From ASAM Weekly: An Editorial by Nora Volkow

Guest Editorial – Advancing Reduction of Drug Use as an Endpoint in Addiction Treatment Trials

Nora D. Volkow, Director, National Institute on Drug Abuse

For many people trying to recover from a substance use disorder, perhaps for the majority, abstinence may be the most appropriate treatment objective. But complete abstinence is sometimes not achievable, even in the long-term, and there is a need for new treatment approaches that recognize the clinical value of reduced use.

According to a recently published analysis of data from the 2022 National Survey on Drug Use and Health, two thirds (65.2 percent) of adults in self-identified recovery used alcohol or other drugs in the past month (1). There is increasing scientific evidence to support the clinical benefits of reduced substance use and its viability as a path to recovery for some patients. Reducing drug use has clear public health benefits, including reducing overdoses, reducing infectious disease transmission, and reducing automobile accidents and emergency department visits, not to mention potentially reducing adverse health effects such as cancer and other diseases associated with tobacco or alcohol.

The FDA has historically favored abstinence as the endpoint in trials to develop medications for substance use disorders. Abstinence has been evaluated using absence of positive urine drug tests, absence of self-reported drug use, and regularly attending sessions where drug use is assessed. But abstinence is a high bar comparable to requiring that an antidepressant produce complete remission of depression or that an analgesic completely eliminate pain. Recognizing this limitation, the FDA encourages developers of opioid (2) and stimulant (3) use disorder medications to discuss with the FDA alternative approaches to measure changes in drug use patterns.

A model for reduced use as an endpoint exists with treatments for alcohol use disorder (AUD). Reduction in alcohol use is relatively easy to measure since alcoholic beverages tend to be purchased and consumed in standard quantities, and substantial evidence supports the clinical benefit of reduction in heavy drinking days (defined as 5 or more drinks/day for men and 4 or more drinks/day for women). Consequently, the percentage of participants with no heavy drinking days is accepted by the FDA as a valid outcome measure in trials of medications for AUD (4). The FDA recently announced a new tool through which investigators can determine if proposed treatments for AUD work based on whether they reduce “risk drinking” levels. The new tool can be used as an acceptable primary endpoint in studies of medications to treat adults with moderate to severe AUD.

Use reduction could readily be used as an endpoint in the development of treatments for tobacco use disorder too, since the number of cigarettes smoked per day is easily measured and there is evidence that 50 percent reduction in cigarette use produces meaningful reduction in cancer risk (5). Thus, the NIH and FDA have recently called for consideration of meaningful study endpoints in addition to abstinence in research on new smoking-cessation products (6), though abstinence is still required as the main outcome for medication approval.

Objective assessment of use reduction for illicit substances presents a greater difficulty given variability and uncertainty of the composition and purity of illicit drugs purchased. This challenge may account for part of the reluctance of the pharmaceutical industry to invest in developing new medications aimed at reducing drug use. Also, anecdotally, the expectation that medications that can produce complete cessation are the only treatments that will advance to market has discouraged addiction neuroscientists and some in the pharmaceutical industry from advancing new medication targets or compounds relevant to reduced use or other endpoints besides abstinence. Nevertheless, there is increasing research demonstrating the relative strength of quantitative measures of drug use frequency versus binary measures of abstinence in assessing the efficacy of drug use disorder treatments.

A 2023 analysis of pooled data from 11 clinical trials of treatments for cocaine use disorder found that reduction in use, as defined by achieving at least 75 percent cocaine-negative urine screens, was associated with short- and long-term improvement in psychosocial functioning and measures of addiction severity (7). A 2024 secondary analysis of data from 13 clinical trials of treatments for stimulant use disorders (cocaine and methamphetamine) found that reduced use was associated with improvement in several indicators of recovery, including measures of depression severity, craving, and domains of symptom improvement (legal, family/social, psychiatric, etc.) (8).

A secondary analysis of 7 clinical trials of treatments for cannabis use disorder found that reductions in use short of abstinence were associated with meaningful improvements in sleep quality and reduction of cannabis use disorder symptoms (9). Fifty percent reduction in days of cannabis use and 75 percent reduction in amount of cannabis used were associated with the greatest clinician-rated improvement.

Little research has been conducted on alternative endpoints in opioid use disorder treatment, but it will be needed to advance medication development in this area. Among the important research questions that still need answering is whether treatment aimed at reducing opioid use could produce better overdose-related outcomes than treatment aimed at cessation of use, since many fatalities arise from a return to use after tolerance to the drug is lost following periods of abstinence. Even in the absence of clinical trial evidence, however, any reduction in illicit substance use can reasonably be argued as beneficial, entailing less risk of overdose or of infectious disease transmission, less frequent need to obtain an illegal substance with the attendant dangers, and so on (10). Decreased substance use also makes it more likely that the individual can hold a job, be a supportive family member, and so on.

Broadening the goals of treatment to include reduced use or other clinically meaningful outcomes as a main outcome for medication approval could potentially expand therapeutic interventions and help increase the number of people in treatment. It could also reduce the stigma that is typically associated with return to use. Setting abstinence as the goal of treatment can be an obstacle to treatment engagement for those who are unready or unwilling to make that commitment. And when attempts at abstinence falter, these expectations can compound the sense of failure the patient experiences.

There is little scientific evidence to support the stereotype that people who return to use after a period of abstinence inevitably do so at the same intensity. Some research on post-treatment patterns of alcohol and other drug use in adolescents suggests that returns to use, when they occur, are often at a lower intensity than before (11). People in recovery sometimes draw a distinction between resumption of a heavy and compulsive use pattern and isolated, one-time returns to substance use, recognizing that brief “slips” or “lapses” don’t need to be catastrophic to recovery efforts and may even strengthen the person’s resolve to recover.

When returns to use are catastrophic, the sense of failure at living up to the abstinence expectation could play a role in exacerbating further substance use. So could the rules of treatment programs or recovery communities that require abstinence. It too often happens that patients are discharged from addiction treatment if they return to use, which as the American Society of Addiction Medicine notes in its recent guidance document Engagement and Retention of Nonabstinent Patients in Substance Use Treatment, is illogical and inconsistent with our understanding of addiction as a chronic disease: excluding a person from treatment for displaying symptoms of the disorder for which they are being treated (12).

Recognizing that recovery is often nonlinear, a more nuanced view of treatment is needed, one that acknowledges that there are multiple paths to recovery. Expecting complete abstinence may be unrealistic in some cases and can even be harmful. It can pose a barrier to seeking and entering treatment and perpetuate stigma and shame at treatment setbacks. By the same token, reduction of substance use has important public health benefits as well as clinical benefits for patients, and recognition of this could greatly advance medication development for treatment of addiction and its symptoms.

References

Pasman E, Evans-Polce RJ, Schepis TS, Engstrom CW, McCabe VV, Drazdowski TK, McCabe SE. Nonabstinence among US Adults in Recovery from an Alcohol or Other Drug Problem. J Addict Med. 2024 Nov 15. doi: 10.1097/ADM.0000000000001408. Epub ahead of print. PMID: 39792600.

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Opioid Use Disorder: Endpoints for Demonstrating Effectiveness of Drugs for Treatment Guidance for Industry. October 2020. Retrieved March 6, 2025, https://www.fda.gov/media/114948/download

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Stimulant Use Disorders: Developing Drugs for Treatment Guidance for Industry. October 2023. Retrieved March 6, 2025, https://www.fda.gov/media/172703/download

Falk D, Wang XQ, Liu L, Fertig J, Mattson M, Ryan M, Johnson B, Stout R, Litten RZ. Percentage of subjects with no heavy drinking days: evaluation as an efficacy endpoint for alcohol clinical trials. Alcohol Clin Exp Res. 2010 Dec;34(12):2022-34. doi: 10.1111/j.1530-0277.2010.01290.x. PMID: 20659066.

Chang JT, Anic GM, Rostron BL, Tanwar M, Chang CM. Cigarette Smoking Reduction and Health Risks: A Systematic Review and Meta-analysis. Nicotine Tob Res. 2021 Mar 19;23(4):635-642. doi: 10.1093/ntr/ntaa156. PMID: 32803250.

Warraich HJ, King BA, Compton WM, Herrmann ES, Hai MT, Califf RM, Bertagnolli MM. Opportunities for Innovation in Smoking Cessation Therapies: A Perspective From the National Institutes of Health and U.S. Food and Drug Administration. Ann Intern Med. 2025 Jan;178(1):122-125. doi: 10.7326/ANNALS-24-02318. Epub 2024 Oct 15. PMID: 39401434.

Loya JM, Babuscio TA, Nich C, Alessi SM, Rash C, Kiluk BD. Percentage of negative urine drug screens as a clinically meaningful endpoint for RCTs evaluating treatment for cocaine use. Drug Alcohol Depend. 2023 Jul 1;248:109947. doi: 10.1016/j.drugalcdep.2023.109947. Epub 2023 May 26. PMID: 37276806; PMCID: PMC10498479.

Amin-Esmaeili M, Farokhnia M, Susukida R, Leggio L, Johnson RM, Crum RM, Mojtabai R. Reduced drug use as an alternative valid outcome in individuals with stimulant use disorders: Findings from 13 multisite randomized clinical trials. Addiction. 2024 May;119(5):833-843. doi: 10.1111/add.16409. Epub 2024 Jan 10. Erratum in: Addiction. 2024 Oct;119(10):1849-1852. doi: 10.1111/add.16590. PMID: 38197836; PMCID: PMC11009085.

McClure EA, Neelon B, Tomko RL, Gray KM, McRae-Clark AL, Baker NL. Association of Cannabis Use Reduction With Improved Functional Outcomes: An Exploratory Aggregated Analysis From Seven Cannabis Use Disorder Treatment Trials to Extract Data-Driven Cannabis Reduction Metrics. Am J Psychiatry. 2024 Nov 1;181(11):988-996. doi: 10.1176/appi.ajp.20230508. Epub 2024 Oct 9. Erratum in: Am J Psychiatry. 2024 Dec 1;181(12):1134. doi: 10.1176/appi.ajp.20230508correction. PMID: 39380374.

McCann DJ, Ramey T, Skolnick P. Outcome measures in medication trials for substance use disorders. Curr Treat Options Psych. 2015;2:113–21. https://doi.org/10.1007/s40501-015-0038-5

Chung T, Maisto SA, Cornelius JR, Martin CS. Adolescents' alcohol and drug use trajectories in the year following treatment. J Stud Alcohol. 2004 Jan;65(1):105-14. doi: 10.15288/jsa.2004.65.105. PMID: 15000509.

American Society of Addiction Medicine. Engagement and Retention of Nonabstinent Patients in Substance Use Treatment: Clinical Consideration for Addiction Treatment Providers. October 2024. Accessed March 6, 2025. https://www.asam.org/quality-care/clinical-recommendations/asam-clinical-considerations-for-engagement-and-retention-of-non-abstinent-patients-in-treatment

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.