methadone

General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

**REMS Drug**

Pronunciation:
meth-a-done


Trade Name(s)

  • Dolophine
  • Metadol Canadian Tradename
  • Metadol-D Canadian Tradename
  • Methadose

Ther. Class.

opioid analgesics

Pharm. Class.

opioid agonists

Controlled Substance Schedule: II

Indications

  • Moderate to severe chronic pain in opioid-tolerant patients requiring use of daily, around-the-clock long-term opioid treatment and for which alternative treatment options are inadequate (extended-release)
  • Detoxification and maintenance therapy for opioid use disorder.

Unlabeled Use(s):

Neonatal abstinence syndrome.

Action

  • Binds to opiate receptors in the CNS.
  • Alters the perception of and response to painful stimuli, while producing generalized CNS depression.

Therapeutic Effect(s):

  • Decrease in severity of pain.
  • Suppression of withdrawal symptoms during detoxification and maintenance from heroin and other opioids.

Pharmacokinetics

Absorption: Well absorbed from all sites (50% absorbed following oral administration). IV administration results in complete bioavailability.

Distribution: Widely distributed. Crosses the placenta; enters breast milk.

Protein Binding: 85–90%.

Metabolism and Excretion: Mostly metabolized by the liver; some metabolites are active and may accumulate with chronic administration.

Half-life: 15–25 hr; ↑ with chronic use.

TIME/ACTION PROFILE (analgesic effect)

ROUTEONSETPEAKDURATION
PO30–60 min90–120 min4–12 hr
IM, IV, subcut10–20 min60–120 min8–12 hr

Contraindication/Precautions

Contraindicated in:

  • Hypersensitivity;
  • Significant respiratory depression;
  • Acute or severe bronchial asthma;
  • Paralytic ileus;
  • Known alcohol intolerance (some oral solutions);
  • Concurrent MAO inhibitor therapy.

Use Cautiously in:

  • Structural heart disease, concomitant diuretic use, hypokalemia, hypomagnesemia, history of arrhythmia/syncope, or other risk factors for arrhythmias;
  • Concurrent use of drugs that prolong the QTc interval or are CYP3A4 inhibitors;
  • Head trauma;
  • Seizure disorders;
  • ↑ intracranial pressure;
  • Severe renal, hepatic, or pulmonary disease;
  • Hypothyroidism;
  • Adrenal insufficiency;
  • Alcoholism;
  • Undiagnosed abdominal pain;
  • Prostatic hyperplasia or ureteral stricture;
  • OB:   Use with addiction control: weigh risk against potential for illicit drug use. Counsel mother about potential harm to fetus. Prolonged use of methadone during pregnancy can result in neonatal opioid withdrawal syndrome;
  •  Lactation: May lead to excessive sedation or respiratory depression in infant. Use while breast feeding only if potential maternal benefit justifies potential risk to infant;
  • Geri:  ↑ risk of respiratory depression (dose ↓ suggested).

Adverse Reactions/Side Effects

CV: TORSADES DE POINTES, hypotension, bradycardia, QT interval prolongation

Derm: flushing, sweating

EENT: blurred vision, diplopia, miosis

Endo: adrenal insufficiency

GI: constipation, nausea, vomiting

GU: urinary retention

Neuro: confusion, sedation, dizziness, dysphoria, euphoria, floating feeling, hallucinations, headache, unusual dreams

Resp: RESPIRATORY DEPRESSION (including central sleep apnea and sleep-related hypoxemia)

Misc: physical dependence, psychological dependence, tolerance

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  • Use with extreme caution in patients receiving  MAO inhibitors  (may result in severe, unpredictable reactions–↓ initial dose of methadone to 25% of usual dose).
  • Use with extreme caution with any drug known to potentially prolong QT interval, including  class I and III antiarrhythmics, some  neuroleptics  and  tricyclic antidepressants, and  calcium channel blockers.
  • Use with extreme caution with CYP3A4 inhibitors, including  ketoconazole,  itraconazole,  erythromycin,  clarithromycin,  calcium channel blockers, or  voriconazole.
  • Concurrent use with  laxatives,  diuretics, or  mineralocorticoids  may ↑ risk of hypomagnesemia or hypokalemia and ↑ risk of arrhythmias.
  • Drugs that affect serotonergic neurotransmitter systems, including  tricyclic antidepressants,  SSRIs,  SNRIs,  MAO inhibitors,  TCAs,  tramadol,  trazodone,  mirtazapine,  5–HT3  receptor antagonists,  linezolid,  methylene blue, and  triptans  ↑ risk of serotonin syndrome.
  • Concurrent use of  CYP3A4 inhibitors,  CYP2C9 inhibitors,  CYP2C19 inhibitors, or  CYP2D6 inhibitors  including  ritonavir,  ketoconazole,  itraconazole,  fluconazole,  clarithromycin,  erythromycin,  nefazodone,  diltiazem,  verapamil,  nelfinavir,  fosamprenavir, and  fluvoxamine  ↑ levels and risk of opioid toxicity; careful monitoring during initiation, dose changes, or discontinuation of the inhibitor is recommended.
  • Concurrent use with  CYP3A4 inducers,  CYP2C9 inducers, or  CYP2C19 inducers  including  barbiturates,  carbamazepine,  efavirenz,  corticosteroids,  modafinil,  nevirapine,  oxcarbazepine,  phenobarbital,  phenytoin,  rifabutin, or  rifampin  may ↓ levels and analgesia; if inducers are discontinued or dosage ↓, patients should be monitored for signs of opioid toxicity and necessary dose adjustments should be made.
  • Use with  benzodiazepines  or other  CNS depressants  including other  opioids,  non-benzodiazepine sedative/hypnotics,  anxiolytics,  general anesthetics,  muscle relaxants,  antipsychotics, and  alcohol  may cause profound sedation, respiratory depression, coma, and death; reserve concurrent use for when alternative treatment options are inadequate.
  • Administration of  agonist/antagonist opioids  may precipitate opioid withdrawal in physically dependent patients.
  •  Nalbuphine  may ↓ analgesia.
  •  Interferons (alpha)  may ↓ metabolism and ↑ effects.
  • May ↑ blood levels and effects of  zidovudine  and  desipramine.
  • May ↓ level and effects of  didanosine  and  stavudine.
  • Concurrent abuse of methadone with  benzodiazepines  has resulted in death
  •  Mixed agonist/antagonist analgesics, including  nalbuphine  or  butorphanol  and  partial agonist analgesics, including  buprenorphine , may ↓ methadone's analgesic effects and/or precipitate opioid withdrawal in physically dependent patients.

Drug-Natural Products:

Route/Dosage

Moderate-to-Severe Pain

PO (Adults and Children  ≥50 kg): Usual starting dose for moderate to severe pain in opioid-naive patients– 2.5 mg every 8–12 hr;

PO (Adults and Children  <50 kg): 0.1 mg/kg/dose every 4 hr for 2–3 doses then every 6–8 hr prn; maximum: 10 mg/dose.

PO IV (Neonates): Initial 0.05–0.2 mg/kg/dose every 12–24 hr or 0.5 mg/kg/day divided every 8 hr; taper dose by 10–20% per wk over 1–1.5 mo.

IV IM Subcut (Adults and Children  ≥50 kg): 10 mg every 6–8 hr.

IV IM Subcut (Adults and Children  <50 kg): 0.1 mg/kg every 6–8 hr; maximum: 10 mg/dose.

Opioid Detoxification

PO (Adults and Children  ≥50 kg): 15–40 mg once daily or amount needed to prevent withdrawal. Dose may be ↓ every 1–2 days; maintenance dose is determined on an individual basis.

PO (Adults and Children  <50 kg): 0.05–0.1 mg/kg/dose every 6 hr; ↑ by 0.05 mg/kg/dose until withdrawal symptoms controlled; after 1–2 days lengthen dosing interval to every 12–24 hr; taper by ↓ dose by 0.05 mg/kg/day.

IV IM Subcut (Adults and Children  ≥50 kg): 15–40 mg once daily or amount needed to prevent withdrawal. Dose may be ↓ every 1–2 days; maintenance dose is determined on an individual basis.

Availability (generic available)

Tablets: 1 mg Canadian Tradename, 5 mg, 10 mg, 25 mg Canadian Tradename

Oral concentrate (cherry and unflavored): 10 mg/mL

Oral solution (contains alcohol) (citrus): 5 mg/5 mL, 10 mg/5 mL

Solution for injection: 10 mg/mL

Tablets for oral suspension: 40 mg (available only to licensed detoxification/maintenance programs)

Assessment

  • Pain:

    Assess type, location, and intensity of pain prior to and 1–2 hr (peak) following administration. When titrating opioid doses, increases of 25–50% should be administered until there is either a 50% reduction in the patient's pain rating on a numeric or visual analogue scale or the patient reports satisfactory pain relief. Dose increases should be made no more frequently than every 3–5 days because of variability in half-life between patients. Cumulative effects of this medication may require periodic dose adjustments.

    • Doses of methadone for patients on methadone maintenance only prevent withdrawal symptoms;  no analgesia is provided. Additional opioid doses are required for treatment of pain.
  • An equianalgesic chart (see equianalgesic dosing guidelines) should be used when changing routes or when changing from one opioid to another.
  • Assess BP, pulse, and respirations before and periodically during administration. If respiratory rate is <10/min, assess level of sedation. Dose may need to be decreased by 25–50%. Initial drowsiness will diminish with continued use. Monitor for respiratory depression, especially during initiation or following dose increase; serious, life-threatening, or fatal respiratory depression may occur. May cause sleep-related breathing disorders (central sleep apnea [CSA], sleep-related hypoxemia).
  • Assess bowel function routinely. Prevention of constipation should be instituted with increased intake of fluids and bulk and with laxatives to minimize constipating effects. Stimulant laxatives should be administered routinely if opioid use exceeds 2–3 days, unless contraindicated. Consider drugs for opioid induced constipation.
  • Prolonged use may lead to physical and psychological dependence and tolerance. This should not prevent patient from receiving adequate analgesia. Patients who receive methadone for pain rarely develop psychological dependence. Progressively higher doses may be required to relieve pain with long-term therapy.
  • Assess for history of structural heart disease, arrhythmia, and syncope. Obtain a pretreatment ECG to measure QTc interval and follow-up ECG within 30 days and annually. Additional ECGs recommended if dose >100 m g/day or if patients have unexplained syncope or seizures. If QTc interval is >450 ms but <500 ms, discuss potential risks and benefits with patients and monitor more frequently. If the QTc interval >500 ms, consider discontinuing or reducing dose; eliminating contributing factors (drugs that promote hypokalemia) or using an alternative therapy.
  • Assess risk for opioid addiction, abuse, or misuse prior to administration. Abuse or misuse by crushing, chewing, snorting, or injecting dissolved product will result in uncontrolled delivery of methadone and can result in overdose and death.
  • Opioid Detoxification: Assess patient for signs of opioid withdrawal (irritability, runny nose and eyes, abdominal cramps, body aches, sweating, loss of appetite, shivering, unusually large pupils, trouble sleeping, weakness, yawning). Methadone maintenance is undertaken only by federally approved treatment centers. This does not preclude maintenance for addicts hospitalized for other conditions and who require temporary maintenance during their care.

Lab Test Considerations:

May ↑ plasma amylase and lipase levels.

Toxicity and Overdose:

If an opioid antagonist is required to reverse respiratory depression or coma, naloxone is the antidote. Dilute the 0.4-mg ampule of naloxone in 10 mL of 0.9% NaCl and administer 0.5 mL (0.02 mg) by IV push every 2 min. For children and patients weighing <40 kg, dilute 0.1 mg of naloxone in 10 mL of 0.9% NaCl for a concentration of 10 mcg/mL and administer 0.5 mcg/kg every 2 min. Titrate dose to avoid withdrawal, seizures, and severe pain.

Implementation

  • High Alert: Do not confuse methadone with dexmethylphenidate, ketorolac, memantine, Mephyton (phytonadione), methylphenidate, or metolazone.
  • When used for the treatment of opioid addiction in detoxification or maintenance programs, methadone is dispensed only by opioid treatment programs certified by the Substance Abuse and Mental Health Services Administration approved by the designated state authority.
  • Explain therapeutic value of medication prior to administration to enhance the analgesic effect.

    • Regularly administered doses may be more effective than prn administration. Analgesic is more effective if administered before pain becomes severe. For patients in chronic severe pain, the oral solution containing 5 or 10 mg/5 mL is recommended on a fixed dose schedule.
    • Coadministration with nonopioid analgesics may have additive analgesic effects and may permit lower doses.
    • Avoid the use of mixed agonist/antagonist (nalbuphine, butorphanol) or partial agonist (buprenorphine) analgesics in patients taking methadone.
    • Medication should be discontinued gradually after long-term use to prevent withdrawal symptoms. For patients on long-acting agents who are physically opioid-dependent, initiate the taper by a small enough increment (less than 10% of total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 wk. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. Monitor frequently to manage pain and withdrawal symptoms (restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate). If withdrawal symptoms occur, pause the taper for a period of time or raise the dose of opioid analgesic to the previous dose, and then proceed with a slower taper. Also, monitor patients for changes in mood, emergence of suicidal thoughts, or use of other substances. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic.
  •  REMS: FDA strongly encourages health care professionals to complete a REMS-compliant education program that includes all the elements of the FDA Education  Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain,  available at www.fda.gov/OpioidAnalgesicREMSBlueprint. Information on programs can be found at 1-800-503-0784 or www.opioidanalgesicrems.com.
  • Discuss availability of naloxone for emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing therapy, especially if patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any patient.
  • PO Doses may be administered with food or milk to minimize GI irritation.
    • Dilute each dose of 10 mg/mL oral concentrate with at least 30 mL of water or other liquid prior to administration.
    • Diskettes (dispersible tablets) are to be dissolved and used for detoxification and maintenance treatment only. Available only to licensed detoxification/maintenance programs.
  • Subcut IM IM is the preferred parenteral route for repeated doses. Subcut administration may cause tissue irritation.
  • IV Push:  Administer undiluted.
  • Rate: Inject slowly.
  • Y-Site Compatibility:
    • amifostine
    • amikacin
    • aminocaproic acid
    • MORE...
      • aminophylline
      • amiodarone
      • amphotericin B lipid complex
      • amphotericin B liposome
      • ampicillin
      • ampicillin/sulbactam
      • anidulafungin
      • argatroban
      • arsenic trioxide
      • atropine
      • azithromycin
      • aztreonam
      • bleomycin
      • bumetanide
      • busulfan
      • calcium chloride
      • calcium gluconate
      • carboplatin
      • carmustin
      • caspofungin
      • cefazolin
      • cefepime
      • cefotaxime
      • cefotetan
      • cefoxitin
      • ceftazidime
      • ceftriaxone
      • cefuroxime
      • chloramphenicol
      • chlorpromazine
      • ciprofloxacin
      • cisatracurium
      • cisplatin
      • clindamycin
      • cyclophosphamide
      • cyclosporine
      • cytarabine
      • dacarbazine
      • dactinomycin
      • daptomycin
      • daunorubicin hydrochloride
      • dexamethasone
      • dexmedetomidine
      • dexrazoxane
      • diazepam
      • digoxin
      • diltiazem
      • diphenhydramine
      • dobutamine
      • docetaxel
      • dopamine
      • doxorubicin hydrochloride
      • doxorubicin liposome
      • doxycycline
      • droperidol
      • enalaprilat
      • ephedrine
      • epinephrine
      • epirubicin
      • eptifibatide
      • ertapenem
      • erythromycin
      • esmolol
      • esomeprazole
      • etoposide
      • etoposide phosphate
      • famotidine
      • fenoldopam
      • fluconazole
      • fludarabine
      • foscarnet
      • fosphenytoin
      • gemcitabine
      • gentamicin
      • glycopyrrolate
      • granisetron
      • haloperidol
      • heparin
      • hydralazine
      • hydrocortisone
      • idarubicin
      • ifosfamide
      • imipenem/cilastatin
      • insulin, regular
      • irinotecan
      • isoproterenol
      • ketorolac
      • labetalol
      • leucovorin calcium
      • levofloxacin
      • lidocaine
      • linezolid
      • lorazepam
      • magnesium sulfate
      • mannitol
      • melphalan
      • meropenem
      • mesna
      • methotrexate
      • methylprednisolone
      • metoclopramide
      • metoprolol
      • metronidazole
      • midazolam
      • milrinone
      • mitomycin
      • mitoxantrone
      • morphine
      • moxifloxacin
      • mycophenolate
      • nafcillin
      • naloxone
      • nicardipine
      • nitroglycerin
      • nitroprusside
      • norepinephrine
      • octreotide
      • ondansetron
      • oxaliplatin
      • oxytocin
      • paclitaxel
      • palonosetron
      • pamidronate
      • pancuronium
      • pantoprazole
      • pemetrexed
      • phenobarbital
      • phenylephrine
      • potassium acetate
      • potassium chloride
      • potassium phosphates
      • procainamide
      • prochlorperazine
      • promethazine
      • propranolol
      • quinupristin/dalfopristin
      • rocuronium
      • sodium acetate
      • sodium bicarbonate
      • sodium phosphates
      • streptozocin
      • succinylcholine
      • tacrolimus
      • theophylline
      • thiotepa
      • tirofiban
      • tobramycin
      • topotecan
      • vancomycin
      • vasopressin
      • vecuronium
      • verapamil
      • vinblastine
      • vincristine
      • vinorelbine
      • voriconazole
      • zidovudine
      • zoledronic acid
  • Y-Site Incompatibility:
    • acyclovir
    • allopurinol
    • dantrolene
    • MORE...
      • fluorouracil
      • ganciclovir
      • methohexital
      • pentobarbital
      • phenytoin
      • piperacillin/tazobactam
      • thiopental
      • trimethoprim/sulfamethoxazole.

Patient/Family Teaching

  • Instruct patient on how and when to ask for and take pain medication.
  •  REMS: Instruct patient to take methadone exactly as directed. If dose is less effective after a few wk, do not increase dose without consulting health care professional. Discuss safe use, risks, and proper storage and disposal of opioid analgesics with patients and caregivers with each Rx. The Patient Counseling Guide (PCG) is available at www.fda.gov/OpioidAnalgesicREMSPCG.
  • Advise patient that methadone is a drug with known abuse potential. Protect it from theft, and never give to anyone other than the individual for whom it was prescribed. Store out of sight and reach of children, and in a location not accessible by others.
  • Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Inform patients and caregivers about various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (by prescription, directly from a pharmacist, or as part of a community-based program).
  • May cause drowsiness or dizziness. Advise patient to call for assistance when ambulating or smoking and to avoid driving or other activities requiring alertness until response to medication is known.
  • Inform patient of the potential for arrhythmias and emphasize the importance of regular ECGs.
  • Caution patient to notify health care professional if signs of overdose (difficult or shallow breathing, extreme tiredness or sleepiness, blurred vision, inability to think, talk, or walk normally, and feelings of faintness, dizziness, or confusion) occur. Methadone has a prolonged action causing increased risk of overdose.
  • Advise patient to change positions slowly to minimize orthostatic hypotension.
  • Advise patient to tell health care professional what medications they are taking and to avoid taking new Rx, OTC, vitamins, or herbal products without consulting health care professional. Caution patient to avoid concurrent use of alcohol or other CNS depressants with this medication.
  • Encourage patient to turn, cough, and breathe deeply every 2 hr to prevent atelectasis.
  • Rep:  Advise patient to notify health care professional if pregnancy is planned or suspected, or if breast feeding. Inform patient of potential for neonatal opioid withdrawal syndrome with prolonged use during pregnancy. Monitor neonate for signs and symptoms of withdrawal symptoms (irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight); usually occur the first days after birth. Monitor infants exposed to methadone through breast milk for excess sedation and respiratory depression. Chronic use may reduce fertility in females and males. During pregnancy, a woman's methadone dose may need to be increased or the dosing interval decreased due to increased clearance.

Evaluation/Desired Outcomes

  • Decrease in severity of pain without a significant alteration in level of consciousness or respiratory status.
  • Prevention of withdrawal symptoms in detoxification from heroin and other opioid analgesics.

methadoneis the Anesthesia Central Word of the day!