Methadone

Is methadone safe?

Methadone is two things at once. As a molecule, it is one of the hardest opioids to use safely: it builds up in the body over several days, its effect on breathing outlasts its pain relief, it can upset heart rhythm, and dozens of medicines change its levels. We score it 22, level with prescription fentanyl and below morphine.

As a treatment for opioid addiction, it is one of the most effective tools medicine has. People who stay in methadone treatment are several times less likely to die of an overdose than those who leave it. The score describes the drug's own risks. It is not a verdict on methadone treatment, and nobody should stop or cut a dose because of it.

Why methadone is hard to dose

The US label spells out the problem. Pain relief from one dose lasts 4 to 8 hours, but the half-life is 8 to 59 hours, so methadone accumulates with each dose and levels only settle after at least 3 to 5 days. The label says it has a narrow therapeutic indexOverdose marginHow far a normal dose is from a harmful one. A wide margin means an accidental extra dose is unlikely to cause serious harm.More in the glossary, especially with other drugs, and that deaths have occurred in early treatment from this build-up, and during switches from high doses of other opioids.

That is why addiction treatment starts low: 20 to 30 mg, with the first day's total not ordinarily above 40 mg, then slow increases. Most people become stable on 80 to 120 mg a day, a dose that could be fatal for someone without tolerance. Anyone who has not taken opioids for more than 5 days may have lost their tolerance.

For pain, the CDC's 2022 guideline says methadone should not be the first choice of long-acting opioid. In a 2012 report the CDC found methadone was involved in 31.4% of prescription painkiller deaths in 13 states in 2009, and 39.8% of deaths involving a single painkiller, far more than its share of prescriptions.

Heart rhythm

Methadone can lengthen the QT intervalQT prolongationA delay in the heart's electrical recovery between beats, seen on an ECG. Some medicines cause it, and in rare cases it leads to a serious heart rhythm problem.More in the glossary, and cases of torsades de pointes, a rhythm that can cause fainting or sudden death, have been reported. The label says they are more common at doses above 200 mg a day and mostly in pain patients on large doses, but they have also occurred at usual maintenance doses. The label asks for close monitoring of people with risk factors for a long QT interval, a history of heart conduction problems, or other medicines that affect heart rhythm.

Interactions with other medicines

Few drugs have a longer interaction warning. The boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary names inhibitors of five liver enzymes, CYP3A4CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary, 2B6, 2C19, 2C9 and 2D6, as able to push methadone levels high enough to stop breathing, and stopping an inducer such as rifampin, carbamazepine, phenytoin or St John’s wort can do the same. Starting an inducer, including several HIV medicines, can do the opposite and lower methadone levels. Every new prescription, antibiotic or herbal remedy should be checked with a pharmacist.

Benzodiazepines such as alprazolam, alcohol, sleeping pills and gabapentinoids add to the effect on breathing. The label warns against the combination but also says addiction treatment should not be categorically denied to people who use these drugs, because barriers to treatment can be more dangerous than the combination.

Methadone as addiction treatment

The evidence that methadone saves lives is strong. A 2017 BMJ meta-analysis of cohorts covering 122,885 people found all-cause deaths of 11.3 per 1,000 person-years during treatment against 36.1 out of it, and overdose deaths of 2.6 against 12.7. Among 17,568 Massachusetts adults who survived an overdose, methadone treatment was linked to a 59% lower risk of opioid-related death. The CDC's guideline asks clinicians to offer or arrange such treatment for people with opioid use disorder.

The same data show the two riskiest moments: the first four weeks, while the dose is being built up, and the weeks after leaving treatment, when tolerance falls. In the US, methadone for addiction is dispensed through certified opioid treatment programmes. A 2024 federal rule made pandemic-era take-home flexibility permanent, allowing up to 28 take-home doses for stable patients.

Staying safe

• Keep naloxone at home and make sure people around you know how to use it; repeated doses may be needed because methadone outlasts it.
• Store take-home doses in a lockbox. A single dose can kill a child or an adult without tolerance.
• Tell every prescriber and pharmacist that you take methadone, and do not add sedatives or alcohol without discussing it.
• If you are pregnant, talk to your treatment team before changing anything. The label calls newborn withdrawal expected and treatable, and notes that untreated opioid addiction in pregnancy is linked to preterm birth, low birth weight and fetal death.
• Plan any reduction with your prescriber, slowly, and ask about extra support in the weeks afterwards.

How we scored it

Track record (85) is strong after almost 80 years of use. Regulatory warnings (5), overdose marginOverdose marginHow far a normal dose is from a harmful one. A wide margin means an accidental extra dose is unlikely to cause serious harm.More in the glossary (10), interactions (10) and dependence (10) sit at the bottom of the scale because of its build-up, enzyme interactions and full boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary, and serious side effects (25) add the QT risk. These are the risks of the drug; for people with opioid addiction, staying in treatment is far safer than going without.