Opiate Treatment with Agonists Including Methadone, Buprenorphine, and Suboxone

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1. Effectiveness of Methadone Treatment

"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"

Alford, Daniel P., et al., "Collaborative Care of Opioid-Addicted Patients in Primary Care Using Buprenorphine - Five-Year Experience," Archives of Internal Medicine, 2011;171(5):425-431.

2. NIH Consensus Statement on the Safety And Effectiveness Of Methadone And Opioid Substitution Treatment

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

Effective Medical Treatment of Opiate Addiction. NIH Consensus Statement 1997 Nov. 17-19; 15(6): 4.

3. NIH Consensus Statement on Methadone and Opioid Substitution Treatment

"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."

National Institutes of Health, Office of the Director, "NIH Consensus Statement: Effective Medical Treatment of Opiate Addiction," (U.S. Department of Health: Bethesda, MD, November 1997) Vol. 15, No. 6., p. 16.

4. Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder

"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."

Wakeman SE, Larochelle MR, Ameli O, et al. Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder. JAMA Netw Open. 2020;3(2):e1920622. doi:10.1001/jamanetworkopen.2019.20622

5. Effectiveness of Different Treatment Pathways for Opioid Use Disorder

"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 research11,15,27-29 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 studies33,34 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."

Wakeman SE, Larochelle MR, Ameli O, et al. Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder. JAMA Netw Open. 2020;3(2):e1920622. doi:10.1001/jamanetworkopen.2019.20622

6. Effectiveness of Different Treatment Pathways for Opioid Use Disorder

"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 studies15,35 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."

Wakeman SE, Larochelle MR, Ameli O, et al. Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder. JAMA Netw Open. 2020;3(2):e1920622. doi:10.1001/jamanetworkopen.2019.20622

7. Methadone Treatment Associated with Reductions in Frequency of Opioid Use, Fewer Injections, and Lower Rates of HIV

"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."

Sullivan, Lynn David S. Metzger, Paul J. Fudala & David A. Fiellin, "Decreasing International HIV Transmission: The Role of Expanding Access to Opioid Agonist Therapies for Injection Drug Users," Addiction, February 2005, Vol. 100, No. 2, p. 152.

8. Methadone Maintenance And Opioid Substitution Treatment (MMT and OST) Have Highest Probability Of Effectiveness

"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."

National Institutes of Health, Office of the Director, "NIH Consensus Statement: Effective Medical Treatment of Opiate Addiction," (U.S. Department of Health: Bethesda, MD, November 1997) Vol. 15, No. 6., p. 7.

9. Methadone Dosing

"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."

National Institutes of Health, Office of the Director, "NIH Consensus Statement: Effective Medical Treatment of Opiate Addiction," (U.S. Department of Health: Bethesda, MD, November 1997) Vol. 15, No. 6., p. 14.

10. Methadone Maintenance as a Treatment for Opioid Dependence

"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 minutes61-63 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."

Mori J. Krantz, MD; Philip S. Mehler, MD, "Treating Opioid Dependence: Growing Implications for Primary Care," Archives of Internal Medicine, (Chicago, IL: American Medical Association, February 2004), Vol. 164, p. 279.

11. Undertreated Chronic Pain and Development of Substance Dependence

"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."

Rosenblum, Andrew, PhD, Herman Joseph, PhD, Chunki Fong, MS, Steven Kipnis, MD, Charles Cleland, PhD, Russell K. Portenoy, MD, "Prevalence and Characteristics of Chronic Pain Among Chemically Dependent Patients in Methadone Maintenance and Residential Treatment Facilities," Journal of the American Medical Association (Chicago, IL: American Medical Association, May 14, 2003), Vol. 289, No. 18, pp. 2376-2377.

12. Availability and Utilization of Medication-Assisted Treatment in Drug Courts

"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%)."

Matusow H, Dickman SL, Rich JD, et al. Medication Assisted Treatment in US Drug Courts: Results from a Nationwide Survey of Availability, Barriers and Attitudes. Journal of substance abuse treatment. 2013;44(5):473-480. doi:10.1016/j.jsat.2012.10.004.

13. Racial, Ethnic, and Economic Discrimination In Buprenorphine Treatment for Opioid Use Disorder

"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."

Lagisetty PA, Ross R, Bohnert A, Clay M, Maust DT. Buprenorphine Treatment Divide by Race/Ethnicity and Payment. JAMA Psychiatry. Published online May 08, 2019. doi:10.1001/jamapsychiatry.2019.0876

14. Treatment with Methadone or Buprenorphine Following Nonfatal Overdose Leads to Decreased 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."

Larochelle MR, Bernson D, Land T, Stopka TJ, Wang N, Xuan Z, et al. Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality: A Cohort Study. Annals of Internal Medicine. Epub ahead of print 19 June 2018. doi: 10.7326/M17-3107.

15. Opioid Substitution Treatment, Treatment Programs, and Insurance Coverage

"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."

Samantha J. Harris, Amanda J. Abraham, Christina M. Andrews, and Courtney R. Yarbrough. Gaps In Access To Opioid Use Disorder Treatment For Medicare Beneficiaries. Health Affairs 2020 39:2, 233-237.

16. Methadone-Associated Mortality

"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)."

Center for Substance Abuse Treatment, "Methadone-Associated Mortality: Report of a National Assessment," May 8-9, 2003, CSAT Publication No. 28-03 (Rockville, MD: Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration, 2004), p. 24.

17. Methadone, Pain Management, and Overdose

"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."

Paulozzi, Leonard J., "Opioid Analgesic Involvement in Drug Abuse Deaths in American Metropolitan," American Journal of Public Health (Vol 96, No. 10), October 2006, p. 1756.

18. Reduced Efficacy of Naltrexone (Vivitrol) Treatment

"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."

Krupitsky, Evgeny, Zvartau, Edwin, and Woody, George, "Use of Naltrexone to Treat Opioid Addiction in a Country in Which Methadone and Buprenorphine Are Not Available," Curr Psychiatry Rep. 2010 October; 12(5): 448–453. doi:10.1007/s11920-010-0135-5.

19. Efficacy of Extended-Release Injectable Naltrexone

"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"

Kjome, Kimberly L. and Moeller, F. Gerard, "Long-Acting Injectable Naltrexone for the Management of Patients with Opioid Dependence," Substance Abuse: Research and Treatment 2011:5 1–9, doi: 10.4137/SART.S5452

20. Compliance Problems with Naltrexone (Vivitrol)

"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"

Kjome, Kimberly L. and Moeller, F. Gerard, "Long-Acting Injectable Naltrexone for the Management of Patients with Opioid Dependence," Substance Abuse: Research and Treatment 2011:5 1–9, doi: 10.4137/SART.S5452