美沙酮
美沙酮是一種合成的強效 **μ-鴉片類受體促效劑 (mu-opioid agonist)**，在獸醫學中常作為犬貓的麻醉前給藥與鎮痛藥。與嗎啡相比，它在靜脈注射時較不易引起組織胺釋放，且較少導致嘔吐或過度鎮靜。 **臨床重點與藥理優勢：** * **三重機制：** 與大多數傳統鴉片類藥物不同，美沙酮不僅是 μ-受體促效劑，同時也是 **非競爭性 NMDA 受體拮抗劑** 以及 **單胺類（血清素與正腎上腺素）再回收抑制劑**。 * **神經病理性疼痛：** 由於其 NMDA 拮抗作用，美沙酮在治療頑固性疼痛、神經病理性疼痛以及預防中樞敏感化（「痛覺過敏」或「wind-up」現象）方面特別有價值。 * **生體可用率：** 在犬隻的口服生體可用率極差，因此在獸醫臨床上標準給藥途徑為注射（IV、IM、SC）。 * **法規：** 由於對人類具有高度成癮與濫用風險，本藥屬於第二級管制藥品 (Schedule II)。
作用機制: 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.
各物種劑量
- For perioperative pain control · 0.05-0.5 mg/kg IV , IM or SC q4-6h · IV, IM, SC · q4-6h
- As a pre-anesthetic · 0.1-0.2 mg/kg SC, IM; or a combination of methadone 0.1-0.3 mg/kg with acepromazine 0.02-0.05 mg/kg SC, IM · SC, IM
- For moderate to severe pain · 0.1-0.2+ mg/kg IM or SQ · IM, SQ, IV · Duration of effect is 2-6 hours (IM/SQ) or 1-4 hours (IV) · For IV dosing use ½ the low end dose, titrate over 35 minutes
- For pain · 0.1-0.2 mg/kg SC, IV · SC, IV · Duration of effect 2-3 hours
- Analgesia · 0.1-0.5 mg/kg · IM · prn · Duration of action is typically 3-4 hours.
- Analgesia · 0.1-0.3 mg/kg · IV · prn · Monitor respiratory function if anaesthetized.
- Analgesia · 0.6 mg/kg · OTM · prn · Authorized preparation contains preservative and causes salivation when given by the OTM route.
- As an analgesic · 0.1-0.2 mg/kg PO · PO · Anecdotal; author has not prescribed this drug
- As a pre-anesthetic · 0.2-0.5 mg/kg SC, IM; or a combination of methadone 0.1-0.3 mg/kg with acepromazine 0.02-0.05 mg/kg SC, IM · SC, IM
給藥途徑
禁忌症
- 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.
不良反應
- Panting
- Whining or vocalization
- Sedation
- Defecation
- Constipation
- Bradycardia
- Respiratory depression
- 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)
藥物相互作用
- Class I & III Antiarrhythmics (e.g., lidocaine, procainamide, quinidine, amiodarone) · May increase risks for arrhythmias
- Alpha2-Agonists (e.g., medetomidine, xylazine) · Potentiates sedative and analgesic effects; combination with medetomidine may cause severe hypoxemia in dogs breathing room air
- Azole Antifungals (fluconazole, itraconazole, ketoconazole) · May increase methadone levels in humans (does not appear to be true for dogs)
- Calcium Channel Blockers · May increase risks for arrhythmias
- CNS Depressants (anesthetics, antihistamines, phenothiazines, barbiturates, tranquilizers) · May cause increased CNS or respiratory depression
- Corticosteroids (Mineralocorticoids) · May increase potential for electrolyte abnormalities
- Diuretics · Opiates may decrease diuretic efficacy in CHF patients
- Macrolide Antibiotics (erythromycin, clarithromycin) · May inhibit metabolism of methadone and increase levels in humans (does not appear to be true for dogs)
- Monoamine Oxidase Inhibitors (MAOIs) (e.g., amitraz, selegiline) · Potential for severe CNS/behavioral reactions; concomitant use should be avoided
- Skeletal Muscle Relaxants · Methadone may enhance neuromuscular blockade
- Phenobarbital, Phenytoin · May decrease methadone levels in humans (probably does not affect dogs)
監測
- 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)
過量
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.
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