METHADONE 5MG/ML ORAL SOLUTION

Indications

• Chronic pain management
• Opioid dependence treatment
• Opioid withdrawal syndrome

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing recommendations

Adults: Refer to the BNF for specific dosing guidelines based on the condition being treated. Dosing varies widely based on the patient's opioid tolerance and the clinical context.

Mechanism of action

Methadone functions primarily as a full agonist at the µ-opioid receptor, responsible for its analgesic properties. It also acts as an agonist at κ- and σ-opioid receptors and antagonizes the N-methyl-D-aspartate (NMDA) receptor. Additionally, methadone inhibits the reuptake of serotonin and norepinephrine, further contributing to its pain-relieving effects.

Pharmacodynamics

Methadone produces a range of pharmacological effects including analgesia, sedation, suppression of opioid withdrawal symptoms, miosis, sweating, hypotension, bradycardia, and gastrointestinal effects such as nausea and constipation. Its lower risk of neuropsychiatric toxicity compared to other opioids makes it a favorable option for managing severe pain or addiction. Dependence and tolerance may develop with repeated use, similar to other opioids.

Pharmacokinetics

Methadone is characterized by its long half-life, which allows for once-daily dosing in many cases. It undergoes extensive metabolism in the liver, primarily through CYP450 enzymes. The drug is available in a racemic mixture of its (R)- and (S)-isomers, with the (R)-isomer being significantly more potent at the µ-opioid receptor. Its pharmacokinetic profile includes lower risk of neurotoxic effects and fewer active metabolites than other opioids.

Adverse effects

• Sedation
• Miosis
• Sweating
• Hypotension
• Bradycardia
• Nausea
• Vomiting
• Constipation
• Flushing
• Pruritus
• Urticaria

Interactions

• dabrafenib+methadone: Moderate (decreases exposure)
• bosentan+methadone: Moderate (decreases exposure)
• mitotane+methadone: Moderate (decreases exposure)
• nirmatrelvir boosted with ritonavir+methadone: Moderate (decreases concentration)
• St John's Wort+methadone: Moderate (decreases exposure)
• rifampicin+methadone: Moderate (decreases exposure)
• dronedarone+methadone: Unknown (increases exposure)
• antifungals, azoles+methadone: Unknown (increases exposure)
• bictegravir+methadone: Unknown (increases exposure)
• crizotinib+methadone: Unknown (increases exposure)

Pregnancy

Methadone should only be used during pregnancy if the benefits outweigh the risks. It may cause neonatal withdrawal syndrome.

Breast-feeding

Methadone is excreted in breast milk. Caution is advised if the mother is using methadone while breastfeeding.

Storage

Store in a cool, dry place, protected from light. Keep out of reach of children.

Formulations

• Oral solution
• Tablets
• Injection

Indications

• Opioid dependence
• Management of severe pain
• Chronic pain management in opioid-tolerant patients

Dosage

Children: For neonates, the initial dose is

Adults: Initial dose for opioid dependence is 5 to 10 mg every 6 to 8 hours, adjusting as necessary based on clinical response. For severe pain, the initial dose is 500 micrograms once daily for 3 days, increased to 500 micrograms twice daily for 4 days, then to 1 mg twice daily for 11 weeks.

Mechanism of action

Methadone acts primarily as an agonist at the mu-opioid receptor, which is responsible for its analgesic effects. It also exhibits NMDA receptor antagonism, which may contribute to its efficacy in chronic pain management by preventing central sensitization and reducing the perception of pain. Additionally, methadone has effects on serotonin and norepinephrine reuptake, further enhancing its analgesic properties.

Pharmacodynamics

Methadone's analgesic effects typically develop within 30 minutes to an hour after administration, peaking in 2 to 4 hours, and can last for 4 to 8 hours, depending on the dose and individual patient factors. Due to its long half-life, it allows for once-daily dosing in opioid dependence treatment. The drug's effects can be influenced by genetic variability in opioid receptors and metabolic enzymes.

Pharmacokinetics

Methadone is well-absorbed from the gastrointestinal tract, with bioavailability ranging from 36% to 100%. It is extensively metabolized in the liver primarily by cytochrome P450 3A4 and 2B6, with a half-life averaging between 8 to 59 hours, which can be highly variable among individuals. The drug is excreted mainly in urine as metabolites, with less than 10% of the dose excreted unchanged.

Contra-indications

• Respiratory depression
• Acute bronchial asthma
• Severe hepatic impairment
• Concurrent use of monoamine oxidase inhibitors

Adverse effects

• Constipation
• Nausea
• Vomiting
• Sedation
• Dizziness
• Sweating
• Mood changes
• Respiratory depression
• Dependence and withdrawal symptoms

Interactions

• CNS depressants may enhance sedative effects
• Antiretroviral drugs may affect methadone metabolism
• Monoamine oxidase inhibitors can cause severe interactions

Precautions

• Use with caution in patients with a history of substance abuse
• Monitor for signs of respiratory depression in those with compromised respiratory function
• Careful dose adjustment in the elderly and in those with hepatic or renal impairment

Pregnancy

Use during pregnancy is generally not recommended due to potential risks; consult guidelines.

Breast-feeding

Avoid, as methadone is excreted in breast milk; consult guidelines.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral solution
• Tablets
• Injection

Mechanism of action

Methadone is a synthetic opioid analgesic with full agonist activity at the µ-opioid receptor. While agonism of the µ-opioid receptor is the primary mechanism of action for the treatment of pain, methadone also acts as an agonist of κ- and σ-opioid receptors within the central and peripheral nervous systems. Interestingly, methadone differs from [morphine] (which is considered the gold standard reference opioid) in its antagonism of the N-methyl-D-aspartate (NMDA) receptor and its strong inhibition of serotonin and norepinephrine uptake, which likely also contributes to its antinociceptive activity. Methadone is administered as a 50:50 racemic mixture of (R)- and (S)-stereoisomers, with (R)-methadone demonstrating ~10-fold higher affinity and potency for the µ-opioid receptor than the (S) stereoisomer. The analgesic activity of the racemate is almost entirely due to the (R)-isomer, while the (S)-isomer lacks significant respiratory depressant activity but does have antitussive effects. While methadone shares similar effects and risks of other opioids such as [morphine], [hydromorphone], [oxycodone], and [fentanyl] it has a number of unique pharmacokinetic and pharmacodynamic properties that distinguish it from them and make it a useful agent for the treatment of opioid addiction. For example, methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. Methadone hydrochloride is a mu-agonist; ... . Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The contribution of NMDA receptor antagonism to methadone's efficacy is unknown. Methadone activates opioid receptors to increase a potassium conductance mediated by G-protein coupled, inwardly rectifying, potassium (K(IR) 3) channels. Methadone also blocks K(IR) 3 channels and NMDA receptors. However, the concentration dependence and stereospecificity of receptor activation and channel blockade by methadone on single neurons has not been characterized. Intracellular and whole cell recording were made from locus coeruleus neurons in brain slices and the activation of mu-opioid receptors and blockade of K(IR) 3 and NMDA channels with l- and d-methadone was examined. The potency of l-methadone, measured by the amplitude of hyperpolarization was 16.5-fold higher than with than d-methadone. A maximum hyperpolarization was caused by both enantiomers (~30 mV), however, the maximum outward current measured with whole cell voltage-clamp recording was smaller than the current induced by [Met](5) enkephalin. The K(IR) 3 conductance induced by activation of a(2) -adrenoceptors was decreased with high concentrations of l- and d-methadone (10-30 uM). In addition, methadone blocked the resting inward rectifying conductance (K(IR) ). Both l- and d-methadone blocked the NMDA receptor-dependent current. The block of NMDA receptor-dependent current was voltage dependent suggesting that methadone acted as a channel blocker. Methadone activated mu-opioid receptors at low concentrations in a stereospecific manner. K(IR) 3 and NMDA receptor channel block was not stereospecific and required substantially higher concentrations. The separation in the concentration range suggests that the activation of mu-opioid receptors rather than the channel blocking properties mediate both the therapeutic and toxic actions of methadone. Opioid agonist, analgesic. Action of methadone is to bind to mu-opiate and kappa-opiate receptors on nerves and inhibit release of neurotransmitters involved with transmission of pain stimuli (such as Substance P). Methadone also may antagonize NMDA (n-methyl D-asparate) receptors, which may contribute to the analgesic effect, decrease adverse CNS effects, and inhibit tolerance. ...

Pharmacodynamics

Overall, methadone's pharmacological actions result in analgesia, suppression of opioid withdrawal symptoms, sedation, miosis (through binding to receptors in the pupillary muscles), sweating, hypotension, bradycardia, nausea and vomiting (via binding within the chemoreceptor trigger zone), and constipation. Like many basic drugs, methadone also enters mast cells and releases histamine by a non-immunological mechanism leading to flushing, pruritus, and urticaria, which can commonly be misattributed to an allergic reaction. Compared to other opioids, methadone has fewer active metabolites and therefore a lower risk of neuropsychiatric toxicity. This means that higher doses needed to manage severe pain or addiction are less likely to result in delirium, hyperalgesia, or seizures. Similar to morphine, both methadone isomers are 5-HT(3) receptor antagonists, although l-methadone produces greater inhibition than d-methadone. Methadone's effects are reversible by naloxone with a pA2 value similar to its antagonism of morphine. **Dependence and Tolerance** As with other opioids, tolerance and physical dependence may develop upon repeated administration of methadone and there is a potential for development of psychological dependence. Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. **Cardiac Conduction Effects** Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Methadone should be administered with particular caution to patients already at risk for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia). Careful monitoring is recommended when using methadone in patients with a history of cardiac conduction disease, those taking medications affecting cardiac conduction, and in other cases where history or physical exam suggest an increased risk of dysrhythmia. **Respiratory Depression and Overdose** Serious, life-threatening, or fatal respiratory depression may occur with use of methadone. Patients should be monitored for respiratory depression, especially during initiation of methadone or following a dose increase. Respiratory depression is of particular concern in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Methadone should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, and CNS depression or coma. In these patients, even usual therapeutic doses of methad