Methadone is an opioid of diphenylpropylamine class. It is a synthetic analgetic, which in 1965 was proposed as an alternative to heroin by Dole and Nyswander for treatment of addicts. High oral bioavailability, long elimination time, and corresponding effects gave hope that such substitution treatment in these patients could contribute to improving the overall therapeutic effect in the fight against "chronic relapsing disorder". It is known, that the most negative effect of methadone is an interindividual variability of absorption and metabolism, which makes it impossible to predict the clinical effect and the optimal dose and concentration for treatment of opioid addiction. Subjective effects of methadone are similar to other synthetic opiates`, meanwhile, euphoria is more pronounced. Methadone is produced in large volumes, and therefore, it is highly available on the market. The specific optical rotation is -32 degrees at 20 degrees Celsius. When heated to decomposition, it releases toxic vapors/nitric oxide. pKa = 8.94 (conjugated acid). The pH level for methadone hydrochloride injections is from 3 to 6.5, and the oral methadone hydrochloride concentrate has a pH of 1-6. Methadone has several trade names: amidone, Biodone, Dolophine, Hydrochloride, Methadone, Metadol, Metasedin, Methaddict, Methadone, Methadone Hydrochloride, Methadose, Methex, Phenadone, Phymet, Physeptone, Pinadone, Symoron and other. Methadone is a controlled substance, included into the list II of Drug Enforcement Administration. Substances, included in list II DEA, have a high potential for abuse, which can cause severe psychological and physical addiction.
In its structural formula, methadone (RS-6-dimethylamino-4,4-diphenylheptan-3-one) contains two phenolic rings attached to the R4 carbon in the 2-oxo-6-dimethylamino heptane chain; it exists as a racepic mixture of the right - and left-rotating enantiomer. It is somewhat similar in its structure to tepanthadol and dextropropoxyphen. Its protonated form has a wide conformation, and the free base is more compact. It is produced in tablets, ampoules with solutions of 10 mg/ml, most often in the form of hydrochloride; in illegal laboratories in form of white or light yellow/beige/crème crystals somewhat cloudy and translucent. Its melting point varies from 233-236 degrees Celsius, it is soluble in water, alcohol and chloroform, and insoluble in diethyl ether. It is a fairly lipophilic substance, as a result of which it is widely distributed throughout all tissues of the body, and the R-enantiomer is 30-50 times more powerful than its left-rotating enantiomer.
Pharmacokinetics and Pharmacodynamics.
Methadone is rapidly absorbed when administered orally and can be detected in plasma after 15-45 minutes. When administered orally, the peak concentration lasts from 2.5 to 4 hours. Absorption of methadone depends on several factors: the physico-chemical properties of the substance, the peristalsis of the gastrointestinal tract, intestinal perfusion and the pH of gastric juice.
The average oral bioavailability is 70-80%, this value can vary from 36 to 100%. This effect is explained by a significant individual variability in the activity of cytochrome P450 CYP3A4, which is responsible for metabolism of methadone. Bioavailability with rectal administration is 76%. The drug has a long duration of action, which lasts on average about 10 hours. When administered intramuscularly, the pharmacokinetics of the drug is affected by the place of administration. After injection into the gluteal muscles, the peak concentration in the blood is reached 2.2-2.5 times faster than when injected into the deltoid muscle. The average volume of distribution is 4.0 l / kg (1.9-8.0 l/kg), that is why methadone is widely distributed throughout the body tissues. Methadone accumulates rapidly in tissues and is slowly released back into the plasma during redistribution and elimination, thereby contributing to its long-term excretion. It penetrates well through the placenta, and its concentration in the amniotic fluid becomes equal to the concentration in the maternal plasma. In the blood plasma, the fraction of free (unbound) methadone is on average 13%, but it can vary significantly, up to fourfold increase.
Methadone binds to alpha-1-acid glycoprotein (orosomucoid) in the blood, and its connection with albumin and globulin has also been established. It should be noted that orosomucoid is an acute-phase protein and its concentration may increase with cancer development as well as with development of opioid addiction. For example, patients with cancer have a high level of alpha-1-acid glycoprotein, which leads to a decrease in the concentration of the free fraction methadone, which is a pharmacologically active concentration in blood flow. Currently, there is conflicting data on the safety of prescribing methadone as a substitution treatment. For example, the American Academy of Pediatrics suggests that doses of up to 20 mg within 24 hours are not dangerous for a nursing mother. There are recommendations for women receiving substitution treatment not to give up breastfeeding. It is estimated that only 2.8% of the daily methadone dose of 40 mg gets into breast milk.
The main pathway of methadone metabolism is oxidative biotransformation. Methadone is N-demethylated with the formation of N-ethyldin-1,5-dimethyl-3,3-diphenylpyrolidine (EDDP), which is an inactive substance excreted by kidneys. Methadone is also metabolised into the other inactive metabolite 2-ethy-5-methyl-3,3-diphenyl-1-pyrroline (EMDP) and in small amounts into two active metaboites: methadol and normethadol. The main enzymes involved in oxidative N-demethylation are cytochrome CYP3A4 and CYP2B6, other studies also suggest the participation of CYP2C9, CYP2C19,32 CYP2D6, and CYP2C8. Methadone undergoes stereoselective metabolism (N-demethylation) with the participation of CYP2D6, mainly being metabolised to inactive S-methadone and with the participation of CYP2C19 being metabolised to active R -methadone. In vitro study, it was established that metabolic clearance of R-methadone with CYP3A4 was about 4 times higher than that of S-methadone. It was also established that the amount of S- and R-methadone is equally reduced in acute poisoning. The minimum lethal dosage is 30 mg, according to the study, and the semi-lethal dose is 2-5 mg/kg. Methadone accumulation is due to a long elimination half-life of the drug (on average 55 hours after single dose and 22-25 with chronic use).
Methadone is an agonist of μ-opioid receptorsm a weak agonist of the N-methyl-D-aspartate (NMDA) receptor. At the cellular level, opioids inhibit adenylate cyclase and reduce the production of cyclic AMP (cAMP). With chronic use, tolerance is developed, as a result, there is a compensatory increase in the activity of adenylate cyclase and the concentration of cAMP with a partial increase in the content of intracellular calcium and an increase in NDMA-activity. Methadone prevents opioid tolerance and opioid withdrawal syndrome because of its competitive agonistic activity on NDMA receptors. Pharmacokinetics of methadone is characterized by pronounced individual variability. The table shows several key pharmacokinetic parameters. In the modern literature, there is a lot of information about the impact of methadone on vital systems, primarily on the central nervous, respiratory, cardiovascular and urinary systems. Acute methadone intoxication causes hypoxic brain damage and the appearance of ischemic foci, as well as direct damage to the cerebellum. There is information about hearing disorders in patients who are on substitute treatment. These disorders can occur in patients both with acute and chronic methadone toxicity. Usually, patients describe hearing loss during the period of awakening from the state of consciousness depression. In addition, there may be other vestibulocochlear disorders, such as tinnitus, ear congestion and dizziness. However, pathophysiological mechanisms of methadone effects on the human hearing are not fully known, nor has the treatment of these hearing disorders been developed.
When studying the effect of methadone on the respiratory system in both animals and humans, respiratory depression is noted with the development of pronounced hypoxemia and hypercapnia. The mechanisms of respiratory depression are associated with the effect on the central nervous system, although there is also an effect on the peripheral mechanisms of chemoreception. Depression of respiratory center is the main mechanism of methadone action due to μМОР receptors blockade, μ2 in medulla oblongata specifically. This is also proved by the fact that methadone-induced respiratory depression is dose dependant and can be managed by naloxone injection. Impairment of the external respiratory functions is characterized by a decrease in respiratory volume (VT), oxygen tension and pH in arterial blood with an increase in carbon dioxide tension.
In addition to the central mechanisms of damage to the respiratory system in acute methadone toxicity, pulmonary edema is sometimes present as well. Its pathogenesis is described as follows. First, hypoxemia and respiratory acidosis, which develop with central respiratory depression, lead to an increase in capillary permeability. Secondly, it affects histamine action on the pulmonary capillaries. Methadone is the stimulant of both local and systemic mechanisms of histamine release. Histamine increases the permeability of capillaries. It is established that methadone affects cardiovascular system. It is proved in experiment that methadone cardiotoxic properties affect cardial functions in different ways. Despite the allegations that methadone is a safe drug, there are descriptions of cases of methadone cardiotoxicity. Prolongation of the QT interval is mainly associated with a change in heart rate. In studies in 16% of patients receiving substitution treatment, cardiotoxicity in the form of prolongation of the QT interval has been proven. Pirouette tachycardia occurs accompanied by prolongation of the QT interval. In studies, there is information about severe kidney damage in patients with acute methadone toxicity, sometimes reaching its extreme form — acute renal failure in the anuric stage. Kidney damage can be caused by the following reasons: prerenal-hypotension, centralization of blood circulation; renal — rhabdomyolysis, hypoxia.
Polymorphism of genes, encoding μ-opioid receptors and enzymes, involved in the metabolism, utilization and action of methadone, make a great contribution to individual differences in the clinical pharmacology of this substance. There are only a few studies on epigenetic mechanisms of methadone action, but there is some experimental data on reduced metabolism and effects of methadone in the 118A4G mutation in the OPRM1 gene, which encodes μ-opioid receptor. In subjects with genotypes AA, AP and P, the average reduction in the size of the pupil diameter was 45%, 33% and 24%, respectively. No association was found between the effect of methadone and polymorphisms of P-glycoprotein GP3A, 2 B6, 1 A 2, 2C8, 2C9, 2C19, 2D6. However, it was found out that in the case of CYP2D6 polymorphism, there is a correlation between the methadone serum concentration and the dose adjusted for body weight. This correlation in people with very fast metabolism was 54% of the entire sample of subjects.
Clinical presentation of methadone effects.
“Pain relief” effect is the basic methadone effect, associated with its main mechanism of action. It consists of the absolute suppression of negative pain sensations (nociceptive blockade), sense of general satisfaction. Euphoria induced by methadone is different from that of heroin or morphine because the intensity of methadone-induced positive euphorigenic effects is significantly less in equivalent doses. However, there is some statistically significant data about a “special” form of euphoria from methadone use, which some users consider as more positive, than that of heroine or morphine; respiratory depression; itching; constipation; defecation disorder; absence of bronchial spasm; disorder of urination up to the complete impairment of detrusor contractility; pronounced sedation; nausea, vomiting; pupil constriction; decreased libido; inability to ejaculate; suppression of appetite.
In general, pharmacological effects of methadone include analgesia, depression of opioid withdrawal syndrome, sedation, myosis (through binding to receptors in the pupillary muscles), sweating, hypotension, bradycardia, nausea and vomiting (through binding to the trigger zone of chemoreceptors) and constipation. Like many other medications, methadone penetrates into mast cells and causes the release of histamine by a non-immunological mechanism, which manifests as a rush of blood to the face, itching and urticaria, which can usually be mistaken for an allergic reaction. Compared to other opioids, methadone has less active metabolites, and, therefore, has lower risk of neuropsychiatric toxicity. It means that higher doses are required for strong analgesic effect or addiction, it is less likely to cause delirium, hyperalgesia or convulsions. Similar to morphine, both methadone isomers are 5-HT antagonists, however L-mehadone has a stronger inhibitory effect than D-methadone.
The main risks of methadone use are respiratory depression, as well as, to a lesser extent, insufficient blood supply, respiratory arrest, shock and cardiac arrest. The most common negative reactions are associated with a feeling of emptiness in the head, dizziness, lethargy, nausea, vomiting, increased sweating and orthostatic hypotension. Some of these effects, most often in ambulatory patients, can be reduced if patients are positioned horizontally. Central nervous system: euphoria, dysphoria, weakness, headache, insomnia, excitability, disorientation and visual disorders, confusion, convulsive seizures, serotonin syndrome.
Digestive system: dry mouth, glossitis, xerostomia, anorexia, abdominal pain, constipation, spasms of the gallbladder and / or biliary tract.
Endocrine system: adrenal insufficiency.
Urinary and reproductive systems: urinary retention and difficulty urinating, antidiuretic effect, decreased diuresis, decreased libido and / or impotence, amenorrhea, decreased mobility and abnormalities in sperm morphology.
Immune system: itching, urticaria, other skin reactions, edema, hemorrhagic urticaria is rarely observed.
Delayed ventricular repolarization manifests itself as an increase in the QT time on the ECG. Increase in this time, in turn, is associated with an increased risk of arrhythmia, and especially potentially fatal arrhythmia torsade de pointes. In 2001 and 2002 first cases of such arrhythmia in patients receiving methadone treatment were published. Currently, there has been irrefutable data about the occurrence of initially stable increase in QT in the range of 11-20 ms after methadone intake. People, using methadone, with a history of chronic arrhythmogenic triggers or congenital long QT syndromes are at almost 99% risk of developing potentially fatal torsade de pointes arrhythmia.
Methadone effects are reversible by naloxone with an indicator of pA2, similar to its antagonism with morphine. Addiction and tolerance. As in the case of other opioids, tolerance and physical dependence can develop with repeated methadone intake and can cause psychological dependence. Physical dependence and tolerance reflect neuroadaptation of opioid receptors to chronic opioid effects, and are different from abuse or addiction. Tolerance, as well as physical dependence, can develop with multiple occurrence of opioid intake, and they are not evidence off addiction or substance abuse themselves. Patients receiving long-term treatment should gradually decrease the administration of the drug if it is no longer required for pain relief. Withdrawal symptoms can occur after abrupt cancellation of treatment or intake of opioid antagonists. Some of the symptoms associated with abrupt cancellation of opioid analgetic include: body pain, diarrhea, goosebumps, loss of appetite, nausea, nervousness or anxiety, restlessness, runny nose, sneezing, tremor or trembling, stomach cramps, tachycardia, problems with sleeping, an unusual increase in sweating, rapid heartbeat, unexplained fever, weakness and yawning.
Methods of use and doses.
As a rule, recreational use of methadone is carried out by oral or intravenous administration. Sometimes, methadone crystals are ground into powder and administered intranasally. In case of oral use, it is recommended to start with minimum dose 5-15 mg, with the interval between use no less than 4-6 hours. It is necessary because, given the bioavailability, the development of clinical effects rate is rather slow with this way of administration, but the effects are long-lasting. With systemic oral use, dose should not exceed 70 mg a day. Medium oral dose is 10-20 mg, high and potentially dangerous one is more than 20 mg with singe use. In case of intravenous administration, it is recommended to use methadone exclusively laboratory-made solutions officially sold in pharmacies. As a rule, concentration of these methadone solutions is 5 mg/ml or 10 mg/ml. It is not recommended to use more than 0,5 ml at a concentration of 5 mg/ml if it is your first time.
Methadone interactions with other substances.
Simultaneous use of methadone and any inhibitors of cytochrome P450 3A4, 2B6, 2C19, 2C9 or 2D6 can cause increase in the concentration of methadone in plasma. This can lead to life-threatening respiratory depression. Moreover, discontinuation of the use of cytochrome P450 inducers 3A4, 2B6, 2C19 or 2C9 can also lead to an increase in the methadone concentration in blood plasma. Patients` condition should be thoroughly monitored for signs of respiratory depression and sedative effect. The need for decreasing the dosage of medicine should be considered when any changes involving the increase in methadone concentration occur. So, sedation and respiratory depression can occur in patients receiving methadone together with some antidepressants (amitriptyline in particular). Methadone concentration in serum can increase when methadone and macrolide antibiotics (for example, erythromycin) or azole antifungal drugs (for example, ketoconazole), which are strong inhibitors of CYP3A4, are used together for treatment.
Also, the same effects occur, when methadone is used with fluoxetine, sertraline or other SSRI antidepressants. Simultaneous use of methadone with cytochrome P450 3A4 inductors (such as rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort) can lead to a decrease in methadone concentration in blood plasma and withdrawal syndrome symptoms. Some drugs used for the HIV treatment (nevirapine, efavirenz, as well as some of the protease inhibitors, especially in combination with a small increasing dose of ritonavir) also increase metabolism of methadone, provoking the symptoms of withdrawal syndrome.
Urine acidifiers, such as ascorbic acid, reduce the level of methadone in blood plasma, and urine alkalizers, for example, sodium bicarbonate (baking soda), increase the level of methadone. When methadone is used with desipramine or other tricyclic antidepressants, the concentration of the tricyclic antidepressant in the blood plasma increases. Simultaneous use of methadone with other CNS depressants, including other opioid analgesics, general anesthetics, phenothiazines, tranquilizers, sedatives and hypnotics, alcoholic beverages, can lead to a strong sedative effect, respiratory depression, coma and death. Mortality rate due to illegal methadone use is often caused by simultaneous abuse of methadone and benzodiazepines.
When used with cyclizine or other sedative antihistamines, hallucinations are possible. With simultaneous use of methadone and serotonergic drugs (for example, SSRIs, SIOSSiN, triptans, TCA), lithium, St. John's wort, IMAO, drugs that affect the metabolism of methadone (for example, CYP2D6 and 3A4 inhibitors), a potentially deadly complication-serotonin syndrome can occur. Caution should be exercised when using methadone with arrhythmia-inducing medications, such as antiarrhythmic drugs of various classes, some neuroleptics and tricyclic antidepressants, calcium channel blockers. Caution is also advised when prescribing methadone simultaneously with medicine that can cause electrolyte disorders (hyponatremia, hypokalemia), which can increase the QT interval: such drugs include diuretics, laxatives and, in rare cases, mineralocorticoid hormones. Smoking cigarettes can weaken the effects of methadone.
Low risk or no amplification of effects: mushrooms, LSD, DMT, mescaline, Dox, NBOMes, 2C-x, 2C-Tx, aMT, 5-MeO-xxT, MDMA, caffeine. Low risk with amplification of effects when methadone is used with cannabis.
Low risk or high risk: PСP, N20, amphetamines and other psychostimulants(cocaine included) MAOI, grapefruit.
High risk or extremely high risk: ketamine, MXE, DXM, alcohol, GHB/GBL, tramadol, benzodiazepines, 5-htp, SNRI, cocaine.
Methadone effects are reversible by naloxone with an indicator of pA2, similar to its antagonism with morphine. Addiction and tolerance. As in the case of other opioids, tolerance and physical dependence can develop with repeated methadone intake and can cause psychological dependence. Physical dependence and tolerance reflect neuroadaptation of opioid receptors to chronic opioid effects, and are different from abuse or addiction. Tolerance, as well as physical dependence, can develop with multiple occurrence of opioid intake, and they are not evidence off addiction or substance abuse themselves. Patients receiving long-term treatment should gradually decrease the administration of the drug if it is no longer required for pain relief. Withdrawal symptoms can occur after abrupt cancellation of treatment or intake of opioid antagonists. Some of the symptoms associated with abrupt cancellation of opioid analgetic include: body pain, diarrhea, goosebumps, loss of appetite, nausea, nervousness or anxiety, restlessness, runny nose, sneezing, tremor or trembling, stomach cramps, tachycardia, problems with sleeping, an unusual increase in sweating, rapid heartbeat, unexplained fever, weakness and yawning.
Methods of use and doses.
As a rule, recreational use of methadone is carried out by oral or intravenous administration. Sometimes, methadone crystals are ground into powder and administered intranasally. In case of oral use, it is recommended to start with minimum dose 5-15 mg, with the interval between use no less than 4-6 hours. It is necessary because, given the bioavailability, the development of clinical effects rate is rather slow with this way of administration, but the effects are long-lasting. With systemic oral use, dose should not exceed 70 mg a day. Medium oral dose is 10-20 mg, high and potentially dangerous one is more than 20 mg with singe use. In case of intravenous administration, it is recommended to use methadone exclusively laboratory-made solutions officially sold in pharmacies. As a rule, concentration of these methadone solutions is 5 mg/ml or 10 mg/ml. It is not recommended to use more than 0,5 ml at a concentration of 5 mg/ml if it is your first time.
Methadone interactions with other substances.
Simultaneous use of methadone and any inhibitors of cytochrome P450 3A4, 2B6, 2C19, 2C9 or 2D6 can cause increase in the concentration of methadone in plasma. This can lead to life-threatening respiratory depression. Moreover, discontinuation of the use of cytochrome P450 inducers 3A4, 2B6, 2C19 or 2C9 can also lead to an increase in the methadone concentration in blood plasma. Patients` condition should be thoroughly monitored for signs of respiratory depression and sedative effect. The need for decreasing the dosage of medicine should be considered when any changes involving the increase in methadone concentration occur. So, sedation and respiratory depression can occur in patients receiving methadone together with some antidepressants (amitriptyline in particular). Methadone concentration in serum can increase when methadone and macrolide antibiotics (for example, erythromycin) or azole antifungal drugs (for example, ketoconazole), which are strong inhibitors of CYP3A4, are used together for treatment.
Also, the same effects occur, when methadone is used with fluoxetine, sertraline or other SSRI antidepressants. Simultaneous use of methadone with cytochrome P450 3A4 inductors (such as rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort) can lead to a decrease in methadone concentration in blood plasma and withdrawal syndrome symptoms. Some drugs used for the HIV treatment (nevirapine, efavirenz, as well as some of the protease inhibitors, especially in combination with a small increasing dose of ritonavir) also increase metabolism of methadone, provoking the symptoms of withdrawal syndrome.
Urine acidifiers, such as ascorbic acid, reduce the level of methadone in blood plasma, and urine alkalizers, for example, sodium bicarbonate (baking soda), increase the level of methadone. When methadone is used with desipramine or other tricyclic antidepressants, the concentration of the tricyclic antidepressant in the blood plasma increases. Simultaneous use of methadone with other CNS depressants, including other opioid analgesics, general anesthetics, phenothiazines, tranquilizers, sedatives and hypnotics, alcoholic beverages, can lead to a strong sedative effect, respiratory depression, coma and death. Mortality rate due to illegal methadone use is often caused by simultaneous abuse of methadone and benzodiazepines.
When used with cyclizine or other sedative antihistamines, hallucinations are possible. With simultaneous use of methadone and serotonergic drugs (for example, SSRIs, SIOSSiN, triptans, TCA), lithium, St. John's wort, IMAO, drugs that affect the metabolism of methadone (for example, CYP2D6 and 3A4 inhibitors), a potentially deadly complication-serotonin syndrome can occur. Caution should be exercised when using methadone with arrhythmia-inducing medications, such as antiarrhythmic drugs of various classes, some neuroleptics and tricyclic antidepressants, calcium channel blockers. Caution is also advised when prescribing methadone simultaneously with medicine that can cause electrolyte disorders (hyponatremia, hypokalemia), which can increase the QT interval: such drugs include diuretics, laxatives and, in rare cases, mineralocorticoid hormones. Smoking cigarettes can weaken the effects of methadone.
Low risk or no amplification of effects: mushrooms, LSD, DMT, mescaline, Dox, NBOMes, 2C-x, 2C-Tx, aMT, 5-MeO-xxT, MDMA, caffeine. Low risk with amplification of effects when methadone is used with cannabis.
Low risk or high risk: PСP, N20, amphetamines and other psychostimulants(cocaine included) MAOI, grapefruit.
High risk or extremely high risk: ketamine, MXE, DXM, alcohol, GHB/GBL, tramadol, benzodiazepines, 5-htp, SNRI, cocaine.
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