INTRODUCTION

Efforts to integrate addiction care into general medical settings have increased in response to the opioid overdose crisis, which claimed nearly 50,000 American lives in 20171,2,3,4. Hospitalizations for overdose, injection drug–associated infections, trauma, or other medical issues are opportunities to engage high-risk patients and initiate medications for opioid use disorder (MOUD), which in the United States (US) include methadone, buprenorphine, and extended release naltrexone1, 5,6,7. Methadone is a long-acting, full opioid agonist delivered daily in specialized clinics to manage opioid use disorder (OUD) in the US7. Buprenorphine is a partial opioid agonist with a ceiling effect, a flattening of the dose response curve at higher doses, co-formulated with naloxone to deter intravenous use that is prescribed using a special waiver from the Drug Enforcement Agency7. Finally, extended release naltrexone is a long-acting injectable opioid antagonist which requires 7 days without opioids for initiation without precipitated withdrawal7. Methadone and buprenorphine have been shown to reduce all-cause mortality in people who have experienced an overdose8, 9, decrease against medical advice (AMA) discharges10,11,12, and reduce readmission in patients with injection drug–related infections13. Unfortunately, patients with OUD for whom methadone, buprenorphine, and extended release naltrexone are not desired, tolerable, or beneficial rapidly exhaust their treatment options14. Such patients, who have received multiple trials of evidence-based treatments without reduction in drug use, with multiple negative health and social consequences of drug use, and/or with persistent high risk for overdose, may be termed as having “refractory OUD”15.

Reducing barriers to MOUD is central to an evidence-based response to the opioid overdose crisis. In-hospital initiation of MOUD with linkage to outpatient care has emerged as an important way to engage high-risk patients into life-saving care13, 16, 17. Strategies used successfully elsewhere should be considered to help improve care in the US18. We present the case of a patient with refractory OUD hospitalized with recurrent infections in Boston, MA, US, and compare the OUD treatment and harm reduction options available in Boston and Vancouver, British Columbia, Canada, to illustrate the care options across different settings.

CASE

A middle-aged, unhoused male presented to the emergency department with back pain, low-grade fevers, and injection drug use in December 2017. His past medical history is notable for OUD with injection heroin and fentanyl use. Previous complications include 27 admissions in the prior 2 years, 22 of which ended in AMA discharges for vertebral osteomyelitis with evolving antimicrobial resistance (methicillin-resistant Staphylococcus aureus (MRSA) with emerging resistance to vancomycin and daptomycin) in the setting of incomplete antibiotic courses, sternal osteomyelitis, tenosynovitis, and bacteremias with multiple organisms (Fig. 1). He also experienced multiple overdoses, including one during a prior admission in the hospital restroom after injecting drugs from outside the hospital, which required rescue with naloxone.

Figure 1
figure 1

Hospitalizations and addiction interventions, 2015–2017. MSSA, methicillin-sensitive Staphylococcus aureus; L, lumbar; DC, discharge; SNF, subacute nursing facility; RLE, right lower extremity; MRSA, methicillin-resistant Staphylococcus aureus; S. mitis, streptococcal mitis; T, thoracic; VISA, vancomycin insensitive Staphylococcus aureus; Bup/nlx, buprenorphine/naloxone; OD, overdose; AMA, against medical advice discharge.

Full size image

He developed OUD more than a decade ago, after receiving prescription opioids for back pain; he initiated heroin after they were stopped. His longest period of abstinence was 7 months while treated with buprenorphine-naloxone shortly after initiating heroin. He continued to receive a monthly prescription for buprenorphine from an outside provider, though after 7 months, he reported little benefit and started using heroin again, while taking buprenorphine. He was treated with methadone in the past, but left care before his dose could be increased high enough to adequately control his cravings.

The addiction service consulted with the primary team during most of his previous hospitalizations. Treatment with buprenorphine-naloxone and methadone was attempted several times in the hospital with a plan to link to an outpatient methadone clinic without interruption. The patient did not attend outpatient methadone appointments and declined outpatient buprenorphine with increased monitoring and shorter prescription intervals. The patient was unable to abstain from opioids for a sufficient period to initiate oral or extended release naltrexone. He utilized a syringe service program out of the hospital, received further counseling about safer injection practices, and naloxone rescue kits. His psychiatric history was notable for self-reported depression, but inpatient psychiatric consultants had attributed his symptoms to substance use. He had been previously employed but was on disability with few social supports.

During this hospitalization for back pain and fever, he was diagnosed with a vancomycin-insensitive Staphylococcus aureus (VISA) epidural phlegmon with no drainable collection at the site of his recurrent vertebral osteomyelitis. His inpatient providers offered withdrawal and pain management and urged him to remain in the hospital to receive antibiotics. The patient successfully completed 6 weeks of ceftaroline and buprenorphine-naloxone in the acute care hospital as no subacute care facilities accepted him. He acknowledged sporadic injection fentanyl use while in the hospital and had syringes confiscated by security. After completion of antibiotics, he was discharged to a local homeless shelter with a 7-day prescription for buprenorphine-naloxone until he could see his outpatient physician. The patient continued to inject opioids following this presentation and had several more hospital admissions for infections with similar courses.

Case Discussion

This patient’s case highlights some of the challenges of treating individuals with refractory OUD and serious bacterial infections in general medical settings despite access to addiction consultation services, buprenorphine, methadone, peer supports, and improved handoffs to bridge clinics following hospitalization. Alternative strategies to manage refractory OUD are necessary for some patients to reduce the harms from injection drug use, particularly when a patient is not interested or does not benefit from the medications approved for OUD in the US.

In this case, the patient had experience with methadone but could not tolerate attending a daily clinic and did not achieve an effective dose. As methadone is long acting with a variable half-life, the dose is raised slowly in the outpatient setting. While he received higher doses when hospitalized, he did not attend outpatient appointments and declined methadone on subsequent admissions. The patient requested buprenorphine-naloxone while hospitalized for management of both OUD and pain but still had frequent AMA discharges. At the time of these hospitalizations, long-acting injectable formulations of buprenorphine and naltrexone were not available to inpatients with OUD in our hospital system. When these additional treatments become available, they will be options for him (Table 1).

Table 1 A Comparison of Modalities for the Treatment of Opioid Use Disorder Between Vancouver, British Columbia, Canada, and Boston, MA, US7, 19, 20
Full size table

TREATMENT OPTIONS AVAILABLE IN CANADA

Like the US, Canada has experienced a rapid rise in overdose deaths first due to rising prescription opioid availability and subsequently due to contamination of the heroin supply with fentanyl21. However, the Canadian national practice guidelines for OUD present several additional treatment options that are not available in the US and which may have benefitted this patient19 (Table 1). In this narrative review, we included evidence from the most recent US and Canadian national governmental clinical guidelines for treatment of OUD as well as the guidelines produced by the British Columbia Ministry of Health in conjunction with the British Columbia Centre on Substance Use. To demonstrate the variability of OUD care by location, we selected the British Columbia guidelines because they specifically focus on OUD treatments which are restricted in the US and employed a structured literature review to identify and weight evidence according to its quality, prioritizing meta-analyses of randomized control trials, individual randomized control trials, observational reports and lastly expert opinion. Focusing on systematic reviews and randomized control trials, we selected several studies from North America and Europe which were cited in the practice guidelines to elucidate clinical comparisons among the treatment options. We also included an additional systematic review which was published after the practice guidelines and selected several studies which were not included in the guidelines due to study design or specified outcome but nonetheless have clinical and policy importance (e.g., pharmacodynamics, side effects, quality of life, satisfaction, cost-effectiveness). For harm reduction approaches included in this review which were not directly addressed by governmental treatment guidelines, we also selected key systematic reviews and observational studies. Where the quality of evidence is weak, we note that and cite relevant narrative reviews or commentaries. These studies and their conclusions are summarized in Table 2. We explicitly focus on MOUD and harm reduction approaches over behavioral interventions due to the strength of evidence and their central role in the management of OUD, especially in inpatient medical settings22. Studies were largely conducted among adult outpatients, but the treatments are nonetheless available to hospitalized patients in Vancouver, Canada.

Table 2 Summary of Cited Evidence Related to Sustained Release Oral Morphine, Injectable Opioid Agonist Therapy, and Hospital-Based Syringe and Supervised Injection Facilities
Full size table

Medications for Opioid Use Disorder: Pharmacy-Dispensed Daily Methadone

In Canada, pharmacists at retail pharmacies can dispense and witness daily ingestion of methadone after a primary care physician writes a prescription for methadone for OUD15, 23. Pharmacy-based methadone reduces barriers, improves access, and blunts stigma directed toward methadone treatment23. In the province of British Columbia, as of 2018, there were 1354 pharmacies operating, 1131 of which dispensed opioid agonist treatment (OAT), including methadone, to 29,667 patients24, 25. Though concerns about confidentiality, risk of diversion, safety of pharmacy staff and clients, and crime in the surrounding neighborhood, as well as need for pharmacy training and regulatory frameworks have been raised, these concerns have largely been refuted in the literature23. In the US-based opioid treatment system, regulations only allow for the witnessed administration of methadone for OUD through clinics typically separate from the rest of the healthcare system. In the patient’s case, pharmacy-based methadone may have enabled the patient to access methadone daily in his community so he could reach an effective dose and adhere to treatment.

Medications for Opioid Use Disorder: Slow-Release Oral Morphine

The 2018 Canadian national clinical practice guidelines include slow-release oral morphine (SROM) as a third-line option for patients with OUD refractory to buprenorphine and methadone19. Formulated to deliver morphine at a controlled dose over 24 h, SROM has been used to treat OUD in Europe since the 1990s and is the most common treatment in Austria26, 27. It is similar to other long-acting mu-opioid receptor agonists such as methadone, but has fewer cardiotoxicities, drug-drug interactions, and can be titrated more rapidly. The peak effect is delayed 6–8 h28.

A recent meta-analysis including four randomized control trials showed that SROM is equivalent to methadone in retaining patients in treatment and reducing illicit heroin use 29. In two of these studies, SROM was associated with reduced cravings compared to methadone, though this outcome was not included in the meta-analysis30, 31. Other small trials have suggested that, compared to methadone, SROM improves depression, anxiety, and treatment satisfaction, but evidence is mixed on quality-of-life improvements compared to treatment with methadone or buprenorphine32,33,34,35,36. As the majority of SROM trials are small and unblinded, further studies are necessary.

In practice, community pharmacists dispense and witness SROM ingestion daily like methadone. Treatment can be initiated in the community, or by an in-hospital physician who arranges transition to a community provider on discharge. Pharmacists witness ingestion of slow-release beads from opened capsules to minimize diversion risk. Given the more predictable half-life compared to methadone, the dose can be increased every 48 h until a patient is stabilized15. When heroin is the most common opioid used by a person with OUD, it is difficult to distinguish SROM from illicit opioids on toxicology testing, as both test positive for opiates on screening tests. However, as fentanyl use has increased, clinicians can now directly detect fentanyl in urine toxicology, easing this concern.

SROM therapy may have been beneficial for this patient who suffered from pain in addition to OUD. Additionally, he may have successfully engaged in treatment with a more rapid titration to an effective dose.

Medications for Opioid Use Disorder: Injectable Opioid Agonist Therapy

Injectable opioid agonist therapy (iOAT) with either hydromorphone or diacetylmorphine (pharmaceutical heroin) is available in Canada and several Western European countries for the treatment of refractory OUD20. Trials of injectable diacetylmorphine demonstrate a reduction in illicit substance use, improved treatment retention, decrease in illegal activities and incarceration, and a possible mortality benefit37. Quality of life measures and reports of treatment satisfaction are also better in patients treated with diacetylmorphine compared to methadone38, 39. A recent, large Canadian study evaluated injectable hydromorphone as an alternative to diacetylmorphine and found that when compared with diacetylmorphine, there was a non-inferior reduction in opioid use40.

There are three iOAT models in Canada: (1) dedicated supervised iOAT programs, (2) iOAT programs integrated into outpatient medical clinics, or (3) pharmacy-based iOAT programs20. All approaches have been adopted successfully. Patients must have a history of injection drug use without co-existing alcohol or sedative use disorder and meet criteria for severe OUD that has not benefitted from oral treatments or remain at high risk of overdose. Two independent physicians screen for eligibility. Following acceptance, the patient is treated with escalating doses of medication twice daily under the supervision of a nurse, until clinically stable. Then, patients present two or three times daily for witnessed self-administration of the medication, either intravenously in the upper extremities or by intramuscular injection in large leg muscles. A long-acting opioid formulation such as methadone or SROM is typically given in the evenings to provide treatment at night20.

Given the logistical requirements and resources involved in iOAT treatment, this is an addiction specialist-led approach for severe OUD. Multiple cost-effectiveness analyses have suggested a net benefit compared to oral methadone for refractory OUD41,42,43,44. Though iOAT is more costly, there are significant savings from reduction in criminal activity and improved treatment retention42.

When asked theoretically about this treatment as it is not available in the US, this patient showed an interest in iOAT, particularly expressing his concerns about overdose from fentanyl, inability to consistently utilize safer injection practices, and ongoing cravings with other treatments.

Additional Harm Reduction Approaches: Hospital-Based Syringe Services and Supervised Injection Sites

There are multiple strategies to reduce the harms associated with substance use while hospitalized and/or after discharge for individuals who use substances despite access to methadone, buprenorphine, SROM, or iOAT45. These approaches can be offered alongside other evidence-based treatments. Promoting abstinence alone may drive patients to hide their drug use in the hospital or leave AMA10, 46. In several Canadian cities, patients are provided sterile syringes, and in Vancouver and Edmonton, they are offered access to a supervised injection space within the hospital, staffed by peers or nurses. The supervising staff provide access to sterile equipment, instruction on improving injecting practices, and immediate medical attention should an overdose occur. Sterile syringes are routinely recommended for people who inject drugs in the US, but access is geographically limited and rarely, if ever offered in the hospital setting47. Many patients who inject drugs and are hospitalized in Canada utilize syringe services if they are available48.

While hospital-based supervised injection facilities are not well studied, there is robust evidence supporting community-based supervised injection facilities. They attract marginalized individuals, promote safer injection practices, and reduce overdose mortality and public injecting without increasing drug use or neighborhood crime49. Following the publication of a needs assessment showing two-thirds of individuals who injected drugs would utilize hospital-based supervised injection facilities if they were hospitalized in Vancouver, Canada, several are operating. They are particularly popular among those who inject heroin daily, have used illicit drugs in the hospital previously, or have recently used a supervised injection facility50.

These harm reduction tools may have benefited this patient and helped prevent overdose and recurrent infections. Though he did access sterile syringes in the community, he did not always use sterile techniques while attempting to hide his drug use, including in the hospital where syringes were confiscated. Given his ambivalence toward decreasing his drug use, these strategies may have decreased the risk from such use and facilitated a more therapeutic alliance with his care team.

CONCLUSION

While efforts to expand access to methadone, buprenorphine, and extended release naltrexone are crucial to treat OUD, these medications are not universally desired, tolerated, or beneficial. Slow-release oral morphine, injectable opioid agonist therapy, and provision of sterile syringes and injection equipment at in-hospital supervised injection facilities are evidence-based strategies used to treat and reduce the negative consequences of injection drug use in Canada, while pharmacy-based distribution of methadone has the potential to significantly improve access to this life-saving medication for those who need it. In the midst of the opioid overdose crisis, barriers to implementing these approaches in the US should be addressed.