Table 1.

Office-based methadone and pharmacy studies

Author, Year	Design N	Setting Country	Intervention	Main Findings	Limitations
U.S.-based Randomized Clinical Trials
Fiellin 2001(12)	RCT N=46 SAMHSA and DEA exceptions	Office-based primary care New Haven, CT	To compare methadone opioid agonist therapy in primary care versus OTP in stabilized patients on methadone A: Primary care methadone dispensed in office (n=22) B: OTP methadone opioid agonist therapy (n=24)	Similar rates of illicit drug use, functional status, and use of health, legal, or social services; primary care methadone maintenance more likely to be rated excellent by patients	Small samples
King 2006 (13) 12-month follow-up results for King 2002	RCT N=92 SAMHSA and DEA exceptions	Primary care, office-based specialty setting vs OTP Baltimore, U.S.	A: Methadone in office-based setting with 27 take-homes (n=33) B: Methadone in OTP with 27 take-homes (n=32) C: Usual methadone in OTP (n=27)	Low rates of drug use or failed medication recall, treatment satisfaction high in all groups Methadone patients initiated more new employment or family/social activities than usual methadone	Small samples
King 2002 (14) Same study as King 2006 with fewer study participants and six months of follow-up	N=73	Same as above	Same as above	Six months of follow-up. Overall, 1% of urine specimens positive for illicit drugs, no evidence of methadone diversion, and low rates of medication misuse.
Senay 1993 (15)	RCT N=130 FDA IND	Office-based specialty setting U.S.	A: Medical methadone in office-based setting (n=89) B: usual methadone in OTP (n=41). OTP dispensed methadone for both patient groups.	Retention 73% for medical methadone vs. 73% for usual methadone treatment in OTP at 1 year. Addiction severity similar in both groups at 1 year. No difference in positive urine toxicology screens	Small sample, dated study
Tuchman 2008 (16) Tuckman 2006 (17)	RCT N=26 SAMHSA and DEA exceptions	Primary care Santa Fe and Albuquerque, NM, U.S.	A: Medical methadone in primary care setting (physician office, community pharmacy, and social work) (n=14; analyzed 13) versus B: Methadone in OTP (n=12; analyzed 9)	At 12 months, retention 100% vs. 89%, illicit opiate use 23% vs. 78%, urine toxicology positive for cocaine 23% vs. 44%, urine toxicology positive for benzodiazepines 8% vs. 44%	Small samples, women only, loss to follow-up, allowed participants to switch conditions following randomization.
Non-U.S. Randomized Clinical Trials
Carrieri 2014 (18)	RCT N=221	Primary care or specialty care in France. Methadone dispensed at pharmacies for patients in primary care	A: Methadone induction in primary care (n=155) B: Methadone induction in specialty care (n=66)	Methadone induction in primary feasible and acceptable to physicians and patients, and similar to induction in specialized care for abstinence and retention
Lintzeris 2004 (19)	RCT N=139	Primarily primary care (18 general practitioner practice sites and 1 office-based specialist clinic). Australia	A: Office-based buprenorphine (with pharmacy dispensing) (n=73) B: Methadone clinic-based buprenorphine (n=66)	Heroin use, retention similar in both groups	Study focused on initiation of buprenorphine. Methadone patients had to be below 60 mgs before they tried to initiate buprenorphine
U.S.-based Observational Studies
Fiellin 2004 (30) Qualitative analysis of Fiellin 2001	Clinical chart audit of the 22 patients who received office-based methadone and focus group with 6 participating physicians providing care in the 2001 RCT of office-based methadone		To evaluate processes of care during office-based treatment of OUD with methadone	Lapses in care (urine drug monitoring, paperwork completion) and barriers (logistics of dispensing, receipt of urine toxicology results, difficulties arranging psychiatric services, communications with OTP, and non-adherence to medication) identified. Physicians recommended dispensing in pharmacies rather than their office.	Small sample no comparison group
Drucker 2007 (20) Includes pharmacy dispensing	Observational study uncontrolled retrospective treatment series N=10 Used FDA IND from Harris 2006	Office-based specialty setting Lancaster, PA, U.S.	To evaluate methadone agonist therapy in an office-based specialty setting with pharmacy dispensing in stabilized patients	10 patients enrolled in office-based methadone and able to receive methadone in a community pharmacy. 1% (2/216) of urine drug tests positive for illicit substances; patients reported increased satisfaction	Small sample, no comparison group
Harris 2006 (21) Includes pharmacy dispensing	Observational study uncontrolled retrospective treatment series N=127 FDA IND	Office-based specialty setting NYC, U.S.	To report outcomes of office-based medical methadone program (n=127)and a comparison with OTP patients (n=3,342). Medical methadone patients were 1) employed (or unemployed due to disability or retirement); 2) no evidence of opioid, cocaine, or benzodiazepine abuse in last 3 years; 3) psychiatric stability. Methadone dispensed from a central pharmacy	Patients in office-based methadone medical were older than traditional OTP patients (52 vs. 44 years), more likely male (72% vs. 59%), and more likely Caucasian (50% vs. 17%). Proportion with urine sample positive for non-prescribed opiates 0.8% and for cocaine 0.4%	Small sample, in office-based group
Merrill 2005 (22) Includes pharmacy dispensing	Observational study uncontrolled retrospective treatment series N=30 SAMHSA and DEA exceptions	Primary care Seattle, WA, U.S.	To evaluate medical methadone therapy in primary care settings in stabilized patients. The hospital pharmacy dispensed the methadone	Retention at 1 year 93%, positive urine drug screen 6.7%, improvement in Addiction Severity Index over time and patient satisfaction high.	Small sample, no comparison group
Des Jarlais 1985 (23) Initial patients for Novick series	Observational study uncontrolled retrospective treatment series N=28 (first 28 patients) at 12-month follow-up FDA IND	Office-based specialty setting. NYC, U.S. Office-based (providers with experience in drug abuse treatment)	To evaluate methadone agonist therapy in an office-based specialty setting in stabilized patients	At 12 months, 89% (25/28) retention; 1 patient successfully detoxified, 1 required short-acting opioid for surgery and back pain, and 1 requested transfer back to methadone clinic. Patients reported more mobility and privacy, less anxiety about treatment, improved employment situation, and improved selfesteem, and perceived reduction in stigma.	Small sample, no comparison group
Novick 1988 (25)	Patients transferred from Rockefeller University to Beth Israel OTP N=40 (first 40 participants)	Same as above	Methadone was from the hospital pharmacy and dispensed in the primary care office	12 to 55 months of follow-up. 83% remained on medical methadone with 94% annual retention rate. 5 returned to OTP because of cocaine use.	Same as above
Novick 1994 (24)	N=100 Follow-up data for 3.5 to 9.25 years (or status at discharge)	Same as above	Same as above	Retention 98%, 95%, and 85% at 1, 2, and 3 years. Cumulative proportional survival in treatment 0.74 at 5 years and 0.56 at 9 years. After 42 to 111 months, 72 patients remained in good standing, 15 patients had unfavorable discharge, 7 voluntarily withdrew in good standing, 4 died, 1 transferred to chronic care facility, and 1 voluntarily left program	Same as above
Salsitz 2000 (26) Report on 15 years	N=158	Same as above	Same as above	132 (84%) were program compliant and treatable within office-based settings. Retention at 1 year (99%), 2 years (96%), three years (89%). 13% died (no overdoses). 16% returned to OTP	Same as above
Schwartz et al, 1999 (27)	Observational study uncontrolled retrospective treatment series N=21 FDA IND	Primary care Baltimore, U.S.	To evaluate medical methadone therapy in primary care settings in stabilized patients Methadone was dispensed in the primary care office	After 12 years, 29% of patients dropped out, 0.5% urine samples positive for drugs; no methadone overdose or diversion; participants reported significant improvement in quality of life	Small sample, no comparison group
Non-U.S. Observational Studies
Gossop 2003 (28)	Observational study Prospective sample N=240	Primary care vs. drug clinic United Kingdom	A: Methadone in general practitioner clinics with dispensing from the office or community pharmacy (n=79) versus B: Methadone in drug clinics with dispensing in the clinic or community pharmacy (n=161)	Reductions in illicit drug use, injecting, sharing injection equipment, psychological and physical health problems, and crime decreased in both groups at 1 and 2 years. Patients in general practitioner settings had less frequent benzodiazepine and stimulant use, and fewer psychological health problems
Mullen 2012 (29)	Retrospective randomly selected sample of methadone admissions in 1999, 2001 and 2003 N = 1,269	Central methadone treatment list Ireland	Random sample of new patients receiving methadone treatment from specialty clinics, community medical clinics and trained physicians in 1999, 2001 and 2003 to assess variables associated with retention in care	Participants were primarily men (69%) with a mean age of 26 years (75% under 30 years of age). 95% received daily dosing with a mean dose of 58 mg/day. Doses in primary care were lower (53 mg/day) compared to specialty clinics (60 mg/day). 61% remained in care for more than 1 years. Primary cause of leaving in less than one year was “treatment failure”. Logistic regression suggested retention at 12 months was associated with gender (women were more likely to remain in care). Patients in specialty clinics were two times more likely to leave care than those in physician care. Patients with a daily dose less than 60 mg/day were 3 times more likely to leave care than patients with doses greater than 60 mgs.
U.S. and non-U.S. Pharmacy Studies
Bowden 1976 (31)	Descriptive, uncontrolled retrospective treatment series of OTP patients with pharmacy dispensing N=96 Began prior to FDA regulations	Community pharmacies San Antonio, TX, U.S.	To describe community pharmacy dispensing of methadone for OUD (n=96). Data collection began prior to the 1973 FDA regulations that restrict dispensing to OTPs	Retention 70% at 1 year, 3% voluntarily abstinent, 10% using heroin, 9% jail, prison, or hospital, 1% dead, 63% employed and 15% partially employed. Proportion arrested one or more times in the prior year decreased from 66% to 58%	Small sample, no comparison group
Joudrey 2020 (4)	Descriptive, cross sectional analysis of travel time to OTPs and pharmacies N=7,918 census tracts in five states	OTPs vs community pharmacies U.S	To compare drive time to OTP vs. community pharmacies	Median drive time longer to OTP than chain pharmacies (19.6 vs. 4.4 minutes); difference greater in increasingly rural census tracts (11.5 to 35.2 minutes)
Kleinman, 2020 (5)	Descriptive, cross sectional analysis of travel time to OTPs and pharmacies N=72,443 census tracks in U.S.	OTPs vs community pharmacies U.S.	To compare drive time to OTPs (n = 1,682) vs community pharmacies (n = 69,475)	Mean population weighted driving time was 20.4 minutes to OTPs and 4.5 minutes to pharmacies. Drive times increased in metropolitan and noncore counties
Keen 2002 (32)	Descriptive, ecological analysis of methadone deaths before and after pharmacy dispensing of methadone as an opioid agonist therapy N=400	Primary care United Kingdom	To evaluate trends in methadone associated mortality in city following implementation of widespread methadone prescribing in primary care Dispensing in community pharmacy	Decrease in methadone deaths in city following implementation of widespread methadone prescribing in primary care, despite increase in methadone prescribing

Abbreviations: DEA = Drug Enforcement Administration, FDA = Food and Drug Administration, HIV = human immunodeficiency virus; IND = Investigational New Drug, NTP = narcotic treatment program, NYC = New York City, OTP = opioid treatment program; OUD = opioid use disorder; PWID = people who inject drugs; RCT = randomized controlled trial; U.S. = United States; vs = versus