How Genes Influence The Breakdown Of Codeine?

What Is Codeine?

Codeine is a drug used to treat mild or moderate pain in the body. It is a natural plant extract derived from opium.

Opium is a latex extract of the Papaver somniferum (opium poppy) plant and contains about 12% morphine.

Morphine is a chemical that affects the Central Nervous System (CNS) and alters pain sensations.

Codeine is available as pills, capsules, or oral solutions.

This drug is a part of the 2021 World Health Organization’s (WHO’s) Essential Medicines List.

What Is Codeine Used For?

Codeine is an opioid drug used to relieve moderate pain and cough.

It is commonly used in combination with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) or acetaminophen (a drug to treat fever and pain).

Opioid drugs act on the opioid receptors, a part of the opioid system that regulates pain, addictive behaviors, and rewards.

Upon interaction, they bring down the ability of the body to feel the pain.

What Kind Of Pain Does Codeine Help With?

Codeine can be used to treat chronic pain resulting from a medical condition or injury.

It is also prescribed after surgery for post-surgical pain.

It is also given in case of chronic pain that regular painkillers cannot treat.

Codeine is added to certain drugs that treat chronic cough and diarrhea.

Is Codeine An Anti-Inflammatory?

No, codeine is not an anti-inflammatory drug.

It is, however, often used in combination with NSAIDs to improve its efficacy.

How Does Codeine Work?

Codeine belongs to the narcotic analgesics and antitussives class of medications.

Narcotic analgesics change the way the body experiences pain, and antitussives are drugs that prevent coughing.

Codeine is converted into morphine in the liver.

Morphine now attaches itself to the opioid receptor in the CNS.

The CNS regulates pain sensations.

Morphine prevents the neurotransmitters from sending pain signals to the brain, hence lowering the intensity of pain.

https://staging.xcode.life/wp-content/uploads/2021/12/how_does_codeine_morphine_work_in_the_body.png

Image: How codeine works in the body

Is Tramadol Stronger Than Codeine?

Tramadol is another similar opioid pain killer, but this is manufactured industrially and not extracted from natural substances like codeine.

Both these pain killers are equally effective. However, studies show that tramadol may have a slightly increased risk of all-cause mortality compared to codeine.

Side Effects Of Codeine

Some of the common side effects of codeine are:

Constipation
Nausea
Vomiting
Excessive sleepiness
Vertigo (dizziness)
Dry mouth
A state of confusion
Headaches

Some of the more severe side effects of codeine are:

Breathing difficulties
Stiffness in muscles
Low blood pressure (which may cause dizziness and excessive tiredness)
Hallucinations, aggressiveness, and other behavioral changes
Seizures or shivering
Fever
Rashes and itching
Low libido (decreased sexual drive)

How Long Does Codeine Stay In Your System?

In most cases, codeine can be detected in the urine for up to 48 hours after using the drug.

In long-term codeine users, the drug can be detected in the urine for up to one week.

In a small study, a group of 10 volunteers consumed eight doses each of a cough syrup containing 4.5 mg of codeine phosphate.

The study reported that codeine was present in the urine samples for 30 hours after the last dose.

Interactions With Other Drugs

Codeine can interact with other drugs and lead to changes in drug efficacies or worsen the side effects. Notify your doctor if you are on any of the following drugs:

Other narcotic medications
Sedatives like valium
Cold, cough, and allergy medications
Serotonin-affecting medications prescribed for anxiety, depression, or other mood disorders
Tricyclic antidepressants (used to treat depression and mood disorders)
5HT3 serotonin blockers (used to treat chemotherapy-induced nausea and vomiting)
Seizure medications
Medicines used to treat weak or paralyzed muscles (calcium, magnesium, or potassium oxybates)
CYP2D6 inhibitor drugs
Certain antibiotics like linezolid (used to treat Gram-Positive bacterial infections)

Can You Take Ibuprofen With Codeine?

Yes. Ibuprofen, an NSAID, can be taken along with codeine.

Studies show that a combination of these drugs acts as a very effective analgesic and can help handle post-operative pain.

However, you can take ibuprofen with codeine only after consulting a qualified medical practitioner.

Codeine: Gene-Drug Interactions

CYP2D6 Gene

The CYP2D6 gene provides instructions for producing the Cytochrome P450 2D6 enzyme.

This enzyme is expressed in the liver and helps metabolize more than 25% of all prescription drugs, including codeine.

It converts codeine into its active form – morphine.

CYP2D6 gene has more than 100 star alleles.

Star alleles are used to name different haplotypes. A haplotype is a group of gene changes that are inherited together.

Alleles (CYP2D6)	Functioning
1, 2, 27, 33	Normal-function alleles
10, 17, 41, 49	Decreased-function alleles
3, 4, 5, 6, *36	Non-function alleles

Normal functioning alleles produce normal levels of the CYP2D6 enzyme with optimal activity.

Decreased functioning alleles produce lower levels of the CYP2D6 enzyme with lowered activity.

Non-functioning alleles do not produce any enzyme.

There are three kinds of CYP2D6 metabolizers identified depending on the combination of alleles they have.

Metabolizers	Genotype	Implications
Ultrarapid	Have more than 2 copies of the normal-function alleles	Increased enzyme activity and high risk of toxicity
Normal	Have 1 normal-function and 1 decreased-function alleles or 2 normal-function alleles	Normal enzyme activity and no additional risk of codeine toxicity
Intermediate	Have 1 decreased-function and 1 no-function alleles or 2 decreased-function alleles or 1 normal-function and 1 no-function alleles	Intermediate enzyme activity and slightly reduced morphine levels
Poor	Have 2 no-function alleles	No enzyme activity and significantly reduced morphine levels

Ultra-rapid metabolizers with more than 2 normal-functioning alleles have high levels of morphine in the body and may experience codeine overdose and toxicity. It is recommended these individuals get an alternate drug or reduced doses of codeine.
Poor metabolizers with 2 no-function alleles may not feel the analgesic effects of codeine due to low levels of morphine. They can consider choosing an alternative medicine.

OPRM1 Gene

The opioid receptor mu 1 gene (OPRM1 gene) provides instructions for producing the mu-opioid receptor.

This receptor controls the opioid system and is the primary target area for codeine and other opioid medicines.

rs1799971 is a Single Nucleotide Polymorphism (SNP) in the OPRM1 gene.

A 2015 meta-analysis studied different OPRM1 gene changes and their effects on opioid drug usage in a study sample of 5902 students.

The results revealed that people with the G allele of this SNP had to consume more opioid drugs than people with the A allele but still ended up with higher pain levels.

Allele	Implications
G	Consumed more opioid drugs to experience analgesia, yet reported higher pain
A	Normal doses of opioid drugs resulted in effective analgesia

Recommendations To Use Codeine

Allergic Reactions

Some people may have allergic reactions to codeine and experience breathlessness, hives, itching, and swelling immediately after consuming the drug.

If you face any discomfort, rush to your nearest Emergency Room or dial 911.

Risk Of Abuse

Since codeine is an opioid drug and contains about 12% morphine, it can increase the risk of drug dependence, especially with prolonged use.

People with the following conditions have a higher chance of overusing the drug and getting dependent on it.

History of substance abuse
Alcohol abuse
Mental health conditions like depression

If you think you are overusing the drug, contact your doctor immediately.

Usage In Children

In 2017, the Food and Drug Administration (FDA) restricted the use of codeine in children.

According to FDA, codeine may cause life-threatening conditions, including breathlessness and death in individuals younger than 18.

Usage In People With Respiratory Conditions

Since one of the side effects of codeine is breathing difficulties, it needs to be used very cautiously in people with existing respiratory conditions.

Lung diseases
Lung infections
Asthma
Wheezing
Chronic Obstructive Pulmonary Disease (COPD)
Sleep Apnea

Usage In Pregnant Mothers

A study analyzed the relationship between codeine usage during pregnancy and fetal harm in 7640 pregnant mothers.

According to the study, the risk of major birth defects was 4.9% with codeine usage (which is not different from the general population risk).

However, codeine usage in pregnancy can cause a condition called neonatal withdrawal in newborns.

Neonatal withdrawal or Neonatal Opioid Withdrawal Syndrome (NOWS) is a condition where the infant, being exposed to opioid drugs in the womb, is suddenly deprived of the same after delivery and goes through severe withdrawal symptoms.

The symptoms may include:

Nausea
Vomiting
Irritability
Tremors
Muscle tightness
Seizures
Diarrhea

NOWS is a severe condition and can turn life-threatening too.

Infants of women who are treated with opioid drugs in the last trimester have a higher chance of experiencing NOWS.

Is Codeine Safe In Pregnancy?

Minimal amounts of the drug taken for short periods during early pregnancy may be safe if the benefits outweigh the risk and no alternate pain medications can be used.

Your doctor will be able to take a call about this.

Codeine overuse and use during the last trimester may lead to a serious infant condition called Neonatal Opioid Withdrawal Syndrome (NOWS).

Usage In Nursing Mothers

Codeine may be expressed in breast milk and may expose your baby to morphine, leading to the following side effects in the infant.

Shallow breathing
Breathlessness
Excessive sleepiness
Limpness

Talk to your doctor if you are breastfeeding and are on codeine.

Genetic Testing

Genetic testing may help understand if a person will need higher, normal, or lower doses of codeine to achieve the expected analgesic effects.

This can prevent the risk of overdoses and make the treatment process more effective.

Analyze Your Genetic Response to Codeine

Summary

Codeine is an opioid drug used to treat mild or moderate pain and cough.
Codeine is extracted from the opium poppy plant and contains about 12% morphine.
Opioid drugs attack the opioid system, change the way the body experiences pain, and help bring down pain levels.
Some of the common side effects of codeine are nausea, vomiting, constipation, dizziness, dry mouth, and headaches.
Codeine may interact with other narcotic medications, sedatives, serotonin drugs, seizure medications, and CYP2D6 inhibitors.
Star alleles of the CYP2D6 gene influence how people respond to codeine.
Ultra-rapid metabolizers have an increased risk of codeine toxicity and poor metabolizers may not experience the analgesic effect at normal doses.
A specific change in the OPRM1 gene is associated with increased codeine dosage for analgesia.
Codeine is prohibited for use in children less than 18 years of age.
Codeine use in the last trimester of pregnancy may lead to Neonatal Opioid Withdrawal Syndrome.
The risk of abuse of opioid drugs like codeine is high. Hence patients need to prevent overdosing or using the medicine for a longer-than-prescribed period.
Genetic testing will help understand the exact drug dosages needed for effective pain management. It will also help choose between codeine and other pain medications.