Revisiting methadone : pharmacokinetics , pharmacodynamics and clinical indication *

BACKGROUND AND OBJECTIVES: Methadone is a synthetic long-duration opioid with pharmacological properties qualitatively similar to morphine for its action on μ-opioid receptor. It is primarily used to treat cancer pain refractory to morphine. This study aimed at presenting a review of this drug with focus on pharmacokinetic and pharmacodynamic aspects, in addition to its clinical indication. CONTENTS: Articles available in Medline, Scielo, Cochrane library and Pubmed platforms until July 2014 were reviewed using the following descriptors: Methadone; Acute Pain; Chronic Pain; Cancer Pain; and Opioids. CONCLUSION: Its pharmacological properties make methadone a unique opioid analgesic, since it is less susceptible to tolerance, prevents hyperalgesia, is less conducive to abusive consumption and has a possible better action on neuropathic pain. However, risks of accidental death due to overdose, of arrhythmias and of pharmacological interactions should not be overlooked. In addition, there is lack of conclusive clinical trials comparing methadone to other analgesics with regard to risks and benefits.


INTRODUCTION
Methadone is a synthetic long-lasting opioid primarily used to treat cancer pain refractory to morphine 1 .This study aimed at presenting a historical review of this drug, as well as introducing pharmacokinetic and pharmacodynamic aspects, in addition to its clinical indication.

CONTENTS
Articles available in Medline, Scielo, Cochrane library and Pubmed platforms until July 2014 were reviewed using the following descriptors: Methadone; Acute Pain; Chronic Pain; Cancer Pain; and Opioids.

Background
Methadone was synthesized in 1938 by Max Bockmuhl and Gustav Erhart, supposedly by order of the then German leader (Führer) -Adolf Hitler, to replace morphine, the supply of which was plummeting since the beginning of World War II.By that time, it received the trade name of Dolophine, after the first name of Hitler 2 .However, this information is controversial since the word Dolophine has its origin in Latin, where Dolor means pain and Fin end 3 .This opioid was used by German soldiers during the war period to control pain, however with poor acceptance due to its adverse effects.
REVIEW ARTICLE DOI 10.5935/1806-0013.20150012The name methadone derives from fragments of its chemical name (6-dimethylamine-4,4-diphenyl-3heptanone) 4 and is currently accepted to designate its racemic mixture.Notwithstanding its recent appearance, the stigma of having been extensively used to detoxify heroin users has limited the acceptance of this drug to control pain 2 .However, the recognition of its special pharmacological characteristics, added to its low cost, has helped the spread of its use to treat chronic pain, especially cancer and neuropathic pain 5 .

Farmacokinetics
Methadone is a basic liposoluble drug with pKa of 9.2, which is administered as a racemic mixture of two enantiomers: R--methadone and S-methadone 6 .When orally administered it has fast and almost complete absorption.It may be detected in the plasma 30 minutes after oral dose, and time to reach plasma peak concentration is 2.5h for oral solution and 3h for tablets.Bioavailability is high, varying from 67 to 95% 7 .Drug absorption by oral mucosa is also possible 7 .
It is an opioid agonist with long half-life, approximately 24h, and with wide variability among individuals (8 -90h), being far superior than other opioids used for pain therapy, such as morphine (t 1/2 =2-4h), hydromorphone (t 1/2 =2-3 hours) or fentanyl (t 1/2 =4 hours) 8 (Table 1).Time for analgesia onset after administration of a single intravenous bolus is approximately 10 to 20 minutes and duration is from 4 to 8h, which is less than excretion time and increases build-up risk after repeated doses 8 .It is a lipophilic substance extensively distributed throughout tissues such as brain, intestine, kidney, liver, muscles and lungs.This characteristic justifies the large distribution volume of this opioid described in human studies 9 .And due to the fact that tissue distribution is superior to plasma proteins binding capacity, its apparent distribution volume during the balance state is much higher than plasma volume itself.This volume varies according to the study, depending on the profile of included patients 10 .Methadone extensively binds to plasma proteins (reaching 86%) and, being a basic substance, it is predominantly bound to acid α-glycoprotein.Since it is a plasma protein which increases in acute phase reactions, this variability may determine the variation of drug plasma concentration, especially in cancer patients 11 .Clinically, these pharmacokinetic properties lead to building--up of methadone in tissues after the administration of repeated doses, thus increasing the risk of overdose.And when the analgesic is withdrawn, a small plasma concentration is maintained due to gradual methadone redistribution to the intravascular.Also, this is probably the reason why this opioid is less prone to induce withdrawal syndrome.It is metabolized in the liver and excreted by the kidneys.As result of its basic pH (pKa=9.2) and lipophilic properties, changes in urinary pH may alter its excretion.When urinary pH is above 6, kidney excretion is responsible for just 4% of total excreted drug, while in pH below 6, 30% of total dose are excreted by the kidneys 12 .
As to liver excretion, methadone has low extraction ratio, which implies high bioavailability after oral administration, in addition to bringing relevant consequences with regard to interindividual variability, since the excretion of this substance depends both on drug free fraction and intrinsic liver enzymatic activity 7 .Methadone is metabolized in the liver metabolism by several P450 cytochromes which degrade it to its inactive metabolites (2-ethyl-1.5-dimethyl-3.3-diphenylpyrrolidine and 2-ethyl-5-methyl-3.3-diphenyl-pyrroline) 13.In vitro experimental data suggested that CYP3A4 would be the isoform with highest responsibility for methadone metabolism in humans 14 .However, recent data suggest that CYP2B6 would be the primary isoform for methadone metabolism and excretion in vivo 15 .
In addition to methadone, cytochrome CYP2B6 is also responsible for the metabolism of other drugs, such as: bupropion, efavirenz and clopidogrel, which implies risks of interaction among such drugs 7,16 .Table 2 shows examples of pharmacological interaction with methadone.
A wide variability of responses has been observed among individuals exposed to methadone, which may be attributed to genetic polymorphism in the encoding of cytochromes involved with its metabolism, in addition to the polymorphism of carrier proteins and opioid receptors 17 .Normally, methadone or its metabolites are excreted by the urine (20-50%) and by feces (10-45%), but in the presence of kidney failure there is increased fecal excretion both of metabolism products and methadone itself, to the point of being able to eliminate the whole drug 18 .This way, methadone may be considered safe for kidney failure in patients undergoing dialysis.But some authors recommend dose reduction when glomerular filtration rate is below 10mL/min 18 .Methadone can be found in breast milk, but in concentrations which, in theory, are harmless to the infant and it is also able to cross the placental barrier, but by this route it may induce withdrawal syndrome in the neonate 19,20 .

Pharmacodynamics
Methadone is an opioid agonist acting by binding to µ, κ and δ opioid receptors (MOR, KOR and DOR, respectively).Its pharmacodynamic properties, such as analgesia, respiratory depression, dependence and tolerance are primarily triggered by MOR activation 7 .
Tolerance is defined as decreased opioid agonist analgesic potency after previous exposure to the same opioid.Cross--tolerance is a phenomenon resulting from decreased response to an opioid agonist after previous exposure to a different opioid 21 .An experimental study has shown that methadone is an opioid less sensitive to tolerance, since its ED 50 was not altered after previous exposure to morphine 21 .Chronic opioid therapy may also produce opioid-induced hyperalgesia (OIH) which sensitizes patients or triggers acute pain episodes 21,22 .
It has been shown that chronic opioid exposure, predominantly to methadone, decreases coronary disease extension, as compared to non-exposed patients 23 .This finding was confirmed by an experimental study where exposure to morphine (MOR agonist) has decreased the area of myocardial infarction when administered before ischemia and reperfusion 24,25 .Methadone has the effect of decreasing myocardial ischemia through MOR activation, and is dependent on ischemic injury duration 26 .

Isomers pharmacodynamics
R-Methadone has 10 times higher affinity for MOR and DOR receptors than its S isomer, and its analgesic activity may be 50 times higher.S-Methadone is seemingly inactive as opioid, and as R-Methadone, it is a non-competitive antagonist of the N-methyl-D-aspartate receptor (rNMDA) which is responsible for OIH and participates in the tolerance phenomenon 27 .
Silverman 28 has summarized the mechanisms responsible for hyperalgesia: rNMDA activation; inhibition of the glutamate carrier system (increases the amount of available glutamate to activate the receptor); calcium-regulated intracellular kinase C protein participation as a link between OIH cell mechanisms; chronic morphine administration (induces neurotoxicity via spinal cord dorsal horn apoptosis).
In addition to its action on rNMDA, S-Methadone promotes strong serotonin and norepinephrine uptake inhibition in the central nervous system 29 .Due to the combination of those properties, methadone is a tool to help managing chro-nic neuropathic pain, tolerance and OIH as a function of its pharmacodynamic properties [30][31][32] .

Pharmacogenetics
The polymorphism of genes encoding opioid receptors and the enzymes involved in methadone metabolism contribute for the wide variability of its pharmacology among individuals 33 .
A study with healthy volunteers has shown that mutation of 118A4G in the OPRM1 gene, which encodes MOR, is associated to decreased levomethadone single dose effect evaluated by pupillometry.However, data on the relationship between genetic variability and methadone pharmacological effect are not consistent and there is incongruence among results.This same study has not found association between methadone effect and polymorphism of genes encoding glycoprotein-P, cytochromes P3A, 2B6, 1A2, 2C8, 2C9, 2C19 and 2D6 33,34 .

Administration routes
Methadone, as other opioids, is preferably orally administered, but other routes are possible, such as: rectal, venous, muscular, subcutaneous, nasal, sublingual, spinal and epidural.
The rectal route is used in the clinical practice through micro--enemas or suppositories 35,36 .Bioavailability after rectal administration is in average 76%, which is very similar to the oral route (86%), it has faster onset time, plasma peak time is 1.4h and duration is 10h 37 .It may be intravenously administered via patient-controlled analgesia pump (PCA), continuous infusion and/or intermittent bolus 38,39 .Analgesia onset after venous bolus is 10-20 minutes and its duration is 4-8h 39 .
The subcutaneous route is used to replace the oral route, but it is recommended to decrease 50% of the dose 40 .Subcutaneous administration is limited by local inflammatory reaction which requires injection site rotation 41 .Although there is no consensus among authors about the recommendation of this route, studies have shown positive experiences with this use 40 .To prevent inflammatory reactions, it is recommended to rotate the injection site, the addition of hyaluronidase and dilution in 16mL of 0.9% saline [40][41][42] .Methadone may be used by subarachnoid route although being rapidly distributed to plasma.However, few studies were carried out to evaluate this route 43 .Epidural route may be used to control chronic and postoperative pain 44 .This opioid may be also administered by intranasal or sublingual routes 45 .In a pilot study, significant breakthrough pain relief was obtained 5 minutes after sublingual methadone administration 46 .

Clinical indications
Methadone is indicated to treat moderate to severe pain which cannot be totally controlled by simple analgesics.

Perioperative period
More than 40% of patients submitted to surgeries report uncontrolled pain, or moderate to severe pain, in spite of the treatment.Acute postoperative pain is a risk factor for the development of chronic pain [47][48][49] .Anesthetic care trend in the last decades is to use short-lasting and short half-life opioids (fentanyl, alfentanil, sulfentanil and remifentanil), but the transition of the intraoperative to the postoperative period, especially in very painful surgeries, may be a challenge.As the effect of used drugs is dissipated, patients may experience severe pain 50 .At this moment, it is indicated the use of long-lasting opioids.The methadone is an effective alternative to conventional opioids to control postoperative pain 38,44,[51][52][53][54][55] .

Cancer pain
Pain is highly prevalent in cancer patients, to an extension that, depending on the severity of the disease and type of tumor, 30 to 70% of patients have pain since the onset of the disease 56 .However, the recommendation published by the World Health Organization (WHO) to use the concept of steps to treat cancer patients' pain, has provided up to 90% relief 56 .Breakthrough pain is responsible for uncontrolled pain in 40-80% of cancer patients and is defined as transient worsening of pain (referred as intense or excruciating) as from a moderate or mild baseline pain [56][57][58] .Breakthrough pain reaches its peak in approximately 3 minutes 59 and lasts in average 30 minutes, and methadone is a feasible opioid for this scenario.Since oral methadone has its onset in approximately 10 minutes (lower than morphine, for example, which is approximately 30 minutes), it could relieve or minimize pain in an adequate time period, that is, before its spontaneous resolution 56,58,59 .Methadone for cancer pain has been evaluated in a Cochrane review (2008) 60 which has concluded that its effect was similar to morphine.The author also concludes that there has been a higher non-adherence rate to methadone due to its adverse effects.In a recent review evaluating oral methadone as compared to other oral or transdermal opioids, the author has concluded that methadone may be used as first line opioid therapy, it has low cost and there is a trend to sedation and build-up.
The author also states that initial dose should be calculated as from a morphine dose converted as from a 4:1 relationship 61 .
Notwithstanding the lack of adequate clinical trials, opioid switching to methadone is indicated when a different opioid fails 62 .However, this drug titration may be a challenge for the following reasons: lack of reliable conversion to/from methadone; increased methadone potency in patients exposed to moderate to high doses of a different opioid; wide variability of methadone pharmacokinetics and of the potential to interact with other drugs 63 .
Several switching methods to methadone have been already published, but two strategies are more frequently used.In one of them, the progressive increase of methadone equianalgesic dose is simultaneous to the decrease of previous opioid 64,65 .
The other strategy involves totally withdrawing the opioid being used and the dose is totally replaced by equianalgesic dose 66 .
Incomplete cross-tolerance should be taken into consideration when opioid is switched to methadone, because a higher potency than that anticipated is to be expected.For this reason, methadone dose is decreased in 50-90% of total dose calculated as from previous opioid 67 .Table 3 shows the conversion of morphine to methadone adopted by the American Academy of Hospice and Palliative Care.In a systematic review studying the use of opioids in moderate to severe cancer pain in patients with kidney failure, the authors have concluded that methadone, fentanyl and alfentanil are opioids posing less risks when adequately used 68 .
In managing cancer pain, the combination of two strong opioids is a strategy being investigated.The rational is that the association of two different opioids would promote a synergic action on analgesia, allowing the use of lower doses of each one, in addition to limiting the development of opioid tolerance and decreasing adverse effects 6 .However, this study is just beginning and data are mostly from experimental models.

Non-cancer chronic pain
Chronic pain is pain persisting beyond tissue healing period, which is approximately three months 70 .When chronic pain is not associated to cancer or end-of-life care, it is generally called "non-cancer chronic pain" [71][72] .
Opioids have been used to manage pain and are among most frequently prescribed drugs for this objective.Their use in non-cancer chronic pain patients is growing in the last decades 73,74 .Opioids may be considered for patients with at least moderate pain and who had no pain control with other classes of analgesics.However, some clinical conditions have knowingly lower response to opioids and are those that have psychosocial aspects as aggravating factors (chronic low back pain, headache and fibromyalgia) [75][76][77] .
Results of two studies show that up to 50% of cases in which opioids were switched to methadone had prolonged satisfactory analgesia 79 .When used for neuropathic pain, methadone has decreased pain in up to 43%, has improved quality of life in 47% and sleep quality in 30% 79 .

Opioid-induced hyperalgesia (OIH)
Chronic opioid therapy may paradoxically sensitize patients to pain or even induce acute pain, phenomenon known as OIH, as already discussed 22 .Some clinical situations seem to more frequently predispose to the appearance of this phenomenon: intraoperative remifentanil infusion 80 and use of high opioid dose 22,81,82 .Table 4 shows a strategy to diagnose and treat OIH.
Table 4. Strategies for diagnosis and treatment of opioid-induced hyperalgesia 3 1 -Increase opioid dose and evaluate whether there is increase in efficacy (tolerance).
2 -Decrease or withdraw opioid and evaluate OIH.
3 -Use opioids with properties able to decrease OIH.

-Associate non-steroid anti-inflammatory drugs
Methadone is the opioid with the highest ability of decreasing high opioid dose-induced hyperalgesia through NMDA receptor inhibition.This hypothesis was confirmed by several studies showing that switching to methadone has decreased or even resolved hyperalgesia 27,84,85 .This because NMDA receptor and central glutaminergic system play a central role in the development of OIH, as well as in tolerance and sensitization (Table 5) Table 5. Role of N-methyl-D-aspartate on opioid-induced hyperalagesia 83 1. NMDA receptors are activated after exposure to opioids.When inhibited, they prevent tolerance and OIH 2. Glutamate carrier system is inhibited, increasing available glutamate concentration to bind to rNMDA 3. Intracellular calcium-regulated kinase C protein is probably a binding between tolerance cell mechanisms and OIH 4.There might be interchange between neural pain and tolerance mechanisms.

Adverse effects
Methadone adverse effects are similar to those described for morphine.However, for being a long-lasting opioid with unpredictable half-life, methadone demands special attention due to the risk of build-up and intoxication, especially during the first days of use or during analgesic dose titration.Building-up of this opioid may induce respiratory arrest and eventually death, since severe respiratory depression may be seen with doses as low as 30mg in non-tolerant individuals 86 , and with higher doses in tolerant individuals.A characteristic of methadone-induced respiratory depression is that its peak occurs after the analgesic peak and is maintained for a longer period, especially in the beginning of treatment 86,87 .Approximately 30% of analgesic-related deaths in the United States in 2009 were attributed to methadone, although this drug responds for just 2% of opioid consumption 88 .
There is no question that opioid analgesics expose users to risk of intoxication and even of death.So, the use of methadone should include systematic evaluations and measures to minimize such risk, such as patients' education and symptoms monitoring in the beginning of treatment or dose titration 5 .

Effects on QT interval
Prolonged QT interval is a pro-arrhythmic state associated to increased risk for ventricular arrhythmia, especially Torsade de Pointes (TdP) which is a polymorphic ventricular tachyarrhythmia presenting variation of polarity along ECG baseline tracing.Clinically, patient presents with palpitation, syncope and even sudden death 39,89 .This electrocardiographic alteration may be induced by drugs and is related to potassium channels block (Ether-a-go-go) with consequent potassium flow inhibition during myocardial repolarization, which increases repolarization time, represented on tracing as longer QT interval 39 .The risk for TdP is directly proportional to QT interval duration, and is particularly higher when this interval is above 500ms, in addition to methadone doses above100mg/day [90][91][92] .
In spite of the risk for ventricular arrhythmia, there is no evidence supporting screening ECG for patients with no risk factors.However, authors recommend that patients with risk factors be submitted to ECG before starting treatment and during dose titration 93,94 .When intravenously administered, it is recommended to record ECG in the following moments: before starting therapy and after 24h of use; whenever there is significant dose increase; whenever there is major clinical alteration (hydroelectrolytic disorder, congestive heart failure, new drugs) 95 .Electrolytes monitoring is also recommended for patients at higher risk 39 .

CONCLUSION
Its pharmacological properties make methadone a unique opioid analgesic, since it is less susceptible to tolerance, prevents hyperalgesia, is less prone to abusive consumption and has better theoretical action on neuropathic pain, in addition to convenient dosage schedule allowed by its prolonged action time.However, methadone should be used based on the knowledge of its pharmacological properties, safe opioid prescription practices and good clinical judgment.

Table 3 .
66nversion table from morphine to methadone66