Palliative Care in SUD

I recently enjoyed a PCSS webinar on the concept of staging in substance use disorder. The speakers were Dr. Edwin Salsitz, MD, DFASAM and Karen Bachi, PH, LCSW of the Addiction Institute of Mount Sinai. The webinar discussed the issue of people with chronic substance use disorders who have gone to detox and had multiple treatments but fail to stabilize. They keep showing up in the ER over and over. The presenters noted that staging is common in medicine for many chronic disorders, including cancer, COPD, and kidney disease. The DSMV uses staging as well, with criteria for mild, moderate, severe, etc. Therapy is based on the staging. Dr. Salsitz noted that social determinants may play some role in the chronicity of all medical disorders, but that may be especially true in addiction disorders. Social factors may contribute to stress, repeated trauma, repeated exposure to cues, triggers. They proposed that people with psychosocial complexities may be a different subgroup and require a different treatment plan than people who have more resources and fewer social stressors. It has clearly been shown in research that childhood maltreatment results in structural changes in the brain. I think most of us working with substance use disorders have figured this out. These people usually (not always) have a more difficult time stabilizing.

Dr. Salsitz discussed a treatment program in Seattle’s King’s County from several years ago. They created a list of 200 of the most chronic people with substance use disorder who were costing the county the most money in terms of ER visits, homelessness, and use of other resources. They had all failed at least 6 past efforts at treatment, and had been struggling with SUD and living on the streets for several years. They offered 75 of them an apartment in a new building. They were allowed to drink in their rooms, were not required to attend AA, and they did not have to make a commitment to drink less. According to some of the participants in the webinar, this program is still in existence.

Dr. Salsitz defined palliative care as “specialized medical care for people living with a serious illness where treatments directed at recovery have not been effective. This type of care is directed at relief of the symptoms and stress of a serious illness. The goal is to reduce harm and improve quality of life for both the patient and the family.”

Does this make sense for some of our patients? I can certainly think of patients that I’ve seen who would fit this category. Of course, the Seattle program is controversial. We would like to think that we never give up on the possibility that one more treatment will work. We have all seen people who did finally stabilize after the 10 th or 15th treatment. I think Dr. Salsitz would say that being in palliative care doesn’t preclude making sure that treatment is available if the person decides that they want it. The Seattle program was motivated largely by financial considerations. The goal was to save money from the frequent ER visits, jail time, resources utilized on homelessness. Did this savings pay for the program? I don’t know the answer. It was a creative attempt to solve a complex problem. Is it time that we begin to think outside the box for our terminal patients? And how do we decide when someone is terminal? Dr. Salsitz agrees that we need to better understand what factors should be used for staging.

One of the most interesting slides in the webinar came from a 2019 article in JAMA, Association Between Life Purpose and Mortality Among US Adults Older than 50 Years, JAMA New Open. 2019; 2(5):e194270. doi:10.1001/jamanetworkopen.2019.4270. This study showed that lack of a sense of purpose in life resulted in worse survival than those with a strong sense of purpose. I sometimes ask patients what their goals were when they were younger, in high school. Although my observations are purely that, I feel that people who had no goals, no aspirations in the past have a poorer prognosis than those who had a sense of possibility. Medication is very important, but most people participating in the webinar agreed that it takes something more to restore a sense of purpose, and that’s where the relationship with treatment providers comes i

Colleen Ryan, MD

An Update on OTC Naloxone

Martika Martin, PharmD, MBA, BCGP is the Director of Clinical Outreach for the Kentucky Pharmacy Education and Research Foundation. Her role on the Overdose Data to Action Grant, through the CDC and the Kentucky Injury Prevention and Research Center is to be an academic detailer, providing education and resources to clinicians in the state of Kentucky on opioids, opioid use disorder, and harm reduction.

In 2015, Narcan®, became the first commercially available form of naloxone for opioid overdose that was easy to administer by non-healthcare professionals. Before that, the only form of naloxone was an injectable, stored in a glass vial or ampule that would have to be drawn in a syringe for administration or using an off-label atomizer to convert it into a nasal spray. Generic Narcan nasal spray was approved by the FDA in 2019. In 2021, the FDA approved an 8mg naloxone nasal spray, Kloxxado™, which is twice the dose of Narcan®. In 2021, the FDA also approved a 5mg dose of injectable naloxone, Zimhi™, supplied in a pre-filled syringe.

Since the introduction of these “community use” naloxone products, estimated sales and dispensed prescriptions for naloxone use has increased across all healthcare settings from 2017 to 2021. In 2021, an estimated 1.5 million prescriptions for naloxone we dispensed from pharmacies, 95% of those for the nasal spray. These estimates did not include donations from manufacturers or direct sales to community-based distribution programs. While sales and prescriptions of naloxone have increased, overdose deaths have risen in the past few years, reflecting a possible need for increased access and availability of naloxone in non-healthcare settings.

On November 16, 2022, the FDA released a federal notice stating that it was their opinion that naloxone nasal spray up to 4mg and naloxone autoinjector for intramuscular or subcutaneous injection up to 2 mg have the potential to be safe and effective for use as directed in nonprescription drug labeling without the supervision of a healthcare provider. In other words, they are voicing their interest in having manufacturers apply for over-the-counter status, either through an application for a non-prescription naloxone or a supplemental application to switch an FDA-approved naloxone product from prescription to nonprescription status. The public comment period for this notice is open until January 17, 2023.

In the Federal Notice, the FDA cited evidence for the positive benefits of increasing naloxone access, including evidence supporting community-based overdose education and naloxone distribution programs leading to positive patient outcomes such as high rates of opioid overdose reversal attempts, The FDA estimates that nearly 20,000 deaths were averted because of layperson naloxone administration from 1999 to 2020. While the major adverse effect of naloxone is precipitated withdrawal in individuals physically dependent on opioids, which may cause other serious adverse events such as pulmonary edema, cardiac arrhythmias, and agitation, the benefit of reversing potentially fatal overdose is significant and likely outweighs these risks.

Martina Martin, PharmD

The FDA stated that they believe that the prescription requirements for certain naloxone products may not be necessary to protect public health. The FDA recognized the efforts of community-based naloxone distribution programs and state naloxone access laws that illustrate that naloxone can be used safely and effectively without patient-specific prescriptions. To ease the process of bringing over-the-counter naloxone to market, the FDA has developed a model naloxone Drugs Facts Labeling (a requirement for over-counter-drugs) and assessed it’s understandability by consumers, a major and time-consuming process for manufacturers wishing to bring an over-the-counter product to market.

While the impact of naloxone products going over-the-counter is not fully known, especially for community-based naloxone distribution programs, the thought is that over-the-counter status will continue to reduce barriers to access that persist despite these community-based programs and naloxone access laws.

On December 6, 2022 Emergent BioSolutions announced that the FDA has accepted for priority review its supplemental New Drug Application for Narcan® Nasal Spray as an over-the-counter emergency treatment for known or suspected opioid overdose, with a Prescription Drug User Fee Act goal date of March 29, 2023 (the date by which the FDA must respond to the application).

A New Way to Initiate Buprenorphine

There has been a lot written about using micro-dosing for buprenorphine induction especially now that fentanyl is such a common issue. As a matter of fact, the recent issue of JAM, Journal of Addiction Medicine, contained an article titled “Low Dose Initiation of Buprenorphine: A Narrative Review and Practical Approach,” dealing with this very issue. Another article in the same issue, “A Plea From People Who Use Drugs to Clinicians: New Ways to Initiate Buprehorphine Are Urgently Needed in the Fentanyl Era” emphasized the predicament of many people who use drugs (PWUD). I found both of these articles very compelling, and suggest that you take a look at them. This was also a common theme at the ASAM meeting in April. There were several presentations on alternative methods of buprenorphine/naloxone induction.

The changes of precipitated withdrawal are greater when fentanyl is present especially with the tradition method of induction which is usually 2-3 days of withdrawal followed by a maximum dose of 8 mg the first day. Then over the next couple of days, the dose is increased to 12-16 mg if necessary. Most clinicians these days rarely go above 16 mg. However, fentanyl, though short acting pharmacologically, is very lipophilic and is present in the body tissues much longer. Microdosing (also called the Bernese Method) has been utilized to try and overcome this hurdle. Probably some of you have tried it. There are variations on the micro dosing protocol, but basically very small doses of buprenorphine, for example 0.5 mg or even 0. 25 mg, are gradually used over several days while the full agonist is still on board. This gradually displaces the full agonist, but not in amounts enough to cause precipitated withdrawal. The key here is that the patient continues to use the full agonist until the buprenorphine dose is large enough that all mu receptors are occupied. Then the full agonist is discontinued with no withdrawal symptoms.

The second article, coming out of the Internal Medicine Program of the Yale School of Medicine, is a narrative review of the mechanism, rationale, and existing methods for performing buprenorphine low dose initiation. I will not go into the details of the process they outline here, but they do list four Guiding Principles for Low Dose Initiation. 1. Choosing the Appropriate Clinical Situation, 2. Initiating at a Low Buprenorphine Dose (0.2-0.5 mg), 3. Titrating the Dose Slowly, and 4. Continuing the Full Opioid Agonist, Even if Nonmedical. At the ASAM meeting, I spoke to several people who had tried microdosing, some successfully, some not. One concern was the availability of such low doses of buprenorphine. In some states, there may be regulations about buprenorphine formulations that make this strategy difficult (but regulations can be changed via advocacy). Also, several clinicians failed to have the patient maintain the full opioid agonist during the induction, a key point in the process.

Another alternate strategy to initiate buprenorphine is macro-dosing. In this case, the patient is usually in withdrawal, and the h igh doses of buprenorphine are used, such as 32 mg. The theory is that this large dose will displace the full agonist and fully bind to the unoccupied mu opioid receptors. However, this approach has a very limited literature on its use. More research is needed on both of these approaches.

A recent article by Howard Hassman et.al. reviewed cases of prison inmates being transitioned from methadone to buprenorphine. The authors did a retrospective chart review of all inmates admitted to a prison in Germany between March 2019 and May 2020. In some cases methadone was tapered and a traditional induction was done. However, in one case a patient on 80 mg of methadone was directly switched to buprenorphine by stopping methadone for one day and then giving 4 mg buprenorphine sublingually followed by an injection of 16 mg of depot buprenorphine. In Germany, the weekly depot formulation is available. He was maintained on this dose weekly for 5 months and then switched to sublingual buprenorphine. He was also on 125 mg of gabapentin. In another case, a patient on 110 mg of methadone was given a 4 mg sublingual dose of buprenorphine after one day of withdrawal from methadone. He was then given 16 mg of a weekly depot formulation. He received another 8 mg buprenorphine sublingually the next day. He was stabilized on 32 mg of weekly depot formulation and eventually on 128 mg of a monthly formulation.

What these articles say to me is that we are missing many people who need to be on buprenorphine/naloxone, but aren’t for one reason or another. This is another case where we sometimes try to fit the patient to our available methods of treatment, rather than fitting the treatment to the patient. Here in Kentucky, we are somewhat limited by regulations guiding the use of MOUD. It is possible to change this. These articles suggest to me that we are missing the toughest patients. We may believe that access to medications for opioid use disorder are available. But we forget that some people still fall through the cracks, and they are the people who need it the most.

Cohen S, Weimer M, Levander X, Peckham A, Tetrault J, Morford K. Low Dose Initiation of Buprenorphine: A Narrative Review and Practical Approach. J Addict Med 2022;16 (4):399-406.

Sue K, Cohen S, Tilley J, Yocheved A. A Plea From People Who Use Drugs to Clinicians: New Ways to Initiate Buprenorphine are Urgently Needed in the Fentanyl Era. J Addict Med. 2022; 16(4): 389-391.

Howard Hassman, Stephanie Strafford, Sunita N. Shinde, Amy Heath, Brent Boyett, Robert L. Dobbins. (2022) Open-label, rapid initiation pilot study for extended-release buprenorphine subcutaneous injection. The American Journal of Drug and Alcohol Abuse 0:0, pages 1-10.