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Methadone is an opioid (or narcotic) drug and a controlled substance - this drug has a risk of misuse and may cause dependence.
Methadone is also available as the brand-name drug Methadose. It is used as an oral soluble tablet.
Methadone is used to treat moderate to severe pain.
It is sometimes prescribed in cases where the patient has an addiction to another opioid. Methadone helps prevent withdrawal symptoms.
Methadone relieves pain by changing the way your brain and the nervous system respond to pain. It does so by working on the pain receptors.
Methadone relieves pain much slower than other painkillers like morphine.
Some common side effects of methadone are:
Some serious side effects are:
Opioid medication can interact with many other drugs and cause dangerous side effects. Make sure you notify your doctor if you use other:
Methadone maintenance treatment is the use of methadone for a prolonged period of time to treat pain in patients who have faced addiction issues with other opioids like heroin.
The UGT2B7 gene is located at chromosome 4q13. It contains instructions for the production of UDP-Glucuronosyltransferase-2B7.
It is associated with withdrawal symptoms, treatment efficacy, and side effects in methadone maintenance treatment.
rs4292394
rs4292394 is a single nucleotide polymorphism or SNP in the UGT2B7 gene. It is associated with opioid withdrawal when undergoing methadone maintenance treatment.
| Genotype | Effect |
| GG | May have increased severity of opiate withdrawal symptoms |
| CG | May have decreased severity of opiate withdrawal symptoms |
| CC | May have decreased severity of opiate withdrawal symptoms |
The CYP3A enzymes are the most abundant of the CYP450 isozymes, comprising ∼40% of the hepatic CYP450 content.
The CYP3A4 gene contains instructions for the production of the Cytochrome P 450 3A4 enzyme. CYP3A4 plays a role in the metabolism of 40–60% of all drugs ingested.
A few studies have reported the role of CYP3A4 polymorphisms in methadone toxicity.
rs4646437
rs4646437 is an SNP in the CYP3A4 gene. Studies have demonstrated that the CYP3A4 enzyme expression and activity are increased in females carrying the T allele.
Increased levels of CYP3A4 result in increased conversion of methadone to inactive metabolites (substances that result from the metabolism of methadone). This increases the risk of fatal methadone intoxication in the female population with the T allele.
Notify your doctor of any health conditions you may have, like heart, lung, or kidney disease, as methadone may not be safe to consume in these cases.
Make sure your doctor knows all the drugs you are currently on/have had in the recent past in order to avoid drug interactions.
Women who are pregnant or breastfeeding may take methadone; however, methadone can cross the placenta and can go into the breast milk. So seek the advice of your medical practitioner if you are pregnant or breastfeeding.
The correct dosage varies according to the purpose - whether to treat pain, for detoxification of opioid addiction, or for maintenance of opioid addiction.
In case you take too much or experience symptoms of overdosing like slow pulse, cold, clammy skin, slowed breathing, or dizziness, immediately call your doctor or local poison control. If the symptoms are severe, call 911.
Methadone can cause severe allergic reactions. If you have trouble breathing or experience swelling of your tongue and throat, seek medical attention immediately.
Acetylcholine is a parasympathomimetic drug that is used for ophthalmological applications. Parasympathomimetic drugs are also called cholinomimetic drugs, and these activate the parasympathetic nervous system (PSNS).
The sympathetic nervous system is a part of the brain that is involved in the "fight or flight" response, and the PSNS is the "rest and digest" side.
The PSNS uses acetylcholine, a neurotransmitter (chemical messenger) that helps in brain-body coordination. Cholinomimetic drugs delay the breakdown or promote the release of acetylcholine.
Acetylcholine in drug form is available as eye drops. It is used to create rapid miosis (shrinking of the pupil) during cataract surgery after the lens is placed or during general eye surgery.
This drug has no value when intravenously administered as it is quickly deactivated by a group of enzymes in the Central Nervous System called cholinesterase. The eye drop form, however, helps quicken recovery after eye surgery.
When administered inside the eyes, Acetylcholine controls nerve impulse transmission and causes rapid shrinking of the pupil.
A nerve impulse is the way nerve cells (neurons) communicate with one another. Nerve impulses are mostly electrical signals.
About 0.5-2 ml of the 1% solution is introduced into the eyes, and miosis occurs (pupil shrinks to less than 2mm). Miosis lasts for about 10 minutes
Some common side effects of acetylcholine are:
Rarer side effects of acetylcholine are:
Acetylcholine can interact with certain drugs and lower the efficiency of the drug or cause extreme side effects. Therefore, make sure to notify your doctor if you are on any of the following drugs.
The ACE gene (angiotensin-converting gene) helps produce the ACE enzyme.
The ACE enzyme regulates blood pressure and fluid balance in the body by constricting the blood vessels.
In a study, researchers introduced enalaprilat, an ACE inhibitor drug, to 56 patients with atherosclerosis (a condition caused by the build-up of fat and cholesterol).
ACE inhibitor drugs interfere with the ACE enzyme activity and relax the blood vessels.
Image: Action of ACE Inhibitors
These patients were then administered acetylcholine. Changes in the coronary blood flow, vascular resistance, and epicardial diameter were then measured.
People with the DD and ID types of the ACE gene had a better blood flow and relaxation of blood vessels than those with the II type.
| Genotype | Implications |
| DD | Increased coronary blood flow |
| ID | Increased coronary blood flow |
| II | Lowered coronary blood flow |
As a topical eye solution, acetylcholine is very unstable. Therefore, the solution has to be prepared and used immediately.
Acetylcholine overdose can lead to cardiovascular complications or constriction of the airways. Drugs that can counteract this constriction effect have to be kept ready while administering acetylcholine.
Rarely, some people can have an allergic response to acetylcholine and develop the below symptoms.
If you experience any of the above-mentioned symptoms when treated with acetylcholine, notify your doctor immediately.
Genetic testing can help understand how your body responds to acetylcholine. This can enable your doctor to administer the drug at correct dosages with proper precautions.
Analyze Your Genetic Response to Acetylcholine
The CYP2E1 enzyme is a part of the Cytochrome P450 family and plays a role in drug metabolism.
Drug metabolism is the process by which the body breaks down pharmaceutical drugs and other chemicals from the system using enzymatic systems. Drug metabolism can make the drug more active, inactive, or convert it into a more toxic metabolite (intermediary substance).
This enzyme makes up less than 1% of the total CYP450 enzymes and helps in clearing 2% of the total prescription drugs in the market.
CYP2E1 is mostly concentrated in the liver. It is also found in the lungs, brain, and kidney.
There are many variations (changes) in the CYP2E1 gene. These genetic variations create a difference in drug metabolism and increase/decrease the risk of different health conditions like diabetes, Non-Alcoholic Fatty Liver Disease (NAFLD), liver inflammation, and cancer.
The CYP2E1 enzyme can activate small, low molecular weight compounds. Some of them include:
Ethanol is a simple alcohol that is commonly used as a food additive. It is the basic ingredient in most types of alcohol like wine, beer, and brandy. It is also added in food colors to evenly distribute the color. Ethanol is added to varnish and household cleaning products too.
The CYP2E1 enzyme is responsible for ~20% of ethanol metabolism in the brain.
Acetone is a flammable colorless liquid that is commonly used as thinners and nail polish removers. Internally, acetone is produced as a result of various metabolic activities in the body. The CYP2E1 enzyme eliminates excess acetone from the body and prevents acetone toxicity.
Inhalational anesthetics are administered using a face mask. Such anesthetics are made stronger and safer by adding fluorine to them. Below are some fluorinated anesthetics.
The CYP2E1 enzyme plays a role in the metabolism of most of these fluorinated anesthetics.
Benzene is a sweet-smelling chemical that is flammable. Benzene is both man-made and naturally occurring. Naturally, benzene is released during forest fires and volcanic eruptions. Benzene is also a side-product released during the production of pesticides, lubricants, and rubber.
Over-exposure to benzene leads to anemia and certain types of cancers.
The CYP2E1 converts benzene into benzene dioxide and plays a role in clearing the toxin from the body.
N-nitrosodimethylaminen is also called dimethylnitrosamine (DMN), and this is produced as a result of chlorine water treatment. DMN is also found in cured meat and fish. Inhaling tobacco products increases the risk of DMN exposure too.
CYP2E1 metabolizes DMN in the body.
Acrylamide is a chemical released when food is roasted, baked, or fried at very high temperatures. The chemical is found more in starchy foods like potatoes. This chemical is highly toxic and can increase the risk of developing cancer.
CYP2E1 metabolizes acrylamide in the body and prevents its build-up in the body.
4-nitrophenol is a chemical used in the manufacturing of pesticides, fungicides, dyes, and leather. People who work in these manufacturing units are at high risk for 4-nitrophenol exposure. Exposure to this chemical can lead to nausea, drowsiness, and headaches. The long-term effects of exposure to this chemical are still being researched. The CYP2E1 enzyme metabolizes this chemical in the body.
Acetaminophen is a pain-reliever. It is also commonly called paracetamol. This drug is used in treating fever and mild body aches. The CYP2E1 enzyme metabolizes acetaminophen and converts it into a more toxic form called N-acetyl-p-benzoquinone imine (NAPQI).
Hepatotoxicity is also called toxic hepatitis and causes serious liver damage. CYP2E1 encourages acetaminophen hepatotoxicity. NAPQI, in large amounts in the body, can lead to cellular damage. NAPQI needs to be quickly removed from the body with the help of glutathione or converted back to acetaminophen.
Inducers are substances that increase the metabolic activity of the enzyme. Inhibitors are substances that bind to the enzyme to reduce its activity.
There are multiple variations in the CYP2E1 gene that influence the activity of the CYP2E1 enzyme.
| Haplotype | Effect |
| CYP2E1*2 | Decreased enzyme activity |
| CYP2E1*6/CYP2E1_marker9 | Increased enzyme activity |
| CYP2E1*7B | Increased enzyme activity |
| CYP2E1 *5B | Increased enzyme activity |
A haplotype is a group of gene changes that are inherited together. The *2, *6, *5B, and *7B are all star alleles. Star alleles are used to name different haplotypes.
Foods rich in omega-3 fatty acids induce CYP2E1 levels in the body.
Some food sources of omega-3 fatty acids are:
Here is a list of foods that inhibit CYP2E1 activity.
Both Vitamin C and vitamin E prevent oxidative stress and lipid peroxidation (free radicals damage the lipids in cell membranes, leading to cell damage) in the body. These vitamins also prevent a decrease in the CYP2E1 enzyme activity in the liver and improve CYP2E1 drug metabolism.
Genetic testing can help identify the metabolizer status of an individual for a gene (or group of genes) or a drug (or group of drugs). Depending on the genetic results, doctors can then plan drug dosages and opt for safer medications.
The CYP2D6 gene or the cytochrome P450 2D6 contains instructions for the production of the CYP2D6 enzyme. The enzyme production predominantly occurs in the liver. CYP2D6 is responsible for the metabolism and elimination of approximately 25% of clinically used drugs.
Drug metabolism is the process by which the body breaks down pharmaceutical drugs and other chemicals from the system using enzymatic systems. Drug metabolism can make the drug more active, inactive, or convert it into a more toxic metabolite (intermediary substance).
CYP2D6 belongs to the group of enzymes that are responsible for activating and metabolizing certain drugs. In some cases, the enzyme converts the inactive drug (called the prodrug) into its active form. Most ACE inhibitor drugs used to treat hypertension are prodrugs.
Amitriptyline, an antidepressant drug, on the other hand, is broken down and inactivated by the CYP2D6 in the liver.
Considerable differences exist in the efficiency and amount of CYP2D6 enzyme produced across individuals. Depending on this, they are categorized into one of the four metabolizer statuses:
Poor metabolizers (PM) - These are people who produce no or very little of the CYP2D6 enzyme. These individuals cannot process certain medicines well, and in some cases, drugs remain in the body for a longer time without getting cleared out. This increases the toxicity of the drug.
Intermediate metabolizers (IM) - These people can produce and process moderate amounts of the CYP2D6 enzyme. About 3 in 10 people are intermediate metabolizers.
Normal/extensive metabolizers (EM) - About 6 in 10 people are normal metabolizers. Their bodies produce normal levels of the CYP2D6 enzyme and activate and clear drugs at a normal rate.
Ultra-rapid metabolizers (UM) - These people have excess CYP2D6 enzyme activity. Drugs are metabolized very quickly and cleared from the body rapidly. This reduces the effectiveness of the drugs.
Codeine - Codeine is an opioid pain reliever commonly prescribed to treat chronic cough, pain, and diarrhea. It needs to be activated to morphine by the CYP2D6 enzyme for it to function efficiently.
PM have low CYP2D6 enzyme levels and may not convert codeine to morphine effectively. As a result, they may not experience the pain-relieving effect of morphine at normal codeine doses.
Tramadol - Tramadol is also an opioid pain reliever used to treat moderate to moderately severe pain. It is converted into O-desmethyltramadol (M1) in the liver, which produces the opioid pain-relieving effect. This conversion is facilitated by the CYP2D6 enzyme.
Amitriptyline - Amitriptyline helps treat anxiety and depression by preventing serotonin reuptake and thereby boosting serotonin levels in the body. CYP2D6 is involved in the metabolism of amitriptyline.
The FDA-approved drug label for amitriptyline states that CYP2D6 PM have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. In such cases, a lower starting dose or an alternative drug is recommended.
Metoprolol and propranolol - Both metoprolol and propranolol are beta-blockers. These are used in the treatment of heart diseases and hypertension.
They are primarily metabolized by CYP2D6. PM who lack CYP2D6 activity tend to have almost 5-fold higher levels of metoprolol and may be at an increased risk of side effects if administered the normal start dose.
Fluoxetine, Paroxetine - Both Fluoxetine and Paroxetine are Selective Serotonin Reuptake Inhibitors (SSRI) and are popular antidepressants.
The CYP2D6 enzyme helps convert the drugs into their active forms.
In PM, the drugs remain in the system for a longer time, risking overexposure. A lower starting dosage is recommended for such individuals.
Natural hormones and lipid - The CYP2D6 enzyme also metabolizes few naturally occurring substances in the body, including:
Inducers are substances that increase the metabolic activity of the enzyme. Inhibitors are substances that bind to the enzyme to reduce its activity.
Inducers speed up the metabolism of the drugs, resulting in lower concentrations for drugs that are metabolized to an inactive form. In the case of antibiotics, inducers make the enzymes quickly convert them into their inactive forms, not giving the drugs enough time to fight the bacterial infections.
Many drugs inhibit the activity of the CYP2D6 enzyme. Some of them include:
Estimates suggest that up to nearly a third of patients on tamoxifen are also taking antidepressants. Tamoxifen is a drug used to prevent breast cancer in women and treat breast cancer in women and men. Antidepressants like Fluoxetine (Prozac) and Paroxetine (Paxil) can substantially inhibit CYP2D6 and may reduce tamoxifen efficacy.
The CYP2D6 gene has a lot of variations (changes) that affect the efficiency of the CYP2D6 enzyme.
| Haplotype | Effect |
| CYP2D6*3 | Inactive enzyme |
| CYP2D6*4 | Inactive enzyme |
| CYP2D6*6 | Inactive enzyme |
| CYP2D6*7 | Inactive enzyme |
| CYP2D6*8 | Inactive enzyme |
| CYP2D6*9 | Decreased enzyme activity |
| CYP2D6*11 | Inactive enzyme |
| CYP2D6*12 | Inactive enzyme |
| CYP2D6*14 | Inactive enzyme |
| CYP2D6*41 | Decreased enzyme activity |
A haplotype is a group of gene changes that are inherited together. The *3, *4, *14, *41, etc., are star alleles. Star alleles are used to name different haplotypes.
The *4 allele is one of the most common mutations in Caucasians, resulting in a decrease in or complete lack of CYP2D6 enzyme activity. This allele accounts for 70% of all inactivating alleles that Caucasians are born with.
Genetic testing will help identify the metabolizer status of an individual for a gene (or group of genes) or a drug (or group of drugs). Depending on the genetic results, doctors can then plan drug dosages and opt for safer medications.
Even if you are not a poor metabolizer genetically, the use of CYP2D6 inhibitors will bring down the enzyme activity. This can cause over-exposure to drugs that the CYP2D6 enzyme acts on.
For CYP2D6 poor metabolizers, CPIC recommends using an alternative hormonal therapy instead of tamoxifen for postmenopausal women.
