The Opioid Epidemic: Moving Toward an Integrated, Holistic Analytical Response

Abstract

In many jurisdictions, public safety and public health entities are working together to enhance the timeliness and accuracy of the analytical characterization and toxicology testing of novel synthetic opioids. The improved sharing and early detection of these analytical data are intended to inform surveillance, interdiction efforts, patient intervention and treatment, all of which are critical to curbing the opioid epidemic. Forensic practitioners working to identify novel synthetic opioids struggle to provide timely results when encountering new or unknown substances, such as the fentanyl analogs. These compounds, which mimic heroin in pharmacologic effect but can be far more potent, are inconsistently present in chemical identification libraries, and are currently largely unavailable as reference materials for analytical comparison. Additionally, federal, state and local governments as well as nongovernmental organizations require potency, toxicity and potential-for-abuse data to evaluate the potential health risks of emerging drug threats. Subsequent scheduling efforts and criminal prosecutions also require these thorough drug characterization studies. Pilot programs have demonstrated that early communication of real-time drug toxicity and analytical data significantly impacts the successful response to emerging opioids. High-quality, real-time, national-level data on chemical composition, toxicological test data, drug toxicity and overdoses, and analysis of seized materials by law enforcement are needed to track drug trends. However, the USA still lacks a national system to coordinate and communicate toxicology, medical and medical examiner and coroner data with the broader medical and law enforcement communities. Opportunities to address these gaps as well as recent advancements collected through interagency efforts and technical workshops in the toxicology and analytical chemistry communities are presented here. Opportunities for partnership, increased communication and expanding best practices to move toward an integrated, holistic analytical response are also explored.

Introduction

Opioids, including fentanyl and its many analogs, are flooding the illicit drug market along with other novel psychoactive substances (NPS), contributing to unprecedented numbers of fatal and nonfatal drug overdoses. In the USA, deaths due to drug toxicity have increased from 63,632 in 2016 (1) to 65,000 to 69,000 in 2017 (provisional data) (2). This escalation has been driven largely by rising numbers of overdoses involving synthetic opioids other than methadone like fentanyl (3). In 2016, synthetic opioids (other than methadone) were involved in 19,413 overdose deaths representing 30.5% of total drug deaths; 3.5 times the number observed in 2014. Provisional 2017 data show that deaths involving synthetic opioids continued to rise in 2017. One limitation to our public health and law enforcement surveillance efforts is that the drugs involved in fatal overdoses are sometimes unspecified on death certificates. Reporting efforts have improved in recent years: 85.4% of death certificates specified the drug/drug type present in 2016, up from 76.0% in 2012. Additionally, officials conducting medicolegal death investigations (MDIs) believe it is possible that a lack of uniform investigations, including the toxicological evaluations necessary to confirm the drug and drug interactions responsible for an overdose death, might cause an underestimation of drug toxicity deaths (4).

In addition to the dramatic increase in deaths due to overdose, there are many community consequences to the opioid epidemic, including health and economic burdens that place a significant strain on local, state, tribal and federal resources (5–7). Stakeholders identified in these reports: hospitals, emergency rooms, first responders, local law enforcement, medical examiners (ME), coroners and public safety officials, would benefit from rapid drug detection, compound identification, toxicology testing and potency studies. As stated in Table I, this paper summarizes the efforts of subject matter experts from across government, academia and relevant industry to identify significant advancements and opportunities for improvements to data, technology and methods identified by the stakeholder community in order to guide tangible decisions, including public health actions such as the distribution and administration of naloxone (compound used as an emergency antidote to treat acute opioid poisoning) or other opiate antagonist. The identification of novel compounds circulating in the illicit market as well as locations experiencing increases in overdoses and deaths is critical to assessing the evolving opioid epidemic. Furthermore, rapid communication of these data should follow model systems developed for seized drugs to share information and overcome the analytical challenges in real time (8). For example, the US Drug Enforcement Administration’s (DEA) National Forensic Laboratory Information System (NFLIS) collects drug chemistry analytical results from over 277 laboratories in the USA (9). In 2017, DEA announced its planned 2018 expansion to collect data from ME and coroner offices and the toxicology laboratories that service them. Another exemplary system is the DEA’s Synth-Opioids Real Time Communication Network (10) that works to link over 130 forensic practitioners to regional drug identification alerts (8). Effective dissemination of this information also targets law enforcement, public health, medical and addiction services resources.

Table I.

Recent advancements and identified needs to address remaining capability gaps

Recent advancements	Development of novel search algorithms (e.g., Hybrid Similarity Search).
	Development of state and regional data integration systems.
	Enhancement of communication between analytical communities of toxicology and drug chemistry.
Identified needs	Provide quicker access to analytic reference materials and methods.
	Provide guidance for reporting presence of impurities and complex mixtures.
	Develop improved metabolite prediction capabilities, toxicity assays, and potency and drug impairment data.
	Improve guidance for emergency room and clinical sample collection, protocols for sharing samples and required clinical testing.
	Equip clinical testing laboratories with ability to identify novel synthetic opioids as part of a national syndromic surveillance capability to alert regional public health officials and potentially save lives.
	Provide access to high-quality, real-time, national-level data on chemical composition, drug toxicity and overdoses, MDI and toxicological test results, and analysis of seized materials by law enforcement to track drug trends.

Background

Analog diversification has exploded since earlier fentanyl crises beginning in the late 1980s (11–13) and again in 2005–2007 when ~100 deaths were ultimately tied to a single clandestine lab in Toluca, Mexico (14, 15). Since the early 2000s, clandestine laboratory high-production technology have yielded novel, highly potent, unscheduled substances (16); standard drug tests (parent drug and metabolite detection) have failed to identify the novel compounds in overdose patients; and drug trafficking organizations have revolutionized the way synthetic opioids are used and sold across the country, circumventing international trade enforcement. Despite the best efforts of law enforcement entities working to schedule, detect and interdict emerging compounds, novel synthetic opioids continue to surface in the drug market, resulting in toxicity deaths (3). In 2015, the DEA attempted to eliminate new compounds by temporarily scheduling some of the fentanyl analogs on a compound-by-compound basis (21 CFR Part 1308). To date, there are over 30 fentanyl analogs scheduled under DEA, United Nations and other regulatory requirements (17), yet there are nearly 20 times as many patented fentanyl compounds and an estimated 1,900 potential structural analogs (18). To assist scheduling efforts, in February 2018, the DEA temporarily scheduled fentanyl-related substances that have similar structures (19) to respond to the rapidly emerging analogs. In an unprecedented move, this temporary scheduling according to drug class is not founded on toxicity/potency data and future scheduling approaches may also need to allow for potency prediction of fentanyl analogs through defined structural modifications (20).

To further complicate matters, the purity of new fentanyl analogs found in seized materials varies (e.g., seized material at the southwest border/from Mexico [~7% pure], but materials shipped direct to consumers from China are considerably more pure/potent [>90%]) (21) or may be part of a complex mixture of drugs and other impurities (22). Analysis of these impurities and mixtures can aid the attribution process, however, they also challenge detection, identification, reporting and patient treatment. For example, a small amount of very potent carfentanil in a large quantity of seized heroin may not be evident when processing the material for drug chemistry characterization. Additionally, it is increasingly common that overdose toxicology results reveal the presence of highly potent fentanyl analogs in a complex mixture with heroin, other drugs and nonnarcotic substances (23, 24).

In many cases, toxicologists are the first to identify emerging analytes as they work with law enforcement, public health officials, physicians, medical examiners and coroners (ME/Cs) to identify the cause of overdoses and deaths. Although there have been efforts to provide timely access to death data, there are scattered examples of suspected drug-related deaths being reported in real-time to relevant stakeholders via multi-agency task forces (25–27). Best practices rely on timely toxicological testing, reporting and coordination with public health officials (28–30). However, many hard-hit communities are struggling to keep pace with the dramatic increase in overdoses and deaths (31, 32). Fast turnaround for toxicology testing and swift information sharing is the cornerstone to successfully identifying a surge in overdoses within a jurisdiction. Unfortunately, workshop participants stated state testing capabilities and reporting infrastructure are grossly under-resourced and overburdened to support the growing demands of the current epidemic. Information critical to mitigating overdose outbreak events remains largely siloed. Additionally, drug overdose death certificates are the slowest of those reported to the Centers for Disease Control and Prevention (CDC) and the National Center for Health Statistics, taking nearly 16 weeks to complete 50% of cases (33).

This paper identifies strategies to enhance the analytical capacity for chemical characterization, toxicology and postmortem drug testing required to rapidly identify new analogs and communicate these data through a newly envisioned national drug syndromic surveillance capability (Table I). This national syndromic surveillance capability would use a common platform to improve real-time communication and coordination of data resources identified according to novel drug-use and exposure syndromes. Additionally, such efforts to reduce the time-lag for MDI and toxicology reporting can hasten emerging substance identification and scheduling. This paper summarizes findings from multiple workshops and scientific meetings to propose a framework for real-time surveillance of novel drugs that moves beyond seized-drug analysis for law and border enforcement purposes to support public health and safety missions. This paper offers opportunities for academic, industry and government partnership to more effectively address the dynamic and rapidly expanding response to the opioid epidemic consuming the USA.

Chemical identification of novel synthetic opioids

The increased prevalence of synthetic opioids has created new and complex challenges to government and private entities charged with identifying illicit substances in seized materials and toxicological samples. Fentanyl analogs are often mixed with other illicit substances such as heroin, cocaine and methamphetamine (22). The chemical structure of the synthetic opioid, fentanyl, is easily manipulated in clandestine labs, resulting in a wide array of analogs that may be difficult to detect using traditional analytical techniques (17). Further, some fentanyl analogs are extremely hazardous when ingested, inhaled or accidentally contact broken skin or exposed membranes (34). Each of these factors challenge an already strained forensic laboratory system in which many jurisdictions face mounting caseloads as the epidemic widens.

Government agencies and private entities have established analytical detection, identification and characterization capabilities to recognize novel synthetic opioids; prevent opioids from entering the country; remove opioids from the streets and prevent overdoses. Some promising field technologies, such as ion mobility spectrometry, can be useful for qualitative screening of street drugs by non-technical personnel. Versatile laboratory-based methods including Direct Analysis in Real Time-Mass Spectrometry (DART-MS) are sensitive and capable of discriminating nanogram concentrations of fentanyl, even in the presence of heroin (35). However, these technologies are rarely available for field screening applications and additional validation is needed to apply these instruments in a forensic setting, especially for fieldwork. US Customs and Border Protection (CBP) currently screens packages at 328 points of entry into the USA. However, the breadth of potential analytes coupled with the task of screening over 67,000 cargo containers a day pose significant challenges for CBP (36). The DEA operates seven regional chemistry labs that, in emergency situations, strive to provide from 24- to 48-h turnaround on substance identifications when law enforcement officials seize presumptive novel synthetic opioids. Even with these resources, many jurisdictions are facing mounting case backlogs as the epidemic widens; rapid turnaround times for chemical analysis are needed to inform public health officials of potential threats, as the analogs have likely changed during the time it takes to validate and analyze.

To support law enforcement and improve the timeliness of chemical characterization, the forensic laboratory community is refining analytical methods for rapid identification and characterization of novel synthetic opioids. All methods for seized-drug identification must be performed according to quality assurance and quality control procedures as well as evidence collection protocols as developed by the Scientific Working Group for the Analysis of Seized Drugs (SWGDRUG) (37). SWGDRUG recommendations are the guidelines most frequently cited by forensic laboratories nationwide for the development of testing and validation methods. The recommendations create a framework that allows individual laboratories to decide which methods to use when characterizing a substance, ensuring appropriate sensitivity and specificity. Laboratories must conduct rigorous method validation against known reference materials to confidently report results that are appropriate for the identification of synthetic opioids and NPS.

Efforts are underway to improve method development and validation in forensic laboratories. Published standards provided by ASTM International guide seized-drug chemical analysis to high-quality, reliable results (i.e., standards addressing the identification of seized drugs, sampling for qualitative and quantitative analysis, and measurement uncertainty assessments). An ASTM task group is currently working on a standard for the analysis and reporting of opioid identification to address some of the analytical challenges associated with novel synthetic opioids. Additionally, SWGDRUG is in the process of developing appropriate standards and methods validation to verify the performance of new technologies and provide confidence in routine analytical methods. Once recommended standards are published, the Organization of Scientific Area Committees for Forensic Science (OSAC) (38) will work to include them in the OSAC Registry of Standards. Such efforts to articulate and share validated methods and laboratory best practices will improve synthetic opioid characterization. Guidance for the collection and safe handling of samples and evidence is also available to support this evolving threat (39). While great progress has been made, these efforts generally take considerable time.

Reference materials are used to enhance the timeliness and accuracy of compound identification; however, access to these reference materials is challenging when emerging illicit fentanyl analogs first enter the drug market. Reference materials are critical components to analytical method validation and quality control and assurance; they are required to confirm the identity of a new compound. Reference standards are high-purity and highly characterized (structural elucidation by nuclear magnetic resonance spectroscopy) to support law enforcement attribution purposes. Some reference materials for novel synthetic opioids are developed and supplied by private and federal government laboratories (e.g., DEA creates reference materials to support DEA and other government laboratory characterization efforts). However, analytical reference standards for novel compounds that require custom synthesis can take 3 to 6 months from identification of a compound to commercial availability when the compound is novel and requires custom synthesis. Companies that provide reference materials to forensic laboratories struggle to keep up with the rapidly changing substances and policies governing the distribution of those substances for legitimate manufacturing purposes. Additionally, it is challenging for producers to provide quality control and quality assurance in the material manufacturing process while simultaneously responding to the dynamic market with a cost-effective material.

Chemical structural data and libraries, including reference data, can enhance the timeliness and accuracy of identification of emerging illicit fentanyl analogs. In addition to working with SWGDRUG to update the Mass Spectral Library to include more novel substances, the National Institute of Standards and Technology (NIST) created the Hybrid Similarity Search to assist in the identification of designer drugs and chemical derivatives in a validated mass spectral library (40, 41). NIST is working with European counterparts and the DEA to create a web forum for chemical characterization data and emerging structural information used for identification of novel compounds (42).

Laboratory toxicology testing and medicolegal death investigation

Improved guidance for clinical sample collection in emergency rooms and death scenes, protocols for sharing samples, and required clinical testing are needed to aid in the surveillance and identification of novel synthetic opioids. Prompt recognition and treatment can help reduce morbidity and mortality. The American College of Emergency Physicians published a paper highlighting the complexity of the NPS problem and provided a listing of surveillance sources for healthcare providers (43). Although drug screening is not routinely performed in all emergency departments (ED), when performed, ED drug screens do not identify all NPS compounds (44). Newer efforts include Kentucky’s syndromic surveillance system that identifies and alerts stakeholders to overdose outbreaks in near real-time (45), as well as federal agencies’ and academic institutions’ efforts to evaluate how to support real-time decisions while thoughtfully accounting for limitations in rapid methods (46, 47).

The MDI system is a function that supports public health and safety. ME/Cs have the statutory jurisdiction to investigate all potential drug overdose deaths. Data on deaths are the sources for national drug mortality communicated by way of the death certificate. However, analyses indicate that on nearly 15% of death certificates, the medical certifiers fail to specify the types of drugs involved in the cause of death (48). In some cases, this may be because they have not completed toxicology. Although time for national death certificate data to become available has recently been reduced from 2 years to 1 year, and provisional data are available with a 6-month lag, the time to reporting is still excessive for the rapid assessment of morbidity and mortality trends required for more strategic allocation of resources to combat the availability of lethal drugs. The delay in reporting overdose death data is complex and related to chronic underfunding and understaffing of ME/C offices, resulting in delays in the completion of autopsy evaluations and the long turnaround times for toxicology results.

Prolonged toxicological testing times are attributed to laboratory backlogs and the increasingly sophisticated testing procedures required to identify novel synthetic opioids. Additionally, in some cases, the tests for the novel synthetic opioids are more expensive; therefore, ME/Cs may opt to do the less expensive test panel for commonly occurring opioids first. Test panels for novel opioids are pursued once common panels are negative, potentially prolonging the time to death reporting and leading to an underestimation of deaths associated with novel compounds (frequently common drugs and novel synthetic opioids are present). Moreover, many ME/C offices will complete testing after a lethal concentration of one drug is determined. Hence, in a case where heroin is identified, further testing to identify carfentanil may not be pursued. Therefore, efforts to advance and expand test panels remain vitally important.

Many state toxicology laboratories are similarly under-resourced and backlogged. Enhancing the toxicology analytical laboratory infrastructure and developing postmortem toxicology analytical standards are required to reduce the delays and improve specificity in drugs detected. Forensic toxicology investigations are performed when the cause of death is unknown, or drug toxicity is suspected. Many laboratories lack the equipment, workforce and/or expertise to perform forensic toxicological investigations when an unknown drug or complex mixture of drugs is suspected.

In cases when more sophisticated toxicological analysis is required than can be provided at an in-house facility, a sample is sent to a reference laboratory to develop confirmatory characterization of the drug toxicants present. Routine toxicology testing is performed by state, local, public and private laboratories. Standards development efforts for toxicological test panels are advancing, and reference laboratories are working to confront the growing demands of the current epidemic. Reference laboratories are often private entities that have the analytical instrumentation, workforce, and economy of scale to develop forensic toxicological analysis and synthesize reference compounds to verify the drug identity. However, broader access to reference laboratory testing capabilities is needed to provide quick turnaround times for the confirmatory testing of suspected overdoses that informs public health interventions and assists patient care providers. Although some hospital systems have resources to recognize and expedite toxicology testing when NPS overdose is suspected (49, 50), many of these facilities are associated with large research institutions, and this testing is not yet widespread.

As with seized material analysis, standard practices, quality control procedures, and reference materials are required for definitive identification of drugs and their metabolites in antemortem and postmortem samples. All laboratories conducting toxicological testing must follow validated procedures to sustain measurement assurance and accreditation requirements. Standards development efforts for toxicological test panels are advancing under the OSAC Subcommittee on Toxicology (38). The National Institute of Justice (NIJ) Forensic Technology Center of Excellence recently developed the “Opioid Crisis—A Public Health Enemy Webinar Series” that provides a multidisciplinary approach to advance knowledge sharing, data reporting, surveillance and research needed to address both analytical and policy issues (51). Additionally, US federal agencies are creating funding opportunities to address the analytical, workload and workforce challenges created by the opioid crisis. Last year, the CDC Enhanced State Surveillance of Opioid-Involved Morbidity and Mortality program announced supplemental funding for ME/Cs to conduct timely and comprehensive toxicology testing of suspected drug overdose deaths, including testing for emerging synthetic opioids (52). Similarly, NIJ plans to allocate over half of the FY 2018 Coverdell National Forensic Science Improvement Grants Program funds (53) to target the challenges that the opioid abuse crisis has brought to the forensic science community. Grant opportunities can be found at agency-specific grant websites as well as Grants.gov (54).

Furthermore, toxicity and potency data required for federal drug scheduling allow for epidemiological surveillance of public health. These data provide the foundation for cause of death determinations when suspected drug toxicity deaths are encountered. Historically, when fewer compounds were entering the illicit drug market annually, it was an achievable goal to develop a research program that included potency, toxicity and metabolite generation. However, with emerging compounds entering the market faster and with greater diversity and toxicity every year, attributing death or overdose to a specific drug is becoming more challenging. Additional complications arise when a mixture of drugs, including novel synthetic opioids, is identified during a toxicological investigation; the lethality of combined drug exposure is difficult to assess and report. Standard drug test panels may simply reveal that a complex mixture is present in the sample, resulting in inconclusive toxicology reports when the compound is completely novel. Guidance is needed for reporting impurities, complex mixtures and drug toxicity panel selection with consistency to assist interpretation of the impact of fentanyl analogs when a toxicology report is negative, but an overdose is indicated in an ED patient or at a death scene.

Analytical communities lack the comprehensive data on novel synthetic opioid metabolites required to inform forensic toxicology, patient care and MDIs. For many of the new and emerging analogs, there is little information about metabolism, toxicity and potency. Toxicologists, physicians, -healthcare providers,and ME/Cs must search the literature to determine potency and toxicity as well as anticipate any potential drug interactions. However, the treatment of patients, death statistics, and the eventual scheduling of novel synthetic opioids depends on the knowledge available to the medical community. New methods to assess novel synthetic opioid toxicity (55) are needed to enable the timely scheduling of these substances. The research community must develop better metabolite prediction capabilities, toxicity assays, potency information and drug impairment data to address this growing, dynamic challenge. Furthermore, toxicity and potency data are needed for a breadth of population elements, including opioid use history, race, ethnicity, age, sex and other factors, to understand the largely unknown variation in metabolic processing.

Eliminating data system stovepipes and implementing data integration strategies

Overall, integrated data on drug toxicity, information generated by law enforcement regarding seized materials, and MDI/toxicological/clinical test results are needed to create timely and accurate regulation and drug scheduling. This information must be high quality, real-time and available nationally. Efforts are underway to make national data available more rapidly. Many states’ ME/C and vital statistics offices are providing information more quickly to stakeholders, including federal, state, tribal, and local governments, to inform programs, policies, rule-making and other decisions to meet specific needs. These same data are more valuable to local communities to understand and react to public health issues, improve medical interventions and focus law enforcement efforts to isolate and eliminate highly toxic drugs from the streets. However, states face numerous challenges when collecting, analyzing and integrating analytical information on the current opioid crisis to enhance response efforts.

High-quality and highly curated data on seized materials, toxicology, health data (e.g., fatal or nonfatal overdose) and chemical analysis are stored in secure databases. Many state and regional crime labs generate data on seized materials, overdoses and other law enforcement information, which is captured nationwide via NFLIS. Furthermore, CBP, through the High Intensity Drug Trafficking Area program, hosts a monthly Scientific Trends Online Network Exchange call to discuss the latest border trends and report newly discovered drugs. Law enforcement has had the traditional role of investigating illicit drug markets and associated crimes using highly secure data systems to preserve and communicate information. Toxicology and health data are commonly collected for health and public health statistics and stored in secure databases. The result is highly curated data being stored in disparate public health and law enforcement databases that often have restricted access, with distribution based on state legislative mandates (e.g., Prescription Drug Monitoring Program, PDMP, medical history and law enforcement sensitive databases like NFLIS). Silos in data communication hinder national policies for drug surveillance.

Therefore, to characterize and combat the epidemic, affected states are developing tools and capabilities that can pull in these diverse sources of data as well as information for naloxone administration or other antidote, and overdose and death locations. The CDC’s State Unintentional Drug Overdose Reporting System (SUDORS) currently collects data from 32 states and Washington, DC. As further proof of concept, several jurisdictions actively implementing data integration systems are beginning to see the results of their surveillance efforts. Several pilot programs provide real-time overdose surveillance data across jurisdictions to mobilize an immediate response to an overdose spike (29, 30, 56, 57). These data tools must be expanded to provide knowledge and visibility on local, regional, national and international scales to ensure that policies are robust and adequate to halt the epidemic effectively. Timely access to high-quality data ensures the accurate representation of true population events and allows for actionable situational awareness. Pilot programs have demonstrated the ability to sustain high-performing data integration, accounting for chemical identification information on seized materials, clinical laboratory testing, toxicology results and other data streams for public health decision-making. Jurisdictions that have successfully navigated the data access and integration difficulties are working to make their strategies and pipelines available to others around the country (29).

However, translating success at a jurisdiction level to a national program has been challenging. Individual state laws, guidelines and regulations that restrict data access hinder critical information sharing among stakeholders including law enforcement, medical and public health personnel, and across state lines. Access and optimal operational use of existing data are prohibited by law enforcement due to its sensitive nature. Similarly, Health Insurance Portability and Accountability Act of 1996 (HIPAA) protected data sources, legal constructs, and information technology infrastructure limitations all hinder interagency cooperation (58). The DEA Synth-Opioids Real-Time Communication Network is attempting to connect all vested stakeholders (e.g., chemists, toxicologists, law enforcement, jurisprudence) throughout the USA and internationally. This network, created in August 2017, has over 130 members representing over 80 laboratories/organizations (10). The network is growing rapidly to connect more organizations and is working to expand into a permanent platform. Jurisdictional level data are often aggregated to inform national policy and program decisions; however, despite considerable efforts to authenticate and make these data as robust as possible, data aggregation techniques may result in lost critical local information on emerging drug threats that can shape our understanding of the situation.

A national system of robust, authentic and consolidated data is needed to determine the extent of the epidemic, rapidly identify new substances, identify hot spots and measure the effectiveness of policies, interventions and treatments. Integrated data and open communication are needed to guide investments of national policy and program development to increase response capabilities from a local to an international scale. Data integration is impeded further by inconsistent data languages, lack of metadata standards and inconsistent database platforms. Furthermore, establishing such a data sharing capability further mandates increased communication between toxicology and drug chemistry analytical communities. This can be as straightforward as informing toxicology with chemistry testing, especially when initial toxicology panels are negative.

Novel drug syndromic surveillance

Syndromic surveillance has proven effective in the early recognition of infectious disease outbreaks of public health importance. Model syndromic surveillance systems were designed to enable medical professionals, including those operating in ED, urgent care, ambulatory care (59) and ME/C settings (60) to recognize fatal infections and deaths due to bioterrorism or cases of special public health importance. Syndromic surveillance systems utilizing health-related data to identify clusters of illness or disease outbreaks—often before official confirmation and diagnosis—are proving valuable to mobilize rapid response by public health officials to other health outcomes, including drug overdose. Drug overdose frequently surfaces initially in ED and death scene investigations; however, current indicators of the epidemic often fail to fully utilize syndromic categories that clearly account for these early clinical and MDI indicators as well as the routine criminal, social and public health analytical characterization efforts.

A syndromic model based on those used for biological threat identification, focused on early elucidation of drug poisoning deaths, would create similar opportunities for response action by public health and safety authorities. Ideally, all deaths entered into a novel drug syndromic surveillance model would receive autopsies and comprehensive toxicology testing to identify an accurate cause of death related to drug poisoning. However, rapid identification of drug overdose trends with crude, often incomplete, indicators still provides useful data, when followed by information collected from a more comprehensive MDI. Valuable syndromes could include illicit drug abuse, prescription drug abuse, suicidal poisoning and unexpected death in a teenager or young adult. Syndromes should specify a combination of historical, circumstantial information and autopsy findings—for example, death scene and/or interview indicators that include a history of drug abuse, drug use, carousing, at home resuscitation attempts, naloxone or other opiate antagonist rescue attempts, or discovery of drug or drug paraphernalia. Relevant syndromic indicators should incorporate autopsy findings that strongly indicate drug exposure (stigmata of recent injection-drug abuse) as well as non-specific findings (e.g., pulmonary edema, cerebral edema, distended urinary bladder) or absent of definitive gross non-drug-related cause of death reflective of prolonged respiratory depression (e.g., acute bronchopneumonia, anoxic encephalopathy).

Partnership network and increased communication

Integrated, multiregional scale analysis and data communication capability is required to provide national syndromic surveillance for novel drug compounds as well as sustain the needed local context to support the communities responding to the epidemic. Multidirectional communications among public health and public safety authorities, ME/Cs and forensic toxicologists can enable a more rapid response to novel synthetic opioids and other toxic drugs. For example, forensic toxicology investigations can benefit from information regarding the chemical composition of materials seized from the scene of an overdose or death. Equally valuable is the communication of toxicology results with law enforcement and the healthcare community to alert them to the presence of a novel compound circulating in the illicit drug market and aid in patient treatment. Best practices are emerging to connect case information on seized materials with biological samples for drug toxicity testing by using common case identifiers, making unified case information possible and drug scheduling more efficient. Additionally, best practices are needed for ED to recognize novel drug chemistries (61) and collect appropriate samples for analytical testing as well as foster communication with public health and law enforcement networks.

The community recognizes that communication starts by building a common language and promoting tools that enhance efficacy. Drug classification and nomenclature standards as well as data provenance are critical for consistent communication across the diverse members of the opioid response stakeholder community. Additionally, reporting data in a meaningful way to make timely decisions at a local level has required new and robust data analytics and visualization tools. The community needs ways to verify performance of data integration and visualization tools to work toward building a nationally accepted technology. Data visualization can be used to provide decision-makers with spatial and multivariate heterogeneous time series data that include all available evidence for indicator development and monitoring, as well as intervention assessment. Current tools piloted to track the evolving epidemic are effective at mapping drug occurrences, demonstrated by statewide and local decisions including directed law enforcement efforts and medical countermeasures (29); these efforts should be expanded. Furthermore, communicating public health indicators for policymaking is challenging because of the complexity of the data, lack of adequate indicators for emerging threats, and diversity of audiences and their needs. All stakeholders engaged in this response require information with different contextual details and knowledge about the epidemic, as well as confidence in the data quality and provenance. Additionally, the sources and proportion of data available at the time of a decision are critical to understanding the impact of various interventions on the extent of an epidemic. A common practice in law enforcement and public health is the corroboration of data streams that work to acquire a threshold when making potential high-risk decisions—these same practices find value when applied to novel drug syndromic surveillance. Communities affected by the epidemic are seeking scientific community partners such as research scientists, clinicians, data scientists and other public health officials to assist in responding to the new challenges of the highly dynamic and increasingly fatal illicit drug markets. Experts are encouraged to scan grant opportunities, look for local calls for engagement and reach out to public health and law enforcement entities to offer their support.

Conclusion

Current best practices focus on enhanced timeliness and accuracy of the analytical characterization of novel synthetic opioids and the associated toxicological testing needed to guide law enforcement, public safety and public health decisions. The improved sharing of these analytical data is needed to inform and improve surveillance efforts and timely patient treatment. Early detection of novel synthetic opioids in seized materials and in toxicological samples, when effectively communicated, can focus critical intervention and treatment opportunities on curbing the epidemic. Furthermore, although the current overdose death numbers may seem alarming, the real numbers may be worse: lack of adherence to uniform practice standards by ME/Cs and requirements for ED to record drug identities may be leading to an underestimation of the number of deaths from NPS and other drug exposure. Given the expanding epidemic of drug-related deaths and the frequency of novel synthetic opioids, there is an urgent need to review and re-establish requirements for routine clinical and postmortem toxicology testing guidelines and procedures, develop new technologies for assessing drug identity and potency in biological matrices (including metabolites), develop reference materials for drug identification (in seized and toxicological samples), and provide guidance on the interpretation of negative toxicology results to enable rapid drug scheduling. The lack of these critical data can hinder enforcement and scheduling efforts that have previously demonstrated a positive effect on outcomes. Providing access to high-quality, real-time, national-level data on chemical composition, drug toxicity and overdoses and analysis of seized materials by law enforcement and MDI/toxicological test results is mandatory to track drug trends. The acquisition and well-coordinated dissemination of data regarding the effects of emerging compounds on health and community well-being are foundational to curbing the largest drug epidemic in American history.

Workshops held between September 2016 and October 2017 and this publication were intended to capture external perspectives related to NIST standards, measurement and testing-related efforts. These external perspectives can come from industry, academia, government and others. This publication is intended to document external perspectives and do not represent official agency positions.

Acknowledgments

The many participants in a series of workshops, relevant federal government agencies, state and local government subject matter experts, and representatives of the science stakeholder community have worked to identify opportunities to enhance science and technology capabilities in responding to the opioid crisis. The authors wish to recognize for the following individuals for their contributions to this article: Luli Akinfiresoye (DEA), Paula Braun (CDC), Roxanne Franckowski (Cayman Chemical Company), R. Matthew Gladden (CDC), Jill Head (DEA), Marc Lebeau (Federal Bureau of Investigation), Katrice Lippa (NIST), William MacCrehan (NIST), Julie O’Donnell (CDC), Edward Sisco (NIST), Mark Stolorow (NIST), Aaron Urbas (NIST), Jennifer Verkouteren (NIST), William Wallace (NIST), Margaret Warner (CDC), and Victor Weedn (George Washington University). The purpose of this article is to share the recognized gaps in knowledge and capability, recent advancements, and opportunities for engagement. Presented with the many challenges faced by communities responding to the current opioid crisis, this article focused on immediate functional requirements that can quickly provide positive impacts as well as potentially scalable approaches that require longer-term solutions and additional research and development capabilities.