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“Ms Rose” is a 63-year-old African-American female with schizoaffective disorder. Her psychotic disorder has been stable on ziprasidone, venlafaxine, and zolpidem as needed. She had surgical repair of a torn rotator cuff and was prescribed opioids (oxycodone) for postoperative pain. Two weeks later, her husband found her on the porch, unresponsive and not following commands. She was brought to the local 

 by ambulance. Work-up for acute stroke and other causes of altered mental status was negative/unremarkable. Her discharge diagnosis was orthostatic hypotension secondary to medication polypharmacy, and she was advised to discontinue opioids.

 in the United States are filled by patients with comorbid mental health disorders, including patients with concomitant antipsychotic use.

 Compared to the general population, patients with severe mental illness are 2.5 times more likely to be treated with opioids for chronic pain.

 In 2016, the US Food and Drug Administration (FDA) issued a black-box warning about the combined use of opioids and antipsychotics due to risks of respiratory depression.

 However, there is substantial heterogeneity amongst individual antipsychotics in regards to sedative properties and the potential for respiratory depression, which is mediated through antagonism of histamine-1 receptors.

 Risks of overdose in patients co-prescribed opioids and sedating versus nonsedating antipsychotics has not been investigated.

 investigated this association in a population-based cohort. The authors studied patients aged 15 to 85 who filled an opioid prescription between 2004 and 2017, nested in the IBM MarketScan Commercial and Medicare supplemental claims database.

The investigators identified all individuals who filled a prescription for an antipsychotic (index date). Other inclusion criteria were continuous medical and prescription drug benefit coverage for 180 days before the index date, no evidence of 

, and at least 1 opioid prescription filled within 14 days preceding the index date. Antipsychotics were classified as sedating (eg, chlorpromazine, clozapine, olanzapine, and quetiapine) and nonsedating (eg, aripiprazole, haloperidol, lurasidone, risperidone, and ziprasidone) based on histamine-1 receptor affinity (

The primary outcome measure was emergency department visit or 

 due to an overdose even within 30 days of the index date. Patients were followed until the occurrence of the outcome, death, end of the study, or 30 days, whichever came first. Szmulewicz et al compared baseline characteristics between patients receiving opioids and sedating versus nonsedating antipsychotics using propensity score matching. Incidence rates (IRs) and their 95% confidence intervals (CIs) were calculated for each exposure group. Hazard ratios (HRs) and 95% CIs were estimated with Cox proportional hazard models. 

After 1:1 propensity score matching, the cohort consisted of 62,604 patients newly exposed to a sedating antipsychotic plus opioids (“exposed”) and an equal number of patients newly exposed to a nonsedating antipsychotic plus opioids (“referent”). Mean patient age was 50, and 33% of the cohort was male. The most commonly prescribed opioids were hydrocodone, oxycodone, tramadol, and buprenorphine. The IR of overdose was 35 events per 1000 person-years in the exposed group, and 26 events per 1000 person-years in the referent group, corresponding to an adjust HR of 1.34 (95% CI 1.07-1.68). In sensitivity analyses, there was evidence for a dose-response relationship based on antipsychotic dosage. Findings were consistent across a number of other sensitivity and subgroup analyses.

The authors concluded that among patients receiving prescription 

, sedating antipsychotics are associated with an increased risk (up to 60%) of unintended overdose compared to nonsedating antipsychotics. Findings support the FDA black-box warning about the combined use of opioids and antipsychotics.

Strengths of the present study include the large sample size, consideration of many potential confounders, use of an active comparator, and multiple sensitivity analyses. Limitations include the observational study design, the potential for medication nonadherence during the follow-up period, and the use of a commercially insured population, and that fatal unintentional overdoses prior to hospitalization would have been missed.

Clinicians should consider the risk of unintentional overdose when prescribing 

 to patients taking opioids. Depending on the clinical situation, use of nonsedating antipsychotics may help mitigate this risk.

is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

Prescription opioid use among adults with mental health disorders in the United States.

2. FDA Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. FDA. March 2019. Accessed October 26, 2021. 

https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-serious-risks-and-death-when-combining-opioid-pain-or

Receptor-binding profiles of antipsychotics: clinical strategies when switching between agents.

4. Szmulewicz AG, Bateman BT, Levin R, et al. 

Risk of overdose associated with co-prescription of antipsychtoics and opioids: a population-based cohort study.

Unintentional overdose with antipsychotics plus opioids. Researchers performed a population-based cohort study of the risk of overdose associated with co-prescription of antipsychotics and opioids.

Risk of Overdose with Antipsychotic and Opioid Co-Prescription

The question: Why don't we hear about the opioid crisis in America anymore? Did it go away during COVID?

This week, Thomas R. Kosten, MD, takes on the question about opioids in the US.

is the Jay H. Waggoner Endowed Chair and co-founder at the Institute for Clinical and Translational Research. He is also a professor of psychiatry, neuroscience, pharmacology, and immunology at Baylor College of Medicine in Houston, Texas.

Did the opioid crisis go away during COVID-19? Or has it gotten worse? 

Opioid Crisis Awareness

 has progressed during the past 2 decades, more and more patients have left their doctors’ offices with prescriptions for benzodiazepine medications (BZDs). Across the medical profession, the percentage of outpatient visits resulting in a BZD prescription has increased from 3.8% in 2003 to 7.4% in 2015.

 It is estimated that concurrent use of BZDs and opioids may occur in as many as 50% of 

 This shocking statistic suggests the possibility that more cautious and conservative use of BZDs by all who prescribe them has the potential to save thousands of lives per year. 

During the time period studied by Agarwal et al,

 outpatient psychiatrists manifested a stable pattern of BZD prescribing, delivering BZD prescriptions to the patient in 30% of psychiatric visits. Overall, BZD prescriptions written by psychiatrists account for approximately one-sixth of the more than 25 million prescriptions that are written each year.

 In the years 2015 and 2016, 30.6 million US adults reported BZD use in the past year; of these, 5.3 million were deemed to be misusing BZDs.

 The most common type of BZD misuse occurs when prescribed BZDs are diverted and utilized by individuals who are not receiving them for a legitimate medical indication. 

These threads of data suggest that some BZDs prescribed by psychiatrists end up being misused by individuals who are also misusing opioids, and that some of these 

opioid overdose deaths are potentiated by BZDs

 prescribed by a trusting psychiatrist. Are these BZDs that originate in mental health settings a factor in hundreds of yearly opioid overdose deaths, or in thousands? Although the magnitude of this problem is not known, it is likely that psychiatrists who exercise more caution in prescribing BZDs can play a role in doing less inadvertent harm.

 performed a comprehensive review of studies on the combined use of opioids and BZDs. They concluded that “that the co-abuse of opioids and BZDs is ubiquitous around the world,” that BZDs are utilized by many opioid abusers to potentiate opioid intoxication, and, that the co-abuse of opioid and BZDs “has negative consequences for general health, overdose lethality, and treatment outcome.”

Perhaps their 2012 conclusion that physicians should exercise more caution and vigilance in prescribing BZDs is reflected in the fact that psychiatrists have paid attention, and not increased our rate of BZD prescribing. Whereas psychiatric BZD prescriptive practices have remained stable, other physicians, especially primary care providers, are delivering nearly twice as many BZD prescriptions to patients.

 However, in view of the subsequent progression of the opioid crisis and the mounting overdose death toll, reducing the rate of BZD prescriptions in psychiatric practice may indeed be a worthwhile, life-saving consideration.

 suggest that by adhering to universal precautions in pain medicine, physicians are able to routinize a cautious, non-stigmatizing clinical approach that facilitates their ability to limit opioid prescriptions. It would likely be helpful for psychiatrists to adopt a parallel set of best practices and universal precautions with regards to prescribing BZDs and other psychoactive pharmaceuticals with abuse liability. Gourlay’s original 10 universal precautions can be found in the 

 for a list of 8 universal precautions adapted from Gourlay et al

 for use by psychiatrists faced with the decision to initiate or continue pharmacotherapy with BZDs.

Epidemiological studies suggest that individuals with untreated anxiety and mood disorders may be prone to self-medicate with nonmedical use of opioids. Use and misuse of opioid drugs may themselves aggravate symptoms of anxiety.

 It is not surprising, then, that outpatient psychiatrists sometimes provide BZD prescriptions to patients who may covertly be suffering from 

. As substance use disorders (SUDs) have long been associated with behaviors that may be deemed antisocial,

 and one such behavior is deceptive communication,

 community-based psychiatrists in high-volume clinic settings may be at risk of being fooled by drug-seeking patients.

The ease of integrating some or all of the 8 suggested universal precautions for initiating or continuing BZD pharmacotherapy will vary from treatment setting to treatment setting. At the very least, this aspirational list of precautions may facilitate the ability of mental health professionals to offer a clinically sound integrated approach for the treatment of co-occurring psychiatric and SUDs. Integrated treatment of co-occurring disorders is the accepted standard of care for this challenging, high-risk patient population.

a coaching and consulting psychiatrist, and is board-certified in psychiatry, addiction medicine, and coaching (BCC). He launched

after 8 years directing Physician Health Services, Inc. On the faculty of the University of Massachusetts Medical School, he is a consultant in psychiatry in the Division of Alcohol and Drug Abuse of McLean Hospital, an affiliate of Harvard Medical School.

Patterns in outpatient benzodiazepine prescribing in the United States.

Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study.

Benzodiazepine use and misuse among adults in the United States.

Polydrug abuse: a review of opioid and benzodiazepine combination use.

Universal precautions in pain medicine: a rational approach to the treatment of chronic pain.

6. Martins SS, Fenton MC, Keyes KM, et al. 

Mood and anxiety disorders and their association with non-medical prescription opioid use and prescription opioid-use disorder: longitudinal evidence from the National Epidemiologic Study on Alcohol and Related Conditions

Natural history of male alcoholism V: is alcoholism the cart or the horse to sociopathy?

Common and challenging behaviors among individuals on long-term opioid therapy. 

Integrated treatment of substance use and psychiatric disorders.

Are benzodiazepine prescriptions contributing to the opioid overdose epidemic? 

The Case for Caution When Prescribing Benzodiazepines 

This week, Steve Adelman, MD, takes on the question about opioids in the US. 

a coaching and consulting psychiatrist, is board-certified in psychiatry, addiction medicine, and coaching (BCC). He launched 

after 8 years directing Physician Health Services, Inc. On the faculty of the University of Massachusetts Medical School, he is a consultant in psychiatry in the Division of Alcohol and Drug Abuse of McLean Hospital, an affiliate of Harvard Medical School.

Fighting the Opioid Crisis

In 2016, drug-related overdoses became the 

 with opioids as the primary culprit. Although significant state-by-state variability exists, with some geographical areas impacted more than others, 

opioid-related overdose deaths have been a national epidemic

 with the death rate at historic highs in the first quarter of 2021.

 Aside from federal legislative efforts, states have independently implemented policies and deployed resources to address this issue. Interestingly, some states that had high overdose deaths in 2016 experienced a drastic decline in 2017 upon implementation of prevention and response efforts. In this article, the authors qualitatively examine the efforts of these successful states and look for 

 What are the core elements of overdose prevention and response activities in states with high rates of opioid-related overdose deaths that experienced a decrease in overdose deaths from 2016 to 2017?

 Retrospective qualitative thematic analysis of successful states’ overdose prevention programs based on predetermined categories to organize their activities.

: Individuals from Massachusetts, New Hampshire, New Mexico, and Utah who died by opioid-related overdose from 2016 to 2017 and who have been reported to the Centers for Disease Control and Prevention (CDC)’s Wide-ranging Online Data for Epidemiological Research.

: Mortality data from the CDC was used in identifying the 25 states with the highest age-adjusted opioid-related overdose mortality rates in 2016. Only the 4 states that experienced a decrease in age-adjusted mortality rates from 2016 to 2017 were selected for analysis. The authors then used data from the 4 states’ progress reports (generated for the CDC as condition of their funding), to identify overdose-related programs and their outcomes. This was supplemented by an environmental scan of websites and other strategic planning documents to further capture information on overdose prevention and response. Three of the authors then compiled draft program narratives summarizing their findings. Ten predetermined categories developed according to the 3 authors’ reviews and supplemented by CDC’s recommended prevention strategies were used to organize activities implemented by each of the 4 states. For each of the states, overdose program implementers were also tasked to review the draft program narratives to ensure accuracy and comprehensiveness. Data regarding historical progression of some of the efforts pre-2016 was also considered.

 The 3 authors performed a systematic content analysis of the completed program narratives using an iterative thematic approach to coding to elucidate prevention activities and to generate hypotheses for further research. Analysis used the organizing categories as the first level in the hierarchical coding framework. The authors distilled descriptions of each activity in a category into thematic codes to identify common themes across multiple program narratives, which were then used to identify activities implemented by all 4 states (dubbed “core activities”). Additionally, thematic codes that did not occur across all 4 programs narratives yet were believed by the 3 authors to exemplify approaches tailored to the local content were used to identify context specific activities (“additional elements”).

 From the predetermined categories, the following core elements of overdose prevention and response were identified: comprehensive state policies; strategic planning; local engagement; data access, capacity, and dissemination; targeted training for professional audiences; treatment infrastructure; and harm reduction (

The authors also developed a list of additional elements that some states utilized. These includes ways to handle populations with needs uniquely specific to the area (rural communities, homelessness, ethnic/minorities such as Hispanic or tribal populations, diversion/drug courts). All 4 also described various approaches to public awareness through campaigns specific to the local context and hotlines for access to resources. Although the approaches differ, they all focus on linkage to treatment resources (ie, the hub-and-spoke model in New Hampshire or the peer support and coaches in New Mexico and Massachusetts).

 serves as a valuable opportunity to understand how states can be successful in their efforts towards overdose prevention and response. The authors identified comprehensive state policies, strategic planning efforts, local engagement, data collection and dissemination, targeted training for professional audiences, treatment infrastructure, and harm reduction, as the core elements of overdose programs in states that experienced a decline in the rate of opioid involved overdose deaths from 2016 to 2017. These elements contribute to successful overdose prevention and responses, and such activities can be extrapolated to other public health crises beyond just the opioid overdose epidemic, especially as new drug threats emerge. 

 This study represents an attempt at elucidating the core elements of successful 

 and response programs. These can broadly help states consider new policies, partnerships, and activities to enhance their own programs against the current, and future, overdose deaths. Comprehensive policies, timely dissemination of key data, and building capacity through training, treatment infrastructure, and harm reduction activities are prevention efforts shared by the 4 successful states; however, each state tailored its programs to its own context, with emphasis on the needs of the target population. These elements are also enmeshed by partnerships and collaborations among various segments of the public health response and public and private sectors. The 4 states had robust foundations of multifaceted policies (ie, Good Samaritan laws, PDMP access, and policies to enhance naloxone distribution) which preceded the development of programmatic efforts.

In addition, all 4 states also had comprehensive strategic planning at both state and local levels in the form of commissions, workgroups, and advisory committees. Another common theme was the local engagement by state health departments, which facilitated support and capacity building via technical assistance (implementation and evaluation of prevention activities, using data to inform interventions, and disseminating evidence-based data to inform interventions). Aggregating data also allowed for targeted identification of populations disproportionately affected and interventions. Training pharmacists, law enforcement, and other professional audiences as well as using harm reduction activities (such as syringe and naloxone distribution) were also strong building blocks.

It is important to note that all 4 states evaluated received opioid-focused funding from the CDC, as well as from other federal and nonfederal sources, in order to implement prevention and overdose reduction strategies, and/or to improve overdose data collection.

The question is, are these findings generalizable to other drug related overdose deaths or epidemics? This is one of the limitations—yet of importance given that we are currently also dealing with a quiet 

 The 4 states had program narratives that included description of drug overdose more broadly, beyond just opioids, which is reassuring. 

Applicability to overdose prevention programs in other states

. It does not address whether states that did not see a decrease in opioid related mortality shared the same core elements in their overdose prevention programs with those states that did. This information is necessary to determine both the importance of certain core elements when it comes to decreasing mortality and the applicability of these core elements in other states. If other states were found to have implemented the same core elements and failed to see a decrease in opioid overdose mortality, it would limit the external validity of this study.

. The scope of the study was focused on states with decreased opioid overdose mortality from 2016 to 2017. However, it should be asked whether the states involved in the study experienced a plateau or a further decrease in their opioid overdose mortality in subsequent years. If a state involved in the study was found to have an increase in their opioid overdose mortality in subsequent years, it may indicate that the drop in deaths from 2016 to 2017 was a natural fluctuation. Additionally, it would bring into question the possible correlation between decreased overdose mortality and the implementation of the core elements identified.

The selection of states investigated in this study is not fully explained in the methods section

. It was not discussed how the 4 states with decreased overdose mortality were selected from the 25 states with the highest mortality rates that were included for consideration. Additionally, the paper fails to identify the absolute or relative decrease in overdose mortality that the included states experienced. Although this is separate from the main goal of the paper, this information could be pertinent to how the findings may be interpreted. If one of the included states experienced a decline of 20 opioid deaths from 400 deaths in the previous year, this would be a 5% decline but may be more likely a product of variability and less likely related to the implementation of the core elements discussed due to the low change in absolute mortality.

Variability between states in reporting opioid-related overdose deaths to the CDC

. Because of this, the death rates used to identify the 25 states with high rates of opioid overdose mortality and those 4 states who saw a decrease in opioid overdose mortality from 2016 to 2017 may be underreported in some states more than others. More information on how these states, especially the 4 with decreased opioid overdose mortality, report deaths to the CDC could support the finding that mortality decreased in these states and was not a result of underreporting. This variability exists because states have different policies and capacities for postmortem testing. For example, some state laboratories may not evaluate the deceased for synthetic opioids, like fentanyl, or may avoid toxicology screens altogether in certain situations. Another possible confounding factor revolves around the reported cause of death. Some opioid related overdose deaths may not be reported to the CDC as an overdose, but instead could be reported as a related cause like anoxic brain injury. Given interstate variability in reporting, it may be pertinent to acknowledge how the 4 states identified in this study report their opioid overdose deaths to the CDC and how this reporting compares to the other 25 states with high rates of opioid overdose mortality.

The paper does not detail how the 10 categories they used to organize activities in overdose prevention program narratives were determined.

 It mentions that categories were developed by the authors’ review of data obtained by the preliminary environmental scan and informed by CDC’s recommended evidence-based prevention strategies, but it does not explain further how the authors came to the conclusion to use the 10 categories listed. Given that the 7 core elements are derived from these 10 categories, it would be relevant to address how the authors decided upon them. This would provide readers with better insight into this study and could serve to validate the choice of the 10 categories.

This study mentions that only activities with opioid-related CDC funding were included and that separate nonfederal and federal non-CDC donations may have been made that were beyond the scope of the study

. Such donations, however, could have had a substantial impact on additional activities in the states that experienced a decrease in overdose mortality. Although the purpose of the study was not focused on attributing changes in overdose mortality to any particular funding, choosing to ignore these other sources may influence what activities were identified as the most prominent or impactful, since only a subset of activities is being investigated. Even within the states included in the analysis, authors state that CDC funding varied with 3 states receiving funding for both implementing prevention strategies and improving data collection, while New Hampshire only received funding to improve data collection. Identifying if the states being investigated had additional funding, and how this funding compared to the funding in other states, would be relevant to interpreting the results of this study. If states were working with similar amounts of funding, it would detract from the number of possible confounding factors in this study. If funding was not similar across states, it still may be pertinent to compare the states that had decreased opioid-related overdose mortality from 2016 to 2017 to other states that did not experience a decrease but who had a similar amount of funding. This could help either elucidate more core elements or strengthen the argument for those identified in this study.

Despite the limitations, this is an important study with the data providing valuable insight. Since the beginning of the COVID-19 pandemic, overdose related deaths are once again on the rise with a 20% increase noted in the 12-month period ending last June. The 4 states evaluated here interestingly sustained much 

lower numbers of deaths compared to the national average

is assistant professor of psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. He is Addiction Section Editor for

is a fourth-year medical student at Dartmouth’s Geisel School of Medicine who rotated through the Addiction Services at New Hampshire Hospital, Concord, NH.

Increases in drug and opioid-involved overdose deaths—United States, 2010-2015.

 National Center for Health Statistics. 2021.

A thematic analysis of overdose prevention and response efforts in states experiencing declines in rates of opioid-involved overdose deaths. 

Trends and geographic patterns in drug and synthetic opioid overdose deaths—United States, 2013–2019.

5. Baumgartner JC, Radley DC. The spike in drug overdose deaths during the COVID-19 pandemic and policy options to move forward. March 25, 5021. Accessed August 12, 2021. 

https://www.commonwealthfund.org/blog/2021/spike-drug-overdose-deaths-during-covid-19-pandemic-and-policy-options-move-forward

In this journal club, a medical student and an addiction psychiatrist review a thematic analysis of successful prevention efforts in states with declining rates of opioid-related overdose deaths. 

Reducing Opioid-Involved Overdose Deaths: States’ Prevention and Response Efforts 

Overdose awareness day, which occurs on August 31, raises particular concerns about substances adulterated with illicitly manufactured fentanyl, which has spread from being the 

major cause of not only overdoses from opioids, but also from nonopioids

 Look-alike versions of other prescription opioids (Percocet), benzodiazepines (Valium), and stimulants (Adderall) have been imported to the United States’ illicit drug markets and they often contain toxic or lethal doses of fentanyl. Moreover, even during the COVID-19 pandemic when the volume of drug screens dropped significantly, those tested showed a 

marked increase in urine drug screens positive for illicit fentanyl 

(35%), and more strikingly for methamphetamine (89%), which heralded the fourth wave of the opioid epidemic with combined stimulants and opioids.

 Because of the increasing morbidity and mortality from this combination of stimulants and fentanyl, neither of which have effective or pharmacotherapies approved by the US Food and Drug Administration, therapeutic strategies have expanded to include immunization with vaccines.

A History of Vaccines for Substance Use Disorder

Vaccines for addictive substances were first conceptualized in the late 1960s, based on introducing a foreign substance (ie, heroin) to induce T-cells and B-cells to make antibodies against the substance. Once the individual has antibodies, using the drug would lead to the formation of a drug-antibody complex that can be excreted rather than crossing the blood brain barrier and producing psychoactive effects. 

 of substantial portions of any amount of the drug taken. That 

 limits the drug’s reinforcing properties.

 faced the problem of being too small to generate an antibody response. To address this size problem, the drugs must be conjugated to an immunogenic carrier protein (eg, cholera toxin, keyhole limpet hemocyanin (KLH), tetanus toxoid) and mixed with an adjuvant such as alum to enhance the immune response. Still, these 

 have struggled to produce sufficient levels of antibodies and have a high affinity for the free drug. To date, a 

 using different combinations of adjuvants and carrier proteins to increase the magnitude, affinity, and durability of antibodies, as well as reduce the substantial variability among individuals in the magnitude of their antibody responses.

With this background on anti-addiction vaccines, we faced the start of the 

 in the 1990s with the introduction of oxycodone (OxyContin) by Purdue Pharma. Over the past 20 years we have undergone 

. In the late 1990s, overdose deaths rose due to prescription opioids, transitioning to the second wave of heroin overdoses in 2010. The third wave of deaths began in 2013 with illicitly manufactured synthetic opioids, particularly fentanyl and fentanyl analogs. More recently, a fourth wave has begun with the combination of fentanyl disguised in counterfeit opioid, sedative, and stimulant pills looking like the marketed pharmaceutical products. In 2019,

 over 36,000 deaths involved synthetic opioids

, accounting for nearly 73% of all opioid-related deaths that year. In the 12 months leading up to May 2020, deaths due to fentanyl increased 38.4% compared to the previous year with many of those overdoses in combinations with sedatives and stimulants.

An ideal vaccine would induce antibodies specific to the misused opioids (eg, fentanyl) while allowing for medical interventions with other classes of opioids when necessary. In a study by Kosten et al, the morphine vaccine KLH-6-SM (6-succinylmorphine linked to lysine groups on KLH) attenuated morphine-induced behavioral responses in rats. Vaccinated rats also showed a 

 diminished heroin reward and heroin-induced drug-seeking, and vaccinated rats required significantly higher doses of heroin for analgesia.

 against oxycodone prevented oxycodone-induced analgesia and respiratory depression in vaccinated rats with minimal cross-reactivity to methadone, buprenorphine, and opioid antagonists.

Vaccines against fentanyl are now of particular interest because our well-established treatments of methadone, buprenorphine, and naltrexone do not block fentanyl, and because the adulteration of other substances with fentanyl has led to a rapid increase in overdoses among unwitting users. Because 

fentanyl is 50 to 100 times more potent than morphine

, the lethal dose is very small at approximately 2mg and even at 1000 times smaller doses for fentanyl analogs.

 Therefore, vaccines against fentanyl may be particularly effective because the concentration of antibodies needed is much lower than concentrations needed for blocking other 

 have shown promising results for overdose prevention as vaccinated animals required much higher doses of fentanyl for analgesic and respiratory depressant effects.

Anti-fentanyl vaccines combined with methadone, buprenorphine, or naltrexone will likely be highly successful because increasing the fentanyl dose sufficiently is unrealistic in human use due to the antibody levels appearing to be 100 or more times greater than the lethal blood levels of fentanyl found in overdoses. These anti-fentanyl vaccines will be life-saving adjuncts to opiate agonist treatments and provide complete overdose protection from fentanyl and its derivatives, against which current treatments cannot protect.

Researchers have made significant progress in vaccine development for substance use disorder, and now have a more comprehensive understanding of vaccine design, as well as human behavior after vaccination. Despite the success of several vaccines in animal studies, the ones advancing to human clinical trials against cocaine and nicotine failed to demonstrate efficacy against placebo. Even at adequate antibody titers for typical abused doses, cocaine users can increase their use to compensate for the blockade, and clearly intrinsic personal motivation for abstaining is essential for most vaccines to be helpful in maintaining abstinence. The introduction of the stronger, more lethal fentanyl has rekindled interest and persistence in improving vaccines as we aim to minimize toxicity and prevent overdose from fentanyl.

1. National Institute on Drug Abuse. Overdose death rates. 2021. Accessed August 9, 2021. 

https://www.drugabuse.gov/drug-topics/trends-statistics/overdose-death-rates

2. Niles JK, Gudin J, Radcliff J, Kaufman HW. 

The opioid epidemic within the COVID-19 pandemic: drug testing in 2020.

The rate hypothesis and agonist substitution approaches to cocaine abuse treatment. 

4. Abreu ME, Bigelow GE, Fleisher L, Walsh SL. 

Effect of intravenous injection speed on responses to cocaine and hydromorphone in humans.

The continuing search for an addiction vaccine.

Current status and future prospects for the development of substance abuse vaccines.

Current status of immunotherapies for addiction. 

8. O’Donnell JK, Gladden RM, Seth P. Trends in deaths involving heroin and synthetic opioids excluding methadone, and law enforcement drug product reports, by census region — United States, 2006–2015. Centers for Disease Control and Prevention. September 1, 2017. Accerssed August 9, 2021. 

https://www.cdc.gov/mmwr/volumes/66/wr/mm6634a2.htm

9. Mattson CL, Tanz LJ, Quinn K, et al. Trends and geographic patterns in drug and synthetic opioid overdose deaths — United States, 2013–2019. Centers for Disease Control and Prevention. February 12, 2021. Accerssed August 9, 2021. 

https://www.cdc.gov/mmwr/volumes/70/wr/mm7006a4.htm

10. National Center for Health Statistics. Provisional drug overdose data. 2021. Accessed August 9, 2021. 

https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm

11. Kosten TA, Shen XY, O’Malley PW, et al. 

A morphine conjugate vaccine attenuates the behavioral effects of morphine in rats.

Prog Neuropsychopharmacol Biol Psychiatry

12. Schlosburg JE, Vendruscolo LF, Bremer PT, et al. 

Dynamic vaccine blocks relapse to compulsive intake of heroin.

13. Raleigh MD, Peterson SJ, Laudenbach M, et al.

 Safety and efficacy of an oxycodone vaccine: addressing some of the unique considerations posed by opioid abuse.

A review: fentanyl and non-pharmaceutical fentanyls.

15. Bremer PT, Kimishima A, Schlosburg JE, et al. 

Combatting synthetic designer opioids: a conjugate vaccine ablates lethal doses of fentanyl class drugs.

16. Tenney RD, Blake S, Bremer PT, et al. 

Vaccine blunts fentanyl potency in male rhesus monkeys.

17. Stone AE, Scheuermann SE, Haile CN, et al. 

Fentanyl conjugate vaccine by injected or mucosal delivery with dmLT or LTA1 adjuvants implicates IgA in protection from drug challenge.

Manufactured fentanyl is a major cause of overdoses for opioids and nonopiods. Can a vaccine immunize against overdose? 

Anti-Fentanyl Vaccines as Medical Solutions to Overdose Deaths

North America is currently experiencing an opioid overdose crisis driven mainly by fentanyl and fentanyl analogs, such as carfentanyl.

fatalities involving opioids in the United States

 The COVID-19 pandemic has only heightened the 

 of opioids on individuals who use the drugs, their families, and communities across 

 Novel solutions are needed for this complex problem.

Much is already being done. In an effort to mitigate the overdose crisis, both Canada and the United States have implemented multiple public health and treatment strategies. Extant strategies include providing opioid agonist therapies (OAT), naloxone for reversing fatal opioid overdoses, and access to harm reduction services. In addition, injectable/implantable buprenorphine is available in both countries. However, the opioid receptor antagonist naltrexone, while available in the oral formulation in both Canada and the United States, is not available in the depot formulation in Canada. Currently, OAT with methadone or buprenorphine/naloxone are the first-line interventions for individuals with moderate to severe 

 Although buprenorphine/naloxone is preferable over methadone in terms of its superior safety profile, there are many limitations to these treatments. Moreover, in Canada, there are barriers to accessing OAT, including reduced access to OAT prescribers in rural areas, and the shortage of pharmacies offering on-site OAT.

OAT clinics often lack psychosocial supports, and there are often high out-of-pocket expenses that prove problematic for individuals with OUD who have limited financial means.

 Similar economic, geographic, attitudinal, and organizational barriers exist in the United States.

 Additionally, in the United States, health insurance barriers, where public insurance providers favour methadone while private insurance favours buprenorphine/

, have caused rampant racial and economic disparities in OAT access across the United States.

Since the start of the opioid crisis, Canada has taken several novel harm reduction approaches to combat the opioid crisis. Harm reduction refers to a wide array of public health policies intended to reduce the adverse consequences of human behaviours, including—but not limited to—substance use. In the context of the opioid crisis, harm reduction interventions have included rapid access addiction medicine services, providing take-home naloxone kits, supervised consumption facilities (SCFs), and education around overdose risk mitigation.

Historically, the success of harm reduction services for OUD has been difficult to quantify; most studies have small sample sizes and poorly defined outcome measures. These studies have limited generalizability to most individuals with OUD, who respond to first-line treatments. However, there is mounting evidence that demonstrates proof of efficacy and effectiveness for a range of harm reduction services. Recent studies have shown that they can reduce opioid overdose mortality, infection-related complications, and crime amongst individuals with treatment-refractory OUD (TR-OUD).

In recent years the Canadian health care providers have implemented 3 critical harm reduction measures that have curtailed opioid-related fatalities: (1) heroin-assisted therapy, (2) hydromorphone-assisted therapy, and (3) supervised consumption facilities (SCFs). A summary of each of these novel treatments is provided in 

Following the Canadian example, we advocate for the provision of 

 in the United States that could save countless lives by increasing access to evidence-based treatment options for OUD.

Heroin-assisted treatment (HAT), or heroin maintenance, is an evidence-based intervention for managing the symptoms of treatment-refractory OUD (TR-OUD). While there are varying definitions of TR-OUD, most studies refer to the failure to respond meaningfully to 1 or more first-line treatments for OUD (eg, methadone or buprenorphine/suboxone). HAT is available in Canada (eg, Vancouver and Montreal) and in some European countries (eg, Germany, Switzerland, and the United Kingdom) and has shown efficacy in select groups experiencing TR-OUD. To receive HAT, individuals with TR-OUD must visit designated 

, where they will receive injectable medical-grade heroin (diacetylmorphine) up to 3 times daily under strict nursing and medical supervision.

 In essence, most HAT clinics operate under a supervised consumption model.

Results from randomized controlled trials have shown promising findings for individuals with TR-OUD. In one trial, HAT reduced illicit heroin use, improved treatment retention, reduced criminal activities, and improved mental and physical health compared with methadone therapy.

How can understanding the opioid crisis in Canada inform strategies in the United States?

International Overdose Awareness

Risk of Overdose with Antipsychotic and Opioid Co-Prescription

Opioid Crisis Awareness

The Case for Caution When Prescribing Benzodiazepines

Fighting the Opioid Crisis

Reducing Opioid-Involved Overdose Deaths: States’ Prevention and Response Efforts

Anti-Fentanyl Vaccines as Medical Solutions to Overdose Deaths

Lessons from Novel Harm Reduction Methods

A Tale of Two Crises: Fighting the Overdose Problem During the Pandemic

Addressing the Opioid Crisis: A New Approval

Lloyd Sederer, MD: A Conversation About Addiction and the Opioid Epidemic