Author: Michele Brattoli
Date: 29/01/2013


What is it?

Methadone is an opioid (synthetic opiate) that was originally synthesized by German pharmaceutical companies during the Second World War.
Its IUPAC name is 6 dimetyilamino-4,4 diphenyl-3 heptanone, while it’s formula is C 21 H 27 N 1 O 1 .
It is a potent analgesic drug, used in medicine to relieve severe pain and as replacement therapy of opioid drug addiction.

Methadone is a chiral substance, therefore, presents itself as a racemic mixture of two enantiomers in mutual relationship of 1:1, respectively the levorotatory form of methadone (L)-methadone and dextrorotary shape (D)-methadone: the dextrorotatory form possesses potent antitussive properties, but is almost completely devoid of analgesic properties; the levorotary one is about two times more effective as an analgesic, than the racemic form of methadone.


Methadone is produced entirely by synthetic, unlike heroin is obtained from semi-natural substances produced synthetically from opium alkaloids, such as morphine.
The process of chemical synthesis of racemic methadone is obtained from the nitrile with the synthesis of Kolbe and with the difenilacetonitrile . One can obtain the formation of a racemate L-(+) with the tartaric acid.

More informations and details:

Synthesis of Methadone


Methadone has multiple actions quantitatively similar to those at morphine, the most prominent of which involves the central nervous system and organs composed of smooth muscle. However, methadone is more active and more toxic than morphine.

It mainly acts as an agonist at µ-opioid receptors , secondly as an antagonist at N-methyl-D-aspartate ( NMDA ) receptors : in particular  (L)-methadone is a full µ-opioid agonist, while (D)-methadone  does not affect opioid receptor but binds to the glutamatergic NMDA  receptors.

Mu receptors

The μ-receptors (MOR) are a particular kind of opioid receptors, which are highly distributed in the human brain (hypothalamus, thalamus, nucleus caudatus, putamen, posterior amygdala), spinal cord, peripheral sensor neurons, gastrointestinal tract.
They can exist either presynaptically or postsynaptically depending upon cell types.
MOR can mediate acute changes in neuronal excitability via "disinhibition" of descending fibres through inhibition of Gamma-Aminobutyric acid (GABA)-ergic neuronal inputs, which modulates other descending pathways in turn, such as noradrenergic neurons, to produce analgesia  Activation of the MOR leads to different effects on dendritic spines depending upon the agonist, and may be an example of functional selectivity at the μ receptor.

How do they work?

μ receptors works as G proteins coupled receptor (Gi / Go).
Normally neurotransmitter release from neurons is preceded by depolarization of the nerve terminal and Ca2+ entry through voltage-sensitive Ca2+ channels. 
But, after methadone binds μ receptors, G protein:

  • inhibits adenylate cyclase (AC), the enzyme which converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP)
  • inihibits the opening of Ca2+ channel -> Decreased Ca2+ entry
  • stimulates the opening of rectifying K+ channels resulting in membrane hyperpolarization-> Increased outward movement of K+

In particular stimulation of presynaptic μ receptors causes inhibition of N-type calcium channels to and therefore a reduction of the production of neurotransmitters, while stimulation of postsynaptic μ receptors produces hyperpolarization by activating the potassium channels and those inhibiting the L-type Calcium.

More informations and details: Opioid receptor

NMDA receptor

The NMDA receptor is a postsynaptic receptor of glutamic acid. It is a ionotropic receptor (a class of receptors that work themselves from ion channels after binding with the respective ligand and / or activation by other factors, which mediates most of the fast excitory synaptic transmissions in the CNS ).
It consists of several subunits, the innermost of which constitutes the wall of the ionotropic channel that allows the flow of ions across the plasma membrane.

How does it work?

Normally, the binding between NMDA receptor and the ligand, such as glutamic acid or aspartate, lets Na+ and Ca2+ ions to flow inside the neuron and K+ ions outside.
Methadone is a competitive antagonist of NMDA receptor, since binds to and block the binding site of the neurotransmitter glutamate: seeing glutamate is a chemical mediator with excitory action, this competitive blocking determines a non excitatory action (reducing the electrical transmission).


Methadone is a highly lipophilic molecule that is suitable for a variety of administration routes.


It is metabolized in the liver, mainly with N-demethylation and cyclization.
It has two main metabolites:

  • 2-etilidine-1, 5-dimethyl-3 ,3-difenilpirrolidine (EDDP),

  • 2-ethyl-3 ,3-difenl-5-metilpirrolidine,

both are inactivated in the liver.
Methadone is metabolized by isoenzymes of cytochrome P450, in particular CYP3A4, CYP2B6 and CYP2D6, with great variability between individuals. The N-demethylated by CYP3A4 is an inactive metabolite of methadone.


Approved for oral and intramuscular use, methadone also is used rectally, intravenously, subcutaneously, epidurally, and intrathecally. Oral methadone has a bioavailability close to 80 percent compared with 26 percent for morphine.

It is absorbed rapidly from the stomach, with little absorption occurring beyond the pylorus. Following absorption, it is distributed to the brain, liver, kidneys, muscles, and lungs. Tissue binding predominates over binding to plasma proteins (in particular α1-acid glycoprotein), and accumulation of the drug occurs in these tissues with repeated dosing.  Plasma concentrations are maintained by this peripheral reservoir. Methadone reabsorption from the tissues may continue for weeks after administration has ceased.

It has an elimination half-life of about 22 hours, but metabolism varies in each person. 

Unlike morphine, it usually is not necessary to adjust the dosage of methadone in patients with renal insufficiency. The duration of analgesia is approximately three to six hours when methadone therapy is initiated, and this duration typically extends to eight to 12 hours with repeated dosing.
The metabolites are excreted in the feces and urine together with not metabolized methadone. The urinary excretion of methadone is pH-dependent: lower pH -> greater excretion.
Methadone treatment for pain states, 2005

Therapeutic Uses

Methadone is mainly used in :

  • Cessation treatment for opiate dependance (i.e. heroin and morphine )

In the treatment of opioid abstinence or detoxification from opioids, methadone is initially administered in sufficient doses to suppress withdrawal symptoms. In fact methadone acts at lower doses, for a longer time and, if it is administered orally, it doesn’t give euphoric effect. -> i.e.:

Morphine can be taken orally, sublingually, bucally, rectally,  subcutaneously,  intravenously,  intrathecally or epidurally and inhaled via a nebulizer.
In particular after IM or SC injections, morphine plasma levels peak in approximately 20 minutes, while its elimination half-life is approximately 120 minutes.
Instead methadone plasma level peak is reached after approximately 4 hours, while elimination half-life varies considerably from 15 to 60 hours!!!

In some patients treated with methadone, physicians have noticed that, after the administration of this drug, an increase in blood levels of glucocorticoids has been.
Glucocorticoids are a class of steroid hormones, especially products in the zona fasciculata of the adrenal cortex. The glucocorticoid secretion is stimulated by the adrenocorticotropic hormone (ACTH), secreted by pituitary gland, whose production is in turn stimulated by hypothalamic corticotropin-releasing hormone (CRH).
Morphine acts on endorphins, replacing their natural role and inhibiting their production. Endorphins derives from proopiomelanocortic (POMC), that is also the precursor of other molecules, such as ACTH. So, the inhibition of POMC leads to both a decrease of endorphins and ACTH -> decrease of glucocorticoid secretion . (Morphine inhibits the pituitary-adrenal response to ovine corticotropin-releasing hormone in normal subjects, 1985)
As time goes, a high dosage of opiates leads to changes in the number or in the properties of the receptors to which these drugs bind: this results in a reduced response of the receptors to the drug or else to changes of intracellular signal transduction pathways resulting in a lower response of the receptor stimulation. (Desensitization)
So, in this case, in morphine addicted patients methadone, being assimilated slowly from the blood and in constant doses, allows the resumption of the production of POMC; cells receptors however still show the modifications induced by desensitization and require a greater amount of endorphins to receive an effective stimulation, with consequent increase in ACTH.

The increase of ACTH induces an increased secretion of glucocorticoids from the adrenal glands which, sometimes, can lead to an excessive development of these organs, generating hyperplasia (Cushing's syndrome).

MMT (methadone Maintenance therapy) is prescribed to individuals who wish to abstain from illicit drug use but have failed to maintain abstinence from opiates for significant periods. The duration of methadone maintenance can be for months or even years. Methadone reduction programmes are suitable for addicted persons who wish to stop using drugs altogether. The length of the reduction programme will depend on the starting dose and speed of reduction and this varies from clinic to clinic and person to person. In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with opiate injection, such as hepatitis and HIV. The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates. When used correctly, methadone maintenance has been found to be medically safe and non-sedating. It is also indicated for pregnant women addicted to opiates.

  • Pain syndromes of severe entity in patients who no longer respond to a sequential treatment with analgesics, NSAIDs, weak opioids.

Opioid-mediated analgesia is mediated by modulation of ascending and descending pain pathways . Accordingly, MOR has been confirmed in dorsal root ganglia, the spinal cord, and trigeminal nucleus of the ascending pain pathway as well as the central Gray area, pontine, gigantocellulare, and intermediate reticular nuclei of the descending pain pathway. Endogenous opioid analgesia in peripheral tissues and the clinical implications for pain control, 2005

Methadone has been studied as a therapy for cancer pain and other chronic pain states.  It is an appropriate replacement opioid when pain remains poorly controlled or when side effects of other opioids limit dosage escalation. Available data suggest that methadone is effective in relieving cancer pain and has a similar analgesic efficacy and side effect profile to morphine. 
 In a study of cancer patients with uncontrolled pain or significant side effects from opioids, 80 percent of patients reported improvement in pain control and reduction of adverse effects following transition to methadone.  It may be used in patients with morphine allergy because methadone is synthetic and offers no cross-allogenicity. Methadone treatment for pain states, 2005

Compared to morphine it is an agonist to a broader spectrum of opiod receptors and, being also antagonist at the NMDA receptor, inhibits the re-uptake oh both noradrenaline and serotonin. These action are believed to contribute to its increased analgesic efficacy for patients with chronic pain syndromes, hyperalgesia e neuropathic pain.
The use of methadone for cancer pain, 2002
However, a 2004 Cochrane Review stated several considerations in evaluating trials of methadone for cancer pain. The majority of studies reviewed involved single-dose comparisons or short-term use, which does not adequately represent clinical practice. Therefore, there is a highly significant danger that the trials do not reflect delayed adverse effects from methadone accumulation during chronic administration. The same review reported there is no trial evidence to support the proposal that methadone has a particular role in neuropathic pain of malignant origin.

Indications for Methadone Treatment for Pain States

  1. Cost
  2. Morphine allergy
  3. Neuropathic pain
  4. Opioid adverse effects
  5. Pain refractory to other opioids
  6. Uncontrolled pain

Tolerance and dependence

As with other opioid medications, tolerance and dependence usually develop with repeated doses. There is some clinical evidence that tolerance to analgesia is less with methadone compared to other opioids; this may be due to its activity at the NMDA receptor. Tolerance to the different physiological effects of methadone varies; tolerance to analgesic properties may or may not develop quickly, but tolerance to euphoria usually develops rapidly, whereas tolerance to constipation, sedation, and respiratory depression develops slowly (if ever).

Drug warnings

Side effects associated with methadone are similar to those incurred with other muopioid agonists, including pruritus, nausea, constipation, confusion, sedation, and respiratory depression. Excess sweating (diaphoresis) and flushing are common with oral methadone dosing. Caution should be taken with initiation of therapy and dosage increases because severe toxicities may not become apparent for two to five days.
 In a study of patients converted to methadone therapy in an outpatient setting, 20 of 29 participants experienced some degree of toxicity, most frequently mild drowsiness, during initial titration. Methadone: outpatient titration and monitoring strategies in cancer patients, 1999

 Side effects such as sedation and respiratory depression are increased when methadone is combined with alcohol or other drugs. An Australian study  found benzodiazepines present in 74 percent of deaths related to methadone and urged particular caution when methadone was prescribed with benzodiazepines.
Methadone dosage should be selected carefully and titrated slowly, even in opiate-tolerant patients, and patients should be monitored carefully during treatment initiation, transfer to methadone from other opiate therapy, and dosage titration. Patients should be instructed to take methadone exactly as prescribed and advised not to initiate or discontinue use of other drugs or dietary supplements without consulting their clinician; patients also should be informed of the signs and symptoms of overdosage and symptoms suggestive of a cardiac arrhythmia.




Francesca Boccadoro
Michele Brattoli

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