Archive for the ‘Risk Evaluation and Mitigation Strategy’ Category

Probuphine Implants: Impractical?

Probuphine

The more I learn about Probuphine, the less I think it will be practical for use in the average office-based opioid use disorder treatment setting. I predict it will be a specialty medication implanted by a few practitioners who take referrals from other doctors.

Braeburn Pharmaceuticals is sponsoring conferences for doctors to learn how to insert Probuphine, the form of buprenorphine that’s implanted under the skin like Norplant, the birth control medication. This medication is marketed by Titan Pharmaceuticals. Probuphine consists of four slender rods that are inserted just under the skin at the upper arm. These rods release buprenorphine over six months, when they have to be removed, and new rods implanted.

I wasn’t sure I wanted to do Probuphine implants, but I liked the idea of being able to do it, so I asked to attend one of their conferences to learn the procedure.

Alas, the company says only doctors who have performed minor surgical procedures over the past ninety days are eligible to learn to be an implanter of Probuphine. I can still prescribe it if I take the course, their letter says, but I’d have to refer to someone else to implant Probuphine.

Huh? I thought I could prescribe it already, since I have an “X” number. Maybe not.

If I can prescribe it but I can’t administer it, why would the patient see me at all? Why not just go directly to the doctor who can prescribe and implant?

I looked around the room during my recent addiction medicine conference and tried to imagine how many of these specialists had done surgical procedures over the past three months. There was one surgeon, and a few obstetricians, so I decided three out of sixty or so of the doctors who presently prescribe buprenorphine.

Even if the FDA approves Probuphine in May, I have a hard time imagining how Probuphine could be used in a typical office-based buprenorphine practice.

Because besides the implantation conundrum, who pays for it? Drug company representatives were unable to answer questions about the cost.

And how does the implant, the implanting physician, and the patient all arrive at the appointment time? Is the doctor expected to order the implant, store it in her office, and hope the patient shows up for the implantation? Surely we couldn’t give a prescription to the patient to take to a pharmacy for the implant, so I’m not sure how that’s going to work.

Won’t this medication need prior approval? Representatives from the drug’s manufacturer say “no,” but I have a hard time believing that.

I picture one or two sites in North Carolina that will have the resources to do the implants and probably keep them in stock, perhaps at a hospital pharmacy. Maybe the teaching hospitals will have the resources to do this.

Also, the Probuphine delivers drug levels equivalent to six to eight milligrams of sublingual buprenorphine, so patients at higher probably won’t be considered.

I’m starting to doubt the practicality of Probuphine at an average addiction medicine physician’s office.

Benzodiazepines Associated with Increased Risk of Death

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

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

I know many people, without a history of addiction, can take sleeping pills without apparent problems, so I was surprised to read about this recent study. This relatively large study looked at the medical records of over 10,000 patients who were prescribed hypnotics for sleep, and compared their outcomes to over 23,000 matched control patients, similar except the controls weren’t taking sleeping pills.
The sleeping pills, also called “hypnotics” were associated with significant increases in mortality and significant increases in cancer incidence.

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

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

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

The use of hypnotic medications was also associated with an increased risk of cancer, and reached statistical significance in patients taking the most hypnotics. Lung, colon, and prostate cancers were significantly more likely to occur in these hypnotic medication users, as well as lymphoma.
The author estimated that hypnotic medications are associated with 320,000 to 507,000 deaths in the U.S. over the year 2010.

This study raises some important questions, since hypnotic drugs are the most commonly prescribed drugs in the U.S., with an estimated 6 to 10% of the population being prescribed these medications.

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

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

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

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

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

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

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

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

New Forms of Buprenorphine for Opioid Addiction Treatment

depot injection of buprenorphine

depot injection of buprenorphine

At this year’s American Society of Addiction Medicine conference, researchers talked about innovative ways to dose buprenorphine (formerly known as Suboxone) that may be available in the future.

One of the new products doesn’t yet have a trade name. Researchers call it “CAM 2038.” It’s made by Camurus Pharmaceuticals, a small Swedish company that invented a nanoscale drug delivery system, as they say on their website. This “Fluidcrystal” injection containing buprenorphine comes in preparations of varying doses, and can be dosed once per week or once per month, depending on the preparation.

The liquid substance containing buprenorphine is injected subcutaneously (under the skin), where it forms a gel. Then a capsule-type substance surrounds it, allowing buprenorphine to be into the body over time. The capsulized gel makes the medication time release. Started weekly, the dose can be adjusted to meet patient needs. Eventually, the patient can move to once-monthly injections. The matrix of material is biodegradable, and eventually completely absorbed by the body.

This subcutaneous injection of medication has a very low viscosity, meaning it can be given with small needles that cause less pain to the patient. The medication is already pre-mixed, making it convenient for medical providers, and it is stable at room temperature for up to three years.

This form of buprenorphine is in Phase II trials in Germany now, so it will be some time before it’s even considered in the U.S. for FDA approval. Per the Drug Addiction Treatment Act of 2000, without this FDA approval, it can’t be used to treat opioid addiction. As we know, the buprenorphine implant (Probuphine) was turned down for approval by the FDA earlier this year, likely because the implants didn’t deliver a high enough dose of buprenorphine to patients.

Initial trials with CAM 2038 don’t appear to have this problem. The company’s initial studies show a fast delivery of medication, giving rapid onset and a steady blood level over one week or one month, depending on the preparation given. Safety data was pretty good; other than some headache and a low rate of inflammation at the injection site, it was well-tolerated. Because of the Fluidcrystal technology, if an addict attempts to inject into the vein, it will form a deposit at the injection site, blocking the vein.

Reckitt-Benckiser, the company who makes sublingual brand name Suboxone and Subutex, is developing a medication using a depot technology called Atrigel. Buprenorphine is put into the Atrigel preparation, a precipitation polymer that must be mixed before being injected. This delivery form of buprenorphine is also in Phase II trials now. RB apparently bought exclusive rights to use the Atrigel technology about four years ago.

These injectable depot forms of buprenorphine may be superior to sublingual forms of buprenorphine in the treatment of opioid addiction for several reasons:

First, with daily buprenorphine dosed sublingually, some patients relapse. They may decide to stop taking the buprenorphine for a few days so that they can use their opioid of choice and get high again. True, they have to do a little more planning to relapse than if they were not on buprenorphine, but relapse rates are still too high. The depot forms make relapse less likely, I think, because compliance is assured once the medication is injected.

Second, with the depot forms of buprenorphine, the patients don’t have to think about taking something to treat their addiction. They don’t have to think about their medication at all, and their addiction doesn’t have the chance to urge them to take more of their medication than prescribed. Thankfully with buprenorphine there is a ceiling to its opioid effect, so that patients already on a blocking dose of sublingual buprenorphine won’t usually feel any intoxication from taking more of their medication. But the disease of addiction is always telling the addict, “More!” so injectable forms thwart that urge completely.

Third, we’ve seen recent increases in the numbers of emergency department visits due to buprenorphine. Pediatric exposure remains a huge concern. Unlike pills which must be swallowed to have an effect, children who put the sublingual forms in their mouths will absorb the medication. Any pediatric exposure to buprenorphine is too much; unfortunately there have been a few pediatric deaths as well. With depot forms of buprenorphine, I don’t see how pediatric exposure would be possible.

Fourth, and probably politically most important, diversion of buprenorphine into the black market is getting much attention from press and law enforcement officials. More people are being arrested with illicit buprenorphine tablets and films, and law enforcement personnel believe buprenorphine is a desirable street drug. Of course, research shows most people using it illicitly are trying to prevent withdrawal and not trying to get high. The actual proportion of this medication getting into the black market hasn’t really risen; it’s being prescribed much more, so there’s more buprenorphine to be diverted. But diversion makes buprenorphine look like a desired street drug, and puts the DATA 2000 program at risk. I don’t see how a depot injection can be diverted, though I don’t doubt someone will try.

According to the Drug Addiction Treatment Act of 2000, the FDA must give approval to any form of buprenorphine that’s to be used to treat opioid addiction. At present, only the sublingual form of buprenorphine has that FDA approval. Other forms of buprenorphine in patch (Butrans) or injectable form are illegal for a doctor to prescribe to treat opioid addiction. If these new preparations of buprenorphine get approved, there will be a second delivery form that can be used in patients with addiction.

I like the idea of these depot injections. I’ve decided I don’t want to learn to do the minor surgery required to place Probuphine implants, but I can already do intramuscular and subcutaneous injections. Plus, I’d be seeing the patients once a week or once a month, rather than every six months with the implants. That’s more opportunity to keep track of what is happening with the patient’s addiction treatment counseling, a key component of recovery from addiction.

I’m looking forward to more research on these new forms of treatment.

In Utah, Pain Medicine Specialists have the Highest Death-to-Prescription Rates

Of all fifty states in the U.S., Utah has the fourth highest opioid overdose death rate. In a study presented at this year’s American Academy of Pain Medicine conference, one researcher compared data from Utah’s prescription monitoring program with information regarding prescription opioid deaths in that state. She did this to discover which physician specialties have the highest death-to-opioid prescription rates. (1)

The results were somewhat surprising. Though pain medicine specialists wrote only 1% of all opioids prescribed in the state, their patients accounted for 3% of the state’s overdose deaths. Family practice physicians prescribed the highest amounts of opioids in Utah, but had half the death rates of pain medicine specialists. Other specialties with high death-to-prescription rates were anesthesiologists, physiatrists (physical medicine and rehabilitation doctors), and physician extenders (nurse practitioners and physicians’ assistants).

Specialties with the lowest risk were internal medicine doctors, orthopedic surgeons, emergency room doctors, and dentists.

Of course, pain medicine specialists correctly responded to this data by reminding us that association doesn’t prove causation. The pain medicine specialists say they care for the most complicated of patients, referred when primary care physicians feel they need expert help.

This is an important point. You have to look at the population being treated.

I’m reminded of a similar example in my region. A few years ago, a local suburban community hospital claimed that patients admitted to their hospital had the lowest complication rates of any hospital in the area. They were correct, but it was because they referred very sick patients to a nearby urban tertiary care hospital. That hospital, caring for the sickest of the sick, had a high complication rate for their inpatients. In other words, the data was accurate but still misleading, due to the marked differences in the patient population treated by each hospital.

In the same way, pain medicine experts aren’t likely to be caring for uncomplicated, easily treated patients. The tough, complicated cases will be referred to them from primary care doctors.

Pain medicine specialists also point out that dentists and primary care doctors may be prescribing for many patients with acute, short-term pain. This type of patient is likely at less risk than patients with chronic pain from serious illnesses. The amount and strength of opioids that dentists and primary care doctors prescribe is likely to be lower than the amount and strength of opioids prescribed by pain specialists. And we know that the higher the dose of opioids prescribed, the more likely the patient is to suffer an overdose death.

The author of the study acknowledged the difficulty in interpreting the data, but also said she felt this information indicated a need for education for all the state’s physicians. Adding support for her recommendation is a report released last fall that describes the results of a survey of pain medicine specialists. (2) Only 70% of these specialists answered questions correctly about opioid abuse and the FDA’s new Risk Evaluation and Mitigation Strategies. Thirteen percent say they don’t assess their pain patients for risk of opioid misuse, which is now the recommended standard of care for all patients receiving long-term opioid prescriptions.

Getting back to the Utah study: It’s important to note that even in this state with a high overdose death rate, only .475% of all opioid prescriptions were associated with fatalities

1.Drug and Alcohol Dependence News, Feb. 28, 2012, citing Porucznik C, et al, “Physician specialty and opioid prescribing in the Utah controlled substance database 2005-2009 AAPM; Abstract 201.

2. http://www.medscape.com/viewarticle/749713