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:

  • It is used in detoxification and maintenance treatment of opioid addiction for example in heroin or other morphine-like drugs, along with appropriate social and medical input. This injection is not a permanent treatment in patients who cannot tolerate orally.
  • Limitations of use: In Injection form, it is Not approved for outpatient treatment of opioid addiction. It has only been used in patients unable to take oral medication like in hospitalized patients.

• 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):
    • The oral form is used in the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment, and for which alternative treatment options are not enough.
  • Limitations of use:
    • Reserve for use in patients for whom alternative treatment options like nonopioid analgesics and opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient control of pain.
    • Dolophine is not recommended for use as an as-needed analgesic.

Methadone Dose in Adults:

• Concoct the dosing regimen for each patient individually, taking into account the patient's intensity of pain, his/her response, previous analgesic treatment experience, and risk factors for addiction, abuse, and misuse.
• Methadone has high patient to patient variability in absorption, metabolism, and relative analgesic potency and exposure accumulates with frequent dosing, resulting in increased methadone potency.
• Therefore, equivalent analgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals and will vary depending on baseline opioid requirements.
• Deaths have occurred during conversion from chronic high-dose treatment with other opioids and in patients who previously abused high doses of other opioids. strict clinical acumen is required during treatment initiation, during conversion from one opioid to another, and during dose increase.
• Steady-state plasma concentrations and full analgesic effects are not achieved until at least 3 to 5 days on a dose, Methadone has a narrow therapeutic index, especially when combined with other drugs, and has more risk of increased toxicity.

Methadone Dose in the Detoxification:

Note: Diskettes can be administered only in 10 mg increments. However, it may not be an appropriate product for initial dose or dose reductions.

• IV:
  • It should be noted that its use is only allowed in patients unable to take oral medication such as those in patient facilities.
  • For dosing, convert patient's oral methadone dose to an equivalent parenteral dose using the conversions provided in Pain Management.
• Oral:
  • Initially, it can be given as 20 to 30 mg as a single dose when there are no signs of sedation or intoxication and the patient shows symptoms of withdrawal.
  • The maximum initial dose is 30 mg.
  • Lower doses should be considered in patients with low tolerance at initiation like in absence of opioids for more than 5 days.
  • An additional 5 to 10 mg may be provided if withdrawal symptoms have not been terminated or if symptoms reappear after 2 to 4 hours.
  • The total daily dose should not exceed 40 mg on the first day.
  • The dose should not be increased without waiting for a steady-state to be achieved.
  • Levels will accumulate over the first few days. Fatalities have occurred in early treatment due to cumulative effects.
  • Maintenance:
    • Titrate to a dose that prevents opioid withdrawal symptoms for 24 hours, prevents craving, alleviates the euphoric effect of self-administered opioids, and tolerance to sedative effects of methadone.
    • The usual range is 80 to 120 mg/day and titration should be done judiciously.
  • Withdrawal:
    • Dose reductions should be greater than 10% of the maintenance dose, every fortnight.

Methadone Dose in the short-term Detoxification: Oral:

• The initial dose is given as, titrate to approximately 40 mg/day in divided doses to achieve stabilization.
• Maintenance:
  • It can be continued as a 40 mg/day dose for 2 to 3 days.
• Withdrawal:
  • After 2 to 3 days of stabilization at 40 mg, gradually taper the dose on a daily basis or at 2-day intervals.
  • Keep dose at a level sufficient to keep withdrawal symptoms at a level at which the patient can feel comfortable.
  • Hospitalized patients may tolerate a total daily dose decrease of 20%. Ambulatory patients may require a more slow reduction.

Methadone Dose in the management of Pain:

• Opioid-naive: Oral:

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

    • Initially, it can be given orally as 2.5 mg every 8 hours and can be increased up to  2.5 mg per dose or 5 mg per day every 5 to 7 days.
    • Once a stable dose is reached, the administration interval can be extended to every 8 to 12 hours or longer.

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

    • Initially, it can be given as 2.5 mg every 6 to 8 hours and can be increased by 2.5 mg per dose as often as every day over about 4 days.
    • Once a stable dose is reached, the dosing interval can be extended to every 8 to 12 hours or longer.
  • Manufacturer's labeling: Dosing in the literature might not concur with current clinical practice.
  • Opioid-naive (use as the first opioid analgesic):
    • Oral (Dolophine only): Initially as 2.5 mg every 8 to 12 hours
    • IM, IV, Subcutaneously: Initially as 2.5 to 10 mg every 8 to 12 hours

Methadone Conversion recommendations:

• Opioid-tolerant:

  • Conversion from oral morphine to oral methadone:

    • There is not a linear relationship when converting to methadone from oral morphine however, the higher the daily morphine equivalent dose the more potent methadone is, and conversion to methadone is more of a process than a calculation.
    • In general, the starting methadone dose should not be in excess of 30 to 40 mg/day, even in patients on high doses of other opioids.
    • Patient response to methadone needs to be monitored closely throughout the process of the conversion.
    • There are several proposed ratios for converting from oral morphine to oral methadone.
    • The estimated total daily methadone dose should then be divided to reflect the indicated dosing schedule (eg, divide by 3 and administer every 8 hours).
    • Patients who have not previously taken an opioid for 1 to 2 weeks should be considered opioid naïve.
    • Manufacturer's labeling:
      • The dosing regimen in the literature might not reflect current clinical practice.
      • stop all other around-the-clock opioids when methadone therapy is initiated.
      • Fatalities have occurred in opioid-tolerant patients during conversion to methadone.
      • Substantial patient to patient variability exists in relative potency.
      • Therefore, it is much safe to underestimate a patient's daily methadone requirement and provide breakthrough pain relief with rescue medication (eg, immediate-release opioid).
      • It is better than to overestimate requirements. Patient response to methadone needs to be assessed closely throughout the process of the conversion.
      • For patients on a single opioid, add the current total daily dose of an oral opioid, convert it to a morphine equivalent dose according to the conversion factor for that particular opioid, then multiply the morphine equivalent dose by the corresponding percentage to calculate the near close oral methadone daily dose.
      • Ration the total daily methadone dose by intended dosing schedule (i.e, divide by 3 for administration every 8 hours).
      • Round down, if required, to the nearest strength available. For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and add the total to obtain the approximate total methadone daily dose, and divide the total daily methadone dose by the indicated dosing schedule (i.e, divide by 3 for administration every 8 hours).
      • For patients on a regimen of fixed-ratio opioid-nonopioid analgesic medications, only the opioid component of these medications should be used in the conversion.
      • It is noteworthy that conversion factors listed below are only for the conversion from another opioid analgesic to methadone and cannot be used to convert from methadone to another opioid as doing so might lead to fatal overdose due to overestimation of the new opioid.

  • Conversion from oral opioids to oral methadone:

    • The daily oral morphine dose is less than 100 mg. Then approximate daily oral methadone dose is 20% to 30% of total daily morphine dose
    • Daily oral morphine dose 100 to 300 mg. Then approximate daily oral methadone dose is 10% to 20% of total daily morphine dose
    • Daily oral morphine dose 300 to 600 mg. Then approximate daily oral methadone dose is 8% to 12% of total daily morphine dose
    • Daily oral morphine dose 600 to 1,000 mg. Then approximate daily oral methadone dose is 5% to 10% of the total daily morphine dose.
    • Daily oral morphine dose >1,000 mg. Then approximate daily oral methadone dose is less than 5% of the total daily morphine dose.

  • Conversion from oral morphine to parenteral methadone:

    • The daily oral morphine dose is less than 100 mg. Then approximate daily intravenous methadone dose is 10% to 15% of total daily morphine dose
    • Daily oral morphine dose  is 100 to 300 mg. Then approximate daily intravenous methadone dose is 5% to 10% of total daily morphine dose
    • Daily oral morphine dose 300 to 600 mg. Then approximate daily intravenous methadone dose is 4% to 6% of total daily morphine dose
    • Daily oral morphine dose 600 to 1,000 mg. Then approximate daily intravenous methadone dose is 3% to 5% of the total daily morphine dose.
    • Daily oral morphine dose more than 1,000 mg. Then approximate daily intravenous methadone dose is less than 3% of the total daily morphine dose.

  • Conversion from parenteral morphine to parenteral methadone:

    • Total daily parenteral morphine dose is 10 to 30 mg. Then approximate daily parenteral methadone dose is 40% to 66%
    • The total daily parenteral morphine dose is 30 to 50 mg. Then approximate daily parenteral methadone dose is 27% to 66%
    • The total daily parenteral morphine dose is 50 to 100 mg. Then approximate daily parenteral methadone dose is  22% to 50%
    • The total daily parenteral morphine dose is 100 to 200 mg. Then approximate daily parenteral methadone dose is 15% to 34%
    • The total daily parenteral morphine dose is 200 to 500 mg. Then approximate daily parenteral methadone dose is 10% to 20%

  • Conversion from parenteral methadone to oral methadone:

    • Initial dose: Parenteral: Oral ratio= 1:2 (for example 5 mg parenteral methadone equals 10 mg oral methadone)
    • Titration and maintenance:
      • The dose can be adjusted no more frequently than every 3 to 5 days. Due to high interpatient variability, substantially longer periods between dose increases may be necessary for some patients (up to 12 days).
      • If adverse reactions are observed, then a reduction in dose or dosing interval (ie, every 8 or 12 hours) might be required.
      • Breakthrough pain may require a dose increase or rescue therapy with an immediate-release analgesic.
      • Some guidelines note that dose increases should not be more than 10 mg per day every 5 to 7 days.

• Discontinuation:

  • When stopping this drug, gradual tapering off should be done, such as decreasing the dose by no more than 10% to 25% in a physically dependent patient and continue downward titration every 2 to 4 weeks.
  • If the patient shows withdrawal symptoms, temporarily withhold the taper or increase the dose to the previous level and then reduce the dose more slowly by increasing the duration between dose reductions and decreasing the amount of daily dose reduction, or both.

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

It may be used to slow the development of tolerability when escalation with other opioids is required. Unpredictable pharmacokinetics/pharmacodynamics in opioid-naive patients are also observed. Monitor QTc interval strictly.

• Orally as 10 to 40 mg every 6 to 12 hours
• Intravenously as 2.5 to 10 mg every 8 to 12 hours. However, IV infusion not recommended.
• Enteral (off-label route):
  • It has been used to wean prolonged continuous opioid infusions.

Methadone Dose in Childrens:

Methadone Dose in the treatment of severe Pain:

Note:

• Doses should be titrated up for the required effect as the potency of methadone varies according to the patient’s current exposure to opioids.
• Use of lower doses in opioid naïve patients is recommended.
• Methadone has high patient-patient variability in absorption, metabolism, and relative analgesic potency and exposure accumulates with repeated doses, which results in increased methadone potency.
• Therefore, equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals and will vary depending on baseline opioid requirements.
• Methadone may accumulate due to its long half-life.
• If sedation occurs, stop further doses until sedation resolves and consider a reduction in dose and increase the dosing interval (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:

Limited studies have been done and the optimal regimen is not defined. Methadone dose and taper schedule must be individualized and will depend upon the patient's previous opioid dose, length of time on opioids, and severity of opioid withdrawal.

• Prevention:

  • Children and Adolescents:
    • Several studies have shown the variability in conversion equivalence factors, when to convert to oral, and how long the taper should be, none of which have been proven to be superior to another.
    • One should follow institutional protocols as and when needed. Patients receiving opioids for more than 14 days are more likely to experience opioid withdrawal and usually require opioid doses to be weaned, which may require transition to methadone.
    • Once the methadone dose is stabilized, a weaning schedule of approximately 10% to 20% reduction of the original dose every 24 to 48 hours has been recommended.

• Treatment:

  • Infants and Children: Oral:
    • Initially as 0.05 to 0.1 mg/kg/dose every 6 hours.
    • Increase the dose by 0.05 mg/kg/dose until withdrawal symptoms are under control.
    • After 24 to 48 hours, the dosing interval can be lengthened to every 12 to 24 hours.
    • Taper the dose and wean it as tolerated until a dose of 0.05 mg/kg/day, then discontinue.

Methadone Pregnancy Category: C

• Methadone crosses over the placenta, and can be easily detected in fetal urine and amniotic fluid.
• Methadone can cause more harm than good for the fetus, according to studies.
• Information gathered by the Teratogen Information System can be complicated by maternal use illicit drugs, nutrition, infected, and psychosocial conditions.
• 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.
• Also, abnormal fetal nonstress test results have been reported.
• [US Boxed Warning]Infants can experience withdrawal symptoms from opioids. If not treated, it can be life-threatening.
• Based on the risk factors associated with maternal pain or addiction, the balance between neonatal opioid withdrawal syndrome's risks and the benefits of maternal methadone may be different.
• It is important that mothers are informed about the possible adverse effects of neonates.
• Opioid exposure can cause symptoms such as fever, temperature instability, gastrointestinal problems (eg diarrhea, vomiting), poor nutrition/weight gain, or neurologic (eg high-pitched crying 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 also need to be given the same pain management options for labor and delivery as women who are not using opioids. Methadone maintenance doses will not provide sufficient pain relief.
• 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.
• Treatment has been shown to result in decreased ejaculate volume, lower seminal and prostate secretions, and abnormalities of sperm motility.
• 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.
• You can manage mild, intermittent or short-term pain with other medications.
• 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 monitored closely in patients at high risk for QT interval, such as those with cardiac hypertrophy, concomitant use of diuretics, hypokalemia and hypomagnesemia, a history cardiac conduction abnormalities and those who take medications that affect cardiac conduction for changes to the cardiac rhythm during initiation or titration.
  • 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.
  • Patients should only be treated if the potential benefit is greater than the risk of QT prolongation or development of dysrhythmias.
  • Patients with a baseline QTc interval greater than 500 msec are advised to use other agents.

• Respiratory depression [US Boxed Warning]

  • Methadone has been associated with fatalities and respiratory depression in patients who were converted to it.
  • 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.
  • Methadone's peak respiratory depressant effects are found in the latter phase.
  • They last longer than its peak analgesic effects, especially during the initial dose period.
  • The sedating effects of opioids can be exacerbated by carbon dioxide retention due to opioid-induced respiratory depression.

• Serotonin syndrome:

  • Serotonin syndrome can occur with concurrent use of serotonergic agents (eg, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, triptans, tricyclic antidepressants), lithium, St. John's wort, agents that impede metabolism of serotonin (eg, monoamine oxidase inhibitors), or agents that impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors).
  • Monitor patients for signs of serotonin syndrome (eg, agitation or hallucinations, and coma).
  • Also, autonomic instability such as tachycardia and labile blood pressure has been noted. Common observations include hyperthermia, neuromuscular disorders (eg. hyperreflexia and incoordination) as well as GI symptoms (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.
  • Methadone should only be administered to opioid addiction treatment in detoxification and maintenance programs.
  • It should only be administered by opioid treatment programs (or agencies or practitioners with formal agreements with program sponsors) that have been certified by the substance abuse mental health services administration.
  • The state authority has also approved the methadone.
  • Only certified treatment programs may prescribe and administer methadone in oral formulation according to the Federal Opioid Treatment Standards.
  • 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):
  • For oral administration only; do not inject (contains insoluble excipients).
  • Disperse tablet in ~120 mL of water, orange juice, or other acidic fruit beverage prior to administration.
  • If insoluble excipients remain and do not entirely dissolve, add a small amount of liquid to the cup and administer the remaining mixture.
  • Do not chew or swallow the tablet before dispersing it in liquid.

Injection:

• Administer IM, SubQ, or IV.
• The rate of IV administration not defined.
• The absorption of SubQ and IM appears to be unpredictable.
• Local tissue reactions may occur.

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: 4 to 8 hours (single-dose studies), increases to 22 to 48 hours with repeated doses; slow release from the liver and other tissues may prolong the duration of action

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 noteworthy that Methadone may persist in the liver and other tissues.
• Slow-release from tissues may prolong the pharmacologic effect despite low serum concentrations

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.