Methadone
Methadone hydrochloride
Also known as: Dolophine · Methadose · Diskets · Comfortan · Synthadon · Amidine HCl · amidone HCl · methadoni hydrochloridum · Phenadone · Methadone hydrochloride · Metadona
Reviewed by the VetSheet Veterinary TeamUpdated Apr 5, 2026Evidence-based veterinary reference
Audited v13 dosing evidence
Reviewed non-calculator evidenceReviewed non-calculator evidence (1)
Evidence only — not for automatic calculation
Anesthesia premedication (extra-label)
Anesthesia premedication (extra-label): Methadone 0.1 – 0.6 mg/kg IV, IM, or SC 70,74
Governing clinical context (2)
- NOTE: All listed dosages are based on the methadone HCl salt formulation (10 mg methadone HCl is equivalent to ≈8.9 mg of methadone). Most products are labeled with methadone HCl strength but check before administering to patients.
- Methadone injection should be stored at room temperature of 20°C to 25°C (68°F-77°F) and protected from light. Store vials in the manufacturer’s carton until ready for use.
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Overview
Methadone is a synthetic, highly efficacious mu-opioid receptor agonist used primarily as a preanesthetic and analgesic in dogs and cats. Compared to morphine, it causes significantly less histamine release when administered intravenously, and generally results in less vomiting and sedation.
Clinical Pearls & Pharmacological Advantages:
- Triple Mechanism: Unlike most traditional opioids, methadone is not only a mu-agonist but also a non-competitive NMDA receptor antagonist and a monoamine (serotonin and norepinephrine) reuptake inhibitor.
- Neuropathic Pain: Because of its NMDA antagonism, methadone is particularly valuable for treating refractory pain, neuropathic pain, and preventing central sensitization ("wind-up" pain).
- Bioavailability: It has very poor oral bioavailability in dogs, making parenteral administration (IV, IM, SC) the standard route in veterinary medicine.
- Regulatory: It is a Schedule II (C-II) controlled substance due to its high potential for human abuse.
Mechanism of action
Methadone provides analgesia through a unique, multi-modal mechanism of action:
- Mu-Opioid Receptor (MOR) Agonism: Binds to MORs in the central nervous system → inhibits adenylyl cyclase → decreases cAMP → promotes opening of inward-rectifying potassium channels and closing of voltage-gated calcium channels → hyperpolarization of neurons and decreased release of nociceptive neurotransmitters (e.g., Substance P, glutamate).
- NMDA Receptor Antagonism: Acts as a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor → blocks glutamate binding → reduces central sensitization and hyperalgesia.
- Monoamine Reuptake Inhibition: Inhibits the presynaptic reuptake of serotonin (5-HT) and norepinephrine (NE) → increases monoamine concentrations in the synaptic cleft → enhances descending inhibitory pain pathways in the spinal cord.
Safety & warnings
Contraindications
- Late-term pregnancy (due to risks of respiratory depression and stillbirths)
- Known hypersensitivity to methadone
- No specific contraindications available in the monograph, but use with caution in patients with severe respiratory compromise or hepatic impairment.
Adverse effects
- Panting
- Whining or vocalization
- Defecation
- Constipation
- Bradycardia
- Pronounced CNS excitement (in horses at IV doses ≥ 0.1 mg/kg)
- Respiratory depression (primarily under general anaesthesia)
- Transient excitation (when given IV)
- Salivation (when given via oral transmucosal route in cats due to preservatives)
- Constriction of gastrointestinal sphincters (e.g., pyloric sphincter)
- Reduction in gastrointestinal motility (with prolonged use)
- Neonatal sedation (crosses the placenta)
Precautions
All opiates should be used with caution in patients with heart failure, hypertension, head injuries, elevated CSF pressures, and in geriatric or severely debilitated patients.
Note: Methadone can increase plasma amylase and lipase values up to 24 hours following administration due to increased biliary tract pressure.
Drug interactions
May increase risks for arrhythmias
Potentiates sedative and analgesic effects; combination with medetomidine may cause severe hypoxemia in dogs breathing room air
May increase methadone levels in humans (does not appear to be true for dogs)
May increase risks for arrhythmias
May cause increased CNS or respiratory depression
May increase potential for electrolyte abnormalities
Opiates may decrease diuretic efficacy in CHF patients
May inhibit metabolism of methadone and increase levels in humans (does not appear to be true for dogs)
Potential for severe CNS/behavioral reactions; concomitant use should be avoided
Methadone may enhance neuromuscular blockade
May decrease methadone levels in humans (probably does not affect dogs)
May decrease methadone levels in humans (probably does not affect dogs)
May increase methadone levels
May decrease methadone levels in humans (probably does not affect dogs)
Methadone may exacerbate the effects of tricyclic antidepressants
Opiates may potentiate anticoagulant activity
Methadone may increase zidovudine levels
Increased CNS or respiratory depression
Monitoring
- Analgesic or preanesthetic efficacy
- Respiratory rate and depth (monitor for respiratory depression, especially at higher doses)
- Heart rate (bradycardia)
- CNS depression or excitation
- Respiratory rate and depth (especially under general anaesthesia)
- Pain scores (due to individual variation in response)
- Level of sedation
- Gastrointestinal motility (with prolonged use)
Pharmacokinetics
Half-life
Absorption
In dogs, methadone has poor oral bioavailability (not significantly affected by ketoconazole or omeprazole). Subcutaneous bioavailability is ~80% with peak levels around 1 hour. In horses, orally administered methadone is well absorbed but rapidly eliminated.
Distribution
Highly lipid-soluble and widely distributed. In humans, it is extensively bound to plasma proteins (60-90%).
Metabolism
Hepatic. Unlike in humans, CYP3A does not appear to be a major metabolic pathway for methadone biotransformation in dogs. Metabolites are inactive.
Elimination
In dogs, clearance is about 25-30 mL/kg/min.
Overdose
Overdosage may produce profound respiratory and/or CNS depression in most species. Newborns are particularly susceptible. Other toxic effects include cardiovascular collapse, hypothermia, and skeletal muscle hypotonia.
Treatment:
- Naloxone is the reversal agent of choice for treating respiratory depression. In massive overdoses, naloxone doses may need to be repeated because naloxone's effects might diminish before sub-toxic levels of methadone are attained.
- Mechanical respiratory support should be considered in severe cases.
- Dialysis, charcoal hemoperfusion, or forced diuresis do not appear to be beneficial.
Available products
Formulations
- Injection
- Oral tablets
- Dispersible tablets
- Oral solution/liquid concentrate
- Injectable: 10 mg/ml solution (including generic preservative-free preparations)
- Oral: 10 mg tablets
Veterinary
- Comfortan 10 mg/ml solution for injection
- Synthadon 10 mg/ml solution for injection
Human-labeled
- Methadone HCl Injection: 10 mg/mL
- Methadone HCl Oral Tablets: 5 mg & 10 mg
- Methadone HCl Dispersible Tablets: 40 mg
- Methadone HCl Oral Solution/Liquid Concentrate: 1 mg/mL, 2 mg/mL & 10 mg/mL
- Generic methadone 10 mg tablets
Regulatory status
Authorized veterinary preparations available.
Subject to strict safe custody and register requirements.
No regulatory data for: 🇺🇸 US · 🇭🇰 HK · 🇹🇼 TW · 🇯🇵 JP · 🇰🇷 KR · 🇦🇺 AU
Storage & stability
Store at room temperature and protect from light. Methadone injection is reportedly stable when mixed in a syringe with acepromazine, but is NOT compatible with pentobarbital, phenobarbital, amobarbital, or thiopental.
Client information
Methadone is a potent, strictly controlled opioid analgesic. When given by injection, it is typically administered in a hospital setting under direct veterinary supervision.
If you are sent home with oral methadone for your pet's pain control:
- Strictly follow the prescribed dosage. Do not give more or less without consulting your veterinarian.
-
EXTREME DANGER: Keep this medication in a secure location, completely out of reach of children and other pets. Accidental ingestion by a human (especially a child) can cause fatal respiratory depression.
- Watch for side effects such as mild sedation, panting, whining, or constipation.
- Seek immediate veterinary care if your pet becomes extremely lethargic, has difficulty breathing, or if their breathing becomes abnormally slow.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturer’s current label.