Frequently Asked Questions (FAQs) - and Answers

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Responses to Frequently Asked Questions (FAQs) were developed by the editorial staff of Addiction Treatment Forum and made possible by an educational grant from Mallinckrodt Inc., a manufacturer of methadone and naltrexone.

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Methadone Prescribing

What is the best dose of methadone?

methadone prescribing Traditionally, healthcare practitioners seek to prescribe the lowest practical dose of a medication to “get the job done,” believing this will help reduce unwanted side effects. However, in the case of methadone, inadequately low doses often have been prescribed more for philosophical, moral, or psychological reasons than for sound pharmacological and clinical ones.

These misguided practices stemmed from stigmatization of methadone as “evil,” and a belief that patients should be administered the lowest possible amounts and then discontinue methadone as soon as possible. It also was falsely believed that it would be easier to eventually withdraw patients from lower rather than higher doses.

However, there is no evidence of lower doses being truly adequate for the vast majority of patients. Just how large a dose is “enough” depends on individual patient needs. Numerous clinical trials through the years have compared various doses of methadone for MMT. A consistently reported finding is that patients receiving higher doses exhibit superior outcomes, compared with those at lower dose levels. Trials have looked at such outcome variables as illicit-opioid abstinence, retention in treatment, psychosocial rehabilitation, and others. Doses compared have ranged from placebo (0 mg/day) up to 780 mg/day.

It is important to note that clinical trials to date have rarely examined doses above 100 mg/day, even though there is considerable evidence to demonstrate that this only might be an average adequate dose for a great many patients. Those studies that have looked at higher doses found that many patients thrive on and are more successful in MMT on vastly higher daily doses.

Minimum and maximum doses decided by clinic policy rather than by medical criteria are contrary to best practices in MMT mandated by federal regulations. Although individual state requirements may vary, federal regulations do not require special permission for doses above specific levels; nor are there limits on levels of methadone for dose increases or amounts provided for take-home.

Sources:

Donny EC, Brasser SM, Stitzer ML, Bigelow GE, Walsh SL. Relatively high doses of methadone are necessary to suppress heroin self-administration in the human laboratory Paper presented at: CPDD (College on Problems of Drug Dependence) 65 th Annual Meeting; June 2004; San Juan, Puerto Rico.

Federal Register. Narcotic drugs in maintenance and detoxification treatment of narcotic dependence; repeal of current regulations and proposal to adopt new regulations. Federal Register. July 22, 1999;64(140):39809-39857. 21 CFR Part 291; 42 CFR Part 8.

Leavitt SB. Methadone Dosing & Safety in the Treatment of Opioid Addiction. Addiction Treatment Forum [Special Report]. September 2003. Available at: http://www.atforum.com/SiteRoot/pages/addiction_resources/DosingandSafetyWP.pdf

Leavitt SB, Shinderman M, Maxwell S, Eap CB, Paris P. When “enough” is not enough: new perspectives on optimal methadone maintenance dose. Mt Sinai J Med. 2000;67(5-6):404-411. Available from AT Forum at: http://www.atforum.com/SiteRoot/pages/addiction_resources/Enough.pdf

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What can be done about my methadone dose not holding me all day?

An adequate daily methadone dose will prevent withdrawal symptoms and drug craving for at least 24 hours. The simple fact is, however, that patients respond differently to methadone and there is no single best dose that works for everyone.

Some patients need higher doses of methadone to hold them throughout a day. This can be due to the amount and purity of street heroin the person was used to, a current physical ailment, or methadone interactions with prescription medicines or other drugs. Also, some patients are “fast metabolizers” – they digest the methadone more quickly – due to how their digestive tracts and livers function.

A blood test can be used to measure the amount of methadone in a patient’s system at various times. This is called a serum methadone level or SML test. When blood is tested just before taking the dose and 3-4 hours later, it helps indicate how fast the methadone is being metabolized. This test alone, however, rarely tells the whole story. An important measure is how the patient feels throughout the day: withdrawal sickness and drug craving coming at the same time each day are good indicators that a dose adjustment is needed.

Some patients in methadone maintenance treatment (MMT) are not prescribed sufficient daily methadone doses. When MMT for opioid addiction was developed during the mid-1960s, doses in the 80 mg/day to 120 mg/day range were recommended, with some persons requiring much more. Today, many clinics consider 100 mg/day as the very highest allowable dose, possibly because special permission was once required from state or federal authorities for higher dosing. Research has shown that there really is no upper limit as to what certain patients may require and find beneficial, with some needing as much as 200 to 300 mg/day, or even much more.

Another approach helpful for some patients is splitting the dose; for example, taking half early in the day and half in the evening. This allows them to have a steady serum level of methadone in their systems throughout the day, without an extremely low period that produces withdrawal or craving. Patients must be honest with clinic staff in describing problem symptoms and to work patiently with staff in arriving at a methadone dose and dosing schedule that is best.

For further information and references, see:

Understanding Methadone Split Dosing. Addiction Treatment Forum. 2003;12(4):3. Available at: http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2003.shtml#anchor1484222

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Does the particular formulation or brand of methadone make a difference?

mmt treatment As with many medications, there are several forms of methadone to make dispensing and administration more convenient. Pharmacologically – that is, the way they work in the body – the different formulations must be equivalent to be approved by the FDA.

Some patients may perceive that one formulation is easier on the stomach or seemingly more rapid acting. This may be due to individual differences in absorption and metabolism; but is not due to differences in the essential methadone ingredient. It also could be due to how the liquid or dispersible tablets are diluted (e.g., with juice versus plain water). Finally, the preservatives or fillers – inactive ingredients – used in the various formulations may differ and some persons can be sensitive to one of those compounds for unknown reasons.

Practitioners and patients have often debated whether methadone liquid, tablets, or dispersible tablets are more potent. Patients sometimes bitterly complain when switched to a different formulation, but pharmacologic advantages of one formulation over another are not supported by the research.

Investigators at Albert Einstein College of Medicine, Bronx, NY (Gourevitch et al. 1999), enrolled MMT patients in an experiment whereby each received either methadone liquid, tablets, or dispersible tablets for a period of 3 weeks. Each subject was then switched to one of the other formulations for a similar period of time.

There were no significant differences in methadone blood levels among the 3 formulations during a 24-hour dosing period (see graph). Additionally, patient-reported subjective opioid-withdrawal symptoms did not differ at any time by methadone formulation.

The researchers concluded that patient intolerance to changes in methadone formulation appear to have no basis in the pharmacologic action of methadone itself, whether in liquid or solid forms. Any difficulties attributed solely to a particular methadone formulation may be due more to patient-specific psychosocial factors. However, this is not to say that patient comments about particular formulations working better for them than others should be dismissed as meaningless. The very real placebo effect of merely “believing” that one formulation is better than the other can be a strong influence. And, in rare cases, a patient might indeed digest a particular formulation of solid methadone differently than the liquid; so, possible variable effects of different formulations cannot be entirely discounted.

Furthermore, there is sometimes a misperception that Methadose ® and methadone are different drugs, potentially having different effects. It is important to understand that Methadose is simply an FDA-approved brand name of the generic product – methadone HCl – produced by Mallinckrodt, Inc. of St. Louis, MO, and used for marketing purposes. At equivalent doses, both the branded product and the generic version have the same potency and effects – that is, 10 mg Methadose ® should have exactly the same pharmacologic action and effect as 10 mg of generic methadone. Similarly, Tylenol® (McNeil-PPC, Inc.) is a brand name for the generic medication acetaminophen, Vicodin® (Abbott Laboratories) is a brand name for generic hydrocodone bitartrate and acetaminophen, and so forth.

Sources:

Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone. Implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14)1153-1193.

Gourevitch MN, Hartel D, Tenore P, et al. Three oral formulations of methadone. A clinical and pharmacodynamic comparison. J Substance Abuse Treatment. 1999;17(3):237-241.

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Is it safe to take methadone with other medications?

Many drugs are digested (metabolized) by chemicals in the liver called enzymes. Methadone is metabolized this way and other drugs broken-down by the same liver enzymes may interfere with methadone and change its effects – this is called a “drug interaction.”

drug interactions A drug interaction occurs when the amount or action of a drug in the body is altered – usually increased or decreased – by the presence of another drug or multiple drugs. During clinical use spanning more than 40 years, oral methadone has proven to be a well-tolerated medication with minimal adverse reactions when prescribed in appropriate doses and taken daily as a component of methadone maintenance treatment. However, there are potential methadone-drug interactions – involving prescribed medications, illicit drugs, OTC products, and other substances – which sometimes can be difficult to predict, may be potentially harmful, and/or can lead to treatment failures.

Methadone works best when administered in adequate therapeutic doses. However, given the individual variability in methadone absorption and metabolism, it becomes difficult to accurately predict the effects of drug combinations in any one patient, or how methadone dosing may need adjustment. Several points might be kept in mind:

Just because certain drugs can interact does not mean that they will, or indicate to what extent.
If a patient is responding unexpectedly or unfavorably to methadone – with signs/symptoms of under- or overmedication – a search for potentially interacting substances would be appropriate. Taking a comprehensive history from the patient can be important in this search.
When an interaction is suspected, adjustments of medication dosages with followup monitoring, substitutions of non-interacting agents, or other therapeutic modifications might be made.
In many cases, the daily dose of methadone may need to be either increased or decreased, depending on the interaction.

Also, it is always best for MMT patients to inform their healthcare providers that they are taking methadone and to express concern about possible interactions with any prescribed medications. MMT clinic staff should become familiar with drugs or drug combinations that may affect methadone so they can advise these outside providers.

For more information and references about drugs that might interact with methadone, see: Leavitt SB. Methadone-Drug Interactions. Addiction Treatment Forum [Special Report]. January 2004. Available at: http://www.atforum.com/SiteRoot/pages/rxmethadone/methadonedruginteractions.shtml
A companion Quick Reference Guidebook is available at: http://www.atforum.com/mdi_booklet.shtml

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Does methadone spoil or go bad?

methadone spoilage Since up to 30 days of methadone may be prescribed at one time in the U.S. for take-home, there has been concern about the extended shelf life of liquid methadone. Manufacturers can provide little guidance once the seal of the original container is broken and methadone maintenance treatment (MMT) clinic staff add other ingredients to the product.

Independent research and commentary confirms that methadone itself is a stable medication. In one published report, pharmacists noted that potential problems relate more to what is used to dilute the methadone at the time of dispensing, due to possible contamination with mold or fungal growth.[1]

Bacterial growth also might be a concern. One investigation found that storage of methadone mixtures at room temperature fostered visibly unacceptable bacterial growth within 2 weeks, unless appropriate preservatives were included (such as, sodium benzoate). As for potency, methadone mixed with Kool-Aid, Tang, apple juice, or Crystal Light and refrigerated (41°F) maintained its strength for 30 days or much longer.[2]

Based on a review of existing literature and a consensus of opinion among consulted pharmacists, the American Association for the Treatment of Opioid Dependence (AATOD) issued several recommendations in June 2004:[3]

Dilution of methadone products should be with distilled water only.
New, clean, air tight, light resistant containers should be used for dispensing.
Take-home containers should be securely refrigerated as soon as possible, and remain refrigerated until used.

AATOD specified that, if these procedures are followed, liquid methadone should remain stable for up to 30 days from the date of MMT clinic dispensing.

However, there may be a question as to whether dilution at the time of clinic dispensing is required or necessary. Federal Regulations do not specifically require dilution.[4] Typically, product labeling specifies, “to be diluted with water or other liquid to 30 mL (1 fluid oz.) or more before oral administration.”[5] This could mean dilution “just before the dose is taken,” in which case the patient might be the one to add liquid for dilution. Tap water or other fluid could be used, since storage is not a concern. Dilution simply makes it easier to consume the full amount of otherwise thick, undiluted methadone that is in the take-home container.

Sources:

1. Allen LV, Stiles ML. Methadone lemonade. U.S. Pharmacist. 1988(September):82.

2. Lauriault G, LeBelle MJ, Lodge BA, Savard C. Stability of methadone in four vehicles for oral administration. AJHP. 1991;48:1252-1256.

3. Parinno MW. Shelf life for methadone hydrochloride products following OTP compounding [memo]. June 11, 2004. AATOD.

4. Federal Register. Opioid drugs in maintenance and detoxification treatment of opiate addiction; final rule. 2001 (Jan 17);66(11):4085. 42 CFR Part 8. Available at: http://www.atforum.com/SiteRoot/pages/addiction_resources/Methadone%20Fed%20Regs.pdf

5. Package Insert. Methadose® Oral Concentrate. 2001. Mallinckrodt, Inc.; St. Louis.

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