Methadone

Oral🕒 Plan

Route dataPsychonautWiki

🧬 Receptor activityPHDC

Mechanism of actionPHDM

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. ...

PharmacodynamicsPH

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 methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative, non-opioid analgesics should be considered, and methadone should be employed only under careful medical supervision at the lowest effective dose. Infants exposed in-utero or through breast milk are at risk of life-threatening respiratory depression upon delivery or when nursed. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, in the short-term use setting. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. **Head Injury and Increased Intracranial Pressure** The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce effects which may obscure the clinical course of patients with head injuries. In such patients, methadone must be used with caution, and only if it is deemed essential. **Incomplete Cross-tolerance between Methadone and other Opioids** Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of particular concern for patients tolerant to other µ-opioid agonists who are being converted to methadone, thus making the determination of dosing during opioid conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. A high degree of “opioid tolerance” does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Crosstolerance between morphine and methadone has been demonstrated, as steady-state plasma methadone concentrations required for effectiveness (C50%) were higher in abstinent rats previously dosed with morphine, as compared to controls. **Misuse, Abuse, and Diversion of Opioids** Methadone is a mu-agonist opioid with an abuse liability similar to morphine. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion. Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when dispensing Methadone in situations where the clinician is concerned about an increased risk of misuse, abuse, or diversion. **Hypotensive Effect** The administration of methadone may result in severe hypotension in patients whose ability to maintain normal blood pressure is compromised (e.g., severe volume depletion). **Gastrointestinal Effects** Methadone and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. This primarily occurs through agonism of opioid receptors in the gut wall. Methadone may obscure the diagnosis or clinical course of patients with acute abdominal conditions. **Sexual Function/Reproduction** Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility.

Pharmacokinetics

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