1 Michael E. DeBakey VA Medical Center"Prescribing Controlled Substances: Problematic Use of Opioids and Benzodiazepines in Clinical Care" Daryl Shorter, MD Staff Psychiatrist Michael E. DeBakey VA Medical Center March 2, 2017

2 Objectives - By the completion of the presentation, learners will be able to: (1) List risk factors for misuse, diversion, and/or dependence upon opioid medications and benzodiazepines (2) Identify clinical scenarios in which there is problematic use/prescribing of opioid medications and benzodiazepines (3) Employ treatment algorithms to successfully taper opioid medications and benzodiazepines (4) Discuss strategies for patient monitoring and mitigating risk factors for opioid and benzodiazepine misuse

3 Definitions Misuse Diversion Dependence

4 Definitions Misuse Diversion Dependence

5 Misuse (1) Any medication use that occurs without prescription (therapeutic benefit v intoxication?) Legitimately prescribed medication used for intoxication/euphoria Medication use in context of dependence (methadone, buprenorphine)

6 Misuse (2) Motives for Non-Prescribed Medication Use IntoxicationHigh dose, intravenous Combined with alcohol or other drugs Therapeutic use Bona fide condition/appropriate indication Correct dosing pattern Barrett SP et al. What constitutes prescription drug misuse? Problems and current conceptualizations. Curr Drug Abuse Reviews. 2008;1:

7 Misuse (3) Group differences Adolescents College students Older adultsSedative/hypnotics, opiates = therapeutic > recreation Stimulant medications = recreation College students Therapeutic benefit > recreation Older adults Withdrawal, dependence

8 Misuse (4) Quasi-legitimate Reasons? Immediate/acute needUnable to seek formal medical consultation Barriers to access Socioeconomic Geographic Temporal Provider reluctance to prescribe Under-medication

9 Misuse (5) Clinical implications of different forms of misuseIncreased risk of overdose Mitigation of other substance effects

10 Definitions Misuse Diversion Dependence

11 Diversion Exchange of prescription medicationsLeads to drug use by unintended persons Under conditions associated with “Doctor shopping” Misrepresentation of medical problems Theft Trading, selling, loaning, giving away

12 Diversion (2) Gender differences in diversion patterns20% of girls, 13% of boys borrow and/or share medications Of the girls 16% borrowed 15% shared 7% shared meds more than 3 times

13 Diversion (3) Motivations for sharing drugs & genderReceiving person ran out of drug: 40% of girls, 27% of boys Received from family: 33% of girls, 27% of boys Daniel KL et al. Sharing prescription medication among teenage girls: potential danger to unplanned/undiagnosed pregnancies. Pediatrics 2003;111:

14 Definitions Misuse Diversion Dependence

15 Dependence Physiological and/or psychological CompulsiveUse despite negative consequences Compulsive, rather than impulsive

16 Risk Factors - Opioids Personal Hx of Substance AbuseRx drugs > Illegal drugs > Alcohol Family Hx of Substance Abuse Equivalent danger of illegal drugs and EtOH in men

17 Risk Factors - Opioids Age between 16-45 yearsHistory of preadolescent sexual abuse Psychological/mental health concerns ADD, OCD, Bipolar disorder, Schizophrenia Depression

18 Naturally occurring - Opium - Morphine - Codeine- The nectar of the opium poppy (native to southeastern Europe and western Asia (Iran, Turkey, Holland, Poland, Romania, the former Czechoslavakia, Yugoslavia, and India, as well as Canada, Central and South American countries The nectar, or latex, is harvested from immature seed capsules after the poppy has flowered and is collected by making incisions in the wall of the seed pods The latex exudates are collected and dried Opium, morphine, and codeine can be isolated from this material Opium poppy, Papaver somniferum

19 Opioid Formulations Morphine Hydromorphone Oxycodone OxymorphoneOral immediate-release: MSIR® Oral extended-release: MS Contin®, Oramorph®, Avinza®, Kadian® Others: solution, suppositories, intravenous Hydromorphone Oral immediate-release: Dilaudid® Oxycodone Oral immediate-release: Oxy IR®, Roxicodone Oral extended-release: Oxycontin® Others: solution Oxymorphone Oral immediate-release: Opana® Oral extended-release: Opana ER® Others: intravenous

20 Mixed agonists/ antagonistsOpioid Formulations Fentanyl Transdermal patch: Duragesic® Oral lozenge: Actiq® Others: intravenous Methadone Oral immediate-release: Methadose®, Dolophine® Others: solution, intravenous Meperidine Oral immediate-release: Demerol®, Mepergan® Others: solution, intravenous Mixed agonists/ antagonists Butorphanol (Stadol®), Nalbuphine (Nubain®) Pentazocine (Talwin®) Partial agonists Buprenorphine (Subutex®, Suboxone®)

21 Opioid Formulations Combination Products HydrocodoneLortab®, Lorcet®, Vicodin®, Norco® Oxycodone Percocet®, Endocet®, Roxicet®, Combunox® Codeine Tylenol #3®, Tylenol #4® Propoxyphene Darvocet®

22 20.8 million Americans (~8%) current users of illicit substances2.6 million persons with Opioid Use Disorder 2.0 million persons with pain reliever abuse or dependence 591,000 persons with heroin abuse or dependence

23 ED Visits for Drug Misuse

24 DAWN (2009) 1.2 million ED visits involving nonmedical use of pharmaceutical or dietary supplement Hydrocodone (alone or in combination) 104,490 ED visits Oxycodone (alone or in combination) 175,949 ED visits Methadone (alone or in combination) 70,637 ED visits These 3 medications account for roughly 30% of the ED visits involving nonmedical use of pharmaceuticals/dietary supplements

25 CASE – Steve 62y Vietnam Era male veteran presents to PCP PMHx PSHxHTN ─ GERD Hypercholesterolemia ─ Obesity Gout ─ Chronic back pain Chronic shoulder pain PSHx Right knee arthroscopy x 2 Left shoulder – rotator cuff repair

26 CASE – Steve PΨHx Medications Major Depression ─ Generalized AnxietyLisinopril ─ Gemfibrozil HCTZ ─ Simvastatin Allopurinol ─ Omeprazole Citalopram ─ Trazodone Sildenafil PRN ─ Hydrocodone 10mg Q4H

27 CASE – Steve Family Hx Substance Use HxDad – CAD, MI, Alcohol Use Disorder Mom – HTN, DM, Dementia Brother – CAD, Obesity, Alcohol Use Disorder Substance Use Hx “Social” alcohol – two 6pks of beers on weekends Denies tobacco or illicit substance use

28 CASE – Steve Exam (pertinent findings)Appearance: Older than stated age, but NAD Gastrointestinal: protuberant abdomen, no TTP, HSM Musculoskeletal: TTP R shoulder (subscapular region); ↓(?) ROM with lateral arm raise; no ROM deficits for trunk/lower back; gait WNL Mental Status: Mild dysphoric mood, anxiety

29 Strategic Focus Accurate diagnosis Appropriate pharmacotherapyReferral to specialty services

30 Three Common Scenarios…Patient presents with previous or self-diagnosis of Opioid Use Disorder (OUD) Suspicion of OUD Self Referring provider Family Incidental finding of OUD Suspicion of OUD seems to be most common. There are cases where PCPs or surgeons refer to psychiatrist because the patient is unable to wean off medications, expresses a great deal of anxiety about discontinuation, family may provide collateral information, or during the course of treatment, we as the psychiatrist begin to develop concern secondary to overt statements or through implication Incidental finding – thinking of those cases where UDS finds opioids that should not be there, patients admitted to medical or psychiatric units for another reason and then opioid withdrawal sets in

31 DSM-5 Opioid Use DisorderOpioid Intoxication Opioid Withdrawal Opioid Delirium (Intoxication/Withdrawal) Opioid Depressive Disorder (I/W) Opioid Panic and Anxiety Disorder (W) Opioid Induced Sexual Dysfunction (I/W) Opioid Sleep Disorder (I/W)

32 DSM-5 Opioid Use DisorderTolerance Withdrawal Attempts to cut down Much time spent using Use larger amounts Neglecting roles Hazardous use Physical/psychological problems from use Social/interpersonal problems from use Activities given up Craving Talk about CROSS tolerance

33 OUD Specifiers In early remission – none of the criteria met for at least 3 months, but less than 12 months In sustained remission – none of the criteria met for 12 months or longer Note: Craving may be present!

34 OUD Specifiers On maintenance therapy In a controlled environmentMethadone Buprenorphine Naltrexone (oral or depot) In a controlled environment

35 OUD Caveats Symptoms of tolerance and withdrawal occurring during appropriate medical treatment are not counted when diagnosing SUD Opiates are not listed in DSM-5 as causative agent for substance-induced psychosis

36 Opioid Intoxication Small, constricted pupils Slowed breathingDecreased alertness Decreased HR, BP Reports of fatigue

37 Opioid Withdrawal Dysphoric (sad) mood Muscle achesLacrimation (tearing) or rhinorrhea (runny nose) Pupillary dilation, piloerection (goose flesh), or sweating Nausea/vomiting Diarrhea Yawning Fever Insomnia

38 Assessment Clinical Opiate Withdrawal Scale Resting heart rateSweating Restlessness Pupil size (dilation) Bone/Joint aches Runny nose or tearing GI upset Tremor (outstretched hands) Yawning Anxiety Gooseflesh skin Score = Mild 13-24 = Moderate 25-36 = Moderately Severe More than 36 = Severe

39 Assessment “Has a family member ever expressed concern about your Rx opioid use?” “Has a physician ever expressed concern about your Rx opioid use?” “Have you ever used your Rx opioid to treat other symptoms (e.g., sleep, irritability, sadness) These are among the questions with high predictive value in regards to OUD diagnosis, particularly since those with OUD in comparison to those without OUD are much more likely to report a “yes” or affirmative answer to these questions. Adapted from Prescription Drug Use Questionnaire (PDUQ)

40 DSM-5 Opioid Use DisorderOpioid Intoxication Opioid Withdrawal Opioid Delirium (Intoxication/Withdrawal) Opioid Depressive Disorder (I/W) Opioid Panic and Anxiety Disorder (W) Opioid Induced Sexual Dysfunction (I/W) Opioid Sleep Disorder (I/W)

41 Assessment Aberrant drug related behaviorsMultiple prescribers Early prescription refills Dose/frequency escalation ER visits for analgesics Use of alcohol/psychoactive drugs Taking a family member’s medication Personal history of opioid detox

42 Assessment PMP AWARxE Urine drug screeningPrescription drug monitoring program through Texas State Board of Pharmacy Urine drug screening

43 CASE – Steve You are concerned that Steve may have OUD, but decide a short-term prescription for opioids is appropriate while laboratory studies and imaging are obtained You decrease from Hydrocodone 10mg Q4H PRN to Hydrocodone 10mg Q6H PRN

44 CASE – Steve Lab WNL UDS +opiates; negative MJ, bzdp, coc ImagingPrevious right shoulder procedure Mild osseous changes in lower spine

45 CASE – Steve Visit #2 Reports ↓ hydrocodone  ↑ shoulder/lower back pain Diminished activity, functioning ↑ Depression/anxiety

46 Strategic Focus Accurate diagnosis Appropriate pharmacotherapyReferral to specialty services

47 Patient diagnosed with OUDYes Naloxone Overdose? No Acute intoxication/withdrawal? Medical complications? Yes No Inpatient Admission Outpatient Management As with all clinical scenarios, must first assess the patient, collecting history (if possible), performing physical examination, and collecting labs. Study out of Norway looked prospectively at cases where Naloxone was used in heroin overdose. Found that nearly half (45%) of the 1192 episodes where Naloxone was used were associated with adverse effects attributed to the medication. Most common adverse events related to opioid withdrawal (33%), followed by confusion/restlessness (32%), and HA/sz (25%) Abrupt Discontinuation Plus Clonidine Opioid Substitution with Taper Opioid Agonist (Methadone, Buprenorphine) Naltrexone (oral or sustained release)

48 Clonidine DetoxificationDay From short-acting opioid (heroin, oxycodone) From methadone (25mg or less) 1 mg/day (includes 0.1-mg test dose) 2 mg/day mg/day 3-6 mg/day, then reduce daily dose by 50% each subsequent day; daily reductions not to exceed 0.4mg mg/day 6-10 Consider more gradual taper of clonidine (by mg/day) in order to avoid rebound hypertension, headaches Adapted from Kosten & Kleber, 1994

49 Clonidine Most effective in suppressing autonomic signs of withdrawal, less effective for subjective symptoms Lethargy, restlessness, insomnia, craving are likely to persist Adjuvant therapy may be needed NSAIDs (for myalgia) Trazodone (for insomnia) Antiemetics (for GI distress) Propranolol (for restlessness) Can allow COWS score to objectively determine if more methadone is needed

50 Withdrawal Management (1)Symptom-triggered clonidine Rx For COWS > 8, give mg clonidine On day 1, target dose of mg May  to mg/day, as necessary Once stabilized, reduce daily dose by 50% per day

51 Clonidine Agonist Opioid Withdrawal Antagonist Long term Rx of OUD

52 Withdrawal Management (2)Use opioid agonist to  symptoms Methadone Up to 30mg/day  10-20% every 1-2 days over 2-3 weeks Better than α2-adrenergic agonist based Rx Buprenorphine Up to 8mg/day ↓ by 2mg every 1-2 days over 7-10 days

53 Clonidine Agonist Opioid Withdrawal Antagonist Long term Rx of OUD

54 Long-term Rx of OUD Opioid Antagonist TherapyIntramuscular naltrexone (Vivitrol) Administer every 30 days Prevents opioid high Low compliance No other FDA-approved medications

55 Long-term Rx of OUD (2) Methadone maintenance treatment (MMT)Taken daily by mouth Obtained through federally-regulated program Optimal dose varies (target = 80mg/day) -- Must ↑ dose slowly to avoid OD

56 MMT Drawbacks Overdose common in early treatmentCannot be prescribed from general practice Strict government control and paperwork Stigma of daily clinic attendance

57 Office-Based BuprenorphineTaken daily, sublingually Rx in offices of physicians with special training Individual dose varies (target = 16-24mg/day) Daily visits not necessary Alcohol Medical Scholars Program

58 Buprenorphine PharmacologyPartial agonist at μ-opioid receptor Slow dissociation from receptor Half-life = hrs Metabolizes quickly, if give orally So Rx is sublingual or buccal Alcohol Medical Scholars Program

59 Buprenorphine Pharmacology (2)Clinical impact Less subjective euphoria than methadone Long-lasting clinical action Partially blocks intoxication Reduced overdose risk Alcohol Medical Scholars Program

60 Alcohol Medical Scholars ProgramFormulations Buprenorphine alone (Subutex) Buprenorphine + naloxone (Suboxone) Naloxone = antagonist  risk of diversion and IV misuse Combined in 4 mg bup:1 mg naloxone Combo in sublingual or buccal film Alcohol Medical Scholars Program

61 More Buprenorphine InfoSide effects Neuro: Sedation, dizziness, headache GI: Constipation, nausea/vomiting Respiratory depression Availability and cost Prescribed by MDs with special training Reimbursed by Medicaid, health insurances ─ But costs more than methadone Alcohol Medical Scholars Program

62 Buprenorphine TreatmentInitiation Goal: avoid precipitated withdrawal & OD Patient stops opioid misuse hrs prior Patient demonstrates early withdrawal COWS rating > 8 Alcohol Medical Scholars Program

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64 CASE – Alfred 57y Vietnam Era male veteran presents to PCP PMHx PSHxHTN ─ Migraine HAs Chronic pain ─ Gastritis Gastric neoplasm (benign) PSHx Tonsillectomy – childhood Multiple EGDs

65 CASE – Alfred PΨHx Medications Major DepressionLisinopril ─ Omeprazole ASA ─ Sumatriptan PRN Loratadine ─ Alprazolam (Xanax) 2mg TID Hydrocodone 5mg Q6H PRN

66 CASE – Alfred Family Hx Substance Use Hx Dad – CVA, DMMom – Depression, HTN, obesity Substance Use Hx Alcohol – oz. beers/session ~1-2x/week Occasional marijuana (<1 joint/use) H/o cocaine use in 20s and 30s

67 CASE – Alfred Vague report “Do I have to answer that?”6-year history of Alprazolam use Obtained from both providers and illicit sources Anxious between dosages Insomnia if he runs out

68 CASE – Alfred Exam (pertinent findings)Appearance: Older than stated age, fidgety Gastrointestinal: protuberant abdomen mild TTP, no HSM Mental Status: Mildly dysphoric, anxious appearing and irritable

69 BZD Formulations Diazepam Alprazolam Clonazepam LorazepamOral immediate-release: Valium®, Diastat® Others: intramuscular, intravenous, suppository Alprazolam Oral immediate-release: Xanax® Oral extended-release: Xanax-XR® Others: solution Clonazepam Oral: Klonopin®, Klonopin wafer® Others: orally disintegrating tablet Lorazepam Oral immediate-release: Ativan® Others: intramuscular, intravenous, sublingual, solution

70 Indications (FDA) Alcohol withdrawal Insomnia Anxiety disordersPanic disorder Muscle relaxant Antiepileptic Anesthesia adjunct Alcohol withdrawal: Tx of choice for alcohol withdrawal syndrome. Use with Clinical Institute Withdrawal Assessment for Alcohol (CIWA) Insomnia: Not 1st choice! Ramelteon 1st choice Sleep initiation Triazolam Sleep maintenance Temazepam Panic disorder: Efficacy of benzodiazepine for panic d/o is comparable to SRRI’s, SNRI’s, and tricyclic antidepressant ( TCA’s) Use benzodiazepine in the first 2-3 week after initialing SSRI’s, SNRI’s, and TCA’s, etc Cochrane review found that adding a benzodiazepine to CBT didn’t lead to significant results then CBT alone. Generalized anxiety disorder (GAD): Studies show SSI’s, SNRI’s, and pregabalin comparable to benzodiazepine. Use benzodiazepine in the first 2-3 week after initialing SSRI’s, SNRI’s, etc. 2nd line treatment for treatment-resistant GAD Social anxiety: Meta-analysis found that for treating social anxiety, benzodiazepines have better efficacy then SSRI’s, monoamine oxidase inhibitors, and anticonvulsants

71 Clinical use (non FDA) Catatonia Agitation Abnormal movementsTourette’s syndrome Delirium

72 Epidemiology (1) 2011: Alprazolam, Lorazepam, Diazepam were the most common prescribed 2011: million Alprazolam prescriptions written (137 million Hydrocodone Rx) 2.3% of adults in US report nonmedical use of sedatives 10% of those meet criteria for abuse or dependence These benzo related ED visits From SAMHSA NSDUH (2012), DAWN (2010)

73 Epidemiology (2) 2011: 345,528 ER visits related non illicit drugs25% related with non medical use of BZD 10% Alprazolam 5% Clonazepam 3.5% Lorazepam 2% Diazepam 41,257 (3.3%) ER visits related non medical use of SSRIs From SAMHSA NSDUH (2012), DAWN (2011)

74 BZD & Mental Health (1) 30% of psychiatry pts receive BZDAffective disorders Long duration of illness High utilizers of psychiatric services

75 BZD & Mental Health (2) High risk patientsPersonal AUD history (15-20% misuse BZD) Family h/o of alcohol use disorder Personal h/o of opioid use disorder Methadone maintenance (47%) Say this part: including those on maintenance treatment

76 BZD and Suicide 2009: 2nd most common class of drug used in suicide attempt Alprazolam most commonly used BZD in SA (12%) Clonazepam second most common (8%) Zolpidem third most common (6%) From SAMHA 2011.

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78 CASE – Alfred You are concerned about Alfred’s combined use of BZD and opiates as well as his patterns of BZD use. You decide a taper off the BZD is appropriate

79 Assessment “Legitimate” Prescription BZD Use DisorderGOAL: Treat underlying illness FOCUS: Assess risk of SUD GOAL: Confirm SUD dx FOCUS: Safe discontinuation

80 Clinical Approach (1) Identify risk factorsCo-occurring SUD or psychiatric d/o Highest abuse: diazepam, lorazepam, alprazolam Prior BZD treatment > 8 wks

81 Clinical Approach (1) Minimize potential harmsAggressive short-term treatment Use high dose over few weeks while SSRI/SNRI take effect Short-term treatment PRN versus continuous schedule Drug holiday implementation Intermittent use of medication Only during high demand situations

82 Clinical Approach (2) Recognize TYPES of BzUDUnderlying (anxiety) disorder; tolerant Recreational user Complicated High-dose Poly-BZD use

83 Clinical Approach (2) DSM V Criteria for SUDAberrant drug related behaviors Early refills, ER visits Multiple providers Taking the medication as prescribed UDS + for illicit substances

84 BZD Discontinuation (1)Convert from fast/short acting to slow/long acting BZD over 2-4 weeks Drug Comparative dose Diazepam 5mg Alprazolam 0.5mg Clonazepam 0.25mg Lorazepam 1mg Chlordiazepoxide 25mg Temazepam 10mg Pregabalin  shown to improve insomnia during withdraw from long-term benzodiazepine use

85 BZD Discontinuation (2)Cross taper with alternative agent GABAergic Buspirone Valproate** Carbamazepine Gabapentin Pregabalin Serotonergic TCA (Imipramine) Pregabalin  shown to improve insomnia during withdraw from long-term benzodiazepine use **indicates improved rates of long-term abstinence

86 BZD Discontinuation (3)Cross taper with medication for anxiety reduction Hydroxyzine Quetiapine Trazodone** Inpatient management Flumazenil Flumazenil  shown to reduce craving and improve 1 month post-treatment abstinence rate. Only draw back is risk of seizure

87 Patient is overtaking benzodiazepineNo Wean patient gradually Does the patient have primary anxiety disorder? Yes GAD PTSD OCD PANIC D/O SOCIAL ANXIETY

88 Wean patient graduallyNo Use greater than 1 yr? Decrease the total daily dose by 25% in the first week STEP 1 Decrease by 10% q1-2wks STEP 1 Yes When 20% of the original dose remains then decrease 5% reduction of dose q2-4wks. STEP 2 Another 25% on week two STEP 2 Followed by 10% per week until d/c STEP 3

89 Currently taking an SSRI/SNRI?Anxiety d/o No Currently taking an SSRI/SNRI? Yes Start SSRI/SNRI + Switch to long acting BZD Maximize SSRI/SNRI + Switch to long acting BZD & initiate taper Yes Continue AD + Wean BZD, if possible Sx controlled? Imipramine, buspirone, gabapentin, VPA, CBZ. Cont to wean off BDZ if possible No

90 Take Home Points Risk Factors for Opioid MisusePersonal or family h/o substance use Age (16-45y) Psychiatric conditions (such as MDD, OCD, SCZ) Preadolescent sexual abuse (women)

91 Take Home Points Risk Factors for BZD Use DisorderPersonal h/o substance use Long term BZD use High dose BZD use Concomitant opioid use (esp. Methadone)

92 Take Home Points Screening and assessment should include urine drug screening Initiation of taper should take into consideration length of time patient has been on medication and may require patience