Methadone

Methadone is a prescription opioid medicine with very strong painkiller (narcotic analgesic) effect that is used to relieve severe and persistent pain in people who are expected to need an opioid pain medication around the clock for a long time and who cannot be treated with other medications ¹. Methadone should not be used to treat mild or moderate pain, short-term pain, or pain that can be controlled by medication that is taken as needed. Methadone also is used to prevent withdrawal symptoms in patients who were addicted to heroin and opioid addiction (opioid use disorder) and are enrolled in the Opioid Treatment Programs (OTPs) in order to stop taking or continue not taking the drugs. Methadone is in a class of medications called opiate (narcotic) analgesics. Methadone works to treat pain by changing the way the brain and nervous system respond to pain. Methadone works to treat people who were addicted to opiate drugs by producing similar effects and preventing withdrawal symptoms in people who have stopped using these drugs.

Methadone is a long-acting opioid agonist that reduces opioid craving and withdrawal and blunts or blocks the effects of opioids ¹. Long-acting means methadone stay in your body for a long time.

Methadone is a controlled substance and classified as a Schedule 2 drug, indicating that it has medical usefulness, but also a high potential for physical and psychological dependency and abuse. Use of methadone as a part of a Opioid Treatment Program (OTP) requires special certification. Methadone is available in all states and counties via opioid treatment programs (https://dpt2.samhsa.gov/treatment/directory.aspx). This is because your doctor thinks that the benefits of methadone outweigh the risks of long-term use. If you are concerned about the risks of methadone, speak to your doctor. If your doctor has prescribed methadone for drug dependency, do not stop taking the medicine without first discussing it with your doctor.

Methadone is available generically and under the brand names Dolophine and Methadose among others, in tablets of 5, 10 and 40 mg, oral solutions of 5 and 10 mg/5 mL (and concentrate of 10 mg/mL), and as a solution for injection in concentrations of 10 mg/mL. Typical oral doses vary by indication and clinical response. For opiate abstinence syndrome the dose is highly individualized, but maintenance doses are generally in the range of 20 to 120 mg daily.

If you have kidney problems or your kidney function is impaired, your doctor will need to adjust your dosage of methadone.

There are other factors that may limit your use of methadone — for example, if you drink alcohol or take other medicines that can cause drowsiness.

You can also develop tolerance when you take methadone. This means you need to take larger amounts of the opioid to get the same effect. As the dosage increases, so does the risk of side effects. If you stop taking methadone suddenly, you may experience withdrawal symptoms.

Your doctor is the best person to advise you on whether methadone is the right medicine for you, how much you need and how long to take it for. Your doctor can also guide you on when and how to stop taking methadone.

Always check with your doctor before adjusting your dosage either up or down — do not change your dose without checking with your doctor first.

Methadone side effects include sedation, respiratory depression, confusion, euphoria, agitation, itching, sweating, abdominal bloating, nausea, vomiting and constipation, adverse effects which are typical of the opioids.

While taking methadone, you should talk to your doctor about having a Opioid Overdose Reversal Medication (OORM) called naloxone. Naloxone is used to reverse the life-threatening effects of an methadone overdose. Naloxone helps stop the harmful effects of opioids, and it can save your life if you have an opioid overdose. It works by blocking the effects of opiates to relieve dangerous symptoms caused by high levels of opiates in the blood. Your doctor may also prescribe you naloxone if you are living in a household where there are small children or someone who has abused street or prescription drugs. You should make sure that you and your family members, caregivers, or the people who spend time with you know how to recognize an methadone overdose, how to use naloxone, and what to do until emergency medical help arrives. Your doctor or pharmacist will show you and your family members how to use naloxone. Ask your pharmacist for the instructions or visit the manufacturer’s website to get the instructions. If symptoms of an overdose occur, a friend or family member should give the first dose of naloxone, call for emergency help immediately, and stay with you and watch you closely until emergency medical help arrives. Your symptoms may return within a few minutes after you receive naloxone. If your symptoms return, the person should give you another dose of naloxone. Additional doses may be given every 2 to 3 minutes, if symptoms return before medical help arrives.

Methadone Safety

Methadone is safe and effective, when taken as prescribed. Methadone medication is specifically tailored for the individual patient and doses are often adjusted and readjusted and is never to be shared with or given to others. This is particularly important for patients who take methadone at home and are not required to take medication under direct supervision at an OTP.

Methadone special precautions

Patients should share their complete health history with their doctor to ensure the safe use of methadone medication. Other medications may interact with methadone and cause heart conditions. Even after the effects of methadone wear off, the medication’s active ingredients remain in the body for much longer. Unintentional overdose is possible if patients do not take methadone as prescribed.

Before taking methadone:

• Tell your doctor and pharmacist if you are allergic to methadone, any other medications, or any of the ingredients in the methadone product you plan to take. Ask your doctor or pharmacist or check the Medication Guide for a list of the ingredients.
• Tell your doctor or pharmacist if you are taking the following medications or have stopped taking them within the past two weeks: isocarboxazid (Marplan), linezolid (Zyvox), methylene blue, phenelzine (Nardil), selegiline (Emsam, Zelapar), or tranylcypromine (Parnate).
• The following nonprescription or herbal products may interact with methadone: St. John’s wort and tryptophan. Be sure to let your doctor and pharmacist know that you are taking these medications before you start taking methadone. Do not start this medication while taking methadone without discussing it with your doctor.
• Tell your doctor if you have any of the conditions mentioned in the IMPORTANT WARNING section or have or have ever had a blockage in your intestine or paralytic ileus (condition in which digested food does not move through the intestines) or a blockage in the stomach or intestines. Your doctor may tell you that you should not take methadone.
• Tell your doctor if you have or have ever had difficulty urinating; an enlarged prostate (a male reproductive gland); adrenal insufficiency (condition in which the adrenal glands do not produce enough of certain hormones needed for important body functions); diabetes; seizures; or thyroid, pancreas, gallbladder, liver, or kidney disease.
• Adrenal insufficiency is a rare endocrine disorder that occurs when the adrenal glands don’t produce enough hormones. Cases of adrenal insufficiency have been reported following methadone use, characterized by nausea, vomiting, anorexia, weakness, dizziness, and hypotension. Methadone-induced adrenal insufficiency can also manifest with high blood calcium level (hypercalcemia) ², ³. Adrenal insufficiency management involves measures such as discontinuing or reducing the dose of opioids and initiating corticosteroid replacement therapy ⁴.
• The concomitant use of anticholinergics may increase the risk of urinary retention and ileus. Doctors should monitor patients for signs of urinary retention or decreased gastric motility when methadone is administered concurrently with anticholinergic medications ⁵.
• Tell your doctor if you are breastfeeding. If you breastfeed during your treatment with methadone, your baby may receive some methadone in breastmilk. Watch your baby closely for any changes in behavior or breathing, especially when you start taking methadone. If your baby develops any of these symptoms, call your baby’s doctor immediately or get emergency medical help: unusual sleepiness, difficulty breastfeeding, difficulty breathing, or limpness.
• You should know that methadone may decrease fertility in men and women. Talk to your doctor about the risks of taking methadone.
• If you are having surgery, including dental surgery, tell the doctor or dentist that you are taking methadone.
• You should know that methadone may make you drowsy. Do not drive a car or operate machinery until you know how methadone affects you.
• You should know that methadone may cause dizziness when you get up too quickly from a lying position. This is more common when you first start taking methadone. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
• You should know that methadone may cause constipation. Talk to your doctor about changing your diet or using other medications to prevent or treat constipation while you are taking methadone.
• Methadone is also associated with life-threatening QTc prolongation (>450 ms) and leads to heart dysfunction ⁶. QTc stands for heart-rate corrected QT interval, and it’s a measure of how well your heart’s left ventricle repolarizes. QTc prolongation (>450 ms) is a condition where the heart’s QT interval is longer than normal, which can increase the risk of a potentially fatal heart arrhythmia called Torsades de pointes. Although most cases involve patients receiving high, multiple daily doses of methadone for pain management, instances have also been reported in patients receiving standard doses for opioid addiction maintenance treatment. Therefore, it is crucial to closely monitor patients with risk factors for prolonged QT interval, a history of heart conduction abnormalities, or medications that impact cardiac conduction. Baseline electrocardiograms (ECGs) should be obtained for all patients, with a follow-up within 30 days to assess for acute changes. Annual repeat electrocardiograms are recommended. If the methadone dose exceeds 100 mg/dL or if the patient is symptomatic, additional cardiac assessments should be conducted. In cases where the QTc interval exceeds 500 ms, doctors should consider reducing the methadone dose or discontinuing it, opting for alternative therapies such as buprenorphine-naloxone ⁶. In addition, regular monitoring for changes in cardiac rhythm should be implemented during the initiation and titration of methadone injection ⁷.
• Methadone can cause severe low blood sugar level (hypoglycemia) in certain patient populations ⁸. Individuals at high risk for hypoglycemia (low blood sugar level), such as cancer patients and those experiencing rapid methadone dose escalation, should undergo regular serum glucose screening. Signs indicating a patient is experiencing hypoglycemia include unexplained lethargy, perspiration, and palpitations ⁸.
• Risks associated with the concomitant use of benzodiazepines and other central nervous system (brain and spinal cord) depressants: Combining opioids with benzodiazepines or other central nervous system depressants, such as alcohol, can lead to significant sedation, respiratory depression, coma, and even fatal outcomes. Prescribing methadone and benzodiazepines or central nervous system depressants simultaneously should be reserved for cases where alternative treatment options are inadequate. In addition, it is advisable to minimize dosages and durations to the essential minimum and closely monitor patients for signs of sedation and respiratory depression ⁹.
• Methadone has the potential to induce postural hypotension (orthostatic hypotension) and fainting or passing out (syncope) in ambulatory patients. Orthostatic hypotension (postural hypotension) is a condition where a person’s blood pressure drops when they stand up or sit down. Fainting or passing out (syncope) is a brief loss of consciousness caused by a sudden drop in blood flow to the brain, usually due to low blood pressure (hypotension). Vital signs should be monitored after the initiation or titration of methadone. It is advisable to refrain from using methadone in patients experiencing shock (a life-threatening medical condition that occurs when the body doesn’t get enough blood flow).
• Addiction, abuse, and misuse of the drug: The U.S. Food and Drug Administration (FDA) warns that methadone injection injection poses risks of opioid addiction, abuse, and misuse, potentially leading to a fatal overdose. A thorough risk-benefit evaluation is essential before prescribing methadone injection, and ongoing patient monitoring is crucial to detect and address any potential misuse.

Methadone Drug Interactions

A number of medications can change methadone’s absorption, distribution, and metabolism. Methadone’s absorption is mediated by gastric pH and P-glycoprotein (Pgp), a transport protein. Changes in gastric pH or the activity of P-glycoprotein (Pgp) brought about by certain medications (e.g., verapamil [Calan], quinidine) may change methadone absorption ¹⁰, ¹¹.

Methadone is brokendown (metabolized) principally by the CYP3A4 and CYP2D6 enzymes ¹². The concomitant use of methadone with inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 may result in elevated methadone plasma concentrations, potentially resulting in methadone overdose leading to fatal respiratory depression or withdrawal symptoms. Discontinuation of concurrently administered CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers may increase methadone concentration. Many medications interact with methadone via their effects on these enzymes, by inducing or inhibiting methadone metabolism ¹², ¹³, ¹⁰, ¹¹, ¹⁴. Therefore, it is advisable to contemplate methadone dosage reduction when making changes to concomitant medications that could potentially elevate methadone levels. Notably, CYP2B6 polymorphisms can influence methadone plasma concentrations ¹⁵. It is essential to closely monitor patients taking medications that may impact clearance, being vigilant for signs of withdrawal or overdose ¹⁶.

Analgesics with opioid-blocking properties (e.g., buprenorphine [Subutex], butorphanol [Stadol], dezocine [Dalgan], nalbuphine [Nubain], nalorphine [Nalline], pentazocine [Talwin]) should not be used with methadone because they can displace methadone from mu (μ) opioid receptors.

Drugs that may increase methadone effects and overdose risk: These drugs include ciprofloxacin, benzodiazepines ⁹., alcohol, fluconazole, cimetidine, fluoxetine, urine alkalizing agents, and grapefruit juice ¹⁷.

Drugs that may decrease methadone effects and risk of withdrawal symptoms: These drugs include efavirenz, phenobarbital, phenytoin, carbamazepine, urine acidifying agents, and rifampin ¹⁸.

The examples listed above do not constitute an exhaustive list of drug interactions but provide some commonly documented drug interactions that should be monitored when using methadone ¹⁹.

Table 1. Methadone Drug Interactions

How does methadone work?

Methadone is a synthetic opioid agonist that eliminates withdrawal symptoms and relieves drug cravings in opioid addiction (opioid use disorder) by acting on opioid receptors (predominantly mu [µ] type opioid receptors) in the brain (but ), the same opioid receptors that other opioids such as heroin, morphine, and opioid pain medications activate. These mu (μ) opioid receptors are located in different parts of your brain, such as your brainstem, locus coeruleus, periaqueductal gray matter, and various parts of your heart, lung, blood vessels and gastrointestinal tract. These opioid receptors are important in regulating various neurochemical activities linked to pain relieve (analgesia), euphoria (a feeling or state of intense excitement and happiness), and sedation. Methadone activates the mu (μ) opioid receptors, initiating the same pathways. This activation results in downstream effects through G-protein signaling, interrupting neuronal transmission of pain impulses between the brain and the body, producing analgesic effects. In addition, it induces receptor internalization and recycling, contributing to reduced opioid tolerance in patients ²⁰, ²¹.

Although methadone occupies and activates these opioid receptors, it does so more slowly than other opioids and, in an opioid-dependent person, treatment doses do not produce euphoria (a feeling or state of intense excitement and happiness). When methadone is used to replace another opioid, it helps to lessen the effects of withdrawal and reduces the harm associated with heroin and opioid addiction. In this way, methadone makes it easier for people to stop their harmful drug use. In the treatment of opioid addiction, clinicians titrate methadone to a higher daily dose, preventing withdrawal signs and establishing a narcotic blockade to deter euphoria from other shorter-acting opioids. The extended half-life of methadone of approximately 8 to 60 hours results in a less severe withdrawal time course and milder symptoms ²², ²⁰, ²¹.

Methadone has non-opioid actions, including inhibition of the reuptake of monoamines (e.g., serotonin, norepinephrine) and noncompetitive inhibition of N-methyl-D-aspartate (NMDA) receptors, potentially enhancing its efficacy in managing neuropathic (nerve) pain ¹³, ²³, ²⁰, ²⁴. Activation of the NMDA receptor can produce central sensitization (i.e., lowering central nervous system pain thresholds), so blocking this receptor may help prevent the development of tolerance.9 In vitro studies have shown that morphine also will antagonize NMDA receptors but at concentrations eight to 16 times higher than required by methadone.10 Beyond the initial titration, frequent or large dosage changes usually are not necessary with methadone.

Methadone uses

Methadone is a prescription medication approved by the U.S. Food and Drug Administration (FDA) for detoxification and to treat opioid addiction (opioid use disorder) as well as for severe pain that does not respond to non-narcotic drugs ¹. Methadone has the longest history of use for opioid addiction (opioid use disorder) treatment, having been first approved for use as an opioid analgesic in the United States in 1947 ²⁵. Methadone commonly comes in the form of liquid and is mainly prescribed to treat heroin and opioid dependency as part of the Opioid Treatment Program (OTP). The aim of Opioid Treatment Program (OTP) is to help people who are dependent on opioids to stabilize and reduce the harms associated with opioid use. When taken as prescribed, methadone is safe and effective. Methadone helps individuals achieve and sustain recovery and to reclaim active and meaningful lives. Methadone is one component of a comprehensive treatment plan, which includes counseling and other behavioral health therapies to provide people with opioid addiction (opioid use disorder) with a whole-person approach. Under federal law, patients receiving treatment in Opioid Treatment Programs (OTPs) must be able to receive counseling through the OTP, along with medical, job, educational, and other assessment and treatment services ²⁶.

A large number of studies support methadone’s effectiveness at reducing opioid use. A comprehensive Cochrane review in 2009 compared methadone-based treatment (methadone plus psychosocial treatment) to placebo with psychosocial treatment and found that methadone treatment was effective in reducing opioid use, opioid use-associated transmission of infectious disease, and crime ²⁷, ²⁸, ²⁹, ³⁰, ³¹, ³². Patients on methadone had 33 percent fewer opioid-positive drug tests and were 4.44 times more likely to stay in treatment compared to controls ²⁷. Methadone treatment significantly improves outcomes, even when provided in the absence of regular counseling services ³⁰, ³¹, ³³; long-term (beyond 6 months) outcomes are better in groups receiving methadone, regardless of the frequency of counseling received ³⁴, ³⁵.

Methadone and buprenorphine are equally effective at reducing opioid use. A comprehensive Cochrane review comparing buprenorphine, methadone, and placebo found no differences in opioid-positive drug tests or self-reported heroin use when treating with methadone or buprenorphine at medium-to-high doses ³⁶.

Methadone is also FDA approved but rarely used to treat severe pain when other treatments do not work or cannot be tolerated. Methadone is frequently prescribed to treat severe pain associated with cancer, neuropathy, or other conditions in children ³⁷, ³⁸. However, the use of Methadone for pain relieve (analgesia) in children is considered off-label due to limited clinical data that comprehensively assess the risks and benefits in this specific population ²³. In a study of cancer patients with uncontrolled pain or significant side effects from opioids, 80 percent of patients reported improvement in pain control and reduction of adverse effects following transition to methadone ³⁹. Methadone may be used in patients with morphine allergy because methadone is synthetic (man-made) and offers no cross-allogenicity. However, a 2004 Cochrane Review stated several considerations in evaluating trials of methadone for cancer pain ⁴⁰. The majority of studies reviewed involved single-dose comparisons or short-term use, which does not adequately represent clinical practice. Therefore, there is a highly significant danger that the trials do not reflect delayed adverse effects from methadone accumulation during chronic administration. The same review reported there is no trial evidence to support the proposal that methadone has a particular role in neuropathic pain of cancer origin ⁴⁰.

Before initiating methadone for non-cancer chronic pain, the patient must undergo an assessment of risk factors that may contribute to drug misuse or diversion. In addition, it is essential to confirm that the benefits of the therapy outweigh any potential harms. Psychosocial factors contributing to underlying chronic pain, such as comorbid psychiatric disorders and issues related to social support, should be considered in the assessment ⁴¹.

Methadone is sometimes used off-label for the treatment of neonatal abstinence syndrome (NAS), although this application is not FDA-approved and falls under pregnancy category C drug ⁴². Neonatal Abstinence Syndrome (NAS) s a group of conditions caused when a baby withdraws from certain drugs he’s exposed to in the womb before birth. Neonatal Abstinence Syndrome (NAS) is most often caused when a woman takes opioids during pregnancy. But it can also be caused by antidepressants (used to treat depression), barbiturates or benzodiazepines (sleeping pills). When you take these drugs during pregnancy, they can pass through the placenta and cause serious problems for your baby. The placenta grows in your uterus (womb) and supplies your baby with food and oxygen through the umbilical cord. Babies with neonatal abstinence syndrome (NAS) may have health conditions that need treatment in the newborn intensive care unit (NICU) after birth. In addition to having withdrawal signs, babies with neonatal abstinence syndrome (NAS) are at increased risk of:

• Low birthweight. This means your baby is born weighing less than 5 pounds, 8 ounces.
• Jaundice. This is when your baby’s skin and eyes look yellow. It’s caused when your baby’s liver isn’t fully developed or working.
• Seizures
• Sudden infant death syndrome (SIDS). This is unexplained death of a baby younger than 1 year old. SIDS usually happens when a baby is sleeping.

Methadone and pregnancy

Methadone has been used to treat opioid use disorder (opioid addiction) in combination with counseling and behavioral therapy for heroin addiction during pregnancy since the early 1970s ⁴³, ⁴⁴, ⁴⁵.

Studies have found that following your treatment plan for opioid use disorder can help increase the chances of a healthy pregnancy and baby. People who stop taking the medication used to treat opioid use disorder often have a relapse into misusing opioids again. Misusing opioids (using in greater amounts than recommended by a doctor or using an opioid without a prescription) could cause pregnancy complications. Because of how the body changes during pregnancy, your doctor might talk with you about changing your methadone dose during the pregnancy.

If you have been taking methadone regularly you should not just stop taking it suddenly. Stopping an opioid medication suddenly could cause you to go into withdrawal. It is not known if or how withdrawal might affect a pregnancy. If you and your doctor decide to cut back on methadone, it is suggested that any reduction be done slowly and under the direction of your doctor.

I take methadone. Can it make it harder for me to get pregnant?

It is not known if taking methadone can make it harder to get pregnant.

Does taking methadone increase the chance of miscarriage?

Miscarriage is common and can occur in any pregnancy for many different reasons. Based on the studies reviewed, it is not known if methadone increases the chance for miscarriage.

Does taking methadone increase the chance of birth defects?

Every pregnancy starts with a 3-5% chance of having a birth defect. This is called the background risk. Based on the studies reviewed, it is not known if methadone increases the chance of birth defects above the background risk. Most studies on methadone have not reported a higher chance of birth defects. There are studies that have suggested that using methadone in the first trimester of pregnancy increases the chance for birth defects. However, there was no specific pattern of birth defects noted which suggests that other factors besides just the medication could be involved. These pregnancies in the studies also had other exposures. Overall, concern about a potential small increased risk of birth defects associated with methadone therapy during pregnancy should be weighed against the clear risks associated with the ongoing misuse of opioids by a pregnant woman.

During pregnancy, chronic untreated addiction to heroin is associated with lack of prenatal care, increased risk of fetal growth restriction, abruptio placentae, fetal death, preterm labor, and intrauterine passage of meconium ⁴⁴. Additionally, untreated addiction is associated with engagement in high-risk activities, such as prostitution, trading sex for drugs, and criminal activities. Such behaviors expose women to sexually transmitted infections (STIs), violence, and legal consequences, including loss of child custody, criminal proceedings, or incarceration.

Does taking methadone in pregnancy increase the chance of other pregnancy-related problems?

Some studies have found higher chances of preterm delivery (birth before 37 weeks of pregnancy) and low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth) when methadone is used during pregnancy. These outcomes might be more likely if a person takes methadone in greater amounts than recommended by their doctor, or if someone is using methadone but not under the care of a doctor.

People who take opioids in higher doses or for longer than recommended by their doctor also have a higher chance of poor growth of the baby, stillbirth, preterm delivery, and C-section.

Will my baby have withdrawal (neonatal abstinence syndrome) if I continue to take methadone?

Studies have reported neonatal abstinence syndrome (NAS) with methadone use during pregnancy. NAS is the term used to describe withdrawal symptoms in newborns from opioid medication(s) that a person takes during pregnancy. NAS symptoms can include irritability, crying, sneezing, stuffy nose, poor sleep, extreme drowsiness (tired), yawning, poor feeding, sweating, tremors, seizures, vomiting, and diarrhea. Not all babies will develop NAS. Symptoms of NAS may appear after birth and may last more than two weeks. If needed, babies can be treated for withdrawal while in the hospital. Tell your baby’s doctor if you took methadone in pregnancy, so that they know to check for symptoms of NAS to help your newborn get the best possible care.

Does taking methadone in pregnancy affect future behavior or learning for the child?

Some studies, including one that followed children up to age 3 years old, did not find differences in development among children who were exposed to methadone during pregnancy compared to those who were not. Other studies on methadone and opioids as a general group have found problems with learning and behavior in children exposed during pregnancy. It is hard to tell if this is due to medication(s), environment, genetics, or other factors that may increase the chance of these problems.

Breastfeeding while taking methadone

The amount of methadone that gets into breast milk varies from person to person, based on the dose and people’s different abilities to metabolize (break down) the medication. Taking up to 100 mg of methadone per day is not expected to cause problems for most healthy, full-term breastfed babies who were already exposed to methadone during pregnancy. Some studies have found that babies who were exposed to methadone during pregnancy and are breastfed have shorter hospital stays, less need for neonatal abstinence syndrome (NAS) treatment, and shorter lengths of NAS treatment than those who are not breastfed. Talk with your doctor about your specific situation, as information on breastfeeding might change based on factors such as the age of your baby and the dose of medication.

Methadone program

Methadone products, when used to manage opioid addiction in detox, must only be dispensed or prescribed by opioid treatment programs (OTPs), institutions, or practitioners certified by the U.S. Substance Abuse and Mental Health Services Administration (SAMHSA) and sanctioned by the state authority.

• To find methadone programs near you go here: https://dpt2.samhsa.gov/treatment/directory.aspx
• To find practitioners authorized to treat opioid dependency with buprenorphine by state please go here: https://www.samhsa.gov/medication-assisted-treatment/find-treatment/treatment-practitioner-locator
• FindTreatment.gov locator provides information on state-licensed providers who specialize in treating substance use disorders and mental illness.
• If you, or someone you know, need help to stop using substances – whether the problem is methamphetamine, alcohol or another drug – call SAMHSA’s National Helpline at 1-800-662-HELP (4357) or TTY: 1-800-487-4889

Certified treatment programs are obligated to prescribe and dispense methadone in accordance with the treatment requirements outlined in the Federal Opioid Treatment Standards (42 CFR 8.12) ⁴⁶.

The length of time a person receives methadone treatment varies. According to the National Institute on Drug Abuse publication Principles of Drug Addiction Treatment: A Research-Based Guide (Third Edition) ⁴⁷, the length of methadone treatment should be a minimum of 12 months. Some patients may require long-term maintenance. Patients must work with their practitioner to gradually reduce their methadone dosage to prevent withdrawal.

Methadone dosage

Methadone is a controlled substance and classified as a Schedule 2 drug, indicating that it has medical usefulness, but also a high potential for physical and psychological dependency and abuse. Methadone is available in various formulations, including a lipophilic hydrochloride salt, and can be administered orally, intramuscularly (IM), intravenously (IV), subcutaneously, epidurally, and intrathecally ⁴⁸, ⁴⁹, ¹⁹. The choice of methadone dosing and formulation is dependent on the intended purpose, with oral formulations in tablet or concentrated syrup being the most common.

Methadone instructions:

• Methadone oral is taken by mouth. The injection is given as an intravenous, intramuscular or subcutaneous injection.
• Measure liquid methadone with the supplied measuring device (not a kitchen spoon).
• Dissolve the dispersible tablet in water, orange juice, or other citrus-flavored non-alcoholic beverage. Stir and drink this mixture right away.
• Take methadone regularly with or without food
• Never crush a pill to inhale the powder or inject it into your vein. This could result in death.
• You should not stop using methadone suddenly. Ask your doctor before stopping methadone.

Adult dosage for Pain management

In pain management scenarios, individualize methadone dose. Methadone dosing recommendations vary between opioid-naive individuals and opioid-tolerant patients and should only be considered as suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient ¹⁹.

Methadone has a narrow therapeutic index, especially when combined with other drugs; monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy.

• Opioid-naive: For opioid-naive individuals, the recommended oral dosage is 2.5 mg every 8 hours, with the option for incremental dose increases approximately once per week if necessary ¹⁹.
• Opioid-tolerant: For opioid-tolerant patients, a methadone dosage of 10 mg orally is approximately equivalent to a 15-mg dose of oral morphine. Following dosing charts that provide equivalent dosing and conversion factors tailored to the individual patient is advised ¹⁹.

Adult dosage for Opioid Use Disorder (opioid addiction)

According to the American Society of Addiction Medicine guidelines of 2020, the following recommendations are outlined for the initiation, titration, and maintenance phases ⁵⁰.

• Initiation (induction): The recommended initial dose ranges from 10 to 30 mg, and reevaluation is advised within 2 to 4 hours, once peak levels have been attained. The timing of reassessment should not impede the initiation of methadone. Due to the risk of toxicity within the initial 2 weeks, maintaining a focus on tolerance is paramount for safety. Federal regulations mandate that the initial dose should not surpass 30 mg, and the total dose on the first day should not exceed 40 mg. For individuals with minimal or no opioid tolerance, reinitiating methadone after a relapse is advisable at a lower dose range of 2.5 to 10 mg.
• Titration: Due to methadone’s extended half-life, caution is essential to prevent rapid dose escalation within the initial 1 to 3 weeks of therapy. Doses do not consistently align with blood concentration levels. Therefore, dosing decisions should be individualized based on the patient’s response, recognizing that there can be considerable variation between individuals. Methadone is increased by no more than 10 mg approximately every 5 days based on opioid withdrawal symptoms and sedation. Although a low methadone dose of <30 mg/d can alleviate acute withdrawal, it may not effectively suppress cravings. Patients should be informed that experiencing discomfort is expected during the initial days of methadone titration.
• Maintenance: Some individuals may respond to a daily dosage of 30 to 60 mg, whereas most patients manage well when their initial dose is progressively elevated to a maintenance level ranging from 60 to 120 mg/d. Higher doses, specifically within the range of 80 to 100 mg/d, tend to enhance retention in treatment compared to lower doses. In certain cases, dosages exceeding 120 mg/d may be cautiously considered, especially for patients misusing highly potent opioids such as fentanyl and other synthetic opioids.

Adult dosage for Opioid Use Disorder during Pregnancy

Maintenance treatment should be continued in pregnant women with Opioid Use Disorder (opioid addiction) ¹. Buprenorphine should be considered instead, as it is known to cause less sedation in neonates ⁵¹. According to a recent study, the use of buprenorphine during pregnancy is associated with a lower risk of adverse neonatal outcomes than methadone. However, the risk of adverse maternal effects is similar for buprenorphine and methadone ⁵².

Adult dosage for Opioid Use Disorder during Breastfeeding

Breastfeeding infants of mothers undergoing methadone maintenance therapy receive an approximate dose equivalent to 1% to 3% (occasionally 5% to 6%) of the mother’s weight-adjusted methadone dosage ¹. Although breastfeeding may potentially diminish neonatal withdrawal symptoms, it does not necessarily lead to a reduction in the dosage of opiates used for therapy ⁵³. According to the American College of Obstetricians and Gynecologists (ACOG) guidelines and the Substance Abuse and Mental Health Services Administration (SAMHSA), breastfeeding is encouraged in patients who are stable on methadone maintenance therapy and are not using illicit drugs ⁵⁴.

Opioid withdrawal

Managing opioid withdrawal in both adults and neonates involves carefully tailored dosing strategies.

• Adults: Oral dosing for adults is initiated at 10 to 20 mg and is incrementally adjusted at 5 to 10 mg given orally after 2 to 4 hours if withdrawal symptoms have not been suppressed or if symptoms reappear until the withdrawal symptoms are controlled, usually about 40 mg (maximum day 1 dose). Stabilization of dosing is recommended for 2 to 3 days, followed by a gradual reduction in dose by 10% to 20% daily while monitoring for withdrawal symptoms ¹.
• Neonates: The oral dosage in neonates begins at 0.05 to 0.1 mg/kg every 6 hours until withdrawal symptoms stabilize. Subsequently, the dose should be systematically decreased by 10% to 20% daily, with ongoing serial monitoring of withdrawal symptoms ⁴².

Dose Adjustments

• Elderly patients: Start at the low end of the dosing range and closely monitor for signs of respiratory and central nervous system (brain and spinal cord) depression.
• Concomitant use with central nervous system depressants:
  • Assess the appropriateness of concomitant use
  • If the decision is made to begin methadone: Initial dose: 2.5 mg every 12 hours
  • Monitor for signs of sedation and respiratory depression; consider a lower dose of the concomitant central nervous system depressant.
• Cessation of chronic pain therapy: In physically-dependent patient: Gradually reduce dose every 2 to 4 days
• Cessation of opiate-dependence therapy: There is considerable variability in the rate at which patients taper off; abrupt discontinuation is not advised. Methadone dose reductions should generally be in increments of less than 10% every 10 to 14 days.
• Pregnancy: During pregnancy, a women’s methadone dose may need to be increased or the dosing interval decreased to achieve therapeutic effectiveness. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Kidney Dose Adjustments

• Kidney impairment: Start at the low end of the dosing range using longer dosing intervals and titrate slowly; closely monitor for signs of respiratory and central nervous system depression.

Liver Dose Adjustments

• Liver impairment: Start at the low end of the dosing range and titrate slowly; closely monitor for signs of respiratory and central nervous system depression.

What should I do if I forget a dose?

If your doctor has told you to take methadone for pain, take the missed dose as soon as you remember it and then continue your regular dosing schedule. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

If you are taking methadone to treat opioid addiction, skip the missed dose and take the next dose the next day as scheduled. Do not take a double dose to make up for a missed one.

Methadone overdose

Methadone overdose occurs when someone accidentally or intentionally takes more than the normal or recommended amount of methadone. This can be by accident or on purpose.

Methadone overdose can also occur if a person takes methadone with certain painkillers. These painkillers include oxycodone (Oxycontin), hydrocodone (Vicodin), hydromorphone (Dilaudid), or morphine.

Methadone overdose symptoms include the following

• Blue or purple fingernails and lips
• Cold, clammy skin
• Tiny pupils
• Low blood pressure
• Weak pulse
• Heartbeat slows or stops
• Breathing problems, including slow, labored, or shallow breathing
• Making gurgling noises
• No breathing
• Coma (decreased level of consciousness and lack of responsiveness)
• Confusion
• Disorientation
• Dizziness
• Drowsiness
• Cannot be awakened or are unable to speak
• Fatigue
• Muscle twitches
• Weakness
• Constipation
• Nausea and vomiting
• Spasms of the stomach or intestines.

If you suspect someone is experiencing methadone overdose, take action immediately:

• Call your local emergency services number and ask for an ambulance.
• Begin CPR if the person has stopped breathing or if breathing is very weak (best performed by someone who has training)
• Treat the person with naloxone or nalmefene to reverse opioid overdose (if available). Naloxone is a life-saving medication that can reverse an overdose from opioids, including methadone, and is often available to the general public without prescription.
• Pregnant women can be safely given both naloxone and nalmefene in limited doses under the supervision of a doctor. Nalmefene can cause opioid withdrawal in an unborn baby so it is important that doctors know Nalmefene has been used so the patient and baby can be monitored.

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

The doctor in the emergency room will measure and monitor your vital signs, including temperature, pulse, breathing rate, and blood pressure.

Tests that may be done include:

• Blood and urine tests
• Chest x-ray
• CT scan
• Electrocardiogram (ECG)

Additional treatment for methadone overdose may include:

• Fluids through a vein (by IV)
• Medicine to reverse the effects of the methadone (an antidote) and to treat other symptoms
• Activated charcoal
• Laxative
• Breathing support, including tube through the mouth and connected to a breathing machine (ventilator).

What Is Naloxone?

Naloxone is a medication approved by the Food and Drug Administration (FDA) designed to rapidly reverse opioid overdose. Naloxone is an opioid antagonist—meaning that it binds to opioid receptors and can reverse and block the effects of other opioids, such as heroin, morphine, and oxycodone. Naloxone is administered when a patient is showing signs of opioid overdose. Naloxone can be given by intranasal spray (into the nose), intramuscular (into the muscle), subcutaneous (under the skin), or intravenous (into a vein) injection.

Naloxone is a temporary treatment and its effects do not last long.

A doctor should assess the need to prescribe naloxone for patients who are taking methadone or buprenorphine receiving or otherwise considered a risk for opioid overdose.

In March 2023, the FDA approved naloxone nasal spray as the first over the counter opioid overdose reversal medication and is available in many pharmacies, through community-based distribution programs, local public health organizations or local health departments, free of charge. Check with your state for your local naloxone availability and restrictions.

Patients prescribed an automatic injection device for naloxone or who use the nasal spray should keep the item available at all times. It is important to remember to replace medication when the expiration date passes and if exposed to temperatures below 39°F or above 104°F.

What Is Nalmefene?

Nalmefene is another FDA-approved opioid overdose reversal medication nasal spray that is available by prescription only and is intended for use in health care and community settings for individuals who are 12 years old and over.

Nalmefene is an opioid receptor antagonist used to treat acute opioid overdose. However, it has a higher half-life than naloxone which means it can stay in the body for longer. This can make withdrawal symptoms more severe and last longer.

Nalmefene should be kept at room-temperature and away from direct sunlight. It is important to remember to replace medication when the expiration date passes.

Methadone overdose prognosis

In methadone overdose, How well someone does depends on the amount of methadone swallowed and how quickly treatment is received. The faster medical help is given, the better the chance for recovery.

If an antidote can be given, recovery from an overdose begins right away. However, since methadone’s effects can last for about a day, the person often stays in the hospital overnight. They may receive several doses of the antidote.

People who take a large methadone overdose may stop breathing. They may have seizures if they do not get the antidote quickly. Complications such as pneumonia, muscle damage from lying on a hard surface for a long time, or brain damage from lack of oxygen may cause permanent disability.

Death can occur in severe cases.

Methadone side effects

Like all opioid medicines, methadone can cause life-threatening breathing problems. The risk of these is higher:

• when you first take methadone
• after a dosage increase
• if you are older
• if you have an existing lung problem.

Methadone affects everyone differently. Your chances of experiencing side effects may depend on:

• if you regularly use methadone
• if you take methadone while also taking other drugs or medicines
• your dosage
• your weight
• your general health.

Common side effects of methadone include:

• Restlessness
• Nausea or vomiting
• Slow breathing
• Itchy skin
• Heavy sweating
• Constipation
• Headache or dizziness
• Fatigue or drowsiness (especially soon after a dose)
• Loss of appetite, nausea and vomiting.
• Sexual problems. Decreased sexual desire.

Methadone may make it difficult for you to drive or operate heavy machinery. If you have recently started taking an opioid medicine or changed dosage, you may be at a higher risk of having an accident.

Serious side effects of methadone include:

• Difficulty breathing or shallow breathing
• Feel lightheaded or faint
• Hives or a rash; swelling of the face, mouth, lips, tongue, or throat; hoarseness; difficulty breathing or swallowing
• Chest pain
• Fast or pounding heartbeat
• Hallucinations (seeing things or hearing voices that do not exist), agitation, or confusion
• Seizures
• Extreme drowsiness
• Fever, sweating, shivering, severe muscle stiffness or twitching, loss of coordination, or diarrhea
• Nausea, vomiting, loss of appetite, weakness, or dizziness
• Inability to get or keep an erection
• Irregular menstruation
• Difficulty urinating

If you experience any of the side effects symptoms or those mentioned in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical help. Always take methadone exactly as prescribed by your doctor.

Opioid withdrawal

Opioid withdrawal symptoms include:

• Feeling nervous, restless, or irritable
• Body aches
• Dizziness or weakness
• Diarrhea, stomach pain, or nausea
• Fever, chills, or goose bumps
• Sneezing or runny nose in the absence of a cold

If you take methadone regularly, you may become dependent on methadone, even if you take it exactly as prescribed and only for a short time. Your doctor will monitor how you use methadone to reduce your risk of harm.

Typical symptoms of opioid withdrawal include generalized pain, muscle pain, nausea, diarrhea, sweating, rhinorrhea, tearing, dilated pupils, tremor, gooseflesh, restlessness, and anxiety. For long-acting opioids, such as methadone, withdrawal symptoms usually begin within 24 to 36 hours of use and may last for several weeks. Unlike alcohol withdrawal, opioid withdrawal is rarely associated with severe morbidity and can be readily treated.

If you experience side effects while taking methadone, or you are concerned about your drug use, speak with your doctor.

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