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Methadone Reincarnated: Novel Clinical Applications with Related Concerns

Scott M. Fishman MD, Barth Wilsey MD, Gagan Mahajan MD, Patricia Molina BA
DOI: http://dx.doi.org/10.1046/j.1526-4637.2002.02047.x 339-348 First published online: 1 December 2002

Abstract

Methadone has numerous advantages as an analgesic, which have supported its recent increase in use. However, methadone also has a pharmacological profile as an opioid that differentiates it from other, better known or more widely used opioids. It also has unusual pharmacodynamics, pharmacokinetics, and metabolism that must be considered for safe use of methadone as an analgesic. This review looks at the history of methadone use as an analgesic and its properties that distinguish it as an unusual, and potentially, unstable opioid.

  • Methadone
  • Analgesia
  • Pain
  • Tolerance
  • Opioid
  • Rotation
  • Neuropathic
  • Drug Interactions

Introduction

Methadone has undergone a reincarnation as an analgesic medication. This is due to its many attractive features as an analgesic, such as high bioavailability, lack of known metabolic products that produce neurotoxicity, and multiple receptor affinities. Most of its oral dose is absorbed and active within 30 minutes. Methadone's putative lack of neurotoxic metabolites theoretically positions it as a common second-line opioid for patients who require high doses of opioids and are subject to the accumulating effects of metabolites that produce sedation, confusion, hallucinations, and myoclonus. Not only does methadone have activity at the μ–opioid receptor, it is also an inhibitor of serotonin reuptake and a moderate antagonist at the N-methyl-D-aspartate (NMDA) receptor. These properties have raised interest in using methadone for neuropathic pain as well as for opioid tolerance. The pharmacoeconomic benefit of methadone has also prompted reappraisal of this medication, since it is much less costly than proprietary sustained-release opioids. However, there is a “fly in the ointment.” Methadone undergoes N-demethylation via the cytochrome P450 group of enzymes to such a variable extent that there can be interindividual variability in steady-state serum levels. Thus, there are multiple potential drug interactions with medications commonly employed in pain management. There is also potential instability in methadone's effects related to variability in protein binding, excretion, and equianalgesic potency. All of this has led to a divergence between the supporters and critics of methadone utilization. This review discusses the major issues surrounding the use of methadone as an analgesic.

The History of Methadone

Myth has it that methadone was developed by Hitler as an alternative to the declining stores of morphine during WWII, and that the trade name, Dolophine, was derived from Hitler's first name, Adolph [1]. Although this is compelling lore, it appears to be false. Methadone was developed by I.G. Farbenindustrie at Hoechst-Am-Main in Germany. In 1938, Drs. Max Bockmuhl and Gustav Ehrhart created Hoechst-10820, which would later become known as methadone. There is conflict as to whether it was originally produced as an analgesic or spasmolytic. Bockmuhl and Ehrhart filed an application for a patent for their compound in 1941. Not long after its production, it was renamed Polamidon or Palamidon, with some question as to the exact spelling. Unlike other known analgesics, such as Pethidine (meperidine), which had been previously discovered in 1937, its analgesic value was not initially appreciated. The work on this drug was later discovered once the Hoechst factory came under American control. The U.S. Department of Commerce subsequently published a report suggesting the drug's properties were similar to morphine, and methadone's formula was made available to the public. Eli-Lilly eventually produced the drug and renamed it Dolophine, thought to be a derivative of “dolor” for pain and “fin” for end [1]. According to the American Heritage Dictionary, the name methadone derives from extracting and reconnecting fragments from the chemical name for methadone: 6-dimethylamino-4,4-diphenyl-3-heptanone(Figure 1)[2].

Figure 1

Chemical structure of methadone highlighting diphenylheptanone and dimethylamine components.

Methadone was first used as a treatment for opioid abstinence syndrome in the 1950s by the U.S. Public Health Service hospitals. Eventually, it was more widely accepted as a treatment for opioid addiction in the mid-1960s, in part, as a response to the post-World War II heroin epidemic in New York City [3]. Hypothesizing that heroin addiction was a biological disorder with behavioral manifestations, Dole, Nyswander, and Kreek at the Rockefeller University began to test the hypothesis that a long-acting opioid agonist could be used in the chronic maintenance of heroin addiction. Over the last four decades, methadone maintenance has become widely used in maintenance therapy for opioid addiction [3].

Sources Of Instability: Pharmokinetics, Pharmacodynamics, Metabolism, and Excretion

Methadone is structurally unrelated to any of the opium-derived alkaloids (Figure 2). It is a lipophylic, basic drug (pKa 9.2) available as a hydrochloride powder formulation that can be reconstituted for oral, rectal, or parenteral administration. It usually exists as a racemic mixture of its two enantiomers, S-methadone (S-Met or d-isomer) and R-methadone (R-Met or l-isomer). The d-isomer (S-methadone) antagonizes the NMDA receptor and prevents 5-hydroxytryptamine and norepinephrine reuptake, while the l-isomer (R-methadone) possesses significant opioid-receptor- agonist properties. In comparison with morphine, methadone is reported in animal models to have a lower affinity for the μ–opioid receptor. In mice, Blake et al. found the μ–opioid receptor affinity constant (K1) for morphine to be 1.41 nM versus lesser affinity for methadone at 3.51 nM [4]. Some believe this may underlie why methadone may have fewer μ-receptor-related side effects. One small study even found improvement in constipation resulting in a decrease in laxative requirements following opioid rotation to methadone [5]. Conversely, methadone has a greater affinity for the delta-receptor in comparison with morphine [6]. While delta-receptor activity is felt to be crucial to the development of morphine-induced tolerance and dependence, methadone's delta agonism leads to its desensitization. This feature may partially account for methadone's ability to counteract opioid-induced tolerance and dependence [7]. Similarly, Blake et al. also found methadone to have a desensitizing effect on the μ–opioid receptor that was the opposite of the sensitizing effect seen with morphine. These authors postulate that this desensitization of the μ–opioid receptor may underlie the beneficial chronic effects of methadone in the treatment of addiction [4].

Figure 2

Structure of common opioids.

Unlike morphine and other opioids whose breakdown products are associated with neurotoxicity, methadone has no known active metabolites. It has high, but unpredictable, bioavailability and can be administered orally, rectally, or parenterally. When administered orally, its bioavailability is approximately 80% (range: 40–99%) [8,9], which is approximately threefold that of oral morphine. The pharmacokinetics and pharmacodynamics of methadone are characterized by high interindividual variability, which can make it difficult to accurately determine appropriate doses and increases the potential for delayed neurotoxicity. Although its distribution in the human body has not been well studied, methadone appears to be extensively distributed throughout peripheral tissues, perhaps related to its high degree of lipophilicity [10]. Likewise, its volume of distribution has been reported to be high, but the exact numbers can vary depending upon the population studied.The volume of distribution at steady state has been reported to range from 4.2–9.2 1/kg in patients with opioid addiction [11] to 1.71–5.34 1/kg in patients with chronic pain (12).

Given its large volume of distribution (mean: 6.7 l/kg), the plasma elimination of methadone usually occurs slowly (mean half-life: 26.8 hours) [11]. Methadone's slow clearance from the body (mean: 3.1 ml/min/kg) provides the rationale for dosing it once per day in methadone maintenance therapy, thereby preventing the onset of opioid withdrawal syndrome for 24 hours or more. Unfortunately, prolonged pain relief is not similarly sustained. There is considerable interindividual discrepancy in the relationship between changes in plasma methadone concentration and analgesia [12]. Methadone undergoes a biphasic pattern of elimination, with an β-elimination phase persisting 8–12 hours and a β-elimination phase ranging from 30–60 hours. The α-elimination phase equates to the period of analgesia that typically does not exceed 6–8 hours. Initial dosing for analgesia may need to be frequent, because steady-state kinetics are required for reaching the biphasic profile. Although the 30–60 hour β-elimination phase can prevent withdrawal symptoms, it is usually subanalgesic. Thus, the biphasic elimination probably accounts for the dissociation between the brief analgesic effect and the longer plasma elimination half-life. This likely underscores why methadone is prescribed every 24 hours for opioid maintenance therapy and every 4–8 hours for analgesia.

Unlike morphine, which undergoes hepatic glucuronidation, methadone is metabolized in the liver by the type I cytochrome P450 (CYP450) group of enzymes, with the major portion being excreted via the fecal route and a minor portion via the kidneys. Changes in urine pH can alter the extent of the fraction that is excreted by the kidneys. When urine pH drops below six, the unchanged methadone fraction excreted by the renal route is approximately 30–40% of the total dose administered. However, when urine pH rises above six, renal clearance can decrease to approximately 4% of the total dose administered, with a subsequent increase in circulating methadone levels [13]. In spite of the pH influence on renal excretion, methadone does not accumulate in renal failure and does not appreciably filter during hemodialysis. Excretion of metabolites from fecal and renal routes accelerates from 22% during acute-phase dosing to 62% in chronic-phase dosing. Pregnancy can also affect methadone metabolism and elimination, such that its oral bioavailability and half-life are lower and its clearance is greater [6]. Since methadone crosses the placenta, withdrawal symptoms in the neonates are possible but not absolutely obligatory. For mothers who are breastfeeding, infants are exposed to 2.79% of the maternal dose [14].

CYP3A4 is the main CYP450 subtype enzyme mediating N-demethylation of methadone, with lesser involvement by CYP1A2 and CYP2D6 [15]. CYP3A4 and CYP1A2 metabolize both methadone enantiomers, whereas CYP2D6 predominantly metabolizes the R-methadone (l-isomer) enantiomer [6]. Genetic polymorphisms exist for all three enzymes, accounting for wide variations in metabolism. For example, in some adults, CYP3A4 activity can vary by as much as 50-fold, explaining some of the unpredictability in methadone's metabolism, effects, and side effects. Methadone's drug interactions are largely attributed to inducers or inhibitors of CYP3A4. Even in the absence of other drugs, CYP3A4 is an autoinducible enzyme. Thus, methadone can bring about its own metabolism, increasing its clearance over time. The effects of this process may be misinterpreted as pharmacological tolerance. Cigarette smoking can also accelerate the elimination of methadone by stimulating CYP1A2 activity. Alcohol can have variable affects, depending on the degree of chronic exposure. Acute alcohol consumption augments methadone toxicity, whereas chronic alcohol use decreases methadone levels by accelerating its metabolism [6].

While methadone's drug interactions are largely attributed to inducers or inhibitors of CYP3A4, induction or inhibition at CYP1A2 and CYP2D6 may play a role as well. Induction of the CYP3A4 enzyme can potentially lead to symptoms of opioid withdrawal, as described in a report on heroin addicts undergoing antiretroviral therapy [16]. Among the antiepileptic drugs (AEDs), phenytoin, carbamazepine, and phenobarbital stimulate CYP3A4 activity. Phenytoin has been shown to lower blood levels of methadone by as much as 50% in 3–4 days [17]. Similar to methadone, carbamazepine autoinduces its own metabolism using the CYP3A4 enzyme ([18,19]. Thus, concomitant administration of carbamazepine and methadone can concurrently decrease the serum level and half-life of both drugs. Of note, while carbamazepine decreases circulating methadone levels by inducing CYP3A4 activity, this may be offset by its ability to also inhibit metabolic transformation of methadone, resulting in increased circulating levels [15]. Neither valproic acid nor gabapentin appear to interact with methadone [6].

P450 enzyme inhibition at CYP3A4 can increase circulating methadone levels, amplify methadone's effects, and possibly, induce toxicity. For example, the serotonin reuptake inhibitors (SSRIs) can decrease the activity of any one of the three CYP450 enzymes involved in methadone metabolism [20–22]. The SSRI, fluvoxamine, and to a lesser extent, fluoxitine, directly inhibit CYP3A4 activity, reducing elimination of methadone and raising its serum levels and potential for opioid toxicity, including sedation and respiratory depression [20–22]. Bertschy et al. found that fluvoxamine, in doses ranging from 50–250 mg/day increased serum methadone by 40–100%[21]. Inhibitors of CYP3A4 activity include, from greatest to least amount of influence: nefazadone, fluvoxamine, norfluoxetine, paroxetine, fluoxetine, and sertraline. Inhibitors of CYP1A2 activity include, from greatest to least amount of influence: fluvoxamine, paroxetine, sertraline, fluoxetine, norfluoxetine, and nefazadone. Inhibitors of CYP2D6 activity include paroxetine and fluoxetine. Venlafaxine has the lowest probability of interaction with methadone, as it marginally inhibits CYP1A2 activity and does not inhibit CYP3A4 activity [6].

In patients taking methadone and benzodiazepines, respiratory depression is of particular concern. Since respiratory activity is reduced with benzodiazepine-related enhancement of GABAergic inhibitory action, as well as methadone's NMDA-mediated inhibition of glutamergic excitatory action [23], the combined effects from these two medications may be significant. Three deaths have been associated with the coadministration of alprazolam and methadone, with serum methadone levels shown on autopsies that were lower than in other methadone overdose fatalities [6]. There are other potential drug–drug interactions between methadone and benzodiazepines that are related to hepatic P450 enzyme interactions, such as with clonazepam and diazepam, which can cause higher-than-expected circulating methadone levels.

Methadone's activity can also interfere with and be intensified by antibiotics. Rifampin, an antituberculosis medication commonly used in patients with acquired immunodeficiency syndrome (AIDS), can accelerate methadone metabolism by inducing CYP3A4 activity. Among the antiviral agents, chronic methadone use can decrease the excretion of zidovudine (AZT) by 26%, due to both reduced glucuronidation of zidovudine and reduced renal clearance. Nevirapine and ritonavir can induce CYP3A4 activity and reduce serum methadone levels. Among the antifungal agents, fluconazole and ketoconazole inhibit CYP3A4 activity. Fluconazole decreases methadone clearance by 28%, while ketoconazole's relative effect is suspected to be related to its greater potency as a CYP3A inhibitor [6]. Table 1 provides a listing of many of the drugs metabolized by the CYP3A4, CYP1A2, and CYP2D6 enzymes. Taking into account all of the above nuances, when patients are on one of these drugs, one must anticipate making appropriate adjustments in their dose of methadone.

View this table:
Table 1

Listing of substrates of oxidative metabolizing enzymes for methadone in humans

P450 enzymeSubstrate
CYP3A4Alfentanil, alprazolam, amiodarone, astemizole, budesonide, bupropion, carbamazepine, cisapride, cyclosporin, diltiazem, diazepam, erythromycin, ethinyl estradiol, ethosuximide, etoposide, fentanyl, ifosphamide, imipramine, lidocaine, loratadine, lovastatin, meperidine, midazolam, nefazodone, nifedipine, omeprazole (S-oxidation), quinidine, sertraline, tacrolimus, teniposide, terfenadine, triazolam, verapamil, R-warfarin
CYP1A2Caffeine, clozapine, imipramine, theophylline, R-warfarin
CYP2D6Amitriptyline, clomipramine, codeine, desipramine, dextromethorphan, encainide, fenfluramine, flecainide, fluvoxamine, fluoxetine, haloperidol, hydrocodone, imipramine, metoprolol and other beta-blockers, nortriptyline, paroxetine, perphenazine, propafenone, risperidone, thioridazine, tramado
  • This table is reproduced with permission from W.B. Saunders Company.

Another potential source of variability in methadone levels comes from methadone's protein-binding properties, which are largely related to the acute phase reactant, alpha-1-acid-glycoprotein (AAG) [12]. In general, 11% of methadone remains unbound [6]. However, plasma levels of AAG can fluctuate depending upon physiologic and pathological events. AAG levels may be elevated in the presence of opioid addiction, cancer, stress reactions, and concurrent administration of drugs such as amitriptyline [24,25]. Increased circulating AAG levels may decrease methadone effects and can lead to inadequate analgesia or even withdrawal. For example, rifampin, which induces CYP3A4, also may upregulate AAG production, thereby offering dual, and potentially additive, routes of decreasing methadone effects [9]. Alternatively, conditions that lower AAG concentrations can increase free-circulating methadone levels, thereby increasing methadone's effect and potential for toxicity.

Ultimately, any of the aforementioned scenarios, including pH effects on renal clearance, induction or inhibition of P450 hepatic enzymes, or changes in protein binding, may alter free-circulating methadone levels. Such occurrences can theoretically provoke toxicity with subsequent overdose or inadequate analgesia with withdrawal symptoms. While signs of toxicity are often clear, signs of involuntary decreases in free-circulating methadone resulting in decreased analgesia or withdrawal symptoms may not be as self-evident. Such patients may be confused for drug seekers, as they manifest signs and symptoms of pseudoaddiction, requiring increased methadone dosing.

Clinical Settings Where Methadone May Be Advantageous

Changing patterns in opioid prescribing have resulted in increased acceptance as well as concerns. A burgeoning issue relates to the rising cost of certain opioids, especially the sustained-release compounds. The wholesale cost of methadone is approximately 1/15th–1/20th that of the more expensive proprietary sustained-release medications, which offers a potentially sizable pharmacoeconomic benefit. For instance, in the year 2000, in the United States, sales of methadone for pain and addiction management combined were approximately $35 million. In comparison, sales of sustained-release morphine, transdermal fentanyl, and sustained-release oxycodone approached $200 million, $500 million, and $1 billion, respectively [26]. Other apprehensions relate to the potential for opioid-induced tolerance and physical dependence, as well as opioid-induced neurotoxicity, such as delirium, hallucinations, myoclonus, seizures, and hyperalgesia. Methadone's unusual μ–opioid-receptor-affinity profile and its extra-opioid properties may make it less prone to these adverse effects. On the other hand, some patients may be reluctant to consider methadone as a therapeutic analgesic, given the stigmata associated with its use in addiction therapy.

While morphine has long been the “gold standard” by which other opioid analgesics have been compared, methadone has been proposed as a suitable alternative because of its lower potential for opioid-induced neurotoxicity, absence of active metabolites, lower μ–opioid-receptor affinity and NMDA-receptor-antagonist activity. Because of this NMDA antagonism, methadone also has been theorized as an ideal opioid for neuropathic pain. Unfortunately, this concept has not been widely studied and, at present, there are no prospective clinical studies that have evaluated the applicability of NMDA antagonists in the treatment of neuropathic pain conditions [27]. Nonetheless, Gagnon and Bruera hypothesized that the equianalgesic dose ratio of hydromorphone or morphine to methadone would be different in patients with neuropathic pain than in those with non-neuropathic pain [28]. However, their retrospective study found no significant difference between the groups. To further complicate understanding the clinical significance of NMDA inhibition, most agents that potently block NMDA receptors produce limiting adverse effects, including memory impairment, psychotomimetic effects, ataxia, and motor incoordination. Recently, evidence based on studies in animal models suggests that moderate-affinity NMDA channel blockers (such as methadone) may have a superior safety profile with fewer side effects than higher affinity NMDA antagonists. Also, these moderate-affinity NMDA-receptor antagonists may slow or prevent the development of opioid tolerance, hinting at their possible utility for the treatment of chronic pain, either alone or in combination with opioids [29].

Another theoretical advantage of methadone might be mitigation of opioid-induced tolerance. Recent data support the conclusion that S-methadone (d-isomer), by virtue of its NMDA-receptor-antagonist activity, affects the development of morphine-induced tolerance and hyperalgesia. Using animal models of neuropathic pain, Davis and Inturrisi examined the ability of S-methadone to attenuate the development of morphine tolerance and to modify NMDA-induced hyperalgesia [30]. Administration of intrathecal S-methadone reversed tolerance induced by intrathecal morphine, as measured by a reduction in the ED50. In a related series of experiments, those investigators demonstrated an S-methadone-mediated reduction in hyperalgesia following administration of NMDA by d-methadone [30]. These results support the inhibitory effect of S-methadone on the development of morphine tolerance as a result of its NMDA-receptor-blocking activity [30]. Notwithstanding, there remains limited clinical data relating to methadone's potential advantage in treating neuropathic pain, hyperalgesia, and tolerance. Thus, its potential role in these conditions remains a compelling concept that requires further investigation.

There are several other settings where methadone may be advantageous. Methadone may be ideal for those patients with renal impairment, as it does not accumulate in renal failure and is insignificantly removed during dialysis. Because of its intrinsic extended analgesic effects, methadone may also have an advantage over sustained-release formulations in those with rapid bowel transit times or in those with “short gut syndrome.” Unfortunately, the dosing frequency required in such cases is unclear.

Opioid Rotation and Equianalgesic Dosing

Opioid rotation has long been employed to manage tolerance as well as other side effects associated with opioid therapy. Sequential trials of different medications may be needed to find the most effective opioid analgesic with the least side effects. Kloke et al. studied patients with cancer pain and found opioid rotation was successful 65% of the time [31]. The authors' indications for changing opioids in their patient population were insufficient analgesia (43%), intolerable side effects (20%), both a combination of insufficient analgesia and intolerable side effects (15%), and reasons other than those above (22%). The requirement for opioid rotation was not reduced by adjuvants or coanalgesics, apart from corticosteroids. Somewhat contrary to popular opinion, intolerable side effects were not found to be dose related. Instead, the authors concluded that toxicity reflected interindividual differences in tolerability. Just as unpredictable was the incomplete cross-tolerance between opioids, which would mandate careful titration of new opioids proposed in the process of opioid rotation. Because of this incomplete cross-tolerance, a lower-than-expected equianalgesic dose of a new opioid is often required to replace the one producing tolerance, perhaps thereby favoring analgesia more than side effects. This process may involve differential sub-opioid and non-opioid receptor activities.

Methadone is an increasingly common choice for opioid rotation, since it offers different properties than other opioids and is not prone to abuse by conversion to a short-acting agent via crushing. While methadone's distinctive properties relative to other opioids may make it a compelling choice to use once another opioid has lost its effectiveness or side effects preclude its continued use, exactly how much methadone to use in place of the previous opioid dose remains controversial. Quang-Cantagrel et al. conducted a retrospective chart review evaluating the efficacy of opioid substitution and improved analgesia in chronic nonmalignant pain [32]. The authors concluded that, if it is necessary to employ opioid rotation, the chances of successful rotation increased with each new opioid. In addition, they commented upon the lack of predictive power of failure of one opioid to predict the patient's response to another. Whether methadone is superior to other opioids as a subsequent agent in opioid conversion is not clear. In some cases, it may be reserved as a late choice and, thus, benefit from the effect noted above of increased probability of efficacy with each new opioid. On the other hand, due to difficulty in determining accurate conversion ratios, use of methadone as a second- or third-line agent may be challenging.

Rotating from a short-acting opioid (SAO) to a long-acting opioid (LAO) may have some advantages, such as establishing stable analgesia in order to minimize variable high and low serum concentrations thought to be associated with SAOs and avoiding symptoms of withdrawal or tolerance [33]. While the use of LAOs theoretically offers less risk of stimulating addiction, this has not been well studied. Finding a predominance of diverted street opioids to be either SAOs or sustained-release opioids converted to the short-acting preparation by crushing or grinding supports this belief. With their rapid onset and high peak serum levels, SAOs may be better suited than LAOs for provoking euphoric effects. The use of relatively longer acting opioids (e.g., methadone, levorphanol, sustained-release preparations of morphine and oxycodone, and transdermal fentanyl) has been advocated by some because of their gradual onset and reduced chance of eliciting psychoactive effects. Since methadone is not prone to conversion to a short-acting agent via crushing, has a longer analgesic duration than common SAOs, and has a longer terminal half-life, it may be a better choice as a chronic opioid analgesic than SAOs or some other sustained-release opioid preparations. The significance of this relative advantage is not clear, particularly since methadone appears to have a street value and to be abusable.

The equianalgesic dose conversion is relatively predictable for most opioids. However, it appears that this may not always be the case with methadone, particularly when rotating from or to high doses of other opioids. Converting from morphine to methadone has been noted to be difficult to perform without incurring the adverse effects of excessive sedation and even respiratory depression [34]. Equianalgesic dose ratios for converting from morphine to methadone can vary by as much as 10–50% or more [35]. Early studies predicted morphine to methadone conversion ranging from 1:1 (i.e., 1 mg oral methadone/24 hours = 1 mg oral morphine/24 hours) to 4:1 (i.e., 1 mg oral methadone/24 hours = 4 mg oral morphine/24 hours) [36,37]. However, these guidelines were based on early data, most of which are more than 20–25 years old, compiled from studies done predominantly with single dosing in normal control subjects or patients with acute pain. But in repeated dosing, methadone may be five to ten times more potent, likely related to a long elimination half-life of 15–60 hours [10]. In addition, these studies did not account for present or prior history of opioid use.

Adding complexity to the uncertainty of methadone dose conversions, dose ratios may not be stable in both directions. Converting from methadone to other opioids appears to be problematic, with few studies or proven ratios to guide clinicians [38]. The relationship between methadone and a second opioid may be nondirectional, with different ratios in changing from one direction or the other. For instance, the ratio of morphine to hydromorphone may be 10:2, while the conversion ratio of hydromorphone to morphine may be 2:5 [39]. Early reports suggest poor initial outcomes at the time of changing from methadone to the next opioid marked by increased pain or side effects [38].

Concerns about the unpredictable equianalgesic conversion ratios related to methadone have led some to advocate that rotation from any high-dose opioid to methadone be undertaken in a hospital setting [40]. Others, however, feel that it can be performed safely in an outpatient setting if one titrates slowly and carefully monitors for toxicity or symptoms of withdrawal. This transition also requires time for equilibration of methadone's lengthy β-half-life. Interval changes in dose should allow several times the β-half-life, thus precluding major dose change within 3–7 days, depending on the urgency of the case. Outpatient management may be further facilitated by initially having the patient return for frequent follow-up visits and by educating the patient and family members about steps to take in the event of adverse effects.

An inpatient protocol to rotate from either morphine or hydromorphone to methadone over a 3-day period was developed at the Health Centre in Edmonton, Alberta, Canada [41,42]. Known as the “Edmonton Palliative Care Approach to Changing Opioids to Methadone,” the dose of the previous opioid is decreased by 33% and replaced by 50% of the calculated methadone equivalent dose using a 10:1 ratio of morphine to methadone (i.e., becoming 20:1 with the 50% reduction). This process is modified based on the amount of break-through-pain medication required and is continued until the conversion is completed. This phased approach is used to diminish the risk of methadone toxicity associated with its long β-half-life and with its wide interpatient pharmacokinetic variability.

Outpatient protocols have also been published. One recommendation involves prescribing methadone at lower than equianalgesic doses in fixed intervals along with an SAO for break-through pain. Due to side effects, cost, or unrelieved pain, oncologists at the University of Calgary advised outpatients with cancer to add methadone 5 mg orally every 4 hours to their current medication regimen [43]. If satisfactory pain relief was inadequate, they were to increase their dose of methadone by 5 mg every 4 hours at 3-day intervals. This dose escalation of methadone was performed while the patients were taking their entire previous daily opioid. It was continued until pain was improved or adverse effects occurred. At all times, break-through-pain medication was available, using the previous break-through opioid initially and, later, during the titration, using methadone. When an analgesic effect was achieved, the dose of the previous baseline opioid was reduced by approximately one third. The methadone dose was then escalated upward, and relief of pain was achieved through the use of the previous break-through opioid and upward titration of methadone. When this occurred, the second one third of the previous opioid was discontinued, and methadone was again titrated upward. Ultimately, the final one third of the baseline opioid was discontinued, and the methadone was proportionately increased based on the relative potency of methadone used earlier during the titration phase. Titration in this series took an average of 25.2 days (range: 1–79 days). The average daily dose of methadone at the end of the titration was 208 mg/day (range: 12–1520 mg) compared with 1024 mg/day (range: 30–2800 mg/day) of morphine equivalents at the start of the study. Thus, the average conversion ratio of morphine to methadone in this study was 1024:208, or approximately 5:1. However, there was a wide range, and some patients required much larger ratios.

Higher previous doses of morphine appear to require lower conversion ratios. Ripamonte et al. studied 38 consecutive cancer patients who were converted from morphine to methadone due to side effects, need to change route of administration, or inadequate analgesia [18]. Prior to initiating methadone, daily morphine doses ranged from 30–800 mg/day (median: 145 mg/day). The conversion ratio was based on the patient's baseline morphine dose. Those on morphine 30-90 mg/day, 90–300 mg/day or>300 mg/day were converted at ratios of 4:1, 6:1, or 8:1, respectively (i.e., the higher the dose of previous morphine, the larger the conversion ratio of morphine to methadone). After opioid rotation, daily methadone doses ranged from 9–60 mg/day (median: 21 mg/day). The authors correctly anticipated a greater milligram-to-milligram potency of methadone in patients exposed to higher doses of morphine, and vice versa. Mercadante et al. reported similar findings [19]. Twenty-four consecutive cancer patients were converted to methadone from sustained-release morphine due to side effects. The conversion protocol used an initial 5:1 conversion ratio of morphine to methadone. Fourteen of the 24 patients were on relatively low doses of morphine (<90 mg/day), and 10 were at higher levels. Patients with lower preswitch morphine doses required lower relative methadone doses (milligram-per-milligram) than patients with higher preswitch morphine doses. Those authors corroborated the findings of the previous study by Ripamonte et al., finding a proportional predictive relationship between methadone potency and previous opioid dose. These data strongly suggest that clinicians should proceed with caution when converting a patient from a high dose of a previous opioid to methadone. Rather than starting with a predetermined equianalgesic dose, the safest course may be to use gradual titration over time, essentially “starting low and going slow.”

Should Methadone be a First or Second-Line Opioid?

While analgesic use of methadone is on the rise, it is not clear if this is due to its newfound properties that distinguish it from other opioids, its relatively low cost, its lack of known metabolites, or its potential opioid-sparing effects. Its action at multiple receptor sites that affect pain transmission has garnered it a reputation as a “broad-spectrum opioid.” However, the clinical impact of its NMDA-receptor antagonism and monoamine reuptake inhibition is not yet well established.

Traditionally used as a second-line opioid in the treatment of cancer pain, methadone is increasingly prescribed for the management of chronic nonmalignant pain. Methadone may be avoided as a first-line opioid due to lack of familiarity with its use as an analgesic, fear of toxic accumulation related to its long plasma half-life, appreciation of its potentially unpredictable metabolism, or the stigma associated with its use in heroin detoxification. However, in light of its somewhat counterintuitive equianalgesic dose conversion based on the amount of previous opioid, methadone may be a problematic second- or third-line opioid. This conclusion stands in contradistinction to what seems to be the common practice of starting chronic opioid therapies with sustained-release preparations of morphine, or oxycodone or transdermal fentanyl, and utilizing methadone only when there is a reason to change. Theoretically, administering methadone to opioid-naïve individuals may possess a greater margin of safety than after exposure to other opioids. This follows from observations of opioid rotation noted above, where the highest risk of methadone-related complications was seen after switching patients from high doses of other opioids, and the lowest risk was seen in patients on low doses of other opioids. Thus, methadone may be better as a first-line opioid than as a traditional second or third line choice.

Conclusion

Methadone use is increasing as it acquires a reputation as a special analgesic. As described above, it has potential advantages over other opioids, prompting interest in making the most of this relatively inexpensive drug. However, the special properties of methadone come with pharmacological complexity that may complicate its use, particularly in patients with significant intercurrent illness or those on polypharmacy regimes. Methadone's advantages as a special opioid with an extended spectrum of effects are counterbalanced by its atypical elimination profile, potential for metabolic instability, and its uncertain equianalgesic dosing conversion (Table 2). The counterintuitive proportional potency relationship between methadone and other opioids is a challenge with potential dangers. Contrary to logic as it relates to tolerance, methadone appears to be more potent, on a milligram-per-milligram basis, in individuals who are changing from high doses of other opioids. Methadone presents the inexperienced clinician with the challenge of predicting effects, not only in the face of unreliable equianalgesic dosing ratios that may be nondirectional, but also due to fluctuations related to altered hepatic metabolism that can be influenced by drug–drug interactions, protein-binding changes, and altered renal clearance. Without knowledge of these potential areas of variability in free-methadone levels, it may be all too easy to either underestimate or overestimate a methadone dose. Thus, experience suggests erring on the side of underestimating doses with adequate time intervals for upward titration and intercurrent use of other opioids in downward titration to avoid suboptimal analgesia.

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Table 2

Factors related to methadone's potential advantages and disadvantages

Potential advantages
  No known active metabolites
  Longer analgesic and serum half-life than common short-acting opioids
  Extended duration of analgesia that is intrinsic rather than from sustained-release formulation
  Broad spectrum of opioid-receptor effects with reduced fraction from μ–opioid receptor agonism
  Extra-opioid properties involving NMDA blockade and 5HT reuptake inhibition
  Lower cost
Potential disadvantages
  Variable cytochrome P450 enzyme expression
  Variable cytochrome P450 enzyme inhibition and/or stimulation by other drugs and substances
  Variable protein binding related to alpha-1 acid glycoprotein levels
  Variable urine clearance related to pH changes
  Variable equianalgesic dose ratios related to previous opioid dose

It remains to be seen whether or not methadone will live up to its potential as a superior opioid, in general, and for treating patients with neuropathic pain, in particular. Its use as a second or third choice after other opioids have failed also must be questioned. Likewise, we must await confirmation of methadone's benefit for those with opioid tolerance, rapid transit bowel function, constipation, or a history of prescription drug abuse. Until then, methadone's cost advantages and other potential enhanced benefits must be balanced with an informed appraisal of its inherent and somewhat less well-known risks.

References

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