Physeptone Mixture (T&R)
Physeptone Mixture (T&R) Uses, Dosage, Side Effects, Food Interaction and all others data.
Physeptone Mixture (T&R) is a potent synthetic analgesic that works as a full µ-opioid receptor (MOR) agonist and N-methyl-d-aspartate (NMDA) receptor antagonist. As a full MOR agonist, methadone mimics the natural effects of the body's opioids, endorphins, and enkephalins through the release of neurotransmitters involved in pain transmission. It also has a number of unique characteristics that have led to its increased use in the last two decades; in particular, methadone has a lower risk of neuropsychiatric toxicity compared to other opioids (due to a lack of active metabolites), minimal accumulation in renal failure, good bioavailability, low cost, and a long duration of action.
Due to its unique mechanism of action, methadone is particularly useful for the management of hard to treat pain syndromes such as neuropathic pain and cancer pain requiring higher and more frequent doses of shorter-acting opioids. Compared with morphine, the gold standard reference opioid, methadone also acts as an agonist of κ- and σ-opioid receptors, as an antagonist of the N-methyl-D-aspartate (NMDA) receptor, and as an inhibitor of serotonin and norepinephrine uptake. Specifically by inhibiting the NMDA receptor, methadone dampens a major excitatory pain pathway within the central nervous system. Compared to other opioids, methadone's effects on NMDA inhibition may explain it's improved analgesic efficacy and reduced opioid tolerance.
Physeptone Mixture (T&R) shares similar effects and risks of other opioids such as morphine, hydromorphone, oxycodone, and fentanyl. However, it also has a unique pharmacokinetic profile. Compared with short-acting and even extended-release formulations of morphine, methadone displays a comparatively longer duration of action and half-life. These effects make methadone a good option for the treatment of severe pain and addiction as fewer doses are needed to maintain analgesia and prevent opioid withdrawal symptoms. However, methadone also has an unpredictable half-life with interindividual variability, which leads to an unpredictable risk of respiratory depression and overdose when initiating or titrating therapy.
| Trade Name | Physeptone Mixture (T&R) |
| Availability | Prescription only |
| Generic | Methadone |
| Methadone Other Names | Metadona, Methadone, Methadonum |
| Related Drugs | Subutex, Sublocade, Zubsolv, Probuphine, Buprenex, Bunavail, aspirin, acetaminophen, tramadol, duloxetine |
| Type | |
| Formula | C21H27NO |
| Weight | Average: 309.4452 Monoisotopic: 309.209264491 |
| Protein binding | Methadone is highly bound to plasma proteins. While it primarily binds to α1-acid glycoprotein (85-90%), it also binds to albumin and other tissue and plasma proteins including lipoproteins. Methadone is unusual in the opioid class, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the plasma. |
| Groups | Approved |
| Therapeutic Class | |
| Manufacturer | Martindale Pharma, an Ethypharm Group Company |
| Available Country | United Kingdom |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Physeptone Mixture (T&R) is an opioid analgesic indicated for management of severe pain that is not responsive to alternative treatments. Also used to aid in detoxification and maintenance treatment of opioid addiction.
Physeptone Mixture (T&R) is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatment options are inadequate. It's recommended that use is reserved for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
Physeptone Mixture (T&R) is also indicated for detoxification treatment of opioid addiction (heroin or other morphine-like drugs), and for maintenance substitution treatment for opioid dependence in adults in conjunction with appropriate social and medical services.
Physeptone Mixture (T&R) is also used to associated treatment for these conditions: Opioid Addiction, Opioid Detoxification, Severe Pain
How Physeptone Mixture (T&R) works
Physeptone Mixture (T&R) 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.
Physeptone Mixture (T&R) 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.
Toxicity
In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur.
Food Interaction
- Avoid alcohol.
- Take with or without food. Food does not significantly affect absorption.
[Moderate] GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of methadone.
The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.
In 8 study subjects stabilized on methadone maintenance treatment, ingestion of regular strength grapefruit juice (200 mL one-half hour before and 200 mL simultaneously with the daily methadone dose) for five days resulted in an approximately 17% mean increase in methadone peak plasma concentration (Cmax) and systemic exposure (AUC) and a 14% mean decrease in apparent clearance for both the R(+) and S(-) enantiomers.
Grapefruit juice did not affect the time to peak level (Tmax), terminal half-life, or apparent volume of distribution of methadone.
No signs or symptoms of methadone toxicity or changes in intensity of withdrawal symptoms were reported in the study.
MANAGEMENT: Given the interindividual variability in the pharmacokinetics of methadone, a more significant interaction with grapefruit juice in certain patients cannot be ruled out.
Patients treated with methadone should preferably avoid or limit the consumption of grapefruit juice, particularly during the induction of maintenance treatment.
Physeptone Mixture (T&R) Alcohol interaction
[Moderate] GENERALLY AVOID:
Ethanol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics.
Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills.
In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.
Concomitant use of opioid analgesics with ethanol should be avoided.
Physeptone Mixture (T&R) Drug Interaction
Major: zolpidem, zolpidem, clonazepam, clonazepam, pregabalin, pregabalin, gabapentin, gabapentin, acetaminophen / hydrocodone, acetaminophen / hydrocodone, quetiapine, quetiapine, alprazolam, alprazolamModerate: amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, duloxetine, duloxetineUnknown: cholecalciferol, cholecalciferol
Physeptone Mixture (T&R) Disease Interaction
Major: impaired GI motility, infectious diarrhea, liver disease, prematurity, acute alcohol intoxication, drug dependence, gastrointestinal obstruction, hypotension, intracranial pressure, respiratory depressionModerate: adrenal insufficiency, biliary spasm, hypothyroidism, renal dysfunction, seizure disorders, urinary retention, arrhythmias
Volume of Distribution
Due to interindividual differences in pharmacokinetics, estimates of methadone's volume of distribution have ranged from 189-470 L with monographs listing it between 1.0-8.0L/kg. As this is higher than physiological volumes of total body water, methadone is highly distributed in the body including brain, gut, kidney, liver, muscle, and lung. A population pharmacokinetic study found that subject gender and weight explained ~33% of the variance in the apparent volume of distribution of methadone.
Physeptone Mixture (T&R) is found to be secreted in saliva, sweat, breast milk, amniotic fluid and umbilical cord plasma. The concentration in cord blood is about half the maternal levels.
Elimination Route
Physeptone Mixture (T&R) is one of the more lipid-soluble opioids and is well absorbed from the gastrointestinal tract. Following oral administration of methadone, bioavailability ranges from 36-100%, with a marked interindividual variation. It can be detected in blood as soon as 15-45 minutes following administration with peak plasma concentrations achieved between 1 to 7.5 hours. A second peak is observed ~4 hours after administration and is likely due to enterohepatic circulation. Dose proportionality of methadone pharmacokinetics is not known.
Following administration of daily oral doses ranging from 10 to 225 mg the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated.
Slower absorption is observed in opioid users compared to healthy subjects, which may reflect the pharmacological effect of opioids in slowing gastric emptying and mobility.
Due to the large inter-individual variation in methadone pharmacokinetics and pharmacodynamics, treatment should be individualized to each patient. There was an up to 17-fold interindividual variation found in methadone blood concentrations for a given dosage, likely due in part to individual variability in CYP enzyme function. There is also a large variability in pharmacokinetics between methadone's enantiomers, which further complicates pharmacokinetic interpretation and study.
Half Life
Due to interindividual differences in pharmacokinetics, estimates of methadone's half-life have ranged from 15–207 hours with official monographs listing it between 7-59 hours.
Clearance
Due to interindividual differences in pharmacokinetics, estimates of methadone's clearance have ranged from 5.9–13 L/h hours with approved monographs listing it between 1.4 to 126 L/h.
Elimination Route
The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree.
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