Author Archive

Subcutaneous Buprenorphine Injections for Treatment of Opioid Use Disorders

 

 

 

 

 

I’ve blogged in the past about studies conducted on CAM2038, a new preparation of buprenorphine that can be given in a subcutaneous injection weekly or monthly. I think this delivery system holds great promise for the treatment of opioid use disorder.

Earlier this year, pharmacokinetic data from healthy volunteers showed that blood levels with the subcutaneous injections equaled the levels provided by sublingual means. This data supports the idea that the injections should provide therapeutic levels in patients with opioid use disorder. [1]

Later this year, a Phase II study was published in JAMA Psychiatry. Weekly subcutaneous preparation of buprenorphine was administered to 47 subjects with opioid use disorder. These patients were not seeking treatment, but had agreed to take part in this study, and all were diagnosed with opioid use disorder, either moderate or severe.

These subjects were given dose of either 24mg or 32mg one week apart, and had complete suppression of opioid withdrawal at both doses. The subjects were then challenged with varying doses of hydromorphone, and had sustained blockade of response to the hydromorphone. [2]

The six-month implant, brand name Probuphine, hasn’t been widely prescribed. As I predicted, the confusion over cost, insurance coverage, and implantation regulations have so complicated Probuphine’s use that mainstream medical providers aren’t considering its use. Also, it’s only indicated for patients on 8mg or less of sublingual buprenorphine, and patients have concerns about what will happen if it doesn’t work well. They ask if their insurance companies would pay for supplemental buprenorphine if the implant doesn’t work as well for them. I don’t know for sure, but I’m guessing they would not pay for supplemental medication.                                                                                                                                                                                                                                                                                                                                                                                                                 My biggest concern with Probuphine was that patients may be less inclined to come for counseling sessions if they have had a six-month implant that keeps them feeling normal. They have no monthly incentive to see their physicians. Many physicians require counseling as a condition for ongoing monthly prescription for sublingual buprenorphine.

I like the idea of injections for weekly or monthly buprenorphine. If it works as well or better than sublingual buprenorphine, it could be the solution to some difficult problems.

  • It would save time for my patients on buprenorphine at the opioid treatment program. One of the complaints we hear is of the regulations surrounding treatment in our setting. Unlike in the office-based setting, buprenorphine prescribing at the opioid treatment program demands we follow the sometimes onerous rules of both state and federal laws governing opioid treatment programs.
  • It would resolve our diversion dilemma.But injections can’t be diverted, so far as I’m aware.
  • Because buprenorphine has a high street value in my community, patients are sometimes tempted to spit out their medication to sell it, or even to inject it into themselves. We don’t want this, given the high rates of complications with intravenous use. We don’t want patients to sell medication because it hurts our reputation in the community. We don’t want to be known as suppliers of illicit buprenorphine.
  • It would be a godsend for patients who have to go to jail unexpectedly.
  • Most of the time, jails won’t bring incarcerated patients to the OTP for their daily dose of buprenorphine (or methadone), so they suffer opioid withdrawal and are at risk for relapse upon being released, with increased risk of overdose death. But if we can give them a monthly or even weekly shot, it will keep them feeling better, and serve as a blocker if they do leave jail and use illicit opioids like Opana or oxycodone or heroin.
  • Patients wouldn’t have to think about taking medication each day; with the injections they wouldn’t have to take a dose of anything each day, just show up for weekly or monthly injections given to them by a medical professional
  • Subcutaneous injections are much less complicated to administer than Probuphine, with rods that require a minor surgical procedure to implant, then explant six months later.The FDA plans to discuss this new preparation of buprenorphine at their advisory committee meeting November 1, 2017. Several days prior to this meeting, data to be discussed at this meeting should be available online for interested readers. [3]If this new option is approved by the FDA, it can give us yet another tool with which to treat patients, always a good thing.
  • 1. Albayaty et al., Advanced Therapeutics, 2017, Feb; 34 (2)

 

  • 2.Walsh et al., JAMA Psychiatry, 2017;74(9):894-902.

 

Advertisements

Maximum Daily Dose of Buprenorphine

Hser et al., 2014, Addiction

 

 

 

 

 

I’d like to thank my readers for their patience during my recent break from blogging. Now that I’m rested, it’s time to start barbequing some sacred cows.

First on my list: limiting the dose of sublingual buprenorphine to 16mg per day.

Recently I’ve heard from physicians who have been told 16mg of sublingual buprenorphine is the highest daily dose that should be prescribed, because studies show that opioid receptors in a human brain are saturated at that dose in most people. While this is true, limiting all patients to 16mg or less neglects research from real life patients.

Some governmental agencies have gone as far as forbidding daily doses higher than 16mg. For example, the Virginia Board of Medicine passed a regulation earlier this year that the highest dose that physicians could prescribe was 16mg per day. In Tennessee, patients can’t go above 16mg per day unless they are seen by an addiction specialist physician.

However, the FDA has approved doses up to 24mg SL per day. Who is right? Did the FDA get it wrong? Are patients who want to go higher than 16mg all drug seekers? Or do all such patients plan to sell their excess medication?

If you read the REMS document created by the manufacturer of Suboxone film, it says the target dose should be no higher than 16mg per day, and that doses higher than 24mg haven’t been shown to provide additional benefit. That leaves a question mark about dosing between 16 and 24mg.

The American Society of Addiction Medicine (ASAM) issued a statement addressing the tendency of state prescription monitoring programs to assign MME (morphine milligram equivalents) values to buprenorphine doses. In that statement, issued earlier in 2017, they said, “The US Food and Drug Administration (FDA) approves dosing to a limit of 24 mg per day. There is some evidence regarding the relative efficacy of higher doses.” [1]

If ASAM says 24mg is OK for some patients, and the FDA has already approved that dose, that’s good enough for me…assuming the patient truly needs a higher dose.

Some patients do better on a dose of 24mg than on 16mg. I work at an opioid treatment program where we observe the patients taking their doses on site, and we pay close attention to any attempt at diversion of the dose. Therefore, we have no question about whether a patient is taking less than the dose I’m prescribing.

When I see new patients within a week or two of admission, I ask how they are feeling. Some patients dosing at 16mg per day of buprenorphine describe symptoms consistent with opioid withdrawal by late evening. I increase their dose above 16mg when I also see physical signs of withdrawal, like large pupils, sweaty palms, and the like. Many patients feel improvement to the point we don’t have to consider switching to methadone.

I increase these patients’ doses because I am sure they are getting their full dose each day, and because I see signs of withdrawal with my own eyes. I know experts say a dose of 16mg is “supposed” to block all the opioid receptors according to studies of this drug, and I believe that is true for many patients. I also think there are patients for whom increasing the dose above 16mg provides benefit, and can eliminate the need to switch to methadone.

Not that there’s nothing wrong with methadone. It has a proven track record, but it does have more medication interactions than buprenorphine, and is more dangerous with certain medical problems.

Methadone patients were under-dosed for years, when physicians had the misperception that no patient needed more than 70mg per day to treat withdrawal. With further studies and information, we know that’s not true, and best evidence shows most patients need between 80-120mg, and sometimes much more than that.

I think in years to come, we will see that by limiting patient doses to 16mg, we are under-dosing some buprenorphine patients.

Why are so many agencies trying to keep buprenorphine doses low?

First, the U.S. has a “less is more” attitude regarding medication-assisted treatments for opioid use disorder. Given the existing bias against these medications, of course some peoples’ attitudes will be grudging acceptance of the medications, but trying to limit the doses to be as low as possible.

Second, there’s the very real concern about diversion of buprenorphine. The more buprenorphine that’s being prescribed and dispensed, the more that may end up being diverted to the black market. I know this is true.

However, opinions can differ regarding the potential harm of providing more buprenorphine to the black market. Some experts might think since buprenorphine is one of the safest opioids manufactured, increased black market access could help save lives. Though many more people embrace harm reduction now than ten years ago, we are not yet in a place where the law-and- order types would allow a serious conversation about this.

Third, I’m worried that some decisions about dose maximums for buprenorphine may be driven by cost. In a state where many patients prescribed buprenorphine products are on Medicaid, higher doses would cost the state more. The same would be true for managed care organizations and the insurance companies and the like. I hate to sound cynical, but financial concerns often drive medical decisions.

By now you know my opinion; if a patient dosing with buprenorphine 16mg SL per day reports withdrawal symptoms and has physical signs that match these symptoms, I’m willing to increase the dose to 20 to 24mg per day. We have a pretty good study, by Hser et al., 2014, that shows higher treatment retention rates with higher doses. Plus, the FDA has already approved doses up to 24mg per day. [2]

I’m cautious about take home dose in patients at the opioid treatment program. If the patient has a history of injecting drugs, I’d like them to have more time in stable recovery before granting take homes. For patients on 24mg per day, I may do more frequent pill counts and bottle recalls, as a precaution against drug diversion. But I’m not sure a patient on 16mg is any less likely to sell part of her prescription than a patient dosing at 24mg.

  1. https://www.asam.org/advocacy/find-a-policy-statement/view-policy-statement/public-policy-statements/2016/10/11/public-policy-statement-on-morphine-equivalent-units-morphine-milligram-equivalents
  2. Hser et al., “Treatment Retention among Patients Randomized to Buprenorphine/naloxone Compared to Methadone in a Multi-site Trial,” Addiction, 2014, Jan; 109(1) 78-87.

 

Taking a Break

Hurricane Harvey and Other Emergency Situations

 

Hurricane Harvey

 

 

 

 

 

We all felt heartbroken as we watched the plight of citizens of Houston and other locations deal with the latest weather emergency. I worry most about debilitated senior citizens, children, and animals, all of whom won’t understand what’s happening. I’ve prayed for all people affected by the storm, but that didn’t feel like enough, so I donated to an emergency relief fund.

I said special prayers for patients on medicated assisted treatment. By that I mean any patient who can’t get much needed medications during the flood for serious illnesses. That includes patients with diabetes, heart disease, depression, asthma, opioid use disorder, and many other illnesses.

After Katrina, my state pushed for all opioid treatment programs (OTPs) to formulate emergency planning for their patients for these situations. In New Orleans, patients on methadone (there weren’t many patients on buprenorphine in 2005) had no way to get their medication, and no way to contact their home clinic for confirmation of their dose if they were re-located to a new area with a new OTP. It was only one aspect of the giant disaster that was Katrina.

I thought about what our OTP would do if struck by weather so bad that the facility shut down.

We have a disaster plan, and we just updated it a few weeks ago, coincidently. It’s easier now, since we have a sister OTP located about an hour away. Since both are owned by the same company, sharing data should be simple. We use a server that stores data off-site and can be accessed off-site. Obviously, electronic data retrieval has grown much more sophisticated since Katrina in 2005.

Since my OTP has about nine times the number of patients as our newer sister program, we would need to transport medication to meet the needs of the extra patients routed there for their dose. I feel like that could be easily accomplished, though we’d have to get the approval of the DEA and follow protocols already arranged for these situations.

There are several other OTPs, all about forty-five to ninety minutes’ drive away, surrounding my work site. Patients living closer to those programs could be easily dosed at those facilities as well, if needed. I have a good relationship with the medical directors of those programs, and I feel sure they would go out of their way to help in an emergency. I know I would do the same if they suffered an emergency.

Office-based buprenorphine patients are a little easier. There’s a number of ways to accommodate these patients, since prescriptions could be called in to pharmacies in a pinch. I have records of my office-based patients’ phone numbers both on paper an stored electronically, so if my office can’t open I can still communicate with them for alternative arrangements, assuming phone systems are operable.

Several weeks ago, my fiancé (who also provides counseling for my office-based patients) and I drove to my office practice but forgot the keys to the front door. No problem, we thought, our health services manager, Daniel, will have his keys. Nope. He forgot too. OK, we thought, we can get the landlord, who has an office at the front of our building, will have a master key. Nope. She was out of the country.

It was a pleasant day, not too hot and still shady on the bench in front of my office door where I was sitting. While the other two went in search of another person who may have a master key, my first patient arrived. I explained the situation and asked him if he minded if we conducted the session outside. He thought that was a splendid idea, so we had a very nice fifteen-minute chat. He was doing well, as he has been for about ten years. I couldn’t do a drug screen, but I didn’t make that into an obstacle. At the end of our visit, he gave me his pharmacy’s phone number and I called in his prescription. By the time my second patient arrived, the others had found a key and we proceeded as usual.

In other words, creative solutions to problems can be easy. However, we do need to plan for how to handle situations such as floods, power outages, and other emergencies.

I spent some time on the internet trying to find something about how OTPs in Houston were handling the storm, and how their patients were faring, but so far, I can’t find anything. I hope someone in that area can tell the rest of the nation what happened, so we can better learn how to handle medical issues during emergencies. 

Avoiding Overdoses

August 31: Overdose Awareness Day

 

 

 

“I’m not gonna overdose. I know my limits.”

I really hate hearing these words. Usually patients say this in response to my concerns about their pattern of drug use while I’m prescribing methadone or buprenorphine. But many patients feel like they are the experts. They can’t imagine making a deadly mistake with their drug use. But I’ve heard this phrase, or something close to it, from at least five people who are now dead from overdoses.

I was reminded of this situation after reading an article in the latest issue of Journal of Addiction Medicine. Najman et al. wrote an article titled “When Knowledge and Experience Do Not Help: A Study of Nonfatal Drug Overdoses.”

The author of the study looked at nonfatal overdoses in Australia in 2013, where overdose deaths have risen steadily since 2007. In that country, unlike the U.S., heroin use is declining while pharmaceutical opioid misuse is rising.

This study looked at nonfatal overdoses in people who inject drugs. These people, identified by the needle and syringe exchange programs in Australia, were interviewed about the circumstances surrounding these overdoses, in order to get a better understanding of the risks. A total of 50 people were interviewed for this study.

Most of these people were male, middle-aged, single, and unemployed. Nearly all were smokers. Half had a diagnosis of liver disease and almost all reported a mental health diagnosis. Most injected pharmaceutical opioids, though some also injected heroin and methamphetamine. These were very experienced drug users, with an average of 21 years of intravenous drug use.

Surprisingly, more than half of the study subjects were in some form of treatment for substance use disorder. This finding is contrary to other studies, which have found being in treatment lowered the risk for overdose. Around 46% were in medication-assisted treatment with either methadone or buprenorphine. However, some of the overdoses happened on days that the person missed dosing for some reason, and substituted another opioid such as heroin or fentanyl. Thirty-two percent of study subjects dosed with either methadone or buprenorphine in the twenty-four hours prior to experiencing their overdose.

Most of these overdoses happened in private homes, and around half received some sort of folk remedy for overdose such as being slapped, put into cold water, or being shaken. Naloxone kits weren’t routinely being distributed at the time of this study.

When asked about the cause of their overdose, many the subjects said they were impaired by alcohol or benzodiazepines. Over half said they used benzodiazepines within twenty-four hours of their overdose. Of the 50 subjects, 64% said they had been prescribed anti-anxiety medications sometime in the year prior to overdose, and 38% said they’d been prescribed sleeping pills. Another 36% said they’d been prescribed some sort of tranquilizer in the year prior to overdose. I’m assuming many of the subjects were prescribed more than one of these groups of medications.

Alcohol was not as prominent as sedative medications as contributory cause of overdose; only 34% of subjects said they had some amount of alcohol in the twenty-four hours prior to their overdose.

Over a third of subjects had used fentanyl, a very powerful opioid, leading up to the overdose.

The authors of the study concluded that these experienced drug users were aware of common risks for overdose, yet drug intoxication from sedatives such as alcohol or benzodiazepines may have clouded the user’s thinking when injecting opioids. They also found that unexpected availability of drugs contributed to overdoses.

It’s an interesting study, and a little disturbing to me, particularly the data about overdoses in people who were enrolled in medication-assisted treatments. It does underline the importance of daily dosing of MAT, and the importance of avoiding alcohol and benzodiazepines in patients on MAT.

And if you didn’t know…August 31 is International Overdose Awareness Day.

Stop Sharing Medication!

 

 

 

 

 

I read a tragic article in my local paper today. A young man pled guilty to involuntary manslaughter and received a sentence of four to seven years. The article said he gave another woman a prescription opioid pill, and she died after drinking alcohol after taking the pill. He was prosecuted for her death.

The article went on to say that if a person gives or sells another person an opioid pill (or any other controlled substance) and that person dies as a result of ingesting that medication, involuntary manslaughter or second-degree murder can be charged.

People don’t realize it’s illegal to share their prescribed controlled substance medication with other people. The law says it doesn’t matter if you sell it or just give it to someone else…it’s illegal.

I can’t tell you how many times I have a patient test positive on a drug test, and they tell me they were offered a Xanax at a funeral, or a Vicodin for muscular pain from a relative.

This is not OK.

I’ve had people tell me that once they pay for and fill their medication, it should be theirs to do with what they want. That’s not true. It is a felony to give or sell that medication to anyone besides for whom it was prescribed.

So that old Lortab pill you have in your medicine chest…don’t be tempted to give it to your brother when he has a migraine. You don’t know what other medication he’s on, and you can’t know if it is safe for him. And if he dies, you could be charged with a felony, on top of the guilt you would feel for contributing to his death.

Numerous studies have also shown young people who develop opiod use disorder often get their first opioids from friends or relatives. Parents spend energy worrying about their children being approached by drug dealers, but it’s far more likely that the first opioids used by their children will be obtained from someone’s medicine cabinet.

This means it’s important to change cultural attitudes about sharing medication and saving medication.

 

 

News You Can Use

 

 

 

 

 

 

 

 

New ACOG Recommendations:

The American College of Obstetrics and Gynecology (ACOG) just released an updated recommendation about the treatment of opioid use disorder in pregnant women: https://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Obstetric-Practice/Opioid-Use-and-Opioid-Use-Disorder-in-Pregnancy

Their last statement was issued in 2012, in cooperation with the American Society of Addiction Medicine (ASAM). This newer statement was released earlier this month, also in cooperation with ASAM.

By my reading, this update is more direct about recommending medication-assisted treatment for pregnant women with opioid use disorder, and specifically discouraged medically supervised withdrawal from opioids during pregnancy.

This statement was in the update’s conclusions: “For pregnant women with an opioid use disorder, opioid agonist pharmacotherapy is the recommended therapy and is preferable to medically supervised withdrawal because withdrawal is associated with high relapse rates, which lead to worse outcomes. More research is needed to assess the safety (particularly regarding maternal relapse), efficacy, and long-term outcomes of medically supervised withdrawal.”

I suspect this released update may have been prompted by the actions of obstetricians in certain locations (Tennessee, for example), where medically supervised withdrawal is routinely recommended by obstetricians. As you recall in a blog earlier this summer, I showed you a letter written by OBs from TN, recommending “medically supervised withdrawal” for patients on medication-assisted treatment of opioid use disorders.

As the ACOG update emphasizes, there’s scant evidence to show medically supervised withdrawal provides any better outcomes for the baby, but certainly places the mother at risk for relapse.

I am pleased to see this update, and plan to mail it to a few obstetrics practices in my own area. Some OBs may be giving patients recommendations not supported by their own professional organization out of ignorance, in which case more information can help. Other OBs do it for ideological reasons, in which case I doubt any amount of information can help, but at least I’ll know I’ve tried to do something.

Screening for substance use disorders was also strongly emphasized in the new document, with specific recommendations about how this should be done. In other words, asking a pregnant patient, “You don’t take any drugs, do you?” is not considered to be adequate or recommended screening.

Increased Risk for Death in Patients with Opioid Use Disorder who Leave Buprenorphine Treatment

We have multiple studies, dating back decades, showing patients with opioid use disorder who leave treatment with methadone have higher risks of overdose deaths. We believe the same thing is true with buprenorphine treatment, but now we have more data to support that assumption.

A French study of 713 buprenorphine patients showed that being out of buprenorphine treatment was associated with a 30-fold increase in death, compared with patients who stay on buprenorphine treatment.

Now that’s impressive.

This was a study done in France, where most patients with opioid use disorder are treated by general practitioners in private practice. This would be roughly equivalent to what physicians do now in the U.S. in their office-based buprenorphine practices, often called OBOT treatment.

The study was published in the July/August 2017 issue of the Annals of Family Medicine, by Dupouy et al. It looked at new patients admitted onto buprenorphine treatment from early 2007 until the end of 2011, and covered over 3,000 person -years of treatment.

The authors say that the data showed, “…being out of treatment was associated with sharply elevated mortality risk.”

We already knew that people with opioid use disorder have an increased risk of death. Early in this article, the authors state that the accepted mortality rate of untreated heroin use disorder is around 2 people per 100 patient years. This means that if you follow 100 heroin users for a year, it is likely that 2 will be dead at the end of the year. An older study, by Hser et al., followed people with opioid use disorder over time, and found that around 50% were dead at 30 years.

We’ve had other studies that show being in treatment with buprenorphine or methadone decreases risk of death, but this may be the first study showing that getting help in a primary care setting reduces the risk of death so remarkably.

This was a very large study, so the data is more impressive to me All this data supports the conclusion that opioid use disorder is a serious and potentially fatal disease, and that being in medication-assisted treatment markedly reduces the risk of death.