Posted July 6, 2014 by janaburson in Methadone dosing. Tagged: split dosing of buprenorphine, split dosing of methadone. 36 Comments

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.