Medications for Opioid Use Disorder (Methadone, Buprenorphine, Suboxone, and Diacetylmorphine)

"A wealth of evidence about medications to treat OUD has been amassed over the past half century from clinical studies, randomized controlled trials, systematic reviews, and meta-analyses. The verdict is clear: effective agonist medication used for an indefinite period of time is the safest option for treating OUD. According to a recent review of medications to treat OUD, “the evidence for efficacy both in reducing opioid use and retaining patients in care is strongest for agonist treatment” (Connery, 2015, p. 64).

"People with OUD are less likely to die when they are in long-term treatment with methadone or buprenorphine than when they are untreated. Treatment using agonist medication is associated with an estimated mortality reduction of approximately 50 percent among people with OUD (Degenhardt et al., 2014; Larochelle et al., 2017; Ma et al., 2018; Pierce et al., 2016; Sordo et al., 2017). Both methadone and buprenorphine treatment retention have been linked to substantially decreased risks of both all-cause and overdose-related mortality among people with OUD (Sordo et al., 2017). Increased access to treatment using agonist medication is associated with reduced opioid overdose deaths (Schwartz et al., 2013). Studies of extended-release naltrexone have not had sufficient power or duration of follow-up to detect a mortality benefit (Jarvis et al., 2018).

"Treatment with methadone or buprenorphine is also associated with lower rates of other opioid use (Kakko et al., 2003; Mattick et al., 2009, 2014; Thomas et al., 2014), improved social functioning (Bart, 2012), decreased injection drug use (Woody et al., 2014), reduced HIV transmission risk behaviors (Gowing et al., 2011), reduced risk of HIV diagnosis (MacArthur et al., 2012), reduced risk of hepatitis C virus (HCV) infection (Peles et al., 2011), and better quality of life compared to individuals with OUD not in treatment (Ponizovsky and Grinshpoon, 2007). Methadone is also associated with reduced levels of criminality for individuals with OUD (Bukten et al., 2012; Gearing, 1974; Schwartz et al., 2009, 2011; Sun et al., 2015). Limited evidence suggests that, compared with a placebo, extended-release naltrexone may be associated with reduced opioid use, but more rigorous studies are needed (Jarvis et al., 2018).

"Compared with a placebo, both buprenorphine alone and buprenorphine in combination with naloxone administered in office-based treatment settings significantly reduce opioid use and opioid cravings (Fudala et al., 2003). In women who are pregnant, buprenorphine treatment has been linked to improved maternal and fetal outcomes; infants also tend to have less severe symptoms of neonatal abstinence syndrome when their mothers were treated with buprenorphine during pregnancy (Thomas et al., 2014)."

"Evidence demonstrates that patients who receive longer-term treatment with medication for OUD have better treatment outcomes; they are also less likely to die from overdose if they return to use while on medication. In fact, people with OUD are up to 50 percent less likely to die when they are being treated long term with methadone or buprenorphine. Further research is needed to define an optimal treatment regimen for each of the available medications and to directly compare the effects of the three medications’ long-term use. Nonetheless, in spite of the need for more research, the body of evidence amassed over the past 50 years underscores the benefits of longterm retention on medication."

"Access to medications for OUD remains inequitable across different treatment settings as well. In the United States, methadone can only be administered through specialty facilities known as opioid treatment programs (OTPs), even though the available evidence shows that delivering it through an office-based medical practice setting is also effective. Moreover, most residential treatment facilities do not offer medications, and if they do, they rarely offer all three medications.

"Despite the large and increasing numbers of people with OUD entering the criminal justice system in the United States, evidence-based medications are often withheld or are only provided on a limited basis for medically supervised withdrawal. As a result, few people with OUD receive medication while incarcerated or under the supervision of drug courts. In addition, justice-involved people who do receive medication for OUD are often not linked with care upon release, leading to treatment discontinuation and the concomitant risks of overdose and death. Given that these medications are known to save lives, it is arguable that withholding them from persons with OUD is unethical, as withholding insulin or blood pressure medications would be.

"Pharmacies, mobile medication units, community health centers, emergency departments, and other care settings provide opportunities to engage people with OUD and link them to evidence-based care. Expanding medications for OUD into a broader range of care settings would save lives and build the capacity to make real progress against the epidemic."

"Treatment with a combination of medication and evidence-based behavioral interventions (e.g., contingency management approaches, cognitive behavioral therapy, and structured family therapy) can be effective for many people with OUD. However, little is known about which combinations of medication and behavioral interventions are most effective, which patients are most likely to benefit from behavioral interventions, and which patients may do well with medications and appropriate medical management alone. Even among patients who would benefit from the addition of behavioral interventions, it is better for them to receive medication with appropriate medical management than to have it withheld. The life-saving aspects of these medications have been established even in the absence of accompanying behavioral interventions. Given the resource limitations faced in many settings, it is critical that providers do not withhold medications from their patients just because behavioral interventions are not available."

"Most people with OUD in the United States do not receive any treatment at all, and those who do receive any type of treatment may wait years to do so. Of the small proportion of people who do receive treatment, just a fraction receive medication. Access to evidence-based treatment is poor across the board, but it is starkly inequitable among certain generational, racial, ethnic, social, and economic groups. Although the research is not yet granular enough to develop tailored treatment guidelines for specific subpopulations, the available evidence supports the effectiveness of medication for treating OUD in all groups, including adolescents, pregnant women, and people with comorbidities. However, the treatment gap is exacerbated for vulnerable populations, whose members face steep barriers in accessing medications."

"Of the various treatments available, Methadone Maintenance Treatment, combined with attention to medical, psychiatric and socioeconomic issues, as well as drug counseling, has the highest probability of being effective."

"For more than 45 years, research has confirmed that opioid agonist therapy (ie, methadone hydrochloride) is a highly effective treatment for opioid addiction provided outside primary care.^4-6"

"The safety and efficacy of narcotic agonist (methadone) maintenance treatment has been unequivocally established."

"Prolonged oral treatment with this medicine [methadone] diminishes and often eliminates opiate use, reduces transmission of many infections, including HIV and hepatitis B and C, and reduces criminal activity."

"In summary, data from studies conducted in Australia, Europe, Asia and the United States have, with few exceptions, found strong associations between participation in methadone treatment and reductions in the frequency of opioid use, fewer injections and injection-related HIV risk behaviors, and lower rates of HIV prevalence and incidence. Few randomized controlled trials have been conducted due to ethical concerns regarding the random assignment of individuals to no treatment or other potentially less effective treatment modalities. Despite this fact, the consistency of findings from the observational and case-controlled studies cited here provide a preponderance of evidence suggesting that sustained treatment of opioid-dependent injection drug users with methadone is associated strongly with protection from HIV infection."

"Residential treatment is often considered the highest intensity of treatment for individuals with OUD [40], and may by particularly important for those with unstable housing, co-morbid mental health conditions, or high medical need [41]. However, evidence supporting this assumption is mixed and has primarily focused on treatment completion, retention, and abstinence outcomes [9, 13]. Few studies have directly compared residential treatment with outpatient treatment for clinical outcomes such as overdose [20,21,22]. In this analysis, we used a linked Medicaid dataset to compare outcomes for individuals with OUD who received residential or outpatient treatment. After adjustment for a variety of physical, mental, and addiction-related comorbidities, we found that rates of overdose, opioid-related, and all-cause ED or hospitalizations were not reduced for individuals receiving residential treatment compared to those treated as an outpatient. While residential treatment was associated with higher retention at 6-months, this difference was not significant at 12-months. In stratified analyses, the benefits of residential treatment on retention appeared to be confined to those not receiving MOUD.

"Historically, public perception has assumed residential treatment to be the gold standard, a view often endorsed by the addiction treatment community despite its greater cost and limited evidence [8, 13]. Efforts to further refine selection of patients most likely to benefit from residential treatment are likely to be eclipsed by increasing the use of MOUD in, and following, residential treatment. Opioid agonist treatment for OUD improves a variety of addiction-related outcomes and markedly reduces the risk of overdose and all-cause mortality [7, 42]. In our study, MOUD was associated with a 55% reduction in the risk of opioid overdose independent of treatment setting. About one-third of individuals receiving treatment were prescribed MOUD which is comparable to other reports and suggests missed opportunities for improving OUD treatment outcomes [1, 24].

"This study adds to a mixed literature demonstrating the potential benefits of residential treatment for individuals with OUD with respect to treatment retention [13, 21, 22, 43]. Studies using SAMHSA TEDS data exclusively have generally shown that individuals entering residential facilities have higher treatment completion rates [43, 44]. Consistent with this literature, we found that residential treatment was associated with enhanced retention. While treatment completion is associated with improved some clinical and social outcomes, it is a surrogate indicator of improved addiction-related health outcomes. Moreover, OUD is now universally recognized as a chronic condition requiring long-term outpatient management. Although residential care was associated with improved retention in our study, it was not associated with improvements in overdose or other opioid-related outcomes. This largely comports with recent claims-based analyses that suggest outpatient treatment may be clinically superior to inpatient or residential treatment, especially when coupled with MOUD [21, 22].

"Our subgroup analyses found that among individuals receiving MOUD, outpatient treatment was associated with improved opioid-related ED or hospitalizations compared to residential treatment. Using a similar retrospective cohort design, Morgan et al. found outpatient-based MOUD to be associated with improved rates of opioid overdose and all-cause admissions compared to inpatient treatment initiation [21]. Additional research is required to identify whether other subgroups of patients might benefit from residential treatment in the fentanyl era, such as those with a history of previous unsuccessful attempts at outpatient treatment, housing instability, and adolescents."

"In a national cohort of 40,885 insured individuals between 2015 and 2017, MOUD [Medication for Opioid Use Disorder] treatment with buprenorphine or methadone was associated with a 76% reduction in overdose at 3 months and a 59% reduction in overdose at 12 months. To our knowledge, this was the largest cohort of commercially insured or MA individuals with OUD [Opioid Use Disorder] studied in a real-world environment with complete medical, pharmacy, and behavioral health administrative claims.

"Treatment with buprenorphine or methadone was associated with a 32% relative rate of reduction in serious opioid-related acute care use at 3 months and a 26% relative rate of reduction at 12 months compared with no treatment. In contrast, detoxification, intensive behavioral health, and naltrexone treatment were not associated with reduced overdose or serious opioid-related acute care use at 3 or 12 months.

"Despite the known benefit of MOUD treatment with buprenorphine or methadone, only 12.5% initiated these evidence-based treatments. Most individuals in this cohort initiated treatment with psychosocial services alone or inpatient detoxification, both of which are less effective than MOUD. It is possible that individuals accessed public sector treatments that were not captured in our data, particularly for methadone, which was not covered by Medicare and may not have been covered without co-payment for all commercial plans during this time. Low rates of MOUD use among an insured population highlight the need for strategies to improve access to and coverage for MOUD treatment."

"Our results demonstrate the importance of treatment retention with MOUD [Medication for Opioid Use Disorder]. Individuals who received methadone or buprenorphine for longer than 6 months experienced fewer overdose events and serious opioid-related acute care use compared with those who received shorter durations of treatment or no treatment. These findings are consistent with prior research^11,15,27-29 demonstrating high rates of recurrent opioid use if MOUD treatment is discontinued prematurely. Despite the benefit of MOUD in our study, treatment duration was relatively short. Given the chronic nature of OUD and the evidence that longer treatment duration may be associated with improved outcomes, patient-centered MOUD treatment models explicitly focused on engagement and retention are needed. Low-threshold treatment, which aims to reduce barriers to entry and is tailored to the needs of high-risk populations,³⁰ may be a strategy to improve retention; however, to our knowledge, no rigorous studies have evaluated these models to date.^31,32 In addition, patient-centered MOUD care, which allows participants to determine the services they need rather than requirements, such as mandatory counseling, are noninferior to traditional treatment.³²

"Numerous barriers limit sustained engagement in MOUD, including a lack of access to waivered practitioners, high co-payments, prior authorization requirements, and other restrictions on use. Previous studies^33,34 have demonstrated that restrictions on use for MOUD are associated with limited access and harm. Addiction treatment programs in states that require Medicaid prior authorizations for buprenorphine are less likely to offer buprenorphine, and the more restrictions on use in state Medicaid programs, the fewer treatment programs that offer buprenorphine.³³ Requiring prior authorization for higher doses of buprenorphine may also result in increased recurrence rates among patients.³⁴ Our finding that MOUD treatment with buprenorphine or methadone was associated with lower overdose and serious opioid-related acute care use supports expanded coverage of these medications without restrictions on use.

"Our findings are also consistent with analyses showing that MOUD treatment with buprenorphine or methadone is significantly associated with reduced overdose and recurrence of opioid use compared with no treatment or non-MOUD treatment. A previous cohort study¹⁵ of individuals in Massachusetts demonstrated a reduction in overdose-related mortality associated with treatment with buprenorphine (AHR, 0.62; 95% CI, 0.41-0.92) or methadone (AHR, 0.41; 95% CI, 0.24-0.70), results that are similar to our finding of an AHR of 0.41 (95% CI, 0.31-0.55) for overdose at 12 months for methadone or buprenorphine. A large meta-analysis¹¹ examining mortality when individuals were in or out of treatment with buprenorphine or methadone similarly showed decreased overdose mortality during treatment. A study¹² examining proxies for recurrent OUD among Massachusetts Medicaid enrollees found that treatment with buprenorphine or methadone was associated with lower recurrence rates and costs. No studies, to our knowledge, have examined the effect of different OUD treatment pathways on overdose and serious opioid-related acute care use among a national sample of commercially insured and MA enrollees."

"Our finding that MOUD [Medication for Opioid Use Disorder] treatment with naltrexone was not protective against overdose or serious opioid-related acute care use is consistent with other studies^15,35 that found naltrexone to be less effective than MOUD treatment with buprenorphine. The mean (SD) treatment duration for naltrexone in this cohort was longer than prior observational studies at 74.41 (70.15) days. 

"The findings that nonintensive behavioral health treatment was associated with a reduced risk of overdose at 12 months but not 3 months and a reduced risk of opioid-related acute care use was surprising. Although we attempted to control for differences among various treatment groups, individuals referred to nonintensive behavioral health may represent a less complex patient population than those who receive MOUD treatment or are referred to intensive behavioral health or inpatient treatment."

"Growing evidence suggests that outpatient treatment, when coupled with MOUD, may be superior to other treatment settings. Studies among commercial or Medicare Advantage enrolled patients demonstrate that outpatient treatment involving MOUD is associated with fewer overdoses, readmissions, or subsequent inpatient detoxification stays compared to inpatient detoxification or residential treatment [21, 22]."

"First, we confirmed that the rate of diagnosed OUD has increased steadily among commercially insured adults, and we documented how the age distribution of OUD has changed. In 2008 diagnosed OUD among the youngest age group (ages 18–24) was more than double that among the oldest group (ages 55–64). However, in 2017 diagnosis rates exhibited a hump-shaped pattern in age, with the highest rate (4.75 per 1,000 enrollees) among the middle-aged (people ages 35–44) and the greatest increase among the near-elderly (ages 55–64).

"Second, even as diagnosed OUD rates have increased and overdose deaths have soared, the likelihood that patients would receive any treatment has plunged. This decrease was driven by a reduction in MAT rates, coupled with relatively steady rates of medication-free treatment (except for the youngest age group, which experienced a surge in this treatment modality). In 2008, 60 percent of those diagnosed with OUD in our primary sample had at least one claim for OUD medication, but that rate had declined to 50 percent by 2017. Notably, there has been a course reversal: The nadir of 43 percent occurred in 2016, and the subsequent surge in MAT among patients with OUD has coincided with a sharp increase (27 percent) in the number of practitioners who completed the training required to prescribe buprenorphine.5,6 However, the aggregate time-series trend in treatment rates is deeply concerning in light of the high and increasing reported prevalence of OUD and its life-threatening sequelae.

"Third, our analysis of medical spending for commercially insured patients with OUD revealed several new facts and points to areas for future research. We documented high average spending for patients with OUD, both before and after diagnosis (around $30,000 per person during the twelve-month period spanning a diagnosis). We found that receiving an OUD diagnosis was followed by a sizable increase in medical spending, but that increase was much larger for patients who chose medication-free treatment than for those who chose medication or no treatment. However, we also found significant differences in prediagnosis spending across these groups, which implies that selection effects must be addressed before a causal link between treatment modality and spending is inferred."

"A number of barriers, both social and systemic, prevent people with OUD from accessing the life-saving medications they need. Making headway against the opioid crisis will require addressing barriers related to stigma and discrimination, inadequate professional education, overly stringent regulatory and legal policies, and the fragmented systems of care delivery and financing for OUD.

"The stigmatization of people with OUD is a major barrier to treatment seeking and retention. Social stigma from the general public is largely rooted in the misconception that addiction is simply the result of moral failing or a lack of self-discipline that is worthy of blame, rather than a chronic brain disease that requires medical treatment. Evidence demonstrates that social stigma contributes to public acceptance of discriminatory measures against people with OUD and to the public’s willingness to accept more punitive and less evidence-based policies for confronting the epidemic. Patients with OUD also report stigmatizing attitudes from some professionals within and beyond the health sector, further undercutting access to evidence-based treatment. The medications, particularly the agonist medications, used to treat OUD are also stigmatized. This can manifest in providers’ unwillingness to prescribe medications due to concerns about misuse and diversion and in the public’s mistaken belief that taking medication is “just substituting one drug for another.” Importantly, the rate of diversion is lower than for other prescribed medications, and it declines as the availability of medications to treat OUD increases.

"Despite the mounting crisis, the health care workforce in the United States does not receive adequate, standardized education about OUD and the evidence base for medication-based treatment. This has created a shortage of providers who are knowledgeable, confident, and willing to provide medications to patients. Many rural areas are being overwhelmed by the opioid epidemic and have very few, if any, trained and licensed providers who can prescribe the medications. Misinformation and a lack of knowledge about OUD and its medications are also prevalent across the law enforcement and criminal justice systems."

"Methadone's half-life is approximately 24 hours and leads to a long duration of action and once-a-day dosing. This feature, coupled with its slow onset of action, blunts its euphoric effect, making it unattractive as a principal drug of abuse."

"Methadone emerged as a maintenance treatment modality for heroin dependence in the mid-1960s. Mark Parrino, added that opioid treatment programs (OTPs) came into existence because of a rejection by the medical community to treat this particular patient population.

"By 1972, the Food and Drug Administration (FDA) and the Drug Enforcement Administration (DEA) had instituted severe regulations that restricted access, said Roberts. These regulations were designed primarily to prevent methadone from being diverted to the street, he said. For example, patients were required to receive medication under close supervision at federally approved clinics and submit to regular urine testing. Some states also employed coercive tactics, such as requiring participation in a methadone program in order to receive public benefits or to obtain release from prison, said Roberts. Physicians were also subject to close scrutiny and were required to have complicated security systems to prevent diversion."

"The safety and efficacy of nurse prescribing of MOUD is well established, and its expansion can provide a range of advantages to people who are dependent on opiates. This includes increasing access to treatment, but nurse prescribing of MOUD can increase the numbers of people in treatment from ‘hard-to-reach’ cohorts such as those in rural settings, or those with less financial means [19, 34]. This in itself holds a significant potential to reduce a wide range of harms and costs associated with high-risk opiate use [35, 36]. Developing NP of MOUD can also help to create new and innovative treatments which can allow services such as detoxification for complex clients, normally only considered appropriate for in-patient settings, to be delivered in a person’s own home [37]. Where MOUD treatment is already available, it is likely that developing NP will also provide opportunities for enhanced key working and more responsive services [38]. Within England and Scotland, it has been found that the number of non-medical prescribers has grown considerably in the recent past and this has provided an opportunity for nurses particularly in England to work at an advanced level [39].

"The studies included in this review, although mostly from the USA, are reflective of the European context, in that the development of nurse prescribing of MOUD is subject to the efforts made within each jurisdiction to progress it. There are significant variations across regions in terms of levels of training, autonomy and scope of practice and indeed whether nurse prescribing of MOUD happens at all [40]. For example, in the UK, nurses can prescribe MOUD independently, but ‘nurse practitioner’ is not a legally protected title as it is in other regions [41]. In this respect, the already established potential and recognition of the role of NP of MOUD has yet to be realized globally. Recent initiatives such as the ‘safer supply’ policy in British Columbia in Canada provide good examples of how the nursing workforce can provide service users access to range of MOUD treatments including injectable medications [42]. Given the increasing international policy focus placed on expanding access to harm reduction interventions such as methadone, which reduce drug-related deaths [43], it is imperative that initiatives such as NP of MOUD be fully recognised and developed by legislators, policymakers and planners. In this context, there is some guidance available that clarifies the NP role and illustrates the advantages of NP to non-experts [44]. Developing greater international consensus on this, bolstered by more research, and better ‘marketing’ of the NP model would enhance awareness of the advantages of NP of MOUD even further [40].

"To build on current success, the expansion of NP of MOUD also requires ‘whole-systems’ support. In the first instance, this should start with passing the necessary legislation to allow nurse prescribing to take place [16]. Secondly, in order to ensure maximum uptake and to optimise positive impacts on service users, this legislation should allow NPs to prescribe autonomously [12, 23]. Both third-level institutions and healthcare providers also need to collaborate on how to provide the most appropriate institutional training and support, and this should incorporate ongoing education and ‘in-practice’ supervision [45, 46]. Where relevant, this education and supervision should aim to address negative attitudes of non-specialist prescribing nurses towards people who use drugs [47]. More broadly, this should involve delivering addiction education and ‘pro-social’ messaging into the nursing ‘water supply’ at the undergraduate and postgraduate levels [48]. Assurances should also be provided to potential practitioners by properly resourcing ‘joined-up’ services with adequate clinical governance and appropriate input from multi-disciplinary teams which can support practitioners in caring holistically for people with complex needs [49]. These measures should, in turn, increase the uptake of non-specialist nurse prescribers to MOUD treatment and increase the desire for more nurses to specialise in this area."

"Facility Operation
"Table 2.2 and Figure 2. The operational structure of the substance abuse treatment system (i.e., the types of entities responsible for operating facilities) had some notable changes between 2010 and 2020.

"● Private non-profit organizations operated 58 percent of all facilities in 2010, decreasing to 50 percent in 2020 [Table 2.2 and Figure 2].

"● Private for-profit organizations operated 30 percent of facilities in 2010, increasing to 41 percent of facilities in 2020 [Table 2.2 and Figure 2].

"● Local, county, or community governments operated 6 percent of facilities in 2010, decreasing to 4 percent in 2020 [Table 2.2 and Figure 2].

"● State governments operated 3 percent of facilities in 2010, decreasing to 2 percent in 2020 [Table 2.2 and Figure 2].

"● The federal government operated 2 to 3 percent of facilities each year between 2010 and 2020 [Table 2.2 and Figure 2].5

"● Tribal governments operated 1 to 2 percent of facilities each year between 2010 and 2020 [Table 2.2 and Figure 2].

"Type of Care Offered6
"Table 2.3 and Figure 3. The proportions of facilities that offered outpatient, residential (non-hospital), and hospital inpatient care were stable between 2010 and 2020. OTPs, certified by SAMHSA, provide MAT with methadone, buprenorphine, and naltrexone. Facilities with OTPs can be associated with any type of care. Facilities with OTPs made up 8 to 11 percent of all facilities between 2010 and 2020 [Table 2.4].

"● Outpatient treatment was provided by 81 to 83 percent of facilities during this period [Table 2.3].

"● Residential (non-hospital) treatment was provided by 24 to 26 percent of facilities in this period [Table 2.3].

"● Hospital inpatient treatment was provided by 5 to 6 percent of facilities during this time period [Table 2.3].

"● Outpatient treatment was provided by 90 to 95 percent of facilities with OTPs between 2010 and 2020 [Table 2.3].

"● Residential (non-hospital) treatment was provided by 7 to 9 percent of facilities with OTPs between 2010 and 2020 [Table 2.3].

"● Hospital inpatient treatment was provided by 7 to 10 percent of facilities with OTPs between 2010 and 2020 [Table 2.3].

"Facilities That Use MAT
"Table 2.4. MAT includes the use of methadone or buprenorphine for the treatment of opioid use disorder (OUD) and the use of naltrexone for relapse prevention in OUD. Methadone for OUD is available only at the OTPs that are certified by SAMHSA’s Center for Substance Abuse Treatment.7 Buprenorphine may be prescribed by physicians or other authorized medical practitioners (physicians, physician assistants, and nurse practitioners) who have received Drug Addiction Treatment Act of 2000 (DATA 2000) specific training and received a waiver to prescribe the medication for treatment of OUD; some of these authorized medical practitioners are affiliated with facilities (either OTPs or other). All medical practitioners with prescribing privileges can prescribe injectable naltrexone.

"● The proportion of OTPs that provided methadone-only treatment decreased from 52 percent of all facilities with OTPs in 2010 to 17 percent of all facilities with OTPs in 2020 [Table 2.4].

"● The proportion of OTPs that provided only methadone and buprenorphine treatment decreased from 47 percent of all facilities with OTPs in 2010 to 42 percent in 2020. Between 2012 and 2020, the proportion of facilities with OTPs that offered methadone, buprenorphine, and injectable naltrexone increased from 12 percent in 2012 to 31 percent in 2020; over the same period, the proportion of facilities that offered only buprenorphine and injectable naltrexone increased from less than 1 percent to 6 percent [Table 2.4].8

"● The proportion of facilities (either OTP or non-OTP) that provided any buprenorphine services increased from 18 percent of all facilities in 2010 to 44 percent of all facilities in 2020 [Table 2.4].

"● The percentage of all facilities that provided any extended-release injectable naltrexone treatment increased from 10 percent in 2012 to 37 percent in 2020 [Table 2.4]."

"A study in Canada found that personal beliefs of NPs often pose a barrier to providing treatment, for example, views such as patients with OUD deserve less care than other patients [12], this was also reported as a barrier in the study by Spetz and colleagues [31]. Participants on the study acknowledged that some prescribers would avoid prescribing methadone for personal reasons [12]. NPs also discussed that public stigma remains a significant barrier, one stating that “there’s stigma of just going every day to the pharmacy and being there, exposed, people staring at you…” Another NP reflected that stigma may be addressed by educating prescribers and increasing their experience of working with people with OUD. It was also reported that patient’s willingness and lack of education regarding MOUD presented as a barrier to practice [33]. Elliot and colleagues [27] conducted a quasi-experimental study in which five NP doctoral students attended lectures and 16 h of direct clinical experience with OUD patients. Students reported positive attitude changes and personal reflections which suggest that such educational experiences can be beneficial for developing more confident, skilled and compassionate NPs to address the opioid crisis."

"This study indicates that the SSP+MOUD [Syringe Service Program + Medications for Opioid Use Disorder] combination program is an effective harm-reduction strategy to prevent HCV cases among opioid IDUs and is cost-effective if payers are willing to pay $4,699 or more per avoided case of HCV. There is evidence to support the effectiveness of these harm-reduction strategies in reducing injection-risk behaviors as well as reducing HCV and HIV transmission.^17,18 The base-case analysis suggested that (a) the combination strategy, compared with SSP alone, would cost $4,699 to avoid an additional HCV case; (b) the combination and the SSP-alone groups dominated both the MOUD-alone and no intervention groups; and (c) the MOUD-alone group dominated the no intervention group.

"Most of the recent studies on the cost-effectiveness of SSP and MOUD alone and in combination were conducted outside the United States, were conducted from a societal or health care system perspective, did not directly compare the interventions used in the base case, had moderate evidence of the cost-effectiveness in some sites, estimated the outcome in terms of quality-adjusted life years, and did not examine the number of cases avoided in a 1-year time horizon.^{19,31,32,37-39} To date, studies have not examined the cost-effectiveness of these harm-reduction strategies in terms of incremental cost savings per HCV case avoided, and none has undertaken a public payer perspective in the United States.

"Based on the analysis, the combination of MOUD and SSP appears to be the most effective policy, from a public health perspective. By including both the direct medical and nonmedical costs due to injection drug use-related crime in the calculation, the combination program will save public payers $347,573 per HCV case avoided compared with costs for no intervention. SSP-alone and MOUD-alone interventions will also save public payers $363,821 and $317,428, respectively. Given that the total direct economic burden of HCV-related liver disease in the United States is estimated to be $6.5 billion ($4.3 to $8.2 billion) annually and 2.4 million people in the United States live with an HCV infection, these interventions could dramatically reduce HCV-related annual costs.^7,40,41 The savings associated with these interventions would allow public institutions to redirect funds toward other health care services or public service investments. In addition, the results indicated that all the harm-reduction strategies were less costly and more effective than no intervention even though they required some up-front investments. It is also important to point out that the largest benefits could occur in the future. This is because HCV-related liver disease such as cirrhosis and hepatocellular carcinoma may take several years to occur, and SSPs are associated with reducing the risk of other diseases transmitted via needle sharing, such as HIV.^23,26

"The 1-way sensitivity analysis shows that the base-case cost effectiveness analysis was sensitive to the probabilities of injection-risk behavior for the SSP and SSP+MOUD combination groups, probability of no HCV with no intervention, and costs of MOUD and HCV antivirals. Despite varying the model parameters by ± 50%, the base-case ICER was not sensitive to a majority of the key variables in the model. Considering that the cost for the combination intervention was assumed to be the sum of the costs of the SSP and MOUD individual interventions, our results can be considered as conservative estimates, given that in reality, savings and economies of scale can be achieved by a combination of efforts."

"Methadone is a long-acting µ-opioid receptor agonist, introduced in the 1960s, after being developed in Germany at the end of World War II.⁶⁰ It has an onset of action within 30 minutes^61-63 and an average duration of action of 24 to 36 hours. Its oral bioavailability is excellent and approaches 90%. These unique pharmacologic properties ideally lend themselves to once-daily dosing for maintenance therapy, although, when used to treat chronic pain, methadone is generally dosed 3 times daily. When the dosage is judiciously titrated, methadone treated patients generally do not experience euphoria or sedation, nor do they suffer impairment in the ability to perform mental tasks. One of the most important advantages of methadone is that it relieves narcotic craving, which is the primary reason for relapse. Similarly, methadone blocks many of the narcotic effects of heroin,⁶⁴ which helps reinforce abstinence. Once a therapeutic dose is achieved, patients frequently can be maintained for many years with the same dose.⁶⁵

"Methadone hydrochloride is available in 5- and 10-mg tablets as well as a 40-mg dispersible wafer. However, it is most frequently used for maintenance in a 10-mg/mL liquid concentrate. An intravenous solution is also available but has been linked with bradycardia when administered for sedation."

"Long-term retention on OAT in trials and observational studies is suboptimal, which limits the effect of OAT with regard to reducing drug-related deaths.¹³¹ There was consistent evidence that retention was slightly better on methadone than buprenorphine across RCTs and observational studies at timepoints beyond 1 month, although few RCTs examined long-term retention.

"The amount and reporting of other outcome data for comparisons between buprenorphine and methadone were inconsistent. There was inconsistent evidence that extra-medical opioid use and use of cocaine might be lower among people prescribed buprenorphine. Limited evidence (typically from single studies) suggested that some other outcomes might differ between buprenorphine and methadone, more commonly favouring buprenorphine, but overall there remains considerable scope for expanding evidence for many outcomes.

"Previous reviews have shown good evidence that, compared with methadone, sublingual buprenorphine has a lower risk of death due to overdose during the first month of treatment, but not after that time,¹¹ which might be linked to differences in effects on respiratory depression.⁹ Despite that risk, given the poorer retention in treatment and the absence of clear evidence of strong benefits in other areas, it is not clear that buprenorphine should yet be recommended as a first-line treatment.

"Only one observational study⁵⁴ has directly compared methadone with extended-release buprenorphine, and few studies have been published on retention in treatment with this new formulation of buprenorphine. Despite small study numbers and an absence of well powered RCTs, there are indications that retention might be higher with extended-release than sublingual buprenorphine, suggesting that the changed formulation might partly address issues related to retention; however, large-scale RCTs and real-world data showing outcomes from large-scale implementation are needed.

"Many outcomes showed no statistically significant difference between medications. Given that few differences were found between methadone and buprenorphine, other factors such as patient preference,¹³² access to unsupervised dosing, and cost¹³³ to the individual are important factors to consider. Studies should also examine the effect of an individual's medication preference on treatment outcomes, particularly retention."

"In our study, there was greater evidence for an association between substance use and chronic pain among inpatients than among MMTP [Methadone Maintenance Treatment Program] patients. Among inpatients, there were significant bivariate relationships between chronic pain and pain as a reason for first using drugs, multiple drug use, and drug craving. In the multivariate analysis, only drug craving remained significantly associated with chronic pain. Not surprisingly, inpatients with pain were significantly more likely than those without pain to attribute the use of alcohol and other illicit drugs, such as cocaine and marijuana, to a need for pain control. These results suggest that chronic pain contributes to illicit drug use behavior among persons who were recently using alcohol and/or cocaine. Inpatients with chronic pain visited physicians and received legitimate pain medications no more frequently than those without pain, raising the possibility that undertreatment or inability to access appropriate medical care may be a factor in the decision to use illicit drugs for pain."

"Virtually all drug courts (98%) reported that at least some of their participants were opioid-dependent in 2010. Prescription opioids were more frequently cited as the primary opioid problem than heroin (66% vs. 26%). This trend is particularly apparent in less densely populated areas: prescription versus heroin rates across the three population areas were: rural (76% vs. 12%), suburban (67% vs. 33%), and urban (prescription opioids less likely to be selected than heroin as the primary opioid; 38% vs. 50%); p < .01. Almost half (48%) of the drug courts estimated that more than 20% of their participants were opioid-dependent; 20% of drug courts estimated 10–20% of their participants were addicted to opioids, and 28% of drug courts estimated that 1–10% of their participants were addicted to opioids; 2% answered, “none,” and 2% reported “don’t know.” As shown in Table 3, 56% of drug courts reported at least some of their opioid dependent participants were receiving some type of MAT, 76% of urban courts, 58% of suburban, and 45% of rural courts (p<.01). Overall, 47% report that agonist medications are available under certain conditions (62% of urban courts, 48% of suburban courts, 40% of rural courts), and 18% report that naltrexone -- oral or long-acting injectable -- is available for the treatment of opioid dependence. Buprenorphine maintenance was more likely to be reported than methadone maintenance, 40% vs. 26%, respectively. Fifty percent of drug courts also reported that at least some of their participants with an alcohol disorder were receiving MAT for alcoholism: oral naltrexone (40%), extended-release naltrexone (28%); disulfiram (43%), acamprosate (30%)."

"Within a large cohort of people with opioid use disorder in New South Wales, Australia, we performed a self-controlled study to test the effect of incarceration and OAT transitions on the risk of hospitalization with injection drug use-associated bacterial infections. Compared to time between five and 52 weeks continuously living in the community, incidence of injecting-related infections increased before incarceration; was similar during the first two weeks of incarceration; and then substantially decreased among people in prison for more than three weeks. Risk was again elevated in the weeks immediately following release from prison. Compared to time between five and 52 weeks continuously receiving OAT, incidence of injecting-related infections was highest during the weeks both before and after OAT initiation and OAT discontinuation. Overall, we found that risk for injecting-related bacterial infections varies greatly within-individuals over time. Social contextual factors likely contribute to the substantially raised risks around transitions in incarceration and OAT exposure. People entering and leaving prison, and people starting and stopping OAT, may benefit from improved access to harm reduction programs and health and social services to prevent injecting-related bacterial infections. Changes in the risk of hospital admissions with injecting-related infections in and out of prison and OAT may also reflect changes in the ability to access primary and secondary health services.

"The increase in risk immediately following prison release may reflect return to injection use, poor access to health and social supports, and material deprivation (poverty and homelessness) (Binswanger et al., 2012; Joudrey et al., 2019; Treloar et al., 2021). This underscores that people leaving prison would benefit from better health, social, and economic supports, and linkages to harm reduction services and primary care. The excess risk for injecting-related infections during this time period (when compared to people injecting drugs in the community at other times, we estimate 1.45 times the risk, 95% CI 1.22-1.72) may be more modest than that seen for overdose (e.g., 2.44 times higher fatal overdose rate in a cohort study from New South Wales, Australia (Degenhardt et al., 2014); 2.76 times higher nonfatal overdose risk in a self-controlled cases series from British Columbia, Canada (Keen et al., 2021)). Incarceration often leads to loss of opioid tolerance, especially among people not receiving OAT in prison (Degenhardt et al., 2014; Joudrey et al., 2019), which likely increases overdose risk more so than infection risk. Given that the median duration of prison stay was only 16 days, excess risk of infection-related hospitalization after release may also reflect people seeking treatment outside prison for infections that initially developed before or during incarceration (Lloyd et al., 2015)."

"The findings revealed that exposures to MOUD, even if not continued throughout the six-month exposure period was associated with reduced risk of a fatal poisoning compared to non-MOUD forms of treatment and no treatment exposure. It is also clear that risk of death associated with exposure to non-MOUD forms of treatment was no less than that for no treatment; indeed, non-MOUD treatment might have produced worse outcomes than no treatment. Comparing the relative risk for the treatments for which agency-based numbers are available revealed that any exposure to methadone in the six months prior to death in 2017 was associated with 65% reduced relative risk of fatal opioid poisoning compared to exposure to any non-MOUD treatment recorded in the DMHAS database. Even more apparent, based on the available data from 2017, the relative risk of fatal opioid death in the six months following exposure to non-MOUD treatments ranged from 1.5 to 1.74 compared to no treatment. This is an unacceptably high probability for treatments that are purported to benefit patients with OUD and likely to be paid for by public tax revenues. In fact, it seems likely, based on our estimates of the number of people with OUD not exposed to treatment, that non-MOUD treatments were inferior to no treatment.

"There is a century of data demonstrating that non-MOUD treatment is followed by a high rate of relapse to opioid use – especially for morphine and heroin – approaching 90% at six months (Musto, 1999, Broers et al., 2000, Heimer et al., 2019). Relapse rates for those regularly using fentanyl may be even higher (Stone et al. 2018). There is ample evidence from the U.S. and elsewhere that longer-term non-MOUD treatments place those who relapse at an especially high risk of opioid overdose and death.(Strang, Beswick and Gossop, 2003; Wakeman et al. 2020). There is also compelling evidence that agonist MOUD decreases opioid-involved and all-cause mortality (Santo et al. 2021), and nearly thirty years of evidence that methadone reduces HIV-related mortality (Fugelstad et al., 1995, Parashar et al., 2016, Sordo et al., 2017). Our analysis was based on exposures to treatment, not their completion or retention, therefore our findings indicate that exposures to agonist MOUD treatment convey more benefit that non-MOUD even if the treatment is incompletely adhered to or terminated."

"At midyear 2019, fewer than two-thirds (63%) of local jail jurisdictions conducted opioid use disorder (OUD) screenings at intake and more than half (54%) of jail jurisdictions provided inmates medications to treat opioid withdrawal (figure 1). Nearly a quarter (24%) of jail jurisdictions continued medication-assisted treatment (MAT) for OUD for persons admitted with a current prescription or for those who were getting services from a methadone clinic prior to admission. Nearly a fifth (19%) of jail jurisdictions initiated MAT. A quarter (25%) of jail jurisdictions provided overdose reversal medications upon release to persons with OUD."

"At midyear 2019, the highest percentage of confined persons receiving MAT was reported in jails in the Northeast (3%), followed by jails in the Midwest and West (1% each) and jails in the South (0.4%) (table 7). Jails in the South accounted for more than half (53%) of the confined jail population at midyear 2019 but nearly a quarter (24%) of jail inmates receiving MAT (not shown in tables). In comparison, jails in the Northeast accounted for 10% of confined persons but 32% of those receiving MAT (not shown in tables). 

"Jail jurisdictions holding fewer than 50 inmates reported the highest percentage of confined persons at midyear 2019 receiving MAT (2%), while jail jurisdictions in each group holding 50 or more inmates reported fewer than 1%. Fewer than 1% of persons confined in urban and rural jails were receiving MAT at midyear 2019.

"Jails located in states with the highest rates of opioid overdose deaths (24.0 or more per 100,000 U.S. residents ages 15 to 74) reported the highest percentage of confined persons receiving MAT (1.4%). In comparison, jails located in states with the lowest rates of opioid overdose deaths (fewer than 10.0 per 100,000) reported the lowest percentage of confined persons receiving MAT (0.3%). 

"About 5% of persons confined in jails in New Mexico, 4% in New Jersey and Washington, and 3% in New York were receiving MAT for OUD (map 6; appendix table 5). A total of 31 states reported that fewer than 1% of their midyear 2019 confined jail population were receiving MAT, of which 20 states reported fewer than 0.5%."

"Although model projections can only provide estimates of health benefits and costs, such analyses can provide intuition around critical mechanisms and assumptions to inform decision making. Our main finding is that, over 20 y, high coverage (enrollment of 50% of the eligible population) of OAT [Opioid Agonist Therapy], NSPs [Needle and Syringe Programs], and Test & Treat in combination could avert nearly 43,400 (95% CI: 23,000, 74,000) HIV infections among PWID [People Who Inject Drugs] and reduce HIV prevalence among PWID by 27% (95% CI: 12%, 45%). The construction of such a portfolio has the potential to be cost-effective at each incremental expansion, with projected ICERs below US$50,000 per QALY [Quality-Adjusted Life Year] gained. Moreover, our analysis suggests that the estimated benefit obtainable by PrEP alone (measured in QALYs) could potentially be achieved and even surpassed at substantially lower cost by combining other prevention interventions into high-value portfolios.

"Advocates for efficient investment in PWID-specific interventions have asked, “What good is preventing HIV if we do not first save that life at HIV risk?” [77]. Our analysis suggests that the high competing mortality risks of PWID can explain why interventions that immediately improve quality of life can have substantially higher estimated benefits than those that focus on HIV prevention alone. Our analysis estimates that OAT, in particular, which we assume has a direct impact on the length and quality of life of treated individuals [27,28,30–32,60,61], can provide substantially more benefit, measured in QALYs, than other interventions, even when it prevents fewer infections (Table 2).

"Although our analysis did not identify a scenario in which OAT was not a cost-effective addition to a high-value portfolio, deterministic and probabilistic sensitivity analyses can provide intuition regarding scenarios in which NSPs could replace OAT as the priority investment. Because the assumed delivery cost of NSPs is so much lower than that of other programs, our findings suggest that it is reasonable to invest in NSPs concurrent with OAT scale-up. While Test & Treat is often estimated in our analysis to be a cost-effective addition to the portfolio, our model does not project it to be a priority investment. Our estimates for ART’s reduction of transmission risk via injection-based contact [13,44] are lower than those for sexual contact [14,41,44], which may explain our projection of smaller benefits in the PWID population. It should also be noted that HIV prevalence in US PWID is less than 10% [18], and the direct QALY increases from Test & Treat programs were therefore low relative to programs that served the entire PWID population."

"This study demonstrates that buprenorphine treatment is concentrated among white persons and those with private insurance or use self-pay. This finding in nationally representative data builds on a previous study that reported buprenorphine treatment disparities on the basis of race/ethnicity and income in New York City.² It is unclear whether the appearance of a treatment disparity may reflect different prevalence in OUD by race/ethnicity. We did not restrict the analysis to individuals with OUD because the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey are unlikely to accurately capture OUD prevalence, but a recent analysis of the National Survey on Drug Use and Health suggests that the prevalence of opioid misuse is similar for black (3.5%) and white (4.7%) adults.⁴

"Despite the enactment of both mental health parity legislation and Medicaid expansion, the proportion of self-pay buprenorphine visits remained relatively steady across the study period.⁵ A recent study demonstrated that half of the physicians prescribing buprenorphine in Ohio accepted cash alone,⁶ and our findings suggest that this practice may be widespread and may be associated with additional financial barriers for low-income populations.

"This study provides a snapshot of the national differences in buprenorphine treatment for OUD. With rising rates of opioid overdoses, it is imperative that policy and research efforts specifically address racial/ethnic and economic differences in treatment access and engagement."

"Forty-one percent of local jail jurisdictions initiated behavioral or psychological treatment for OUD, 24% continued MAT for persons admitted with a current prescription or getting services from a methadone clinic prior to admission, and 19% initiated MAT for inmates with OUD at midyear 2019. Regardless of region, jail jurisdiction size, locality, or opioid overdose death rate, larger percentages of jail jurisdictions initiated behavioral or psychological treatment for OUD than initiated or continued MAT. 

"In states with 24.0 or more opioid overdose deaths per 100,000 U.S. residents ages 15 to 74, 28% of jail jurisdictions continued MAT, while 25% initiated MAT. In states with fewer than 10.0 opioid overdose deaths per 100,000, 19% of jail jurisdictions continued MAT and 13% initiated MAT for OUD."

"Opioid substitution therapy (OST) is an evidence-based treatment for opioid dependency, with treatment engagement shown to be protective against drug related deaths (Santo et al., 2021). In England, the primary OST medications prescribed are methadone and buprenorphine, with provision ranging from daily supervised consumption at pharmacy services to take-home weekly doses. There were an estimated 261,294 people dependent on opioids in the England in 2017 (Hay, Rael de Santos, Reed, & Hope, 2017) with approximately 140,599 (or 54%) receiving OST (OHID, 2021). Barriers to ‘treatment engagement’ for the 46% of those who are not receiving OST can include concerns regarding disclosure; experiences or fears of stigmatising treatment; geographical isolation; reluctance or inability to engage with often inflexible treatment requirements; poor treatment access/availability and/or dislike of medication effects (ACMD, 2015; Harris & Rhodes, 2013; Marshall, Maina, & Sherstobitoff, 2021). People who are multiply marginalised, including women who use drugs, those who are unstably housed, living with multiple social problems, and/or cycling through the criminal justice system can face additional barriers to treatment access and be at highest risk of a drug related death (Medina-Perucha et al., 2019; Public Health England, 2018). It is crucial therefore, that treatment systems are more responsive and innovative to engage the most vulnerable, reduce health harms and risk of premature mortality."

"In the 12 months after a nonfatal overdose, 2040 persons (11%) enrolled in MMT for a median of 5 months (interquartile range, 2 to 9 months), 3022 persons (17%) received buprenorphine for a median of 4 months (interquartile range, 2 to 8 months), and 1099 persons (6%) received naltrexone for a median of 1 month (interquartile range, 1 to 2 months). Among the entire cohort, all-cause mortality was 4.7 deaths (95% CI, 4.4 to 5.0 deaths) per 100 person-years and opioid-related mortality was 2.1 deaths (CI, 1.9 to 2.4 deaths) per 100 person-years. Compared with no MOUD, MMT was associated with decreased all-cause mortality (adjusted hazard ratio [AHR], 0.47 [CI, 0.32 to 0.71]) and opioid-related mortality (AHR, 0.41 [CI, 0.24 to 0.70]). Buprenorphine was associated with decreased all-cause mortality (AHR, 0.63 [CI, 0.46 to 0.87]) and opioid-related mortality (AHR, 0.62 [CI, 0.41 to 0.92]). No associations between naltrexone and all-cause mortality (AHR, 1.44 [CI, 0.84 to 2.46]) or opioid-related mortality (AHR, 1.42 [CI, 0.73 to 2.79]) were identified."

"However, one problem markedly reduces naltrexone’s efficacy and has limited its use for treating heroin and other forms of opioid dependence worldwide: patients often do not like it and do not take it on a daily basis. The dropout rate with oral naltrexone has been better in the limited number of patients in whom there is substantial external motivation to remain abstinent, such as physicians who are in monitoring programs and could lose their license if they relapse, those involved in the criminal justice system who could go to prison if they relapse, and those facing loss of employment [1•, 2–4].

"A few US studies have shown positive effects with psychosocial or behavioral therapies. In two, contingency management combined with naltrexone was helpful [5, 6]. In another, naltrexone combined with individual [7] and group [2] psychotherapy yielded positive effects. A third tested a behavioral therapy that used rewards for negative urine tests [8]; however, it had a relatively limited effect and was identified by Nunes et al. [9] as one of several examples indicating that there appears to be a ceiling effect on the degree to which behavioral interventions can be used to improve naltrexone treatment outcomes."

"Originally approved for use in the treatment of opioid dependence by the United States Food and Drug administration (FDA) in 1984, naltrexone is a competitive ?-opioid receptor antagonist with negligible agonist effects, blocking euphoric and physiological effects of opioid agonists.^11,12 Naltrexone does not cause the development of dependence or tolerance over time, and dosing cessation does not result in withdrawal.¹³

"Orally dosed naltrexone is subject to first pass metabolism, where it is converted to active (6-? naltrexol) and inactive metabolites.¹⁴ ­First-pass metabolism of orally dosed naltrexone is high, evidenced by the peak dose of naltrexone and its ­metabolites 1 hour after oral dosing.15 Serum ­half-life for chronic oral administration is approximately 10 hours.¹⁵ The half-life, when compared to naloxone, another ?-opioid antagonist, is longer, and naltrexone is able to block the agonist effects of other opioids for 48 hours.¹⁶ Oral dosing is accomplished by either 50 mg daily dosing or three times weekly dosing with two 100 mg doses and one 150 mg dose."

"In 2016 only 13.8 percent of substance use treatment programs accepted Medicare and offered an FDA-approved medication for opioid use disorder treatment (exhibit 1). While the percentage of programs that offered such treatment was low across all insurance types (24.8 percent among programs that accepted Medicaid and 28.6 percent among programs that accepted private insurance), access for Medicare beneficiaries was nearly twice as limited. Furthermore, just 20.8 percent of US counties—home to roughly 60 percent of the Medicare population—had at least one treatment program that accepted Medicare and offered buprenorphine or injectable naltrexone for older adults (exhibit 2). The majority of counties with at least one treatment program that accepted Medicare and offered an opioid use disorder treatment medication (65.1 percent) were in urban areas (data not shown). In 2016, 36.4 percent of treatment programs accepted Medicare, compared to 63.7 percent that accepted Medicaid and 70.3 percent that accepted private insurance. Of the treatment programs that accepted private insurance, 46.5 percent also accepted Medicare. Of those that accepted Medicaid, 52.1 percent also accepted Medicare."

"Findings from a 24-week randomized controlled trial comparing extended-release injectable naltrexone (Vivitrol, Alkermes) to placebo in individuals with current opioid dependence have been considered in the recent indication for extended-release injectable naltrexone for the treatment of opioid dependence. In this trial, subjects having completed 30-day detoxification were recruited from 13 sites in Russia received either 380 mg intramuscular injections of extended-release naltrexone (n = 126) or placebo injection (n = 124) every 4 weeks for 24 weeks. Primary outcome data of opioid abstinence, measured by urine and self-report as well as secondary data including opioid craving, dependence relapse and study ­retention were measured. Opioid-free weeks from week 5 to 24 were significantly different between treatment groups (P, 0.0002), with a median of 90% percent of opioid-free urines in the extended-release ­ naltrexone group and 35% in the placebo group. Total ­abstinence measured as 100% opioid-free weeks in weeks 5 through 24 was 35.7% in the extended-release ­naltrexone group versus 22.6% in the placebo group. With extended-release naltrexone, subjects reported a 50% mean reduction in ­subjective craving compared with no change in craving for subjects receiving placebo, and retention in the extended-release naltrexone group was significantly longer compared to the placebo group (168 days vs. 96 days, P = 0.0042).⁴³"

"Three primary scenarios characterize current reports of methadone-associated mortality:

"1. In the context of legitimate patient care, methadone accumulates to harmful serum levels during the first few days of treatment for addiction or pain (that is, the induction period before methadone steady state is achieved or tolerance develops).

"2. Illicitly obtained methadone is used by some individuals who have diminished or no tolerance to opioids and who may use excessive and/or repetitive doses in an attempt to achieve euphoric effects.

"3. Methadone - either licitly administered or illicitly obtained - is used in combination with other CNS depressant agents (such as benzodiazepines, alcohol, or other opioids)."

"Pain was very prevalent in representative samples of 2 distinct populations with chemical dependency, and chronic severe pain was experienced by a substantial minority of both groups. Methadone patients differed from patients recently admitted to a residential treatment center in numerous ways and had a significantly higher prevalence of chronic pain (37% vs. 24%). Although comparisons with other studies of pain epidemiology are difficult to make because of methodological differences, the prevalence of chronic pain in these samples is in the upper range reported in surveys of the general population. The prevalence of chronic pain in these chemically dependent patients also compares with that in surveys of cancer patients undergoing active therapy, approximately a third of whom have pain severe enough to warrant opioid therapy."

"The large contribution to mortality from oxycodone and methadone may be because of the long duration of action of methadone and OxyContin. Drug users may accidentally overdose by overlapping doses when the desired euphoric or analgesic effect is slow in coming. Abusers have learned to ingest and inject pulverized OxyContin pills, defeating the controlled-release mechanism and releasing dangerous amounts of the drug within a short time."

"In this trial, patients assigned to receive injectable diacetylmorphine were more likely to stay in treatment and to reduce their use of illegal drugs and other illegal activities than patients assigned to receive oral methadone. These findings are consistent with the results of European studies that suggest greater effectiveness of diacetylmorphine than methadone as maintenance treatment for long-term, treatment-refractory opioid use.^10,12,13 Two of these trials showed no differences between groups in the rate of retention in treatment for addiction. However, the fact that control patients were eligible to receive diacetylmorphine at the end of the study period may have introduced a bias in the observed retention rates. In addition, patients currently enrolled in methadone maintenance treatment were eligible for the European trials but not for the present study. Although the definitions of clinical response varied among the trials, all of them considered the same variables (drug use, illegal activities, health, and social adjustment) and showed greater effectiveness of diacetylmorphine than of methadone for maintenance treatment.

"Secondary analyses showed that both groups had significant improvement in many of the variables that were evaluated. The diacetylmorphine group had greater improvements with respect to medical and psychiatric status, economic status, employment situation, and family and social relations. These results are particularly noteworthy in view of the nature of the population and the time frame. The fact that patients who received diacetylmorphine had significant improvement in these areas suggests a positive treatment effect beyond a reduction in illicit-drug use or other illegal activities."

"Despite the ease of outpatient dosing and its ability to effectively block the euphoric effects of ?-opioid agonists, naltrexone has had limited success for relapse prevention when compared with maintenance t­herapy with methadone or buprenorphine. Studies have shown that fewer patients choose to start t­reatment with naltrexone,²¹ and few of those remain compliant with medications.^22,23 Patients who have been treated previously with methadone are also less likely to sustain opioid abstinence with naltrexone compared with individuals who had only had naltrexone for treatment of opioid dependence.^24–26 Poor compliance with naltrexone is also associated with higher dosages of heroin used daily.²⁶ Of patients in treatment with naltrexone, many drop out quickly within the first few weeks, especially if they used opioids again after missing ­ naltrexone doses.²⁷ The numbers of drop-outs from naltrexone treatment are very high, with over one quarter dropping out after a few days,²⁸ and almost one-half dropping out in first few weeks.²⁹"

"The unnecessary regulations of methadone maintenance therapy and other long-acting opiate agonist treatment programs should be reduced, and coverage for these programs should be a required benefit in public and private insurance programs."

"Facilities were asked how many clients in treatment on March 31, 2016, received medication-assisted opioid therapy drugs for detoxification or maintenance purposes. MAT includes the use of methadone and buprenorphine for the treatment of opioid addiction or dependence, and the use of extended-release injectable naltrexone (Vivitrol®) for relapse prevention in opioid addiction. Methadone is available only at OTP facilities that are certified by SAMHSA’s Center for Substance Abuse Treatment. Buprenorphine may be prescribed by physicians who have received DATA 2000 specific training and received a waiver to prescribe the medication for treatment of opioid addiction; some of these physicians are affiliated with facilities (either OTPs or other).22 All physicians or approved medical personnel can prescribe extended-release injectable naltrexone (Vivitrol®).

"• Of the total 1,150,423 clients in treatment, 365,064 (32 percent) received MAT in OTP facilities.
"• There were 345,443 clients receiving methadone in OTP facilities.
" • Of the clients receiving methadone, 215,576 clients (62 percent) were provided treatment at private for-profit OTPs and 109,504 clients (32 percent) were provided treatment at private non-profit OTPs.
"• There were 18,716 clients receiving buprenorphine in OTP facilities and 42,770 clients receiving buprenorphine in non-OTP facilities.
" • Of the clients receiving buprenorphine in OTPs, 12,495 clients (67 percent) were provided treatment at private for-profit OTPs and 4,675 clients (25 percent) were provided treatment at private non-profit OTPs.
" • Of the clients receiving buprenorphine in non-OTP facilities, 19,309 clients (45 percent) were provided treatment at private for-profit non-OTPs and 18,117 clients (42 percent) were provided treatment at private non-profit non-OTPs.

"• There were 905 clients receiving extended-release injectable naltrexone (Vivitrol®) in OTP facilities and 9,223 clients receiving extended-release injectable naltrexone (Vivitrol®) in non-OTP facilities.
" • Of the clients receiving extended-release injectable naltrexone (Vivitrol®) in OTPs, 500 clients (55 percent) were provided treatment at private non-profit OTPs and 251 clients (28 percent) were provided treatment at private for-profit OTPs.
" • Of the clients receiving extended-release injectable naltrexone (Vivitrol®) in non-OTP facilities, 4,464 clients (48 percent) were provided treatment at private non-profit non-OTPs and 3,085 clients (33 percent) were provided treatment at private for-profit non-OTPs."

Heroin
"• Heroin was reported as the primary substance of abuse for 26 percent of TEDS admissions aged 12 and older in 2015 [Table 1.1b].

"• Sixty-seven percent of primary heroin admissions were non-Hispanic White (41 percent were males and 26 percent were females). Non-Hispanic Blacks made up 14 percent (9 percent were males and 5 percent were females). Admissions of Puerto Rican origin made up 7 percent of primary heroin admissions (6 percent were males and 1 percent were females) [Table 2.3b]. See Chapter 3 for additional data on heroin admissions.

"• Injection was reported as the usual route of administration by 68 percent of primary heroin admissions; inhalation was reported by 25 percent. Daily heroin use was reported by 63 percent of primary heroin admissions [Table 2.4b].

"• Twenty-two percent of primary heroin admissions had no prior treatment episode, and 25 percent had been in treatment five or more times previously [Table 2.5b].

"• Primary heroin admissions were less likely than all admissions combined to be referred to treatment by the court/criminal justice system (14 vs. 30 percent) and more likely to be self or individually referred (61 vs. 41 percent) [Table 2.6b].

"• Medication-assisted opioid therapy was planned for 37 percent of heroin admissions [Table 2.7b].

"• Only 17 percent of primary heroin admissions aged 16 and older were employed (vs. 25 percent of all admissions that age); 45 percent were not in labor force (vs. 39 percent of all admissions that age) [Table 2.8b].

"• Sixty-one percent of primary heroin admissions reported abuse of additional substances. Marijuana/hashish was reported by 18 percent, alcohol by 14 percent, and non-smoked cocaine by 13 percent [Table 3.8].

Opiates Other than Heroin
"• Opiates other than heroin were reported as the primary substance of abuse for 8 percent of TEDS admissions aged 12 and older in 2015 [Table 1.1b]. These drugs include methadone, buprenorphine, codeine, hydrocodone, hydromorphone, meperidine, morphine, opium, oxycodone, pentazocine, propoxyphene, tramadol, and any other drug with morphine-like effects.

"• Admissions for primary opiates other than heroin were more likely than all admissions combined to be aged 20 to 39 (74 vs. 58 percent) [Table 2.1b].

"• Non-Hispanic Whites made up approximately 82 percent of admissions for primary opiates other than heroin (43 percent were males and 39 percent were females) [Table 2.3b].

"• The usual route of administration most frequently reported by admissions of primary opiates other than heroin was oral (61 percent); next were inhalation (18 percent) and injection (16 percent) [Table 2.4b].

"• Admissions for primary opiates other than heroin were more likely than all admissions combined to report first use after age 18 (66 vs. 39 percent) [Table 2.5b].

"• Medication-assisted opioid therapy was planned for 31 percent of admissions for primary opiates other than heroin [Table 2.7b].

"• Fifty-eight percent of admissions for primary opiates other than heroin reported abuse of other substances. The most commonly reported secondary substances of abuse were marijuana/hashish (22 percent), alcohol (16 percent), and tranquilizers (12 percent) [Table 3.8]."

"Nationally, in 2012, the rate of opioid abuse or dependence was 891.8 per 100,000 people aged 12 years or older compared with national rates of maximum potential buprenorphine treatment capacity and patients receiving methadone in OTPs of, respectively, 420.3 and 119.9. Among states and the District of Columbia, 96% had opioid abuse or dependence rates higher than their buprenorphine treatment capacity rates; 37% had a gap of at least 5 per 1000 people. Thirty-eight states (77.6%) reported at least 75% of their OTPs were operating at 80% capacity or more."

"In 2011, 9 percent of all substance treatment facilities had OTPs (Figure 1). This percentage has consistently been between 8 and 9 percent since 2001, when the Substance Abuse and Mental Health Services Administration began certifying OTPs. While the number of facilities with OTPs has remained constant at around 1,100 to 1,200 since 2003, the number of clients receiving methadone on the survey reference date⁵ increased from about 227,000 in 2003 to over 306,000 in 2011 (Figure 2). Clients receiving treatment with methadone accounted for approximately 21 to 25 percent of all substance abuse treatment clients each year. The increase in the number of clients receiving methadone treatment coupled with the stability of the proportion of clients receiving this treatment suggest that the overall availability of methadone treatment has increased over time."

"As compared with patients taking low-dose methadone, those taking levomethadyl acetate had a significantly higher rate of continuous abstinence from opioids, and those taking high-dose methadone and buprenorphine had a trend toward a higher rate of continuous abstinence."

Effectiveness of Opioid Substitution Treatment (OST)

"In summary, levomethadyl acetate, buprenorphine, and high-dose methadone were more effective than low-dose methadone in reducing the use of illicit opioids. As compared with low-dose methadone, levomethadyl acetate produced the longest duration of continuous abstinence; buprenorphine administered three times weekly was similar to levomethadyl acetate in terms of study retention and was similar to high-dose methadone in terms of abstinence."

"The unparalleled international epidemic of injection drug use as a major cause of global HIV transmission, coupled with the research evidence supporting the efficacy of methadone treatment in decreasing drug injection and HIV transmission, and the unique pharmacological properties and potential acceptance of buprenorphine and the buprenorphine/naloxone combination, mean that the world is poised for implementation and evaluation of these treatments as a method to stem the spread of HIV."

"There is evidence from published and unpublished observational studies that opiate substitution treatment is associated with an average 54% reduction in the risk of new HIV infection among people who inject drugs. There is weak evidence to suggest that greater benefit might be associated with longer measured duration of exposure to opiate substitution treatment. All of the eligible studies examined the impact of methadone maintenance treatment, indicating that there are few data regarding the impact of buprenorphine or other forms of non-methadone opiate substitution treatment in relation to HIV transmission. We found no evidence that methadone detoxification is associated with a reduction in the risk of HIV transmission."

A study reported in the March 8, 2000 edition of the Journal of the American Medical Association showed that traditional methadone maintenance therapy (MMT) is superior to both short-term and long-term detoxification treatment as a method to treat heroin dependence, concluding, "Our results confirm the usefulness of MMT in reducing heroin use and HIV risk behaviors. Illicit opioid use continued in both groups, but frequency was reduced. Results do not provide support for diverting resources from MMT into longterm detoxification."

"Our results support the hypothesis that harm-reduction-based methadone maintenance treatment decreases the risk of natural-cause and overdose mortality. Furthermore, our data suggest that in harm- reduction-based methadone programs, being in methadone treatment is important in itself, independent of the pharmacologic effect of methadone dosage. To decrease mortality among drug users, prevention measures should be expanded for those who dropout of treatment."

"Methadone maintenance treatment (MMT) has been shown to improve life functioning and decrease heroin use; criminal behavior; drug use practices, such as needle sharing, that increase human immunodeficiency virus (HIV) risk; and HIV infection."

"Over the past two decades, clear and convincing evidence has been collected from multiple studies showing that effective treatment of opiate dependence markedly reduces the rates of criminal activity. Therefore, it is clear that significant amounts of crime perpetrated by opiate dependent persons are a direct consequence of untreated opiate dependence."

"MMT [methadone maintenance treatment] facilitates a process of gradual reduction in heroin use, reduction of syringe sharing and HIV risk, and reduction of criminal activities."

According to the National Institutes of Health (NIH), "Methadone maintenance treatment is effective in reducing illicit opiate drug use, in reducing crime, in enhancing social productivity, and in reducing the spread of viral diseases such as AIDS and hepatitis."

"Although a drug-free state represents an optimal treatment goal, research has demonstrated that this goal cannot be achieved or sustained by the majority of opiate-dependent people. However, other laudable treatment goals, including decreased drug use, reduced criminal activity, and gainful employment can be achieved by most MMT [methadone maintenance treatment] patients."

The New England Journal of Medicine published a study comparing methadone with LAAM and buprenorphine. The authors concluded that "Levomethadyl acetate, buprenorphine, and high-dose methadone were all effective in treating opioid dependence and were were superior on multiple measures to low-dose methadone. The percentage of patients retained at 17 weeks compared favorably with rates reported elsewhere for these medications."

An editorial in the March 8, 2000, edition of The Journal of the American Medical Association states that following the Scottish example and allowing primary care physicians to dispense methadone "can provide a 3- to 5-fold increase in access. It can also reduce the cost per patient, although added access will clearly increase short-term substance abuse treatment costs while reducing long-term costs associated with overdose emergencies, HIV infection, and crime."

"Government agencies and professional societies,* including the American Society of Addiction Medicine, have recommended against using AAROD in clinical settings (9). There is insufficient knowledge regarding how widely AAROD is used in the United States and the frequency of AAROD-associated adverse events in community practice settings. At least seven deaths occurred following AAROD among 2,350 procedures performed in one practice during 1995–1999.†
"The New York City clinic investigation revealed that AAROD was performed on 75 patients during January–September 2012 and was associated with two deaths and five additional adverse events requiring hospitalization, a serious adverse event rate of 9.3%. No standard protocol exists for AAROD; however, the clinic’s practice was consistent with AAROD use described elsewhere (7). All events occurred after and in close temporal proximity to AAROD. Although a common mechanism linking these events to AAROD is not evident, the events are consistent with previously proposed mechanisms of AAROD-associated adverse events, including electrolyte disturbance, catecholamine release, altered cardiopulmonary functioning, acute lung injury, and other physiologic effects associated with administration of high doses of opioid antagonists under general anesthesia (10). Given the ongoing epidemic of prescription opioid dependence, further increases in the demand for substance use disorder services are to be expected. AAROD has substantial risks, including a risk for death, and little to no evidence to support its use. Safe, evidence-based treatments of opioid dependence (e.g., MAT [Medication-Assisted Treatment]) exist and are preferred (2)."

^{* Additional information available at http://www.nice.org.uk/. Care Med 2000;28:969–76.
† Additional information available at http://njlaw.rutgers.edu/coll….}

Office-Based Opioid Substitution Treatment (OBOT)

"This study has implications for future treatment of opioid dependence. First, the results support the feasibility of transferring stable patients from NTPs to the offices of trained primary care physicians and extends prior research in this field. These findings, along with recent trials demonstrating the effectiveness of buprenorphine for untreated opioid-dependent patients in primary care settings, offer encouragement regarding the use of primary care offices to help expand access to treatment for opioid dependence."

"Our results demonstrate that methadone maintenance using weekly physician office-based dispensing is feasible, that treatment retention and patient and clinician satisfaction are high, and that illicit drug use does not differ significantly compared with continued treatment in an NTP [narcotic treatment program]. Stable patients demonstrated high functional status and low levels of health and social service use on transfer from an NTP to office-based care. The high level of patient and clinician satisfaction with office-based care and the outcomes observed with office-based treatment run counter to concerns regarding the potential quality of this type of care and the ability to identify a group of physicians interested in providing treatment for opioid-dependent patients."

"Office-based methadone maintenance administered by appropriately trained primary care and specialist physicians has the potential to provide an alternative for selected patients to the current narcotic treatment system that would allow for greater physician involvement and perhaps increased quality of care. Potential benefits from this type of care include increased attention to comorbid medical and psychiatric conditions, decreased stigma associated with the diagnosis and treatment, decreased contact with active heroin users, and increased access to treatment. These benefits may increase patient satisfaction and enhance clinical outcomes."

Researchers from Yale University "investigated the use of counseling and different frequencies of medication dispensing in primary care treatment with buprenorphine-naloxone. Neither the primary outcomes (the frequency of illicit opioid use, the percentage of opioid-negative urine specimens, and the maximum number of consecutive weeks of abstinence from illicit opioids) nor the proportion of patients who completed the study differed significantly among the three groups. Specifically, outcomes among patients receiving brief counseling combined with once-weekly medication dispensing did not differ significantly from outcomes among patients receiving either extended counseling or thrice-weekly medication dispensing did not differ significantly from outcomes among patients receiving either extended counseling or thrice-weekly medication dispensing. Patient satisfaction was significantly higher with once-weekly than with thrice-weekly medication dispensing, although because of the large number of statistical tests conducted, this may represent a chance finding."

"Consistent with the findings of previous research with buprenorphine,^1-4 the frequency of illicit opioid use decreased significantly from baseline to induction and was lowest during maintenance for all three groups. The mean percentages of patients who completed the 24-week study, which ranged between 39 and 48 percent, were similar to those found in previous studies, including one conducted in an office-based setting.^1-4 Therefore, the majority of patients who entered this study either left treatment or were considered appropriate for transfer to a more structured treatment setting with methadone. Nonetheless, although we did not demonstrate the superiority of extended counseling or thrice-weekly medication dispensing over the relatively limited nurse-administered counseling and once-weekly dispensing, our findings support the feasibility of buprenorphine–naloxone maintenance in primary care.^10,13,21"

"Opioid dependence and addiction, whether to heroin or prescription pain relievers, is a serious, life-threatening medical condition. Methadone and buprenorphine are medications that permit addicted individuals to function normally within their families, jobs, and communities. While treatment with methadone is more established, it requires daily visits to an OTP. Not all individuals who could benefit from methadone treatment live within easy travelling distance of an OTP. Furthermore, the requirement for daily visits can interfere with jobs and other important activities. The introduction of buprenorphine for the treatment of opioid dependence has provided an alternative to methadone treatment for some opioid dependent persons; however, buprenorphine may not be appropriate for all opioid-addicted persons. The dramatic increase in the number of clients receiving buprenorphine through treatment facilities is an indication of the demand for safe and effective medications for the treatment of opioid addiction in the context of a broader treatment program."

The New England Journal of Medicine published a study comparing methadone with LAAM [levomethadyl acetate] and buprenorphine. According to the report, "Most of the development and evaluation research on buprenorphine has been based on daily doses. Our study used thrice-weekly doses and found that outcomes were approximately equivalent to those with either daily methadone or thrice-weekly levomethadyl acetate. Thus, thrice-weekly buprenorphine may also offer greater convenience to patients and clinic staff."

"Studies conducted in St. Petersburg, Russia, for more than a decade have demonstrated the efficacy and safety of different naltrexone formulations (oral, implantable, injectable) for relapse prevention and maintenance of abstinence in detoxified opioid addicts. The positive results from different formulations seem related to two cultural factors. One is that relatives can be recruited to supervise daily dosing of the oral formulation. However, this advantage is decreasing as the addicted population ages. The second is that substitution therapy is not available; thus, naltrexone is the only effective medication available, which makes it easier to motivate patients to use it. Preliminary findings from studies of long-acting, slow-release formulations of naltrexone (implantable and injectable) suggest that they are more effective than the oral formulations and are likely to be important additions to current treatments. How they compare with maintenance treatment using methadone or buprenorphine in settings in which these three treatment options are available is a topic for future studies."

"Taken together, the data confirm a correlation between increased methadone distribution through pharmacy channels and the rise in methadone-associated mortality. The data, thus, support the hypothesis that the growing use of oral methadone, prescribed and dispensed for the outpatient management of pain, explains the dramatic increases in methadone consumption and the growing availability of the drug for diversion to illicit use. Although the data remain incomplete, National Assessment meeting participants concurred that methadone tablets and/or diskettes distributed through channels other than OTPs most likely are the central factor in methadone-associated mortality."

"The current narcotic treatment system is able to provide the most effective medical treatment for opioid dependence, opioid agonist maintenance, to only 170,000 of the estimated 810,000 opioid-dependent individuals in the United States."

"The financial costs of untreated opiate dependence to the individual, the family, and society are estimated to be approximately $20 billion per year."

"Federal statute, the Drug Addiction Treatment Act of 2000 (DATA 2000), has established a new paradigm for the medication-assisted treatment of opioid addiction in the United States (Drug Addiction Treatment Act of 2000). Prior to the enactment of DATA 2000, the use of opioid medications to treat opioid addiction was permissible only in federally approved Opioid Treatment Programs (OTPs) (i.e., methadone clinics), and only with the Schedule II opioid medications methadone and levo-alpha-acetyl-methadol (LAAM), which could only be dispensed, not prescribed.* Now, under the provisions of DATA 2000, qualifying physicians in the medical office and other appropriate settings outside the OTP system may prescribe and/or dispense Schedule III, IV, and V opioid medications for the treatment of opioid addiction if such medications have been specifically approved by the Food and Drug Administration (FDA) for that indication. (The text of DATA 2000 can be viewed at http://www.buprenorphine.samh….) [NOTE: as of January 2019 that link was no longer valid. The new URL is https://www.ncbi.nlm.nih.gov/…]

"In October 2002, FDA approved two sublingual formulations of the Schedule III opioid partial agonist medication buprenorphine for the treatment of opioid addiction. These medications, Subutex® (buprenorphine) and Suboxone® (buprenorphine/naloxone), are the first and, as of this writing, the only Schedule III, IV, or V medications to have received such FDA approval and, thus, to be eligible for use under DATA 2000."

"Buprenorphine is a long-acting partial opioid agonist^91,92 that is classified as a Schedule III narcotic, in contrast to methadone and levomethadyl, which are Schedule II. Its potential advantages include a higher degree of safety than with methadone, coupled with an ameliorated withdrawal syndrome. This is due to its partial agonist property at the ?-receptor along with its being a weak antagonist at the k-receptor.^93-95 It is available in a tablet form for sublingual administration and in parenteral form. Buprenorphine is metabolized through the cytochrome P450 pathway.^96-97 The brand name for the buprenorphine monotablet is Subutex, and the combination buprenorphine hydrochloride–naloxone hydrochloride tablet is Suboxone (both Reckitt Benckiser Pharmaceuticals, Richmond, Va). Both formulations come in strengths of 2 and 8 mg. The combination product contains 0.5mg of the opioid antagonist naloxone hydrochloride and is designed to decrease the potential for abuse."

"Buprenorphine can be used for either longterm maintenance or for medically supervised withdrawal (detoxification) from opioids. The preponderance of research evidence and clinical experience, however, indicates that opioid maintenance treatments have a much higher likelihood of long-term success than do any forms of withdrawal treatment. In any event, the immediate goals in starting buprenorphine should be stabilization of the patient and abstinence from illicit opioids, rather than any arbitrary or predetermined schedule of withdrawal from the prescribed medication."

"A number of clinical trials have established the effectiveness of buprenorphine for the maintenance treatment of opioid addiction. These have included studies that compared buprenorphine to placebo (Johnson et al. 1995; Ling et al. 1998; Fudala et al. 2003), as well as comparisons to methadone (e.g., Johnson et al. 1992; Ling et al. 1996; Pani et al. 2000; Petitjean et al. 2001; Schottenfeld et al. 1997; Strain et al. 1994a, 1994b) and to methadone and levo-alpha-acetyl-methadol (LAAM) (Johnson et al. 2000). Results from these studies suggest that buprenorphine in a dose range of 8–16 mg a day sublingually is as clinically effective as approximately 60 mg a day of oral methadone, although it is unlikely to be as effective as full therapeutic doses of methadone (e.g., 120 mg per day) in patients requiring higher levels of full agonist activity for effective treatment.

"A meta-analysis comparing buprenorphine to methadone (Barnett et al. 2001) concluded that buprenorphine was more effective than 20–35 mg of methadone but did not have as robust an effect as 50–80 mg methadone -- much the same effects as the individual studies have concluded."

"Buprenorphine and naloxone in combination and buprenorphine alone are safe and reduce the use of opiates and the craving for opiates among opiate-addicted persons who receive these medications in an office-based setting."

The Danish National Board of Health reported in 2000 that "The Buprenorphine project was initiated in the City of Copenhagen during the autumn of 1998 and was evaluated this year. In conclusion the report points out that this type of substitution therapy is suitable for clients who have not previously been subjected to methadone treatment and which are resourceful. Furthermore, the report concluded that buprenorphine treatment may contribute by a significant percentage to the drug addict becoming drug-free and being able to revert to normal life through work, activation and education rather than any other kind of therapy.²⁰"

"Methadone, in use since 1964 for the treatment of opioid dependence, may be dispensed only in federally approved Opioid Treatment Programs (OTPs). Treatment protocols require that a client take the medication at the clinic where it is dispensed daily.⁴ Take-home dosages are allowed only for clients who have been on an established maintenance program for an extended period of time.

"In October 2002, buprenorphine was approved by the Food and Drug Administration (FDA) for the treatment of opioid dependence. Physicians who obtain specialized training may prescribe buprenorphine. Some of these physicians are in private, office-based practices; others are affiliated with substance abuse treatment facilities or programs and may prescribe buprenorphine to clients at those facilities. Additionally, OTPs may also prescribe and/or dispense buprenorphine."

"• Vigorous and effective leadership is needed within the Office of National Drug Control Policy (ONDCP) (and related Federal and State agencies) to inform the public that dependence is a medical disorder that can be effectively treated with significant benefits for the patient and society.

"• Society must make a commitment to offering effective treatment for opiate dependence to all who need it.

"• The panel calls attention to the need for opiate-dependent persons under legal supervision to have access to MMT [methadone maintenance treatment]. The ONDCP and the U.S. Department of Justice should implement this recommendation.

"• The panel recommends improved training of physicians and other health care professionals in diagnosis and treatment of opiate dependence. For example, we encourage the National Institute on Drug Abuse and other agencies to provide funds to improve training for diagnosis and treatment of opiate dependence in medical schools.

"• The panel recommends that unnecessary regulation of MMT and all long-acting agonist treatment programs be reduced.

"• Funding for MMT should be increased.

"• We advocate MMT as a benefit in public and private insurance programs, with parity of coverage for all medical and mental disorders.

"• We recommend targeting opiate-dependent pregnant women for MMT.

"• MMT must be culturally sensitive to enhance a favorable outcome for participating African American and Hispanic persons.

"• Patients, underrepresented minorities, and consumers should be included in bodies charged with policy development guiding opiate dependence treatment.

"• We recommend expanding the availability of opiate agonist treatment in those States and programs where this treatment option is currently unavailable."

"Science-based methadone maintenance treatment [MMT] helps those addicted to opiates sustain their recovery. The result is less crime, fewer emergency room admissions, more citizens working, and less suffering for families and the community. More individuals contribute in taxes instead of costing in health or imprisonment."

"The wide international variation in the availability of opioid agonist treatment for opioid-dependent injection drug users, despite documented scientific evidence in support of its efficacy, highlights the impact of political and philosophical forces that determine the availability of this treatment. Few proven therapies for medical conditions are restricted in this fashion. Therefore, efforts to address the political and philosophical opposition to opioid agonist treatment are needed to meet the global needs to prevent HIV transmission."

"The marginalization of medical care for opioid dependence and the stigma attached to this diagnosis and methadone maintenance treatment play an important role in untreated opioid dependence. Current federal regulations restrict the care of opioid-dependent patients to federally licensed narcotic treatment programs (NTPs) with little to no involvement by community-based physicians. Recent calls from federal and scientific bodies, including the Institute of Medicine, a National Institutes of Health consensus panel, and the Office of National Drug Control Policy, have recommended restructuring the regulatory processes involved in the treatment of opioid-dependent patients, including increased involvement of primary care physicians."

"In order to overcome the issues of poor t­reatment adherence with oral naltrexone, a number of sustained-release implants have been developed internationally for use in alcohol and opioid dependence. A non-randomized retrospective review examined two types of sustained-release naltrexone implants, oral naltrexone, and historical controls revealed a significant difference between immediate and sustained-­release injectable naltrexone in individuals opioid-free 12 months after initiating treatment. Rates combined for the two types of naltrexone implants were 82% opioid free at 12 months compared to 58% opioid free for the oral naltrexone group, and 52% for the historical control group.³²"

"A randomized, double-blind, placebo-controlled trial examined the treatment efficacy of long-acting injectable naltrexone (Naltrel, DrugAbuse Sciences) for relapse prevention in 60 heroin-dependent i­ndividuals. Patients were stratified by sex and years of heroin use and randomized to receive placebo, 192 mg, or 384 mg of long-acting naltrexone intramuscular injections dosed on weeks 1 and 5. In addition to ­medication, patients received relapse prevention therapy and had urine monitored for drug relapse. At the end of 2 months, 39%, 60% and 68% of the placebo, 192 mg naltrexone and 384 mg naltrexone groups, respectively were still in treatment. Mean treatment drop-out occurred in 27 days, 36 days, and 48 days for the placebo, 192 mg naltrexone and 384 mg naltrexone groups. Assuming that missing urine samples were positive, patients receiving placebo had the lowest mean percentage of negative urine samples (25.3%), with the highest mean percentage of negative urine samples in the patient group receiving 384 mg of naltrexone (61.9%). There was a significant main effect of group (P = 0.03), but without assumption of missing urines being positive, was no longer ­significant. This study highlighted the issues of treatment retention with long-acting injectable naltrexone, but was limited by small sample size, and direct comparison to treatment retention with oral naltrexone.⁴⁰"

"LAAM (levo-alpha-acetylmethadol) is no longer approved for use in Europe and is not available for clinical use in the United States. In Europe, reports of several cases of ventricular tachycardia (torsade de pointes: TdP) occurring in patients treated with LAAM led the European Medicines Evaluation Agency (EMEA) to suspend authorization for its marketing in 2001. In the same year, responding to the reports of LAAM-related cases of TdP, the United States Food and Drug Administration (FDA) required the addition of a ‘black box’ warning on the LAAM label. The label states that LAAM should be used only for patients who failed treatment with other agents and that all patients receiving LAAM should have baseline electrocardiogram (ECG) screening and periodic monitoring [1]. Because most clinics were reluctant to initiate such ECG assessments, the use of LAAM (not very high to begin with), dropped sharply. In 2003, Roxane Laboratories, the sole distributor of LAAM, announced its decision to discontinue its sale. However, it remains an FDA-approved therapeutic agent."

"Other potential advantages of levomethadyl’s longer duration of action include reduced dispensing time and less opportunity for illegal diversion. Similar to methadone, it suppresses symptoms of withdrawal and produces cross-tolerance. Adverse effects of levomethadyl are infrequent and, when they occur, are the same as those for methadone. The average daily dose is 75 to 115 mg given 3 times per week. Treatment centers that are not open 7 d/wk dispense a larger dosage of levomethadyl before the 48-hour weekend period."

"Levomethadyl is a synthetic µ-opioid receptor agonist that is commercially available in a liquid suspension. It is rapidly absorbed from the gastrointestinal tract, although its oral bioavailability is somewhat lower than that of methadone.⁸⁷ Because of these properties, the opioid effect of levomethadyl is somewhat slower in onset than that of methadone (90 minutes), but it has a much longer duration of action (48-72 hours) and is therefore able to be dispensed 3 times per week."