Black Box Warning

 

 

Last month the FDA (Food and Drug Administration) announced their decision to require black box warnings on opioid and benzodiazepine prescribing information. This warning will state that co-prescribing these two classes of medications increases the risks to patients of death, coma, sleepiness, and respiratory depression. The FDA also said they would require medication guides for patients, describing these risks.

Black box warnings are the strongest warnings issued by the FDA. These warnings are literally placed in a bold black box at the top of the prescribing, where the information is most noticeable.

I applaud the FDA’s action. I think FDA’s statement will make physicians and other providers think twice before blithely writing a benzodiazepine prescription for a patient already prescribed opioids. A black box means, “Take this seriously!”

Ten years ago, co-prescribing of opioids and benzodiazepines was commonplace for primary care physicians in my area. Earlier this year, our state medical board announced they would investigate the top prescribers of opioids and benzodiazepines together. Since then, I have noticed some prescribers appear to be backing away from the routine prescribing of benzodiazepines..

Most opioid treatment centers have policies in place to address benzodiazepine use, both licit and illicit. There are still a few OTPs who approve benzodiazepines to be prescribed for methadone or buprenorphine patients, but I think they are in the minority. Most opioid treatment program physicians feel that besides the dangers of sedation and overdose, there are few medical indications for long-term (more than three months) benzodiazepine prescriptions, and much better long-term treatments for anxiety disorders.

An article In the April 16^th, 2016 issue of the American Journal of Public Health underlined how important it is to evaluate benzodiazepine prescribing in the U.S., particularly when prescribed along with opioids. [1]

The authors begin the article by stating that benzodiazepines were found to be involved in nearly a third of opioid overdose deaths in 2013. The authors wished to investigate nation trends in benzodiazepine prescribing and in fatal overdoses involving benzodiazepines.

The authors found the percentage of U.S. adults filling benzodiazepine prescriptions increased significantly over past years. They also found that among people who filled benzodiazepine prescriptions, the amount, defined as lorazepam equivalent doses, also increased significantly. Simultaneously, overdose deaths rates involving benzodiazepines rose nearly four-fold, though deaths appear to have plateaued since 2010.

Another study, this time in Canada, evaluated the risk of death in polysubstance users. In a prospective cohort study of IV drug users, done from 1996 through 2013, benzodiazepine use was more strongly associated with death than any other substance of abuse. [2

Many patients ask why they can’t take benzodiazepines while on methadone or buprenorphine. I tell them I’m mainly worried about the increased risk for overdose death, but I also tell them benzodiazepines are over-prescribed. Prescribing information suggests benzodiazepines are most beneficial when prescribed for no more than three or four weeks. Long-term prescribing of benzodiazepines is generally discouraged, due to serious side effects seen even in patients with no substance use disorders.

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.

Although an association of benzodiazepines with these conditions doesn’t necessarily mean benzodiazepines cause these conditions, it’s a good reason to be conservative when prescribing benzodiazepines and other sedatives, pending further studies.

Sedative medications including benzos can make undiagnosed sleep apnea worse, even to the point of causing death. Obesity increases the risk of sleep apnea, and with more adults becoming obese, the risks of benzodiazepines in such patients may be overlooked.

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.

1. Bachhuber et. al., “Increasing Benzodiazepine Prescription and Overdose Mortality in the Unites States, 1996-2013,” American Journal of Public Health, April 16, 2016.
2. Walton et. al., “The Impact of Benzodiazepine Use on Mortality Among Polysubstance Users in Vancouver, Canada,” Public Health Rep., 2016 May-June;13(3)491-9.

September is National Recovery Month!

September is National Recovery Month, so it’s a good time to come back from my blogging break. Following are some things that recovery means to me, and I hope my readers will write in with their own definition of recovery.

Recovery means…

….taking the worst and most embarrassing thing in my life and turning it into my greatest asset.

….becoming less judgmental of other people.

….remaining teachable.

….having more free time, after the burden of looking for the “next one” has been lifted.

…looking in the mirror, and feeling content at what I see.

….being satisfied with the small pleasures in life.

….developing a thicker skin for judgmental people. They aren’t going to ruin my day.

….re-connecting with the human race.

….re-connecting with the God of my understanding.

…reconnecting with myself.

….doing what I need to do for my well-being, even if other people don’t approve.

….being happy when I make progress, no longer expecting perfection.

….understanding it’s more important what I think of me than what other people think of me.

….talking frequently with other people who share my passion for recovery.

Recovery goes beyond 12-step programs or medication-assisted treatment. Recovery can apply to issues other than drug addiction. It can apply to eating disorders, co-dependency, gambling problems, sex addiction, or any other compulsive activity that is bad for our health. We can be in good recovery in one area of our life and be in active addiction in other areas. We have good and bad days. We relapse, and we try again, and we stop listening to the voice of addiction that tells us we should give up because we will always fail. We learn from our failures and come to look at them as opportunities for growth. We turn stumbling blocks into stepping stones. We lift up our fellow travelers when they weaken and they do the same for us.

We do recover.

 

Methadone Overdose Deaths: First Two Weeks

 

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

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

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

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

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

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

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

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

-Age over 60

-Using sedating drugs like benzodiazepines

-Regularly consume alcohol

-Are on prescription medications which can interact with methadone

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

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

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

 

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

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

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

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

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

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

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

This is a powerful study because it was so large.

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

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

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

 

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

Judges Behaving Badly

 

Methadone and buprenorphine treatment for opioid use disorders saves lives. Over five decades, we’ve accumulated more studies to support this treatment than any other medication, device, or intervention that I can think of. And yet, opioid use disorder appears to be the only disease where medically untrained people dictate medical treatment. The above memo from a judge of the 24^th District Court in North Carolina illustrates this all too well.

Let’s change that sentence in the middle of Judge Ginn’s memo: “Therefore, effective immediately, the use of insulin as a treatment for diabetes will no longer be allowed as a part of any probationary sentence in the 24^th Judicial District.”

It wouldn’t make any sense, would it? People would wonder why a judge was involved in a patient’s medical care. They might even be tempted to believe a judge had no authority to dictate medical care.

I worked in Boone, North Carolina, when this memo was issued, and it caused a great deal of suffering for patients. These patients, contrary to the judge’s beliefs, were doing well on medication-assisted treatments. They were no longer injecting drugs or committing crimes to support their active addiction. Their involvement with criminal justice system almost always pre-dated their entry into treatment. Yet the judge proclaimed they must stop the very medications that were helping them become productive members of society again!

I wrote letters of advocacy and information, citing studies that support MAT. I encouraged patients, and told them to expect their lawyer to advocate for them on this issue. The patients said their lawyers often advised them just to do what would make the judge happy. Patients, understandably, were timid about pushing against a judge with so much power over their lives.

Ironically, many of the people Judge Ginn thought were doing well in his court were also our patients. It was widely known that probation officers’ drug tests didn’t detect methadone or buprenorphine at that time. Unless the offender told the truth about being in treatment on buprenorphine or methadone, the court never knew. I’d estimate that dozens of people successfully passed through Judge Ginn’s court while being treated with buprenorphine or methadone, without him ever knowing about it, due to inadequate drug testing. The people who told the truth were penalized by being told to quit life-saving medication.

I know Judge Ginn is now retired, but I suspect attitudes and beliefs of the judiciary in that area haven’t changed much.

One of the opioid treatment programs in the area tried to advocate for their patients, by seeking some sort of censure against Judge Ginn, but I don’t know what came from that.

The National Institute on Drug Abuse (NIDA) and Substance Abuse and Mental Health Services Administration (SAMHSA) both strongly recommend expanding opioid addiction treatment with medications to criminal justice participants. Congress just passed a bill that recommends spending money to treat opioid addiction in jails and prisons That bill pushes for people with opioid use disorder to get treatment instead of jail sentences. Experts everywhere advocate for expanding medication-assisted treatments to patients involved with the legal system, whether in jail, on parole, or on probation.

All of these actions are great. But Judge Ginn is an example of the many obstacles to implementation of the evidence-based treatments that experts recommend. Particularly in rural Appalachian areas, people in positions of power actively thwart life-saving medical treatments.

I don’t understand how judges can get away with such irresponsible actions. To me, it appears Judge Ginn practiced medicine without a license. If I somehow lost my medical license but continued to practice, I’d be committing a felony.

What if Judge Ginn commanded a patient stop buprenorphine or methadone, and the patient died in a relapse? Would Judge Ginn have any liability, civil or criminal?

I don’t know what can be done about judges like him, but don’t they have to answer to someone? Are they appointed, or elected? If elected, perhaps we need to start understanding judges’ positions on medical treatments before we vote for them.

Follow up on Pharmacy Failings

 

In the August 1, 2016, issue of Alcoholism and Drug Abuse Weekly, the editor, Alison Knopf, wrote an interesting article summarizing her research into pharmacy refusal to stock buprenorphine products. (website: http://alcoholismdrugabuseweekly.com )

Regular readers of my blog will recall entries last month that described how our local Walmart pharmacy at first refused to stock any buprenorphine product. Then a few days later, after some political pressure was applied by people with clout,  Walmart  changed their minds, and proclaimed that all Walmart pharmacies will stock buprenorphine products.

Ms. Knopf did more research into what happened, and describes it in the ADAW article. While the local pharmacist didn’t comment directly, a representative from the American Pharmacists’ Organization described what usually happens in such cases.

Apparently, DEA agents came to the North Wilkesboro Walmart Pharmacy, and told employees that they were investigating a buprenorphine prescriber (thankfully not me). Perhaps using some scare tactics, the agents told pharmacists that if they continued to fill buprenorphine prescriptions from the prescriber in question, they could be guilty of conspiracy and charged a large fine. Obviously worried, the Walmart pharmacists “over-reacted” and decided for a brief time not to stock buprenorphine or fill it, in any form.

I have to wonder why the DEA wouldn’t take their concerns to the physician in question, or to the state medical board, rather than try to strong-arm pharmacists.

The ADAW article went on to quote ASAM (American Society of Addiction Medicine) president-elect Kelly Clark, M.D., who said that organization has received reports from other areas of the country of pharmacies refusing to stock buprenorphine.

Dr. Tom Reach, president-elect of the Tennessee Society of Addiction Medicine, was quoted in the same article, saying he’s had the same problem in Eastern Tennessee. In that area, the problem isn’t limited to only Walmart pharmacies, but also Walgreen’s and CVS. Dr. Reach said they are building a class action case against these pharmacies. He also mentioned he’s keeping a database of all the pharmacies in Tennessee and West Virginia that refuse to prescribe buprenorphine.

I’m glad the problem in my area has been fixed. And I’m dismayed to discover the problem still exists in other parts of the country.

With so many people dying of opioid overdoses, physicians need pharmacists to help us treat these patients, not to put up roadblocks to treatment.

To Taper or Not To Taper…

 

Below is a comment responding to my last blog post, and my answer to it. I thought this aspect of buprenorphine treatment was so important that it’s worth a blog of its own.

While I wholeheartedly disagree with a decision not to stock any buprenorphine products at a pharmacy, I understand what led to it. The area has a troubling pattern of buprenorphine use to maintain dependence instead of being tapered to actually treat the dependence and help the patient. A pharmacist should be able to refuse prescriptions that are being prescribed and/or used inappropriately without having to fall back on a blanket “we no longer stock it” statement. Ensuring that patients who are being gradually tapered to treat dependence or bring treated for pain have a harder time getting their medication is not an acceptable way to lessen the abuse.

         Posted by janaburson on July 28, 2016 at 8:56 pm  edit

Aha!! You may be on to something. Maybe these pharmacists think, like you do, that buprenorphine should be tapered, instead of being used as a maintenance medication. When it first came out, I think many of us hoped we could taper people off of it quickly. However, more & more studies are showing that the patients who stay on buprenorphine do the best. By best, I mean not dying, no illicit opioid use, can hold down a job, finish school, be a good parent, etc.
People who taper have a high relapse rate. Relapses can be deadly. Our opioid overdose death rate is already too too high. Let’s not make it worse by insisting opioid use disorder be treated like a short-term illness, rather than the chronic disease that it is.
Having said that, patients are different, and taper may be appropriate in selected patients. But it’s not a quick process and it takes time to get the counseling and make life changes.
Would you tell a diabetic, who is not eating right or exercising, that they should taper off metformin, since if they changed their behavior, they would not need medication?

I forget there are still people who think buprenorphine should only be used temporarily, as a detoxification medication. I’m not saying that’s always wrong. A minority of patients may do well with only a taper, but most patients with opioid use disorder do better if they stay on buprenorphine long-term.

Does that mean these patients should never taper off buprenorphine? I’m not willing to say that either. We don’t have enough information from good studies to show us how long is long enough.

We do have studies now that tell us tapering off buprenorphine after a few months of stabilization isn’t going to produce best outcomes for most patients.[1, 2, 3]

We also know active opioid use disorder is associated with a high mortality risk.

Some people do misuse buprenorphine, and shouldn’t be kept on this treatment. Those patients will do better with another form of treatment, perhaps methadone.

Let’s take what we know about opioid use disorder and its treatment with buprenorphine, and apply it to an imaginary disease that has no moral judgment attached. Let’s call our disease “Syndrome X.”

We know Syndrome X causes a great deal of emotional, physical, and spiritual suffering. It can occur in anyone, and has a high mortality rate. It can be effectively treated with a medication that is relatively safe, and does not cause euphoria when used correctly. However, the medication can cause some withdrawal if it’s stopped suddenly.

While on medication, patients with Syndrome X feel normal, unlike how they feel off medication. On medication, these patients are more likely to be in better physical health, mental health, and are more likely to be employed. They are more likely to be productive members of their families and their communities.

The studies of patients with Syndrome X show pronounced reduction of death rates while patients are on medication, as well as lower rates of infectious diseases. We also know from studies that if patients with Syndrome X are tapered off their medication, their death rates increase anywhere from three times to sixteen times compared to if they stayed on their medication.

Who in their right mind would ever recommend tapering the medication? Who would say to their loved one, “You’ve got to get off of that stuff. You just need to be strong.” Or, “Isn’t it time you stop using that crutch?”

It’s only because of the stigma this country has against people with substance use disorders that tapering off a life-saving medication is even an issue. If we were talking about any other chronic illness, there would be a loud clamor for every person to be able to get on and stay on that medication. In fact, doctors not prescribing a medication with as much benefit as buprenorphine has for opioid use disorder would be accused of malpractice.

I don’t push my patients to taper off buprenorphine. If that is their desire, I’ll do everything I can do to help them. I tell them what I’ve seen work in my other patients, work with them on relapse prevention, and encourage them to go slowly, to give their brain time to adjust as their dose comes down.

I’ve had many patients taper successfully, and most of them did this after at least a few years of stability on buprenorphine. When I see new patients, I tell them this isn’t (usually) a quick fix that they can do in a few months and be cured forever. A few lucky patients are able to taper quickly but I think we now have studies showing this isn’t the situation for most people with opioid use disorder.

How about this: leave the timing of the taper up to the patient and their doctor.

If you aren’t one of these two people, maybe you don’t get to have an opinion on when or even if a taper should be attempted.

1.Fiellin et al, See comment in PubMed Commons belowJAMA Intern Med. 2014 Dec;174(12):1947-54.

This study concluded “Tapering is less efficacious than ongoing maintenance treatment in patients with prescription opioid dependence who receive buprenorphine therapy in primary care.” The taper arm of the study was started after six weeks of stabilization, with a three week taper. Patients on the taper were offered medication to help withdrawal symptoms and also offered naltrexone treatment. Patients who tapered were significantly more likely to have opioid-positive drug screens compared to the patients who remained on buprenorphine maintanence. Patients on maintenance were significantly more likely to remain in treatment for addiction counseling that the patients were tapered.

2.Marsch et al,  See comment in PubMed Commons belowAddiction. 2016 Aug;111(8):1406-15.

This study of fifty-three young people aged 16 to 23 were enrolled in a double-blind, placebo-conrolled trial. Subjects enrolled in the arm of the study where buprenorphine was tapered over fifty-six days were signigicantly more likely to have opioid-negative drug screens and continued participation in treatment compared to subjects given twenty-eight day tapers

3.Weiss et al, Prescription Opioid Addiction Trial

“Adjunctive Counseling During Brief and Extended Buprenorphine-Naloxone Treatment for Prescription Opioid Dependence: A 2-Phase Randomized Controlled Trial.”  Archives of General Psychiatry 2011.

This study of prescription pain pill users found that taper off buprenorphine after stabilization shows a high relapse rate.