"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

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

Definitions

• Misuse

• Diversion

• Dependence

Definitions

• Misuse

• Diversion

• Dependence

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)

Misuse (2) • Motives for Non-Prescribed Medication Use

– Intoxication

• High 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;1:255-62.

Misuse (3) • Group differences

– Adolescents • Sedative/hypnotics, opiates = therapeutic > recreation

• Stimulant medications = recreation

– College students • Therapeutic benefit > recreation

– Older adults • Withdrawal, dependence

Misuse (4) • Quasi-legitimate Reasons?

– Immediate/acute need

– Unable to seek formal medical consultation

– Barriers to access

• Socioeconomic

• Geographic

• Temporal

– Provider reluctance to prescribe

– Under-medication

Misuse (5) • Clinical implications of different forms of

misuse

– Increased risk of overdose

– Mitigation of other substance effects

Definitions

• Misuse

• Diversion

• Dependence

Diversion • Exchange of prescription medications

• Leads to drug use by unintended persons

• Under conditions associated with

– “Doctor shopping”

– Misrepresentation of medical problems

– Theft

– Trading, selling, loaning, giving away

Diversion (2) • Gender differences in diversion patterns

– 20% of girls, 13% of boys borrow and/or share medications

– Of the girls

• 16% borrowed

• 15% shared

• 7% shared meds more than 3 times

Diversion (3) • Motivations for sharing drugs & gender

– Receiving 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;111:1167-70.

Definitions

• Misuse

• Diversion

• Dependence

Dependence

• Physiological and/or psychological

• Compulsive

• Use despite negative consequences

Risk Factors - Opioids • Personal Hx of Substance Abuse

– Rx drugs > Illegal drugs > Alcohol

• Family Hx of Substance Abuse

– Rx drugs > Illegal drugs > Alcohol

– Equivalent danger of illegal drugs and EtOH in men

Risk Factors - Opioids • Age between 16-45 years

• History of preadolescent sexual abuse

• Psychological/mental health concerns

– ADD, OCD, Bipolar disorder, Schizophrenia

– Depression

Opium poppy, Papaver somniferum

Naturally occurring - Opium - Morphine - Codeine

Opioid Formulations

Morphine

Oral immediate-release: MSIR®

Oral extended-release: MS Contin®, Oramorph®,

Avinza®, Kadian®

Others: solution, suppositories, intravenous

Hydromorphone Oral immediate-release: Dilaudid®

Others: solution, suppositories, intravenous

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

Opioid 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®)

Opioid Formulations • Combination Products

Hydrocodone Lortab®, Lorcet®, Vicodin®, Norco®

Oxycodone Percocet®, Endocet®, Roxicet®, Combunox®

Codeine Tylenol #3®, Tylenol #4®

Propoxyphene Darvocet®

20.8 million Americans (~8%) current users of illicit substances

2.6 million persons with Opioid Use Disorder

2.0 million persons with pain reliever

abuse or dependence

591,000 persons with heroin abuse or

dependence

ED Visits for Drug Misuse

0

50,000

100,000

150,000

200,000

250,000

2004 2005 2006 2007 2008 2009

Heroin

Hydrocodone

Oxycodone

Methadone

Morphine

http://DAWNinfo.samhsa.gov/data/report.asp?f=Nation/AllMA/Nation_2009_AllMA_ED_Visits_by_Drug

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

http://www.nida.nih.gov/infofacts/hospitalvisits.html

CASE – Steve • 62y Vietnam Era male veteran presents to PCP

• PMHx – HTN ─ GERD

– Hypercholesterolemia ─ Obesity

– Gout ─ Chronic back pain

– Chronic shoulder pain

• PSHx – Right knee arthroscopy x 2

– Left shoulder – rotator cuff repair

CASE – Steve • PΨHx

– Major Depression ─ Generalized Anxiety

• Medications

– Lisinopril ─ Gemfibrozil

– HCTZ ─ Simvastatin

– Allopurinol ─ Omeprazole

– Citalopram ─ Trazodone

– Sildenafil PRN ─ Hydrocodone 10mg Q4H

CASE – Steve • Family Hx

– Dad – 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

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

Strategic Focus

• Accurate diagnosis

• Appropriate pharmacotherapy

• Referral to specialty services

29

Three Common Scenarios…

1. Patient presents with previous or self-diagnosis of Opioid Use Disorder (OUD)

2. Suspicion of OUD a) Self

b) Referring provider

c) Family

3. Incidental finding of OUD

30

• Opioid Use Disorder

• Opioid 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)

DSM-5 Opioid Use Disorder

DSM-5 Opioid Use Disorder • Tolerance

• 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

32

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!

OUD Specifiers

• On maintenance therapy

– Methadone

– Buprenorphine

– Naltrexone (oral or depot)

• In a controlled environment

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

Opioid Intoxication • Small, constricted pupils

• Slowed breathing

• Decreased alertness

• Decreased HR, BP

• Reports of fatigue

Opioid Withdrawal • Dysphoric (sad) mood

• Muscle aches

• Lacrimation (tearing) or rhinorrhea (runny nose)

• Pupillary dilation, piloerection (goose flesh), or sweating

• Nausea/vomiting

• Diarrhea

• Yawning

• Fever

• Insomnia

37

Assessment

• Resting heart rate

• Sweating

• Restlessness

• Pupil size (dilation)

• Bone/Joint aches

• Runny nose or tearing

• GI upset

• Tremor (outstretched hands)

• Yawning

• Anxiety

• Gooseflesh skin

Clinical Opiate Withdrawal Scale

Score 5-12 = Mild 13-24 = Moderate 25-36 = Moderately Severe More than 36 = Severe

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)

39

Adapted from Prescription Drug Use Questionnaire (PDUQ)

• Opioid Use Disorder

• Opioid 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)

DSM-5 Opioid Use Disorder

Assessment

• Aberrant drug related behaviors

– Multiple 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 41

Assessment

• PMP AWARxE

– Prescription drug monitoring program through Texas State Board of Pharmacy

– www.pharmacy.texas.gov/PMP

• Urine drug screening

42

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

CASE – Steve • Lab WNL

• UDS +opiates; negative MJ, bzdp, coc

• Imaging

– Previous right shoulder procedure

– Mild osseous changes in lower spine

CASE – Steve • Visit #2

– Reports ↓ hydrocodone ↑ shoulder/lower back pain

– Diminished activity, functioning

– ↑ Depression/anxiety

Strategic Focus

• Accurate diagnosis

• Appropriate pharmacotherapy

• Referral to specialty services

46

Patient diagnosed with OUD

No

Yes

Inpatient Admission

Outpatient Management

Overdose? Naloxone

Acute intoxication/withdrawal? Medical complications?

Yes

No

Naltrexone (oral or sustained

release)

Opioid Agonist (Methadone,

Buprenorphine)

Abrupt Discontinuation Plus Clonidine

Opioid Substitution with Taper

Clonidine Detoxification Day From short-acting opioid (heroin,

oxycodone) From methadone (25mg or less)

1 0.3-0.6 mg/day (includes 0.1-mg test dose)

0.3-0.6 mg/day (includes 0.1-mg test dose)

2 0.4-0.8 mg/day 0.4-0.6 mg/day

3-6 0.6-1.2mg/day, then reduce daily dose by 50% each subsequent day; daily reductions not to exceed 0.4mg

0.5-0.8 mg/day

6-10 0.6-1.2mg/day, then reduce daily dose by 50% each subsequent day; daily reductions not to exceed 0.4mg

Adapted from Kosten & Kleber, 1994

Clonidine Most effective in suppressing autonomic signs of withdrawal, less

effective for subjective symptoms

Adjuvant therapy may be needed • NSAIDs (for myalgia)

• Trazodone (for insomnia) • Antiemetics (for GI distress)

• Propranolol (for restlessness)

Lethargy, restlessness, insomnia, craving are likely to persist

Withdrawal Management (1)

• Symptom-triggered clonidine Rx

– For COWS > 8, give 0.1-0.2mg clonidine

– On day 1, target dose of 0.3-0.6mg

– May to 0.6-1.2mg/day, as necessary

– Once stabilized, reduce daily dose by 50% per day

50

•Clonidine

•Agonist Opioid

Withdrawal

•Antagonist

•Agonist Long term Rx of OUD

51

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 52

•Clonidine

•Agonist Opioid

Withdrawal

•Antagonist

•Agonist Long term Rx of OUD

53

Long-term Rx of OUD • Opioid Antagonist Therapy

– Intramuscular naltrexone (Vivitrol)

• Administer every 30 days

• Prevents opioid high

• Low compliance

– No other FDA-approved medications

54

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

55

MMT Drawbacks • Overdose common in early treatment

• Cannot be prescribed from general practice

• Strict government control and paperwork

• Stigma of daily clinic attendance

56

Office-Based Buprenorphine

• Taken daily, sublingually

• Rx in offices of physicians with special training

• Individual dose varies (target = 16-24mg/day)

• Daily visits not necessary

57 Alcohol Medical Scholars Program

Buprenorphine Pharmacology • Partial agonist at μ-opioid receptor

• Slow dissociation from receptor

• Half-life = 24-36 hrs

• Metabolizes quickly, if give orally

• So Rx is sublingual or buccal

58 Alcohol Medical Scholars Program

Buprenorphine Pharmacology (2)

• Clinical impact

– Less subjective euphoria than methadone

– Long-lasting clinical action

– Partially blocks intoxication

– Reduced overdose risk 59 Alcohol Medical Scholars Program

Formulations • 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

60 Alcohol Medical Scholars Program

More Buprenorphine Info

• Side 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

61 Alcohol Medical Scholars Program

Buprenorphine Treatment • Initiation

– Goal: avoid precipitated withdrawal & OD

– Patient stops opioid misuse 12-36 hrs prior

– Patient demonstrates early withdrawal

• COWS rating > 8 62 Alcohol Medical Scholars Program

CASE – Alfred • 57y Vietnam Era male veteran presents to PCP

• PMHx

– HTN ─ Migraine HAs

– Chronic pain ─ Gastritis

– Gastric neoplasm (benign)

• PSHx

– Tonsillectomy – childhood

– Multiple EGDs

CASE – Alfred • PΨHx

– Major Depression

• Medications

– Lisinopril ─ Omeprazole

– ASA ─ Sumatriptan PRN

– Loratadine ─ Alprazolam (Xanax) 2mg TID

– Hydrocodone 5mg Q6H PRN

CASE – Alfred • Family Hx

– Dad – CVA, DM

– Mom – Depression, HTN, obesity

• Substance Use Hx

– Alcohol – 3-4 12oz. beers/session ~1-2x/week

– Occasional marijuana (<1 joint/use)

– H/o cocaine use in 20s and 30s

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

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

BZD Formulations

Diazepam Oral 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

Indications (FDA) • Alcohol withdrawal

• Insomnia

• Anxiety disorders

• Panic disorder

• Muscle relaxant

• Antiepileptic

• Anesthesia adjunct

Clinical use (non FDA) • Catatonia

• Agitation

• Abnormal movements

• Tourette’s syndrome

• Delirium

Epidemiology (1) • 2011: Alprazolam, Lorazepam, Diazepam were

the most common prescribed

• 2011: 47.8 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

From SAMHSA NSDUH (2012), DAWN (2010)

Epidemiology (2) • 2011: 345,528 ER visits related non illicit drugs

– 25% 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)

BZD & Mental Health (1)

• 30% of psychiatry pts receive BZD

–Affective disorders

–Long duration of illness

–High utilizers of psychiatric services

BZD & Mental Health (2) • High risk patients

– Personal AUD history (15-20% misuse BZD)

– Family h/o of alcohol use disorder

– Personal h/o of opioid use disorder

– Methadone maintenance (47%)

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.

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

Assessment “Legitimate” Prescription

• GOAL: Treat underlying illness

• FOCUS: Assess risk of SUD

BZD Use Disorder

• GOAL: Confirm SUD dx

• FOCUS: Safe discontinuation

Clinical Approach (1) • Identify risk factors

– Co-occurring SUD or psychiatric d/o

– Highest abuse: diazepam, lorazepam, alprazolam

– Prior BZD treatment > 8 wks

Clinical Approach (1) • Minimize potential harms

– Aggressive 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

Clinical Approach (2) • Recognize TYPES of BzUD

• Underlying (anxiety) disorder; tolerant

• Recreational user

• Complicated

– High-dose

– Poly-BZD use

Clinical Approach (2) • DSM V Criteria for SUD

• Aberrant drug related behaviors

– Early refills, ER visits

– Multiple providers

– Taking the medication as prescribed

– UDS + for illicit substances

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

BZD Discontinuation (2) • Cross taper with alternative agent

– GABAergic

• Buspirone

• Valproate**

• Carbamazepine

• Gabapentin

• Pregabalin

– Serotonergic

• TCA (Imipramine)

**indicates improved rates of long-term abstinence

BZD Discontinuation (3)

• Cross taper with medication for anxiety reduction

– Hydroxyzine

– Quetiapine

– Trazodone**

• Inpatient management

– Flumazenil

Patient is overtaking

benzodiazepine

Does the patient have primary

anxiety disorder?

Yes

GAD PTSD OCD PANIC D/O

SOCIAL ANXIETY

No Wean patient gradually

Use greater than 1 yr?

Decrease by 10% q1-

2wks

STEP 1

When 20% of the original

dose remains then decrease 5% reduction of dose q2-

4wks.

STEP 2

Yes No

Decrease the total daily

dose by 25% in the first

week

STEP 1

Another 25% on

week two

STEP 2

Followed by 10% per

week until d/c

STEP 3

Wean patient gradually

Anxiety d/o

Currently taking an SSRI/SNRI?

Start SSRI/SNRI

+ Switch to long

acting BZD

Yes No

Imipramine, buspirone, gabapentin, VPA, CBZ. Cont to

wean off BDZ if possible

No

Yes

Continue AD +

Wean BZD, if possible

Continue AD +

Wean BZD, if possible

Yes Sx

controlled?

Maximize SSRI/SNRI +

Switch to long acting BZD & initiate taper

Take Home Points

• Risk Factors for Opioid Misuse

– Personal or family h/o substance use

– Age (16-45y)

– Psychiatric conditions (such as MDD, OCD, SCZ)

– Preadolescent sexual abuse (women)

Take Home Points

• Risk Factors for BZD Use Disorder

– Personal h/o substance use

– Long term BZD use

– High dose BZD use

– Concomitant opioid use (esp. Methadone)

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