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,

Smoked Heroin Leads to Early Lung Disease

 

 

 

 

 

 

 

 

Heroin can be injected, snorted, or smoked. Researchers in England, noting an apparent increase in lung disease in people who smoke heroin, did a study that was just released late last year.

Walker et al, from Liverpool, England, studied 73 heroin smokers who had developed chronic obstructive pulmonary disease (COPD) symptoms before age 40. Researchers did pulmonary testing on these subjects and found significant abnormalities on pulmonary function tests, high-resolution CT scans, and oxygen diffusion capacity. (This last test shows how easily oxygen crosses from the lungs to the blood stream.)

These findings, building on other preliminary similar studies, shows that smoking heroin is associated with very early onset of COPD/emphysema.

Other studies have shown an associating between asthma attacks and smoked drugs, both with heroin and crack cocaine, but this study showed specific types are areas of lung changes which presumably are irreversible, in these very young patients. With cigarette smoking alone, significant COPD is rare before age 40, but all of these patients were younger than 40. Still, cigarette smoking could contribute to the severity of COPD.

Experts discussed the mechanism of lung damage in these heroin smokers. They postulated that heroin smokers tend to take deep breaths and hold the smoke in as long as possible, causing increased pressure in the thorax, which could cause or contribute to the lung damage.

Heroin smokers often put heroin on foil, then apply a heat source beneath and inhale the smoke. This is sometimes called “chasing the dragon.” Perhaps there’s something in the foil that when heated and inhaled, can cause lung disease. If that’s the case, then people who smoke pain pills could also be at risk for COPD from this practice.

Some experts point out that heroin burns at a much higher temperature than tobacco, and wonder if the higher temperature of the smoke causes this type of early lung damage.
For now we don’t know precisely why heroin smokers get early and probably irreversible lung damage, but physicians should be alert to this as a potential cause of early COPD, particularly in patients under age 40.

And here’s another good reason to stop using and get into recovery…

Insomnia Medications for Patients in Medication-Assisted Treatment

In one of my recent blog entries, I talked about some simple measures that can help patients with insomnia, called sleep hygiene. Many times these methods can fix the problem, but other times, patients still can’t sleep well, which interferes with life. In these cases, medications may be of some help.

The “Z” medications
The “Z” group of medications includes zolpidem (Ambien), zaleplon (Sonata), and eszopiclone (Lunesta). These medications, which are not benzodiazepines, have been touted as being safer and less addictive than older benzodiazepines, like temazepam (Restoril), triazolam (Halcion) or clonazepam (Klonopin). However, the “Z” medications stimulate the same brain receptors as benzodiazepines, and are all Schedule IV controlled substances, just like benzodiazepines. This means they all have roughly the same potential to cause addiction, despite enthusiastic marketing by some drug companies.

I don’t prescribe the “Z” medications for patients on medication-assisted treatment with methadone or buprenorphine because they can cause overdose deaths in these patients. Also, these medications can give many patients with the disease of addiction the same impulse to misuse their medication. I’ve had patients develop problems with misuse and overuse of these medicines.

Trazadone
Many doctors, including me, have prescribed trazadone to help patients get and stay asleep. It’s an antidepressant, but daytime use has been limited due to drowsiness. In an effort to use this side effect for benefit, it’s often prescribed at bedtime to treat insomnia. But a recent study called this practice into question. In this study, trazadone was not found to be effective for methadone maintenance patients with insomnia. Test subjects were monitored with sleep study apparatus, and these subjects had no subjective or objective benefit from trazadone, either in initiating or staying asleep. [1]

Because trazadone can affect the QT interval, just like methadone, it’s possible these two drugs used together will dangerously prolong the QT interval. Also, both can cause sedation, also a concern. In view of this data, I have stopped recommending or prescribing it as an insomnia medication.

Quetiapine (Seroquel)
Quetiapine is in the group of medications known as atypical antipsychotics, and is indicated for the treatment of schizophrenia, the mania of bipolar disorder, and treatment-resistant depression. Because it is a sedating medication, many doctors prescribe it for treatment of insomnia, usually at low doses, around 25 to 100mg at bedtime.

Does it work? Two small studies, designed to see if the drug can help insomnia, showed conflicting results. One study showed significant improvement and the other showed no significant improvement.

Furthermore, this medication is not without side effects. At higher doses, used to treat bipolar disorder and schizophrenia, patients can develop diabetes and hyperlipidemia. But even at low doses, we see weight gain, restless legs, dizziness which can lead to night time falls, and dry mouth. There’s a risk, though likely small, of tardive dyskinesia with this drug. This is a serious movement disorder more commonly seen with the older antipsychotics like thorazine; patients on the atypical antipsychotics can also develop this potentially devastating disorder.

With little evidence to support its use, and potential serious side effects, I no longer initiate a prescription for quetiapine in a patient with insomnia. I do have some patients who’ve been started on this medication before they started seeing me. If they still feel it’s effective and I see no side effects, I’ll continue the medication. I make sure they get yearly lipid profiles done and recommend yearly screens for diabetes, and monitor for weight gain.

At addiction medicine conferences, I’ve heard doctors say that some of their patients misuse quetiapine. Personally, I think that must be unusual, and maybe these are patients in an experimental phase of addiction. I don’t see seasoned addicts using this medication to get high.

Ramelteon (Rozerem)
This medication, approved by the FDA for treatment of insomnia in 2005, isn’t addictive. It works by stimulating melatonin receptors and it helps patients get to sleep somewhat more effectively than placebo, but doesn’t help keep them asleep. Ramelteon doesn’t cause the rebound insomnia commonly seen after use of the “Z” medications, and has few clinically significant drug interactions. Last time I checked, it’s more expensive than many sleep medications, and many insurance companies demand a prior authorization before they’ll pay for it. I’ve had a few patients do well with this medication, so I like to prescribe it.

Melatonin
Once hoped to be the miracle treatment for insomnia, studies show that at best, melatonin is mildly more effective than placebo for the treatment of insomnia. Melatonin isn’t a prescription medication, and is sold by many manufacturers with little quality control. Since it is categorized as a dietary supplement, the FDA does not examine or approve these products. Since 2010, the FDA only requires that dietary supplements be made according to “good manufacturing practices,” and that companies make a consistent product, free of contamination, with accurate labeling. As I see it, that’s not much oversight and people take their chances with dietary supplements of any kind.

Diphenhydramine
More commonly known as Benadryl, many over-the-counter sleep medications contain this sedating anti-histamine. It can cause sedation in patients taking methadone, and should be avoided or used with caution. I’ve seen one methadone overdose death I believed was due to the interaction with methadone and diphenhydramine, though the patient had taken more than one 50mg diphenhydramine pill.

Otherwise, the medication is mildly to moderately effect at helping people get to sleep. Don’t take more than 50mg, because higher doses can have a reverse effect, and interfere with sleep.

Hydroxyzine (Vistaril) is another potentially sedating anti-histamine that is felt by some doctors to be safer than diphenhydramine, but I can’t find any data to support that view.

Other medications
Clonidine
I occasionally prescribe clonidine if I think my patient is having a degree of opioid withdrawal as the cause of insomnia. I’m talking about patients who wish to taper, not patients on maintenance. If a patient on maintenance has insomnia from withdrawal, it’s best to increase the dose of the maintenance medication.

Clonidine can help insomnia from withdrawal. Because this is a blood pressure medication, it can drop night-time blood pressure when taken for sleep. This can cause a patient to fall if they get up during the night. I caution patients that if they must get up at night, stand beside their bed for a few minutes to make sure they don’t feel dizzy. I usually prescribe a .1mg pill and have them take only one pill.

Gabapentin (Neurontin)
This anti-seizure medication is used for a little bit of everything, so why not insomnia? Officially, gabapentin is approved by the FDA for treating seizures and for the pain of post-herpetic neuralgia (that’s the pain that stays after a shingles outbreak). But doctors use gabapentin for fibromyalgia, insomnia, migraine headaches, bipolar disorder, and probably other conditions. According to Medscape’s drug interaction checker, gabapentin has no interaction with methadone or buprenorphine, but Epocrates’ drug interaction checker says use with caution with these medications due to possible daytime sedation.

Muscle relaxers
Some patients take these medications at bedtime for their sedating effect, but I don’t think there’s any evidence these medications are particularly effective.

Placebo
I include placebo as a reminder that about thirty percent of people will get benefit from a pill containing no medication. Our minds are powerful. (Parenthetically, I’m highly susceptible to suggestion. As a young adult, I got “drunk” on cider that I was told contained alcohol. I felt intoxicated, to the point of losing my balance and getting dizzy. But my friend had played a trick and there was no alcohol in this cider.) It’s difficult to know if a pill or potion for sleep works because it’s effective, or if it works because of the placebo effect. If you’ve found a medication that works, keep taking it, so long as it’s not doing any harm.

A recent study showed that adults who use sleeping pills are more than three times more likely to die prematurely compared to matched controls who didn’t use sleeping pills. This relatively large study looked at the medical records of over 10,000 patients who were prescribed hypnotics for sleep, and compared their outcomes to over 23,000 matched control patients, similar except the controls weren’t taking sleeping pills. The sleeping pills, also called “hypnotics” were associated with significant increases in mortality and significant increases in cancer incidence. [2]
The patients’ average age was 54, and they were followed for an average of 2.5 years. All were members of a large U.S. healthcare system in Pennsylvania. The data from the two groups were adjusted for age, gender, smoking status, prior cancer diagnoses, body mass index, ethnicity, and alcohol use.

Patients in the group taking prescribed hypnotics most frequently, defined as more than 132 doses per year, had over five times increased risk of dying than patients not taking hypnotics. Even the group of patients taking hypnotics relatively infrequently (up to 18 doses per year) had a three times higher risk of death. These differences were statistically significant. The medications in the study included all of the “Z” medications, as well as temazepam (Restoril), barbiturates, and the sedating antihistamines, such as diphenhydramine (Benadryl).

The author of this study estimated that hypnotic medications are associated with 320,000 to 507,000 deaths in the U.S. over the year 2010.
This study raises some important questions, since hypnotic drugs are the most commonly prescribed drugs in the U.S., with an estimated 6 to 10% of the population being prescribed these medications.

Sleep medicine doctors say that correlation doesn’t mean causation, and we shouldn’t jump to conclusions. One sleep specialist pointed out that the study didn’t control for psychiatric illness, which could be a significant factor. Additionally, patients who are prescribed sleeping medications may be sicker overall, in ways the study didn’t control, and therefore a generally less healthy group. This could distort study findings.

Other scientists say that sleeping pills could make sleep apnea worse, and cause deaths in that way. Obesity increases the risk of sleep apnea, and with more adults becoming obese, perhaps sleeping pills make apnea worse and these people die in their sleep. Other scientists say sleeping pills slow reflexes, and perhaps patients taking these medications are more likely to be involved in car accidents and other accidents, increasing their death rates.

As for my patients, many of whom are prescribed methadone or buprenorphine, the risk of drug interaction and overdose with the hypnotics usually outweighs all of the benefits, and I recommend that patients do not mix these two types of medications.

As a final bit of advice, I want to remind readers that other physical and mental health conditions can cause insomnia. It’s a good idea to see a primary care doctor to screen for these conditions, which can include sleep apnea, asthma, gastroesophagel reflux, hyperthyroidism, bipolar disorder, depression, and anxiety disorders. Sometimes patients need sleep studies to assess for sleep disorders.

1. Stein et al, “Trazadone for sleep disturbance during methadone maintenance: a double-blind, placebo-controlled trial,” Drug and Alcohol Depend., 2012, Jan 1;120(1-3):65-73
2. BMJ Open 2012;2:e000850 doi:10.1136/bmjopen-2012-000850

Insomnia Medications for Patients in Medication-Assisted Treatment

In one of my recent blog entries, I talked about some simple measures that can help patients with insomnia, called sleep hygiene. Many times these methods can fix the problem, but other times, patients still can’t sleep well, which interferes with life. In these cases, medications may be of some help.

The “Z” medications
The “Z” group of medications includes zolpidem (Ambien), zaleplon (Sonata), and eszopiclone (Lunesta). These medications, which are not benzodiazepines, have been touted as being safer and less addictive than older benzodiazepines, like temazepam (Restoril), triazolam (Halcion) or clonazepam (Klonopin). However, the “Z” medications stimulate the same brain receptors as benzodiazepines, and are all Schedule IV controlled substances, just like benzodiazepines. This means they all have roughly the same potential to cause addiction, despite enthusiastic marketing by some drug companies.

I don’t prescribe the “Z” medications for patients on medication-assisted treatment with methadone or buprenorphine because they can cause overdose deaths in these patients. Also, these medications can give many patients with the disease of addiction the same impulse to misuse their medication. I’ve had patients develop problems with misuse and overuse of these medicines.

Trazadone
Many doctors, including me, have prescribed trazadone to help patients get and stay asleep. It’s an antidepressant, but daytime use has been limited due to drowsiness. In an effort to use this side effect for benefit, it’s often prescribed at bedtime to treat insomnia. But a recent study called this practice into question. In this study, trazadone was not found to be effective for methadone maintenance patients with insomnia. Test subjects were monitored with sleep study apparatus, and these subjects had no subjective or objective benefit from trazadone, either in initiating or staying asleep. [1]

Because trazadone can affect the QT interval, just like methadone, it’s possible these two drugs used together will dangerously prolong the QT interval. Also, both can cause sedation, also a concern. In view of this data, I have stopped recommending or prescribing it as an insomnia medication.

Quetiapine (Seroquel)
Quetiapine is in the group of medications known as atypical antipsychotics, and is indicated for the treatment of schizophrenia, the mania of bipolar disorder, and treatment-resistant depression. Because it is a sedating medication, many doctors prescribe it for treatment of insomnia, usually at low doses, around 25 to 100mg at bedtime.

Does it work? Two small studies, designed to see if the drug can help insomnia, showed conflicting results. One study showed significant improvement and the other showed no significant improvement.

Furthermore, this medication is not without side effects. At higher doses, used to treat bipolar disorder and schizophrenia, patients can develop diabetes and hyperlipidemia. But even at low doses, we see weight gain, restless legs, dizziness which can lead to night time falls, and dry mouth. There’s a risk, though likely small, of tardive dyskinesia with this drug. This is a serious movement disorder more commonly seen with the older antipsychotics like thorazine; patients on the atypical antipsychotics can also develop this potentially devastating disorder.

With little evidence to support its use, and potential serious side effects, I no longer initiate a prescription for quetiapine in a patient with insomnia. I do have some patients who’ve been started on this medication before they started seeing me. If they still feel it’s effective and I see no side effects, I’ll continue the medication. I make sure they get yearly lipid profiles done and recommend yearly screens for diabetes, and monitor for weight gain.

At addiction medicine conferences, I’ve heard doctors say that some of their patients misuse quetiapine. Personally, I think that must be unusual, and maybe these are patients in an experimental phase of addiction. I don’t see seasoned addicts using this medication to get high.

Ramelteon (Rozerem)
This medication, approved by the FDA for treatment of insomnia in 2005, isn’t addictive. It works by stimulating melatonin receptors and it helps patients get to sleep somewhat more effectively than placebo, but doesn’t help keep them asleep. Ramelteon doesn’t cause the rebound insomnia commonly seen after use of the “Z” medications, and has few clinically significant drug interactions. Last time I checked, it’s more expensive than many sleep medications, and many insurance companies demand a prior authorization before they’ll pay for it. I’ve had a few patients do well with this medication, so I like to prescribe it.

Melatonin
Once hoped to be the miracle treatment for insomnia, studies show that at best, melatonin is mildly more effective than placebo for the treatment of insomnia. Melatonin isn’t a prescription medication, and is sold by many manufacturers with little quality control. Since it is categorized as a dietary supplement, the FDA does not examine or approve these products. Since 2010, the FDA only requires that dietary supplements be made according to “good manufacturing practices,” and that companies make a consistent product, free of contamination, with accurate labeling. As I see it, that’s not much oversight and people take their chances with dietary supplements of any kind.

Diphenhydramine
More commonly known as Benadryl, many over-the-counter sleep medications contain this sedating anti-histamine. It can cause sedation in patients taking methadone, and should be avoided or used with caution. I’ve seen one methadone overdose death I believed was due to the interaction with methadone and diphenhydramine, though the patient had taken more than one 50mg diphenhydramine pill.

Otherwise, the medication is mildly to moderately effect at helping people get to sleep. Don’t take more than 50mg, because higher doses can have a reverse effect, and interfere with sleep.

Hydroxyzine (Vistaril) is another potentially sedating anti-histamine that is felt by some doctors to be safer than diphenhydramine, but I can’t find any data to support that view.

Other medications
Clonidine
I occasionally prescribe clonidine if I think my patient is having a degree of opioid withdrawal as the cause of insomnia. I’m talking about patients who wish to taper, not patients on maintenance. If a patient on maintenance has insomnia from withdrawal, it’s best to increase the dose of the maintenance medication.

Clonidine can help insomnia from withdrawal. Because this is a blood pressure medication, it can drop night-time blood pressure when taken for sleep. This can cause a patient to fall if they get up during the night. I caution patients that if they must get up at night, stand beside their bed for a few minutes to make sure they don’t feel dizzy. I usually prescribe a .1mg pill and have them take only one pill.

Gabapentin (Neurontin)
This anti-seizure medication is used for a little bit of everything, so why not insomnia? Officially, gabapentin is approved by the FDA for treating seizures and for the pain of post-herpetic neuralgia (that’s the pain that stays after a shingles outbreak). But doctors use gabapentin for fibromyalgia, insomnia, migraine headaches, bipolar disorder, and probably other conditions. According to Medscape’s drug interaction checker, gabapentin has no interaction with methadone or buprenorphine, but Epocrates’ drug interaction checker says use with caution with these medications due to possible daytime sedation.

Muscle relaxers
Some patients take these medications at bedtime for their sedating effect, but I don’t think there’s any evidence these medications are particularly effective.

Placebo
I include placebo as a reminder that about thirty percent of people will get benefit from a pill containing no medication. Our minds are powerful. (Parenthetically, I’m highly susceptible to suggestion. As a young adult, I got “drunk” on cider that I was told contained alcohol. I felt intoxicated, to the point of losing my balance and getting dizzy. But my friend had played a trick and there was no alcohol in this cider.) It’s difficult to know if a pill or potion for sleep works because it’s effective, or if it works because of the placebo effect. If you’ve found a medication that works, keep taking it, so long as it’s not doing any harm.

A recent study showed that adults who use sleeping pills are more than three times more likely to die prematurely compared to matched controls who didn’t use sleeping pills.

This relatively large study looked at the medical records of over 10,000 patients who were prescribed hypnotics for sleep, and compared their outcomes to over 23,000 matched control patients, similar except the controls weren’t taking sleeping pills. The sleeping pills, also called “hypnotics” were associated with significant increases in mortality and significant increases in cancer incidence. [2]

The patients’ average age was 54, and they were followed for an average of 2.5 years. All were members of a large U.S. healthcare system in Pennsylvania. The data from the two groups were adjusted for age, gender, smoking status, prior cancer diagnoses, body mass index, ethnicity, and alcohol use.

Patients in the group taking prescribed hypnotics most frequently, defined as more than 132 doses per year, had over five times increased risk of dying than patients not taking hypnotics. Even the group of patients taking hypnotics relatively infrequently (up to 18 doses per year) had a three times higher risk of death. These differences were statistically significant. The medications in the study included all of the “Z” medications, as well as temazepam (Restoril), barbiturates, and the sedating antihistamines, such as diphenhydramine (Benadryl).

The author of this study estimated that hypnotic medications are associated with 320,000 to 507,000 deaths in the U.S. over the year 2010.

This study raises some important questions, since hypnotic drugs are the most commonly prescribed drugs in the U.S., with an estimated 6 to 10% of the population being prescribed these medications.
Sleep medicine doctors say that correlation doesn’t mean causation, and we shouldn’t jump to conclusions. One sleep specialist pointed out that the study didn’t control for psychiatric illness, which could be a significant factor. Additionally, patients who are prescribed sleeping medications may be sicker overall, in ways the study didn’t control, and therefore a generally less healthy group. This could distort study findings.

Other scientists say that sleeping pills could make sleep apnea worse, and cause deaths in that way. Obesity increases the risk of sleep apnea, and with more adults becoming obese, perhaps sleeping pills make apnea worse and these people die in their sleep. Other scientists say sleeping pills slow reflexes, and perhaps patients taking these medications are more likely to be involved in car accidents and other accidents, increasing their death rates.

As for my patients, many of whom are prescribed methadone or buprenorphine, the risk of drug interaction and overdose with the hypnotics usually outweighs all of the benefits, and I recommend that patients do not mix these two types of medications.

As a final bit of advice, I want to remind readers that other physical and mental health conditions can cause insomnia. It’s a good idea to see a primary care doctor to screen for these conditions, which can include sleep apnea, asthma, gastroesophagel reflux, hyperthyroidism, bipolar disorder, depression, and anxiety disorders. Sometimes patients need sleep studies to assess for sleep disorders.

1. Stein et al, “Trazadone for sleep disturbance during methadone maintenance: a double-blind, placebo-controlled trial,” Drug and Alcohol Depend., 2012, Jan 1;120(1-3):65-73
2. BMJ Open 2012;2:e000850 doi:10.1136/bmjopen-2012-000850

Prostate Specific Antigen and Opioid Use

I’ve posted before about the effects of opioids on PSA levels, used to screen for prostate cancer. Here’s a reminder. This is from a study by Safarinejad et al, in the Journal of Addiction Medicine, Vol 7(1) pages 58-65.

PSA is an enzyme normally found in low levels in the blood of men with healthy prostates. It’s elevated in a variety of prostate diseases. Notably, it’s elevated in men with prostate cancer, but it can also be elevated from other ailments that cause inflammation of the prostate.

Routine screening of men through checking the PSA levels is controversial, because some experts say it leads to unnecessary prostate biopsies. They also say screening doesn’t reduce deaths from prostate cancer. However, many men specifically ask for PSA screening, and many doctors still check the PSA levels as part of a routine physical. PSA levels can be followed after a patient has been treated for prostate cancer, and elevated levels can mean a recurrence of the cancer.
In this study of Iranian men, male opioid addicts had 28% lower PSA levels than subjects that didn’t use opioids.

We already know that opioid use is associated with lower serum testosterone levels, so the authors of the study postulated that lower testosterone levels lead to lower PSA levels, but this was not the case, at least in this group of men. There was no correlation between serum testosterone levels and PSA levels in this study, so it did not appear that testosterone levels caused the lowered PSA levels.

Since prostate biopsies are performed on men with elevated PSAs the study authors were concerned that in opioid addicts, their lower PSA levels will fall below the threshold for biopsy. This could mean cancers could be missed in opioid users that might be detected in non-opioid users. Therefore, prostate cancers may not be detected in opioid addicts until the cancer is more advanced.

Indeed, in this study, more the men on opioids who were diagnosed with prostate cancer during the study period had higher grade prostate cancer than the men not on opioids who were diagnosed with prostate cancer during the study period.

This study suggests that for men on long-term opioids, PSA cut-offs should be lowered when deciding if the patient needs an evaluation for possible prostate cancer.

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: http://www.atforum.com/pdf/Drug_Interactions.pdf

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

News From the World of Addiction Medicine Research

The latest issue of the Journal of Addiction Medicine, Vol. 7 (2) March/April 2013 had several interesting articles relating to opioid addiction and its treatment. Here’s my quick summary and thoughts on one of them, “Promethazine Misuse among Methadone Maintenance Patients and Community-Based Injection Drug Users,” by Brad Shapiro et al, pp. 96-1001.

This study attempted to get an idea of the prevalence of promethazine (better known under its brand name Phenergan) use in opioid addicts both in and out of treatment.

I was interested in this article because I’ve had methadone patients misuse promethazine. Most of these patients say that Phenergan gives them sedation with methadone, but most say it’s not a true euphoria, so I’m puzzled as to why they mix the two. Since promethazine can be sedating in many people, obviously I worry about overdose deaths when it’s mixed with methadone.

The authors of this study tested for promethazine in the patients enrolled in a county hospital methadone clinic in San Francisco. Twenty-six percent were positive for promethazine and only 15% had a prescription for this medication. Also, promethazine use was associated with benzodiazepine use.

The authors then recruited two hundred intravenous drug users, and discovered that only 139 were opioid addicts. Of those 139 addicts, seventeen percent reported promethazine use in the past month. However, of the addicts who had been on methadone in the past, twenty-four percent reported promethazine use in the past month.

What does this study tell us? The authors’ conclusion was that promethazine needs to be investigated further as a drug of abuse in opioid addicts.

Well, yeah.

My clinical experience gave me some thoughts about the study. For one thing, pregnant addicts were excluded. But in my experience, pregnant patients are the ones most likely to be prescribed Phenergan because of morning sickness during pregnancy. And this study doesn’t tell us much about the overdose risk when methadone and Phenergan are combined. Early in their article, they do provide some data: In Kentucky, over 14% of decedents from methadone toxicity overdose deaths also had promethazine present in their system. In Seattle, 2.5% of fatal overdoses had promethazine present.

Promethazine, along with many other medications, prolongs the QT interval just like methadone does. I haven’t seen any studies of methadone patients comparing QT intervals before and after promethazine, which may be helpful to further assess risk.

Hepatitis C: What’s New?

A fair number of my patients screen positive for the Hepatitis C virus. Obviously, they want to know what a positive screening test means, and what they should do next. Since a positive screen doesn’t necessarily mean an infection with Hep C, I’d like to explain more about this test, about the virus, and what’s new in the treatment of Hep C.

Hepatitis C is a virus that mainly affects the liver, as its name implies. There are other viruses that affect the liver, creatively named Hepatitis A, Hepatitis B, and so on. But Hepatitis C is the biggie, with an estimated 3.4 million people in the U.S. with the infection. In fact, it’s the most common chronic blood-borne viral infection in the U.S.  Around the world, 180 million people are estimated to be infected with Hep C.

Anyone with a history of intravenous drug use should be screened for hepatitis C. In the U.S., this is the most common way of contracting the virus. Even if you didn’t share needles, if you shared cookers, water, spoons or other material, you may have contracted the virus. Even people who shared straws to snort drugs appear to be at risk, and should be tested.

It’s a blood-borne illness, so it can also be transmitted through tattoos with unclean needles, re-used medical supplies, and blood transfusion with tainted blood. However, risks of infection through transfusion in the U.S. are very low since testing for the virus became available in 1992.

Most people who have hepatitis C got it from another person’s blood, but it can be transmitted through sex. In monogamous couples with one infected partner, the virus is transmitted to the uninfected partner in only about 1 – 5% of cases. However, multiple sexual partners and high risk sexual activities result in higher transmission rates. You can’t transmit Hep C by hugging, kissing, sharing eating utensils or ordinary household contact, though a person with Hep C shouldn’t share razors or toothbrushes.

In May of this year, the Centers for Disease Control and Prevention recommended one-time testing for Hepatitis C in all baby boomers, meaning people born between 1945 and 1965. About one in thirty baby boomers have hepatitis C, according to the CDC. Because newer treatments can cure chronic Hep C infection, the CDC hopes to save an estimated 120,000 lives by uncovering infections in people who don’t know they’re infected.

The screening test for Hep C is relatively inexpensive, and screens only for antibodies to the Hepatitis C virus. If you screen positive with this test, it means you have been exposed to the Hep C virus. It does not tell us if you have chronic Hepatitis C infection. Up to 20% of people who contract Hepatitis C infections are able to clear the virus on their own, and will not have chronic infection. However, they will remain positive on this screening test, because they will carry antibodies against the virus for the rest of their lives. Patients diagnosed, treated, and cured of Hep C infection will also remain positive for Hep C on this antibody screening test, so it’s not helpful to screen these patients again. In fact, it may be confusing if the provider doesn’t understand what this antibody test means, and explain it adequately to patients.

There are six specific types, called genotypes, of Hepatitis C. Even if you clear the infection to one genotype, you can be re-infected with another genotype of hepatitis C. If you have active Hep C and continue to share needles, it’s possible to become infected with more than one subtype.

There’s no vaccine available for Hep C like there is for Hep A and B. Much like HIV, the Hep C virus undergoes frequent changes, so it’s like making a vaccine against a moving target.

If you test positive on screening for Hep C, you need to have further testing to see if you have Hepatitis C infection. The next step is a qualitative test for hepatitis C. At around $100 at the cheapest, it’s difficult for patients without insurance to afford the proper testing.  If this qualitative test is positive, you should then see a specialist to see if you need a liver biopsy. Most specialists base the decision to treat on a liver biopsy. There are other tests, but biopsy is still the gold standard.

If treatment is contemplated, it will be necessary to have genotype testing, to find out what specific type of Hep C you have. Treatments are different for different subtypes. Two new medications are used in the treatment of type 1, the most frequent type in the U.S., and give cure rates up to 75%. On the other hand, genotypes 2 and 3 are more easily treated and don’t require treatment to be as long as type 1. Quantitative Hep C testing, called viral counts, isn’t needed unless treatment is going to be done, when it is used to follow the response to treatment. Outside of that, the viral count provides little information.

Liver function tests, called LFT’s, are relatively cheap, and are often done at the same time as the first Hep C screening test. If they are elevated, it usually means there’s inflammation in the liver. Many things can cause an increase in LFTs. Alcohol is the most common cause, but all viral hepatitis infections can cause elevations too. However, it’s possible to have normal LFT’s and still have active Hepatitis C. We can’t assume you don’t have Hep C infection even if your LFT’s are normal.

If you have Hepatitis C, you should NEVER drink alcohol. Even patients infected with Hep C but with no problems on liver biopsy will go downhill fast if they drink alcohol. The dangers of alcohol in patients with Hep C cannot be overstated. Don’t. Drink. Ever. Not even a cold beer after mowing the lawn.

In my next blog post, I’ll talk about the exciting new treatment developments.

Doctors Are Poorly Trained About Addiction and Recovery

Addiction? What addiction?

Most medical schools and residency programs place little emphasis on educating future physicians about addiction. A survey conducted by the Center on Addiction and Substance Abuse at Columbia University (CASA) revealed that physicians are poorly trained to recognize and treat addictive disorders. (1)

CASA surveyed nine-hundred and seventy-nine U.S. physicians, from all age groups, practice settings, and specialties. Only nineteen percent of these physicians said they had been trained in medical school to identify diversion of prescribed drugs. Diversion means that the drug was not taken by the patient for whom it was prescribed. Almost forty percent had been trained to identify prescription drug abuse or addiction, but of those, most received only a few hours of training during four years of medical school. More shocking, only fifty-five percent of the surveyed doctors said they were taught how to prescribe controlled drugs. Of those, most had less than a few hours of training. This survey indicates that medical schools need to critically evaluate their teaching priorities.  

Distressingly, my own experience mirrors this study’s findings. My medical school, Ohio State University, did a better job than most. We had a classroom section about alcoholism, and were asked to go to an Alcoholics Anonymous meeting, to become familiar with how meetings work. But I don’t remember any instruction about how to prescribe controlled substances or how to identify drug diversion.

Is it possible that I’ve forgotten I had such a course? Well, yes. But if I can still remember the tediously boring Krebs cycle, then surely I would have remembered something juicier and more practical, like how to prescribe potentially addicting drugs. Similarly, less than half of the surveyed doctors recalled any training in medical school in the management of pain, and of those that did, most had less than a few hours of training.

Residency training programs did a little better. Of the surveyed doctors, thirty-nine percent received training on how to identify drug diversion, and sixty-one percent received training on identifying prescription drug addiction. Seventy percent of the doctors surveyed said they received instruction on how to prescribe controlled substances. (1)

This last finding is appalling, because it means that thirty percent of doctors received no training on how to prescribe controlled substances in their residency programs.  Could it be true that nearly a third of the doctors leaving residency – last stop for most doctors before being loosed upon the populace to practice medicine with little to no oversight – had no training on how to prescribe these potentially dangerous drugs? Sixty-two percent leaving residency had training on pain management. This means the remaining thirty-eight percent had no training on the treatment of pain.

Could it be that many of these physicians were in residencies or specialties that had no need to prescribe such drugs? No. The participating doctors were in family practice, internal medicine, OB/GYN, psychiatry, and orthopedic surgery. The study included physicians of all ages (fifty-three percent were under age fifty), all races (though a majority at seventy-five percent were white, three other races were represented), and all types of locations (thirty-seven percent urban, thirty percent suburban, with the remainder small towns or rural areas). This study reveals a hard truth: medical training programs in the U.S. are doing a poor job of teaching future doctors about two diseases that causes much disability and suffering: pain and addiction. (1)

 I remember how poorly we treated patients addicted to prescription medications when I was in my Internal Medicine residency program. By the time we identified a person as addicted to opioids or benzodiazepines, their disease was fairly well established. It didn’t take a genius to detect addiction. They were the patients with thick charts, in the emergency room frequently, loudly proclaiming their pain and demanding to be medicated. Overall, the residents were angry and disgusted with such people, and treated them with thinly veiled contempt. We regarded them more as criminals than patients. We mimicked the attitudes of our attending physicians. Sadly, I did no better than the rest of my group, and often made jokes at the expense of patients who were suffering in a way and to a degree I was unable to perceive. I had a tightly closed mind and made assumptions that these were bad people, wasting my time.

Heroin addicts were not well treated. I recall a discussion with our attending physician concerning an intravenous heroin user, re-admitted to the hospital. Six months earlier, he was hospitalized for treatment of endocarditis (infected heart valve). Ultimately his aortic heart valve was removed and replaced with a mechanical valve. He recovered and left the hospital, but returned several months later, with an infected mechanical valve, because he had continued to inject heroin. We discussed the ethics of refusing to replace the valve a second time, because we felt it was futile.

I didn’t know any better at the time. We could have started him on methadone in the hospital, stabilized his cravings, and then referred him to the methadone clinic when he left the hospital. Instead, I think we had a social worker ask him if he wanted to go away somewhere for treatment, he said no, and that was the end of that. Small wonder he continued to use heroin.

At a minimum, the attending physician should have known that addiction is a disease, not a moral failing, and that it is treatable. The attending physician should have known how to treat heroin addiction, and how to convey this information to the residents he taught. Instead, we were debating whether to treat a man whose care we had mismanaged. Fortunately, he did get a second heart valve and was able to leave the hospital. I have no further knowledge of his outcome.

 Despite having relatively little training in indentifying and treating prescription pill addiction, physicians tend to be overly confident in their abilities to detect such addictions. CASA found that eighty percent of the surveyed physicians felt they were qualified to identify both drug abuse and addiction. However, in a 1998 CASA study, Under the Rug: Substance Abuse and the Mature Woman, physicians were given a case history of a 68 year old woman, with symptoms of prescription drug addiction. Only one percent of the surveyed physicians presented substance abuse as a possible diagnosis.  In a similar study, when presented with a case history suggestive of an addictive disorder, only six percent of primary care physicians listed substance abuse as a possible diagnosis. (2)

Besides being poorly educated about treatments for patients with addiction, most doctors aren’t comfortable having frank discussions about a patient’s drug misuse or addiction. Most physicians fear they will provoke anger or shame in their patients. Physicians may feel disgust with addicted patients and find them unpleasant, demanding, or even frightening. Conversely, doctors can feel too embarrassed to ask seemingly “nice” people about addiction. In a CASA study titled, Missed Opportunity, forty-seven percent of physicians in primary care said it was difficult to discuss prescription drug addiction and abuse with their patients, for whom they had prescribed such drugs. (2).

From this data, it’s clear physicians are poorly educated about the disease of addiction at the level of medical school and residency. Even when they do diagnose addiction, are they aware of the treatment facilities in their area? Patients should be referred to treatment centers who can manage their addictions. If patients are addicted to opioids, medications like methadone and buprenorphine can be a tremendous help.

1. Missed Opportunity: A National Survey of Primary Care Physicians and Patients on Substance Abuse, Center on Addiction and Substance Abuse at Columbia University, April 2000. Also available online at http://www.casacolumbia.org

2. Under the Rug: Substance Abuse and the Mature Woman, Center on Addiction and

Substance Abuse at Columbia University, 1998. Available online at http://www.casacolumbia.org

Side Effects of Methadone and Suboxone: Constipation

When I ask my patients about side effects of methadone and buprenorphine (active ingredient in Suboxone and Subutex), the most common one they report is constipation. Nearly all people on any opioids have constipation. This is because the bowels contain opioid receptors, and when they are stimulated with opioids, the bowels relax and don’t contract as much.

So what can be done?

Of course, drinking more fluids will help. Then, try adding more fiber to your diet. Either eat more fresh fruits and vegetables, or get some of the fiber-containing agents. Some brand names include FiberCon, Metamucil, and Citrucel.

If that doesn’t get things moving, try adding a stool softener. If no results after all of these, consider trying the Miralax powder. Some people need to take it on a regular basis to keep their bowels moving. Some patients use a teaspoon of mineral oil every morning to keep them moving.

It’s a good idea to see a primary care or gastrointestinal doctor at least once, to rule out causes other than medication. If you have blood in your stool, weight loss, or a family history of colon cancer, we don’t want to ignore the possibility that something more serious could be causing bowel problems.

And anyone over 50 years old is due for a colonoscopy, anyway. (They really aren’t too bad. I had one last year and it was fairly easy.)