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Methadone & Opioid Substitution Therapy

  1. Methadone - General Information

    "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."

    Source: 
    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.
    http://archinte.jamanetwork.com/article.aspx?articleid=216641

  2. "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."

    Source: 
    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.
    http://consensus.nih.gov/1997/1998TreatOpiateAddiction108PDF.pdf

  3. "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)."

    Source: 
    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.
    http://proxychi.baremetal.com/csdp.org/research/methadone.samhsa204.pdf

  4. "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."

    Source: 
    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.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1586142/pdf/0961755.pdf

  5. "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."

    Source: 
    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. 25.
    http://proxychi.baremetal.com/csdp.org/research/methadone.samhsa204.pdf

  6. Basic Data

    "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."

    Source: 
    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.
    http://consensus.nih.gov/1997/1998TreatOpiateAddiction108PDF.pdf

  7. (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"

    Source: 
    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.
    http://archinte.jamanetwork.com/data/Journals/InteMed/5801/ioi05149_425_...

  8. Patient Data

    (Number of Opioid Treatment Programs and Patients in the US, 2012) "Opioid Treatment Programs (OTPs) are certified by SAMHSA to provide medication-assisted therapy in the treatment of opioid addiction. Currently, methadone and buprenorphine are the only opioid medications approved for the treatment of opioid addiction.
    "• Tables 2.3 and 4.21. Clients receiving methadone or buprenorphine in OTPs accounted for 25 percent of all clients in treatment on March 30, 2012, although OTPs were available in only 1,167 (8 percent) of all substance abuse treatment facilities.
    "• Tables 4.1 and 4.21. Private for-profit organizations operated 57 percent of OTPs, but only 31 percent of all substance abuse treatment facilities."

    Source: 
    Substance Abuse and Mental Health Services Administration, National Survey of Substance Abuse Treatment Services (N-SSATS): 2012. Data on Substance Abuse Treatment Facilities. BHSIS Series S-66, HHS Publication No. (SMA) 14-4809. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013, p. 30.
    http://www.samhsa.gov/data/DASIS/NSSATS2012_Web.pdf

  9. (Characteristics of facilities administering Opioid Treatment Programs (OTPs) in the US, 2012) "Of the 313,921 clients receiving medication-assisted opioid therapy in OTPs, 98 percent (306,512) received methadone and 2 percent (7,409 clients) received buprenorphine. (There were also 31,814 clients that received buprenorphine as part of their treatment in non-OTP facilities.)
    "• More than half (60 percent) of clients receiving methadone were in private for-profit facilities with OTPs. Most (92 percent) of the clients receiving methadone were in facilities whose primary focus was the provision of substance abuse treatment services.
    "• Clients receiving buprenorphine in OTPs were more likely than clients receiving methadone to be in federal government-operated facilities (13 vs. 1 percent).
    "• Almost all clients receiving buprenorphine in OTPs were in facilities whose primary focus was either the provision of substance abuse treatment services (74 percent) or a mix of mental health and substance abuse treatment services (21 percent)."

    Source: 
    Substance Abuse and Mental Health Services Administration, National Survey of Substance Abuse Treatment Services (N-SSATS): 2012. Data on Substance Abuse Treatment Facilities. BHSIS Series S-66, HHS Publication No. (SMA) 14-4809. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013, p. 30.
    http://www.samhsa.gov/data/DASIS/NSSATS2012_Web.pdf

  10. (Trends in Heroin Admissions and Opioid Substitution Treatment in the US, 2000-2011) "General measures of heroin abuse among treatment admissions aged 12 and older were relatively consistent from 2001 through 2011. Primary heroin abuse accounted for 14 to 16 percent of TEDS admissions in every year from 2001 through 2011 [Table 1.1b]. In 2011, injection was the preferred route of administration for 70 percent of primary heroin admissions, inhalation for 25 percent, and smoking or other route for 4 percent [Table 2.4]. The majority of primary heroin admissions from 2001 to 2011 were 20 to 34 years of age or older (41 to 43 percent from 2001 through 2007 and 53 percent in 2011) [Table 3.5].
    "However, these measures conceal substantial changes in the age, race/ethnicity, and route of administration of some subpopulations among heroin-using admissions.
    "Table 3.5 and Figure 21. TEDS data show an increase in heroin admissions among young non-Hispanic White adults. Among non-Hispanic Blacks, however, admissions have declined except among older admissions.
    "• In 2001, just over 1 in 5 heroin admissions (23 percent) were non-Hispanic White aged 20 to 34. By 2011, more than 2 in 5 primary heroin admissions (43 percent) belonged to this subgroup. The proportion of primary heroin admissions who were non-Hispanic White aged 35 to 44 fell from 14 percent to 9 percent in the same period, while the proportions of non-Hispanic White admissions aged 12 to 19 and older than 45 remained constant, at 2 to 3 percent and 7 to 8 percent, respectively.
    "• In contrast, the proportion of primary heroin admissions that were non-Hispanic Black aged 20 to 34 fell from 6 percent to 2 percent between 2001 and 2011, while the proportion aged 35 to 44 fell from 10 percent to 5 percent. However, the proportion of non-Hispanic Black admissions aged 45 and older increased from 8 percent in 2001 to 10 percent in 2011. Non-Hispanic Black admissions aged 12 to 19 accounted for one-tenth of 1 percent of all primary heroin admissions."

    Source: 
    Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. Treatment Episode Data Set (TEDS): 2001-2011. National Admissions to Substance Abuse Treatment Services. BHSIS Series S-65, HHS Publication No. (SMA) 13-4772. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013, pp. 30-31.
    http://www.samhsa.gov/data/2k13/TEDS2011/TEDS2011N.pdf


  11. Availability of Treatment & The "Treatment Gap"

    ("Treatment Gap") "NTPs (Narcotics Treatment Programs) are the most highly regulated form of medicine practiced in the US, as they are subject to Federal, State, and local regulation. Under this regulatory burden, expansion of this system has been static for many years. This has resulted in a 'treatment gap' which is defined as the difference between the number of opiate dependent persons and those in treatment. The gap currently is over 600,000 persons and represents 75-80% of all addicts."

    Source: 
    "Buprenorphine Update: Questions and Answers," National Institute on Drug Abuse (Rockville, MD: National Institutes of Health), last updated on May 13, 2009.
    http://archives.drugabuse.gov/bupupdate.html

  12. (Growth in Availability and Utilization of Opioid Treatment Programs in the US) "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."

    Source: 
    Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (April 23, 2013). The N-SSATS Report: Trends in the Use of Methadone and Buprenorphine at Substance Abuse Treatment Facilities: 2003 to 2011. Rockville, MD, p. 2.
    http://www.samhsa.gov/data/2k13/NSSATS107/sr107-NSSATS-BuprenorphineTren...

  13. "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."

    Source: 
    Effective Medical Treatment of Opiate Addiction. NIH Consensus Statement 1997 Nov. 17-19; 15(6): 2.
    http://consensus.nih.gov/1997/1998TreatOpiateAddiction108PDF.pdf


  14. Effectiveness of Opioid Substitution Treatment (OST)

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

    Source: 
    Effective Medical Treatment of Opiate Addiction. NIH Consensus Statement 1997 Nov. 17-19; 15(6): 4.
    http://consensus.nih.gov/1997/1998TreatOpiateAddiction108PDF.pdf

  15. (OST and Reductions in Drug Use) "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."

    Source: 
    Johnson, Rolley E., Pharm. D., Mary Ann Chutuape, PhD, Eric C. Strain, MD, Sharon L. Walsh, PhD, Maxine L. Stitzer, PhD, and George E. Bigelow, PhD, "A Comparison of Levomethadyl Acetate, Buprenorphine, and Methadone for Opioid Dependence," New England Journal of Medicine (Boston, MA: Massachusetts Medical Society, Nov. 2, 2000), Vol. 343, No. 18, p. 1296.
    http://content.nejm.org/cgi/reprint/343/18/1290.pdf

  16. (OST and Rates of Abstinence) "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."

    Source: 
    Johnson, Rolley E., Pharm. D., Mary Ann Chutuape, PhD, Eric C. Strain, MD, Sharon L. Walsh, PhD, Maxine L. Stitzer, PhD, and George E. Bigelow, PhD, "A Comparison of Levomethadyl Acetate, Buprenorphine, and Methadone for Opioid Dependence," New England Journal of Medicine (Boston, MA: Massachusetts Medical Society, Nov. 2, 2000), Vol. 343, No. 18, p. 1295.
    http://content.nejm.org/cgi/reprint/343/18/1290.pdf

  17. "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."

    Source: 
    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.
    http://consensus.nih.gov/1997/1998TreatOpiateAddiction108PDF.pdf

  18. (Opioid Substitution Treatment and Prevention of HIV Transmission) "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."

    Source: 
    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. 153.
    http://www.ncbi.nlm.nih.gov/pubmed/15679744

  19. (Opioid Substitution Treatment and HIV Risk) "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."

    Source: 
    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.
    http://www.ncbi.nlm.nih.gov/pubmed/15679744

  20. (Opioid Substitution Treatment and Risk of New HIV Infection Among IDUs) "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."

    Source: 
    MacArthur, Georgie J., et al., "Opiate substitution treatment and HIV transmission in people who inject drugs: systematic review and meta-analysis," BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e5945 (Published 4 October 2012).
    http://www.bmj.com/content/345/bmj.e5945

  21. (OST and Reductions in HIV-Risk Behaviors) 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."

    Source: 
    Sees, Karen, DO, et al., "Methadone Maintenance vs. 180-Day Psychosocially Enriched Detoxification for Treatment of Opiod Dependence: A Randomized Controlled Trial", Journal of the American Medical Association, 2000, 283:1303-1310.
    http://jama.jamanetwork.com/article.aspx?articleid=192476

  22. "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."

    Source: 
    Langendam, Miranda W., PhD, Giel H.A.van Brussel, MD, Roel A. Coutinho, MD, PhD, and Erik J.C. van Ameijden, PhD, "The Impact of Harm-Reduction-Based Methadone Treatment on Mortality Among Heroin Users," American Journal of Public Health (Washington, DC: American Public Health Association, May 2001), Vol. 95, No. 5, p. 779.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1446673/pdf/11344886.pdf

  23. "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."

    Source: 
    Sees, Karen, DO, et al., "Methadone Maintenance vs. 180-Day Psychosocially Enriched Detoxification for Treatment of Opiod Dependence: A Randomized Controlled Trial", Journal of the American Medical Association, 2000, 283:1303.
    http://jama.jamanetwork.com/article.aspx?articleid=192476

  24. "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."

    Source: 
    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. 12.
    http://consensus.nih.gov/1997/1998TreatOpiateAddiction108PDF.pdf

  25. "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."

    Source: 
    Rosenbaum, et al., "Treatment as Harm Reduction, Defunding as Harm Maximization: The Case of Methadone Maintenance," Journal of Psychoactive Drugs, 28: 241-249 (1996).

  26. 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."

    Source: 
    Effective Medical Treatment of Opiate Addiction. NIH Consensus Statement 1997 Nov. 17-19; 15(6): 4.
    http://consensus.nih.gov/1997/1998TreatOpiateAddiction108PDF.pdf

  27. "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."

    Source: 
    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. 4.
    http://consensus.nih.gov/1997/1998TreatOpiateAddiction108PDF.pdf

  28. (OST and Patient Retention) 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."

    Source: 
    Johnson, Rolley E., Pharm. D., Mary Ann Chutuape, PhD, Eric C. Strain, MD, Sharon L. Walsh, PhD, Maxine L. Stitzer, PhD, and George E. Bigelow, PhD, "A Comparison of Levomethadyl Acetate, Buprenorphine, and Methadone for Opioid Dependence," New England Journal of Medicine (Boston, MA: Massachusetts Medical Society, Nov. 2, 2000), Vol. 343, No. 18, p. 1295.
    http://content.nejm.org/cgi/reprint/343/18/1290.pdf

  29. 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."

    Source: 
    Rounsaville, Bruce J., MD, and Kosten, Thomas R., MD, "Treatment for Opioid Dependence: Quality and Access", Journal of the American Medical Association, (Chicago, IL: American Medical Association, March 8, 2000), Vol. 283, No. 10, p. 1338.
    http://www.doctordeluca.com/Library/DetoxEngage/RxForOpioidDependence2K....

  30. (Risk of Death and Other Adverse Events from Anesthesia-Assisted Rapid Opioid Detoxification (AAROD)) "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/collections/oal/final/bds10905-99_2.pdf.

    Source: 
    "Deaths and Severe Adverse Events Associated With Anesthesia-Assisted Rapid Opioid Detoxification - New York City, 2012," Mortality and Morbidity Weekly Report (Atlanta, GA: Centers for Disease Control, Sept. 27, 2013), Vol. 62, No. 38, p. 780.
    http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6238a1.htm?s_cid=mm6238a1_w
    http://www.cdc.gov/mmwr/pdf/wk/mm6238.pdf


  31. Office-Based Opioid Substitution Treatment (OBOT)

    (Feasibility of 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."

    Source: 
    Fiellin, David A., MD, Patrick G. O'Connor, MD, MPH, Marek Chawarski, PhD, Juliana P. Pakes, MEd, Michael V. Pantalon, PhD, and Richard S. Schottenfeld, MD, "Methadone Maintenance in Primary Care: A Randomized Controlled Trial," Journal of the American Medical Association (Chicago, IL: American Medical Association, Oct. 10, 2001), Vol. 286, No. 14, p. 1730.
    http://jama.jamanetwork.com/article.aspx?articleid=194273

  32. (Feasibility of OBOT) "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."

    Source: 
    Fiellin, David A., MD, Patrick G. O'Connor, MD, MPH, Marek Chawarski, PhD, Juliana P. Pakes, MEd, Michael V. Pantalon, PhD, and Richard S. Schottenfeld, MD, "Methadone Maintenance in Primary Care: A Randomized Controlled Trial," Journal of the American Medical Association (Chicago, IL: American Medical Association, Oct. 10, 2001), Vol. 286, No. 14, p. 1729.
    http://jama.jamanetwork.com/article.aspx?articleid=194273

  33. (Benefits from OBOT) "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."

    Source: 
    Fiellin, David A., MD, Patrick G. O'Connor, MD, MPH, Marek Chawarski, PhD, Juliana P. Pakes, MEd, Michael V. Pantalon, PhD, and Richard S. Schottenfeld, MD, "Methadone Maintenance in Primary Care: A Randomized Controlled Trial," Journal of the American Medical Association (Chicago, IL: American Medical Association, Oct. 10, 2001), Vol. 286, No. 14, p. 1725.
    http://jama.jamanetwork.com/article.aspx?articleid=194273

  34. (Effectiveness of OBOT) 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."

    Source: 
    Fiellin, David A., MD, Michael V. Pantalon, PhD, Marek C. Chawarski, PhD, Brent A. Moore, PhD, Lynn E. Sullivan, MD, Patrick G. O'Connor, MD, MPH, and Richard S. Schottenfeld, MD, "Counseling plus Buprenorphine-Naloxone Maintenance Therapy for Opioid Dependence," New England Journal of Medicine Vol. 355, No. 4, July 27, 2006, pp. 370-371.
    http://content.nejm.org/cgi/reprint/355/4/365.pdf

  35. (Effectiveness of Office-Based Buprenorphine Treatment) "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"

    Source: 
    Fiellin, David A., MD, Michael V. Pantalon, PhD, Marek C. Chawarski, PhD, Brent A. Moore, PhD, Lynn E. Sullivan, MD, Patrick G. O'Connor, MD, MPH, and Richard S. Schottenfeld, MD, "Counseling plus Buprenorphine-Naloxone Maintenance Therapy for Opioid Dependence," New England Journal of Medicine Vol. 355, No. 4, July 27, 2006, p. 371.
    http://content.nejm.org/cgi/reprint/355/4/365.pdf

  36. (Methadone vs. Buprenorphine Treatment) "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."

    Source: 
    Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (April 23, 2013). The N-SSATS Report: Trends in the Use of Methadone and Buprenorphine at Substance Abuse Treatment Facilities: 2003 to 2011. Rockville, MD, p. 2.
    http://www.samhsa.gov/data/2k13/NSSATS107/sr107-NSSATS-BuprenorphineTren...

  37. (Frequency of Dosing with Buprenorphine) 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."

    Source: 
    Johnson, Rolley E., Pharm. D., Mary Ann Chutuape, PhD, Eric C. Strain, MD, Sharon L. Walsh, PhD, Maxine L. Stitzer, PhD, and George E. Bigelow, PhD, "A Comparison of Levomethadyl Acetate, Buprenorphine, and Methadone for Opioid Dependence," New England Journal of Medicine (Boston, MA: Massachusetts Medical Society, Nov. 2, 2000), Vol. 343, No. 18, p. 1296.
    http://content.nejm.org/cgi/reprint/343/18/1290.pdf

  38. (Efficacy of Naltrexone Treatment) "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."

    Source: 
    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.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160743/
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160743/pdf/nihms315485.pdf

  39. "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."

    Source: 
    Fiellin, David A., MD, Patrick G. O'Connor, MD, MPH, Marek Chawarski, PhD, Juliana P. Pakes, MEd, Michael V. Pantalon, PhD, and Richard S. Schottenfeld, MD, "Methadone Maintenance in Primary Care: A Randomized Controlled Trial," Journal of the American Medical Association (Chicago, IL: American Medical Association, Oct. 10, 2001), Vol. 286, No. 14, p. 1724.
    http://jama.jamanetwork.com/article.aspx?articleid=194273

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

    Source: 
    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. 11.
    http://consensus.nih.gov/1997/1998TreatOpiateAddiction108PDF.pdf

  41. Buprenorphine (Subutex® and Suboxone®)

    (Buprenorphine Approval by FDA) "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.samhsa.gov/fulllaw.html.)
    "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."

    Source: 
    Center for Substance Abuse Treatment. "Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction." Treatment Improvement Protocol (TIP) Series 40. DHHS Publication No. (SMA)
    04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004, p. xv.
    http://buprenorphine.samhsa.gov/Bup_Guidelines.pdf

  42. (Buprenorphine Formulation) "Buprenorphine is a long-acting partial opioid agonist91,92 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 μ-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."

    Source: 
    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. 281.
    http://archinte.jamanetwork.com/article.aspx?articleid=216641

  43. (Buprenorphine for Maintenance vs. Detox) "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."

    Source: 
    Center for Substance Abuse Treatment, Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction, Treatment Improvement Protocol (TIP) Series 40, DHHS Publication No. (SMA) 04-3939 (Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004), p. 20.
    http://buprenorphine.samhsa.gov/Bup_Guidelines.pdf

  44. (Effectiveness of Buprenorphine Treatment) "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."

    Source: 
    Center for Substance Abuse Treatment, Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction, Treatment Improvement Protocol (TIP) Series 40, DHHS Publication No. (SMA) 04-3939 (Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004), pp. 20-21.
    http://buprenorphine.samhsa.gov/Bup_Guidelines.pdf

  45. "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."

    Source: 
    Fudala, Paul J., PhD, T. Peter Bridge, MD, Susan Herbert, MA, William O. Williford, PhD, C. Nora Chiang, PhD, Karen Jones, MS, Joseph Collins, ScD, Dennis Raisch, PhD, Paul Casadonte, MD, R. Jeffrey Goldsmith, MD, Walter Ling, MD, Usha Malkerneker, MD, Laura McNicholas, MD, PhD, John Renner, MD, Susan Stine, MD, PhD, & Donald Tusel, MD for the Buprenorphine/Naloxone Collaborative Study Group, "Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone," New England Journal of Medicine, Sept. 4, 2003, Vol. 349, No. 10, p. 949.
    http://content.nejm.org/cgi/reprint/349/10/949.pdf

  46. (Effectiveness of Buprenorphine Treatment) 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"

    Source: 
    Report to the European Monitoring Center on Drugs and Drug Addiction by the Reitox National Focal Point of Denmark, Sundhedsstyrelsen (National Board of Health), "Denmark Drug Situation 2000: National Report on the State of the Drugs Problem in Denmark" (Denmark: National Board of Health and EMCDDA, December 2000), p. 73, citing Leif Skauge, "Erfaringer med implementering af buprenorphinbehandling ved Kobenhavns Kommune," handout at the Drugs Council's research conference in March 2000.
    http://www.emcdda.europa.eu/attachements.cfm/att_34640_EN_NR2000Denmark....

  47. Laws and Policies

    (Regulation and Certification of Opioid Treatment Programs (OTPs)) "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."

    Source: 
    Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (April 23, 2013). The N-SSATS Report: Trends in the Use of Methadone and Buprenorphine at Substance Abuse Treatment Facilities: 2003 to 2011. Rockville, MD, p. 1.
    http://www.samhsa.gov/data/2k13/NSSATS107/sr107-NSSATS-BuprenorphineTren...

  48. In November 1997, the National Institutes of Health (NIH) convened a Consensus Panel on Effective Medical Treatment of Heroin Addiction. The panel of national experts concluded:
    "• 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."

    Source: 
    "Effective Medical Treatment of Opiate Addiction," NIH Consensus Statement 1997, Nov 17-19 (Washington, DC: National Institutes of Health), 15(6), p. 24.
    http://consensus.nih.gov/1997/1998TreatOpiateAddiction108PDF.pdf

  49. "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."

    Source: 
    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. 153.
    http://www.ncbi.nlm.nih.gov/pubmed/15679744

  50. "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."

    Source: 
    Fiellin, David A., MD, Patrick G. O'Connor, MD, MPH, Marek Chawarski, PhD, Juliana P. Pakes, MEd, Michael V. Pantalon, PhD, and Richard S. Schottenfeld, MD, "Methadone Maintenance in Primary Care: A Randomized Controlled Trial," Journal of the American Medical Association (Chicago, IL: American Medical Association, Oct. 10, 2001), Vol. 286, No. 14, p. 1724.
    http://jama.jamanetwork.com/article.aspx?articleid=194273

  51. (Barry McCaffrey on Methadone) "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."

    Source: 
    McCaffrey, Barry, "Methadone Saves Lives, Restores Productivity: Drug's Bad Press Shouldn't Harm Treatment for Addiction," (Sunday Globe-Mail: Charleston, WV) January 28, 2007.
    http://www.mapinc.org/newscsdp/v07/n107/a03.html

  52. Extended-Release Naltrexone & Vivitrol

    (Description of Naltrexone) "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 μ-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-β 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 μ-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."

    Source: 
    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
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411517/
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411517/pdf/sart-5-2011-001....

  53. (Compliance Problems with Naltrexone) "Despite the ease of outpatient dosing and its ability to effectively block the euphoric effects of μ-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"

    Source: 
    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
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411517/
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411517/pdf/sart-5-2011-001....

  54. (Sustained Release Naltrexone Implants) "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"

    Source: 
    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
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411517/
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411517/pdf/sart-5-2011-001....

  55. (Improving Naltrexone Treatment Outcomes) "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."

    Source: 
    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.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160743/
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160743/pdf/nihms315485.pdf

  56. (Efficacy of Long-Acting Injectable Naltrexone) "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"

    Source: 
    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
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411517/
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411517/pdf/sart-5-2011-001....

  57. (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"

    Source: 
    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
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411517/
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411517/pdf/sart-5-2011-001....

  58. (Pain Patients in Methadone Treatment) "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."

    Source: 
    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, p. 2376.
    http://jama.jamanetwork.com/article.aspx?articleid=196537

  59. (Pain Patients in Treatment) "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."

    Source: 
    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.
    http://jama.jamanetwork.com/article.aspx?articleid=196537

  60. Levomethadyl (LAAM)

    "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."

    Source: 
    Jaffe, Jerome, "Can LAAM, Like Lazarus, Come Back From the Dead" (Editorial), Addiction, Aug 9, 2007, Vol. 102, No. 9, p. 1342, doi:10.1111/j.1360-0443.2007.01976.x
    http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2007.01976.x/pdf

  61. "It is now clear that methadone as well as LAAM can prolong the QT interval, and that instances of TdP have been reported with both agents. Screening to identify patients at risk for unacceptable degrees of QT prolongation ought to be a part of agonist treatment with any agent known to be a torsadogen. With proper screening and ECG monitoring it seems likely that arrhythmias associated with agonist therapy can be reduced substantially or prevented. Once such screening becomes routine there may be an opportunity in the United States, where LAAM is still approved, to persuade a pharmaceutical company or the government to make it available again. Many clinicians believe that LAAM adds an important therapeutic option. Perhaps even the EMEA would reconsider its decision to withdraw its approval of LAAM."

    Source: 
    Jaffe, Jerome, "Can LAAM, Like Lazarus, Come Back From the Dead" (Editorial), Addiction, Aug 9, 2007, Vol. 102, No. 9, p. 1343, doi:10.1111/j.1360-0443.2007.01976.x
    http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2007.01976.x/pdf

  62. "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."

    Source: 
    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, pp. 280-281.
    http://archinte.jamanetwork.com/article.aspx?articleid=216641

  63. "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."

    Source: 
    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. 280.
    http://archinte.jamanetwork.com/article.aspx?articleid=216641