Archive for the ‘medical treatment of methadone patients’ Category

Benzodiazepines Associated with Increased Risk of Death

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Adults who use sleeping pills are more than three times more likely to die prematurely compared to matched controls that don’t use sleeping pills, according to a recent study. [1]

I’ve never been a fan of sleeping pills, even the newer, first-line “Z” medications: zolpidem (Ambien), zaleplon (Sonata), and eszopiclone (Lunesta). I’ve seen all of them cause more harm than good in my patients, but that’s not surprising, since I treat patients with addictions.
These newer sleeping medications are touted by many as being safer and less addictive than older medication like temazepam (Restoril), triazolam (Halcion) or clonazepam (Klonopin). However, all of the “Z” medications are Schedule IV controlled substances, just like their benzodiazepine predecessors. This means they all have roughly the same potential to cause addiction, despite some enthusiastic and misleading marketing done by some drug companies.

I know many people, without a history of addiction, can take sleeping pills without apparent problems, so I was surprised to read about this recent study. 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.

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).

Of note, eszopiclone (Lunesta) was associated with the highest risk of death. (This pill’s advertisement has a beautiful butterfly wafting in through an open window, and landing gently by a woman in bed, presumably helping her sleep. I guess the butterfly seemed like a better commercial symbol that the grim reaper.)

The use of hypnotic medications was also associated with an increased risk of cancer, and reached statistical significance in patients taking the most hypnotics. Lung, colon, and prostate cancers were significantly more likely to occur in these hypnotic medication users, as well as lymphoma.
The author 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.

Then in early 2014, a study done in the United Kingdom showed similarly increased mortality for patients prescribed anxiolytic and hypnotic medications. [2]

This second study was a retrospective matched control study, looking at all-cause mortality in patients prescribed these medications as compared to patients with no such prescriptions. Patients in the group prescribed benzodiazepines were more than three times more likely to die than matched controls. There was also a dose-response association; the higher the dose, the more likely the patient was to die. This study shows a correlation, but not necessarily causation. Perhaps sicker patients were prescribed the benzodiazepines in the first place.

We know benzodiazepines are associated with increased risk of auto accidents, increased risk of completed suicide, worsening of mood disorders like depression, increased risk of drug-induced dementia, and increased risk of daytime fatigue. Benzodiazepines are also associated with increased risk of cancer, falls, and pneumonia.

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.

So stay tuned. As time goes on, hopefully we’ll learn more about this correlation between benzodiazepines/hypnotics and death. Both of these studies are helpful because of their large size, and the author points out that 19 other studies have shown a relationship between hypnotics and increased risk for death.

1. BMJ Open2012;2:e000850 doi:10.1136/bmjopen-2012-000850
2. Weich et al, “Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study,” British Medical Journal, 2014

Insomnia Medications for Patients in Medication-Assisted Treatment

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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

aaaaprostate

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

aaaapilsfighting

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

QT Intervals and Methadone: The Cochrane Group Weighs In

Torsade de Pointes

Torsade de Pointes

Over the past five years, doctors and other interested parties have debated methadone’s safety concerning its potential to cause cardiac arrhythmias. Methadone can cause a prolongation of the QT interval. This is calculated from a patient’s electrocardiogram (ECG) as illustrated above. The QT interval corresponds to the length of time it takes the ventricle of the heart to depolarize and re-polarize. When the QT interval exceeds a certain level, scientists believe the patient is at increased risk for a fatal heart rhythm called “torsade de pointes” (often abbreviated TdP). This is the French term for “a twisting of the points.” It’s a fitting description,as you can see above.

An episode of TdP can be fatal. Some scientists thought the increase in death rates seen in patients taking methadone were not all from overdose, but rather from the potentially fatal heart rhythm. It’s still a topic of much controversy. Should opioid treatment programs and pain medicine doctors get ECGs on all patients on methadone, to look at the QT interval? Who bears the cost of getting this ECG, opioid treatment programs or their patients? Who reads them if the OTP doctor is a psychiatrist who is no trained to interpret at ECGs?

What should we do if we find a long QT interval, particularly in a patient who is doing well on methadone to treat opioid addiction? Given the fatal nature of the disease of opioid addiction (about 50% dead at 30 years), what is riskier…stopping the methadone or continuing the methadone? Should a cardiologist (heart specialist) be consulted?

The Cochrane Review Group is internationally recognized for their reports, which are based on all existing primary research on a topic. Their reports are recognized as the highest standard in evidence-based health care, and they cover all sorts of topics on prevention and treatment of diseases, and disease testing. The Cochrane Review Group recently reviewed all available evidence dealing with methadone and the risk of TdP.

Their June 2013 report on ECG testing of patients on methadone said, “…it is not possible to draw any conclusions about the effectiveness of ECG-based screening strategies for preventing cardiac morbidity/mortality in methadone-treated opioid addicts.” The Cochrane Group made this statement because there were no quality studies looking at the specific issues. The group did recommend quality studies looking at the specific issues be done in the future.

I have long suspected that the risk of untreated opioid addiction far outweighs the risk of death from cardiac arrhythmias in most opioid addicts, but this is not what the Cochran Group says. They say there’s no good evidence one way or the other. The lead sentence of the Cochrane Review on this topic is, “No evidence has been found to support the use of ECG for preventing cardiac arrhythmias in methadone-treated patients.”

Which is not, I think, the same as saying we don’t need to do ECGs, just that there’s no evidence one way or the other.

For me, this report reassures me I’m not flying in the face of good medical practice if I do not get an ECG on a patient entering treatment on methadone, particularly if the patient is young and at low risk. For higher risk patients, I still feel ambivalent. I plan to look to my colleagues in the American Society of Addiction Medicine to see what they are doing since this Cochrane report has been released.

More will be revealed.

News From the World of Addiction Medicine Research

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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.

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