Who Needs to Care?
Injection drug use is a risk behavior that may result in acquired immunodeficiency syndrome (AIDS). Treatment for substance abuse may be an important part of AIDS prevention and treatment. Methadone is a medication used as a substitute for heroin or other morphine-like drugs. Supportive services are usually included as part of the methadone treatment. Generally the dose is given orally once a day. Medications used to treat HIV may be used concurrently with methadone.
Methadone can interact with other medications. A drug interaction occurs when one drug changes the effects of another drug. Sometimes the drug interaction is too small to make a difference, other times it may cause problems. For example, a medication may reduce the effects of methadone and lead to symptoms of narcotic withdrawal or increase the effects of methadone and cause increased sleepiness. It can also work the opposite way. Methadone may work the same, but it may increase or decrease the effects of other medications. HIV medications may not work as well, or their blood levels may be elevated and cause unnecessary side effects. The dosages of medications (both methadone and HIV medications) can be adjusted to account for the predicted drug interactions to provide optimal therapy. For example, if the antiretrovirals (ARVs) are causing too many side effects when methadone is started or visa versa, ARVs can be safely adjusted, depending on symptoms and blood tests. There is no need to supplement methadone with heroin, stop antiretroviral medication, or stop other HIV-related medications. Stopping or missing doses of antiretroviral medications can lead to ineffective treatment and/or the development of resistance. It is important for people using methadone to let their healthcare providers know if they suspect a drug interaction.
Highlights of Potential Interactions
Metabolism is how the body eliminates drugs. This occurs mainly through the liver and the kidneys.
Hepatic metabolism is done by the liver. There are three ways drugs can interact with liver metabolism.
Substrate interactions. The liver can do only a limited amount of metabolism at once. When two (or more) drugs are taken at once that need the liver for metabolism, they can compete for specific enzymes in the liver. This can affect the extent to which drugs are metabolized.
Induction interactions. Induction occurs when a medication causes the liver to metabolize certain drugs faster than usual. It takes about 2 weeks for the effects of the induction to fully take place. This may result in decreased blood levels of medications, which may make them less effective.
Inhibition interactions. Inhibition occurs when a medication causes the liver to metabolize certain drugs more slowly than usual. One drug inhibits the metabolism of another drug, so there are extra amounts of that drug around. This can lead to toxic effects. Inhibition can occur soon after the drug is ingested.
Renal excretion is done by the kidneys. This is another way the body eliminates drugs. Methadone is eventually excreted renally, but it usually does not interact with other drugs that are renally excreted.
There are "general rules" about how groups of drugs are metabolized, and being aware of the rules makes it easier to understand specific interactions. The general rules are as follows:
All of these interactions may occur when either methadone is started or stopped, or when other medications are started or stopped. The exact amount of time for these interactions to occur varies between people and depends on a number of factors, such as how long they have received methadone, how well their liver is working, what other medical conditions they have, and whether the interaction is induction (about 2 weeks) or inhibition (immediate or within a couple days).
The liver metabolizes methadone and it tends to interact only with other drugs that are metabolized by the liver.
Most of the nucleoside reverse transcriptase inhibitors (NRTIs) undergo renal excretion, so they do not interact with methadone. However, there are two exceptions, zidovudine and abacavir. But only abacavir may require a methadone dosage adjustment.
All of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized by the liver. They may interact with methadone and require a methadone dose adjustment.
The protease inhibitors (PIs) are metabolized by the liver. The only PI that may require a methadone dosage adjustment is ritonavir.
Any type of liver disease (e.g., hepatitis C, alcoholic hepatitis) may make these interactions more pronounced, because the liver may not work as well.
What Specific Drugs Interact?
Everyone is different. Some people may have these interactions and other people may not. The effect of these interactions may be too small to require a dose adjustment for some people, but other people may need dosage adjustments, and even have to use different medications. When these interactions occur it will be different for each person because everyone's metabolism is a little different. Also, people react differently to medications as their bodies adjust to the effects. Table 1 shows the most important drug interactions. Many drug interactions are unknown. This means there aren't enough studies completed to effectively determine what will happen.
Methadone and Antiretroviral Medications -- Highlights of Potential Interactions
Zidovudine (AZT), didanosine (ddI) and/or stavudine (d4T) effects may change with methadone. The effect and dose of methadone remain the same. Usually the doses of AZT, ddI, and d4T remain the same.
Abacavir, nevirapine, efavirenz, and ritonavir, may reduce the effectiveness of methadone and an increase in the methadone dose may be required. Again this will not happen in every patient, and because this is induction, the effect usually takes about 2 weeks to occur. Whenever there is potential for decreased methadone levels, withdrawal symptoms may be present.
Nelfinavir may reduce methadone levels, but the effect is usually not felt and the methadone dose remains the same. Withdrawal symptoms are not likely.
|Table 1: Potential Methadone Drug Interactions|
|Effect on Methadone||Effect on HIV-Related Medication||Potential Significance/Recommendation|
|Zidovudine (Retrovir®, AZT)||None||May increase AZT||No dose adjustments. Watch for signs/symptoms of AZT-adverse effects (e.g., headache, muscle aches, fatigue, irritability).|
|Didanosine (Videx®, ddI)||None||May decrease ddI||No dose adjustments. Monitor CD4 and viral load to ensure ddI is working.|
|Stavudine (Zerit®, d4T)||None||May decrease d4T||No dose adjustments. Monitor CD4 and viral load to ensure d4T is working.|
|Lamivudine (Epivir®, 3TC)||None||Unknown||Unknown|
|Abacavir (Ziagen®, ABC)||May increase methadone clearance (i.e., it may leave the body faster than before)||May increase the time it takes abacavir to be absorbed.||Monitor for signs/symptoms of withdrawal.|
|Nevirapine (Viramune®)||May decrease methadone levels||Unknown||May need increased methadone dose|
|Delavirdine (Rescriptor®)||May increase methadone levels (predicted)||Unknown||May need decreased methadone dose|
|Efavirenz (Sustiva®)||May decrease methadone levels||Unknown||May need increased methadone dose|
|Ritonavir (Norvir®)||May decrease methadone levels||Unknown||May need increased methadone dose|
|Nelfinavir (Viracept®)||May decrease methadone levels||No||Methadone dose usually stays the same|
|Lopinavir (Kaletra®)||Unknown, but contains ritonavir so may decrease methadone levels||Unknown||Unknown|
|Combination of Ritonavir and Saquinavir used together||May increase the metabolism of inactive S-isomer of methadone; because this is the inactive isomer, the effect on the patient is usually nothing.||Unknown||Methadone dose usually stays the same|
|Table modified from the following:|
- Gourevitch M.N., Friedland G.H. Interactions between methadone and medications used to treat HIV infection: a review. The Mount Sinai Journal of Medicine 2000;67:429-436.
- College of Pharmacists of British Columbia Bulletin. 2001;26:8.
- Bartlett J.G., Gallant J.E. Medical Management of HIV Infection. Baltimore, MD: Johns Hopkins University; 2001.
- Gerber J.G., Rosenkranz S., et al. Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone: results of AIDS clinical trials group (ACTG) 401. JAIDS 2001;27:153-160.
The bottom line is that people taking methadone need to be aware of the possibility of interactions with any of the following medications: nevirapine, efavirenz, ritonavir, nelfinavir, lopinavir/ritonavir. Also, the time it takes for drug interactions to occur is different depending on the person and the drugs involved. People with concerns or questions should talk to their pharmacist or healthcare provider to have the dose of either methadone or the other medications changed. Together, optimal therapy for both methadone maintenance and HIV medications can be worked out.