Archive for the ‘Uncategorized’ Category

Bad News

I knew overdose deaths were increasing since COVID started last year. But data from the Centers for Disease Control and Prevention (CDC) is worse than I’d thought.

You can look at several interesting maps filled with facts here: https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm

Overall, overdose deaths have increased 30.4 percent in the year from February 2020, the beginning of COVID, and February of 2021. At the end of February of this year, 95,133 people died from overdose over the preceding twelve months, compared to 73,344 who died over the twelve months prior to that. Opioids were involved in most of these deaths, though the total number includes deaths from all drugs.

That’s awful.

Some states are worse than others. Nearly all the Appalachian states had large percentage increases in overdose deaths. For example, Tennessee’s increase in overdose deaths was an astounding 51.1percent, while my home state of North Carolina went up by 40.5 percent. Kentucky’s deaths increased by 54.6 percent, and West Virginia increased by 55.2 percent.

Vermont saw the biggest percentage increase, at 74 percent.  New Hampshire, right next to Vermont, was one of the few states that had a reduction in overdose deaths.

Vermont has an innovative hub-and-spoke model, which other states try to emulate, to provide care for people with opioid use disorder. Yet New Hampshire has been lukewarm in its response to treatment of opioid use disorder, so initially this data puzzled me. But the data I’m talking about from the CDC reports the percentage change in overdose deaths. When I look at the actual total of deaths for the last reported 12-month period, they had 194. New Hampshire, however, had 381 over the same time.

But these raw numbers aren’t controlled for the population density. Vermont has, very roughly, about a third of the population that New Hampshire has.

Why have overdose death rates gone up? What’s driving this? The answer, in a word, is fentanyl.

This very potent opioid far surpassed heroin and prescription opioids a few years ago. When I started working at the OTP in my small town in the foothills of the Appalachian Mountains, all my patients were using prescription pain pills. Starting a year or so ago, heroin entered our area, but it wasn’t really heroin. It was the much cheaper and more potent fentanyl and its analogues.

Lately our patients tell us fentanyl is being added to stimulants like cocaine and methamphetamine. It’s also been pressed into pills that look like Xanax and other prescription medications. We had a few people tell us they bought Xanax or knew someone who bought Xanax that turned out to be fentanyl.

Stimulants are also killing people, but usually in combination with an opioid. According to NIHCM (National Institutes of Health Care Management), 63% of stimulant overdose deaths also involved an opioid in 2019, the last year that data is available. Cocaine overdose deaths haven’t increased as much as methamphetamine overdose deaths, which were climbing even before the pandemic. [2]

What are we to do?

First, we don’t give up. We can’t. This issue is too important, and the well-being of people affected by substance use disorders is too important. For workers in the field, it feels like we are trying to empty a swimming pool one teaspoon at a time. It feels overwhelming at times, yet even a teaspoon is something.

Second, use science to guide what we do. Use evidence-based methods to prevent new cases of substance use disorders. Implement the evidence-based methods of harm reduction to help people with substance use disorders. We need to demand funding for treatments that work and stop funding treatments that don’t work. For example, let’s stop cycling patients with opioid use disorder through short-term detox admissions that have little chance of producing real change. Or if patients are sent to detox units, let’s make sure they leave those places on one of the three medications that treat opioid use disorder. Inpatient detox is a great place to start depot naltrexone, for example.

Let’s demand more funding for research into all aspects of substance use disorders. And then, let’s use the data. Let’s refuse to be led by ideology with no evidence.

Third, let’s train new people to work in this field of substance use disorders, and let’s pay them an attractive wage. And let’s voice appreciation to the people working in the field now.

Today is National Addiction Professional Day, so celebrate by telling someone you know who works in the field how much you appreciate them!

  1. Ahmad FB, Rossen LM, Sutton P. Provisional drug overdose death counts. National Center for Health Statistics. 2021.
  2. https://nihcm.org/publications/stimulant-deaths-on-the-rise-compounded-by-rise-in-synthetic-opioids

Lack of Knowledge, Lack Of Understanding

“…Poor management & security. No patients are held accountable for their misuse & the doctor allows patients to use other drugs over & over when getting treatment.”

I was tooling around on the internet. Somewhere between looking at recycled textile art on Etsy and viewing lists of the best audiobooks for 2021, I looked at job satisfaction reports on Indeed and found the above comment. It was written by a nurse who had worked at my facility. She was talking about me!

Before COVID, this nation faced significant nursing and other healthcare personnel shortages. COVD made this worse. Our opioid treatment program has had problems hiring and retaining nurses (and other personnel) just as other healthcare facilities have had. Most OTPs have early hours and lower pay than hospitals and other facilities, making it more difficult.

I wanted to get on Indeed to read about what nurses are saying about their job situations, hoping to find comments from nurses working at OTPs. I never dreamed I’d read a comment from a nurse who had worked at the same facility as me.

I felt angry and hurt when I read the comment, but then I felt sad. I didn’t do a good enough job educating her about the nature of addiction and the purpose of treatment programs. I missed an opportunity.

I can’t emphasize this enough: I can’t keep anyone from using drugs if that’s what they want to do. I don’t have that kind of power. No one does. Even placing people in prison doesn’t always stop people from using drugs.

Since I don’t “allow” or “disallow” anyone’s drug use, what good am I?

First, I can prescribe medication that keeps most opioid users off illicit opioids and on much safer and longer-acting medications. This allows them freedom from chasing opioids several times per day, and freedom from committing crimes to get money to get these illicit opioids. It usually improves their quality of life and here’s the big thing: It reduces their risk of dying. Since they are alive, they have a chance of participating in counseling.

Second, the chronic nature of opioid use disorder and other substance use disorders means we rarely see patients enter treatment and never use another drug. This disease doesn’t work like that. However, we can use evidence-based counseling techniques to assess patients’ willingness to change drug use behavior. We can use those techniques to help them decide what kind of action they’d like to take to change drug use habits.

Behavioral changes don’t happen quickly. Anyone who has tried to lose weight, exercise more, stop smoking or other things can probably relate to the difficulties of changing behavioral patterns. Sometimes we try things that don’t work, but we gain information about what may work for us in the future.

In the old days, I did taper people off their treatment medication (methadone or buprenorphine) if they continued to use illicit drugs. I’ve changed my approach, after learning more about how to support patients and help them in their recovery. These days, especially with fentanyl prowling around the drug scene, patients die when out of treatment. Accepted best practices show patients have best outcomes when we retain them in treatment and keep talking to them.

Obviously, the nurse who wrote the complaint wasn’t educated about this fact. I am one of several people who should have educated her about this.

I do lower doses if there’s another medical condition that makes methadone or buprenorphine dangerous, or if patients’ use of sedative drugs make dosing methadone or buprenorphine too dangerous. Even with these conditions, we try to talk the patient into going to an inpatient program for more intense counseling and help.

In fact, continued use of opioids is an indication to increase methadone/buprenorphine, not to decrease it.

Perhaps the writer of the complaint felt we should have stopped giving any take home doses to patients using illicit drugs. The comment was written after COVID started and we’ve been more liberal with take homes. State and federal regulations around take-home doses were relaxed so patients could dose at home and avoid crowds. We agreed this seemed appropriate to do. For the most part, our patients did well with these extra home doses.

Since I read the comment, I’m more careful to remind nurses and counselors during case staffing that we always must think about the risk/reward of treatment. In very few situations does excluding patients from treatment make sense. On the other hand, we don’t ignore drug use; every positive urine drug screen result must be addressed in counseling. But addressing drug use does NOT mean dismissing patients from treatment.

We recently had a nurse who worked only one day before she decided the job wasn’t for her. I hope she’s the one who wrote the comment. She didn’t have enough time to learn about what we do at the OTP. She didn’t work long enough to see all the miracles we see at OTPs.

I’ve said this many times before: I see more positive changes in people enrolled in opioid treatment programs than I ever saw back when I worked in primary care.

That’s the main reason why I love working at the OTP.  I’m sorry our nurse didn’t get a chance to see this for herself.

The Heartbreak of Methamphetamine

Reference at the end of this blog

Like so many places in the U.S., my area has struggled not only with heroin/fentanyl use, but also with methamphetamine use. We’ve seen a sharp increase in the numbers of patients at the opioid treatment program who also used methamphetamine.

However, sometimes prospective patients show up for admission to our opioid treatment program who have no opioid use at al. They have great expectations that the medication we use to treat opioid use disorder will also help them stop using methamphetamines. They say that if they could take a drug of some kind to “take the edge off” they would no longer crave and use methamphetamine.

Some of these patients have dabbled with opioids, using them with an assortment of drugs, but they have never become physically dependent and aren’t using opioids regularly when they come for help at our opioid treatment program.

I meet with these patients and talk to them myself, to make sure I get an accurate history of their drug use. But then I must tell them that they are not appropriate for admission to our program. I hasten to tell them that they certainly do need treatment, and we can direct them to the most appropriate provider. But these people are terribly disappointed and often vent a great deal of anger towards me.

Of course, thus far there are no medications approved by the FDA to treat methamphetamine use. Many medications have been studied, and some have shown some promise, only to fail to show benefit in later studies. Neither buprenorphine nor methadone have benefit for methamphetamine use disorder.

I tell these people that if I were to start them on buprenorphine or methadone, they would then develop a physical dependence on that medication, adding to their problems rather than helping. They don’t care. They often say things like we really helped their uncle, who used to use drugs and now is doing well, and why can’t we make an exception because they are so desperate for help?

It’s sad because I’d love to be able to help everyone. The other options in our community don’t look attractive to these people. They include a short-term detox unit and outpatient group and individual counseling. Inpatient detox followed by rehabilitation is available for people with substance disorders at a state-funded program several hours from us.

Behavioral therapies are still the most heavily evidence-based treatment for stimulant use disorder. Contingency management is the most effective intervention that we have (see my blog of June 6, 2021). Other techniques include groups that use the Matrix Model, and individual therapies such as cognitive behavior therapy, motivation enhancement, and 12-step facilitation.

There are no FDA-approved medications that treat stimulant use disorder.

We have long lists of medications that were tried and failed to provide benefit for stimulant use disorders. We also have some tantalizing data about drugs and combinations of drugs that might be proven to work after more study, such as the combination of naltrexone and bupropion. The size of benefit from this combination of medication isn’t great, but anything that can help would be a bonus for desperate patients. Transcranial magnetic stimulation is another intriguing technique that is still undergoing study.

As usual with difficult-to-treat illnesses and desperate patients, many sham treatments have been peddled over the years. Anyone remember Prometa (also known as Gabasync), the proprietary combination of flumazenil, gabapentin, and hydroxyzine? This combination of drugs was peddled as a cure for methamphetamine addiction with a hefty price tag of up to $15,000 per patient. As is so often the case with snake oil vendors, salesmanship outpaced science. Eventually, after proper clinical trials were performed, Prometa was found to be no more effective than placebo. We should expect to see more methamphetamine “cures” peddled as problems with methamphetamine climb.

Of course, patients at the opioid treatment program who are being treated with methadone or buprenorphine also can have or develop stimulant use disorder. Over the past several years, we’ve seen the number of methamphetamine-positive urine drug screens climb.

Our patients’ use patterns vary considerably. Some inject methamphetamine nearly daily. Others smoke or snort it several times a week, and others use in a binge pattern, for several days at a time with long stretches of abstinence between episodes. These patterns of use determine the degree of damage caused to our patients.

Nearly all have some problems caused by methamphetamine. We see financial problems, shattered relationships, decline in physical health, and worsening of mental health problems.

We try to increase patients’ “dose” of counseling, or even refer to inpatient care, but that’s difficult. There’s only one facility in our part of the state that will accept our patients and maintain them on their usual methadone or buprenorphine while treating the methamphetamine use disorder.

Even though the below-referenced article for the National Institute on Drug Abuse was published earlier this year, data from 2020-2021 is expected to be even worse. Stress makes everything worse, and COVID stressors have affected all of us.

  1. https://www.drugabuse.gov/news-events/news-releases/2021/01/methamphetamine-overdose-deaths-rise-sharply-nationwide

Oops…I Goofed

One of my astute readers point out an error in my previous post.

Practitioners are no longer required to get eight hours of training if they only want to treat thirty or fewer patients. These prescribers can still prescribe buprenorphine products for their patients with opioid use disorder, but they still to submit Notice of Intent to SAMHSA under established protocols. Then once SAMHSA approves the practitioner’s request, the DEA is notified, and the practitioner is issued an X DEA number to be used for those patients’ buprenorphine prescriptions.

https://www.federalregister.gov/documents/2021/04/28/2021-08961/practice-guidelines-for-the-administration-of-buprenorphine-for-treating-opioid-use-disorder

Using High-dose Buprenorphine Induction in the Emergency Department for Patients with Opioid Use Disorder

In my last blog post, I talked about the new idea of micro dosing buprenorphine in patients who have not yet stopped using full opioids, to switch them to buprenorphine products without going through a time of opioid withdrawal.

I was surprised at the response to that blog. I now feel about micro dosing buprenorphine like I did about sex in high school: everybody but me seems to be doing it and they are having a great time. I’m envious.

In this blog post, I’m going to review a study of “high dose” buprenorphine induction done in an emergency department setting. This study was done on patients already in withdrawal, in contrast to the micro dosing studies.

This recent article, by Herring et al., describes the outcomes of patients with untreated opioid use disorder who were started on doses of buprenorphine that were higher than 12mg sublingual per day while in the emergency department. [1]

This study described 366 encounters of patients with opioid use disorder in the emergency department of one large urban hospital in Oakland, California. The study was done because the authors suspected that the usual buprenorphine induction, which takes several days, could discourage the most fragile patients. They felt an accelerated induction process that could achieve therapeutic buprenorphine blood levels within four hours, and that a quicker process could be more likely to engage patients in further treatment. They hoped to increase both the magnitude of withdrawal suppression as well as the duration.

As a side note, it’s important for emergency departments to provide treatment for opioid use disorder. We know that ED-initiated buprenorphine treatment is lifesaving and cost effective. All the following organizations have recommended ED initiation for opioid use disorders: the American College of Emergency Physicians, the U.S. Surgeon General, the National Institute of Drug Abuse (NIDA), and the Substance Abuse and Mental Health Services Administration (SAMHSA). Now that there is no requirement for an “X” number (as of April 2021), any physician with a DEA number can legally prescribe for patients. Some ER providers protest that they don’t have anywhere to refer these patients. However, many Emergency Departments with many referral options still don’t prescribe, as it is in my little town.

Of the patients in this study, 23% were homeless and 41% had co-occurring psychiatric diagnoses. Around 44% were black, and 15% Hispanic, and 54% of all the patients had no prior formal treatment for their opioid use disorder. The type of study was a retrospective chart review.

The patients were excluded from the study for certain criteria: those with recent methadone use, impending surgery, current intoxication with alcohol, benzodiazepines or other sedatives, post-overdose reversals, serious acute medical issues including kidney failure or respiratory distress.

Those not excluded were asked about time since last use. Patients had to be at least 12 hours from last use of heroin or fentanyl, 24 hours from last use of long-acting opioids, and 72 hours from last use of methadone. These patients were given a COWS (Clinical Opioid Withdrawal Scale) score and those scoring less than 8 were not dosed but were re-checked in 1-2 hours. Those scoring above 8 were given a first dose of 4-8mg of buprenorphine sublingually and re-assessed about 30-60 minutes.

Then patients either underwent standard induction or high-dose induction.

For patients who had improvement in their withdrawal symptoms and no barriers to same-day dispensed buprenorphine were given a total of 8-12mg in the emergency department and a prescription for 16mg SL per day until they could get a follow-up appointment. These were the standard dose patients.

High-dose induction patients were re-assessed 30-60 minutes after their first 4-8mg of buprenorphine, but then were given an additional 8-24mg every 30 minutes until relief of withdrawal or 32mg total. This protocol was done for patients with heavy opioid tolerance, scores of more than 8 after the re-assessment, and for patients who couldn’t reliably fill a buprenorphine prescription, whatever their reason might be. They were also sent home with a prescription for sublingual buprenorphine at a dose of 16mg per day until a follow-up appointment.

Precipitated withdrawal occurred in only .8% of these patients, a very low incidence. Nearly all those cases occurred within the first 8mg of buprenorphine given. Precipitated withdrawal was unrelated to high-dose buprenorphine. Median stay in the emergency department was only 2.4 hours, showing opioid withdrawal can be treated relatively quickly even under trying circumstances. None of the patients needed Narcan rescues, and there was no significant reduction of respiratory rate at doses higher then 28mg.

Three of the study patients had serious adverse events. One patient had diabetic ketoacidosis, and another patient returned to the ED in opioid withdrawal and had to be hospitalized for acute heart attack. None of these three events were felt to be due to buprenorphine, but I would have liked more information about whether that second patient could have had precipitated withdrawal. Some of the study patients were admitted to the hospital for treatment of medical illnesses that included infections such as abscesses and cellulitis, exacerbation of COPD (chronic obstructive pulmonary disease) and other conditions.

Between 10-18% of study patients did return to the ED if they were unsuccessful at accessing follow-up treatment with buprenorphine. I think that’s a remarkably low percentage. This shows this team of providers did a great job at referring patients.

The authors concluded that present dosing guidelines requiring multi-day buprenorphine inductions are unduly burdensome, particularly for patients who are homeless or have few financial resources to access treatment.

They felt the high-dose protocol was shown to be safe, at least for patients without serious illness or sedation from other drugs. The patients’ opioid withdrawal was addressed quickly and didn’t take much time to achieve, with an average stay of 2.4 hours in the ED. They felt this method of accelerated dosing helped removed barriers to treatment and that a higher dose lasted longer and extended the duration of action of buprenorphine.

I wish all ED providers could read this study. They might become convinced opioid use disorder can be treated without extreme burden on their time, with significant rewards.

I did have a few thoughts about the study.

I wish the authors would have told use what the primary opioids of use were in these patients. I suspect it was mostly heroin or fentanyl or both, but that data wasn’t included. If the primary opioid patients had been using was oxycodone or some other short-acting opioid, it could make a difference in the results.

Many patients were excluded from the high-dose option, so the degree of safety shown in this study may not apply to the type of patients that were excluded. For example, patients who received Narcan after an overdose were not included, and neither were patients who were using alcohol or benzodiazepines. The patients who are revived from an overdose may be the most important ones to get into treatment the quickest, since a history of opioid overdose is the leading predictor of future fatal overdose. This study doesn’t help us with this set of patients.

I’m appreciative of the study authors and I think this is an important study that supports induction of buprenorphine in selected patients who come to the Emergency Department for care.

  1. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2781956

Micro dosing of Buprenorphine: Is it an Option Yet?

We all know fentanyl has taken over as the main opioid of use for patients with opioid use disorder. We have three medications that treat opioid use disorder, but some practitioners feel buprenorphine induction has become problematic for some fentanyl users. Even after waiting until patients are in moderate withdrawal, with a COWS (Clinical Opioid Withdrawal Score) of 12 or above, some of these patients have precipitated withdrawal symptoms after their first dose of buprenorphine, with either the mono- or combo product.

Why is this?

Since fentanyl has a relatively short duration of action, we might expect that if we wait until patients have at least moderate withdrawal, starting buprenorphine would be OK. But experts say that fentanyl is lipophilic, meaning it gets distributed into peripheral tissues in a non-dose-dependent fashion. For patients who have been using fentanyl long and hard, the drug has a large volume of distribution and may dissipate slowly, thus causing precipitated withdrawal after administration of the less potent buprenorphine, even if the patient feels a moderate or higher degree of withdrawal.

What can be done about this?

Some physicians ask patients using fentanyl to wait 24 to 48 hours after their last use of fentanyl to take that first dose of buprenorphine. This approach reduces the risk of precipitated withdrawal… but is extremely difficult for patients. No one likes to be sick, and enduring opioid withdrawal for nearly two days is too much for some patients.

At the opioid treatment program, I’ve had only a few cases of precipitated withdrawal in such patients. Patients I treat usually know how long they must wait to take buprenorphine, from prior experience using buprenorphine illicitly for their opioid withdrawal. I can use their knowledge. I do shared decision-making with the patient for the best outcome. Some patients, having had precipitated withdrawal from buprenorphine products in the past, want no part of this medication, and want to start methadone.

That’s fine with me. Methadone has been around for decades and works very well to treat opioid use disorder. It’s a more complicated medication, but is as good as buprenorphine, and studies show methadone retains patients in treatment longer. But office-based practitioners can’t prescribe methadone to treat opioid use disorder. That’s illegal.

Now there may be a new option for buprenorphine induction, called micro dosing. With this technique, patients don’t have to stop using opioids and wait for moderate withdrawal. Micro dosing eliminates the uncomfortable wait time and thus is more attractive to potential patients.

I’ve been scouring the internet for information about micro dosing protocols and have found several. An article from scientists in British Columbia from last year described their technique of micro-dosing buprenorphine. For this method, the patient can continue to use illicit opioids during the induction of buprenorphine, which is started in very low doses, compared to what we usually use. Then once the patient reaches 12mg of buprenorphine per day, the patient hopefully can stop using illicit opioids, without going into withdrawal. [1]

The article describes the following recipe:

  • Day 1: 0.5 mg once a day
  • Day 2: 0.5 mg twice a day
  • Day 3: 1 mg twice a day
  • Day 4: 2 mg twice a day
  • Day 5: 3 mg twice a day
  • Day 6: 4 mg twice a day
  • Day 7: 12 mg (stop other opioids)

Since new patients don’t have to stop using illicit opioids or experience withdrawal with this method, it may make treatment with buprenorphine products more attractive.

How do you dose patients at half a milligram since the lowest tablet and film on the market is a 2/.5mg dose? Even though drug manufacturers have not done studies to assure the active medication is evenly distributed over the film or throughout the tablet, patients have been cutting tablets and films for years. Right now, I have seven office-based patients doing a slow taper who are cutting their 2/.5mg film into multiple pieces, to take much lower doses as they ease off the last bit of medication.

I had one patient who said she could cut a 2mg film into sixteen pieces, with sharp scissors. Then she took one of the sixteenths every other day. I prescribed her one 2mg film per month for many months, until she forgot to take a dose, had no withdrawal, and stopped buprenorphine/naloxone altogether.

My point is that with sharp scissors, a 2/.5mg film can easily be cut into quarters, equaling a half milligram each, roughly.

The original method, called the “Bernese method,” called for starting at .2mg per day and gradually increasing to 12mg over nine days. There are case reports dating back to 2010 that give positive results for induction with this method.

Micro dosing has also been suggested for a quicker and less painful method to transition from methadone to buprenorphine. It’s difficult for some patients to tolerate methadone withdrawal symptoms for long enough to get started on buprenorphine in the traditional manner.

Patients who wish to switch from methadone to buprenorphine currently need to gradually lower their dose of methadone to 40mg or less, then miss several days of dosing before starting buprenorphine under our present protocols. It’s hard for patients to tolerate a slow taper, particularly if they are at doses above methadone 100mg. I usually recommend they lower by 5mg per week, so it takes many weeks to get the dose low enough to make the switch. Some patients get frustrated and chose to remain on methadone. Others get frustrated and drop out of treatment, incurring the risk of overdose death that we see in untreated opioid use disorder.

This micro dose method could help patients make the transition much more quickly and easily… if it works.

It’s an intriguing idea, giving us more options to treat patients. But after my internet search, I haven’t found any large studies of these micro dosing protocols, only a few case reports here and there. Before I try micro dosing, I’ll need more objective information and more expert opinion. Ideally, I’d like to read about results from many patients, transitioned from fentanyl or methadone in a controlled manner.

I also question the reason who people want patients to transition from methadone, which works well as a treatment for opioid use disorder. True, it doesn’t work for everyone, because no medication works for everyone. But it’s a good and acceptable treatment and if a patient is doing well, what is hoped to be achieved by the transition to buprenorphine? If it’s what the patient wants, that’s a great reason. Perhaps the biggest reason patients want to switch is the convenience of office-based treatment available with buprenorphine products. If the patient has side effects or medication interactions with methadone, those are great reasons to switch.

But in one case study, a woman was transitioned from methadone to buprenorphine because she was hospitalized and due to her medical illnesses, needed to live in a nursing home. No nursing home would accept her on methadone, but they would accept her on buprenorphine. That’s why she was switched. [2]

That is not a good reason. It’s an arbitrary reason that reveals the same old bias against methadone we’ve fought for years.

So yes, I agree with transitioning from methadone to buprenorphine if there’s reason to do so, but let’s not agree to do this if the decision is based on stigma.

In other news, at the other extreme, some emergency department practitioners are using high-dose buprenorphine induction to alleviate withdrawal symptoms more quickly. They feel a higher dose provides longer relief of withdrawal, until the patient can access dependable medication treatment for opioid use disorder. I will describe a new study that suggests this can be done safely and without much risk of precipitated withdrawal in my next blog post.

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970598/
  2. Terasaki et al, “Transitioning Hospitalized Patients with Opioid Use Disorder from Methadone to Buprenorphine without a Period of Abstinence Using a Microdosing Protocol,” Pharmacotherapy, July 26, 2019.

Taking A blogging break…back soon…

Education of New Physicians

I read an interesting study in the May/June issue of the Journal of Addiction Medicine. This article, by Shuey et al, described Internal Medicine residents’ knowledge and attitudes towards treatment of opioid use disorder with buprenorphine.

This study reports on results of survey questionnaires sent to Internal Medicine residents in Florida residency programs.

The study showed that Internal Medicine residents cared for patients with opioid use disorder frequently: 73% of the survey respondents said they cared for such patients more than once per month. But only 82% reported having substance use disorder educational curricula. Specifically, 75% said their program didn’t provide training in the treatment of opioid use disorder with buprenorphine.

Respondents’ answers to questions about buprenorphine as used to treat opioid use disorder were uneven. While 88% correctly answered that buprenorphine was a partial opioid agonist, only 16% knew that buprenorphine has a higher affinity for opioid receptors than methadone, morphine, and naloxone. Seventy-six percent were aware of the dangers of precipitated withdrawal, and 69% knew that methadone cannot be prescribed from an office-based setting for the purpose of treating opioid use disorder.

However, only 17% knew that weeklong tapers of buprenorphine are not supported by medical evidence, and 56%, more than half, mistakenly thought resident physicians can’t prescribe buprenorphine.

Residents who indicated an interest in treating patients with buprenorphine scored better than those not interested in getting a buprenorphine waiver to prescribe.

Of the Internal Medicine residents who answered the study, only 2% already had waivers to prescribe buprenorphine. However, the vast majority, at 89%, felt deregulation of buprenorphine to allow any physician with a DEA license to prescribe buprenorphine was a good idea. (This study was done prior to the change in rules earlier this year that allows just that.)

The surveyed residents were also asked about their attitudes towards barriers to prescribing buprenorphine. When asked if they were willing to get trained and prescribe buprenorphine if it was offered by their hospital, 82% agreed. When asked if they felt they had been adequately educated about treatment of opioid use disorder, only 19% said they had, and 48% said they didn’t feel educated, while 33% felt neutral about the question. When the residents were asked if they agreed that opioid misuse and addiction was a serious national crisis, over 80% strongly agreed.

When the respondents were asked about obstacles to the prescribing of buprenorphine, by far the most common response was limited knowledge about diagnosing and managing opioid use disorder. Other answers were a lack of awareness of medication, laws preventing residents from prescribing buprenorphine, and limited understanding of the legal process to obtain a buprenorphine waiver. Less than 5% of survey respondents said they lacked interest in prescribing buprenorphine, around the same percentage who feared legal action against residents who prescribe buprenorphine.

Let’s talk about some interesting things about the study. For example, only around sixteen percent of the residents who were sent this survey responded. That’s a low rate of participation. However, the Internal Medicine (IM) residents who did responded to this survey were relatively diverse. More than half were female, and evenly divided over the three years of residency. Ethnicity was 42% white, 24 % Hispanic or Latino, 23% Asian, and 7% Black or African American.

That’s more diverse than my Internal Medicine residency, way back in 1987. We were 28% female and 85% white, with 15% black, with no Asian or Hispanic residents. And we were the most diverse class to date. The IM residents in the two years prior to mine were 100% white and 7% female. I’m glad residents are more diverse now.

Were minority residents more likely to respond to the survey for some reason? And were residents already interested in treating patients with opioid use disorder more likely to answer the survey? There’s no way to know.

This study indicated IM residents are not getting valuable information about treatment of opioid use disorder. We are now several decades into the opioid epidemic. It’s been over two decades since DATA 2000 was passed, allowing patients to be treated with buprenorphine in office-based settings. That’s a whole generation of physicians.

Why have medical schools and residencies been so slow to teach young doctors about opioid use disorder and its treatments? I used to think it was only because treatment with buprenorphine was so new, but it’s not new anymore.

I’m proud of North Carolina’s efforts to change this. We are fortunate to have the Governors Institute of Substance Abuse, a non-profit foundation that seeks to prevent, identify, and treat substance use disorders. Starting four years ago, they helped to convince and encourage our state’s medical schools and primary care residency programs to teach about opioid use disorder and its treatments. As a result, four (UNC at Chapel Hill, Wake Forest, East Carolina, and Campbell University) of our state’s medical schools already offer eight hours of training on opioid use disorder. Nurse practitioner training programs in NC now mandate a 24- hour training course on opioid use disorder.

This present study of survey responses by IM residents points to significant gaps in the education of young physicians, even twenty years into the opioid epidemic. That’s disappointing. Usually I’m not a fan of governmental mandates in education, but it’s starting to look like some states will need that to change. It’s important. The lives or many people depend on this.

Imagine a chronic illness that causes disability and death. Now imagine there’s a new drug developed that reduced the risk of dying by three-fold. Not by three percent, but it reduces the risk of death three times over.

Now imagine a patient who dies from this chronic illness. Imagine that this unfortunate patient was never offered the life-saving medication. In fact, this patient’s physicians never even told the patient about this l medication, which had been approved twenty years earlier.

It would be a travesty. Malpractice lawyers would salivate to get such an easy case. The negligent physician would be called to account for his actions and possibly investigated by the medical board. There would be consequences.

That’s where we are now, except the chronic illness is opioid use disorder, and there are no lawyers, no consequences for all the missed opportunities to treat this deadly illness.

Why do we allow this to happen, this many years into the opioid epidemic?

Book Review: Empire of Pain: The Secret History of the Sackler Dynasty

This book, by Patrick Radden Keefe, will make you angry, especially if you’ve lost anyone to opioid use disorder or have suffered from it yourself.

The entire book is about how the Sackler family, owners of the pharmaceutical company Purdue Pharma, ruthlessly marketed OxyContin in the face of growing opioid use disorder and opioid overdose deaths. The book details the legal maneuvers undertaken by the Sacklers and their lawyers to avoid taking responsibility, either by financial means or an admission of guilt, for OxyContin sales. Those sales primed the pump for our epidemic of opioid use disorder and death in this country.

The first one-hundred and eighty or so pages describe the family lives of the family patriarch and his three sons, along with their descendants. This background is necessary to understand their motivations, but it’s a bit boring. Basically, the immigrant patriarch worked hard and succeeded on two fronts: he became a physician and he became an excellent salesman. The second generation consisted of three sons, all of whom became physicians, but their primary occupation became making money by owning the drug company that made OxyContin. This second generation created many offspring through multiple marriages. Some members of the third generation of U.S. Sacklers went into the family business, but most went in different directions, funded by the money from the family businesses.

Back in the middle of the last century, Sackers owned the drug company that sold Librium and Valium. The latter was marketed as a non-addicting medication for anxiety and sleep.  That was a harbinger of things to come.

Other books have related the tale of how opioids came to a place of dominance in the last part of the twentieth century, with all the hubris spread about opiophobia. But this book is a tour de force about OxyContin’s role. The author has documented painstaking detail what the Sackler family and their privately-owned drug company, Purdue Pharma, did to sell OxyContin.

IN 2007, John Brownlee, a U.S. attorney for the Western District of Virginia, brought a suit against Purdue Pharma. This book describes how Purdue Pharma lawyers tried to out-maneuver Brownlee at the beginning of his investigation (and the end) by going over his head to his bosses at the Department of Justice. That failed, to some degree, and Brownlee was able to find documents showing damning evidence.

He found evidence that the company knew OxyContin could be injected, but they instructed sales reps to tell doctors that it could not be injected. Brownlee found that Purdue executives had been cozy with the FDA employees charged with keeping the public safe. The FDA employee working with Purdue was later offered a job with Purdue for a mid-six-figure salary.

Brownlee found that sales reps were routinely trained to say things to the doctors they were detailing that were known to be untrue, even finding training videos to prove it. Sales reps were required to call on doctors known to have shady prescribing practices (running pill mills) even when they voiced reservations about calling on such doctors.

Brownlee was up against some powerful attorneys for Purdue Pharma. In the end, Purdue Pharma and three executives, Friedman, Goldenheim, and Udell, pled guilty to fraudulently marketing OxyContin. Purdue paid over $600 million in fines, and the executives got three years’ probation and community service. It was a large fine, but small in relation to the billions in profits Purdue was making. And the Sackler family had no charges brought against them.

It was a valiant attempt to hold Purdue Pharma accountable, and probably a miracle that any guilty plea at all could be gotten with the degree of influence that the Sackler family appeared to have over the government. But it was a disappointing finish.

And if you thought the legal problem was enough to make the Sackler family and Purdue Pharma change their ways…you would be dead wrong. They did not.

The Sacklers and their lawyers continued to trot out tired old lies and half-truths about their part in the opioid use disorder epidemic, while continuing to aggressively market OxyContin.

This present book presents information debunking all the excuses made by the Sackler family to shroud their involvement in the U.S. opioid epidemic

First, defenders of OxyContin, Purdue Pharma, and the Sacklers still claim that OxyContin sales accounted for a small percentage of the vast amounts of pain pills prescribed early in the opioid epidemic. They say it’s unfair to place all the blame on their shoulders. Like most of their arguments, there’s a scrap of truth to their claims, but they ignore inconvenient facts. For example, as the author points out, OxyContin contained much higher doses of oxycodone than other pills made by other companies. Therefore, Purdue Pharma’s OxyContin, though only accounting for a minority of total prescription opioid pills sold, represented a much higher percentage of total milligrams sold. Each OxyContin tablet packed up to eight and even (before the 160mg tablet was taken off the market) sixteen times the opioid firepower compared to short-acting oxycodone tablets. Besides that, the Sacklers bought another drug company, Rhodes Pharmaceuticals) to make generic oxycodone just months after the 2007 verdict in Virginia. According the book, the family wanted a “landing pad” in case they ever needed a fresh start. This facility made generic versions of OxyContin, and well as immediate release oxycodone. It became the seventh-largest manufacturer of opioids in the U.S. But the Sacklers didn’t acknowledge this to the public.

Second, the Sackler family has claimed in the past that their liability for the crimes of Purdue Pharma should be limited, since they had no role in running the company. But this book points out, repeatedly, that not only did many family members sit on the board of Purdue Pharma, but evidence shows that family members directly micromanaged sales and exhorted sales reps to use tactics to sell ever more OxyContin. Records show the Sackler family members were directly involved in running Purdue Pharma and regularly pressured sales reps to sell more OxyContin.

Third, the Sackler family and top officials at Purdue Pharma repeated said that some rogue pharmaceutical representatives of the company aggressively marketed their drug, without company knowledge or approval. OxyContin was falsely advertised as having a lower risk of addiction than other opioids. However, training videos obtained from Purdue Pharma show drug reps were trained to give inaccurate information. Indeed, that what the 2007 conviction was for: false advertising and false claims of safety.

Even when drug reps feared some physicians were running pill mills, they were told to continue calling of these doctors and to keep selling the OxyContin.

The Sacklers and their associates invented IMS, a company that collects data on doctors about what medications they prescribe, along with the quantities. This data is sold to pharmaceutical companies so they can direct sales pitches about their medications. And of course, Purdue Pharma used this information. They didn’t use it to identify bad apples, doctors who were perhaps inappropriately prescribing, though they certainly could have. They could have used their data to report overprescribing doctors to the DEA for investigation. Instead, they used their IMS data to identify areas with high rates of worker’s compensation injuries, where pain medication might be prescribed by naïve family physicians. The company felt these doctors should be targeted for OxyContin sales pitches.

The most enraging part of the book comes near the end, when the author describes more recent lawsuit settlement negotiations.

Eventually, so many states, cities, counties, hospitals, tribes, and school districts brought suits against Purdue Pharma that the Sackler family wanted to settle them all at the same time. Purdue offered to relinquish control of the drug company to a public trust and the family would donate money if they were guaranteed to be immune from future lawsuits. The total settlement would be $10-20 billion.

That’s a big number, until the details revealed that the Sackler family would only be paying from $3 billion up to a possible $4.5 billion. Given the billions the Sacklers had made over the years from the sale of OxyContin, this agreement didn’t sit well with many of the negotiators. Basically, the family said take this agreement or we will declare bankruptcy. Bankruptcy would freeze litigation against Purdue Pharma.

Talks broke down and true to their threats, Purdue Pharma declared bankruptcy. The bankruptcy judge’s rulings favored the Sacklers, particularly when he ruled that the Sacklers would also be protected by Purdue’s bankruptcy. This decision outraged many people. Our own state’s Attorney General Josh Stein said aptly, “Multi-billionaires are the opposite of bankrupt.” But the judge’s ruling stood, protecting the family from liability.

There’s so much more in the book, such as how the Sackler family’s philanthropic gifts to universities, libraries, and museums were retuned and refused, due to public outcry about where their money came from. The author suggests members of the Sackler family were upset about their charitable gifts being declined and returned. That’s truly a problem of the very wealthy.

The book contains information about brave protesters who brought the Sackler’s association with OxyContin to light and pushed venerable institutions into re-thinking gifts from such sources.

Towards the end of the book, the author asks why the Sackler family couldn’t or wouldn’t admit to their complicity in creating the opioid use disorder challenge we now face. How could they be so blind? Even if they were motivated solely by greed, at some point they must have known their lies were now brought into the sunshine. Why have they never taken a more conciliatory tone, at least pretending to have empathy for the millions of families affected specifically by OxyContin abuse?

The author said the Sackler family wouldn’t talk to him. He also said that during interviews with former Purdue Pharma employees, from executives down to sales representatives, he was struck with their “fog of denial.” He wonders if acknowledging complicity in Purdue’s and the Sackler family’s destructive acts would be too much for human conscience to bear, and so they continue to parrot the same old lies: only drug addicts abused OxyContin, only a few wayward drug reps mis-marketed OxyContin, and the company was driven only by a desire to help patients, and not by greed.

At several places in the book, the author compares the Sacklers to Big Tobacco both in their legal strategies and their refusal to admit their part in marketing a dangerous product.

After reading the book I was left feeling discouraged, disillusioned, and tired. It appears that justice for the very rich happens on a different plane, if at all. I couldn’t help but think about the physician (my blog post of May 11, 2021) indicted by the Department of Justice for – among other things – failing to do random drug screens on the patients he was treating for opioid use disorder.

None of the Sacklers have been criminally indicted for anything. Justice for the Sacklers versus justice for this physician feels…uneven…to put it mildly.

Medication Interactions with Methadone and Buprenorphine

Lily Idle on Twitter: "Drug interactions. Coming soon: Positive and  Negative editions.… "

Patients being treated for opioid use disorder with methadone or buprenorphine often need other medications to treat chronic and acute medical conditions. When our opioid treatment program patients fill other prescriptions at retail pharmacies, the pharmacist might not know that the patient is on methadone or buprenorphine. Due to privacy laws, OTPs don’t report patient data to state prescription monitoring programs. That puts the burden on opioid treatment providers to watch for potential drug interactions.

I take that burden seriously.

Methadone, for various reasons, is more likely to have drug interactions than buprenorphine. Buprenorphine’s various pharmacologic properties reduce the risk of drug interactions. It has a high affinity for the opioid receptor, which means it’s not easily displaced off the receptor. Also, buprenorphine has a ceiling effect, so fluctuations in blood levels are less likely to cause sedation than methadone. Drug interactions can still occur, but not with the frequency or severity as with methadone.

Many medications interact with methadone, too many for me to reliably remember. I use a smart phone app to supplement my aging memory with up-to-date data. And if I can use these smart phone apps, believe me…anyone can. I prefer the Medscape app, though it’s only one of many. Other providers like Epocrates or others. If you work at an opioid treatment program and make dose decisions, I strongly recommend you get one of these apps, because there’s no way to remember or keep up with all new data.                                                                                                                  

Here are some of the main ways methadone interacts with other medications.

Sedatives

Any sedative medication can have an increased sedative effect when it is administered to a patient on methadone, or any other opioid, for that matter. Sedatives affect that ancient part of our brain that tells us to breath while we sleep. Opioids also affect that brain center, so when opioids and other sedatives are mixed, patients can fall asleep and stop breathing, which is how overdose deaths occur.

By far, the most commonly consumed sedative that my patients use, by prescription or illicitly, are benzodiazepines. However, other sedatives are just as deadly, and alcohol is a sedative drug too. Recently we’ve had more patients prescribe gabapentin (Neurontin) or its mirror-image molecule, pregabalin (Lyrica). These medications are commonly prescribed by primary care providers for just about any complaint of pain, anxiety, or anything else. When misused, or when taken with methadone, it can lead to impairment and even overdose.

I’ve railed against the inappropriate use of benzodiazepines so many times that even I get tired of hearing myself, so I’ll refer to reader to past blog entries. But let me just say that many patients being treated for opioid use disorder with methadone have been harmed by also taking benzos, prescribed or not prescribed. It’s a hazard that should be avoided if possible.

Cardiac Effects: prolonged QT interval

Methadone can prolong the QT interval in the heart. In the interest of not getting overly technical, let’s just say that the QT interval has to do with how the beats are conducted through the electrical system of the heart. If the QT interval lengthens past a critical point, it puts the patient at risk for a potentially fatal heart rhythm.

Many opioids can cause this, but methadone is probably the most well-known. Other opioids, like tramadol and oxycodone, carry some risk of QT prolongation, but usually not to a clinically significant degree. Some sources say buprenorphine can theoretically cause QT prolongation, but most experts don’t feel it’s clinically significant. In fact, if a patient on methadone develops QT prolongation issues, that patient is often recommended to switch to buprenorphine.

While methadone alone infrequently causes clinically significant QT interval prolongation, other factors can increase patient risk. For example, some patients with certain types of underlying heart problems may already be prone to QT prolongation and starting methadone could make this situation worse.

Many other medications also can cause QT prolongation. When these medications are started in a patient on methadone, the combination can cause significant QT interval prolongation.

For a recent list, go here: https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf

As you will see, many common medications are listed. Common antibiotics, like cipro and erythromycin, cause prolonged QT interval and these are often prescribed to our patients. Many commonly prescribed mental health medications can prolong the QT interval.

What should opioid treatment providers do when a patient on methadone gets a new prescription for a medication which could critically prolong the QT interval? I’ve searched the internet and can’t find exact evidence-based solutions. But that’s not uncommon. Physicians often need to weigh decisions of risks and benefits of medications and act based on this.

First, I inform patients if there might be a problem. Next, I decide if the risk presented by the medication is so high that I need to ask the prescriber to change it. Or, if the patient is young and healthy, I might decide to check an EKG to monitor the QT interval. Lowering the dose of methadone can help reduce the QT interval, but at the risk of de-stabilizing the patient, so that’s rarely the best course of action.

Opioid treatment programs vary widely in their abilities to get and interpret ECGs. Thankfully, I’m trained in Internal Medicine and feel comfortable getting my ECG calipers to calculate the QT interval and yes, of course I correct for heart rate too.

Here are two examples of how I handled potential QT situations.

The first patient was young and healthy, and dosing with methadone at 95mg per day. He was started on ciprofloxacin for two weeks for an infection. The other prescriber had done a culture of the infectious situation and cipro was one of few antibiotics that the bacteria was sensitive to, so antibiotic choices were limited. I decided to check an ECG after my patient had been taking cipro for a few days, and the QT was fine. He was able to remain on the cipro until the infection cleared, with no problems

The second patient was older, nearly 50, with several chronic medical conditions including severe mental health diagnoses. A new psychiatrist changed his medication and started him on ziprasidone (Geodon), a medication infamous for causing QT prolongation. My patient was dosing at 115mg per day, and extremely fearful about any dose change. I did an ECG as soon as I knew he was on Geodon, and his QT interval was significantly lengthened. I called his new psychiatrist and explained the problem and she immediately switched him to a lower-risk medication. A repeat ECG done a few days after the switch showed his QT was back to normal, and he did well on this second medication, with good resolution of his mental health symptoms.

Drug affected methadone metabolism by the Cytochrome P450 System

Other drugs and substances affect methadone blood concentrations by influencing the rate of methadone metabolism. Methadone is an active opioid, while its first metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (called EDDP for short), is not pharmacologically active. That metabolic process is done in the liver via the cytochrome P450 (CYP450 for short) system. Many other medications affect this system.

Some medications that affect the CYP 450 system slow methadone metabolism and are called inhibitors. They can increase methadone blood levels and the opioid effect it has. Conversely, medications called inducers speed metabolism of methadone into its inactive metabolite, and thus can reduce methadone’s blood level and effect.

Of course, rising or falling methadone blood levels affects patient stability.

To add to the complexity, there are different types of cytochrome P450 enzymes. Several are involved with methadone metabolism, named CYP 3A4, CYP 2D6, CYP2B6, and CYP 2C29. And each enzyme’s activity is further determined by what genes we’ve inherited. Other medications that are metabolized by CYP3A4 are thought to be particularly prone to affect methadone metabolism and regarded with more caution.

So…it’s complicated. But as if that complication weren’tt enough, some scientists now say that though in the past we thought methadone was mainly metabolized by CYP 3A4, that’s old data, and now, we should be looking at drugs metabolized by CYP 2B6. In fact, in a recent article I read, “It has now been unequivocally established that CYP2B6, not CYP3A4, is the principle determinant of methadone metabolism, clearance, elimination, and plasma concentrations in humans.”  [1]

Also, some medications act as inhibitors of inducers of methadone in a test tube but not in real life.

What’s a doctor to do?

Again, I’ve searched the internet for evidence-based recommendations. Should we increase the patient’s methadone dose if he’s started on a medication that induces methadone’s metabolism? Or should we wait to see if the patient has symptoms before we change the dose? Conversely, should we decrease a patient’s methadone dose if she is started on a medication that inhibits methadone’s metabolism, in case her blood levels are going to rise? Or should we just prohibit the use of any medication that can affect methadone blood levels?

That last option, though it would make my life easier, isn’t possible. For example, nearly all mental health medications interact with methadone in some way or another. There’s no way for a patient to get treatment without using medications with the potential to affect methadone metabolism.

Same as with the QT interval problem, the degree of risk must be assessed for each patient. The degree of risk varies with patient medical history, and the known risk of the inducers or inhibitors. For example, patients newly started on phenytoin nearly always have a clinically significant drop in methadone blood level. For those patients, I’ll make sure I have an order in place to increase their methadone dose with any symptoms of opioid withdrawal.

Most other cases aren’t so clear-cut. I’ll inform patients of potential risks and ask that they communicate with us regularly.

Almost all medications that treat HIV influence methadone metabolism, making it essential for the opioid treatment provider to communicate directly with the provider prescribing HIV medications.

In fact, good communication is essential with other prescribers and I try to cultivate a cooperative attitude with them, so far as it is possible with me.

Our opioid treatment program patients, particularly as they age, will be prescribed medication with possible interactions with their methadone. For their safety, each OTP must have a system in place that: 1. Gets patients to report new prescriptions as soon as possible 2. Gets that information to the program medical provider in order to make decisions about safety and monitoring 3. Informs patients of potential risks 4.  Arranges follow up meeting with medical providers when appropriate 5. Opioid treatment providers must collaborate with other prescribers when necessary

Each OTP needs a system that works for their facility, and methods can differ widely between OTPs. It doesn’t matter how we get the job done, just that it gets done.

Our patients’ safety depends upon this.

  1. Kharasch, “Current Concepts in methadone metabolism and Transport,” Clinical Pharmacology in Drug Devopement, 2019