Introduction

Globally, drug use remains a significant public health challenge [1]. In 2021, approximately 5.8% (296 million people) of the world population used at least one drug, among which more than 60 million people used opioids, usually illicit and prescription opioids [1]. Mortality could result from an opioid overdose due to its impact on brain parts that regulate breathing. Notably, more than 100,000 people die annually of opioid overdoses [2]. Of the 600,000 deaths attributed to drug use in 2019, 80% were related to opioids, and about 25% of these deaths were caused by opioid overdoses [3].

In the United States (U.S.), the opioid crisis, characterized by an epidemic of prescription opioids and the emergence of highly potent synthetic fentanyl (an opioid analgesic that is 50-100 times more potent than heroin or morphine) in the illicit drug market, continues to contribute to drug overdose mortality in the U.S. [2,4]. In 2017, more than 47,000 lives were lost to opioid overdose [5], reflecting a 345% increase in the overdose fatality rate between 2001 and 2016 [6]. By 2019, drug overdose deaths had surpassed 70,630, with opioid-related death rates reaching 15.8 deaths per 100,000 people [2]. The urgency of addressing this epidemic is further underscored by the fact that over 75% of the 107,000 drug overdose deaths in 2021 involved opioids [7], thereby highlighting the need for immediate intervention to mitigate the devastating consequences of the opioid epidemic.

The waves of opioid crisis in the U.S.

Historically, the U.S. has witnessed three distinct waves of opioid overdose death epidemics: The first wave linked to prescription opioids in the late 1990s, followed by heroin around 2010, and the subsequent wave involving synthetic opioids, particularly fentanyl, which emerged in 2013 [8-11].

Polydrug use, particularly involving opioids, has long been associated with drug overdose deaths [12]. Recent evidence indicates the U.S. is now facing a fourth wave of the opioid crisis, tagged as a “psychostimulant/opioid epidemic,” which reflects the prevalent use of either or both substances [13,14]. The co-use of psychostimulants and opioids is on the rise in the U.S. [14], with methamphetamine, in particular, driving a substantial increase in deaths, up by nearly 50% since 2019 [15,16]. There has been a five-fold increase in psychostimulant-related mortality, mainly attributed to methamphetamine, from 2012 to 2018 (from 0.8 to 3.9 per 100,000) [17].

The use of opioid in isolation presents distinct challenges, and the addition of methamphetamine further complicates the clinical situation [18]. Methamphetamine use has come with a range of consequences, including neurological deficits, cardiovascular symptoms, stroke, suicidal ideation, psychosis, increased hostility and violence, as well as increased sexual excitement [19,20]. Research indicates that individuals who co-use opioids and psychostimulants experience more adverse effects compared to those using either substance alone [19]. Individuals concurrently using opioids and methamphetamine, in comparison to those solely using opioids, exhibit greater injection drug use, a broader spectrum of substances consumed, more severe mental illness, riskier drug use, including a preference for fentanyl, less stable housing, a higher likelihood of unemployment, increased chronic morbidities, higher rates of blood-borne virus infections, and poorer outcomes in drug treatment (such as retention) [20-24]. Thus, urgent and sustainable approaches are needed to address this complex public health issue.

Rural areas as risk environment for the U.S. opioid epidemic

Identifying the geographical patterns of opioid overdose deaths is crucial for developing strategies to enhance opioid use treatment and effectively address the ongoing opioid crisis [25]. Globally, the opioid crisis exhibits some evolving dynamics. Opioid overdose mortality and related harm are spreading fast into rural areas across several continents [26-28]. In the U.S., the waves of the opioid crisis have impacted a more rural population compared to prior opioid epidemics [29]. Over the last two decades in the U.S., opioid overdose deaths increased by over 400 percent, reaching 45,838 in 2016, and growing faster in rural counties across all regions, particularly in the Northeast and Midwest [30]. Mortality resulting from nonmedical prescription opioid misuse is concentrated in states with large rural populations, such as Kentucky, West Virginia, Alaska, and Oklahoma [31]. Drug-related deaths involving opioid analgesics are higher in these rural areas [32]. Also, rural populations are on average older than urban populations; thus, there may be more chronic pain for which management with opioid analgesics is indicated [33].

Patterns of polysubstance use differ between rural and urban areas [34]. There is greater use of methamphetamine in rural areas compared to their urban counterparts [35]. Although contingency management approaches have demonstrated efficacy [36], their scalability remains limited in rural areas [37,38]. Moreover, in rural areas, methamphetamine treatment strategies are limited and constrained, which explains, in part, difficulties with treatment engagement (such as uptake and retention) [39].

There is suboptimal access to harm reduction and treatment services in rural areas of the U.S. [40,41]. Medication for the treatment of opioid use disorders is the gold standard for patients with opioid use disorder (OUD) [42]. These medications include opioid agonist therapy (OAT) (methadone and buprenorphine) and antagonists (naloxone) and are all associated with lower all-cause and opioid-related mortality [43,44]. The U.S. government has made provision for opioid overdose education, increased naloxone distribution, and the implementation and expansion of medication-assisted treatment (MAT) programs to treat OUD [34]. However, people in rural and remote communities experience greater difficulty accessing OAT [45,46]. There are longer travel distances to healthcare services and a 6.3 times longer average travel time to methadone programs compared to urban areas (49.1 minutes vs. 7.8 minutes) [47].

Healthcare providers appear relatively fewer compared to urban areas [48]. About 56 percent of rural counties do not have a provider who can prescribe buprenorphine [49]. Only 30 percent of people living in rural areas are without access to a buprenorphine provider, compared with 2 percent of urban residents [50]. Waivered Buprenorphine and Naloxone providers are also fewer than elsewhere, despite recent increases in the total number of waivered physicians [51,52]. The remoteness of sparsely populated rural areas hinders the availability of drug treatment services, with harm reduction services offered less frequently and situated far from individuals in need [53].

The opioid epidemic has also fueled outbreaks of blood-borne infections (such as immunodeficiency virus (HIV) and hepatitis C virus (HCV)) among people who inject drugs (PWID) in rural areas of the U.S. [54,55]. Sharing an infected needle and syringe is a primary driver of HIV and hepatitis C (HCV) transmission (PWID) [56]. The higher burden of blood-borne infections in rural areas relative to urban communities has been linked to a rise in injection opioid use and insufficient access to harm reduction services [57,58]. New acute HCV infections rose by more than 400% between 2010 and 2020, with about 66700 infections in 2020, mainly attributed to increased use of injection administration drugs [59]. The highest incidences occurred mostly in rural areas of the central Appalachia region (Kentucky, Tennessee, Virginia and West Virginia) [60]. Between 2015 and 2019, seven HIV outbreaks were identified among PWID in the U.S. [61]. Needle and syringe exchange programmes (NSPs) reduce HIV and potentially HCV transmission, especially among high-risk drug users such as PWID [62,63]. NSPs programs have been developed and implemented in the U.S. [64,65], yet there is inconsistent coverage that creates inequities in access for PWID in rural areas of the U.S., thereby posing a risk to the effectiveness of NSPS in mitigating drug-related harm [66].

Rural areas of the US also exhibit some unique features that collectively impact effective opioid crisis management [13]. Sociostructural factors such as poverty, unemployment, stigma, and homelessness, among others and the geographical context, shape the risk of drug use in rural areas [67,68]. Stress resulting from economic deprivation creates a stressful environment that places individuals in rural areas at risk for drug use compared with their urban counterparts [69]. Rural counties have faced job sector and industry shifts, resulting in high rates of unemployment and fewer opportunities for establishing a long-term career with the potential for upward mobility [70]. In rural areas, there are broadband limitations, which hinder the opportunity to take advantage of the recent expansion of telehealth services [71].

Furthermore, evidence has revealed a link between strong social and kinship networks and illicit drug use [72]. Individuals in rural areas engage more closely and longer with their social network and others who are geographically closer than their urban counterparts [73,74]. This strong social network allows faster diffusion of prescription opioids among those at risk of illicit drug use, as well as sources of prescription opioids through families [70]. Thus highlighting a vital roadmap for addressing the dissemination of prescription opioids in rural settings.

Despite several ongoing efforts in the U.S. to combat the opioid crisis, opioid overdose mortality continues to rise, with rural areas experiencing higher rates than urban areas [29]. Challenges in rural areas impede service access, amplify gaps and hinder the effectiveness of national strategies. People residing in rural areas of the U.S. face multifaceted health and social needs that can significantly affect their drug use behaviours. Hence, to tackle the opioid epidemic, particularly in rural areas of the U.S., it is vital to prioritize the interrelated factors influencing the crisis and devise comprehensive interventions.

Recommendations

Integration of healthcare services

The availability of and easy accessibility of harm reduction and other treatment services that rural communities need must be enhanced to strengthen the fight against the opioid epidemic in rural areas of the U.S. [75]. Stigma poses a widespread challenge and can serve as a barrier to providing drug treatment services in resource-poor settings [76]. The primary care setting is characterised by a welcoming, nonjudgmental, respectful, and empathetic atmosphere [77]. Harm reduction and treatment services can be integrated into the mainstream healthcare system [78]. An integrated “one-stop shop” model may be employed to offer buprenorphine, naloxone, mental health counselling, HIV and hepatitis C treatment, and needle and syringe exchange in an existing healthcare facility. In addition to overcoming barriers to care for people who use drugs, patients may receive additional support, including access to clothing, food, job opportunities, and assistance with easy enrollment in health insurance and disability pension support for those with disabilities [79]. This approach may not only curb the opioid crisis in rural areas but also address the socioeconomic factors that contribute to and aggravate the consequences of drug use.

Leveraging technology to address healthcare delivery barriers

Healthcare professionals face some barriers, including geographical, information sharing, and decision-making support, among others, to rendering drug treatment services in rural areas [80]. For instance, the prescription of buprenorphine is constrained by time and a lack of mental health or psychosocial support services for patients in remote locations [81]. Treatment models that use technology to address these barriers have been shown to increase access to and treatment outcomes for harm reduction services in rural populations [82,83]. Implementing and utilising digital solutions can help overcome geographical barriers, improve collaboration among healthcare providers, and provide efficient resources for managing opioid-related cases. This may include telemedicine platforms for remote consultations, electronic health records for streamlined information sharing, and decision-support tools to assist physicians in evidence-based treatment approaches. However, the implementation of technology may encounter challenges, particularly related to broadband availability [71].

Legislation to expand provider workforce

Legislative initiatives could help address workforce shortages and enhance accessibility to opioid treatment services in rural areas of the U.S. [84]. This could include policies incentivizing healthcare professionals to work in underserved regions through loan forgiveness programs and targeted funding for training programs in addiction medicine [85]. Legislative efforts may also focus on streamlining licensing processes to facilitate the deployment of qualified providers to rural areas. Also, lasting partnerships between academic institutions and healthcare organizations can be fostered to promote training programs tailored to the specific needs of rural communities. Legislative action could build a robust and accessible healthcare workforce capable of delivering effective drug treatment services in rural settings.

Community engagement and awareness creation

Engaging communities is pivotal in addressing the opioid crisis in rural areas of the U.S. Community engagement involves collaboratively involving local residents, leaders, and organizations in developing and implementing tailored strategies [86]. This approach helps identify unique challenges and community-specific solutions to the challenges of the opioid crisis. In rural settings, where close-knit communities often play a significant role in shaping individual drug use behaviour, this collaborative approach will create a locally relevant response to the opioid crisis. It will also contribute to individual understanding of how stigma, discrimination and inequities prevent access to prevention, treatment and recovery services. Collaboration between healthcare providers, law enforcement, and community organizations needs to be enhanced to create a unified front against the crisis. Additionally, there is a need to implement community-based education programs using culturally-adaptive mediums to raise awareness about the dangers of opioid misuse and foster a supportive environment.

Enhance local drug surveillance

Drug surveillance remains a critical tool in addressing the opioid crisis in rural areas of the U.S. [87]. Through systematic monitoring of prescription patterns, early detection of emerging trends, and mapping geographic hotspots, surveillance will enable local authorities in the U.S. to effectively utilize data [88]. This will ensure an understanding of the evolving dynamics of opioids in circulation, especially how frequently fentanyl, heroine and other illicit opioids and methamphetamine are changing and interrupting their supplies. The real-time data monitoring will inform decision-making, allowing for timely resource deployment and law enforcement strategies to combat illicit drug trafficking.

Conclusion

To effectively combat the opioid epidemic in rural areas of the U.S., it is essential to recognize the impact of several unique features of rural areas in fueling illicit drug use. The recommended strategies provide a roadmap for comprehensive interventions, ranging from integrated healthcare services to community engagement and awareness creation, the use of innovative technologies to address healthcare delivery barriers, and legislation that expands providers' workforce. Furthermore, it emphasizes the need to enhance local drug surveillance as a critical tool local authorities could leverage to stay ahead of emerging trends and proactively respond to the illicit drug supply and utilization in the community. By implementing these recommendations, a unified and holistic response can be forged, fostering resilience and recovery in the face of the ongoing opioid crisis in rural areas of the U.S.

Role of Authors

RKO, and MOO conceptualized and drafted the first and subsequent versions of this article. Both authors read, revised the drafts and approved the final manuscript.

References

1. United Nations Office on Drug and Crime (2023) Wolrd drug report 2023.
2. The Lancet Regional Health-Americas (2023) Opioid crisis: Addiction, over prescription, and insufficient primary prevention. Lancet Reg Health Am 23: 100557.
3. World Health Organization (2023) Opioid overdose.
4. Jalali MS, Botticelli M, Hwang RC, Koh HK, McHugh RK (2020) The opioid crisis: A contextual, social-ecological framework. Health Res Policy Sys 18: 87.
5. Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G (2018) Drug and opioid-involved overdose deaths-United States, 2013-2017. Morb Mortal Wkly Rep 67: 1419-1427.
6. Gomes T, Tadrous M, Mamdani MM, Paterson JM, Juurlink DN (2018) The burden of opioid-related mortality in the United States. JAMA Netw Open 1: e180217.
7. Center for Disease Control and Prevention (2023) Understanding the opioid overdose epidemic.
8. Perdue T, Carlson R, Daniulaityte R, Silverstein SM, Bluthenthal RN, et al. (2024) Characterizing prescription opioid, heroin, and fentanyl initiation trajectories: A qualitative study. Soc Sci Med 340: 116441.
9. Ciccarone D (2017) Fentanyl in the US heroin supply: A rapidly changing risk environment. Int J Drug Policy 46: 107-111.
10. Ciccarone D (2019) The triple wave epidemic: Supply and demand drivers of the US opioid overdose crisis. Int J Drug Policy 71: 183-188.
11. Brookings (2023) The economic impact of the opioid epidemic.
12. Hall HI, Song R, Rhodes P, Prejean J, An Q, et al. (2008) HIV incidence surveillance group. Estimation of HIV incidence in the United States. JAMA 300: 520-529.
13. Jenkins RA (2021) The fourth wave of the US opioid epidemic and its implications for the rural US: A federal perspective. Prev Med 152: 10654.
14. Shadac (2024) The opioid epidemic in the United States.
15. Glick SN, Burt R, Kummer K, Tinsley J, Banta-Green CJ, et al. (2018) Increasing methamphetamine injection among non-MSM who inject drugs in King County, Washington. Drug Alcohol Depend 182: 86-92.
16. Substance Abuse and Mental Health Services Administration (2019) The national survey on drug use and health: 2019.
17. Hedegaard H, Miniño AM, Spencer MR, Warner M (2020) Drug overdose deaths in the United States, 1999-2020, in NCHS Data Brief.
18. Centers for Disease Control and Prevention (2015) Surveillance for viral hepatitis-United States, 2015.
19. Wejnert C, Hess KL, Hall HI, Van Handel M, Hayes D, et al. (2016) Vital signs: Trends in HIV diagnoses, risk behaviors, and prevention among persons who inject drugs-United States. MMWR Morb Mortal Wkly Rep 65: 1336-1342.
20. Paulus MP, Stewart JL (2020) Neurobiology, clinical presentation and treatment of methamphetamine use disorder: A review. JAMA Psychiatry 77: 959-966.
21. Lappin JM, Darke S, Farrell M (2017) Stroke and methamphetamine use in young adults: A review. J Neurol Neurosurg Psychiatry 88: 1079-1091.
22. Foulds JA, Boden JM, McKetin R, Newton-Howes G (2020) Methamphetamine use and violence: Findings from a longitudinal birth cohort. Drug Alcohol Depend 207: 107826.
23. Shearer RD, Howell BA, Bart G, Winkelman TNA (2020) Substance use patterns and health profiles among US adults who use opioids, methamphetamine, or both, 2015-2018. Drug Alcohol Depend 214: 108162.
24. Daniulaityte R, Silverstein SM, Crawford TN, Martins SS, Zule W, et al. (2020) Methamphetamine use and its correlates among individuals with opioid use disorder in a midwestern U.S. city. Subst Use Misuse 55: 1781-1789.
25. Stringfellow EJ, Lim TY, Humphreys K, DiGennaro C, Stafford C, et al. (2022) Reducing opioid use disorder and overdose deaths in the United States: A dynamic modeling analysis. Sci Adv 8: eabm8147.
26. Belzak L, Halverson J (2018) The opioid crisis in Canada: A national perspective. Health Promot Chronic Dis Prev Can 38: 224-233.
27. King NB, Fraser V, Boikos C, Richardson R, Harper S (2013) Determinants of increased opioid-related mortality in the United States and Canada, 1990-2013: A systematic review. Am J Public Health 104: e32-e42.
28. Rintoul AC, Dobbin MD, Drummer OH, Ozanne-Smith J (2017) Increasing deaths involving oxycodone, Victoria, Australia, 2000-09. Inj Prev 17: 254-259.
29. Peavy KM, Banta-Green C, Owens M (2021) Opioids and stimulants: What are they and how are people using them? Seattle, WA: Addictions, Drug & Alcohol Institute, University of Washington.
30. Monnat S, Rigg K (2018) The opioid crisis in rural and small town America. Carsey School of Public Health.
31. Keyes KM, Cerdá M, Brady JE, Havens JR, Galea S (2014) Understanding the rural-urban differences in nonmedical prescription opioid use and abuse in the United States. Am J Public Health 104: e52-e59.
32. Wunsch MJ, Nakamoto K, Behonick G, Massello W (2009) Opioid deaths in rural Virginia: A description of the high prevalence of accidental fatalities involving prescribed medications. Am J Addict 18: 5-14.
33. Glasgow N (2000) Rural/urban patterns of aging and caregiving in the United States. Journal of Family Issues 21: 611-631.
34. Carpenedo Mun C, Schuler H, Baker R, Byrne F, Bresani E, et al. (2023) Rural communities face more than an opioid crisis: Reimagining funding assistance to address polysubstance use, associated health problems, and limited rural service capacity. J Rural Health 39: 795-803.
35. Ellis MS, Kasper ZA, Cicero TJ (2021) Polysubstance use trends and variability among individuals with opioid use disorder in rural versus urban settings. Prev Med 152: 106729.
36. De Crescenzo F, Ciabattini M, D'Alò GL, De Giorgi R, Del Giovane C, et al. (2018) Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis. PLoS Med 15: e1002715.
37. Glass JE, Nunes EV, Bradley KA (2020) Contingency management: A highly effective treatment for substance use disorders and the legal barriers that stand in its way. Health Affairs Blog.
38. Petry NM (2010) Contingency management treatments: Controversies and challenges. Addiction 105: 1507-1509.
39. Russell C, Law J, Imtiaz S, Rehm J, Foll BL, et al. (2023) The impact of methamphetamine use on medications for opioid use disorder (MOUD) treatment retention: A scoping review. Addict Sci Clin Pract 18: 48.
40. Rosenblum A, Cleland CM, Fong C, Kayman DJ, Tempalski B, et al. (2011) Distance traveled and cross-state commuting to opioid treatment programs in the United States. J Environ Public Health 2011: 948789.
41. Sigmon SC (2014) Access to treatment for opioid dependence in rural America: Challenges and future directions. JAMA Psychiatry 71: 359-360.
42. Priest KC, Gorfinkel L, Klimas J, Jones AA, Fairbairn N, et al. (2019) Comparing canadian and United States opioid agonist therapy policies. Int J Drug Policy 74: 257-265.
43. Santo T, Clark B, Hickman M, Grebely J, Campbell G, et al. (2021) Association of opioid agonist treatment with all-cause mortality and specific causes of death among people with opioid dependence: A systematic review and meta-analysis. JAMA Psychiatry 78: 979-993.
44. McDonald R, Strang J (2016) Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria. Addiction 111: 1177-1187.
45. Stone J, Degenhardt L, Grebely J, Larney S, Altice FL, et al. (2021) Modelling the intervention effect of opioid agonist treatment on multiple mortality outcomes in people who inject drugs: A three-setting analysis. Lancet Psychiatry 8: 301-309.
46. Snell-Rood C, Pollini RA, Willging C (2021) Barriers to integrated medication-assisted treatment for rural patients with co-occurring disorders: The gap in managing addiction. Psychiatr Serv 72: 935-942.
47. Joudrey PJ, Edelman EJ, Wang EA (2019) Drive times to opioid treatment programs in urban and rural counties in 5 US States. JAMA 322: 1310-1312.
48. Hart LG, Larson EH, Lishner DM (2005) Rural definitions for health policy and research. Am J Public Health 95: 1149-1155.
49. Barnett ML, Lee D, Frank RG (2019) In rural areas, buprenorphine waiver adoption since 2017 driven by nurse practitioners and physician assistants. Health Aff (Millwood) 38: 2048-2056.
50. Deyo-Svendsen M, Cabrera Svendsen M, Walker J, Hodges A, Oldfather R, et al. (2020) Medication-assisted treatment for opioid use disorder in a rural family medicine practice. J Prim Care Community Health 11: 2150132720931720.
51. Andrilla CHA, Coulthard C, Larson EH (2017) Barriers rural physicians face prescribing buprenorphine for opioid use disorder. Ann Fam Med 15: 359-362.
52. Rosenblatt RA, Andrilla CH, Catlin M, Larson EH (2015) Geographic and specialty distribution of US physicians trained to treat opioid use disorder. Ann Fam Med 13: 23-26.
53. Dew B, Elifson K, Dozier M (2007) Social and environmental factors and their influence on drug use vulnerability and resiliency in rural populations. J Rural Health 23: 16-21.
54. Allen ST, O'Rourke A, White RH, Schneider KE, Kilkenny M, et al. (2019) Estimating the number of people who inject drugs in a rural county in appalachia. Am J Public Health 109: 445-450.
55. Schranz AJ, Barrett J, Hurt CB, Malvestutto C, Miller WC (2018) Challenges facing a rural opioid epidemic: Treatment and prevention of hiv and hepatitis C. Curr HIV/AIDS Rep 15: 245-254.
56. Artenie A, Stone J, Fraser H, Stewart D, Arum C, et al. (2023) HIV and HCV incidence review collaborative group. Incidence of HIV and hepatitis C virus among people who inject drugs, and associations with age and sex or gender: A global systematic review and meta-analysis. Lancet Gastroenterol Hepatol 8: 533-552.
57. Walters SM, Frank D, Felsher M, Jaiswal J, Fletcher S, et al. (2023) How the rural risk environment underpins hepatitis C risk: Qualitative findings from rural southern Illinois, United States. Int J Drug Policy 112: 103930.
58. Ballard AM, Falk D, Greenwood H, Gugerty P, Feinberg J, et al. (2023) Houselessness and syringe service program utilization among people who inject drugs in eight rural areas across the USA: A cross-sectional analysis. Harm Reduct J 20: 157.
59. Centers for Disease Control and Prevention (2020) Viral hepatitis surveillance report 2020.
60. Zibbell JE, Asher AK, Patel RC, Kupronis B, Iqbal K, et al. (2018) Increases in acute hepatitis c virus infection related to a growing opioid epidemic and associated injection drug use, United States, 2004 to 2014. Am J Public Health 108: 175-181.
61. Lyss SB, Buchacz K, McClung RP, Asher A, Oster AM (2020) Responding to outbreaks of human immunodeficiency virus among persons who inject drugs-United States, 2016-2019: Perspectives on recent experience and lessons learned. J Infect Dis 222: S239-S249.
62. Platt L, Minozzi S, Reed J, Vickerman P, Hagan H, et al. (2018) Needle and syringe programmes and opioid substitution therapy for preventing HCV transmission among people who inject drugs: Findings from a Cochrane Review and meta-analysis. Addiction 113: 545-563.
63. Centers for Disease Control and Prevention (2022) Determination of need for syringe services programs.
64. Centers for Disease Control and Prevention (2020) Integrated viral hepatitis surveillance and prevention funding for health departments.
65. Davis SM, Kristjansson AL, Davidov D, Zullig K, Baus A, et al. (2019) Barriers to using new needles encountered by rural Appalachian people who inject drugs: Implications for needle exchange. Harm Reduct J 16: 23.
66. Galea S, Ahern J, Vlahov D (2003) Contextual determinants of drug use risk behavior: A theoretic framework. J Urban Health 80: iii50-iii58.
67. Galea S, Nandi A, Vlahov D (2004) The social epidemiology of substance use. Epidemiol Rev 26: 36-52.
68. Partridge MD, Rickman DS (2005) High-poverty nonmetropolitan counties in America: Can economic development help? International Regional Science Review 28: 415-440.
69. Drake C, Zhang Y, Chaiyachati KH, Polsky D (2019) The Limitations of poor broadband internet access for telemedicine use in rural america: An observational study. Ann Intern Med 171: 382-384.
70. Wininger PJ (2005) Pharmaceutical overpromotion liability: The legal battle over rural prescription drug abuse. KY Law J 93: 269.
71. Beggs JJ, Haines VA, Hurlbert JS (1996) Revisiting the rural-urban contrast: Personal networks in nonmetropolitan and metropolitan settings. Rural Sociology 61: 306-325.
72. Ranger (2020) Families in troubled times.
73. The Pew Charitable Trust (2019) Opioid use disorder: Challenges and opportunities in rural communities.
74. Andrilla CHA, Moore TE, Patterson DG, Larson EH (2019) Geographic distribution of providers with a dea waiver to prescribe buprenorphine for the treatment of opioid use disorder: A 5-Year Update. J Rural Health 35: 108-112.
75. Korthuis PT, McCarty D, Weimer M, Bougatsos C, Blazina I, et al. (2017) Primary care-based models for the treatment of opioid use disorder: A scoping review. Ann Intern Med 166: 268-278.
76. Humphreys K, Shover CL, Andrews CM, Bohnert ASB, Brandeau ML, et al. (2022) Responding to the opioid crisis in North America and beyond: Recommendations of the Stanford-Lancet Commission. Lancet 399: 555-604.
77. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Examination of the Integration of Opioid and Infectious Disease Prevention Efforts in Select Programs (2020) Opportunities to improve opioid use disorder and infectious disease services: Integrating responses to a dual epidemic.
78. Kavanagh BE, Corney KB, Beks H, Williams LJ, Quirk SE, et al. (2023) A scoping review of the barriers and facilitators to accessing and utilising mental health services across regional, rural, and remote Australia. BMC Health Serv Res 23: 1060.
79. Andrilla CHA, Moore TE, Patterson DG (2019) Overcoming barriers to prescribing buprenorphine for the treatment of opioid use disorder: Recommendations from rural physicians. J Rural Health 35: 113-121.
80. Komaromy M, Duhigg D, Metcalf A, Carlson C, Kalishman S, et al. (2016) Project ECHO (Extension for Community Healthcare Outcomes): A new model for educating primary care providers about treatment of substance use disorders. Substance Abuse 37: 20-24.
81. Zheng W, Nickasch M, Lander L, Wen S, Xiao M, et al. (2017) Treatment outcome comparison between telepsychiatry and face-to-face buprenorphine medication-assisted treatment for opioid use disorder: A 2-Year retrospective data analysis. J Addict Med 11: 138-144.
82. McNeely J, Schatz D, Olfson M, Appleton N, Williams AR (2022) How physician workforce shortages are hampering the response to the opioid crisis. Psychiatr Serv 73: 547-554.
83. Amiri S, McDonell MG, Denney JT, Buchwald D, Amram O (2021) Disparities in access to opioid treatment programs and office-based buprenorphine treatment across the rural-urban and area deprivation continua: A US nationwide small area analysis. Value Health 24: 188-195.
84. Centers for Disease Control (2020) Wide-ranging online data for epidemiologic research (WONDER).
85. Pacula RL, Powell D (2018) A supply-side perspective on the opioid crisis. J Pol Anal Manage 37: 438-446.
86. Blanco C, Wiley TRA, Lloyd JJ, Lopez MF, Volkow ND (2020) America's opioid crisis: The need for an integrated public health approach. Transl Psychiatry 10: 167.
87. Brownstein JS, Green TC, Cassidy TA, Butler SF (2010) Geographic information systems and pharmacoepidemiology: Using spatial cluster detection to monitor local patterns of prescription opioid abuse. Pharmacoepidemiol Drug Saf 19: 627-637.
88. Curtis A, Ajayakumar J, Curtis J, et al. (2020) Geographic monitoring for early disease detection (GeoMEDD). Sci Rep 10: 21753.

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