Methadone is an opioid analgesic that is used in the detoxification and maintenance of opioid-addicted patients and intravenously for pain management.

Methadone Uses:

• Detoxification:

  • Together with adequate social and medical support, it is used in the detoxification and maintenance treatment of opioid addiction, such as that to heroin or other morphine-like substances. In individuals who cannot endure oral care, this injection is not a long-term solution.
  • Restrictions on use: It is not authorised for use in the outpatient treatment of opioid addiction in injection form. It has only been applied to individuals who are unable to take oral medication, such as those who are hospitalised.

• Pain management:

  • Injection:
    • It can be used intravenously in the Management of pain severe enough to require an opioid analgesic and for which alternative treatment options are not enough.
  • Oral (Dolophine only):
    • When other forms of treatment are insufficient to manage a pain that is severe enough to need daily, round-the-clock, long-term opioid treatment, the oral form is employed.
  • Limitations of use:
    • For patients for whom alternative treatment alternatives (such as non-opioid analgesics and opioid combination products) are ineffective, intolerable, or would otherwise be insufficient, reserve the use of non-opioid analgesics and opioid combination medications.

Methadone Dose in Adults:

• Create a dose schedule for each patient separately, taking into account the patient's level of pain, how they are responding, whether they have previously received analgesic treatment, and their propensity for addiction, abuse, and misuse.
• Methadone's relative analgesic effectiveness, absorption, and metabolism vary greatly from patient to patient. Exposure builds up with repeated doses, increasing methadone potency.
• Hence, when applied to individuals, equal analgesic conversion ratios between methadone and other opioids are not realistic and will change based on baseline opioid requirements.
• Deaths have happened in individuals who have previously abused high doses of other opioids as well as after conversion from chronic high-dose treatment with those drugs. While starting a treatment, switching from one opioid to another, and increasing the dose, strict clinical acumen is necessary.
• Full analgesic effects and steady-state plasma concentrations are not reached for at least 3 to 5 days after taking a dose. Methadone has a narrow therapeutic index, especially when coupled with other medications, and there is a higher risk of increased toxicity.

Methadone Dose in the Detoxification:

Note: Diskettes can only be taken in increments of 10 mg. Therefore, it might not be a good product for starting doses or reducing doses.

• IV:
  • It should be mentioned that only individuals who are unable to take oral medication, such as those in healthcare institutions, are permitted to utilise it.
  • Use the conversions in Pain Management to change the patient's oral methadone dose to an equivalent parenteral dose for dosing.
• Oral:
  • When the patient exhibits withdrawal symptoms and there are no indications of sedation or intoxication, it can first be administered as a single dose of 20 to 30 mg.
  • 30 mg is the maximum first dose.
  • Patients with poor tolerance at the beginning, such as those who have been without opioids for more than five days, should be given lower dosages to consider.
  • If withdrawal symptoms have not subsided or if they return after 2 to 4 hours, a further 5 to 10 mg may be given.
  • During the first day, the total daily dose shouldn't be more than 40 mg.
  • Without first achieving a steady-state, the dose shouldn't be raised.
  • For the first few days, levels will build up. Early treatment has resulted in fatalities.
  • Maintenance:
    • Titrate at a dose that avoids craving, reduces the euphoric effects of self-administered opioids, and tolerance to the sedative effects of methadone for 24 hours.
    • Titration should be done carefully and the typical range is 80 to 120 mg/day.
  • Withdrawal:
    • Every two weeks, dose decreases should be larger than 10% of the maintenance dose.

Methadone Dose in the short-term Detoxification: Oral:

• To establish stabilisation, the initial dose is administered as a titration to 40 mg/day in divided doses.
• Maintenance:
  • During two to three days, the dosage can be increased to 40 mg/day.
• Withdrawal:
  • Reduce the dose progressively every day or every two days after the patient has stabilised at 40 mg for two to three days.
  • Maintain dose at a level where the patient can feel comfortable while still experiencing manageable withdrawal symptoms.
  • A 20% reduction in the total daily dose may be tolerated by hospitalised patients. Those who are ambulatory may need a slower reduction.

Methadone Dose in the management of Pain:

• Opioid-naive: Oral:

  • Gradual titration (for chronic noncancer pain and situations where frequent monitoring is unnecessary):

    • It can be administered orally at first in doses of 2.5 mg every 8 hours, and afterwards up to 2.5 mg each dose or 5 mg per day every 5 to 7 days.
    • The administration interval can be increased to every 8 to 12 hours or longer after a steady dose has been obtained.

  • Faster titration (for cancer pain and situations where frequent monitoring is possible):

    • It can be administered initially as 2.5 mg every 6 to 8 hours and then gradually raised by 2.5 mg each dosage up to once daily over the course of roughly 4 days.
  • Manufacturer's labeling: The dosage described in the literature might not match what is done in practise today.
  • Opioid-naive (use as the first opioid analgesic):
    • Oral (Dolophine only): 2.5 mg every 8 to 12 hours at first.
    • IM, IV, Subcutaneously: 2.5 to 10 mg every 8 to 12 hours

Methadone Conversion recommendations:

• Opioid-tolerant:

  • Conversion from oral morphine to oral methadone:

    • While there is no linear link when switching from oral morphine to methadone, the more effective methadone is, the greater the daily morphine equivalent dose, and switching to methadone is more of a process than a calculation.
    • Even in individuals using high dosages of other opioids, the beginning dose of methadone should generally not be higher than 30 to 40 mg/day.
    • Throughout the conversion process, it is important to keep a close eye on the patient's response to methadone.
    • The ratios for switching from oral morphine to oral methadone have been suggested in a number of ways.
    • To reflect the recommended dosing pattern, divide the predicted daily total dose of methadone (eg, divide by 3 and administer every 8 hours).
    • Individuals who haven't taken an opioid in the past one to two weeks should be regarded as opioid naive.
    • Manufacturer's labeling:
      • The dose schedule described in the literature might not be current with clinical practise today.
      • When methadone therapy is started, stop using any other 24/7 opioids.
      • Patients who were opioid-tolerant have died during the methadone conversion process.
      • Relative potency varies significantly from patient to patient.
      • Consequently, it is far safer to supply patients with more rescue medication than they actually need in terms of daily methadone dosage (eg, immediate-release opioid).
      • It is preferable to underestimate needs. It's important to closely monitor the patient's response to methadone
      • For patients taking a single opioid, add the patient's current total daily dose of that drug, convert it to a morphine equivalent dose using that drug's conversion factor, and then multiply the morphine equivalent dose by the appropriate percentage to determine the patient's near-approximate oral methadone daily dose.
      • By the specified dosing schedule, ration the daily dose of methadone as needed (i.e, divide by 3 for administration every 8 hours).
      • If necessary, round down to the closest strength. Calculate the approximate oral methadone dose for each opioid in a patient's regimen, aggregate the results, and then divide the result by the recommended dosing schedule to get the approximate daily methadone dose.
      • Just the opioid component of these drugs should be used in the conversion for patients using a fixed-ratio opioid-nonopioid analgesic regimen.
      • Notably, the conversion factors stated below should only be used to convert from another opioid analgesic to methadone; they should not be used to convert from methadone to another opioid as doing so could result in a deadly overdose from an overestimation of the new opioid.

  • Conversion from oral opioids to oral methadone:

    • Less than 100 mg of oral morphine are taken each day. Therefore, 20% to 30% of the total daily morphine dose is roughly equivalent to the daily oral methadone dose.
    • 100–300 mg of oral morphine each day. In that case, the daily oral methadone dosage should be between 10% and 20% of the daily morphine dosage.
    • 300–600 mg of oral morphine each day. In that case, the daily oral methadone dosage should be between 8% and 12% of the daily morphine dosage.
      daily intake of 600–1,000 mg of morphine. Hence, the daily oral methadone dosage should be between 5% and 10% of the daily morphine dosage.
    • Over 1,000 mg of oral morphine each day. Hence, less than 5% of the total daily morphine dose is approximated to be taken orally each day.

  • Conversion from oral morphine to parenteral methadone:

    • Less than 100 mg of oral morphine are taken each day. Therefore 10% to 15% of the total daily morphine dose should be the approximate intravenous methadone dose.
    • 100 to 300 mg of oral morphine are recommended daily. Then, the daily intravenous methadone dosage should be between 5% and 10% of the daily morphine dosage.
    • 300–600 mg of oral morphine each day. Then the daily intravenous methadone dosage should be between 4% and 6% of the daily morphine dosage.
    • daily intake of 600–1,000 mg of morphine. The daily dose of intravenous methadone would then be between 3% and 5% of the daily dose of morphine.
    • Using more than 1,000 mg of oral morphine every day. The daily dose of intravenous methadone would then be less than 3% of the daily dose of morphine.

  • Conversion from parenteral morphine to parenteral methadone:

    • Parenteral morphine dosage ranges from 10 to 30 mg per day. then the daily parenteral methadone dose ranges between 40% and 66%.
    • 30 to 50 mg of parenteral morphine are administered daily. the daily parenteral methadone dose ranges from 27% to 66%.
    • 50 to 100 mg of parenteral morphine are administered daily. then the daily parenteral methadone dose ranges between 22% and 50%.
    • 100 to 200 mg of parenteral morphine are administered daily. then the daily parenteral methadone dose ranges between 15% and 34%.
    • 200 to 500 mg of parenteral morphine are administered daily. then 10% to 20% of parenteral methadone should be administered daily.

  • Conversion from parenteral methadone to oral methadone:

    • Parenteral: Oral ratio of 1:2 for the initial dose (for example 5 mg parenteral methadone equals 10 mg oral methadone)
    • Titration and maintenance:
      • No more frequently than every 3 to 5 days can the dose be changed. Some patients may need to wait significantly longer between dose increases due to strong interpatient variability (up to 12 days).
      • If negative effects are noticed, a lower dose or shorter dosing interval (e.g., every 8 or 12 hours) may be needed.
      • Increased dosage or rescue therapy using an immediate-release analgesic may be necessary for breakthrough pain.
      • According to certain recommendations, dose increases shouldn't exceed 10 mg per day every five to seven days.

• Discontinuation:

  • While quitting this medication, a patient who is physically dependent should receive a dose reduction of no more than 10% to 25%, and the patient should continue receiving downward titration every two to four weeks.
  • Withhold the taper briefly if the patient exhibits withdrawal symptoms, or increase the dose to the prior level and then reduce the dose more gradually by lengthening the intervals between dose reductions and lowering the daily dose reduction, or both.

Methadone Dose in the treatment of critically ill patients (off-label):

In situations where escalation with other opioids is necessary, it may be used to delay the onset of tolerability. In patients who are unfamiliar with opioids, unpredictable pharmacokinetics and pharmacodynamics are also seen. rigorously observe the QTc interval.

• 10 to 40 mg taken orally every 6 to 12 hours
• 2.5 to 10 mg intravenously every 8 to 12 hours. IV infusion is not advised, though.
• Enteral (off-label route):
  • It's been employed to wean patients off of lengthy continuous opioid infusions.

Methadone Dose in Children:

Methadone Dose in the treatment of severe Pain:

Note:

• Given that the efficacy of methadone varies depending on the patient's current exposure to opioids, doses should be gradually increased to get the desired impact.
• It is advised to use lesser doses in patients who have never used opioids.
• The relative analgesic strength, absorption, and metabolism of methadone vary greatly from patient to patient, and exposure accumulates with repeated dosages, increasing the potency of the drug.
• As a result, when applied to individuals, equianalgesic conversion ratios between methadone and other opioids are inaccurate and will change based on baseline opioid requirements.
• Since methadone has a long half-life, accumulation is possible.
• If sedation develops, stop taking more doses until it goes away. You may also want to explore lowering the dose or extending the time between doses (eg, every 8 to 12 hours).

• Infants ≤6 months, nonventilated:

  • IV, SubQ: 0.025 mg/kg/dose every 4 to 8 hours
  • Oral: 0.025 to 0.05 mg/kg/dose every 4 to 8 hours

• Infants >6 months, Children, and Adolescents, nonventilated:

  • IV, SubQ:
    • Patient weight <50 kg:
      • 0.1 mg/kg/dose every 4 to 8 hours
    • Patient weight ≥50 kg:
      • 5 to 8 mg every 4 to 8 hours
  • Oral:
    • Patient weight <50 kg:
      • 0.1 to 0.2 mg/kg/dose every 4 to 8 hours
    • Patient weight ≥50 kg: 5 to 10 mg every 4 to 8 hours

Methadone Dose in the Iatrogenic opioid dependency:

The ideal regimen has not been established and there have been few research. The patient's previous opioid dose, time spent using opioids, and the severity of opioid withdrawal must all be taken into account when determining the appropriate dose and taper schedule for methadone.

• Prevention:

  • Children and Adolescents:
    • There is no one method that has been demonstrated to be better than another when it comes to conversion equivalence factors, when to convert to oral, or how long the taper should go.
    • When necessary, one should adhere to institutional protocol. Individuals who have used opioids for longer than 14 days are more prone to have opioid withdrawal and typically need to wean off of their opioid doses, which might necessitate switching to methadone.
    • A tapering strategy of roughly 10% to 20% of the initial dose every 24 to 48 hours has been advised once the methadone dose has stabilised.

• Treatment:

  • Infants and Children: Oral:
    • starting with a dose of 0.05 to 0.1 mg/kg every 6 hours.
    • Until withdrawal symptoms are under control, increase the dose by 0.05 mg/kg/dose.
    • The dose interval can be extended to every 12 to 24 hours after 24 to 48 hours.
    • Up until a dose of 0.05 mg/kg/day, taper the dose and wean the animal as tolerated, then stop.

Methadone Pregnancy Category: C

• Methadone can be easily found in foetal urine and amniotic fluid since it crosses the placenta.
• Studies show that methadone can be more harmful to the foetus than beneficial.
• The Teratogen Information System's data can be affected by maternal medication usage, diet, infection, and psychosocial issues.
• Methadone can also be used to treat pregnant women who have been using illicit drugs.
• Infants born to mothers who are opioid-addicted and were treated with methadone during pregnancy may have a decreased growth rate, birth weight, length, or head circumference.
• While growth deficits can be remediated over time, behavioral and psychological effects will persist.
• There have also been reports of aberrant foetal nonstress test results.
• [US Boxed Warning]Infants can experience withdrawal symptoms from opioids. If not treated, it can be life-threatening.
• The balance between the hazards of newborn opioid withdrawal syndrome and the advantages of maternal methadone may vary depending on the risk factors linked to maternal pain or addiction.
• It is important that mothers are informed about the possible adverse effects of neonates.
• When an individual is exposed to opioids, they may experience symptoms including fever, fluctuating body temperature, gastrointestinal issues (such as diarrhoea or vomiting), poor nutrition/weight gain, or neurologic (such as high-pitched wailing and increased muscle tone, irritability).
• Monitor neonates for signs of the opioid-abstinence disorder.
• Pregnant women may be treated with opioid agonist pharmacotherapy using Methadone.
• Dosage adjustment is necessary during pregnancy because the pharmacokinetics of pregnancy are unpredictable.
• Women who are taking methadone to treat addiction should continue to take their daily dose.
• They should be provided with the same options for labour and delivery pain management as women who do not use opioids.
• Methadone-treated women who are pregnant should avoid opioid agonists-antagonists because they can cause acute withdrawal.
• Long-term opioid use can lead to secondary hypogonadism, which can cause infertility or sexual dysfunction in women and men.
• Maintenance doses of methadone won't be enough to relieve your pain.
• Reduced ejaculate volume, reduced seminal and prostate secretions, and altered sperm motility have all been linked to treatment.
• Females can experience amenorrhea as well as pregnancy while using hormonal contraception.
• Unplanned pregnancies can be prevented by counseling with contraception

Use of methadone while breastfeeding

• Breast milk contains Methadone.
• The relative infant dose (RID), for a breastfed infant, has been calculated at 2% to 3.3% of the maternal dose.
• The literature reports that this RID was caused by oral maternal doses of 20-80 mg/day for 12 breastfeeding women.
• Some breastfed infants who are being given methadone by their mothers can detect it in their plasma.
• Breastfed infants are more likely to experience respiratory depression or sedation.
• These adverse events may be more severe for some infants. 
• Two infants were fatally exposed to methadone through breast milk.
• This could be due to genetic factors, but other risk factors could also have contributed.
• According to the manufacturer women should monitor their infants while breastfeeding to ensure they are not experiencing increased drowsiness or breathing problems.
• They should also be trained on when to call their doctor for emergency care.
• Additionally, breastfeeding during therapy should be considered in light of the risks to infants, the benefits to the mother, and the benefits to the mother.
• Guidelines allow breastfeeding if methadone is being used to treat opioid addiction in breastfeeding women.
• However, it is important to ensure that the baby is able to tolerate the medication and does not have any contraindications like illicit drugs, alcohol, or HIV.
• Breastfeeding should be stopped if there are other contraindications.

Methadone Dose in Kidney Disease:

No specific dose adjustment is given in the literature however caution is advised. The patient should be monitored for sedation and respiratory depression.

• The following dosage adjustments have been recommended:

  • CrCl ≥10 mL/minute:
    • No dosage adjustment is necessary.
  • CrCl <10 mL/minute:
    • Administer 50% to 75% of the normal dose
  • Hemodialysis and peritoneal dialysis do not increase elimination of methadone.

Methadone Dose in Liver disease:

• It undergoes hepatic metabolism.
• So in liver disease dose should be adjusted according to clinical acumen.
• And observe for symptoms of respiratory depression and sedation.

Side effects of Methadone:

• Cardiovascular:

  • Bigeminy
  • Bradycardia
  • Cardiac Arrhythmia
  • Cardiac Failure
  • Cardiomyopathy
  • ECG Changes
  • Edema
  • Extrasystoles
  • Flushing
  • Hypotension
  • Inversion T Wave On ECG
  • Palpitations
  • Phlebitis
  • Prolonged Q-T Interval On ECG
  • Shock
  • Syncope
  • Tachycardia
  • Torsades De Pointes
  • Ventricular Fibrillation
  • Ventricular Tachycardia

• Central Nervous System:

  • Agitation
  • Confusion
  • Disorientation
  • Dizziness
  • Drug Dependence (Physical Dependence)
  • Dysphoria
  • Euphoria
  • Hallucination
  • Headache
  • Insomnia
  • Sedation
  • Seizure

• Dermatologic:

  • Diaphoresis
  • Hemorrhagic Urticaria (Rare)
  • Pruritus
  • Skin Rash
  • Urticaria

• Endocrine & Metabolic:

  • Adrenocortical Insufficiency
  • Altered Hormone Level (Androgen Deficiency; Chronic Opioid Use)
  • Amenorrhea
  • Antidiuretic Effect
  • Decreased Libido
  • Decreased Plasma Testosterone
  • Hypokalemia
  • Hypomagnesemia
  • Weight Gain

• Gastrointestinal:

  • Abdominal Pain
  • Anorexia
  • Biliary Tract Spasm
  • Constipation
  • Glossitis
  • Nausea
  • Vomiting
  • Xerostomia

• Genitourinary:

  • Asthenospermia
  • Decreased Ejaculate Volume
  • Male Genital Disease (Reduced Seminal Vesicle Secretions)
  • Prostatic Disease (Reduced Prostate Secretions)
  • Spermatozoa Disorder (Morphologic Abnormalities)
  • Urinary Hesitancy
  • Urinary Retention

• Hematologic:

  • Thrombocytopenia (Reversible
  • Reported In Patients With Chronic Hepatitis)

• Local:

  • Erythema At Injection Site (Intramuscular/Subcutaneous)
  • Local Pain (Intramuscular/Subcutaneous)
  • Local Swelling (Intramuscular/Subcutaneous)

• Neuromuscular & Skeletal:

  • Amyotrophy
  • Bone Fracture
  • Osteoporosis
  • Weakness

• Ophthalmic:

  • Visual Disturbance

• Respiratory:

  • Pulmonary Edema
  • Respiratory Depression

Contraindications to Methadone:

• Methadone and any component thereof are contraindicated in the presence of hypersensitivity.
• Respiratory depression can be severe (in the absence or unmonitored setting)
• Acute bronchial asthma in the absence of resuscitative gear or in an unmonitored environment
• Type 2 respiratory failure
• Paralytic ileus, GI obstruction and confirmed or suspected GI obstruction
• Due to similar chemical and physical properties, cross-sensitivities or allergic reactions cannot be ruled.

Canadian labeling: Additional contraindications not in US labeling

• Diarrhea caused by pseudomembranous or toxic colitis, or until the toxic material is eliminated from the GI tract.
• Concurrent use of the MAOI within 14 days is contraindicated.
• Obstructive airway.
• Management of acute pain
• Patients are naive about opioids.
• Bowel transit diseases and conditions
• Suspected surgical abdomen (eg acute appendicitis, pancreatitis).
• Cor pulmonale
• Acute alcoholism, convulsive disorders and severe CNS depression are all contraindications.
• In addition to the above, breastfeeding and pregnancy are contraindicated as is use during labor.

Warnings and precautions

• CNS depression:

  • It can cause severe CNS depression, so those who handle machineries should be cautious.

• Constipation

  • It can cause constipation. This is a problem for patients with unstable angina or post-myocardial injury (MI).
  • To reduce constipation, consider preventive measures such as stool softener or increased fiber.

• Hypotension

  • It can also cause severe hypotension, orthostatic hypotension, and syncope. 
  • Patients with hypovolemia, heart disease, acute MI or medications that can exaggerate hypotensive effects, such as phenothiazines and general anesthetics, should be cautious.
  • Hypotension should always be monitored closely
  • Patients with circulatory shock should not use this product.

• QT prolongation: [US Boxed Warning]:

  • QT interval prolongation, serious arrhythmias (torsades-de-pointes), and prolongation of QT intervals have been reported during treatment.
  • Patients are often prescribed large daily doses of methadone to treat their pain.
  • Patients who received opioid maintenance treatment have reported cases of addiction.
  • It should be closely watched for changes in the cardiac rhythm during initiation or titration in patients who are at high risk for QT interval, such as those with cardiac hypertrophy, concurrent use of diuretics, hypokalemia, and hypomagnesemia, a history of cardiac conduction abnormalities, and those who take medications that affect cardiac conduction.
  • Higher doses of over 200 mg/day may cause QT interval prolongation or torsades d'pointes.
  • Patients who have had high doses methadone and no previous cardiac history have shown QT prolongation.
  • Only if the possible benefit outweighs the danger of QT prolongation or the emergence of dysrhythmias should patients be treated.
  • Patients with a baseline QTc interval greater than 500 msec are advised to use other agents.

• Respiratory depression [US Boxed Warning]

  • Patients who were converted to methadone have been linked to deaths and respiratory depression.
  • This happened even though the drug was prescribed and not misused.
  • Methadone treatment should be done correctly and administered according to the prescribed dose.
  • Only qualified healthcare professionals should prescribe methadone to patients suffering from opioid addiction.
  • Watch out for signs of respiratory depression, particularly during methadone initiation or after a dose increase.
  • In the latter phase, methadone's respiratory depressive effects reach their climax.
    Particularly during the initial dose interval, they last longer than its peak analgesic effects.
  • The sedating effects of opioids can be exacerbated by carbon dioxide retention due to opioid-induced respiratory depression.

• Serotonin syndrome:

  • Lithium, St. John's wort, serotonergic agents (such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, triptans, and tricyclic antidepressants), agents that interfere with serotonin metabolism (such as monoamine oxidase inhibitors), and agents that interfere with the metabolism of tramadol can all cause serotonin syndrome (eg, CYP2D6 and 3A4 inhibitors).
  • keep an eye out for serotonin syndrome symptoms in patients (eg, agitation or hallucinations, and coma).
  • Furthermore, autonomic instability has been documented, including tachycardia and labile blood pressure.
  • Frequent findings include heat, Gastrointestinal symptoms, and neuromuscular issues (such as hyperreflexia and incoordination) (eg. nausea, vomiting, diarrhea).

• Conditions abdominales:

  • It can cause impedance when diagnosing subacute abdominal disease.
  • Patients with obstruction should be advised not to use this product.

• Adrenocortical Insufficiency

  • Patients with adrenal insufficiency (including Addison disease) should exercise caution.
  • Long-term opioid abuse can lead to secondary hypogonadism. This could cause infertility, sexual dysfunction, mood disorders, and osteoporosis.

• Insufficiency of the biliary tract:

  • Patients with biliary dysfunction (including acute pancreatitis) should exercise caution. It can also lead to constriction in the sphincter Oddi.

• CNS depression/coma:

  • Patients with impaired consciousness and coma should not be used, as they are more susceptible to the intracranial effects CO2 retention.

• Delirium tremens:

  • Patients with delirium-tremens should be taken with caution

• Head trauma

  • Patients with intracranial lesions or a head injury should be used with extreme caution.
  • It is possible to exaggerate the ICP.

• Hepatic impairment

  • Patients with hepatic impairment should be cautious.

• Mental health conditions

  • Patients with mental disorders (e.g. depression, suicidal tendencies or anxiety disorders, posttraumatic Stress disorder, etc.) should be cautious about using opioids for chronic pain management. There is a greater risk of opioid overdose and opioid use disorder.
  • It is recommended to keep strict and frequent surveillance.
  • Methadone has been shown to be ineffective in relieving anxiety.

• Obesity:

  • Patients who are severely obese should be taken with caution

• Opioid addiction: [US Boxed Warning]

  • Methadone should only be used to treat opioid addiction.
  • Only opioid addiction therapy in detoxification and maintenance programmes should use methadone.
  • Only opioid treatment programmes (or organisations or doctors with official contracts with programme sponsors) that have been approved by the substance abuse mental health services administration should be able to administer it.
  • The methadone has also received state approval.
  • According to the Federal Opioid Treatment Standards, only approved treatment programmes are permitted to prescribe and administer oral formulations of methadone.
  • Injunctions that prevent program operation or criminal prosecution may be issued if you fail to comply with these regulations.
  • There are some exceptions to the requirements for certification as a provider of opioid agonist therapy. These include inpatient treatment for other conditions, and an emergency period no longer than three days while definitive treatment is being sought.

• Prostatic hyperplasia/urinary restriction:

  • Patients with prostatic hyperplasia or urinary stricture should exercise caution.

• Psychosis:

  • Patients with toxic psychosis should exercise caution.

• Renal impairment

  • Patients with impaired renal function should exercise caution.

• Respiratory disease

  • Patients with severe chronic obstructive lung disease (cor pulmonale) or significant chronic obstructive breathing problems, as well as those who have a significantly decreased respiratory reserve, hypoxia or hypercapnia or pre-existing respiratory depression should be monitored carefully when initiating or titrating therapy. 
  • Even at therapeutic doses, fatal respiratory depression can occur.
  • You might consider using non-opioid analgesics for these patients.

• Seizure disorders:

  • Patients with seizure disorders should be cautious. It might cause and exacerbate seizures.

• Sleep-related disorders

  • Dose-dependent, opioid use can increase the risk of sleep-related disorders such as central sleep apnea [CSA], and hypoxemia.
  • Patients with sleep-disordered or heart disease should be cautious about chronic pain.
  • Patients who have CSA should be considered for dose reduction.
  • Patients with severe or moderate sleep-disordered breathing should avoid opioids

• Thyroid dysfunction:

  • Patients with thyroid dysfunction should be cautious.

Methadone: Drug Interaction

Monitoring parameters:

These parameters must be respected

• It can be used to relieve pain, improve mental and respiratory health.
• Blood pressure
• Signs of abuse, misuse, and addiction
• Signs and symptoms of hypogonadism/hypoadrenalism
• Also, consider constipation, nausea and pruritus.
• You should monitor your blood glucose levels if you are taking more than 40 mg of glucose daily.
• Before starting therapy, obtain baseline ECG.
• An ECG that was taken within the last 3 months with a QTc of less than 450msec can be used to establish a baseline for patients who have not developed new risk factors. After significant dose increases, repeat the ECG for 2 to 4 weeks.
• If there are any signs/symptoms or risk factors that have not been addressed, an ECG follow-up should be performed.
• When methadone is taken in lower doses, repeat ECG.
• Then again, if the dose exceeds 30-40 mg per day, and then again at 100 mg/day.
• Patients who can self-report pain should use the Numeric Rating Scale in Critically Ill patients.
• Patients who cannot self-report pain can use the Behavioral Pain Score and the Critical Care Pain Observational Instrument in intubated patients.

Alternate suggestions:

• For chronic pain (long-term treatment that is not provided by end-of life or palliative care), active cancer treatment, sickle cells disease or medication-assisted opioid use disorder treatment):
  • Assess the benefits and risks of opioid therapy within one to four weeks after treatment initiation. Dose increases are also considered.
  • Patients at higher risk for overdose or those with opioid addiction should be re-evaluated every 12 weeks.
  • Before initiating any treatment, it is recommended that urine drug testing be done.
  • Re-checking should also be performed at least once a year (includes prescription drugs and illegal drugs of abuse).
  • Clinicians should review state prescription drug monitoring program data (PDMP) prior to initiation, and periodically during therapy (frequency ranging between every prescription to every three months).

How to administer Methadone?

Oral:

• Tablets for oral suspension (for detoxification and maintenance):
  • intended for oral administration; never inject (contains insoluble excipients).
  • Before administering, dissolve the pill with 120 mL of water, orange juice, or any acidic fruit beverage.
  • Add a little liquid to the cup in case any insoluble excipients are still present and haven't completely dissolved before administering the remaining mixture.
  • Before dissolving the tablet in drink, avoid chewing or swallowing it.

Injection:

• Apply IV, SubQ, or IM.
• Undefined is the IV administration rate.
• It seems unpredictable how SubQ and IM will be absorbed.
• There can be local tissue responses.

Mechanism of action of Methadone:

• The CNS binds to the opiate receptors, which causes inhibition of ascending pain pathways.
• This alters the perception and response to pain.
• Methadone also has N-methyl-D–aspartate receptor antagonistism (NMDA).

The onset of action:

• Oral: Analgesic: 0.5 to 1 hour;
• Parenteral: 10 to 20 minutes

Peak effect:

• Parenteral: 1 to 2 hours;
• Oral: Continuous dosing: 3 to 5 days

Duration of analgesia:

• Oral: Repeated doses extend the duration of action from 4 to 8 hours (single-dose studies) to 22 to 48 hours; delayed release from the liver and other tissues may contribute to this.

Protein binding:

• 85% to 90%, primarily to alpha-1 acid glycoprotein

Metabolism:

• Hepatic; N-demethylation primarily via CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6 to inactive metabolites

Bioavailability:

• Oral: 36% to 100%

Half-life elimination: Terminal:

• Children and Adolescents: 19.2 ± 13.6 hours (range: 3.8 to 62 hours).
• Adults: 8 to 59 hours; may be prolonged with alkaline pH

Time to peak, plasma:

• 1 to 7.5 hours

Excretion:

• Urine (<10% as unchanged drug).
• It is increased with urine pH <6.
• It is important to know that methadone may stay in the tissues of the liver and other organs.
• Despite low serum concentrations, slow tissue release may extend the pharmacologic action.

International Brand Names of Methadone:

• Dolophine
• Methadone HCl Intensol
• Methadose
• Methadose Sugar-Free
• Metadol
• Metadol-D
• SANDOZ Methadone
• Adolan
• Amidona
• Amidone
• Biodone
• Biodone Extra Forte
• Biodone Forte
• Depridol
• Dolmed
• Eptadone
• Gobbidona
• Heptadon
• Heptanon
• Ketalgin
• Mephenon
• Metacalmans
• Metadol
• Metadon
• Metasedin
• Methaddict
• Methadone chlorhydrate
• Methadone Hydrochloride
• Methadose
• Methapain
• Methasan
• Misyo
• MISYO
• Mytadon Cristalia
• Mytedom
• Pallidone
• Phymet DTF
• Physeptone
• Pinadone DTF
• Rubidexol
• Sublana

Methadone Brand Names in Pakistan:

No Brands Available in Pakistan.