g., ibuprofen, naproxen)
  • Topical analgesics
  • Antidepressants or anticonvulsants for certain types of pain

Non-Pharmacological Approaches

  • Physical therapy and exercise
  • Cognitive-behavioral therapy
  • Acupuncture and massage
  • Mindfulness and relaxation techniques

These alternatives may provide effective pain relief with potentially fewer risks and side effects compared to opioid medications.

The Role of Healthcare Providers in Safe Opioid Use

Healthcare providers play a crucial role in ensuring the safe use of acetaminophen with codeine:

Careful Prescribing Practices

  • Thorough patient assessment before prescribing
  • Consideration of alternative pain management strategies
  • Clear instructions on proper use and potential risks

Ongoing Monitoring

Regular follow-ups allow providers to:

  • Assess medication effectiveness
  • Monitor for signs of dependence or misuse
  • Adjust treatment plans as needed

Patient Education

Providers should educate patients on:

  • Proper medication storage and disposal
  • Signs of potential overdose or adverse reactions
  • The importance of not sharing medications

By fostering open communication and providing comprehensive education, healthcare providers can significantly reduce the risks associated with acetaminophen and codeine use.

Legal and Regulatory Considerations

The use and distribution of acetaminophen with codeine are subject to strict regulations due to its potential for abuse and overdose:

Prescription Requirements

  • Classified as a Schedule III controlled substance in the United States
  • Requires a valid prescription from a licensed healthcare provider
  • Limitations on refills and prescription duration

Monitoring Programs

Many jurisdictions have implemented prescription drug monitoring programs (PDMPs) to track the dispensing of controlled substances, including acetaminophen with codeine. These programs aim to:

  • Prevent doctor shopping and drug diversion
  • Identify patterns of misuse or overprescribing
  • Improve overall patient safety

Manufacturer Responsibilities

Pharmaceutical companies producing acetaminophen with codeine products are required to:

  • Provide clear labeling and safety information
  • Implement risk evaluation and mitigation strategies (REMS)
  • Report adverse events to regulatory agencies

These regulatory measures are designed to balance the medical benefits of acetaminophen with codeine against its potential risks and societal impacts.

Acetaminophen and codeine overdose: MedlinePlus Medical Encyclopedia

Acetaminophen (Tylenol) and codeine is a prescription pain medicine. It is an opioid pain reliever used only for pain that is severe and is not helped by other types of painkillers.

Acetaminophen and codeine overdose occurs when someone takes more than the normal or recommended amount of this medicine, either by accident or on purpose.

This is for information only and not for use in the treatment or management of an actual overdose. DO NOT use it to treat or manage an actual overdose. If you or someone you are with overdoses, call the local emergency number (such as 911), or the local poison control center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere in the United States.

Acetaminophen combined with codeine

Acetaminophen with codeine is commonly sold under the name Tylenol #3.

Below are symptoms of an overdose of acetaminophen combined with codeine in different parts of the body.

AIRWAYS AND LUNGS

  • Shallow breathing
  • Slow and labored breathing
  • Stopped breathing

EYES

  • Very small pupils

HEART AND BLOOD VESSELS

  • Low blood pressure

NERVOUS SYSTEM

  • Coma (lack of responsiveness)
  • Convulsions (seizures)
  • Drowsiness
  • Stupor (lack of alertness)

SKIN

  • Bluish skin (fingernails and lips)
  • Cold, clammy skin
  • Heavy sweating

STOMACH AND GASTROINTESTINAL SYSTEM

  • Nausea and vomiting
  • Spasms of the stomach and intestines
  • Liver failure

URINARY SYSTEM

  • Kidney failure

Seek medical help right away. This type of overdose can cause death. Do not make the person throw up unless poison control or a health care provider tells you to.

Have this information ready:

  • Person’s age, weight, and condition
  • Name of the medicine and the strength of the medicine (if known)
  • Time it was swallowed
  • Amount swallowed
  • If the medicine was prescribed for the person

Your local poison control center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere in the United States. This national hotline number will let you talk to experts in poisoning. They will give you further instructions.

This is a free and confidential service. All local poison control centers in the United States use this national number. You should call if you have any questions about poisoning or poison prevention. It does NOT need to be an emergency. You can call for any reason, 24 hours a day, 7 days a week.

Take the container with you to the hospital, if possible.

The provider will measure and monitor the person’s vital signs, including temperature, pulse, breathing rate, and blood pressure. Symptoms will be treated. The person may be admitted to the hospital and may receive:

  • Activated charcoal
  • Blood and urine tests
  • Breathing support, including oxygen, and a tube through the mouth into the lungs and breathing machine
  • Chest x-ray
  • CT scan (advanced imaging) of the brain
  • ECG (electrocardiogram, or heart tracing)
  • Intravenous fluids (IV or through a vein)
  • A laxative
  • Medicine to reverse the effects of the poison and treat symptoms

If there is a high level of acetaminophen in the blood, the person will be given N-acetyl cysteine (NAC) as soon as possible.

This drug is called an antidote. It counteracts the effects of the acetaminophen. Without it, deadly liver failure may occur. Several doses may be required until the blood level drops to a safer value.

How well a person does, depends on the amount of medicine swallowed and how quickly the treatment was received. The faster a person gets medical help, the better the chance for recovery. If breathing has been depressed for a long period before treatment, brain injury may occur.

If an antidote can be given, recovery from an acute overdose often occurs within 24 to 48 hours. Recovery takes longer, if the liver is affected, and the person may not fully recover.

Tylenol #3 overdose; Phenaphen with codeine overdose; Tylenol with codeine overdose

Aronson JK. Opioid receptor agonists. In: Aronson JK, ed. Meyler’s Side Effects of Drugs. 16th ed. Waltham, MA: Elsevier; 2016:348-380.

Hatten BW. Aspirin and nonsteroidal agents. In: Walls RM, Hockberger RS, Gausche-Hill M, eds. Rosen’s Emergency Medicine: Concepts and Clinical Practice. 9th ed. Philadelphia, PA: Elsevier; 2018:chap 144.

Hendrickson RG, McKeown NJ. Acetaminophen. In: Walls RM, Hockberger RS, Gausche-Hill M, eds. Rosen’s Emergency Medicine: Concepts and Clinical Practice. 9th ed. Philadelphia, PA: Elsevier; 2018:chap 143.

Nikolaides JK, Thompson TM. Opioids. In: Walls RM, Hockberger RS, Gausche-Hill M, eds. Rosen’s Emergency Medicine: Concepts and Clinical Practice. 9th ed. Philadelphia, PA: Elsevier; 2018:chap 156.

Updated by: Jacob L. Heller, MD, MHA, Emergency Medicine, Emeritus, Virginia Mason Medical Center, Seattle, WA. Also reviewed by David Zieve, MD, MHA, Medical Director, Brenda Conaway, Editorial Director, and the A.D.A.M. Editorial team.

Acetaminophen and Codeine Phosphate | Pain Management for Children

(a-seet-a-MIN-oh-fen) (KOH-deen)

Acetaminophen and codeine (Tylenol® with Codeine Phosphate) is a combination medicine made up of codeine (an opioid medication) and acetaminophen (a non-opioid medication) and is used to relieve pain. Ask the care team (providers and nurses) about your child’s plan. This plan may include other ways such as deep breaths to relax or distract to help keep your child’s mind off the pain.

What Is General Safety Information When Taking Acetaminophen and Codeine Phosphate?

Things to know before you begin taking this medicine:

This medication can cause very serious breathing problems. The following groups of children are more at risk for serious breathing problems:

  • Children under the age of 12 years old.
  • Children between 12 and 18 years old who are very overweight or lung or breathing problems including sleep apnea or any lung disease.
  • Children between 12 and 18 years old who have had a surgery to remove their tonsils or adenoids.

Talk to your doctor before starting this medication if your child is included in one of the groups listed above.

Take the medicine exactly as ordered. Your child should take this medication no more than five times in one day.

Read the insert that comes with the medicine to learn more about the how it works and any possible side effects.

When taking this medication, do not give any other medicines with acetaminophen (Tylenol). More than the safe dose of acetaminophen could cause serious liver damage.

Tell your provider about other medicine your child is taking. Some medicines may need to be changed.

  • Do not take over-the-counter (OTC) medicines without talking to your provider.
  • Do not take the medicine unless it was prescribed for you.
  • Do not share or give the medicine to anyone else.
  • Do not use medicines after the expiration date on the bottle/package.
  • Do not take these medicines while pregnant.
Things to know while taking this medicine:

Watch your child for serious side effects especially after the first dose. Acetaminophen with codeine may decrease how often and deeply your child takes a breath.

Your child is at risk to fall while taking this medicine. Support them when they walk and crawl. Help them when going up and down the stairs.

  • Do not climb, bike or play sports.
  • Do not give this medicine if your child is too sleepy or difficult to arouse (wake up).
  • Do not drive or operate any heavy machines, or make important decisions.
  • Do not drink alcohol or use marijuana while taking this medicine.
  • Do not take other medicines that can cause sleepiness unless you have talked to the doctor and are told to do so.
  • For opioids prescribed for long-term use, do not stop those medicines without talking to your provider.

Keep track of (count) how much medicine you have so you know if someone else is taking the medicine.

What Are Side Effects of Acetaminophen and Codeine Phosphate?

Side effects may include:

  • Feeling sleepy
  • Dizziness
  • Itching
  • Nausea (upset stomach), vomiting (throwing up)
  • Constipation (trouble pooping), trouble peeing
  • Hallucinations (not making sense when they talk)
  • Slowed breathing – This is the most serious side effect; it usually occurs right after taking the opioid medicine.

When Should You Call Your Child’s Provider?

Call your child’s provider if:

  • Your child has any unusual, long lasting, or serious side effects.
  • The current medicine or amount of medicine does not reduce severe pain.

When to Call 911

Call 911 if person who took the medicine becomes:

  • Too sleepy or trouble waking up
  • Does not respond to your voice
  • Trouble breathing

Call the Drug and Poison Information Center if the person who took the drug is still awake and alert at 513-636-5111 or 1-800-222-1222.

What Is Safe Medicine Storage and Disposal?

Storage
  • Lock up opioid medicines in a safe place.
  • Keep medicine in original package.
  • Keep track of how much medicine you have. Count it.
  • Always use a child-resistant cap.
  • Relock the cap after each use.
  • Keep the medicine away from children and animals.
Disposal

Dispose of unused opioid medicines right away. Do not save the medicine for future use. This avoids possible misuse, abuse and intake by accident.

  • Visit Drugs@FDA for exact disposal of the medicine your child is taking.
  • Call your local pharmacy to see if they have a drug drop off site.
  • If a drug drop off site is not readily available, flush the unused opioid medicine down the toilet.

What Are Additional Risks When Taking Acetaminophen and Codeine Phosphate?

Tolerance / Dependence

Those who take opioids for a long period of time can develop a tolerance to them. This means they may need more opioid for the same pain relief.

Withdrawal:

Those who take opioids for a long period of time and suddenly stop taking these medicines may have withdrawal symptoms. This may happen after becoming tolerant or dependent.

Symptoms of withdrawal:

  • Agitation or being anxious
  • Sweatiness
  • Palpitations (fast heart beat)
  • Shortness of breath
  • Diarrhea
  • Nausea (upset stomach), vomiting (throwing up)
  • Goose bumps
Addiction

Long-term use of opioid medicines can be addictive. The goal of the care team is to:

  • Take care of the severe pain
  • Use the lowest amount of medicine that works well
  • Use for the shortest amount of time

It is very rare for a child to become addicted to pain relief medicine.

It is best to talk to your provider if you have concerns about this due to the child or a family member with addiction problems.

Studies in adults (without cancer pain) have shown that opioid use for five days can increase the risk for addiction.

Opioid medicines are listed by the DEA (Drug Enforcement Agency) as controlled substances. These medications are regulated for safety because of their side effects and risk of addiction.

Codeine + Paracetamol instructions for use: indications, contraindications, side effects – description Codeine + Paracetamol Tablets (17649)

💊 Codeine + Paracetamol

✅ Codeine + Paracetamol

Keep for yourself

Search for analogues

Interaction

Description of the active ingredients of the preparation

Codeine + Paracetamol
(Codeine+Paracetamol)

The scientific information provided is general and cannot be used to make decisions.
decisions about the use of a particular drug.

Update date: 2017.06.05

Marketing authorization holder:

MOSCOW ENDOCRINE PLANT, FSUE
(Russia)

ATX code:

N02BE51

(Paracetamol in combination with drugs other than psycholeptics)

Active substances

  • paracetamol
    (paracetamol)
    Rec.INN
    WHO registered
  • codeine
    (codeine)
    Ph. Eur.
    European Pharmacopoeia

Dosage form

Codeine + Paracetamol

Tab. 500 mg + 8 mg: 20 pcs.

reg. No.: LSR-004677/07
from 11.12.07
– Indefinitely

Release form, packaging and composition
Codeine + Paracetamol

10 pcs. – cellular contour packings (2) – packs of cardboard.

Clinical and pharmacological group:

Spasmoanalgesic

Pharmacotherapeutic group:

Analgesic opioid + analgesic non-narcotic drug

Pharmacological action

Combination drug.

Paracetamol – antipyretic analgesic. It has analgesic, antipyretic and weak anti-inflammatory action. The mechanism of action is associated with inhibition of prostaglandin synthesis, with a predominant effect on the thermoregulatory center in the hypothalamus.

Codeine has a central antitussive effect (by suppressing the excitability of the cough center), as well as an analgesic effect due to the excitation of opiate receptors in various parts of the central nervous system and peripheral tissues, leading to stimulation of the antinociceptive system and a change in the emotional perception of pain. To a lesser extent than morphine, it depresses respiration, less often causes miosis, nausea, vomiting and constipation (activation of opioid receptors in the intestine causes relaxation of smooth muscles, decreased peristalsis and spasm of all sphincters).

Duration of analgesic action – 4 hours, antitussive – 4-6 hours.

Pharmacokinetics

Paracetamol is rapidly and completely absorbed from the small intestine. C max in the blood is observed 15-20 minutes after ingestion. Systemic bioavailability is determined by first pass metabolism and, depending on the dose, ranges from 70% to 90%. Paracetamol is rapidly distributed throughout all tissues of the body and has a T 1/2 paracetamol – approximately 2 hours. Paracetamol is metabolized in the liver and excreted in the urine in the form of glucuronides and sulfate compounds (> 80%).

Codeine is rapidly absorbed from the gastrointestinal tract after oral administration. Communication with plasma proteins – 30%. C max is reached in 2-4 hours. Metabolized in the liver to active metabolites; the CYP 2D6 isoenzyme takes part in the metabolism of the drug. 10% by demethylation passes into morphine. It is excreted by the kidneys (5-15% unchanged and 10% as morphine and its metabolites) and with bile. T 1/2 – 2.5-4 hours

Indications of the active substances of the drug

Codeine + Paracetamol

Pain syndrome of mild to moderate severity (migraine, headache and toothache, neuralgia, radicular syndrome, arthralgia, injuries of the musculoskeletal system).

Symptomatic treatment of colds, SARS, influenza (as an antipyretic and antitussive).

Open list of ICD-10 codes

G43 Migraine
J06.9 Acute infection of the upper respiratory tract, unspecified
J10 Influenza due to identified seasonal influenza virus
K08.8 Other specified changes in teeth and their supporting apparatus (including toothache)
M25.5 Joint pain
M54.1 Radiculopathy
M54.3 Sciatica
M54. 4 Lumbago with sciatica
M79.1 Myalgia
M79.2 Neuralgia and neuritis, unspecified
R50 Fever of unknown origin
R51 Headache
R52.0 Acute pain
R52.2 Other persistent pain (chronic)
T14.3 Dislocation, sprain and strain of the capsular-ligamentous apparatus of a joint of an unspecified area of ​​the body

Dosing regimen

The method of administration and dosing regimen of a particular drug depends on its form of release and other factors. The optimal dosage regimen is determined by the doctor. Compliance of the dosage form of a particular drug with indications for use and dosing regimen should be strictly observed.

For oral administration. A single dose can be taken every 4 hours, but not more than 8 times / day.

As an antipyretic, it is not recommended to take more than 3 days without consulting a doctor, and as an analgesic – more than 5 days.

Side effects

From the side of the nervous system: often – drowsiness; sometimes – blurred vision, double vision, tiredness, headache, dizziness, convulsions, involuntary muscle contractions or muscle rigidity, hallucinations, nightmares, depression, feeling unwell, feeling of euphoria.

From the digestive system: often – constipation; sometimes – nausea, vomiting, dry mouth, pain in the epigastric region, anorexia.

Allergic reactions: sometimes – skin rash, itching, angioedema.

From the side of the cardiovascular system: sometimes – facial flushing, bradycardia / tachycardia, arterial hypotension.

From the side of the hematopoietic system: rarely – anemia, thrombocytopenia, methemoglobinemia.

Other: sometimes – sweating, shortness of breath; rarely – violations of the liver and kidneys.

With prolonged use, its effectiveness decreases. It can also be addictive due to codeine. When treatment is stopped, symptoms of restlessness and irritability may occur.

Contraindications for use

Severe renal failure, severe liver failure; violation of hematopoiesis; respiratory disorders due to depression of the respiratory center; bronchial asthma; pulmonary insufficiency; heart failure; increased intracranial pressure; traumatic brain injury in history; acute abdominal pain of unknown etiology; risk of functional intestinal obstruction; taking drugs containing paracetamol; taking MAO inhibitors within the last 14 days; alcoholism; pregnancy; lactation period; children’s age up to 12 years; hypersensitivity to the components of the combination.

Precautions

Arterial hypotension, arrhythmia, cholelithiasis, myasthenia gravis, adrenal disease, prostatic hyperplasia, convulsions, drug dependence (including history), use in elderly patients.

Use during pregnancy and lactation

Use during pregnancy and lactation (breastfeeding) is contraindicated.

Use in hepatic dysfunction

The drug is contraindicated for use in impaired liver function

The drug is used for impaired renal function

The drug is contraindicated for use in impaired renal function

Use in children

The drug is contraindicated for use in children and adolescents under 18 years of age

Special Directions

Avoid co-administration with other medicines containing paracetamol and expectorants.

Do not exceed the recommended dose.

Influence on the ability to drive vehicles and mechanisms

During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug interactions

Long-term regular use of paracetamol enhances the anticoagulant effect warfarin and other coumarins , which may increase the risk of bleeding; a single dose does not have a significant effect.

Codeine enhances the effect of ethanol on psychomotor function.

Microsomal oxidation inducers (barbiturates, antiepileptic drugs, rifampicin and ethanol) increase the risk of hepatotoxicity.

Simultaneous administration with MAO inhibitors causes ataxia, hypotension, paresthesia, disturbance of accommodation.

CNS depressant drugs increase the sedative effect and depress the respiratory center.

Oral contraceptives reduce paracetamol metabolism by 20-30%.

Codeine may slow down the absorption of mexiletine and quinidine, thus reducing their antiarrhythmic effect.

Taking metoclopramide, cisapride or domperidone may increase the rate of absorption of paracetamol.

Colestyramine reduces the absorption of paracetamol .

Keep

If you want to place a link to the description of this drug – use this code

Codeine + Paracetamol . Description of the drug in the reference book Vidal.

Codeine-containing drugs: should they be used?

In May 2012, a disturbing article was published in Pediatrics, the official publication of the American Academy for Pediatrics, with the following caption: “In May 2009We reported the death of a toddler who received codeine after an adenotonsillectomy performed to combat obstructive sleep apnea. The child turned out to be an ultra-fast metabolizer for cytochrome P4502D6 (CYP2D6).” Given the relevance of the topic, we conducted a review of studies to evaluate the clinical efficacy and safety of codeine combination preparations in modern pediatric and therapeutic practice.

Codeine is a prodrug of morphine. The mechanism of action of codeine is that the morphine formed from it binds to the μ- and κ-opioid receptors of the central nervous system, which contributes to the analgesic effect.

Codeine is used for mild to moderate acute and chronic pain in neonates, older children and adults, especially for postoperative pain. At the same time, codeine is used both as monotherapy and in combination with non-narcotic analgesics (paracetamol), nonsteroidal anti-inflammatory drugs (NSAIDs: ibuprofen, acetylsalicylic acid) and antihistamines (diphenhydramine).

Codeine also has antitussive and antidiarrheal effects.

PROBLEMS OF CLINICAL EFFICACY OF CODEINE

COMBINATION DRUGS

Codeine is most often combined with paracetamol. However, in order to judge how appropriate this is, it is necessary to assess how paracetamol / codeine will be more effective than paracetamol monotherapy.

Small additive efficacy in adult clinical studies

There have been many studies in adults comparing paracetamol/codeine combination with paracetamol. Their findings have been summarized in 2 systematic reviews, which are listed below. The conclusions that they allow to draw can be formulated as follows: the combination of paracetamol / codeine eliminates pain more effectively than paracetamol monotherapy. However, the increase in effect due to the addition of codeine to paracetamol was insignificant.

Codeine is used for mild to moderate acute and chronic pain

B A systematic review by A.J.M. de Craen et al. included 24 randomized and/or controlled trials [1]. Its authors concluded that the differences in analgesic effect between paracetamol/codeine combination and paracetamol monotherapy were statistically significant but not significant. The magnitude of the increase in the analgesic effect due to the addition of codeine was only 5%.

It is interesting to note that another systematic review showed that the use of codeine in addition to paracetamol prolongs the effect of the latter by 1 hour [2]. However, the significance of this factor in the context of the low additional effectiveness of codeine and the possible risk of side effects has not been analyzed.

SAFETY ISSUES IN CODEINE COMBINED PREPARATIONS

Codeine causes the same number of side effects and with the same severity as other opioids at equipotent doses

Side effects caused by codeine are divided into more and less severe [3, 4]. More severe side effects include the development of severe respiratory depression, slow heart rate, weak pulse, hypotension, confusion, hallucinations, seizures, and difficulty urinating. Less severe side effects include sedation, dizziness, miosis, dry mouth, nausea, vomiting, abdominal pain, constipation, sweating, and minor skin rashes.

Codeine began to be widely used as an analgesic, especially in children, due to the fact that it was believed to cause fewer or less side effects than other opioids. However, the results of the study do not support this view. In particular, codeine and morphine have been shown to cause the same number of side effects with the same severity at equipotent doses. Examples of some of them are given in the table [5, 6].

Table Comparison of some side effects caused by codeine and morphine at equipotent doses
Side effects Codeine Morphine
Respiratory depression ** **
Seizures * *
Sedation *** ***
Dizziness ** **
Nausea and vomiting ** **
Constipation *** **

Despite the lack or decrease in clinical effectiveness in terms of pain management, side effects associated with taking codeine can be observed over a certain period. Since even without being transformed into morphine, codeine molecules themselves lead to the development of side effects.

Genetic polymorphism of cytochrome CYP2D6 is the cause of the variability of the clinical effects of codeine: from complete lack of effect to its excessive severity with a possible fatal outcome

The ideal option when prescribing codeine would be to conduct genetic testing of patients in order to exclude the use of this drug by slow and ultra-rapid metabolizers. However, today such tests are available only for scientific institutions [7].

Given the above, the researchers concluded that the introduction of codeine into the preparation should be regarded as a complicated and unreliable route for delivering morphine into the body. Considering that at equipotent doses codeine and morphine lead to the same side effects (that is, codeine does not have an advantage over morphine in terms of safety profile), you can use the advice given back in 1964 years, – codeine should be avoided, taking less than 10 mg of morphine instead [5].

Interaction with other drugs may increase or decrease the activity of codeine

Even at normal doses, codeine is capable of cumulating

Studies have shown that repeated administration of codeine leads to accumulation of morphine in the body. On the one hand, this can contribute to an increase in the clinical efficacy of the drug, on the other hand, it can lead to an increase in the number of its side effects [5].

Dependence caused by codeine can lead to the development of toxic effects due to excessive use of those drugs with which it is combined

Codeine, like other opioids, is addictive and physically addictive. At the same time, the patient begins to look for possible ways to acquire it, and, as a rule, combination preparations of codeine become the source of such. In this case, the intake of high doses of codeine is combined with the use of high doses of the substance with which it is combined.

Reference is made to a report describing 77 patients with dependence on codeine, which is part of the combined preparations. Within 2.5 years, they averaged 50 tablets daily. Of the 77 patients, 39 had gastrointestinal bleeding or perforation, 7 had renal failure, and 5 had severe hypokalemia.

In patients with kidney and liver disease, the dose of codeine should be reduced

There are reports that in patients with moderate renal dysfunction the dose of codeine should be reduced by 25%, with severe renal dysfunction by 50%. Such measures can prevent the development of severe opioid intoxication [3].

There are no specific recommendations for dosing codeine in patients with hepatic dysfunction, however, researchers note that the dose of the drug and the frequency of its administration should still be reduced [3].

CODEINE IS GRADED FROM CLINICAL USE

In 2010, WHO retained codeine in the list of essential medicines used to control pain in children (WHO Model List of Essential Medicines for Children, 2010; WHO Model Formulary for Children, 2010). However, later the WHO working group that created the WHO Guidelines on Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses, having studied all available information about codeine, excluded it from the treatment algorithms. This document is currently undergoing the approval process. The development of the guidelines was the basis for raising the issue of deleting codeine from the aforementioned WHO list of essential medicines. This issue is also under consideration.

ARE THERE ALTERNATIVES FOR CODEINE COMBINATIONS?

In 1996, the WHO published the so-called three-step ladder, which offers a 3-step approach to the fight against pain in oncological pathology [8]. Subsequently, this approach began to be used for all types of pain (figure). Non-narcotic analgesics or NSAIDs are prescribed on the first rung of the ladder, a weak opioid (such as coden) is added to the second rung, and a strong opioid (such as morphine) is used instead of a weak opioid on the third rung.

Drawing

Ibuprofen is as effective as codeine combinations, but ibuprofen is well tolerated

Since there is a trend towards eliminating codeine from current treatment algorithms, the above ladder will, in fact, become two-step (the second step will fall out). Therefore, on the first rung of the ladder, it is necessary to use those non-narcotic analgesics or NSAIDs, the effectiveness of which is comparable to that of codeine combination preparations, and on the last rung, strong opioids in low doses (for example, morphine). It is this approach that we will adhere to in the subsequent presentation of the results of modern research.

Most studies show ibuprofen to be as effective as codeine combinations, with fewer side effects

In clinical studies in children and adults, ibuprofen has been shown to be as effective as codeine combination preparations, but ibuprofen is significantly better tolerated. In this regard, most researchers recommend the use of ibuprofen instead of combination preparations of codeine (for example, paracetamol with codeine).

In studies involving children, ibuprofen has been shown to be as effective and better tolerated as compared to the combination of paracetamol with codeine in eliminating pain after tonsillectomy [3], hand fractures [9], various traumatic injuries of the limbs [10] and in general any type of musculoskeletal pain [11].

Interestingly, 1 long-term and 2 short-term randomized controlled trials concluded that ibuprofen should be used instead of paracetamol with codeine in children with hand fractures. Ibuprofen reduces pain to the same extent as paracetamol/codeine and is better tolerated.

In adults, the fact that ibuprofen is not inferior in effectiveness to paracetamol and codeine has been demonstrated in the elimination of perineal pain after childbirth [12]. In addition, similar results with NSAIDs compared with paracetamol/codeine have been shown for postoperative pain after laparotomy [13] and the elimination of various types of pain in dentistry [14].

Which narcotic analgesic should be used instead of codeine?

If NSAIDs such as ibuprofen fail to relieve pain, strong opioids, but at low doses (e.g. morphine) are recommended instead of codeine [8].

CONNECTIONS

A large number of studies have demonstrated low additive efficacy of codeine compared to those drugs with which it was combined. In addition, the clinical effect of codeine combination preparations was often unpredictable (can vary from complete lack of effect to death). At the same time, the prescription of codeine led to the development of additional side effects, cumulation, addiction, dependence, and interaction with other drugs.

Data accumulated in recent years allow NSAIDs such as ibuprofen to be used as a first step in pain management instead of codeine-containing combinations. If the obtained analgesic effect is insufficient, then in addition to NSAIDs, strong opioids (for example, morphine) should be taken, but in low doses.

Andrey Vladimirovich Savustyanenko,
Associate Professor of the Department of Pharmacology
Donetsk National Medical University. Maxim Gorky

The article is published in an abbreviated form

Literature

1. de Craen A.J.M., Giulio G.D., Lampe-Schoenmaeckers A.J.E.M. et al. Analgesic efficacy and safety of paracetamol-codeine combinations versus paracetamol alone: ​​a systematic review//BMJ. – 1996. – V. 313, – N. 7053. – P. 321–325.

2. Toms L., Derry S., Moore R. A., McQuay H.J. Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults //Cochrane Database Syst. Rev. — 2009. — CD001547. – doi: 10.1002/14651858.CD001547.pub2.

3. Buck M.L. Therapeutic Uses of Codeine in Pediatric Patients // Pediatr. Pharm. – 2004. – V. 10, – N. 4.

4. Codeine and Acetaminophen for Pain Relief: A Review of the Clinical Efficacy and Safety // 2012. – www.crd.york.ac.uk .

5. Williams D.G., Hatch D.J., Howard R.F. Codeine phosphate in pediatric medicine // Br. J. Anaesth. – 2001. – V. 86, – N. 3. – P. 413-421.

6. WHO Analgesic Ladder: which weak opioid to use at step two? // 2008. – www.bpac.org.nz.

7. Use of Codeine in Children // www.sickkids.ca .

8. WHO’s pain ladder // www.who.int .

9. Drendel A.L., Gorelick M.H., Weisman S.J. et al. A randomized clinical trial of ibuprofen versus acetaminophen with codeine for acute pediatric arm fracture pain // Ann.