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

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Abstract

Among vaccines aimed at treating substance use disorders, those targeting opioids present several unique medication development challenges. 1) Opioid overdose is a common complication of abuse, so it is desirable for an opioid vaccine to block the toxic as well as the addictive effects of opioids. 2) It is important that an opioid vaccine not interfere with the action of opioid antagonists used to reverse opioid overdose or treat addiction. 3) Some opioids are immunosuppressive and chronic ongoing opioid use could interfere with vaccine immunogenicity. 4) Although antibody-bound oxycodone is unable to enter the brain because of its size, it might still be able to activate peripheral opioid receptors. To assess vaccine impact on opioid toxicity, rats vaccinated with oxycodone conjugated to keyhole limpet hemocyanin subunit dimer (OXY-dKLH) adsorbed to alum or controls vaccinated with dKLH were compared with regard to oxycodone-induced hotplate analgesia and oxycodone-induced respiratory depression and bradycardia. Vaccination shifted the dose-response curves to the right, representing protection, for each of these endpoints. Naloxone was equally effective in both OXY-dKLH and control groups, providing complete and rapid reversal of respiratory depression. The administration of a long-acting naltrexone formulation during vaccination did not impair vaccine immunogenicity in mice. Similarly, serum anti-oxycodone antibody titers were not altered by continuous morphine infusion during vaccination compared to opioid-naïve controls. Competitive ELISA assay showed negligible or low affinity of immune antiserum for endogenous opioids or opioid antagonists. In vitro receptor binding assays showed that antibody-bound oxycodone does not activate mu opioid receptors. These data support further study of OXY-dKLH as a potential treatment for oxycodone abuse and suggest that vaccination might also reduce the severity of oxycodone overdose.

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The Role of Science in Addressing the Opioid Crisis

Nora D. Volkow, Francis Collins (2017)

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Opioid Overdose Prevention Programs Providing Naloxone to Laypersons — United States, 2014

Eliza Wheeler, T Stephen Jones, Michael Gilbert … (2015)

Drug overdose deaths in the United States have more than doubled since 1999 (1). During 2013, 43,982 drug overdose deaths (unintentional, intentional [suicide or homicide], or undetermined intent) were reported (1). Among these, 16,235 (37%) were associated with prescription opioid analgesics (e.g., oxycodone and hydrocodone) and 8,257 (19%) with heroin (2). For many years, community-based programs have offered opioid overdose prevention services to laypersons who might witness an overdose, including persons who use drugs, their families and friends, and service providers. Since 1996, an increasing number of programs provide laypersons with training and kits containing the opioid antagonist naloxone hydrochloride (naloxone) to reverse the potentially fatal respiratory depression caused by heroin and other opioids (3). In July 2014, the Harm Reduction Coalition (HRC), a national advocacy and capacity-building organization, surveyed 140 managers of organizations in the United States known to provide naloxone kits to laypersons. Managers at 136 organizations completed the survey, reporting on the amount of naloxone distributed, overdose reversals by bystanders, and other program data for 644 sites that were providing nalox-one kits to laypersons as of June 2014. From 1996 through June 2014, surveyed organizations provided naloxone kits to 152,283 laypersons and received reports of 26,463 overdose reversals. Providing opioid overdose training and naloxone kits to laypersons who might witness an opioid overdose can help reduce opioid overdose mortality. Since 2008, HRC has maintained a database of organizations providing naloxone kits to laypersons. The Opioid Safety and Naloxone Network is a national network of naloxone experts, program administrators, and advocates. Before the survey, HRC staff polled network participants for information on any new organizations providing naloxone kits to laypersons that should be included in the survey. In July 2014, HRC e-mailed a link to an online survey to managers of 140 organizations known to provide naloxone kits to laypersons. These organizations included public health departments, pharmacies, health care facilities, substance use treatment facilities, and community-based organizations providing services to persons who use drugs, including current or former opioid (heroin or pharmaceutical) users, and other potential witnesses to overdoses. Law enforcement organizations, emergency medical services, and other professional first responders using naloxone were not included in this survey. The survey included questions about the year the organization began operating; the numbers of sites or local programs providing naloxone kits; the number of persons trained in overdose prevention and provided naloxone kits; and the number of reports of overdose reversals (administration of naloxone by a trained layperson in the event of an overdose) (4), as well as whether the reports were based on program data or were estimates. The survey also asked about the naloxone formulations currently provided in kits, models for training and providing naloxone kits, funding sources, and any difficulties obtaining naloxone. To obtain data for a recent full calendar year, organizations providing naloxone kits during calendar year 2013 were asked to provide specific data for that year, including numbers of persons provided naloxone kits, reversals reported, and naloxone vials provided; characteristics of persons who received naloxone kits (e.g., persons who use drugs, friends and family members, service providers); characteristics of persons reporting overdose reversals; and the drugs involved in reported overdose reversals. HRC staff used follow-up e-mails and telephone calls to encourage participation and clarify responses. Managers from 136 (97.1%) organizations completed the survey, including those from 84 community-based organizations, 18 health care facilities, 10 Veterans Administration health care systems, 18 state or local health departments, and six pharmacies. Half of the responding organizations began operating during January 2013–June 2014 (Figure 1). Respondents provided reports for 644 local opioid overdose prevention sites that provide naloxone kits, located in 30 states and the District of Columbia (DC) (Figure 2). Thirty-eight respondents provided consolidated data for multiple local sites providing naloxone kits. Some organizations estimated responses; for example, one health department estimated the number of laypersons receiving naloxone kits on the basis of the number of kits distributed to local sites. Three state health departments (Massachusetts, New Mexico, and New York) oversee operations of statewide naloxone programs, with 334 local sites (51.9% of the 644 local sites). From 1996, when the first organization began providing naloxone, through June 2014, the 136 responding organizations reported providing training and naloxone kits to 152,283 laypersons (range = 1–36,450; median = 100; mean = 1,120).* The 109 organizations that collect reports of reversals documented 26,463 overdose reversals (range = 0–5,430; median = 9; mean = 243).† During 2013, 93 organizations reported distributing or prescribing naloxone to 37,920 laypersons (range = 0–9,000; median = 75; mean = 407.7).§ The 68 (50%) organizations that collect reports of reversals documented 8,032 overdose reversals (range = 0–2,079; median = 10; mean = 118.1).¶ Ninety-three organizations collected information on the characteristics of laypersons who were provided naloxone kits. Laypersons who received naloxone kits were characterized as persons who use drugs (81.6%); friends and family members (11.7%); service providers (3.3%); or unknown (3.4%).** Sixty-eight organizations provided information about lay-persons who reported administering naloxone, characterizing them as persons who use drugs (82.8%); friends and family members (9.6%); service providers (0.2%); or unknown (7.4%).†† Forty-two organizations collected information from laypersons about the drugs that appeared to be involved in the reversed overdoses; heroin was involved in 81.6% and prescription opioids in 14.1%.§§ Various program models were used by organizations to provide naloxone to laypersons, including distribution of naloxone kits by trained nonmedical staff or volunteers under a standing order (60 [44.1%]), by medical staff (49 [36.0%]), prescriptions written by a medical provider and filled at a pharmacy (39 [28.7%]), pharmacists dispensing directly via collaborative practice agreements and other mechanisms (12 [8.8%]), and other protocols (19 [14.0%]). Thirty-three organizations used more than one model. During 2013, 90 (66.2%) of the 136 organizations reported distributing 140,053 naloxone vials, including refills (range = 1–53,200; median = 179.5; mean = 1,556.1).¶¶ Three respondents whose organizations were operational in 2013 did not report on the number of vials because they furnished prescriptions to be filled at a pharmacy. The remaining 43 organizations indicated that they were not yet providing naloxone kits during 2013. Sixty-nine respondents (50.7%) reported their organization provided only injectable naloxone, 51 (37.5%) provided only intranasal naloxone, and 16 (11.8%) provided both injectable and intranasal naloxone.*** A total of 111,602 vials (79.7%) of injectable naloxone (21.4% 10 mL and 58.1% 1 mL) and 28,446 (20.3%) vials of intranasal naloxone were provided to laypersons. Organizations were characterized as small, medium, large, or very large, on the basis of the number of naloxone vials distributed during 2013. The 11 large and very large organizations provided naloxone to 28,604 laypersons, representing 75.4% of all 2013 recipients (Table). Forty (29.4%) organizations reported difficulties maintaining an adequate supply of naloxone, and 73 (53.7%) reported inadequate resources to sustain or expand their organization’s efforts to disseminate naloxone kits. Discussion Organizations that provide naloxone kits to laypersons have expanded substantially since a similar survey in 2010 (5), reflecting a 183% (from 48 to 136) increase in the number of responding organizations; a 243% (from 188 to 644) increase in the number of local sites providing naloxone; a 187% (from 53,032 to 152,283) increase in the number of laypersons provided naloxone kits; a 160% (from 10,171 to 26,463) increase in the number of reversals reported; and a 94% (from 16 to 30) increase in states (including DC) with at least one organization providing naloxone. Half of the responding organizations began operating during January 2013–June 2014. Although early adopters of naloxone kit provision were mainly syringe exchanges, other programs, including substance use treatment facilities, Veterans Administration health care systems, primary care clinics, and pharmacies have started providing naloxone to laypersons. Providing naloxone kits to laypersons reduces overdose deaths (4), is safe (3), and is cost-effective (6). U.S. and international health organizations recommend providing naloxone kits to laypersons who might witness an opioid overdose (3,7); to patients in substance use treatment programs (3,7,8); to persons leaving prison and jail (3,7,8); and as a component of responsible opioid prescribing (8). Although the number of organizations providing naloxone kits to laypersons is increasing, in 2013, 20 states had no such organization, and nine had less than one layperson per 100,000 population who had received a naloxone kit. Among these 29 states with minimal or no access to naloxone kits for laypersons, 11 had age-adjusted 2013 drug overdose death rates higher than the national median (2). Some organizations reported information on the laypersons receiving naloxone kits (N = 99 organizations), using naloxone in overdose reversals (N = 68), and the drugs that appeared to have caused the overdose (N = 42). Persons who use drugs accounted for 81.6% of laypersons who received naloxone kits; they also performed the majority (82.8%) of reported overdose reversals. A majority (81.6%) of the overdoses that were reversed involved heroin, indicating that organizations are reaching laypersons who witness heroin overdoses. A study of a community-based naloxone program in San Francisco also found that persons who use drugs play a major role in reversing heroin overdoses (9). Additional interventions are needed to reach persons who may witness prescription opioid analgesic overdoses, which account for nearly twice as many deaths as heroin overdoses. Forty (29.4%) respondents reported that their organization has experienced problems obtaining naloxone. Prices of intranasal naloxone more than doubled in the second half of 2014 (10) and Opioid Safety and Naloxone Network members report that cost increases are reducing the quantity of naloxone purchased and provided to laypersons (Matt Curtis, VOCAL NY, personal communication, 2015). The findings in this report are subject to at least four limitations. First, despite extensive knowledge of naloxone distribution programs by the Harm Reduction Coalition and Opioid Safety and Naloxone Network, organizations providing naloxone kits are increasing rapidly and some might not yet be known to HRC and therefore, might not be included in the survey, which may underestimate the impact of these programs. Second, survey responses are based on unconfirmed reports from organizations providing naloxone kits. Third, some reports provided by organizations are based on estimates. These three limitations could result in either under or over-reporting of persons provided naloxone kits. Finally, the numbers of overdose reversals likely were under-reported, because some sites, such as pharmacies, do not collect reversal reports. Organizations providing naloxone kits to laypersons receive many reports of overdose reversals and can reach large numbers of potential overdose bystanders. Comprehensive prevention measures that include teaching laypersons how to respond to overdoses and administer naloxone might help prevent opioid drug overdose deaths. This report suggests that many programs reach persons who witness heroin-related overdoses; additional methods are needed to provide naloxone kits to persons who might witness prescription opioid analgesic overdoses. Summary What is already known on this topic? Drug overdose deaths in the United States have more than doubled since 1999, reaching a total of 43,982 in 2013. Heroin and prescription opioids are major causes of drug overdose deaths. Naloxone is the standard medication used for reversal of the potentially fatal respiratory depression caused by opioid overdose. What is added by this report? From 1996 through June 2014, a total of 644 local sites in 30 states and the District of Columbia reported providing naloxone kits to 152,283 laypersons and receiving reports of 26,463 drug overdose reversals using naloxone from 1996 through June 2014. Most laypersons who reported using the kits to reverse an overdose were persons who use drugs, and many of the reported reversals involved heroin overdoses. Medical clinics and pharmacies have started providing naloxone kits to laypersons, and the reported number of organizations providing kits almost doubled from January 2013 through June 2014. What are the implications for public health practice? Organizations training and providing naloxone kits to laypersons can reach large numbers of potential overdose witnesses and result in many reported overdose reversals. Comprehensive prevention measures that include teaching laypersons how to respond to overdoses and administer naloxone prevent opioid-related drug overdose deaths. Additional methods are needed to provide naloxone kits to persons who might witness prescription opioid analgesic overdoses.

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Effectiveness of bystander naloxone administration and overdose education programs: a meta-analysis

Rebecca Giglio, Guohua Li, Charles J DiMaggio (2015)

The objective of this review was to assess the effectiveness of bystander naloxone administration and overdose education programs by synthesizing quantitative results reported in the research literature. Studies meeting predefined criteria were identified and reviewed, and their results were synthesized through meta-analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for overdose recoveries for individuals who received naloxone dispensed by non-medical community members, and the standardized mean difference was calculated for test scores of non-medical volunteers who received training in overdose management versus the scores of untrained volunteers. Pooled data from four studies showed that naloxone administration by bystanders was associated with a significantly increased odds of recovery compared with no naloxone administration (OR = 8.58, 95% CI = 3.90 to 13.25). Data from five studies of overdose education indicated that average scores were significantly higher for trained participants than untrained participants for tests on naloxone administration, overdose recognition, and overdose response (standardized mean difference = 1.35, 95% CI = 0.92 to 1.77). Empirical evidence in the research literature suggests that bystander naloxone administration and overdose education programs are associated with increased odds of recovery and with improved knowledge of overdose recognition and management in non-clinical settings. Electronic supplementary material The online version of this article (doi:10.1186/s40621-015-0041-8) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Raleigh M. D.:

ORCID: http://orcid.org/0000-0002-9715-6962

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Peterson S. J.: Role: InvestigationRole: Writing – review & editing

Laudenbach M.: Role: InvestigationRole: MethodologyRole: Writing – review & editing

Baruffaldi F.: Role: InvestigationRole: MethodologyRole: ResourcesRole: Writing – review & editing

Carroll F. I.: Role: ResourcesRole: Writing – review & editing

Comer S. D.: Role: ConceptualizationRole: MethodologyRole: Writing – review & editing

Navarro H. A.: Role: Formal analysisRole: InvestigationRole: ResourcesRole: VisualizationRole: Writing – review & editing

Langston T. L.: Role: InvestigationRole: Writing – review & editing

Runyon S. P.: Role: MethodologyRole: ResourcesRole: Writing – review & editing

Winston S.: Role: ConceptualizationRole: MethodologyRole: Writing – review & editing

Pravetoni M.: Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing

Pentel P. R.: Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing

Michael Taffe: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 1 December 2017

Publication date Collection: 2017

Volume: 12

Issue: 12

Electronic Location Identifier: e0184876

Affiliations

[1 ] Minneapolis Medical Research Foundation, Minneapolis, MN, United States of America

[2 ] Research Triangle Institute, Research Triangle Park, NC, United States of America

[3 ] New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY, United States of America

[4 ] Winston Biopharmaceutical Consulting, Boulder, CO, United States of America

[5 ] Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, United States of America

[6 ] Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States of America

Scripps Research Institute, UNITED STATES

Author notes

Competing Interests: SW owns the company Winston Pharmaceutical Consulting. Over the past 3 years, SDC received compensation (in the form of partial salary support) from studies supported by Braeburn Pharmaceuticals, Cerecor, Indivior, MediciNova, and Reckitt-Benckiser Pharmaceuticals. In addition, SDC has served as a consultant to the following companies over the past 3 years: Advances in Pain Management, AstraZeneca, Clinilabs, Collegium Pharmaceutical, Daiichi Sankyo, Depomed, Egalet, Endo, Guidepoint Global, Heptares Therapeutics Limited, Inspirion Delivery Sciences, IntelliPharmaCeutics, Janssen, KemPharm, Mallinckrodt, Neuromed, Opiant, Orexo, Pfizer, and Shire. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

* E-mail: rale0011@ 123456umn.edu

Author information

Raleigh M. D. http://orcid.org/0000-0002-9715-6962

Article

Publisher ID: PONE-D-17-24523

DOI: 10.1371/journal.pone.0184876

PMC ID: 5711015

PubMed ID: 29194445

SO-VID: bdcc1f65-404f-4a9f-b715-dcd845890d7f

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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 28 June 2017

Date accepted : 1 September 2017

Page count

Figures: 5, Tables: 1, Pages: 18

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100000026, National Institute on Drug Abuse;

Award ID: DA038876

Award Recipient : Pravetoni Marco

Funded by: funder-id http://dx.doi.org/10.13039/100000026, National Institute on Drug Abuse;

Award ID: DA038876

Award Recipient : Pentel P. R.

This work was supported by National Institutes of Health, National Institute on Drug Abuse ( https://www.drugabuse.gov/) grant DA038876 (MP, PRP). SW was a consultant on this study and owns the company Winston Pharmaceutical Consulting. The specific roles of this author are articulated in the ‘author contributions’ section.

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