RITU VYAS, BS
Philadelphia continues to lead in fatal overdoses amongst large cities in the United States.
Meta-analyses studies vary on retention in methadone treatments compared to buprenorphine
The large increase in the number of “waivered” buprenorphine providers is not reflected in increased buprenorphine prescribing and patient outcomes
Opioid overdose is a leading cause of death in certain populations nationwide. In 2022 Philadelphia was ranked as having the largest number of overdose deaths among major cities in the United States (US) (1). In 2021 alone, there were 1,214 recorded fatal overdoses in the city, while in the past five years the number of reported deaths was over 5,900 (1). Many treatment options have been created to fight opioid addiction with the hopes of decreasing overdose deaths. Pharmacologic therapies have been a major focus of treatment. Amongst these, Opioid Replacement Therapies (ORT) has been a new yet significant initiative Philadelphia has adopted – these therapeutics include Methadone and Buprenorphine. As a result, an increasing number of clinics and clinicians have been “waivered” to prescribe these medications (1). Philadelphia saw a three-fold increase in the number of providers waivered to prescribe buprenorphine from 354 in 2018 to 1,382 providers in April 2022 (1). However, during September 2020, only 24% percent of waivered providers, 243 out of the 1,014 in Philadelphia, prescribed buprenorphine for OUD (2).
Multiple studies have aimed to determine retention rates of these medication-assisted treatments (3) (4). The studies included in this research analysis varied in their definition of retention rate. For example, the meta-analysis by Klimas et al. extracted data that either defined retention rate as a measure of the length of time retained in the study or the presence of the participant on the final day of the study (3). O’Connor et al. extracted data at time points (6 months, 12 months, 2 years, and 3 years) to measure retention rate as the percentage of patients enrolled in the opioid replacement therapy program at those time points (4).
Methadone Maintenance Treatment (MMT) and buprenorphine treatment vary in their mechanisms. Methadone is a μ-opioid receptor agonist (5). Buprenorphine is μ-opioid receptor agonist and κ-opioid receptor antagonist (5). A common formulation of buprenorphine, Suboxone, is mixed with naloxone, an opioid antagonist (5). The addition of naloxone deters the diversion of buprenorphine (5). When taken orally the naloxone effects are minimal but still can precipitate withdrawal in opioid-dependent patients (5). When injected, the naloxone in the suboxone will cause rapid precipitate opioid withdrawal (5). Buprenorphine or Suboxone are considered the first-line treatment for patients who may be at high risk for diversion and misuse (5).
This analysis will review the results of these retention rates studies. This data can help better understand Philadelphia’s current trajectories with ORT prescriptions and subsequent strategies to decrease the number of fatal overdoses in the city.
Several studies were examined for retention rate information between different ORTs. Klimas et al. reviewed 7603 studies, 10 RCTs, and 3 observational studies. The fixed-dose oral buprenorphine was compared with methadone (3). The authors concluded that across studies, the average retention rate was highly variable (3). In randomized controlled trials (RCT) the retention for buprenorphine was between 20.0-82.5% and for methadone, it was between 30.7-83.8% (3). For the observational studies the retention rate for buprenorphine was between 20.2-78.3% and the retention rate for methadone was between 48.3-74.8% (3). This data was based on time spent in the study. The authors also extracted data with the definition of retention rate as a presence on the last day (3). The data showed no significant difference between buprenorphine and methadone treatment retention in RCT (risk ratio [RR] = 0.89; 95% CI 0.73-1.08, p = 0.24; quality of evidence: low) and controlled observational studies (RR = 0.75; 95% CI 0.36-1.58, p = 0.45) (3). The figure below depicts the mean retention rates over 4-6 months for the RCTs studied (3).
Figure 1: Boxplots of mean retention rate for randomized controlled trials (RCTs), 4–6 months of follow-up. Retention rates are for buprenorphine and methadone, where the retention rate was measured as the number of patients who completed the study. All studies had follow-up rates between 4 and 6 months (3).
In a 2019 study, Timko et al. presented a systemic review of 55 articles (6). The authors concluded that there was variation in the retention rates. To elaborate, one of the articles found 74.0% retention in MMT and 46.0% buprenorphine at 6 months (6). Another article concluded a 46.4% retention rate for methadone and a retention rate for 50.0% buprenorphine/ naloxone (Suboxone) at 6 months (6). Another article concluded a retention rate of 45.9% for buprenorphine and a 3.9% retention rate for methadone at 1 month. Due to the variability of retention time points and the inclusion of naloxone with buprenorphine (Suboxone), it is difficult to compare the studies directly (6).
O’Connor et al. conducted a meta-analysis looking at 67 studies to determine factors associated with retention in ORT or treatment dropout (4). The ORTs used were methadone (MMT), buprenorphine (BUP), or mixed OSTs (opioid substitution treatments). Mixed OSTs were defined as patients receiving either methadone or buprenorphine (4). Data from the analysis are shown in Table 1. The retention rate for methadone maintenance treatment was 67% at 6 months and 60.7% at 12 months (4). By comparison, median retention rates for buprenorphine were 56.8% at 6 months and 45.5% at 12 months (4). Furthermore, subsequent retention for patients on methadone at 2 and 3 years was 49.7% and 54% respectively (4). Notably, data was insufficient to determine retention for buprenorphine past the one-year mark. The study found that almost half of those enrolled in all ORT programs had not been retained by the 12-month mark (4). Risk factors associated with this lack of retention were younger age, continued substance use, and incarceration (4).
Table 1. Median retention rates across included studies. Reprinted from O'Connor, Aisling Máire et al. “Retention of patients in opioid substitution treatment: A systematic review.” PloS one vol. 15,5 e0232086. 14 May. 2020, doi:10.1371/journal.pone.0232086 (4)
In the April 2022 Pennsylvania Public Hearing on the Current State of the Opioid Epidemic in the Commonwealth, the health commissioner stated, “the number of Philadelphia residents with opioid use disorder not in treatment is believed to be in the tens of thousands” (1). Due to Philadelphia’s vast multicultural population, a worthy next step would be to identify the different patient populations in ORTs with and associated retention rates. This way, clinicians can provide an educated, data-driven, targeted approach to meet patients where they are and chose therapies suited for social and structural factors which the patient may face.
Nationally, there is an increase in deaths related to an unintended drug overdose. The CDC reports a 31% increase from 2019 to 2020 (7). Philadelphia follows the national trends with an increase from 2017 to 2019 (8). In 2020, 86% of fatal overdoses were opioid-related in Philadelphia while the national average was 75% for opioid-related fatal overdoses (7)(8). The figure below from the Philadelphia Department of Health charts the trends (8).
Figure 2: Key Findings: In 2020, 86% of deaths involved an opioid, such as heroin, oxycodone, or fentanyl, and 60% involved a stimulant, such as cocaine or methamphetamine (8).
With rates above the national average for opioid-related fatal overdoses, Philadelphia would benefit from comprehensive ORT programs.
In addition to gathering data on retention rates for ORT programs in Philadelphia specifically, data should be collected on factors leading to noncompliance in the programs. A 2018 survey with 4,225 clinicians concluded that newly waivered clinicians in the US were prescribing well below their patient limit, with many not prescribing at all (9). Figure 3 illustrates the number of buprenorphine waivered providers per drug overdose in Philadelphia (2). The data show that although there has been an increase in the availability of this ORT, prescribers are still hesitant. Studies focusing on prescriber factors affecting the prescription of buprenorphine and other ORTs are needed.
Figure 3. Buprenorphine-Waivered Health Care Providers Per Drug Overdose
Death in Philadelphia and 23 Other Jurisdictions. Reprinted from Buprenorphine treatment for opioid use disorder in Philadelphia. The Pew Charitable Trusts. https://www.pewtrusts.org/en/research-and-analysis/reports/2021/09/buprenorphine-treatment-for-opioid-use-disorder-in-philadelphia. (2021). Accessed June 2022 (2).
Only about half of patients enrolled in ORT programs are “retained”. Additionally, data regarding retention is limited as different studies have varying definitions of retention, and most do not follow patients for the same duration of time. In Philadelphia, the large increase in the number of “waivered” buprenorphine providers is not reflected in prescriptions and patient outcomes. Many studies have indicated significantly higher rates of retention for methadone treatment, however, there is still large amounts of variation. Future studies should aim to collect retention rates for buprenorphine and methadone from Philadelphia clinics, investigate patient nonadherence, and investigate prescriber factors leading to non-adherence.
Bettigole, C. (2022, April 12). Public Hearing on the Current State of the Opioid Epidemic in the Commonwealth. Retrieved from https://www.legis.state.pa.us/WU01/LI/TR/Transcripts/2022_0051_0004_TSTMNY.pdf
Buprenorphine treatment for opioid use disorder in Philadelphia. The Pew Charitable Trusts. https://www.pewtrusts.org/en/research-and-analysis/reports/2021/09/buprenorphine-treatment-for-opioid-use-disorder-in-philadelphia. (2021). Accessed June 2022
Klimas, J., Hamilton, MA., Gorfinkel, L. et al. Retention in opioid agonist treatment: a rapid review and meta-analysis comparing observational studies and randomized controlled trials. Syst Rev 10, 216 (2021).
O'Connor, Aisling Máire et al. “Retention of patients in opioid substitution treatment: A systematic review.” PloS one vol. 15,5 e0232086. 14 May. 2020, doi:10.1371/journal.pone.0232086
Suboxone versus Methadone for the Treatment of Opioid Dependence: A Review of the Clinical and Cost-effectiveness [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2013 Nov 14. Available from: https://www.ncbi.nlm.nih.gov/books/NBK195153/
Timko C, Schultz NR, Cucciare MA, Vittorio L, Garrison-Diehn C. Retention in medication-assisted treatment for opiate dependence: A systematic review. J Addict Dis. 2016;35(1):22-35. doi: 10.1080/10550887.2016.1100960. Epub 2015 Oct 14. PMID: 26467975; PMCID: PMC6542472.
Centers for Disease Control and Prevention. (2022, June 2). Death Rate Maps & Graphs. Centers for Disease Control and Prevention. Retrieved July 20, 2022, from https://www.cdc.gov/drugoverdose/deaths/index.html
Philadelphia Department of Health. (2020). Unintentional overdose deaths. Substance Use Philly. Retrieved July 20, 2022, from https://www.substanceusephilly.com/unintentional-overdose-deaths
Jones CM, McCance-Katz EF. Characteristics and prescribing practices of clinicians recently waivered to prescribe buprenorphine for the treatment of opioid use disorder. Addiction. 2018;114(3):471-482. doi:10.1111/add.14436.