Download Methadone—metabolism, pharmacokinetics and interactions

Pharmacological Research 50 (2004) 551–559
Methadone—metabolism, pharmacokinetics and interactions
Anna Ferrari∗ , Ciro Pio Rosario Coccia, Alfio Bertolini, Emilio Sternieri
Section of Toxicology and Clinical Pharmacology, University of Modena and Reggio Emilia,
Policlinico, Largo del Pozzo, 71-41100 Modena, Italy
Accepted 4 May 2004
Abstract
The pharmacokinetics of methadone varies greatly from person to person; so, after the administration of the same dose, considerably
different concentrations are obtained in different subjects, and the pharmacological effect may be too small in some patients, too strong
and prolonged in others. Methadone is mostly metabolised in the liver; the main step consists in the N-demethylation by CYP3A4 to
EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), an inactive metabolite. The activity of CYP3A4 varies considerably among
individuals, and such variability is the responsible for the large differences in methadone bioavailability. CYP2D6 and probably CYP1A2
are also involved in methadone metabolism. During maintenance treatment with methadone, treatment with other drugs may be necessary
due to the frequent comorbidity of drug addicts: psychotropic drugs, antibiotics, anticonvulsants and antiretroviral drugs, which can cause
pharmacokinetic interactions. In particular, antiretrovirals, which are CYP3A4 inducers, can decrease the levels of methadone, so causing
withdrawal symptoms. Buprenorphine, too, is metabolised by CYP3A4, and may undergo the same interactions as methadone. Since it
is impossible to foresee the time-lapse from the administration of another drug to the appearing of withdrawal symptoms, nor how much
the daily dose of methadone should be increased in order to prevent them, patients taking combined drug treatments must be carefully
monitored. The so far known pharmacokinetic drug–drug interactions of methadone do not have life-threatening consequences for the
patients, but they usually cause a decrease of the concentrations and of the effects of the drug, which in turn can cause symptoms of
withdrawal and increase the risk of relapse into heroin abuse.
© 2004 Elsevier Ltd. All rights reserved.
Keywords: Methadone; Drug–drug interactions; Pharmacokinetic; CYP3A4; CYP2D6
1. Introduction
Since 1965, the year in which Dole and Nyswander [1]
proposed the introduction of methadone as a substitute for
heroin, its use has spread progressively also in Italy, in particular for the treatment of drug addicts who cannot remain drug-free in spite of detoxication therapies and attendance in therapeutic communities. Maintenance treatment
with methadone, performed with doses adequate to the actual needs of the individual addict, contributes to a drop in
mortality, to stopping or reducing heroin use, to decreasing
or avoiding relapses and criminal activity, to favouring the
finding of a job and improving family and social relationships, to reducing the risk of HIV and hepatitis virus infections [2].
The pharmacological characteristics that support the use
of methadone as a replacement in the long term treatment
∗ Corresponding
author. Tel.: +39 59 4224064; fax: +39 59 4224069.
E-mail address: [email protected] (A. Ferrari).
1043-6618/$ – see front matter © 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.phrs.2004.05.002
of heroin addiction, a pathological condition that has been
defined as a “chronic relapsing disorder” [3], are the high
oral bioavailability, the long elimination time that makes a
single daily administration possible, the lack of behavioural
modifications such as to be detrimental to persons carrying
out normal work activities, and the availability of a specific
antagonist that can be used in the case of overdose. The
most negative kinetic characteristics are the inter-individual
variability of absorption and metabolism [4] which make it
impossible to anticipate, with acceptable approximation, the
relationship between dose, blood concentration, and clinical
effect [3].
2. Pharmacokinetics of methadone
The available methadone hydrochloride on the market
is a racemic mixture of two stereoisomers. l-Methadone
is the pharmacologically active isomer [5–7] (however,
d-methadone retains certain pharmacological effects; for
example, the antitussive activity.) Methadone taken orally is
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A. Ferrari et al. / Pharmacological Research 50 (2004) 551–559
subjected to an important first-pass effect and is detectable
in the plasma about 30 min after administration [8]. Its
bioavailability varies from 41–76 [9] to 85–95% [10]. Thus,
following the administration of equal doses, quite different blood concentrations are obtained in different subjects
[4,11]. This variability must be kept in mind when selecting
the initial doses of methadone, and in settling the optimum
dosages for maintenance treatment. There are considerable
differences also in the time needed to reach the maximum
plasma concentration (Tmax ): from 1 to 6 h, with average
values of 2.5–4.4 h [9,10,12]. The course of methadone
plasma concentrations over time follows a bi-exponential
curve, with a rapid ␣-phase, that corresponds to the transfer
of the drug from the central compartment to the tissue compartment and to the beginning of elimination, and a slow
␤-phase, that corresponds to elimination [13]. The t1/2 of
the first phase of methadone disappearance from the plasma
(␣-phase, distribution) shows remarkable differences between individuals, varying from 1.9 to 4.2 h, with an average
value of 2.95 ± 0.92 h [9]. The t1/2 of the second phase of
drug disappearance from the plasma (␤-phase, slow, elimination) varies even more, from 8.5 to 47 h [9,10,12,14–19].
Due to its high lipid solubility, 98% of methadone that
has reached the central compartment is rapidly transferred to
tissues, particularly liver, kidneys, lungs and, in small proportion, to the brain [20]; 1–2% remains in the blood compartment [9], 60–90% bound to plasma proteins, mostly the
acid ␣1-globulins [21,22], and only in part (13.4–17.4%) to
the ␥-globulins [23]. The extent of protein binding is of obvious importance for methadone activity. So, for example,
the blood concentrations of acid ␣1 -glycoproteins, increase
in stress conditions [23] and in heroin addicts. As a consequence, there is an increase of the amount of protein-bound
methadone and a decrease of free and active methadone
[24].
The size of the tissue compartment can be obtained by
the apparent volume of distribution; in drug addicts this datum is not very consistent: 2.1–5.6 l kg−1 [9]; 4.1 l kg−1 [10]
and 4.2–9.2 l kg−1 [20]. The large volume of methadone
distribution indicates that there is a large sized tissue compartment, in dynamic equilibrium with a small central compartment. The result is that during maintenance treatment
a short-lasting decrease of blood levels of methadone is
usually not associated with clinically evident withdrawal
symptoms [25]. During maintenance treatment, the plasma
half-life of the ␤-phase of elimination varies little in the same
patient, even if the dose of methadone is increased or decreased, from 22 to 25 h, even though maintaining significant
differences between individuals [26]. Some authors [13,27]
are of the opinion that the induction of its own metabolism
may be responsible for the reduction of methadone concentrations during maintenance treatment. According to Verebely [13] after thirty days of treatment at the daily dose of
40 or 80 mg, the plasma levels of methadone decrease by
three to eight-times, while the excretion of the parent drug
and of its metabolites increase from 22.2 to 61.9%. Accord-
ing to Holmstrand [26], instead, the plasma concentrations
of methadone decrease by 15–25% after 5–12 months of
treatment with 60 or 80 mg/day by self-induction of its own
metabolism, thus justifying the requests by some drug addicts to increase the daily dose in order to remain in treatment [28,29]. Individuals who relapse might have insufficient plasma levels of methadone, according to Nilsson [18].
This author examined the kinetics of methadone in a group
of subjects under treatment and in a group of subjects who
had withdrawn from treatment. In the patients of the latter
group the volume of distribution and the t1/2 of the elimination ␤-phase were shorter than in the patients of the former group (dropped-out patients: Vd: 3.09 ± 0.061 l kg−1 ;
t1/2␤ : 24.5 ± 2.6 h; patients under treatment: Vd: 4.56 ±
1.001 l kg−1 ; t1/2␤ : 34.0 ± 7.0 h).
Also the body clearance of methadone varies widely
among individuals, ranging from 0.96 to 6.1 ml/min/kg
[9]; thus, methadone body clearance, too, can contribute
to the large differences in methadone kinetics among drug
addicts.
The role of chronic liver diseases in methadone
metabolism is not clearly defined. Kreek [30,31] hypothesizes that the abnormal kinetics of methadone that are observed in some patients can be explained by the functional
insufficiency of the hepatic microsomal system.
The elimination of methadone and its metabolites occurs mainly through the kidneys: 15–60% during the first
24 h (20% as unmodified drug, and 13% as 2-ethylidene1,5-dimethyl-3,3-diphenylpyrrolidine; EDDP). Elimination
in the faeces accounts for 20–40% [32]. According to Inturrisi [16] the overall elimination is 25% during the first
24 h, and 52% during the first 96 h (58% as methadone and
42% as metabolites). The rate of elimination of unmodified
methadone is dependent on the extent of the pH-dependent
tubular re-absorption in the kidney, and is increased by urine
acidification. When urinary pH is less than 6, the amount of
excreted methadone is three to eight-times greater than at
pH higher than 6 [10,32–34]. Varying the pH also changes
the half-life of plasma concentrations of methadone. Nilsson [32] evaluated the half-life of the ␤-phase, the volume
of distribution and body clearance after acidification (pH
around 5.2) and alkalization (pH around 7.8) of the urines.
The half time of the ␤-phase was 19.5 ± 3.6 h with acidic
urines, and 42.1 ± 8.8 with basic urines. Similar modifications have been found in the extent of the distribution volume, that goes from 3.51 ± 0.41 l kg−1 with acidic urines
to 5.24 ± 0.83 l kg−1 with basic urines, and in body clearance, that goes from 134 ± 31 ml/min with acidic urines to
91.9 ± 9.1 ml/min with basic urines [32]. With acidic urines
renal clearance triples, and the EDDP/methadone ratio decreases [34]. Urinary pH, therefore, has profound effects
not only on methadone excretion, but also on the volume
of distribution of the drug. By keeping the urinary pH constant, the inter-individual differences of methadone elimination and plasma concentrations are considerably reduced
[15,32,34].
A. Ferrari et al. / Pharmacological Research 50 (2004) 551–559
3. Pharmacological interactions and cytochrome P450
(CYP)
Changes in the metabolism and elimination of methadone
are mainly caused by inhibition or induction of cytochrome
P450, with a consequent increase or decrease of the amount
of drug levels in blood and tissues.
P450 and CYP are synonyms. A CYP enzyme is composed of a protein and of a haeme group (as the prosthetic
group). This superfamily is divided into families and subfamilies of enzymes on the bases of their amino acid sequence. Each family has an identity of at least 40% in the
amino acid sequence and is identified by an Arabic number.
Each subfamily has an identity of at least 55% in the amino
acid sequence and is indicated by an upper-case letter. The
genes codifying a subfamily are identified by another Arabic number. For example, CYP3A4 means that the enzyme
belongs to the family 3, to the subfamily A and is codified
by the gene 4 [35].
Metabolic induction develops following the repeated administration of a drug, with the synthesis of new enzyme
and with the increase of its activity. The result is an increase in the metabolism of the drug involved in interaction
and a decrease in the quantity of drug available for pharmacological activity. In order for this to take place 1 or 2
weeks are usually needed. On the other hand, enzymatic inhibition develops quickly since it takes a short time for the
drug to bind to the enzyme. Inhibition of activity of the enzyme decreases the metabolism of the drug, and therefore,
increases its pharmacological activity [36]. Pharmacokinetic
interaction can also occur when two or more drugs that are
metabolic substrates of the same CYP are administered concurrently. In this case the drug that has the greatest affinity
for that cytochrome can prevent in part the metabolism of
the other drugs [37,38].
Most drugs are substrates of only five isoenzymes
(CYP3A4, 1A2, 2C9, 2C19, 2D6); therefore, interactions
can easily take place. The drugs that during absorption
undergo a considerable first-pass effect or that have a low
therapeutic index are the ones most often subject to significant interactions [39]. Many interactions are not clinically
apparent because plasma concentrations with therapeutic
doses are lower than those used to cause the interaction in
vitro.
1 to 11-fold in the gut [42]. The major factor responsible for the variations of methadone bioavailability is the
inter-individual difference in the expression of CYP3A4
[43]. This enzyme is involved also in the metabolism
of other drugs: benzodiazepines, calcium antagonists,
macrolide antibiotics, and anticonvulsants. Its activity is
strongly inhibited by ketoconazole, by fluoxetine and by
grapefruit juice (large amounts). Another enzyme, involved
in methadone metabolism, is CYP2D6 [44]. It is mainly
expressed in the liver, and is not inducible. This enzyme
is subject to genetic polymorphism and many different
CYP2D6 alleles have been identified [45]. The prevalence
of the poor metabolism phenotype shows marked ethnic
differences with a mean value of 7.4% (4–10%) of population in Europe and lower frequencies of 1% (0.6–1.5%) in
Orientals [46,47]. The prevalence of rapid metabolizers is
1% of the German population, 7% of the Spanish and 2–5%
of the Black population [47]. Also CYP1A2 is probably
involved in methadone metabolism, but the available literature data are conflicting [47]. This isoenzyme is induced
also by cigarette smoke, and is not subject to genetic polymorphism. Its activity can vary, according to the individual,
Table 1
Drugs that are inducers or inhibitors of CYP3A4 and of CYP2D6
Inducers
CYP3A4
Barbiturates
Carbamazepine
Dexamethasone
Efavirenz
Felbamate
Hypericum (“St. John’s Worth”)
Nelfinavir
Nevirapine
Oxcarbazepine
Phenytoin
Phosphophenytoin
Rifampina
Risperidone
Ritonavir
Topiramate
Inhibitors
Cimetidine
Ciprofloxacin
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Fluoxetine
Fluvoxamine
Grapefruit juice
Josamycin
Ketoconazolea
Nefazodone
Norfloxacin
Norfluoxetine
Paroxetine
Protease Inhibitors
Venlafaxine
CYP2D6 (It can’t be induced.)
Cimetidine
Chlorimipramine
Fluoxetine
Fluvoxamine
Haloperidol
Levopromazine
Moclobemide
Norfluoxetine
Paroxetine
Protease Inhibitors
Quinidinea
Sertraline
Thioridazine
4. Methadone metabolism
Methadone is metabolised almost exclusively by the liver
[10]. The main biotransformation of the two methadone
enantiomers is the N-demethylation [40] by CYP3A4 [41].
CYP3A4 is found in the small intestine and in the
liver; therefore, it affects both the intestinal and hepatic
metabolism of methadone. This enzyme has no genetic
polymorphism, it is inducible, and its activity varies greatly
among individuals, from 1 to 30-fold in the liver, from
553
a
Selective inducer or inhibitor.
554
Table 2
Drugs that are metabolic substrates of CYP3A4 and CYP2D6
Antidepressants
Antipsychotics
3A4
Amitriptyline
Imipramine
Nefazodone
Sertraline
Venlafaxine
Clozapine
Haloperidol
Risperidone
2D6
Desmethylcitalopram
Fluoxetine
Fluvoxamine
Mianserine
Nefazodone
Norfluoxetine
Paroxetine
Sertraline
Trazodone
Venlafaxine
Clozapine
Haloperidol
Perphenazine
Risperidone
Thioridazine
a
␤-Blockers
Alprenolol
Atenolol
Metoprolola
Propranolol
Timolol
Ca2+ -antagonists
Benzodiazepines
Antiarrhythmics
Opioids
Other drugs
Amlodipine
Diltiazem
Nifedipine
Nimodipine
Verapamil
Alprazolam
Clonazepam
Midazolama
Triazolam
Amiodarone
Lidocaine
Quinidine
Tramadol
Carbamazepine
Clarithromycin
Cortisol
Cyclosporine
Dexamethasone
Erythromycina
Ethinylestradiol
Terfenadine
Testosterone
Theophylline
Topiramate
Troleandomycin
Encainide
Flecainide
Propafenone
Codeine
Dextromethorphana
Ethylmorphine
Methadone
Tramadol
Amphetamines
Chlorpromazine
Sparteine
Cinnarizine
Flunarizine
In vivo probes for studying induction and inhibition of cytochrome P450 enzymes in humans.
A. Ferrari et al. / Pharmacological Research 50 (2004) 551–559
CYP
A. Ferrari et al. / Pharmacological Research 50 (2004) 551–559
555
Table 3
Interactions between methadone, anticonvulsants and psychoactive drugs
Drug
Effect on methadone
Amitriptyline [74]
Carbamazepine [74]
Diazepam/midazolam [74]
Phenytoin/phosphophenytoin [75]
Fluoxetine [49,50]
Fluvoxaminea [49,50]
Risperidone [76]
Moclobemide [76]
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
concentration
concentration
concentration
concentration
concentration
concentration
concentration
concentration
↑, clearance ↓
↓
↑
↓ (up to −50%)
↑
↑ (+20 to 40%)
↓
↑
Severity
Onset
Mechanism
NR
Moderate
Moderate
Moderate pWS
Moderate
Moderate
Moderate
Minor
NR
Delayed
Delayed
Delayed
Rapid
Rapid
Delayed
Rapid
CYP2D6 substrate
CYP3A4 induction
CYP3A4 substrate
CYP3A4 induction
CYP3A4, CYP2D6 inhibition
CYP3A4, CYP2D6 inhibition
CYP3A4 induction
CYP2D6, CYP1A2 inhibition
NR: not reported; ↑: increase; ↓: decrease; pWS: probable Withdrawal Symptoms. Moderate severity: it can worsen the patient’s condition and/or it
requires a change in the therapy; minor severity: clinical effects are limited; it can increase the frequency and/or the seriousness of side effects, but no
medical intervention is necessary. Delayed onset: appearance of clinical effects after more than 24 h from the administration of the drug; rapid onset:
appearance of clinical effects within 24 h from the administration of the drug.
a The discontinuance of treatment has been associated with withdrawal symptoms.
from 1 to 40-fold. The expression of these three enzymes
in the liver is quite different; CYP3A4, CYP2D6, CYP1A2
represent, respectively, 30, 4 and 13% of all CYP enzymes
[42]. Tables 1 and 2 list the inducer, inhibitor and metabolic
substrate drugs of CYP3A4 and CYP2D6.
5. Interactions of methadone
Methadone maintenance treatment must not be interrupted
too early. In fact, its aim is to retain drug addicts on treatment for months or years [2]. During these long periods,
treatments with other drugs may become necessary in consideration of the high comorbidity of drug addicts [48], and
there may be the risk of drug–drug interactions. The classes
of drugs that could be used during methadone maintenance
treatment and that could produce drug–drug interactions—
of the kinetic type—with methadone, are benzodiazepines,
antidepressants, anticonvulsants (Table 3), macrolide antibiotics and anti-fungals (Table 4). These drugs are inhibitors,
inducers or substrates of CYP3A4 or CYP2D6. Particular
mention is made of the interaction with the antidepressant
fluvoxamine, which inhibits both CYP3A4 and 2D6, and
which attains in vivo, at therapeutic doses [48], plasma concentrations that correspond to those that are inhibitory in
vitro [49,50]. Another clinically important interaction may
occur with rifampicin: in order to avoid withdrawal symptoms an increase of up to double the methadone dose [51,52]
is required within a few days after the start of rifampicin
treatment.
Maintenance treatment with methadone is best choice
in HIV positive heroin addicts, therefore, the interactions
that can take place most often and that are clinically most
important are those between methadone and antiretroviral
drugs [53–59] (Table 5). In HIV therapy, three classes of
antiretroviral drugs are currently used: (1) the nucleotide
or nucleoside analogues, that are inhibitors of the reverse
transcriptase (zidovudine, didanosine, zalcitabine, lamivudine, abacavir); (2) the non-nucleoside inhibitors of the reverse transcriptase (nevirapine, delavirdine, efavirenz); (3)
the protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir, amprenavir) [60–62]. The most frequently used associations include two nucleoside analogues and a protease
inhibitor, or two nucleoside analogues and a non nucleoside
inhibitor of the reverse transcriptase [60,61]. Antiretrovirals are metabolic inducers of CYP3A4 and this entails an
Table 4
Interactions between methadone and drugs or substances of possible use in heroin addicts
Drug
Effect on methadone
Severity
Onset
Mechanism
Ketoconazole [77]
Dexamethasone [78]
Disulfiram [54]
Fluconazole [77,79]
Erythromycin [80]
Rifampin [51,52,81]
Rifabutine [52]
Grapefruit juicea [82]
Plasma concentration ↑
Plasma concentration ↓
Plasma concentration ↓
Bioavalability ↑ (AUC: +35%; clearance: −24%)
Plasma concentration ↑
Plasma concentration ↓ (−30%, −65%)
Plasma concentration ↓
Plasma concentration ↑
Minor
NE
NE
Minor
Moderate
Moderate; pWS
Moderate
Moderate
NR
NR
NR
NR
Delayed
Delayed (6–8 h)
Delayed
Rapid
Strong CYP3A4 inhibition
CYP3A4 induction
NR
CYP3A4 inhibition
CYP3A4 inhibition
Strong CYP3A4 induction
CYP3A4 induction
CYP3A4 inhibition
NE: no effect; NR: not reported; ↑: increase; ↓: decrease; pWS: probable Withdrawal Symptoms. Moderate severity: it can worsen the patient’s condition
and/or it requires a change in the therapy; minor severity: clinical effects are limited; it can increase the frequency and/or the seriousness of side effects,
but no medical intervention is necessary. Delayed onset: appearance of clinical effects after more than 24 h from the administration of the drug; rapid
onset: appearance of clinical effects within 24 h from the administration of the drug.
a The increase of methadone concentration is clinically significant only after the ingestion of large amounts of grapefruit juice, several times a day
and for several days.
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A. Ferrari et al. / Pharmacological Research 50 (2004) 551–559
Table 5
Interactions between methadone and antiretroviral drugs
Drug
Effect on methadone
Abacavir [83]
Amprenavir [60,83]
Didanosine [84,85]
Efavirenz [67–69]
Indinavir [60]
Nelfinavir [61]
Nevirapine [66,86]
Ritonavir [87]
Stavudine [84]
Zidovudine [88]
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
concentration
concentration
concentration
concentration
concentration
concentration
concentration
concentration
concentration
concentration
↓
↓
↓
↓
↑
↓
↓
↓
↓
↑
(Cmax : −34%)
(−60%)
(29–47%)
(−46%)
(−40 to 50%)
Severity
Onset
Mechanism
Minor
Minor
Minor
Moderate;
NE
Moderate;
Moderate;
Moderate;
Minor
Moderate
NR
Delayed
Rapid
Delayed (8–10 days)
NR
Delayed
Delayed (4–8 days)
Delayed
Rapid
Delayed
M clearance ↑ (+22%)
NR
Bioavailability ↓ (−41 to 59%)
M metabolism ↑ (CYP3A4 induction)
Bioavailability ↑
M metabolism ↑ (CYP3A4 induction)
M metabolism ↑ (CYP3A4 induction)
M metabolism ↑ (CYP3A4 induction)
NR
M bioavailability ↑
pWSa
pWSa
pWSa
pWSa
M: methadone; NE: no effect; NR: not reported; ↑: increase; ↓: decrease; pWS: probable Withdrawal Symptoms. Moderate severity: it can worsen the
patient’s condition and/or it requires a change in the therapy; minor severity: clinical effects are limited; it can increase the frequency and/or the seriousness
of side effects, but no medical intervention is necessary. Delayed onset: appearance of clinical effects after more than 24 h from the administration of
the drug; rapid onset: appearance of clinical effects within 24 h from the administration of the drug.
a During the methadone treatment it is recommended to check withdrawal symptoms and to increase the dosage on the basis of the intensity of
withdrawal symptoms.
Table 6
Interactions between methadone and combinations of antiretroviral drugsa
Drugs
Effect on methadone
Ritonavir + lopinavir [89–91]
Ritonavir + saquinavir [92]
Ritonavir + nelfinavir [56]
Ritonavir + nelfinavir + nevirapine [64]
Nevirapine + efavirenz [64]
Abacavir + amprenavir [83]
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
concentration
concentration
concentration
concentration
concentration
concentration
Severity
↓ (AUC: −30%; Cmax : −44%)
↓ (−28%)
↓
↓
↓ (AUC: −54%; Cmax : −42%)
↓
Minor
Moderate; pWS
Moderate; pWS
Minor
Minor
Minor
↓: decrease; pWS: probable Withdrawal Symptoms. Moderate severity: it can worsen the patient’s condition and/or it requires a change in the therapy;
minor severity: clinical effects are limited; it can increase the frequency and/or the seriousness of side effects, but no medical intervention is necessary.
a For all these interactions the onset is delayed and the probable mechanism is an increased metabolism of methadone; during the methadone treatment
it is recommended to monitor withdrawal symptoms and to increase the dosage on the basis of the intensity of withdrawal symptoms.
increase in enzymatic activity, a decrease of the amount of
methadone available, and the possible precipitation of opioid withdrawal symptoms [63,64] (Table 6). Because of the
extreme variability of methadone metabolism in the same
subject and among different subjects, the relationship between dose–blood level-effect is not established [65] and
it is impossible to suggest guidelines of management in
order to prevent the onset of the opioid withdrawal syndrome during polytherapy. The degree of the increase of
methadone dosage after the occurrence of withdrawal symptoms in the course of anti-HIV treatment has been extremely
different [55,66,67] even when the antiretroviral drug used
was the same (Table 7). Also the time of onset and the
severity of the withdrawal syndrome were different, in the
above-quoted studies, perhaps because the patients had been
treated for different periods of time and with extremely different daily doses of methadone. The interaction between
efavirenz and methadone, for example, determined a decrease in the plasma concentrations of methadone that varied
between 22 and 80%, with signs and symptoms of morphine
withdrawal that appeared from 4 to 28 days after the beginning of the treatment with the antiretroviral drug [67–69].
Table 7
Interactions between methadone and antiretroviral drugs, and measures taken to abolish withdrawal symptomsa
Drug
Effect on methadone
Days after the beginning
of treatment
Measures taken to treat
withdrawal symptoms
Efavirenz [67]
Efavirenz [56]
Bioavailability ↓ (on average: −60%)
Plasma concentration ↓ (on average: −40%
in patients treated with M 100 mg/day for 1
year)
Plasma concentration ↓ (on average: −65%)
Plasma concentration ↓ (in patients treated
with M 90 mg/day for 2 years)
8–10
28
M dosage ↑ (+66–133%)
M dosage ↑ (up to 180 mg/day)
8–10
7
M dosage ↑ (+65–133%)
M dosage ↑ (up to 130 mg/day)
Efavirenz [69]
Ritonavir + saquinavir [92]
M: methadone;↑: increase; ↓: decrease.
a It is advised to check frequently withdrawal symptoms.
A. Ferrari et al. / Pharmacological Research 50 (2004) 551–559
557
In conclusion, it can only be recommended a careful observation of the patient and, if necessary, an adjustment of the
daily dose of methadone on the basis of the clinical signs.
It is well-known that during methadone maintenance treatment many subjects increase their alcohol consumption [70];
when chronically abused, alcohol induces the activity of
CYP3A4 [71]. In such circumstances the plasma concentrations of drugs that are metabolised by this enzymes (particularly methadone), decrease [72]. Other opioid drugs, such
as codeine and tramadol, are metabolised by the same enzymes, and thus are subjected to the same interactions as
methadone. In particular, buprenorphine is metabolised by
CYP3A4 [73] and should undergo exactly the same interactions as methadone. Data on this subject are anectodal because the use of buprenorphine on a large scale in the treatment of heroin addicts started in France and Italy only a few
years ago. However, there is a clear evidence that the interactions of buprenorphine with antiretroviral drugs are similar to those of methadone [50]: its plasma concentrations
may decrease when it is administered together with protease
inhibitors or other enzyme inducers.
As a rule, in order to prevent, identify and quickly manage
pharmacological interactions, the physicians should:
6. Conclusions
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The possibility that clinically important interactions occur
when methadone is taken concomitantly with other drugs is
substantial. Fortunately, most of such pharmacokinetic interactions are not life-threatening; however, they can have
important consequences: precipitation of withdrawal symptoms, relapse in the use of heroin in an attempt to relieve
them, thus leaving the maintenance treatment. Physicians
must, therefore, carefully follow these patients in order to
avoid, or at least to notice and treat in time, such plights.
Since the pharmacokinetics of methadone is extremely variable from one patient to another, the relationships between
dose, plasma levels and effects are not clearly defined, and
an optimum range of therapeutic concentrations has not yet
been identified for maintenance treatment. The same dose,
even though normalized to weight, produces a bioavailability of methadone that is completely different from subject to
subject. Thus, in the course of long-term maintenance treatments, the daily dose must be personalised; using doses of
methadone in an arbitrary manner, within a limited range, is
clinically incorrect. In choosing the dose, the simultaneous
use of other drugs must be taken into careful consideration.
The effectiveness of maintenance treatment must be evaluated over time. To do this, since it isn’t always possible
to measure the blood levels of methadone (that, in addition,
are not always sufficient to predict the effects of the drug
if it not associated with other pharmacokinetic parameters)
all that can be done is to check the urine for drugs of abuse
and to carefully consider drug addicts’ self-reports. Only on
the basis of these elements it will be possible to adjust the
dosage of methadone to the real needs of the patient under
treatment.
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