Treatment and Interventions for Opioid Addictions: Challenges From the Medical Director s Perspective

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1 Treatment and Interventions for Opioid Addictions: Challenges From the Medical Director s Perspective Dale K. Adair, MD Medical Director/Chief Psychiatric Officer OMHSAS 1

2 Treatment and Interventions for Opioid Addictions: Challenges From the Medical Director s Perspective Dale K. Adair, MD Medical Director/Chief Psychiatric Officer OMHSAS 1

3 Conflicts of Interest None

4 Overview Diagnosis Scope Treatment Options Challenges Warning Signs Tom Corbett, Tom Governor Corbett, Beverly Governor Mackereth, Beverly Secretary Mackereth, Acting Dennis Secretary Marion, Deputy Dennis Secretary Marion, OMHSAS Deputy Secretary OMHSAS

5 Drug Utilization Past Month Illicit Drug Use among Persons Aged 12 or Older: 2012

6 Heroin Use Statistics

7 Drug Utilization Past Month Illicit Drug Use among Persons Aged 12 or Older, by Age: 2011 and 2012

8 Drug Utilization Past Month Illicit Drug Use among Persons Aged 12 or Older, by Race/Ethnicity:

9 Past Month Drug Use Past Month Illicit Drug Use among Persons Aged 18 or Older, by Employment Status: 2011 and 2012

10 Past Month Drug Use Age 12 and older Past Month Illicit Drug Use among Persons Aged 12 or Older, by County Type: 2012

11 Pain Relievers-Nonmedical Use Where Pain Relievers Were Obtained for Most Recent Nonmedical Use among Past Year Users Aged 12 or Older:

12 Illicit Drug Use Age 12 or older First Specific Drug Associated with Initiation of Illicit Drug Use among Past Year Illicit Drug Initiates Aged 12 or Older: 2012

13 Specific Illicit Drugs Past Year Initiates of Specific Illicit Drugs among Persons Aged 12 or Older: 2012

14 Illicit Drugs-Age Specific Mean Age at First Use for Specific Illicit Drugs among Past Year Initiates Aged 12 to 49: 2012

15 Treatment Locations Locations Where Past Year Substance Use Treatment Was Received among Persons Aged 12 or Older: 2012

16 Most Recent Substance Treatment Substances for Which Most Recent Treatment Was Received in the Past Year among Persons Aged 12 or Older: 2012 Past Year among Persons Aged 12 or Older: 2012

17 Recent Treatment-Pain Relievers Received Most Recent Treatment in the Past Year for the Use of Pain Relievers among Persons Aged 12 or Older:

18 Drug Dependence or Abuse

19 Single Day Counts

20 Buprenorphine Treatment

21 Illicit Drug Dependence or Abuse

22 Past Year Drug Use Treatments

23 Overdose Deaths in PA Overdose Deaths in Pennsylvania In 1990, note for the 64 grey counties, the death rate is too low to be accurately counted, at less than 3 deaths per 1,000 citizens. The state average is 2.7 deaths per 1,000 citizens, so any colored counties are above average, while grey is below average.

24 Overdose in PA In 2000, note for the 52 grey counties, the death rate is too low to be accurately counted, at less than 3 deaths per 1,000 citizens. The state average is 7.4 per 1,000 citizens, so the light blue, yellow and orange counties are above average, while grey and dark blue are below average.

25 Prescription Opioids Use Prescription opioids: use Prescription opioids frequently used by adult enrollees 28.3% with any short-acting use in % with any long-acting use Most use for short duration 40.8% filled single prescription in % had <30 days supply *Julie Donohue, PhD Associate Prof University of Pittsburgh

26 Prescription Opioids Prescription opioids: the prescribers Primary care, emergency medicine physicians, dentists are top prescribers 48% opioid prescribers are PCPs 22% are EM physicians 17% are dentists These three specialties write 84% of opioid scripts PCPs write 65% of scripts ED physicians write 10% Dentists write 9% *Julie Donohue, PhD Associate Prof University of Pittsburgh

27 Medication Misuse Misuse is defined as non-adherence to prescription directions and can be either willful or accidental. One-quarter of the prescription drugs sold in the United States are used by the elderly, use more meds than any other age group. Older adults are likely to experience more problems with relatively small amounts of medications because of increased medication sensitivity as well as slower metabolism and elimination. Factors associated with prescription medication misuse and abuse by older adults include female sex, social isolation, history of substance use or psychiatric disorder, poly-pharmacy, and chronic medical problems. Commonly prescribed drugs with misuse potential include those for anxiety, pain, and insomnia, such as benzodiazepines, opiate analgesics, and skeletal muscle relaxants.

28 Risks Populations Who is at greatest risk for medication misuse/abuse? Factors associated with prescription drug misuse/abuse in older adults Female gender Social isolation History of a substance abuse History of or mental health disorder older adults with prescription drug dependence are more likely than younger adults to have a dual diagnosis Medical exposure to prescription meds with abuse potential (Source: Simoni-Wastila, Yang, 2006)

29 Emergency Department Use Emergency Department (ED) Use Related to Misuse/Abuse One fifth of ED visits involving prescription medication misuse/abuse among adults were made by persons aged 70 or older Medications involved in ED visits made by older adults: - Pain relievers (43.5%) - Medications for anxiety or insomnia (31.8%) - Antidepressants (8.6%) In 2008, there were 256,097 such visits, representing an increase of percent 37.5% were admitted to the hospital SAMHSA, DAWN Report, 2010

30 Intervention Referral Simple vs Brief Intervention Referral Attended 1 st Appointment Motivational Session 70% Control Group 32% p =.006 Zanjani F, Oslin D (2005). Telephone Based Referral-Care Management. Grant Supported by Philadelphia Veteran s Affairs: Mental Illness Research Education and Clinical Center (MIRECC)

31 Brief Advice Brief Advice Shown to decrease drinking and adverse health outcomes Two components: Advice Link drinking to health Recommended by the US Preventative Task Force

32 Overdose Deaths In Pa Overdose Deaths in Pennsylvania Number of Age Group Deaths Population Rate per 1, ,886 ### ,257 ### ,882 ### , , , , , , , , , , , ,334 ### ,151 ### ,139 ### , Based on Pennsylvania Department of Health data, overdose deaths in 2011 have the highest rates in age These rates decline with age, but increase again after age 85. Rates among older adults are on the rise.

33 Yearly Statistics in Pa Overdose Deaths in Pennsylvania Drug Overdose Deaths in Pennsylvania Year Number of Deaths PA Population Rate per 1, ,909 12,742, ,550 12,702, ,522 12,448, ,344 12,440, ,278 12,406, ,335, ,281, ,001, ,056, ,052, ,995, ,881, Based on Pennsylvania Department of Health data, overdose deaths have been on the rise over the last two decades with an increase in the rate of death from 2.7 to 15.4 per thousand Pennsylvanians

34 Opioid Use Disorder A problematic pattern of opioid use leading to clinically significant impairment or distress is manifested by two or more of the following within a 12-month period: 1. Opioids are often taken in larger amounts or over a longer period than was intended. 2. Persistent desire or unsuccessful efforts to cut down or control opioid use 3. Great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects 4. Craving, or a strong desire or urge to use opioids 5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home 6. Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids 7. Important social, occupational, or recreational activities are given up or reduced because of opioid use. 8. Recurrent opioid use in situations in which it is physically hazardous 9. Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance 10. Tolerance 11. Withdrawal

35 Opioid Treatment Medication Assisted Treatment Opioid Agonist Opioid Antagonist Drug-free (Medication-free) Treatment

36 Overview of Medications for Opiate Assisted Treatment Overview of Medications for Opiate Assisted Treatment Methadone Buprenorphine Naltrexone Vivitrol Pro Prevents withdrawal symptoms Decreases risky behavior Decreases criminality Allows counseling Promotes access to medical/psychiatric care Promotes rehabilitation Cost as low as $5 per week Dose: Most patients receive mg/day but some receive as much as 325mg/day Less tightly controlled than methadone Lower potential for abuse and are less dangerous in an overdose Progress in therapy may allow for a take-home supply of the medication Prevents Withdrawal Prevents Craving Does not produce a High Blocks or reduces the effect of heroin Reduced diversion issues Fewer transportation issues Better compliance than methadone Dosing every 2-3 days No opiate effect benefits (i.e. high) More limited side effects Helps manage cravings/ relapse risk Benefits found for multiple addictive behaviors including opiates, alcohol and gambling disorders Used to treat alcoholism and heroin addiction Monthly injections block the brain s ability to get intoxicated or high Prospective clients must be sober for at least 7 days prior to beginning treatment Has other side effects like other medications Improved compliance Con Diversion potential Abuse Potential Does not address the effects/use of other substances (e.g. alcohol or benzos) Daily dosing requirements Transportation issues for daily dose Intense withdrawal from medication Higher cost Does not address the effects/use of other substances (e.g. alcohol or benzos) Note: Suboxone consists of a combination of Buprenorphine and Naloxone Possible dysphonic effects High non-compliance rates (self administered, so it is easy to stop) Early gastrointestinal discomfort Expensive for those without insurance coverage ($ /month avg.) High Cost

37 NTP 65 free standing clinics and 4 hospital based Serving over 14,000 individuals

38 Methadone Long Term Care Clinics Delivery by County System Sub-Committee Understanding Older Adults with Behavioral Health Needs Pennsylvania Osteopathic Family Physicians Society August 2, 2014 Tom Corbett, Governor Beverly Mackereth, Acting Secretary Dennis Marion, Deputy Secretary OMHSAS

39 Opioid Agonist Methadone A meta-analysis of 1969 participants in 11 randomized trials compared methadone maintenance therapy to placebo or nonmedication treatment for opioid dependence (Mattick BP et al, Cochrane Database Sys Rev 2009) A 10-year follow up study of 405 patients randomly assigned to receive either methadone or buprenorphine found an association between the duration of treatment with either medication and lower rates of mortality. (Gibson A., et al, Addiction 2008)

40 Methadone Prescribed by NTP Usually mg daily Side effects include constipation, mild drowsiness, excess sweating, and peripheral edema Arrhythmias Overdose

41 Buprenorphine Partial Opioid Agonist Schedule III A meta-analysis that included 4497 participants in 24 randomized trials found that sublingual buprenorphine improved treatment retention and reduced opioid use in patients with opioid dependence compared to placebo treatment Most patients will stabilize on 16 to 20 mg/day of buprenorphine

42 Buprenorphine Use 37% increase in buprenorphine use in 2 years 12,588 (1.1%) enrollees in ,189 (1.5%) enrollees in % of buprenorphine users have an OUD diagnosis recorded in claims *Julie Donohue, PhD Associate Prof University of Pittsburgh

43 Buprenorphine Buprenorphine: the prescribers Most (77.6%) buprenorphine prescribers are primary care providers Psychiatrists and emergency medicine physicians account for another 14.4% of prescribers These 3 specialties write 92% of buprenorphine prescriptions *Julie Donohue, PhD Associate Prof University of Pittsburgh

44 County-level variation Map of Prescribers

45 Naltrexone Opioid Antagonist Effective in patients highly motivated A meta-analysis of 1158 participants in 13 randomized trials compared oral naltrexone maintenance treatment to either placebo or non-medication treatment. No difference was seen between the two groups in sustained abstinence or most other primary outcomes (Minozzi et al, Cochrane Database Sys Rev 2011) 50 mg tablet once daily

46 Long Acting Naltrexone A trial randomly assigned 60 patients with heroin dependence to receive injectable depot naltrexone (Comer et al, AGP 2006) A trial compared a once-monthly, injectable depot formulation of naltrexone to placebo in 250 patients with opioid dependence over 24 weeks (Krupitsky et al, Lancet 2011) A trial in 100 heroin and amphetamine-dependent outpatients compared the efficacy of naltrexone implants to placebo (Tiihonen et al, AJP May 2012)

47 Psychosocial Treatments A National Institutes of Health Consensus Conference in the US concluded that non-pharmacologic supportive services are pivotal to successful treatment (JAMA 1998) Individual and group drug counseling Specific psychosocial interventions Drug-free residential programs Peer support groups Other

48 Vivitrol Claims

49 Challenges/Areas of Concern Increase in opioid related deaths Appropriate prescribing practices Appropriate use of support services

50 PA Initiatives to Address Issue OMHSAS/DDAP Partnership Opioid Workgroups Practice Guidelines Take Back Programs Benzodiazepine Prior Authorization Prescription Drug Monitoring Program Legislation

51

52 Conflicts of Interest None

53 Overview Diagnosis Scope Treatment Options Challenges Warning Signs Tom Corbett, Tom Governor Corbett, Beverly Governor Mackereth, Beverly Secretary Mackereth, Acting Dennis Secretary Marion, Deputy Dennis Secretary Marion, OMHSAS Deputy Secretary OMHSAS

54 Drug Utilization Past Month Illicit Drug Use among Persons Aged 12 or Older: 2012

55 Heroin Use Statistics

56 Drug Utilization Past Month Illicit Drug Use among Persons Aged 12 or Older, by Age: 2011 and 2012

57 Drug Utilization Past Month Illicit Drug Use among Persons Aged 12 or Older, by Race/Ethnicity:

58 Past Month Drug Use Past Month Illicit Drug Use among Persons Aged 18 or Older, by Employment Status: 2011 and 2012

59 Past Month Drug Use Age 12 and older Past Month Illicit Drug Use among Persons Aged 12 or Older, by County Type: 2012

60 Pain Relievers-Nonmedical Use Where Pain Relievers Were Obtained for Most Recent Nonmedical Use among Past Year Users Aged 12 or Older:

61 Illicit Drug Use Age 12 or older First Specific Drug Associated with Initiation of Illicit Drug Use among Past Year Illicit Drug Initiates Aged 12 or Older: 2012

62 Specific Illicit Drugs Past Year Initiates of Specific Illicit Drugs among Persons Aged 12 or Older: 2012

63 Illicit Drugs-Age Specific Mean Age at First Use for Specific Illicit Drugs among Past Year Initiates Aged 12 to 49: 2012

64 Treatment Locations Locations Where Past Year Substance Use Treatment Was Received among Persons Aged 12 or Older: 2012

65 Most Recent Substance Treatment Substances for Which Most Recent Treatment Was Received in the Past Year among Persons Aged 12 or Older: 2012 Past Year among Persons Aged 12 or Older: 2012

66 Recent Treatment-Pain Relievers Received Most Recent Treatment in the Past Year for the Use of Pain Relievers among Persons Aged 12 or Older:

67 Drug Dependence or Abuse

68 Single Day Counts

69 Buprenorphine Treatment

70 Illicit Drug Dependence or Abuse

71 Past Year Drug Use Treatments

72 Overdose Deaths in PA Overdose Deaths in Pennsylvania In 1990, note for the 64 grey counties, the death rate is too low to be accurately counted, at less than 3 deaths per 1,000 citizens. The state average is 2.7 deaths per 1,000 citizens, so any colored counties are above average, while grey is below average.

73 Overdose in PA In 2000, note for the 52 grey counties, the death rate is too low to be accurately counted, at less than 3 deaths per 1,000 citizens. The state average is 7.4 per 1,000 citizens, so the light blue, yellow and orange counties are above average, while grey and dark blue are below average.

74 Prescription Opioids Use Prescription opioids: use Prescription opioids frequently used by adult enrollees 28.3% with any short-acting use in % with any long-acting use Most use for short duration 40.8% filled single prescription in % had <30 days supply *Julie Donohue, PhD Associate Prof University of Pittsburgh

75 Prescription Opioids Prescription opioids: the prescribers Primary care, emergency medicine physicians, dentists are top prescribers 48% opioid prescribers are PCPs 22% are EM physicians 17% are dentists These three specialties write 84% of opioid scripts PCPs write 65% of scripts ED physicians write 10% Dentists write 9% *Julie Donohue, PhD Associate Prof University of Pittsburgh

76 Medication Misuse Misuse is defined as non-adherence to prescription directions and can be either willful or accidental. One-quarter of the prescription drugs sold in the United States are used by the elderly, use more meds than any other age group. Older adults are likely to experience more problems with relatively small amounts of medications because of increased medication sensitivity as well as slower metabolism and elimination. Factors associated with prescription medication misuse and abuse by older adults include female sex, social isolation, history of substance use or psychiatric disorder, poly-pharmacy, and chronic medical problems. Commonly prescribed drugs with misuse potential include those for anxiety, pain, and insomnia, such as benzodiazepines, opiate analgesics, and skeletal muscle relaxants.

77 Risks Populations Who is at greatest risk for medication misuse/abuse? Factors associated with prescription drug misuse/abuse in older adults Female gender Social isolation History of a substance abuse History of or mental health disorder older adults with prescription drug dependence are more likely than younger adults to have a dual diagnosis Medical exposure to prescription meds with abuse potential (Source: Simoni-Wastila, Yang, 2006)

78 Emergency Department Use Emergency Department (ED) Use Related to Misuse/Abuse One fifth of ED visits involving prescription medication misuse/abuse among adults were made by persons aged 70 or older Medications involved in ED visits made by older adults: - Pain relievers (43.5%) - Medications for anxiety or insomnia (31.8%) - Antidepressants (8.6%) In 2008, there were 256,097 such visits, representing an increase of percent 37.5% were admitted to the hospital SAMHSA, DAWN Report, 2010

79 Intervention Referral Simple vs Brief Intervention Referral Attended 1 st Appointment Motivational Session 70% Control Group 32% p =.006 Zanjani F, Oslin D (2005). Telephone Based Referral-Care Management. Grant Supported by Philadelphia Veteran s Affairs: Mental Illness Research Education and Clinical Center (MIRECC)

80 Brief Advice Brief Advice Shown to decrease drinking and adverse health outcomes Two components: Advice Link drinking to health Recommended by the US Preventative Task Force

81 Overdose Deaths In Pa Overdose Deaths in Pennsylvania Number of Age Group Deaths Population Rate per 1, ,886 ### ,257 ### ,882 ### , , , , , , , , , , , ,334 ### ,151 ### ,139 ### , Based on Pennsylvania Department of Health data, overdose deaths in 2011 have the highest rates in age These rates decline with age, but increase again after age 85. Rates among older adults are on the rise.

82 Yearly Statistics in Pa Overdose Deaths in Pennsylvania Drug Overdose Deaths in Pennsylvania Year Number of Deaths PA Population Rate per 1, ,909 12,742, ,550 12,702, ,522 12,448, ,344 12,440, ,278 12,406, ,335, ,281, ,001, ,056, ,052, ,995, ,881, Based on Pennsylvania Department of Health data, overdose deaths have been on the rise over the last two decades with an increase in the rate of death from 2.7 to 15.4 per thousand Pennsylvanians

83 Opioid Use Disorder A problematic pattern of opioid use leading to clinically significant impairment or distress is manifested by two or more of the following within a 12-month period: 1. Opioids are often taken in larger amounts or over a longer period than was intended. 2. Persistent desire or unsuccessful efforts to cut down or control opioid use 3. Great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects 4. Craving, or a strong desire or urge to use opioids 5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home 6. Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids 7. Important social, occupational, or recreational activities are given up or reduced because of opioid use. 8. Recurrent opioid use in situations in which it is physically hazardous 9. Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance 10. Tolerance 11. Withdrawal

84 Opioid Treatment Medication Assisted Treatment Opioid Agonist Opioid Antagonist Drug-free (Medication-free) Treatment

85 Overview of Medications for Opiate Assisted Treatment Overview of Medications for Opiate Assisted Treatment Methadone Buprenorphine Naltrexone Vivitrol Pro Prevents withdrawal symptoms Decreases risky behavior Decreases criminality Allows counseling Promotes access to medical/psychiatric care Promotes rehabilitation Cost as low as $5 per week Dose: Most patients receive mg/day but some receive as much as 325mg/day Less tightly controlled than methadone Lower potential for abuse and are less dangerous in an overdose Progress in therapy may allow for a take-home supply of the medication Prevents Withdrawal Prevents Craving Does not produce a High Blocks or reduces the effect of heroin Reduced diversion issues Fewer transportation issues Better compliance than methadone Dosing every 2-3 days No opiate effect benefits (i.e. high) More limited side effects Helps manage cravings/ relapse risk Benefits found for multiple addictive behaviors including opiates, alcohol and gambling disorders Used to treat alcoholism and heroin addiction Monthly injections block the brain s ability to get intoxicated or high Prospective clients must be sober for at least 7 days prior to beginning treatment Has other side effects like other medications Improved compliance Con Diversion potential Abuse Potential Does not address the effects/use of other substances (e.g. alcohol or benzos) Daily dosing requirements Transportation issues for daily dose Intense withdrawal from medication Higher cost Does not address the effects/use of other substances (e.g. alcohol or benzos) Note: Suboxone consists of a combination of Buprenorphine and Naloxone Possible dysphonic effects High non-compliance rates (self administered, so it is easy to stop) Early gastrointestinal discomfort Expensive for those without insurance coverage ($ /month avg.) High Cost

86 NTP 65 free standing clinics and 4 hospital based Serving over 14,000 individuals

87 Methadone Long Term Care Clinics Delivery by County System Sub-Committee Understanding Older Adults with Behavioral Health Needs Pennsylvania Osteopathic Family Physicians Society August 2, 2014 Tom Corbett, Governor Beverly Mackereth, Acting Secretary Dennis Marion, Deputy Secretary OMHSAS

88 Opioid Agonist Methadone A meta-analysis of 1969 participants in 11 randomized trials compared methadone maintenance therapy to placebo or nonmedication treatment for opioid dependence (Mattick BP et al, Cochrane Database Sys Rev 2009) A 10-year follow up study of 405 patients randomly assigned to receive either methadone or buprenorphine found an association between the duration of treatment with either medication and lower rates of mortality. (Gibson A., et al, Addiction 2008)

89 Methadone Prescribed by NTP Usually mg daily Side effects include constipation, mild drowsiness, excess sweating, and peripheral edema Arrhythmias Overdose

90 Buprenorphine Partial Opioid Agonist Schedule III A meta-analysis that included 4497 participants in 24 randomized trials found that sublingual buprenorphine improved treatment retention and reduced opioid use in patients with opioid dependence compared to placebo treatment Most patients will stabilize on 16 to 20 mg/day of buprenorphine

91 Buprenorphine Use 37% increase in buprenorphine use in 2 years 12,588 (1.1%) enrollees in ,189 (1.5%) enrollees in % of buprenorphine users have an OUD diagnosis recorded in claims *Julie Donohue, PhD Associate Prof University of Pittsburgh

92 Buprenorphine Buprenorphine: the prescribers Most (77.6%) buprenorphine prescribers are primary care providers Psychiatrists and emergency medicine physicians account for another 14.4% of prescribers These 3 specialties write 92% of buprenorphine prescriptions *Julie Donohue, PhD Associate Prof University of Pittsburgh

93 Naltrexone Opioid Antagonist Effective in patients highly motivated A meta-analysis of 1158 participants in 13 randomized trials compared oral naltrexone maintenance treatment to either placebo or non-medication treatment. No difference was seen between the two groups in sustained abstinence or most other primary outcomes (Minozzi et al, Cochrane Database Sys Rev 2011) 50 mg tablet once daily

94 Long Acting Naltrexone A trial randomly assigned 60 patients with heroin dependence to receive injectable depot naltrexone (Comer et al, AGP 2006) A trial compared a once-monthly, injectable depot formulation of naltrexone to placebo in 250 patients with opioid dependence over 24 weeks (Krupitsky et al, Lancet 2011) A trial in 100 heroin and amphetamine-dependent outpatients compared the efficacy of naltrexone implants to placebo (Tiihonen et al, AJP May 2012)

95 Psychosocial Treatments A National Institutes of Health Consensus Conference in the US concluded that non-pharmacologic supportive services are pivotal to successful treatment (JAMA 1998) Individual and group drug counseling Specific psychosocial interventions Drug-free residential programs Peer support groups Other

96 Vivitrol Claims

97 Challenges/Areas of Concern Increase in opioid related deaths Appropriate prescribing practices Appropriate use of support services

98 PA Initiatives to Address Issue OMHSAS/DDAP Partnership Opioid Workgroups Practice Guidelines Take Back Programs Benzodiazepine Prior Authorization Prescription Drug Monitoring Program Legislation

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