Publications
APS Bulletin • Volume 10, Number 5, September/October 2000
Research Update
Richard Gracely, PhD, Department Editor
Methadone: History and Recommendations for Use in Analgesia
Winston M. Gouldin, PharmD; Daniel T. Kennedy, PharmD BCPS; Ralph E. Small, PharmD FCCP FASHP FAPhA
Methadone: A history
Methadone is a synthetic m-opioid receptor agonist that was developed more than 50 years ago. The circumstances surrounding its development have been, and perhaps still are, associated with an interesting myth. Methadone was said to have been developed in response to an order by Hitler to develop an alternative to morphine, which was in short supply at the end of World War II. The trade name Dolophine was said to have been derived from Hitler’s first name Adolph (Payte, 1991). The truth is that methadone was discovered at I.G. Farbendustrie at Hoechst-am-Main in Germany in the course of work on spasmolytic compounds during World War II. Because it lacked any resemblance to known compounds, its narcotic analgesic properties were not expected. Despite the morphine shortage, methadone was not used as an analgesic until the post-war period. It is believed that Germany’s failure to realize methadone’s value as an analgesic was because initial doses were too high and intolerable opioid side effects resulted (Chen, 1948). Concerning nomenclature, the more likely etymology is that Dolophine was derived from dolor for pain and fin for end (Payte, 1991).
By 1950, oral methadone was established at U.S. Public Health Service hospitals as a treatment for the opioid abstinence syndrome, though realization of its distinct pharmacokinetic properties would not occur until the mid-1960s. In response to a growing epidemic of heroin addiction, the New York City Health Research Council awarded a grant for methadone research to Vincent Dole, MD (Payte, 1997). It was he and his colleagues who determined that patients required only one daily dose of methadone to prevent opioid craving and symptoms of withdrawal (Payte, 1991). This early research, done in just two subjects, not only gave insight into the pharmacokinetics of methadone, but also demonstrated its value in enabling heroin abstinence. The enthusiasm for this early success was tempered somewhat by an inability to withdraw these patients from methadone. The study expanded to include 22 patients whose similar success was enthusiastically received by the media, which heralded methadone as a “medical breakthrough.” Following this, there was tremendous expansion of methadone maintenance treatment programs, and by 1971 an estimated 25,000 patients were enrolled. In response to growing criticism that these programs were simply substituting one narcotic for another, strict regulations were enacted in 1973 (Rosenbaum, 1995). As part of these regulations, a closed system was established that required separate registrations for each doctor or pharmacy to prescribe or dispense methadone, regardless of indication. These requirements slowed the growth of methadone maintenance programs tremendously (Payte, 1997). In 1976, the American Pharmaceutical Association successfully sued for the right of pharmacies to dispense methadone as an analgesic. The closed-system regulatory restrictions continue for methadone dispensed for narcotic withdrawal.
Methadone and pain control
Methadone is indicated for relief of severe pain, detoxification treatment of narcotic addiction, and temporary maintenance treatment of narcotic addiction. Methadone’s high bioavailability (79 ± 11.7%) and long half-life (30.4 ± 16.3 h) make it an ideal drug for outpatient maintenance of opioid addiction (Gourlay, Cherry, & Cousins, 1986). While these characteristics also would seem to make it an ideal analgesic for chronic pain, tremendous interpatient pharmacokinetic variability, in addition to poorly defined equianalgesic potency, have made it difficult to dose effectively and safely (Denson, Concilus, Gregg, & Crews, 1990; Irick, 1987). The above difficulties, combined with the fact it is not a patent drug and therefore is not marketed to prescribers, have prevented methadone from being widely used as an analgesic.
When employed by experienced practitioners, in appropriate clinical circumstances, methadone does have several distinct advantages compared with other opioids. First, methadone has no active metabolites. Much of the toxicity associated with other opioids (e.g., morphine, hydromorphone, meperidine, and fentanyl) is the result of metabolite accumulation. Methadone would therefore be a logical choice for the patient experiencing, or at risk for, toxicity associated with metabolite accumulation. Second, because of incomplete cross-tolerance, methadone is an appropriate alternative when intolerable side effects to another opioid have limited further dose escalation. Third, methadone is very inexpensive. Fourth, methadone’s long duration of analgesia with chronic use allows less frequent dosing than with other opioids. Extended-release opioid products are available, but they are costly (see Table). Finally, methadone is highly lipophilic, making it amenable to many routes of administration. While the oral and intramuscular routes are approved by the Food and Drug Administration, the epidural, intrathecal, intravenous, rectal, subcutaneous, and sublingual routes have all been studied (Fainsinger, Schoeller, & Bruera, 1993). The degree of experience (and results) with the different routes varies tremendously, and caution is required when considering an alternative route.
Table 1. Cost Comparison Between Methadone and Extended-Release Opioids |
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| Drug | Strength (brand) | Average Wholesale Price per 100 Tablets |
| Methadone | 5 mg (generic) 10 mg (generic) |
$8.28 $13.74 |
| Morphine Extended Release (12-hour dosing) |
15 mg (MS Contin®) 15 mg (generic) 30 mg (MS Contin®) 30 mg (generic) 100 mg (MS Contin®) 100 mg (generic) |
$99.63 $89.17 $189.34 $169.46 $546.99 $522.43 |
| Morphine Extendend Release (24-hour dosing) |
20 mg (Kadian®) 50 mg (Kadian®) 100 mg (Kadian®) |
$138.32 $333.98 $580.20 |
| Oxycodone Extended Release | 10 mg (Oxycontin®) 20 mg (Oxycontin®) 40 mg (Oxycontin®) |
$140.15 $250.00 $440.82 |
Consideration of methadone’s unique characteristics makes it a logical choice for controlling malignant and nonmalignant chronic pain (Portenoy & Foley, 1986). The lack of understanding regarding methadone’s pharmacokinetics and relative potency confers second-line status to this agent. However, for the experienced clinician, methadone is an extremely valuable tool for patients who have responded adversely or inadequately to other treatments.
Chronic analgesic dosing schedule
It is well established that methadone given every 24 hours is sufficient to suppress opioid withdrawal (Zweben & Payte, 1990). There is, however, no clear consensus on the appropriate interval for analgesic dosing. The recommended dosing intervals range from 3 to 24 hours (Ripamaonti, Zecca, & Bruera, 1997). The duration of analgesia following a single dose of methadone has been shown to be 4 to 6 hours. The brevity of analgesic effect relative to the long half-life of methadone is a result of the drug’s rapid absorption-distribution phase. With repeated dosing, methadone accumulates in the tissues, and the plasma concentration is sustained by this peripheral reservoir (Ripamaonti et al., 1997).
Investigators have conducted several studies in an attempt to identify the most appropriate analgesic dosing regimen for cancer pain. One study in which patients controlled their own dosing interval of a fixed 10-mg dose showed that after a week of repeated dosing, the initial 3- to 7- hour interval lengthened to an average of 10 hours (Sawe, 1986). Another study looked at the resultant dose and interval when patients with advanced cancer pain controlled their own analgesia with oral methadone (Mercadante, Sapio, Serretta, & Caligara, 1996). Opioid-naive patients were initiated at a dose of 35 mg of methadone, and patients switching from morphine received 50% of the morphine- equivalent dose of methadone. Both groups were dosed three times daily for 3 days, after which time only the evening dose was fixed, and subsequent doses were given when pain reappeared. When four or more administrations were required per day, the dose was increased. At the end of 60 days, the mean dosage increase was 0.3 mg/day, with a dosage range of 9 to 80 mg, and the average interval was 10 hours (2.4 administrations/day). In a recent review citing the results of three other studies, the authors recommend a dosing interval of 8 hours (Ripamaonti, et al.,1997).
In light of the above results, it would seem reasonable to start with an 8-hour interval and adjust according to patient response and signs of toxicity. In making adjustments, clinicians must be aware of the interpatient variability that is seen with parameters such as bioavailability, protein binding, and elimination half-life, keeping in mind that autoinduction, pH-dependent renal clearance, and drug accumulation can further complicate the picture (Sawe, 1986).
The appropriate analgesic dose of methadone
Many factors must be considered when dosing methadone, including severity of pain, route of administration, and history of previous opioid use (including agent, duration of use, and resultant efficacy and/or toxicity). In studies of opioid-naive cancer patients, initial doses have ranged from 4 to 35 mg given every 4 to 8 hours (Fainsinger et al., 1993; Mercadante et al., 1996). When converting a patient from another opioid to methadone one would logically rely on the reported equianalgesic potency as a guide for conversion. Equianalgesic tables typically report the morphine:methadone ratio for parenteral dosing as 1:1 and for oral dosing as 3:1 or 3:2. These values are based on single-dose studies and may not be applicable to chronic dosing scenarios.
There have been several case reports of significant differences in the dose of methadone required to control pain in cancer patients compared with other opioid agonists. One series of reports describes four patients with cancer-related pain treated with continuous intravenous hydromorphone (Manfredi, Borsook, Chandler, & Payne,1997). Persistent pain and/or opioid side effects limited further escalation of the hydromorphone dose, and each was switched to methadone. Excellent pain relief without significant side effects was observed in all patients. This was achieved at methadone doses that were approximately 3% of the calculated equianalgesic dose of hydromorphone. In another series of cases, similar results were reported in six terminal cancer patients who were previously on either morphine or hydromorphone (Crews, Sweeney, & Denson, 1993). The resultant methadone doses ranged from 9.8% to 68% of the calculated equianalgesic dose. Interestingly, none of the patients in this report demonstrated similar variability in analgesic response when switched to other opioids. This suggests incomplete cross-tolerance between methadone and other opioids, which the authors point out is supported by other studies. This phenomenon would, at least in part, explain the discrepancy between the actual and the expected methadone doses required for adequate analgesia in these patients. The unpredictable pharmacokinetics of methadone certainly contribute to this effect.
Cross-tolerance may also depend on the previous opioid dose. In a recent study, cancer patients experiencing dose-limiting side effects to oral morphine were switched to oral methadone at a dose ratio of 1:5 (morphine:methadone) (Mercadante, Casuccio, & Calderone, 1999). After dosage titration over 3 days, the average dose on Day 3 was higher than on Day 0 for patients receiving less than 90 mg of morphine daily, whereas the average dose on Day 3 was lower for patients receiving more than 90 mg of morphine. This would seem to suggest that cross-tolerance decreases with increasing daily morphine doses.
These findings of incomplete and variable degrees of cross-tolerance have led to several different approaches being proposed for switching from other opioids to methadone (Mercadante, 1999). Recommendations for initial methadone dose range from 10% to 50% of the previous morphine dose given either as a fixed dose with added breakthrough doses or on a schedule that gradually tapers the previous opioid off. The various recommendations employ different strategies for arriving at a final dose and interval, but all take into account the high interpatient variability in pharmacokinetic parameters as well as the likelihood of incomplete cross-tolerance.
Regardless of whether methadone is being initiated in an opioid-naïve patient or in a patient with a significant history of opioid use, the key to establishing an effective regimen that minimizes adverse effects is careful individualization. For methadone, one size definitely does not fit all.
Conclusion
Beginning with its synthesis, methadone has been a misunderstood and perhaps underappreciated drug. Its unanticipated analgesic effect, the bizarre theories concerning its development and nomenclature, the controversy surrounding maintenance programs, the complexity of its pharmacokinetics, and the lack of a definitive role in pain control are all chapters in the unique and still unfolding story of methadone.
References
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Winston M. Gouldin is a clinical pharmacy specialist at Johnston-Willis Medical Center in Richmond, VA.
Daniel T. Kennedy is an assistant professor at the School of Pharmacy, Virginia Commonwealth University, Medical College of Virginia Campus.
Ralph E. Small is a professor at the Schools of Pharmacy and Medicine, Virginia Commonwealth University, Medical College of Virginia Campus.