Archive for the ‘Methadone dosing’ Category

Methadone Overdose Deaths: First Two Weeks



Methadone is a tricky drug to start, due to the narrow margin between therapeutic dose and fatal dose. Making it more difficult, people vary a great deal in the rate at which they metabolize methadone.  Some people have a methadone half -life as short as 15 hours, while others have half- lives as long as 60hours. The average is 22 hours. So even for people with a high tolerance to other opioids, increasing methadone too quickly can be deadly.

Methadone’s long half-life makes it good for a maintenance medication, since after stabilization, there’s not much fluctuation in the blood levels. However, the long half-life makes it more difficult to adjust the dose. The change I make in a patient’s dose today may not be fully experienced by the patient for five or more days.

The tolerance to the anti-pain effect of methadone builds faster than the tolerance to respiratory suppression, adding to the danger. When methadone is used inappropriately, patients may take more methadone to relieve pain, but by the time the pain is gone, they could easily have taken a methadone overdose.

All of this explains why the first two weeks of methadone maintenance treatment are the most dangerous. According to some studies, death rates for patients starting methadone at opioid treatment programs are actually higher during the first two weeks than when using illicit opioids. (1, 2)

Even so, it’s a risk worth taking, given the proven life-saving benefits of methadone (and buprenorphine) maintenance

Patient overdose during the first two weeks is a serious concern for doctors working at opioid treatment programs. We must do all we can to keep patients safe. It’s a fine line; if we start at too low of a dose or go up too slowly, we risk having our patients drop out of treatment. And if we increase the dose too quickly, it increases the risk of overdose…

The American Society of Addiction Medicine (ASAM) recently updated their methadone induction guidelines. In past years, doctors working at opioid treatment programs (OTPs) tended to start patients at 30-40mg and increase the dose rather quickly. Now, the expert ASAM panel recommends a starting dose of 10-30mg. If that dose isn’t sufficient to suppress withdrawal, a second dose can be given after three hours, so long as the total dose is not greater than 40mg. The expert panel recommends increasing the dose no more quickly than every five days, and no more than five milligrams at a time.

Some patients are more susceptible to overdose, and physicians should consider lower methadone starting doses for these people:

-Age over 60

-Using sedating drugs like benzodiazepines

-Regularly consume alcohol

-Are on prescription medications which can interact with methadone

-Medically fragile patients, for example patients with coronary artery disease, morbid obesity, -chronic obstructive pulmonary disease (COPD), or sleep apnea

-Have risk factors for prolonged QT interval, such as a recent heart attack, personal history of heart rhythm problems, or family history of heart disease

-Patients who have been abstinent from opioids for five or more days (e.g. recent incarceration, recent detoxification or hospitalization). These patients lose some of their tolerance and might be more prone to overdose with any opioid.


Interestingly, the degree of withdrawal that the patient has when entering treatment does not correlate with the dose of methadone they will need to get rid of withdrawal symptoms. In other words, one person in terrible withdrawal may need a smaller dose than another person with milder withdrawal. The degree of withdrawal that a patient feels is only partly due to opioid tolerance. Genetic makeup may be the reason why some people have more severe withdrawal than other people.

While I always ask my new patients how much opioid they have been using per day, that alone doesn’t determine methadone starting doses. There’s incomplete cross-tolerance between other opioids and methadone, meaning we can’t use the table of equianalgesic doses.

Last week I found an interesting article describing a large study of Canadian methadone patients, which will contribute even more to what we already know about risk during the first two weeks of methadone. This study showed which patient characteristics are associated with overdose death.

The study was done in Canada from 1994 until 2010, and covered over 43,000 patients enrolled in an opioid treatment program in those years. The study looked at all overdose deaths in this patient population and found 175 deaths deemed to be from opioids. These cases were matched with patients who entered treatment around the same time as the patient who died, creating a nested case-control study.

This study found, as expected, a higher degree of risk in the first few weeks on treatment. In this study, patients in the first two weeks of treatment were 16 times more likely to die in the first two weeks of treatment than any other time in treatment.

Psychotropic drugs were associated with a two-fold risk of overdose death overall, with antipsychotics associated with a 2.3-fold risk and benzodiazepines a 1.6-fold increased risk. Antidepressants were not associated with increased risk of overdose death. Alcohol use disorder diagnosis was also associated with a two-fold increase risk of overdose death.

Even more interesting, heart disease was associated with over five times increased risk of overdose death, and serious lung disorders (sleep apnea, COPD) were associated with a 1.7 times increase in overdose death.

This is a powerful study because it was so large.

This is information I can use. I’ve been stressing about patients whom I thought were at increased risk – those who use alcohol and benzodiazepines, and those with severe lung disease. While these patients are at higher risk, from this study it appears patients on anti-psychotics are at even higher risk. And I need to do a better job of getting patients to see primary care doctors, to screen for heart disease, which gave the highest risk of all.

As time goes on, I think we’ll get more information about which patients are at higher risk. Those patients need a higher degree of interaction with treatment center staff, and better coordination of care with mental health providers and primary care doctors. I know I plan to implement a system at the OTP where I work to make sure I see patients more often if they have the risk factors described.

Obviously any patient death is a terrible thing. Of course it’s worst for the family, but it also affects the treatment team. I feel badly for the families of those 175 patients in the Canadian study who died, but they gave us information that can hopefully help us provide better care for future patients.


  1. Caplehorn et al, “Mortality Associated with New South Wales Methadone Programs in 1994: Lives Lost and Saved,” Medical Journal of Australia, 1999 Feb 1;170(3):104-109
  2. Cousins et al, “Risks of drug-related mortality during periods of transition in methadone maintenance treatment: A cohort study,” Journal of Substance Abuse Treatment, October 2011, Vol 41(3); pp252-260.
  3. Leece et al, “Predictors of opioid-related death during methadone therapy,” Journal of Substance Abuse Treatment, Oct 2015,

Genetic testing for methadone metabolism





Genomic medicine is growing quickly. This is a branch of medicine that studies an individual’s genetic profile in order to be able to predict which medications may work best. This information can also predict if a patient will have a problem with a specific medication.

Some people have genes that make them slow metabolizers of methadone. This is a particular problem, since methadone is such a long-acting drug. Slow metabolizers are at increased risk of methadone accumulation, leading to over -sedation and overdose death. If we had a way to identify slow metabolizers, perhaps we could prevent these deaths, by starting them at lower methadone doses.

Researchers at Washington University in St Louis have discovered genetic subtypes that are associated with both faster methadone metabolism and slower methadone metabolism.

Researchers took blood samples from normal volunteers for genetic testing, and then gave these test subjects doses of methadone. As expected, these people metabolized methadone at markedly different rates. So far, that’s not news. We’ve known for years that people metabolize methadone at very different rates. But this study showed what genetic variants influenced the rate of methadone clearance. Two genetic subtypes for the gene for cytochrome P2B6 were found; one increased the metabolism of methadone and the other resulted in slower-than-usual metabolism of methadone.

Interestingly, the researchers found that African-American people were more likely to have the subtype of this gene giving slower methadone clearance. These patients may be at increased risk for overdose, if given the same dose as patients with the genetic subtype resulting in faster methadone metabolism.

To the best of my knowledge, it’s not yet practical to get genetic testing done on a patient before I start methadone. Specialty labs do offer the testing, but my patients could not pay for it, unless it was paid for by insurance, including Medicaid.

Even after I get the information, how would I use it? For sure, if a patient had the genetic makeup of a slow metabolizer, I would start at a lower dose and increase more slowly. But I have no studies to guide me – I would be using my best clinical judgment.

What about a patient with the genetic makeup of a fast metabolizer? Would I feel comfortable starting at a higher dose and increasing that dose more quickly?

No, I would not. Perhaps that patient has a lower risk of overdose, perhaps not. Again, I have no studies that tell me for this certain gene, start at “x” dose. I don’t know that we will ever have that sort of specific information, since factors other than genetics must be considered.

I hope in the future I’ll see a role for genetic testing for patients starting medication-assisted treatment of opioid addiction. However, we would need studies showing how we can use the information. For now, the expense, turn-around time of testing, and lack of real-life studies using genetic information make genetic testing unworkable.

Confusion over Methadone Peak and Trough Levels

aaaasplit dose

Recently I’ve had patients write to my blog describing how their opioid treatment program doctors are using methadone blood levels to determine the correct dose. What they described to me was worrisome; patients’ doses rarely need to be checked with methadone peak or trough blood levels. Due to tolerance, a methadone blood level may be adequate for one patient, but far too low for other patients.

A patient’s dose of methadone needs to be determined on clinical grounds. This can include the patient’s description of withdrawal symptoms and their timing related to dosing, physical exam just before the patient is due for a dose, and evaluation of the patient three to four hours after dosing. It may also include an evaluation of ongoing illicit opioid use, other medical issues, and other medication or illicit drug use.

Opioid treatment program physicians rarely need to check methadone blood levels. I usually check peak and trough blood levels when I suspect a patient may be a fast metabolizer who may do better with split dosing. In such a case, the patient describes feeling fine for the first part of the day but in awful withdrawal by night time, despite taking a relatively higher dose. Then if the patient’s peak (highest level) is twice the trough (lowest level) I know they may feel better with twice a day dosing. Certain medications can induce the metabolism of methadone, making the patient metabolize methadone more quickly and drop the blood level. Often in this situation, split dosing helps.

I cringe when patients say things like, “my doctor checks a methadone blood level on everyone when they get to 80mg to see if they need to increase the dose or not.” For the vast majority of patients, getting this blood level won’t be helpful. If it’s used to determine the patient’s dose, it could be harmful. Many patients will still feel withdrawal while dosing at 80mg, even though they may have what would be considered a moderate blood level.

Our patients are tolerant to opioids. For this reason, methadone patients who are doing well, feel fine and have normal lives can have so-called “toxic” blood levels of methadone. A level that would kill someone unaccustomed to methadone may be just what my patient needs.

Some doctors think all opioid addicts want to go higher on their methadone dose than they need, and that these addicts would want limitless dose escalations unless the doctor stops this. In some patients, addiction may drive the addict to ask for dose increases even when not needed. Addiction often tells the patient “more is better.”

I’ve seen this problem too, but not as often as one might expect. More often, I’m the one advocating for a higher methadone dose. Don’t get me wrong, I do want to use the lowest effective dose. Some patients, due to fear of methadone and the stigma against it, are afraid to increase their dose. I point out that studies show patients do the best in methadone treatment if they are on a high enough dose to block the withdrawal symptoms and block the euphoria from other opioids. Particularly if the patient is still using illicit opioids, I recommend a dose increase.

Lab tests aren’t an adequate substitute for talking to the patient and examine the patient. As we used to say when I was in medical school, about a billion years ago, “Treat the patient, not the lab result.”

Revoking Methadone Take home Doses


My decisions to revoke take home doses provoke more anger and outrage from my patients than anything else I do. This is a sensitive issue.

To understand their fury at losing take home doses, I need to describe how hard it is to get those take homes in the first place. Patients don’t waltz into treatment and get take home doses right away.

For patients on methadone at opioid treatment programs, (OTPs), eight criteria must be met before the patient can get any take home doses.
1. Time in treatment
2. Urine drug screens negative for illicit drugs and alcohol
3. Ability to store medication safely
4. Stable home environment, stable social relationships
5. No recent criminal activities
6. Regular clinic attendance – doesn’t frequently miss days
7. No behavioral problems at the opioid treatment program
8. Rehabilitative benefits of take homes outweigh the risk of take homes

Of all the requirements, time in treatment limits patients the most. Many patients do very well right from the start, with no drug use, criminal activity or any other complications. Even so, they must come every day the program is open (often 7 days per week) for a minimum of three months. After that, they can be granted two additional take home doses per week, as long as all of the other seven criteria are met. After three more months, they get one more take home per week, and so on. Once they get to the take home level where they come only once per week, they have to be compliant and in good recovery for at least one year before being allowed to get take homes every two weeks.

Patients expend time, money, and effort to get these take home doses.

That’s for methadone. For buprenorphine (Suboxone, Subutex, Zubsolv, etc.) there is no federal requirement saying how long a patient has to be in treatment to get a take home dose. So long as buprenorphine patients meet the other seven criteria, they can get take homes from the start, as far as the federal standard is concerned. However, state requirements may be stricter than federal requirements. For example, my state didn’t drop the time in treatment criteria for patients in opioid treatment programs on buprenorphine, but is willing to grant exceptions on a case-by-case basis, as long as the request is reasonable.

Most patients manage their take home doses perfectly. This fact gets lost in the hoopla over the few patients who don’t take their take home medication as prescribed. The actions of a few rogue patients, when made public, taint the reputations of all our patients. Their actions unfairly perpetuate stigma and bias against medication assisted treatment.

At any given time, you can google “methadone overdose on take home” or something similar and read news stories about patients who sold or gave their dose to someone who died as a result. It makes big splashy headlines and causes people in the community to wring their hands and lambaste opioid treatment programs for allowing people to get take home doses at all. In reality, many more people have died from methadone diverted from pain medicine clinics.

Part of my job as an OTP medical director is to decide, with the help and input of all staff, when a patient is taking the medication I prescribe as I prescribe it, and when it’s being misused.

Now obviously most people won’t tell OTP staff if they plan to misuse their medication, or divert it to someone for whom it was not intended, so OTPs have to have ways to assure patient compliance. One of those ways is called a “bottle recall.”

In a bottle recall, a staff person, usually the patient’s counselor, calls the patient at the given contact number and asks them to return to the facility within 24 hours so we can see that they have all their bottles and that bottles to be taken later in the week are still sealed and full of medication.

Yes, there are ways to falsify bottle recalls. In the past, patients would pull the plastic bottles apart at the seams, remove the methadone, fill the bottle with red Kool-Aid or similar, and glue the bottles back together. Some patients’ efforts were easily detected, and some do a slick job.

Now that we have pressurized seals on the take home bottles, we think it’s more difficult to get into the bottle without being detected, but some clever patient will invent a way to thwart the pressure seals…or already has done so.

If the patient fails a bottle recall, we must eliminate all take homes, at least temporarily. Sometimes patients don’t give us a working phone number, sometimes they say they never got the call, they just dropped their phone in a mud puddle and it wasn’t working, they got the message but forgot to return to the clinic, they just went out of town and only got the message when they got back, are out of town and can’t make it back for a bottle recall…we hear many reasons for a failed recall. Many are legitimate, and it’s nearly impossible to sort reality from lies.

According to patients, take home medication has been lost, stolen, left in hotel rooms, spilled in the sink, run over by cars, eaten by family pets, black bears, and other animals, burnt up house fires, and dumped out by angry spouses and highway patrolmen. In one creative story, the patient said a tree fell on her house during a storm. The great wind that felled the tree also created a sort of vacuum in her house, and a whirlwind sucked her medication bottle up, up into the sky as she watched helplessly.

Another patient said he couldn’t come in for a bottle recall because he buried his bottles in the back yard and forgot where he buried them, because he had Alzheimer’s dementia. Of course, I asked why he buried them, and he said, “So my wife wouldn’t get into them.” No, he didn’t get any more take homes.

Of course weird things can actually happen, and that’s the problem. What should I do if a patient who appears stable and who appears to be doing well, reports loss of medication? It’s a judgment call. With the help of the rest of the staff, we discuss the past stability of the patient and the believability of the report. We can’t look into the hearts of all our patients and tell who has criminal intent and who doesn’t. People can’t be perfectly assessed. I do the best I can, and with the help of the rest of the staff, make judgment calls about take home doses.

As the prescribing physician, I have a responsibility to make sure every patient who gets a take home stores it safely and takes it as directed. If a patient is unable or unwilling to do this, I have to revoke their take homes, at least for some period of time, especially if there’s evidence my patient is selling or giving away their medication.

Diversion of take home doses to someone other than the patient for whom it was prescribed is always a concern at opioid treatment programs. But we don’t want to limit freedoms for patients doing well because of the illegal activities of other patients. As with so many things relating to human behavior, it’s an issue of balance. I admit we don’t always get it right.

Some anti-methadone activists would like to change the law, and force patients on medication-assisted treatment to come daily for their doses, and eliminate take home doses. That would reduce the problem of diversion, but cause a bigger problem. It would disrupt the lives of thousands of MAT patients who take their medication as prescribed as they go about their life.

In the other extreme, some pro-MAT people say patients should be allowed to be prescribed methadone and buprenorphine a month at a time, just like medication for other chronic illnesses like diabetes and high blood pressure. But the medications I prescribe, methadone and buprenorphine, have street value, and can cause euphoria in people unaccustomed to taking opioids. Therefore, because of the properties of these medications, sound medical practice tells us we have to have some safeguards in place to detect medication misused and diversion.

Split Dosing

Medication blood level with once-daily dosing compared to split dosing

Medication blood level with once-daily dosing compared to split dosing

Split dosing, when used in reference to the medication-assisted treatment of opioid addiction, means instead of once daily dosing, the total medication dose is divided, or split, into two doses.

Methadone and buprenorphine (Suboxone, Zubsolv, etc.) are long-acting opioids. This property makes them ideal for use in opioid addiction. At the proper dose, both medications relieve physical withdrawal symptoms and cravings in opioid addicts without causing a euphoria or impairment.

When we use these medications for opioid addiction, we prefer to dose once per day. This way, the recovering opioid addict only has to think about taking medication once, rather than using opioids numerous times throughout the day. In active addiction, addicts become accustomed to thinking about opioids frequently; in fact, their whole day narrows into finding opioids, using opioids, and getting ever more opioids. We want to help them break this cycle, and these two long-acting opioids can do this.

However, not all patients will feel normal with once daily dosing of methadone. Patients metabolize methadone at very different rates. Some medical literature says there’s a one-hundred fold difference in metabolic rates of methadone between patients. With methadone, a small percentage of the population metabolizes very quickly, and another small percentage metabolizes very slowly.

This is why methadone induction is dangerous in brand-new patients. Slow metabolizers can accumulate a fatal amount of methadone if such patients are started on too high a dose or increased too quickly.

The activity level of the enzyme that metabolize methadone, the cytochrome P450 3A4, varies a great deal between patients. The activity of the enzyme is thought to be determines by the genetics of each patient. Some patients may metabolize very quickly, with an elimination half-life as short as 8 hours. (Elimination half-life refers to the length of time that it takes for the concentration of a drug to drop to half of its original value in the body). Other patients may have an elimination half- life of up to 130 hours. Most patients average around 36 hours.

Buprenorphine has a consistently long duration of action, of 24-60 hours, with less variability between patients than with methadone. Buprenorphine doesn’t need to be given in split doses when treating opioid addiction, though in some special situations, split dosing may help patients.

Patients who need split dosing are given part of their dose in the morning and part of their dose to take later, as close to 12 hours later as they can manage. Since many opioid treatment programs (OTPs) are set up to dose once per day, in the morning hours, patients who split dose are given half to two thirds of their total dose at their OTP. The other half to one third is given to the patient as a take- out dose for later that day.

We decide which patients need split dosing by listening to their symptoms. During induction, we know the patient’s dose isn’t high enough to last the whole day, so the need for split dosing can’t be determined until later in treatment. Patients who are fast metabolizers often get to 120mg or more, yet feel opioid withdrawal late in the day. Or they may feel drowsy after dosing but feel withdrawal later in the day. These patients may be fast metabolizers.

Before I can order split dosing, I need to get permission from the state and federal authorities, just like I would for extra take homes doses for patient emergencies. In my state, methadone peak and trough levels are usually requested before they grant permission for split dosing. We draw the patient’s blood three hours after their dose, which is the peak. That’s the highest blood level the patient will have on that dose. On the next day, right before they take the next day’s dose, we draw another methadone blood level, called the trough, which is the lowest level the patient ever has on that dose.

Then we compare the peak to the trough. If the peak is more than twice the trough level, the patient is probably a fast metabolizer who will feel better taking part of their dose in the morning and part in the evening.

Pregnant women, particularly in the last trimester of pregnancy, may do better with split dosing. It’s common for methadone metabolism to increase during pregnancy. Blood levels also drop during pregnancy due to plasma volume expansion and other factors, so that a given dose gives progressively lower blood levels as the pregnancy proceeds. Also, studies have shown the fetus is less affected by methadone when the total is divided into two doses.

However, the woman’s home environment and other factors must be considered before ordering split dosing. For example, if the pregnant patient is living with a partner in active addiction, that partner may bully the woman into giving him her second dose. If the pregnant patient is struggling with other drug use, splitting the dose may be too risky.

Some medications induce the metabolism of methadone, meaning the metabolism speeds up. The total dose can be increased to compensate for this, but sometimes the effect is so pronounced that the patient needs to change to split dosing to feel normal.

Every time I order split dosing, the nurses become wary. That’s because the proper way to start split dosing is to give the patient’s usual entire amount first thing in the morning on day one. Then, a take home for half the dose is given to the patient to take home for later use that first day. The nurses worry I’m going to overdose the patient. Starting with day two, the patient gets a half dose in the morning and a half dose in the evening.

If you don’t start the day with a full dose, but rather start on day one with half in the morning and half in the evening, the patient will start off in withdrawal, and can de-stabilize for the first four or five days.

Instead of giving half the dose in the morning and half twelve hours later, I sometimes give two thirds in the morning and one third at night.

Dosing of both methadone and buprenorphine can be split for better control of pain. Even though opioid treatment programs’ primary purpose isn’t to treat pain, many patients have both opioid addiction and chronic pain.

The analgesic, or anti-pain, effect of a dose of methadone or buprenorphine lasts for about six to eight hours. That’s why I warn opioid addicted patients with chronic pain that dosing daily may help with pain in the morning hours, but not in the evening or nighttime. I don’t want to mislead them in their expectations for treatment.

If a patient is doing very well in treatment, has no illicit drug use, is making good progress in their recovery, but still has disabling chronic pain, I’ve asked the state and federal authorities for permission to split dose the patient for better pain control. Sometimes it works great, and sometimes it doesn’t help at all.

Before considering split dosing, I have to look at the patient’s overall situation. A patient being considered for split dosing is at an opioid treatment program for a reason: she has lost control over her use of opioids. It may not be realistic for me to expect this patient to be able to appropriately manage a take home dose until/unless this patient has had time to make progress in her recovery. I do want to get the patient on a dosing schedule that helps her feel normal, but I also want her to be safe.

The COWS Score: How Helpful Is It?


COWS stands for Clinical Opioid Withdrawal Scale, and it’s probably the most commonly used tool to determine the degree of opioid withdrawal experienced by the patient. The scale has eleven items related to opioid withdrawal. Some are subjective, like the question about the degree of anxiety or irritability the patient is feeling. Some items are strictly objective, such as pupil size and pulse rate. And some are sort of a combination of objective and subjective, like the question asking about both nausea and vomiting. The patient may report nausea and score points on the scale, and if the patient vomits, this scores more points.

I’ve worked in clinics that used the COWS for each dose increase, and I’ve worked in clinics that didn’t use the COWS at all.

I think it’s a good tool, but has some drawbacks. I use it during dose induction, particularly on a patient new to medication-assisted treatment. Sometimes patients aren’t sure how they’re “supposed” to feel on replacement medication, and a COWS score gives me a better idea of how much withdrawal they are in.

For example, I had a patient who felt much fatigue in the evenings. He’s been on the program about a month, and had been dosing at 70mg for about a week. He worked at a strenuous job, and got off work around 5pm. One day, he told the nurses that he needed an increase, since it felt like his methadone “gave out” as soon as he got home, and he had to take a nap before his evening meal because he was so sleepy. When the nurses heard him say “sleepy,” they correctly became worried he was on too much methadone, and sent him to see me. When I checked him just before dosing the next morning, his pupils were a wide 8 mm and reacted briskly to the bright light I shone in his eyes. He was in withdrawal and he felt better after a few dose increases. His use of the word sleepy was confusing, since to us, we worry “sleepy” means “headed towards a methadone overdose.”

Sometimes, a patient reports severe withdrawal but doesn’t score very high on the COWS. I don’t assume the patient is lying, because some patients don’t tolerate withdrawal symptoms easily. More commonly, I see patients, mostly long-term users, who are in what I would consider to be moderate or severe withdrawal by their COWS score, but they experience it as “not so bad, I’ve felt worse”

In another example, I had a patient on 110mg who reported terrible withdrawal, to the point she couldn’t function during the day. She was restless, anxious, jittery, and felt like her heart was racing. She wasn’t sleeping well. This was puzzling, since a month ago she’d been fine on that same dose. There were no new medications, no change in activities, and she wasn’t drinking alcohol (a common reason for drop in methadone blood level). On the COWS, she scored an 8, but when I looked at the actual COWS, she scored very high on the more subjective items, yet her pupils were pinpoint and her pulse rate in the 60’s

The more we talked, the more I suspected anxiety as the cause of her symptoms. She had a terribly stressful living situation. She was saving money to move out on her own, but felt like she had to endure the circumstances in the short term. In this case, she appeared to be blaming opioid withdrawal for her symptoms of anxiety, and anxiety was a normal response for what she was experiencing. She didn’t need a higher dose of methadone; she needed someone to help her think of better immediate options for safe housing.

I do not think a COWS score is helpful for fine-tuning a patient’s dose of methadone. Many times the COWS score doesn’t pick up subtle withdrawal, so I don’t tend to use it for higher dose changes.

COWS scores are helpful when defending one’s self from regulatory bodies. About five years ago, a state investigator took me to task for authorizing dose increases. “You just believe them when they say they’re in withdrawal?” she asked sarcastically. The investigator didn’t think I should increase the doses of those patients, and yet the studies clearly show methadone patients have better outcomes if they are on an adequate dose. By doing a COWS score, the patient’s signs and symptoms are recorded in the chart for an investigator to see.

In summary, the COWS scale is a useful tool, though probably more useful at lower doses. Like all tools, it’s helpful in some situations, but it’s not perfect. It should be used alongside our other tools, like talking and listening to our patients both before and after dosing, using blood levels in rare cases, and always asking about other medications or new medical problems.

Drug Interactions with Methadone


Recently, medical directors of opioid treatment programs in my state pondered how to handle the risk of medication interactions with methadone. In my area of the country, chart reviews of patients who died while taking methadone revealed many decedents were taking other medications with known interactions with methadone. Obviously, we want to prevent these deaths, and need to protect against drug interactions.

To predict a possible drug interaction, the OTP doctor must know all of the other medications that the patient is taking, both prescription and non-prescription. I assume all doctors at opioid treatment programs ask the patients what medications they are prescribed on the first day, along with what they take over the counter. That’s a good start, but often it’s not sufficient.

On that first day, patients aren’t feeling well. They are in opioid withdrawal and they yearn to feel better. They may forget about some medication or assume it’s not important to mention. They may forget about over-the-counter medications. Sometimes patients deliberately keep silent about medications if they’re worried they won’t be allowed to continue them. Most commonly this happens with benzodiazepines, but doctors can detect prescriptions for these controlled substances, since they are listed on our state’s prescription monitoring program.

Benzodiazepines are the most common drug found in patients who have died while prescribed methadone.

At my opioid treatment programs, we keep lists of our patients’ medications in their charts.
We tell patients to please tell us right away if they are prescribed any medications after they enter our program, so we are alerted to possible drug interactions. Patients are instructed to tell the nurses, since they see nurses most often, and the nurses then tell me. It’s OK for patients to tell counselors, but counselors aren’t medically trained so they must pass the information on the nurses and doctors.

Keeping an up to date list of each patient’s medications is challenging, but do-able with a good system in place. However, the list isn’t worth much unless the doctor is made aware of all prescribed medications, so each opioid treatment program’s system must include a way to provide the doctor with all this information.

At my programs, I sign a form giving my approval (or disapproval) of all medications that are prescribed for the patient, and I write orders if any further action needs to be taken, like asking the patient about any withdrawal symptoms or sedation. But this might happen a few days after the medication is started, so nurses also send me texts with notice of any new medication. This is the best method for me, since I can quickly text back with any orders for enhanced patient monitoring. One program sends emails which I can receive on my smart phone, read immediately, and send my response.

Opioid treatment program physicians need to know which medications can interact with methadone. This list can be long, and varies somewhat depending on the source of information.

Methadone interacts with other drugs in several ways; since it’s metabolized by specific enzymes in the liver, called the cytochrome P450 system, other drugs affect this system can affect the patient’s blood level of methadone. Sometimes other medications can induce, or speed up, methadone’s metabolism, which can drop the patient’s methadone blood level. Other medications inhibit methadone’s metabolism, causing the methadone blood level to rise. In the first situation, a previously stable patient may start to feel withdrawal. In the second situation, the patient may become sedated from methadone and even be at risk for a fatal overdose.

Other medications, mostly sedatives, act on the same centers in the central nervous system as methadone to produce even more sedation. These actions can be synergistic. Synergy between two medications means that the effect of two drugs is greater than you would expect. To put it another way, instead of one plus one equals two, suddenly one plus one equals three or even four. You get more effect than you bargain for.

Then there’s the whole QT interval prolongation that can be caused by methadone. Many other commonly used medications also prolong the QT interval, so that when they are prescribed with methadone, patients are theoretically placed at increased risk of a potentially fatal heart arrhythmia. Relatively common drugs like citalopram (Celexa), erythromycin, and cipro can cause QT interval prolongation.

How can a doctor know about the ways drugs interact with methadone? Most of the main drugs, like sedatives, methadone inducers and inhibitors, we know off the top of our heads, but technology gives us many ways to augment our brain power. Doctors can reference one of the three or four free smart phone apps. These are particularly helpful with the QT interval prolongers, since that list is very long and frequently changing.

Now for the hardest part: what should a doctor to do when a patient gets a medication that can interact with methadone? I’ve scoured the internet, and there are no easy answers. The Addiction Treatment Forum, has published some general guidelines that seem prudent:

As the AT Forum points out, just because an interaction may occur doesn’t mean it will occur. Certainly we should notify the patient of possible drug interactions and ask them to report any sedation or withdrawal while they are taking the new medication so that we can adjust the methadone dose accordingly. If the new medication is only prescribed for a week or two, the patient may not need a dose adjustment.

We may recommend getting an EKG if the new medication is known to prolong the QT interval. It’s nice if that can be done at the opioid treatment program, but OTPs may not be doing regular screening, especially after the Cochrane report of 2013 called routine EKG screening of methadone patients into question. (See my blog post of 9/19/13)

Should an EKG be done? Who should do it? What should we do if the QT interval is prolonged? If the second medication is essential to treat a serious ailment, should the patient’s methadone dose be reduced? Should that patient switch to buprenorphine? Is the risk of partially treated opioid addiction potentially more harmful to the patient than the other serious ailment for which the patient is being treated?

I don’t know the answers and I can’t find anyone else who can give me solid answers about what to do in cases where my patients are prescribed other medications that interact with methadone. For now, I am taking what I feel are prudent precautions, and trying hard not to over-react and pull a patient off methadone, since I know for sure methadone is live-saving. It’s important to remember that just because an interaction is possible doesn’t mean it will happen.

If another doctor prescribes a medication short-term that may interact with methadone, I want the patient to be informed of a possible reaction. I may, with the patient’s permission, call the doctor to ask them if it can be changed to a safer medication, or I may ask the nurses to check with the patient about sedation or withdrawal each day when they come in to dose. Sometimes I’ve asked patients on higher take home levels to come to the OTP more often for closer monitoring until we see the full effects of a new medication, then return them to their usual take home status.

Patients need to tell us when they stop medications, too. I had one patient who was on phenytoin (Dilantin) for the treatment of seizures. Since this medication induces methadone metabolism and drops the serum methadone level, I had increased the patient’s dose of methadone to keep him out of withdrawal. But then, deciding he no longer needed to take phenytoin, he suddenly stopped it and became sedated. Thankfully he reported his sedation to the nurses and we quickly figured out what had happened. His dose had to be lowered quite a bit to prevent overdose, since off phenytoin, his blood level of methadone apparently rose abruptly.

At one of the OTPs where I work, I can easily get an EKG to monitor the QT interval. At the other, I have to ask the other doctor to check and EKG. Particularly with psychiatric medications, this creates difficulties, since psychiatrists usually don’t do EKGs in their offices. The patient has to be referred to a third facility if I feel an EKG is essential. This can become expensive to a patient without insurance, so it’s better if the doctor prescribes a medication that doesn’t affect the QT interval, if possible.

As time goes on, I think we’ll get more information about medication interactions with methadone, and I’d like to see more specific guidelines about how to handle potential