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* From the Wasser Pain Management Pain Center, Mount Sinai Hospital;
the Department of Anesthesia and Pain Management, University Health Network,
University of Toronto; and the Centre for Addiction and Mental Health, A WHO Centre of Excellence, Toronto, Ontario, Canada.
Address correspondence to: Dr. Philip Peng, EC 2-046, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. Phone: 416-603-5118; Fax: 416-603-6494; E-mail: Philip.peng{at}uhn.on.ca
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Abstract |
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 TOP Abstract IntroductionUse of methadone in...Basic pharmacologyInteractions of methadone with...Risk of improper use...Suggested algorithm for managing...Conversion of methadone to...ConclusionReferences |
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Source: A Medline search was performed to obtain the published literature on the pharmacology of methadone and its use perioperatively.
Principal findings: The complexity of methadone’s pharmacology is characterized by a high inter-individual variability, a potential for interaction with other medications, and a long elimination half-life. The postoperative management of methadone patients may be difficult as they are often ‘opioid-tolerant’ but may be ‘pain-intolerant’. For those patients who are taking part in methadone-maintenance programs, there is a potential for the problematic use of opioids or other substances. The management plan for patients taking methadone may differ depending on the type of surgery and the associated perioperative differences in fasting status and gastrointestinal function. In consideration of all the factors listed above, a management algorithm is outlined for the perioperative care of methadone patients.
Conclusion: Methadone is an opioid with complex properties, and a patient that is taking methadone can represent a unique challenge to the anesthesiologist. A good understanding of the pharmacology of methadone and of the type of patients on this medication will help to improve their perioperative care.
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Introduction |
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), it is estimated that the use of methadone for chronic pain patients will increase.2,5
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The purpose of this article is to review the pharmacology of methadone and to apply this knowledge in order to develop a strategy for the perioperative management of methadone patients.
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Use of methadone in Canada and the United States |
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If a MMT patient is admitted to hospital, a physician can obtain an emergency, temporary license after contacting the Office of Control Substances. However, the license is specific for that physician, patient and institution and will expire following the discharge of that patient or after a period of two months. These temporary exemptions allow for continuation rather than initiation of methadone.
In the United States, methadone is considered a schedule II drug according to the drug Enforcement Agency (DEA) Schedule of Controlled Substances. Schedule II drugs are those the DEA considers to carry the highest potential for physical or psychological dependence and abuse. Other examples of schedule II drugs include morphine, meperidine, codeine, and fentanyl. Any of these medications can be prescribed by a DEA licensed Health Care Professional. In this sense, methadone used for the treatment of pain is regulated no differently than any other schedule II drug. In the United States, the use of methadone for the treatment of opioid addiction is highly restricted and in a state of transition. Since the Harrison Narcotic Control Act of 1914, it has been illegal for physicians in the United States to supply patients suffering from opioid addictive disorders opioids for the treatment of their addiction. At the present time, the majority of practitioners who prescribe methadone for use in MMT models do so under the institutional authority of a narcotic treatment program. Pilot projects for methadone maintenance in the office-based setting are underway in several sites. The preliminary results are encouraging.
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Basic pharmacology |
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). Formulated as the hydrochloride powder, it can be reconstituted for oral, rectal or parenteral administration. When used in methadone maintenance for the treatment of opioid addiction, the oral stock solution is often mixed with orange drink or cherry syrup to deter aberrant use via the parenteral route. In Canada, it is also available as a prepared oral solution and more recently, in tablet form (Metadol® Pharmascience, Montreal, QC, Canada). In the United States, the liquid preparation of methadone hydrochloride for injection (10 mg·mL–1) is also available (aaiPharma, Wilmington, NC, USA) and can be administered via the iv, im or sc route. However, the FDA has only given approval for the sc and im routes.7 There are reports of methadone being used for its analgesic properties by continuous epidural administration in children as well as adults.8,9 Intrathecal analgesic use has also been reported.10,11
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Methadone is characterized by its high inter-individual variability. A good understanding of the pharmacokinetics and pharmacodynamics is imperative to the safe use of this medication.
Pharmacokinetics
Following oral administration, time to achieve peak plasma drug concentration is 2.5 hr and three hours for methadone in solution and in tablet form respectively.15 The oral bioavailability is 85% (range: 67–95%), which is three times that of morphine.13 Although there is no data of tissue distribution for methadone in humans, the distribution to various tissues has been shown to be extensive in animal models. This is consistent with the high volume of distribution in humans (4.2–9.2 L·kg–1 in opioids addicts and 1.7–5.3 L·kg–1 in chronic pain patients).16,17
At physiological pH, 86% of methadone is bound to plasma proteins, predominately to 
1-acid glycoprotein (AAG). AAG is an acute-phase reactive protein and the plasma level fluctuates with various physiologic and pathologic conditions such as stress, opioid addiction, cancer, and concomitant administration of certain medications. The clinical implication of increased levels of AAG is that such an individual may be protected from the toxic effects of a dose of methadone as compared to a healthy casual user of methadone that would not have elevated levels of AAG.15
Unlike morphine, methadone is biotransformed rather than conjugated in the liver and at daily doses less than 55 mg, the majority of the metabolites are cleared via the fecal route. Methadone is metabolized by the type I cytochrome P450 group of enzymes. The main enzyme responsible for N-demethylation of methadone is CYP3A4, with lesser involvement from CYP1A2 and CYP2D6.2,18 Current evidence suggests that CYP2B6 may play a very significant role in metabolism as well.19 The main product of N-demethylation, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), is inactive. The activities of these cytochrome enzymes, especially CYP3A4, can be induced or inhibited by other drugs or by the methadone itself, accounting for the large individual variations in methadone pharmacology (refer to section on drug interaction). While the primary metabolite of methadone is inactive, methadol and normethadol are two minor metabolites produced in small amounts that have similar pharmacologic activity to methadone.15,20
Renal excretion is variable and is pH dependent. At a urine pH above 6, renal clearance is only 4% of the total drug elimination. When urine pH drops below 6, the unchanged methadone excreted by the renal route is approximately 30% of the total administered dose. Despite this, methadone does not accumulate in patients with renal failure and is poorly removed by hemodialysis.2,5,15 The renal excretion of the primary metabolite, EDDP is not pH dependent.
Methadone undergoes a biphasic pattern of elimination: slow distribution or -elimination phase (8–12 hr) and a ß-elimination phase (30–60 hr). The -elimination correlates with the duration of analgesia that is typically six to eight hours.2,13 The plasma level in the ß-elimination phase is subanalgesic but is sufficient to prevent withdrawal symptoms. Thus, it accounts for the three or four times daily dosing typically needed when prescribed for analgesia compared to the once a day dosing used in MMT.
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Interactions of methadone with other medications |
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).
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Since methadone dose is titrated to effect, it is tempting to think that drug interactions are of limited significance. In some cases, it may not be the addition of a CYP 450 active drug that causes problems but rather the discontinuation of the active inhibitor or inducer. If a patient is titrated to effect with methadone while on a stable dose of a potent CYP3A4 enzyme inducer such as carbamazepine, discontinuation of the inducing agent may result in a clinically significant elevation in serum concentration of methadone as the patient returns to his/her pre-induced metabolic state. In a similar fashion, discontinuation of a potent CYP3A4 enzyme inhibitor such as fluvoxamine or erythromycin may lead to clinically significant reductions in methadone due to an apparent rapid metabolic state as the previously inhibited 3A4 pathway normalizes.
Drug interactions may also occur independently of the cytochrome system. One mechanism of drug interaction is related to AAG, an acute-phase reactant protein. The circulating levels of AAG may be elevated with concurrent administration of medications such as amitriptyline.17,24 Elevated AAG levels may decrease the effects of methadone leading to inadequate analgesia. Another mechanism is related to the co-administration of a benzodiazepine, a potential respiratory depressant exerting its inhibitory effect through 
-amino-butyric acid (GABA) receptors. Generation of the respiratory rhythm requires phasic activation and inhibition. Within the respiratory centre, the neurotransmitters for excitation and inhibition are mediated through excitatory amino acids such as NMDA and GABA receptors respectively.25 Concurrent administration of a benzodiazepine and methadone can result in enhanced GABA-mediated inhibitory activity and reduction of NMDA-mediated excitatory activity. Fatal overdose from this drug combination has been reported.5
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Risk of improper use of methadone in the perioperative setting |
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Single-dose overdose
In the opioid-naïve adult, a single oral dose of methadone in excess of 40 mg has resulted in death.27 Patients currently on methadone likely have developed some tolerance to all opioids although cross tolerance is variable. However, medication errors can occur when methadone patients receive their methadone dose while hospitalized in the postoperative period. In general, most of the medication errors occur at the stages of ordering and administration.28 Most of the patients who take methadone in liquid form for pain management do so at a fixed concentration such as 5 mg·mL–1. While most physicians describe the dose in mg, many patients communicate in mL. A miscommunication in the concentration can potentially result in overdose. In the case of MMT patients, the standard is to dispense a quantity of drug diluted to a fixed volume of 100 mL. As such, there is no specific concentration of methadone used in this setting.
Accumulated toxicity
Unlike morphine or other short-acting opioids commonly used in the postoperative setting, methadone has a very long elimination half-life, even though its duration of action as an analgesic is markedly shorter. Therefore, life-threatening complications may not result from any one single dose but rather from the accumulation of previous doses.26 This is typically seen in overly aggressive dose titration. The phenomenon of accumulation is not seen with sustained-release preparations (e.g., MS Contin® or OxyContin®) of relatively short-acting agents. In the management of acute postoperative pain, extreme caution should be exercised to titrate the methadone dose according to its analgesic effect while monitoring for signs of sedation, which may be due to methadone accumulation.
Drug-drug interaction
During the perioperative period, medications may be added that can adversely interact with methadone. Sedative-classes of drugs are the most obvious example of medications that can increase the depressant effects of methadone. In some cases the drug interaction occurs not by the addition of a CYP450 active drug but rather through the discontinuation of such an agent.
For example, in the case of the discontinuation of a potent inhibitor such as erythromycin, methadone levels may fall significantly over a matter of days due to a relative increase in methadone metabolism as the 3A4 inhibiting effects of erythromycin abate. This may lead to a state of relative opioid withdrawal, which will make pain management more difficult.
Perhaps more dangerous is the situation when a potent inducer such as rifampin or carbamazepine is discontinued. In this case, the patient will become a relatively slow metabolizer as the 3A4 pathway falls back to its normal metabolic rate. What was previously an adequate dose of methadone may now become excessive leading to clinically significant sedation and respiratory depression.
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Suggested algorithm for managing methadone patients in the perioperative period |
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). The practice of abrupt discontinuation of methadone before surgery is unjustifiable.
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Patients on higher doses of methadone may develop a prolonged QT interval, which may then lead to the development of Torsades de pointes.31 The risk appears to be greatest with the following conditions: iv administration of methadone, oral administration of doses greater than 200 mg·day–1, and medical conditions or medications that predispose patients to QTc interval prolongation.7A Medications to be aware of perioperatively include chlorpromazine, clarithromycin, disopyramide, erythromycin, haloperidol, amiodarone and some of the other antiarrthymic agents that are known to increase QT interval. A preoperative electrocardiogram and vigilance are recommended when dealing with patients on high doses of methadone, especially in patients who are debilitated or have cancer.
Postoperative pain management
It is not advisable to adjust the methadone dose in these patients, so alternate opioids are used for pain control and then tapered as clinically indicated according to the expected convalescence.29 The exception to this would be the case where the patient’s regular MMT dose of methadone has been interrupted for five or more days.32 In these cases, the patient should be restarted on methadone by a practitioner knowledgeable in MMT induction, since there may be a marked change in methadone tolerance as a result of this period of methadone abstinence. Cross-tolerance with other opioids is unreliable, so it cannot be assumed that a patient on even large doses of an alternative opioid will tolerate their original methadone dose.
The use of regional anesthetic techniques for pain control is encouraged, but these patients will often also request the systemic administration of opioids. These patients may have persistently high pain scores despite all interventions and so alternate measures of analgesia may be necessary to facilitate postoperative rehabilitation such as ability to deep breathe, cough and ambulate. Patients may lose faith in their postoperative pain management plan, especially if they experience any degree of opioid withdrawal due to inadequate dose equivalence as may be seen in the fasting patient who is switched to another opioid due to their inability to ingest their regular daily dose of oral methadone.
An opioid agreement may be necessary to make the treatment plan with opioids explicit. In this case, the expectations for how long opioid analgesics will be provided, a plan for discontinuing these medications, outpatient contact numbers and follow-up should be discussed. It is important to use analgesic and adjunctive agents appropriately. Use of short acting immediate-release opioids should be limited to a minimum to control pain occurring with activity; sustained-release preparation of opioids are used to manage the pain preferentially in opioid tolerant patients. In general, in the outpatient setting, it is wise to avoid drugs that previously proved problematic for the patient. Some patients will need outpatient dispensing of medications on a daily or every other day basis, especially if there is no reliable third party at home to help regulate medication intake. These patients often need close follow-up as outpatients compared to the usual postoperative patient, especially if they require the use of high doses of long acting opioids. The Acute Pain Service may need to give advice to the primary care physician and/or the MMT program physician. In some cases, the patient may need to be referred to a pain and addiction medicine specialist. In Ontario, a telephone consultation with the Addiction Clinical Consultation Service of the Centre for Addiction and Mental Health may suffice.B
Patients undergoing an ambulatory or day surgical procedure can resume their regular dose of methadone following discharge on the same day without experiencing withdrawal symptoms. They should be treated as other opioid-tolerant patients and be prescribed pain medication on discharge appropriate for the type of surgery they received, although tighter limits may be necessary (Figure 2
). Since a preadmission dose of methadone offers nothing in the way of acute pain relief, and likely leads to a decrease in the pain threshold,33 additional opioids will often be necessary depending on the clinical scenario and the presence of opioid responsive pain.
Patients receiving surgery as in-patients should resume oral methadone as soon as they can tolerate po fluids well (Figure 2). Because of its long half-life, withholding methadone for one or even two days is unlikely to result in withdrawal. However, alternative analgesia is required as the duration of analgesia from a dose of methadone is six to eight hours. During the period of fasting in the postoperative period, patients should receive alternative analgesia such as iv patient-controlled analgesia (PCA) or regional analgesia/anesthesia. Alternative opioids are usually necessary to prevent the development of an "opioid debt" (see below) although methadone can also be administered via nasogastric tubes or even rectally.3 Alternatively, with dose adjustment, iv methadone can be used if available.
When the patient is unlikely to resume po intake within 48 hr (Figure 2) and the administration of an alternative opioid is considered, PCA is the preferred method. Analgesic efficacy of PCA compared with traditional im prn opioid administration is well established.34 Addition of a background infusion to the on-demand bolus is not commonly used with PCA, because it does not necessarily improve analgesia and sleep.35,36 On the other hand, it increases the overall opioid consumption and contributes to a higher incidence of side effects such as sedation and respiratory depression.34,37 Addition of a background infusion is usually considered for patients with known pre-existing opioid tolerance.34
Patients who regularly use opioids are likely opioid tolerant and may be predisposed to the development of an "opioid debt" preoperatively if their previous daily opioid requirements are not met. "Opioid debt" may be thought of as the daily amount of opioid medication required by an opioid dependent patient to maintain their usual, pre-hospitalization opioid levels. Discontinuation of opioids in a patient who is opioid dependent will result in a lowering of the opioid plasma level below the "comfort zone" into either early (subjective) or late (objective) withdrawal (Figure 3). Furthermore, abnormal pain sensitivity such has hyperalgesia has been observed in association with opioid withdrawal.38 PCA is designed to maintain analgesia, not to establish analgesia.34 In opioid tolerant patients, if the "opioid debt" is not covered, the repeated bolus doses from a PCA pump are unlikely to achieve an analgesia effect (Figure 4a). A background infusion should be considered in opioid tolerant patients currently on a high dose of opioid therapy (Figure 4b). Therefore, we advocate loading the opioid tolerant patient with opioids in the operating room as the patient is awakening from surgery. At our institution, hydromorphone is used in place of morphine if patients have a history of morphine intolerance or allergy. Hydromorphone may also be utilized if the patient comes to the hospital on high doses of another opioid as part of an opioid rotation. Opioid tolerant patients who undergo major surgery are often administered a low dose of intraoperative ketamine (0.25 mg·kg–1 iv, up to 20 mg) for the potential reduction in opioid tolerance and improved postoperative pain control.39,40
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Conversion of methadone to other opioids |
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When converting methadone to other opioids in the postoperative period, two issues need to be considered. The first is the incomplete tolerance between opioids, the second is that the conversion ratio between opioids is not bi-directional.13,48 Conversion of methadone to other opioids appears to be more problematic49 and is associated with worsening pain and dysphoria. Since there is no uniformly accepted conversion ratio for substituting methadone with another opioid, a conservative approach should be adopted. In the authors’ experience, a conservative methadone to morphine ratio (4 or 5:1) is used. For instance, a patient previously on 30 mg methadone per day will be equivalent to roughly 120 mg oral morphine per day. Factoring the oral bioavailability (33%) and a 50% cross-tolerance, the hourly morphine requirement is approximately 1 mg·hr–1 intravenously. On the first day, the maximum background infusion rate of morphine should not exceed 3 mg·hr–1 due to the highly unpredictable nature of the equianalgesic conversion. A PCA device is used separate from the iv infusion if there is an underlying pain condition. After the patient is loaded with adequate amounts of morphine, reassessments of pain, sedation and respiratory rate are made at least once every two hours as the patient approaches a steady state with the morphine and as the methadone continues to clear from their system. The ward nurses and clinicians looking after the patient are informed of the patient’s unique requirements.
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Conclusion |
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Footnotes |
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Accepted for publication December 6, 2004. Revision accepted February 15, 2005.
A aaiPharma product monograph. 
B 1-888-720-2227 is a warm-line answered Monday through Friday, 9 to 4 p.m. out of the Centre for Addiction and Mental Health, 33 Russell Street, Toronto, Ontario M5S 2S1, Canada.
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References |
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