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Abstract

Pain is one of the most common and incapacitating symptoms experienced by patients with advanced cancer. Methadone is a potent opioid with strong affinity for the µ opioid receptor. In addition to being a potent µ opioid receptor ligand, methadone blocks the N-methyl-D-aspartic acid receptor and modulates neurotransmitters involved in descending pain modulation. These 3 properties enhance analgesic activity. Methadone's lack of active metabolites makes it an attractive option when opioid responsiveness declines and renal insufficiency complicates opioid therapy. A lipophilic opioid, methadone can be given by multiple routes. Clinical trial data show equivalence with morphine as an analgesic in moderate to severe cancer pain. Further investigations are needed to define the role of methadone in the management of breakthrough pain and neuropathic pain and to determine whether it is truly superior to morphine, the gold standard of cancer analgesia.

Keywords

methadone pain cancer opioid

Introduction

Pain is one of the most common symptoms experienced by patients with advanced cancer. Current treatment is based on the concept of an “analgesic ladder” by the World Health Organization, which involves a stepwise approach to the use of analgesic drugs.¹ With increasing pain intensity, it is recommended that analgesic potency likewise increase.² Step 3 opioids are used to relieve moderate to severe pain and include hydromorphone, oxycodone, oxymorphone, fentanyl, methadone, and levorphanol. Methadone has features that make it unique, working at 3 levels to provide analgesia. First, it is a potent opioid with strong interactions with the µ opioid receptor. Second, it is an N-methyl-D-aspartic acid (NMDA) receptor antagonist, a receptor that is activated in chronic pain states and, when blocked, can enhance analgesia and reverse opioid tolerance. Third, it works on neurotransmitters such as norepinephrine and serotonin, which play a role in descending pain modulation. This paper reviews the current use of methadone in cancer pain management with a focus on the pharmacokinetics, pharmacodynamics, and clinical uses of methadone.

Methods

The article was prepared by searching MEDLINE 1966–2009 and PubMed 2009, using keywords methadone, methadone and pharmacology, methadone and metabolism, methadone and drug interactions. In addition randomized clinical trials using methadone for cancer pain and methadone and neuropathic pain were sought using the above method.

Structure of Methadone

The chemical structure of methadone differs from that of typical opioids because it is an open chain amine. It is classified as a diphenylheptane.³ These structural differences and the presence of an asymmetric carbon allow for the formation of 2 enantiomeric forms, the d and l isomers.⁴ These isomers differ in their activity at the opioid receptor and the NMDA receptor. The form available in the United States is the racemic form (both d and l isomers). In Germany, the l isomer is the predominant form available for use.⁵

Opioid Receptor Interactions

Methadone is a potent opioid with strong affinity for the µ opioid receptor. The affinity for methadone at the µ opioid receptor is greater than morphine (K_i 5.6 µM vs. K_i 15 µM).⁶ Methadone has a weaker affinity for the δ and κ opioid receptors, with K_i values of 435 and 405 µM respectively.⁷ Differences exist between isomers and their interactions with opioid receptors.⁸ Levorotatory methadone is 20 times as potent as dextrorotatory methadone at the µ opioid receptor and twice as potent as dextrorotatory methadone at the δ opioid receptor.⁴ Both isomers are weak agonists of the κ opioid receptors (K_i for both isomers > 1,000 µM).⁴

NMDA receptor interactions

Methadone is a noncompetitive NMDA receptor antagonist, which means it works on activated NMDA receptors in chronic pain states. Methadone has a high affinity for the NMDA receptor K of 0.85 µM, which is greater than another high-affinity NMDA antagonist, ketamine.⁹

Other analgesic effects

Bothisomers/and d are inhibitors of 5-hydroxytryptamine (serotonin) and norepinephrine uptake. These are important in pain management because they play a role in descending pain modulation in the spinal cord. Levorotatory methadone is nearly 20 times as potent as the dextrorotatory isomer and nearly 70 times as potent as the dextrorotatory isomer for blockade of norepinephrine and serotonin uptake, respectively.¹⁰ Methadone's reuptake of monoamine inhibitor activity does not correlate with its µ receptor affinities. While this has been demonstrated in preclinical models,¹⁰ the clinical importance is becoming more of a concern because the interaction of methadone with antidepressants (serotonin uptake inhibitors) has been reported to cause the serotonin syndrome.¹¹

Formulations

Methadone hydrochloride is a lipid-soluble opioid and is available as an oral tablet, oral elixir, and solution for intravenous (IV) injection or rectal administration.¹²

Compatibility

Methadone is physically compatible with many drugs used in palliative care such as dexamethasone, hyoscine butylbromide (not available in the United States), ketorolac, methotrimeprazine, and midazolam.¹³

Pharmacology and Routes of Administration

Methadone has been administered by oral, IV, rectal, subcutaneous, sublingual, and intrathecal routes. Knowledge of the effects of methadone given by nonoral routes is important in palliative care because patients lose the ability to swallow with progression of the dying process.

Oral route

When given orally, methadone can be detected in the plasma within 5 to 30 minutes after administration.¹⁴ Time to maximum concentration is between 2.5 and 4.4 hours.¹⁵ The bioavailability of methadone is higher than that of morphine and can range from 40% to 90%.¹⁵ A lipophilic drug, methadone is distributed rapidly after it is absorbed from the stomach. Tissue binding predominates, with accumulation of methadone in tissues (α-phase) lasting approximately 3 hours. Methadone is highly bound to plasma proteins(86%), predominantly α-1 acid glycoprotein, which is an acute-phase reactant.¹² The half-life of the second phase of drug disappearance from the plasma (β-phase, slow elimination) varies even more, from 8.5 to 47 hours.¹⁶ Some estimations of half-life are even longer (up to 65 hours).¹⁷

Sublingual route

Methadone is well absorbed when given sublingually. The bioavailability of methadone via this route is 34%, which is superior to other step 3 opioids; with the exception of fentanyl.¹⁸ Onset of analgesia via the sublingual route can be as rapid as 5 minutes.¹⁹

IV Route

The IV route produces a higher concentration with each dose by approximately 23%.⁷ This effect is related to avoidance of first-pass effects in the liver and the gut. The IV volume of distribution is 3.6 L/kg, and the mean half-life is 23 hours.²⁰

Subcutaneous route

The subcutaneous route is interchangeable with the IV route. There are no details on the pharmacokinetics of methadone given by the subcutaneous route.

Nasal route

When given by the nasal route, methadone is taken up rapidly, with onset of maximum concentrations in 7 minutes and bioavailability of 85%.¹⁷

Intrathecal route

When administered into the cerebrospinal fluid, methadone is rapidly cleared because of its lipophilic nature. Methadone migrates to lipid areas outside the spinal cord. In addition, methadone does not follow cerebrospinal fluid flow, making it difficult to use as an intrathecal analgesic, much like fentanyl.²¹

Rectal route

When given rectally, methadone has a high bioavailability (90%) and is rapidly absorbed (within 30 minutes). Rectally administered methadone has a faster onset of action than oral methadone. The pharmacokinetics are similar to oral dosing.²²

Metabolism and Elimination

Methadone is biotransformed in the liver by CYP3A4 and CYP2B6.²³ These CYP enzymes are also located in the intestine and contribute to biotransformation when methadone is swallowed. Metabolic transformation results in inactive metabolites of which the primary one is 2-ethyl-1,5-dimethyl-3,3-dipheny lpyrrolinium.¹⁷ The fecal route plays a major role in elimination and can account for most of the disposition of methadone in patients with renal failure, making methadone an optimal opioid for these patients. Manipulating the pH of the urine can facilitate excretion of methadone. P-glycoproteins may play a role in the metabolism of methadone, but it is not a prominent role.²⁴ Methadone is not glucuronidated.

Drug interactions

Inducible cytochrome oxidase enzymes such as CYP3A4 can play a role in drug interactions and most drug interactions with methadone involve inducers or inhibitors of CYP3A4.⁷ Common drugs that have potential to interact with methadone include antidepressants, antiretrovirals, antifungals, antiseizure medications, antibiotics, neuroleptics, and over-the-counter medications (Table 1). Fatal interactions have been reported for the interaction of methadone and fluconazole.²⁵ In addition to drug interactions mediated via inducers and inhibitors of the cytochrome oxidase system, it must also be remembered that sedative hypnotics and alcohol can interact with opioids to produce increased sedation, respiratory depressant effects, hypotension, and coma.

Table 1

Methadone-drug interactions.

Drug	Effect	Mechanism of action	Clinical importance
Fluconazole⁴⁸	Increased methadone levels; AUC increases by 35%	Inhibition by fluconazole of cytochrome P450 3A4-mediated methadone metabolism	Respiratory depression has occurred
Paroxetine	Increased methadone levels	Paroxetine is a mild inhibitor of CYP1 A2, CYP2C9, CYP2C19, and CYP3A4
St John's Wort⁴⁹	Decreased methadone levels	CYP3A4 induction	Has precipitated withdrawal
Voriconazole ⁵⁰	Increased methadone levels	Inhibits CYP3A4-mediated metabolism	None reported
Ciprofloxacin⁵¹	Increased methadone levels	Inhibits CYP3A4-mediated metabolism	Somnolence reported
Retrovirals⁵² (except zidovudine)	Decreased methadone levels	CYP3A4 induction; P-glycoprotein?
Carbamazepine⁷	Decreased methadone levels	CYP3A4 induction
Desipramine⁷	Increased desipramine levels	Unknown	Increased adverse effects from desipramine
Azithromycin	Increased methadone levels	Inhibits CYP3A4-mediated metabolism
Fluvoxamine⁵³	Increased methadone levels	Inhibits CYP3A4-mediated metabolism
Fosphenytoin⁵⁴	Decreased methadone levels	Decreased methadone trough and AUC	Withdrawal symptom
Desipramine⁷	Increased desipramine levels	Mechanism unknown
Didanosine⁵²	Decreased didanosine levels	Mechanism unknown
MAO inhibitors¹¹	Methadone is a serotonin uptake inhibitor		Serotonin syndrome
Ketoconazole	Increased serum methadone levels	Inhibition of CYP3A4
Nevirapine^52,55		CYP inducer
Efavirenz⁵²		CYP inducer
Phenobarbital⁵²	Decreased methadone levels	CYP3A4 induction	Potential for withdrawal symptoms
Rifampin⁵²	Decreased methadone levels		On the average, methadone levels have been reported to decline by 30% to 65% during rifampin treatment
Sertraline⁵⁶	Increased methadone levels	Inhibition of CYP3A4
Quetiapine⁵⁷	Increased methadone levels	Interaction with CYP2D6 and/or the P-glycoprotein transporter system
Interferon⁵⁸	Increased methadone levels	Unknown

Abbreviation: AUC, area under the curve.

Adverse Effects of Methadone

Common adverse effects

The general adverse effects of opioids such as sedation, nausea, and respiratory depression apply also to methadone. Methadone has caused hallucinations and myoclonus, despite there being no active metabolites.²⁶ When prescribing methadone, prophylactic treatments for constipation and nausea must be addressed.

QT prolongation and torsades de pointes

High-dose IV methadone has been linked to QT prolongation and torsades de pointes (TDP).²⁷ A recent retrospective study also found that oral methadone can cause QT prolongation in 16% of patients.²⁸ It has been postulated that blockade of the cardiac potassium current by the chlorobutanol preservative in IV methadone causes the arrhythmia. Blocking the potassium current leads to longer repolarization time and becomes manifest as a prolonged QTc interval.

Risk factors for the development of QTc prolongation include drug interactions involving CYP3A4 that might increase methadone levels, electrolyte abnormalities (low potassium and magnesium), cardiac ischemia, low cardiac ejection fraction, and other rarer causes of QT prolongation such as the congenital QT prolongation syndrome. Other conditions that lead to measuring a QT interval include a history of syncope, family history of unexplained syncope or sudden death, seizures or congenital deafness, history of abnormal potassium and magnesium levels, renal dysfunction, bradycardia, underlying cardiovascular disease, diabetes, old age, female sex, heart failure, hypotension, hypothermia, myocardial ischemia, and pituitary insufficiency.²⁷ If the baseline QTc is longer than 450 ms in men and 460 ms in women, in the absence of interventricular conduction defects, all medication with potential of prolonging the QT interval should be avoided.^29,30 The development of QTc prolongation can be a serious problem if the patient has good pain relief with methadone. If the baseline QTc interval is normal, more than 10% increase should prompt concern about TDP. EKG monitoring is indicated for patients with the risk factors for QTc prolongation listed above.²⁷ In patients at risk, a screening EKG should be done before the start of methadone therapy, repeated in 24 hours after therapy is started, and repeated after 4 days when steady state is achieved. EKG monitoring should also be done with significant dose escalation, or the development of new conditions that add to the risk of arrhythmia.

Preservative-free methadone has been recommended as a trial when the drug is essential for use.²⁷ There have been problems obtaining preservative-free methadone, including cost, preparation (without contamination), and the lack of clinical evidence proving a beneficial role in management of QTc prolongation.²⁷

A recent prospective study evaluated 100 patients³¹ who were started on oral methadone at doses under 100 mg, and were followed up for QTc prolongation and adverse clinical effects at 2, 4, and 8 weeks. Baseline QTc was determined, and factors leading to QTc prolongation such as medications, cardiovascular diseases, and electrolyte disturbances were documented. A clinically significant increase in QTc occurred in only 1 of 64 patients (1.6%) at week 2, and none at weeks 4 and 8. The study concluded that oral methadone was safe for pain control in patients with advanced cancer and that methadone did not contribute to severe QTc prolongation and its use did not lead to generation of TDP or arrhythmias.

Dermatologic adverse effects

Methadone has been reported to cause local irritation when given subcutaneously. Recommendations for management include rotating infusion sites frequently (daily); changing the method of administration by using intermittent boluses instead of continuous infusion; and adding dexamethasone to the infusion or injecting dexamethasone locally.³²

The Role of Methadone

Second-line agent: role in opioid rotation

The current role for methadone in cancer pain management is as an opioid for use in pain that is poorly responsive to opioids, which is defined as “the degree of analgesia achieved as the dose is titrated to an endpoint defined either by intolerable side effects or the occurrence of acceptable analgesia”.³³ Opioid related symptoms that can improve when methadone is substituted for another opioid are nausea, vomiting, sedation and delirium.³³

Methadone as first-line analgesic for cancer pain

Three studies have compared morphine and methadone as first-line therapy for cancer-related pain. Ventafridda and coworkers³⁵ compared methadone with morphine for moderate to severe cancer pain in 54 patients who had been on step 2 opioids previously. Patients were randomly assigned to receive either morphine or methadone by mouth for 14 days. Both therapies provided clear reductions in pain intensity. There was less stability in analgesia in the morphine arm as there was more need to adjust the dose in this arm than in the methadone arm. Patients receiving morphine had a higher incidence of dry mouth. Otherwise there were no other differences in toxicities or the ability to achieve pain relief.

Mercadante and coworkers³⁶ conducted a prospective randomized study in 40 patients with advanced cancer who required strong opioids for their pain management. These patients were receiving home hospice care. Patients were treated with sustained-release morphine or methadone in doses titrated to pain relief and administered 2 or 3 times daily according to clinical need. Results suggested that methadone more quickly achieved analgesia and methadone analgesia was more stable than that achieved with morphine.

Bruera and colleagues² compared the effectiveness and adverse effects of methadone and morphine as first-line treatment with opioids for cancer pain. In this multicenter international study, 103 patients having pain requiring strong opioids were randomly assigned to receive either methadone or morphine for 4 weeks. Patients with a 20% or more reduction in pain scores were equal in both groups. Patients in both arms reported satisfaction with their therapies (global benefit). One major difference between the arms was the higher number of dropouts in the methadone group than in the morphine group.

Breakthrough pain

Hagen and coworkers³⁷ evaluated oral methadone for the treatment of cancer breakthrough pain. This was an open-label, nonrandomized, crossover study comparing the use of oral methadone for breakthrough pain given in conjunction with the patients’ usual opioids. Methadone dosing for breakthrough pain ranged from 5 to 15 mg, and the methadone dose that successfully controlled pain was determined for each patient. Subsequent episodes of breakthrough pain were treated with that dose. The onset of analgesia was rapid for all patients, and pain relief occurred by 10 minutes after administration. Adverse effects did not differ from those of the previous breakthrough opioid used.

Hagen and coworkers¹⁹ also evaluated sublingual methadone in an open-label feasibility study for cancer-related breakthrough pain. The study consisted of an upward titration phase where the optimal dose of methadone for breakthrough pain was determined. With the predetermined breakthrough dose, pain relief was rapid, with an onset of pain relief in approximately 5 minutes. Methadone as a breakthrough opioid was well tolerated, and there were no unusual toxicities with methadone as a breakthrough agent.

Neuropathic pain

Morley and coworkers³⁸ evaluated the use of placebo vs. 10 and 20 mg daily doses of methadone for neuropathic pain. The pain in most of these patients had been resistant to normal doses of amitriptyline, gabapentin, carbamazepine, or other agents. Included were 5 patients on tramadol and 1 patient on dihy-drocodeine. The 20-mg dose achieved statistically significant pain relief, and the analgesic effects extended over 48 hours. The 10-mg dose did not achieve statistically significant pain relief compared with placebo.

Schedule of Administration

Determining the methadone dose: rotation from morphine

It is now well recognized that when methadone is substituted for morphine, a reversal of established opioid tolerance occurs, meaning that far less methadone is needed to achieve analgesia than would be predicted from equianalgesic tables.³⁴

There is an inverse relationship between total morphine dose and the starting dose of methadone.³³ Methadone becomes as much as 10 times more potent as the total morphine dose increases from 100 to 500 mg.³⁴ The first step in rotating to methadone from morphine involves calculation of the morphine equivalent daily dose (MEDD), then selecting a methadone dose on the basis of the MEDD. Several groups have identified starting ratios of morphine to methadone based on the reversal of tolerance that occurs when the switch occurs. All recommended techniques recognize the potential for reversal of tolerance with use of an NMDA antagonist and dose the methadone accordingly (Table 2). For example, the Edmonton group³⁴ used a 10:1 ratio to start dosing. Ripamonti and coworkers⁴⁶ used 4:1, 8:1, and 12:1 ratios for MEDDs less than 100 mg, between 90 and 300 mg, and more than 300 mg, respectively. The manner of transition to methadone differed between groups, but the Italian and Edmonton groups usually decreased the preexisting opioid by one-third each day until it was discontinued while starting the methadone at one-third dose with escalation to full dose over 3 days. Others³⁹ reported use of a stop-and-go approach in which morphine is stopped and methadone is started. The stop-and-go method may hasten the elimination of toxic metabolites, which are the reason for the switch to methadone.⁴⁰ Gradual switching does not immediately eliminate metabolites but may be associated with better pain control. As with any opioid switch, daily monitoring for adverse is necessary.

Table 2

Methadone dose conversion.²⁶

MEDD, mg	Ratio of oral morphine to methadone based on MEDD
100	5:1
100–300	10–5:1
300–600	12–8:1
600–1,000	20–10:1
> 1,000 mg	20:1

Abbreviation: MEDD, morphine equivalent daily dose.

Escalation of methadone dose

Because of the prolonged half-life of methadone, dose escalation should be done no more often than every 48 hours because of the risk of accumulation and adverse effects such as sedation.⁴⁰ IV dosing should likewise be slow, with infusion rates not increased after the first 12 hours because of accumulation with rapid dose escalation.²⁷

Frequency of administration

The currently accepted schedule for methadone, because of its long half-life, is every 8 hours. Some preliminary data suggest that less frequent dosing might be as efficacious.³⁴

Rotating from other Step 3 Opioids

Hydromorphone

In a retrospective study, Bruera and coworkers⁴¹ evaluated 65 switches between subcutaneous hydromorphone and oral methadone to determine the equianalgesic dose ratio. When switching from hydromorphone, the hydromorphone/methadone ratio average was far more potent than expected on the basis of previous switches from morphine to methadone. The dose ratios of hydromorphone/methadone were 1.6:1 in those receiving more than 330 mg of hydromorphone per day and 0.95:1 in those receiving less than 330 mg of hydromorphone per day (P = 0.023) The dose ratios of hydromorphone/methadone correlated with the total opioid dose, which suggests a relationship between the final methadone dose and the hydromorphone dose.

Fentanyl

Mercadante and coworkers⁴² carried out a prospective study to determine the dose ratio for conversion from transdermal fentanyl to methadone using a fentanyl to methadone ratio of 1:20. For example, a patient receiving transdermal fentanyl, 100 µg/h (2.4 mg/d), was switched to methadone 48 mg daily. Rescue doses were provided, methadone doses were changed according to clinical response, and pain and symptom intensity were monitored. Pain and symptom intensity decreased significantly within 24 hours. No relationship between the final opioid dose and the dose of the previous opioid has been found with use of fentanyl.

Reverse rotation from methadone

Descriptions of methods of reverse rotation from methadone to other opioids are limited to case reports and 1 small retrospective series.⁴³ A concern with reverse rotation has been the potential for increased pain due to reactivation of NMDA activity and development of opioid tolererance.^43,44 A recent study⁴⁵ suggests that these concerns are unfounded. They retrospectively reviewed consecutive medical records of patients undergoing opioid rotation from methadone to an alternative opioid. A stable dose was defined as a 30% or less change in opioid dose from day to day. This study showed that reverse rotation was not associated with exacerbations of pain or other symptoms and provides a guide for dosing in the reverse direction.

Methadone for opioid-naïve patients

The optimal schedule and dose for initiation of methadone treatment in opioid-naïve patients is not known.² The trial reported by Bruera et al² using 7.5 mg twice a day was associated with a considerable number of dropouts. Ripamonti et al⁴⁶ recommended 3 mg every 8 hours on the basis of their clinical trial experience. Other approaches to starting methadone have involved the use of as-needed dosing. The so-called loading dose approach advocates starting methadone at 5 to 10 mg every 4 hours only as needed.⁴⁶ After a week on this regimen, the total dose required is calculated, and this dose is scheduled 2 or 3 times daily; 10% of the total methadone dose is given for breakthrough pain. Another tactic, called the “conservative approach”,⁴⁷ administers methadone, 5 to 10 mg 2 or 3 times daily for 4 to 7 days, adjusting the dose slowly, depending on pain response. This approach recommends a nonmethadone opioid for breakthrough pain. No studies have been conducted to compare these approaches.

Cost

At our pharmacy, the charge for 20 5-mg doses is $11.99 and 20 10-mg doses is $11.33.

Conclusion

Methadone has emerged as a useful analgesic in the management of cancer pain. It is a µ agonist that also has potent activity as an antagonist of the NMDA receptor. Its current role is as a second-line opioid when there is a need to improve opioid responsiveness. Opioid responsiveness is improved by the NMDA activity of methadone, which can reverse opioid tolerance. Methadone appears to be equivalent to morphine in terms of analgesic efficacy as a first line analgesic, according to clinical trials conducted so far. The lipophilic nature of methadone has lead to its exploration as breakthrough analgesic. Methadone when given orally and sublingually has a rapid onset of action which fits the characteristics of breakthrough pain. The optimal dosing of methadone as a breakthrough agent has not been established. Preliminary work suggests that individualization of methadone dose, similar to transmucosal fentanyl, might be an optimal approach. One placebo controlled trial suggests efficacy for neuropathic pain. Methadone is an excellent analgesic to use in patients with renal failure. Continued investigation of methadone as a first-line agent is needed in the management of cancer pain, as well as the use of methadone for breakthrough pain will be needed in order to clarify if indeed it is a superior opioid compared to morphine.

Disclosure

This manuscript has been read and approved by the author. This paper is unique and is not under consideration by any other publication and has not been published elsewhere. The author and peer reviewers of this paper report no conflicts of interest. The author confirms that they have permission to reproduce any copyrighted material.

Footnotes

Abbreviations

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Methadone for Cancer Pain

Abstract

Keywords

Introduction

Methods

Structure of Methadone

Opioid Receptor Interactions

NMDA receptor interactions

Other analgesic effects

Formulations

Compatibility

Pharmacology and Routes of Administration

Oral route

Sublingual route

IV Route

Subcutaneous route

Nasal route

Intrathecal route

Rectal route

Metabolism and Elimination

Drug interactions

Adverse Effects of Methadone

Common adverse effects

QT prolongation and torsades de pointes

Dermatologic adverse effects

The Role of Methadone

Second-line agent: role in opioid rotation

Methadone as first-line analgesic for cancer pain

Breakthrough pain

Neuropathic pain

Schedule of Administration

Determining the methadone dose: rotation from morphine

Escalation of methadone dose

Frequency of administration

Rotating from other Step 3 Opioids

Hydromorphone

Fentanyl

Reverse rotation from methadone

Methadone for opioid-naïve patients

Cost

Conclusion

Disclosure

Footnotes

Abbreviations

References