Monday, January 28, 2019

Comparing medications to treat opioid use disorder

My first day returning to work after being treated for a severe opiate addiction was one of the most daunting moments of my life. Everyone in the office, from my manager to the administrative assistants, knew that forged prescriptions and criminal charges were the reason I had been let go from my previous job. My mind was spinning. What would my coworkers think of me? Who would want to work alongside an “addict”? Would they ever come to trust me? Did I even deserve to be here?

When my life was crashing and burning due to my addiction (detailed in my memoir Free Refills: A Doctor Confronts His Addiction), a return to work seemed like a distant prospect, barely visible on a horizon clouded by relapses, withdrawal, and blackouts. My finances, my professional reputation, and my family life were in terrible shape due to my drug-seeking behavior. Working was not a tenable option until I received treatment and established a solid track record of recovery, which a potential employer could rely on.

The fact that I was now in recovery was a great development, and it was further ratification of my progress that I had landed a job and was returning to work. So, why wasn’t I feeling overjoyed?
How stigma affects the return to work

As it turns out, the transition back to work after someone is treated for an addiction can be profoundly stressful. People recovering from addiction already tend to suffer disproportionately from guilt, shame, and embarrassment, and these feelings are often brought to the forefront during the unique challenges of returning to work.

Stigma is what differentiates addiction from other diseases, and is primarily what can make the return to work so difficult. If I had been out of work to receive chemotherapy or because of complications from diabetes, I certainly wouldn’t have felt self-conscious or self-doubting upon resuming my employment. With addiction, due to the prejudices that many people in our society hold, the return is psychologically complex and anxiety-producing. As I entered my new office, I was walking right into the fears, preconceptions, and potential disdain that my new officemates might share toward people suffering from a substance use disorder. For all I knew, I was the “dirty addict” that they now, against their wishes, had to work with.
“Bring your body and your mind will follow”

What I was taught in recovery, to deal with situations like this, is to “just keep your head up” and to “put one foot in front of the other.” Or, “bring your body, and your mind will follow.” When I first heard these phrases, I thought that they were mere platitudes, phrases without content, provided to motivate us through dark times. Now, I think they hold a great deal of wisdom.

As I walked through the door on my first day back, I did feel everyone’s eyes on me, and I did wonder if they were judging and criticizing me, but I made it to my desk without incident, and managed to power through my self-consciousness and get into the flow of my work. Every day, it became easier as I did a good job, deepened my connections with my colleagues, and accumulated good will, which would eventually replace any negative images that may have accompanied my arrival. Within weeks this was a non-issue, though at office get-togethers, my co-workers still somewhat awkwardly don’t know whether to put a wine glass at my place setting.

With all I had learned in recovery about communication, about humility, about connecting with others, I feel that I was in a better position to thrive in my workplace than I was before my addiction started in the first place. As more of my brothers and sisters in recovery return to employment, and as we succeed, the more difficult will it be for people to hold on to their negative attitudes and prejudices about substance use disorders. We can defeat the stigma by confronting it, putting one foot in front of the other, one step at a time.
This one got by me. I’d never heard of “man flu” but according to a new study of the topic, the term is “so ubiquitous that it has been included in the Oxford and Cambridge dictionaries. Oxford defines it as ‘a cold or similar minor ailment as experienced by a man who is regarded as exaggerating the severity of the symptoms.’”

Another reference called it “wimpy man” syndrome. Wow. I’d heard it said (mostly in jest) that if men had to carry and deliver babies, humankind would have long ago gone extinct. But wimpy man syndrome? I just had to learn more.
What is man flu?

As commonly used, the term man flu could be describing a constitutional character flaw of men who, when felled by a cold or flu, embellish the severity of their symptoms, quickly adopt a helpless “patient role,” and rely heavily on others to help them until they recover. Another possibility is that men actually experience respiratory viral illnesses differently than women; there is precedent for this in other conditions. Pain due to coronary artery disease (as with a heart attack or angina) is a good example. Men tend to have “classic” crushing chest pain, while women are more likely to have “atypical” symptoms such as nausea or shortness of breath. Perhaps the behavior of men with the flu is actually appropriate (and not exaggerated), and based on how the disease affects them.

Here are the highlights from the study:

    Influenza vaccination tends to cause more local (skin) and systemic (bodywide) reactions and better antibody response in women. Testosterone may play a role, as men with the highest levels tended to have a lower antibody response. A better antibody response may lessen the severity of flu, so it’s possible that vaccinated men get more severe symptoms than women because they don’t respond to vaccination as well.
    In test tube studies of nasal cells infected with influenza, exposure to the female hormone estradiol reduced the immune response when the cells came from women, but not in cells from men. Treatment with antiestrogen drugs reduces this effect. Since flu symptoms are in large part due to the body’s immune reaction, a lessened immune response in women may translate to milder symptoms.
    In at least one study reviewing six years of data, men were hospitalized with the flu more often than women. Another reported more deaths among men than women due to flu.
    A survey by a popular magazine found that men reported taking longer to recover from flu-like illnesses than women (three days vs. 1.5 days).

Taken together, these findings suggest that there may be more to “man flu” than just men exaggerating their symptoms or unnecessarily behaving helplessly. While the evidence is not definitive, they suggest that the flu may, in fact, be more severe in men.
If it’s true that men get sicker with the flu, why?

Some have suggested that early man evolved to require more prolonged rest while sick to conserve energy and avoid predators. In more modern times, the advantage of a longer recovery time is less clear beyond the obvious. When you don’t feel well, it’s nice to be taken care of. Of course, that’s true for women as well.
The bottom line

Diseases can look different in men and women. That’s true of coronary artery disease. It’s true of osteoporosis, lupus, and depression. And it may be true of the flu. So, I agree with the author of this new report, who states “…the concept of man flu, as commonly defined, is potentially unjust.” We need a better understanding of how the flu affects men and women and why it may affect them differently.

Until then, we should all do what we can to prevent the flu and limit its spread. Getting the flu vaccination, good handwashing, and avoiding others while sick are good first steps. And they’re the same regardless of your gender. Using medications to treat opioid use disorder is a lifesaving cornerstone of treatment — much like insulin for type 1 diabetes. The flawed but widely held view that medications like methadone or buprenorphine are “replacing one addiction for another” prevents many people from getting the treatment they need. In actuality, people successfully treated with these medications carefully follow a prescribed medication regimen, which results in positive health and social consequences — as in patients with many types of chronic medical conditions.

However, even among those who embrace treating opioid use disorder (OUD) with medication, there is a difference of opinion as to which medications are most effective. A new study offers important insight into the advantages and disadvantages of the two medications for OUD that can be prescribed in a doctor’s office (that is, on an outpatient basis). These medications are buprenorphine and extended-release (ER) naltrexone. This study was widely covered in the press, and many of the sound bites and headlines reporting the two treatments to be equally effective were a bit misleading.
The advantages and disadvantages of buprenorphine (Suboxone, Subutex, Zubsolv, Probuphine, Sublocade)

Buprenorphine is a partial opioid agonist medication. This medication activates the same receptors in the brain as any opioid, but only partly. Because its effects are long-lasting, it can be taken once a day to relieve cravings, prevent withdrawal, and restore normal functioning in someone with opioid use disorder. Because it is a partial agonist, it has a ceiling effect. This means once all the receptors are occupied by the medication, even if a person takes 20 more tablets she wouldn’t feel any additional effect or be at risk of overdose.

Any doctor who has completed special training (a primary care provider, addiction specialist, OB/GYN, etc.) can prescribe buprenorphine. The advantage is, theoretically, that a person with OUD could receive treatment from any provider he or she might see for a routine health issue. I say theoretically because, despite its availability, only about 4% of physicians have done the necessary training to be able to prescribe it. The research on buprenorphine is robust, with multiple studies showing it reduces the risk of death by more than 50%, helps people stay in treatment, reduces the risk that they will turn to other opioids (like heroin), and improves quality of life in many ways.
The advantages and disadvantages of naltrexone (Vivitrol, Revia)

Naltrexone is a pure opioid antagonist. It sticks to an opioid receptor, but instead of activating it to relieve craving and withdrawal it acts as a blocker, preventing other opioids from having any effect. The research on naltrexone has been mixed. Naltrexone in pill form is basically no better than placebo because people simply stop taking it. Studies on extended-release naltrexone are more promising and have shown it to be better than no medication at all. However, there has never been a US trial comparing extended-release naltrexone to either methadone or buprenorphine, until this study.
The X-BOT study: Comparing buprenorphine and extended-release naltrexone

This study enrolled individuals with opioid use disorder who had voluntarily gone to a detoxification program. Researchers then randomly assigned them to either daily buprenorphine or monthly extended-release naltrexone. Both groups were followed for 24 weeks, to see how many people relapsed.

One of the most important things investigators learned is just how hard it was to get participants onto extended-release naltrexone, revealing a potential barrier to its usefulness. Before a person can start taking ER naltrexone, they must be completely off opioids for seven to 10 days. Only 72% of the group assigned to ER naltrexone even got the first dose, and among those who were randomized during the detoxification process, only 53% started the medication. In contrast, 94% of the group assigned to buprenorphine started the medication.

The other important finding was what happened with relapses. The researchers analyzed their data using an “intention to treat analysis.” This means that once a person is randomly assigned to a treatment (or placebo), their data counts even if they don’t stick with the treatment. Here’s why this is important: if you don’t include that data, then you miss other important outcomes that influence how effective a treatment really is. Thanks to this type of analysis, researchers learned that relapse was significantly more likely in the extended-release naltrexone group (65% compared to 57% in the buprenorphine group).

Immediate relapses were even more likely in the naltrexone group due to failures to start the medication — 25% of the naltrexone group had a relapse on day 21, compared to 3% in the buprenorphine group. Overall there were more overdoses in the naltrexone group, but no difference in fatal overdoses between the groups. Most of the overdoses occurred after the study medication was stopped, highlighting the lifesaving importance of getting on, and staying on, treatment. The naltrexone group also had a longer length of stay in inpatient detoxification programs, which may be an important consideration when we think about overall healthcare costs.

So, why did many headlines claim extended-release naltrexone was as effective as buprenorphine? Well, that was the finding of a separate analysis that looked only at people who successfully started each medication. When the data was viewed that way, there was no difference between the two medications, but that’s just part of the picture. If it’s harder to get a person to successfully start and stick with a medication, that should factor in evaluating its “effectiveness.”
Take-home messages from X-BOT

This is an incredibly important study. The findings are generally consistent with what I see in my clinical practice. Overall buprenorphine is a more effective treatment for opioid use disorder, in part because it’s easier to get patients started on it and they are more likely to stick with it. Extended-release naltrexone may be as good for people who can successfully complete the detoxification required before starting on it. Both medications have a place, but as with so many conditions and treatments, one size does not fit all.

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