Safe and Appropriate Use of Opiates...Safe and Appropriate Use of Opiates David Wensel, DO, FAAHPM...

Safe and Appropriate Use of Opiates

David Wensel, DO, FAAHPM

Medical Director, Midland Care

[email protected]

Kevin T. Bain, PharmD, MPH, BCPS, BCGP, CPH, FASCP

Vice President of Medication Risk Mitigation, CareKinesis

[email protected]

Robert Alesiani, PharmD, BCGP

Chief Pharmacotherapy Officer, CareKinesis

[email protected]

NPA Annual Conference 2017October 18, 2017

Objectives

At the end of this webinar, participants should be able to:• Understand the risks associated with opiate drug therapy in

the elderly population• Learn and understand safe and effective pain management

practices with opiates• Ascertain best practice for starting and ending opiate therapy

using evidence-based tools• Know which medications are available for older adults, which

may have pharmacogenomic implications, and how to utilize pharmacogenomic information to assure medication safety and effectiveness

• Access resources to guide clinicians2

Opioid-Related Drug InteractionsEpidemic

“The crisis of opioid addiction is a public health tragedy of enormous proportions. We need to confront it like any explosive epidemic.”- Remarks by Scott Gottlieb, MD, U.S. FDA Commissioner on

July 10, 2017 during the FDA’s Scientific Meeting on Opioids

Opioid Epidemic

Volkow ND, et al. N Engl J Med. 2014;370(22):2063-6.Jones CM, et al. JAMA. 2013;309(7):657-9.

4

The rate of death from ODs of prescription opioids in the United

States more than quadrupled between 1999 and 2010, far

exceeding the combined death toll from cocaine & heroin ODs

2010Prescription opioids: 16,651 OD deaths

Heroin: 3,036 OD deaths

80-90% deemed UNINTENTIONAL

Opioid Epidemic

e.g., hydrocodone, oxycodone

5

Opioid EpidemicWhy?

6SAMHSA. Available at: https://www.samhsa.gov/data/sites/default/files/NSDUH-FRR1-2014/NSDUH-FRR1-2014.pdfRudd RA. MMWR Morb Mortal Wkly Rep. 2016;64:1378-82.

It is estimated that almost 80% of opioid-related overdose deaths are

considered accidental or unintentional

Due, in part, to DRUG INTERACTIONS

Case VignetteIntroduction

Opioid Pain Management CaseBackground

J.D. is an 84-year old male with post-surgical repair of spinal stenosis (L1-L2).

His PMH includes chronic, non-cancer pain with comorbid depression, HTN, COPD, and Diabetes Type II. He has NKDA.

Following surgery, he was started on tramadol by the pain management specialist• Tramadol 50mg: Take 1 to 2 tablets every 4 to 6 hours as

needed for pain

8

Opioid Pain Management CaseBackground

During his follow-up visit with PACE (PCP) approximately a week later, it was evident that he failed to achieve an adequate response and exhibited intolerable side effects with tramadol

• J.D. stated that he tried tramadol 50mg for 2 days but has been taking tramadol 100mg every 4 hours while awake for the past 5 days with only a small reduction in his pain (7/10 at best)

• He also expressed that he has been experiencing nausea, constipation, and dizziness

9

Opioid Pain Management CaseCurrent Medication History

His PCP changes tramadol to hydrocodone/APAPHis current medication profile is as follows:• Hydrocodone/acetaminophen 5/325 mg every 4 hours PRN

pain – NEW

• Senna-S 2 tablets daily – NEW

• Sertraline 50 mg/day

• Metoprolol succinate 50 mg/day

• Hydrochlorothiazide 25 mg/day

• Beclomethasone 80 mcg/inhalation twice daily

• Albuterol MDI 2 puffs every 4 hours as needed10

Unchanged

To Be Continued…

Opioid Pain Management

• How potent is Hydrocodone compared to other opioids?

• Look for Equianalgesic table

• When switching from one opioid to another, reduce dose by 25% to account for cross tolerance

• Always start low and go slow

11


12


• Need to consider how the opioid will be metabolized and excreted

• Opioids are primarily metabolized by CYP2D6

• 2 exceptions are Fentanyl and Methadone

• Both are highly lipophilic

• Need to consider medications that compete for the same enzymes

13


• The number one side effect of all Opioids is

• CONSTIPATION not respiratory suppression

• Always write a prescription for Senna when you prescribe any opioid

• Must think of improving peristalsis to treat constipation

14

Opioid-Related Drug InteractionsPharmacodynamic Mechanisms

Respiratory Depression & Sedation

• Action-related (respiratory effects)• Concomitant administration with drugs that cause respiratory depression

• Exemplar drugs that cause respiratory depression:• Benzodiazepines (e.g. Diazepam [Valium®])

• Use of opioids in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve• COPD, cor pulmonale, morbid obesity

• Action-related (CNS effects)• Concomitant administration with drugs that cause CNS depression

• Exemplar drugs that cause CNS depression:• Benzodiazepine receptor agonists (e.g. diazepam ([Valium®])• Tricyclic antidepressants (e.g. amitriptyline [Elavil®])• Antipsychotics / Neuroleptics (e.g. quetiapine [Seroquel®])

In 2010, among overdose deaths involving opioids, the pharmaceuticals most often also involved in these deaths were benzodiazepines (30.1%; 5,017),

antidepressants (13.4%; 2,239), and antipsychotics or neuroleptics (4.7%; 783)Jones CM, et al. JAMA. 2013;309(7):657-9.

16

Respiratory Depression & Sedation

• Things to consider when respiratory depression occurs:• How long has patient been in pain?

• Are they finally resting and their respirations have slowed?

• What is their SaO2?

• Do they need to be placed on oxygen?

• If they need naltrexone, how much should be given?

17


• When starting opioids or stopping them

• Taper them slowly to monitor effect

• Withdrawal is rare with low dose opioids, but can occur

• If raising dose of opioids and pain is getting worse, think about hyperalgesia due to active metabolites

18

Opioid-Related Drug InteractionsPharmacokinetic Mechanisms

20

Opioid Metabolic Pathways

Opioid Metabolism

21

Opioid CYP2D6 CYP3A4 CYP2B6

Codeine 5* 10

Morphine NON P450

Tramadol 50*

Oxycodone 15* 30

Oxymorphone NON P450

Hydrocodone 10* 55

Hydromorphone NON P450

Fentanyl 90

Methadone 10 50

Tapentadol 25

Dihydrocodeine 25

https://www.intermedrx.com/* = Pro-drug or drug that is converted to a more active metabolite

Strong Moderate Weak

Tramadol Metabolic Pathway

22

Hepatocyte

Gong L. Pharmacogenet Genomics. 2014;24:374-80.

Tramadol

CYP2D650%

M2

Glucuronidation

CYP3A4CYP2B6

M1

M5M3

M4

CYP2D6CYP3A4CYP2B6CYP3A4

CYP2B6

= responsible for the analgesic effect

Oxycodone Metabolic Pathway

23

Oxycodone

CYP2D615%

Glucuronidation

Hepatocyte

Smith HS. Mayo Clinic Proceedings. 2009;84:613-24.

CYP3A4 Noroxycodone

NoroxymorphoneOxymorphone

CYP2D6

CYP3A4


24

Drug-Drug Interaction Examples

Opioid Pharmacokinetic InteractionCompetitive Inhibition

25

ACTIVEMetabolite

Metoprolol CYP2D6 Metabolite

Tramadol CYP2D6

Reduced analgesic response

Expected (normal) analgesic response

Less ACTIVEMetabolite

Opioid Pharmacokinetic InteractionNon-Competitive Inhibition

26

ACTIVEMetabolite

Paroxetine CYP2D6 Metabolite

Hydrocodone CYP2D6Less ACTIVEMetabolite

Reduced analgesic response

Expected (normal) analgesic response

Opioid-Related Drug InteractionsPharmacogenomic (PGx) Mechanisms

28

Impact of Genetic VariationsDrug-Gene Interactions

How genetic variations affect drug disposition & response

PhenoconversionCompetitive Inhibition

29

Metabolite

Drug D CYP2D6 Metabolite

Drug X CYP2D6

PhenoconversionNon-Competitive Inhibition

30

Drug XLess Active Metabolite

CYP2D6

Paroxetine

*1|*1 = Normal Metabolizer (NM)*1|*1 = Poor Metabolizer (PM)

Patients treated with both Paroxetine and Drug X may be phenoconverted into a poor

metabolizer of Drug X.

PhenoconversionInduction

31

Drug XMore Active Metabolite

CYP3A4

Rifampin

*1|*1 = Normal Metabolizer (NM)*1|*1 = Ultra-rapid Metabolizer (UM)

Patients treated with both Rifampin and Drug X may be phenoconverted into an ultra-rapid

metabolizer of Drug X.

Remember: CYP2D6 is not

inducible

But the effect of CYP3A4 inducers on opioid metabolism is a different story. CYP3A4 inducers, such as rifampin, can substantially increase the proportion of opioid (e.g., codeine) that is converted to inactive/less active metabolite (e.g., norcodeine) at the expense of conversion to active/more active metabolite (e.g., morphine), resulting in insufficient response (i.e., analgesia).

Caraco Y. J Pharmacol Exp Ther. 1997;281:330-6.

32

Drug-Gene Interaction Examples

Clinical Relevance Citations:Poulsen L. Eur J Clin Pharmacol. 1996;51:289-95.Gasche Y. N Engl J Med. 2004;351:2827-31.Ciszkowski C. N Engl J Med. 2009;361:827-8. Argoff CE. Clin J Pain. 2010;26:S16-S20.Lurcott G. Anesth Prog. 1998;45:154-6.

Opioids

33

Opioid CYP2D6 CYP3A4 CYP2B6

Codeine 5%* 10%

Morphine NON P450

Tramadol 50% 10% 10%

Oxycodone 15%* 30%

Oxymorphone NON P450

Hydrocodone 10%* 55%

Hydromorphone NON P450

Fentanyl 90%

Methadone 10% 50%

Tapentadol 25%

Dihydrocodeine 25%

https://www.intermedrx.com/* = Pro-drug or drug that is converted to a more active metabolite

Oxycodone Metabolic Pathway

34

Oxycodone

CYP2D615%

Glucuronidation

Hepatocyte

Smith HS. Mayo Clinic Proceedings. 2009;84:613-24.

CYP3A4 Noroxycodone

NoroxymorphoneOxymorphone

CYP2D6

CYP3A4


Oxycodone ResponseNormal Response

35

Oxycodone OxymorphoneCYP2D6

CYP2D6 *1/*1Normal Metabolizer (NM)

Oxycodone ResponseReduced Response

36


CYP2D6 *4/*4Poor Metabolizer (PM)

A CYP2D6 poor metabolizer clears CYP2D6 substrates (e.g., opioids) slowly and, therefore, has greater than expected exposure to the parent drug & lower than

expected exposure to active metabolites

Giving oxycodone to patients without CYP2D6 activity is like giving a placebo

Oxycodone ResponseEnhanced Response

37

Oxycodone Oxymorphone

CYP2D6 *1/*1x2Ultra-rapid Metabolizer (UM)

CYP2D6CYP2D6

CYP2D6CYP2D6

CYP2D6

CYP2D6

Oxycodone ResponseAltered Response – Phenoconversion

38


Bupropion


CYP2D6 behaves like an Intermediate Metabolizer (IM) or

Poor Metabolizer (PM)

This can be mitigated by giving Oxycodone 2-4 hours prior to

Bupropion

Oxycodone ResponseAltered Response – Phenoconversion

39


Amiodarone


CYP2D6 behaves likePoor Metabolizer (PM)

This can NOT be mitigated by changing time of administration

Case VignetteRevisited

Opioid Pain Management CaseExplained – Tramadol

41

Opioid Pain Management CaseContinued

Following his PCP visit, J.D. begins taking the hydrocodone/acetaminophen as prescribed

After several days, he calls his PCP to report that this pain medication does not seem to be helping much more than the tramadol

His PCP writes a new prescription for hydrocodone/acetaminophen 10/325 mg every 4 to 6 hours PRN pain

42What should we expect?

Opioid Pain Management CaseExplained – Hydrocodone

43What happens next?

Opioid Pain Management CaseScenario 1J.D. continues taking the hydrocodone/acetaminophen 10/325 mg as prescribed, with mild to modest analgesic response• Takes 1 tablet 4-5 times per day

• Best 4-5/10 pain score on Likert scale

• Most improvement at night

After several days, he calls his PCP to report that his analgesic response, and reports that his nausea & constipation is mitigated & his dizziness has improved

Unsuspecting of a drug-drug interaction, his PCP orders a PGx test to determine his CYP2D6 genotype-phenotype status• His result comes back as follows: CYP2D6*1/*1 – normal metabolizer (NM)


Opioid Pain Management CaseExplained – Hydrocodone

45What happens next?

Opioid Pain Management CaseScenario 2

Unimpressed with the PGx test result, about a week later, the PCP decides to change J.D. from hydrocodone/acetaminophen to oxycodone

• Oxycodone extended-release 10 mg twice daily (every 12 hours)

• Oxycodone immediate-release 5 mg every 4 to 6 hours PRN breakthrough pain

The PCP also adds pregabalin for potential nerve pain

• Pregabalin 50 mg at bedtime x 3 days then 50 mg twice daily

J.D. begins taking his new prescriptions the following day46

What should we expect?

Opioid Pain Management CaseExplained – Oxycodone

47To Be Continued…

Case VignetteApplied Mitigating Strategies

Opioid Pain Management CaseScenario 3A week and a half later, J.D. calls his PCP to report that his pain control is relatively unchanged & that he tried taking the pregabalin twice daily but could not tolerate it because of fogginess & daytime sleepiness

After consulting with the pharmacist that rotates in his practice, the PCP recognizes that J.D. is suffering from multiple drug interactions• Oxycodone & pregabalin – sedation

• Oxycodone & metoprolol – competitive inhibition & phenoconversion

He also realizes that J.D. has become physically & possibly psychologically addicted to opioids

The PCP decides to stop the pregabalin and switch the metoprolol to atenolol• Atenolol 50 mg/day


Opioid Pain Management CaseExplained – Oxycodone

50To Be Continued…

Opioid Pain Management CaseScenario 4

Several days after changing from metoprolol to atenolol, J.D.’s wife calls 9-11

• She found J.D. slumped over in his chair and difficult to arouse

J.D. is brought to the emergency department for urgent care

51

What could have been done differently?

Opioid Pain Management CaseScenario 4 (cont.)

When changing to atenolol, the PCP should have reduced the oxycodone dosage

• J.D. was not fully metabolizing the previous opioids and, therefore, the concentrations were lower than expected

• However, when the competitive inhibition was mitigated, the opioid concentrations rose, and this occurred over several days (due to relatively high bioavailability of oxycodone)

52


Why?

Opioid Pain Management CaseScenario 4 (cont.)

Instead of changing metoprolol to atenolol, the PCP could have changed the oxycodone to morphine or oxymorphone

• These opioids do not undergo metabolism by the CYP2D6 isoenzyme

• In doing so, still, the estimated conversion should be significantly reduced (50-75%) to account for incomplete cross-tolerance (i.e., treat J.D. like he is opioid naïve)

53


Why?

Improving Opioid PrescribingTreatment of Opioid-Use Disorder (OUD)

A psychiatric diagnosis that involves use despite negative consequences and/or loss of control over

use, compulsion, and cravings

Opioid-Use DisorderAt a Glance• Defined as the repeated occurrence within a 12-month

period of 2 or more of 11 problems (see table)

Diagnostic Criteria for an Opioid-Use Disorder*

Schuckit MA. N Engl J Med. 2016;375(16):1596-97.Diagnostic and Statistical Manual of Mental Disorders, 5th edition.

*If two or three items cluster together in the same 12 months, the disorder is mild; if four or five items cluster, the disorder is moderate; and if six or more items cluster, the disorder is severe.

†If the opioid is taken only as prescribed, this item does not count toward a diagnosis of an opioid-use disorder.

Tapering & DiscontinuingShort-Term Risks

Opioid Withdrawal Syndrome

• Characterized by signs & symptoms of sympathetic stimulation, due to decreased sympathetic antagonism by opioids, including:• Anxiety, restlessness, diaphoresis, hot flashes, tremor, shivering

• Hypertension, tachycardia, dizziness

• Abdominal cramps, diarrhea, anorexia, nausea

• Mydriasis, lacrimation, rhinorrhea, sneezing,

• Insomnia, yawning

• Piloerection, myalgia or arthralgia56

Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42.

What are the risks associated with tapering?

Physical symptoms, psychological symptoms,

and [generalized] pain


Opioid Withdrawal Syndrome• Symptoms start 2 to 3 half-lives after the last dose of opioid

• Most opioids (e.g., morphine, oxycodone)• Half-life of 3-4 hours• Symptoms start after 6-12 hours• Symptoms peak at approximately 48-72 hours• Symptoms resolve within 7-14 days

• Variability depends on specific dose, formulation, duration of use, and speed of taper

• Secondary abstinence syndrome can last up to 6 months (possibly longer)• Craving for opioids, poor tolerance to stress, decreased well-being, general

malaise, and fatigue

57Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42.


Opioid Withdrawal Syndrome

• Tools allow clinicians to measure withdrawal symptoms

• Subjective Opiate Withdrawal Scale (SOWS)• Subjective patient-rated assessment

• Clinical Opiate Withdrawal Scale (COWS)• Objective clinician assessment

58Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42.Handelsman L, et al. Am J Drug Alcohol Abuse. 1987;13(3):293-308.Wesson DR, et al. J Psychoactive Drugs. 2003;35(2):253-9.


Rebound (Increased) Pain

• According to studies of long-term opioid therapy tapers, overall, patients report improvements in function without associated worsening in pain or even decreased pain levels

• Rebound pain following opioid taper & discontinuation appears to be a brief, time-limited phenomenon• Studies indicate that hyperalgesia may appear immediately after

discontinuation of long-term opioid therapy

• Similarly, hyperalgesia has been described postoperatively, when the use of short-acting opioids is abruptly discontinued at the end of surgery


Opportunity to reduce patients’ fear


Dropout

• There is legitimate concern for the following:• A patient will refuse to taper or discontinue opioids; or

• A patient will resume long-term opioid treatment, often with a different prescriber; and/or

• A patient will display aggressive behavior

• Dropout more commonly occurs when there is no plan• In other words, patients without an opioid maintenance treatment option,

in case of taper failure or following discontinuation, are more likely to quit


Opportunity to reduce patients’ fear

Tapering & DiscontinuingLong-Term Risks

Relapse

• Ultimately, the goal is to maintain reduced opioid consumption or abstinence

• Relapse after a full opioid taper is influenced or predicted by:• Higher pain scores at initiation & conclusion of taper

• Conversely, low pain scores at the end of an opioid taper is predictive of long-term abstinence from opioids

• Depressive symptoms at initiation of tapering

• It may also be influenced by the speed of opioid taper & coping strategies of the patient

61Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42.Heiwe S, et al. Eur J Pain. 2011;15(9):966-70.

What are the risks associated with tapering?

Tapering & DiscontinuingManaging Risks

Preventing Taper Failure (Dropout & Relapse)• Appropriate management of depression

• Non-pharmacologic (psychological) & pharmacologic therapies

• Psychological support• Coping strategies• SUD treatment

• Optimizing pain management• Cognitive behavioral therapy (CBT)• Physical therapy• Other non-pharmacologic therapies (e.g., acupuncture, massage)• Non-opioid analgesics


How can the risks associated with tapering be managed?

Interdisciplinary approaches

Tapering & DiscontinuingManaging Risks

Managing Withdrawal Symptoms• Use of α2-adrenergic agonists

• Reduce sympathetic activity (e.g., anxiety, piloerection)

• Comparative studies have not found one to be superior• Therefore, the choice is based on pharmacologic particularities of the

different drugs

• Examples• Clonidine 0.1-0.2 mg orally every 6 hours or transdermally once weekly• Tizanidine 2 mg orally at bedtime, titrated by 2-4 mg every day up to 8 mg

every 8 hours• Side effects common to both include hypotension, dry mouth, & sedation

63Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42.Gowing L, et al. Cochrane Database Syst Rev. 2014.


Tapering & DiscontinuingManaging Risks – Other Therapies

Managing Withdrawal Symptoms

64Schuckit MA. N Engl J Med. 2016;375(16):1596-97.


*A physical examination should be performed, and the patient should be screened for his or her willingness to participate in a rehabilitation program.

†Medications are administered according to symptoms; not all medications are administered to every patient.

‡Doses are approximate.

∫∫Clonidine is used on an off-label basis, and tizanidine is an alternative cited in the literature.

Non-Opioid Therapies for Treatment of Opioid Withdrawal*

Tapering & DiscontinuingMedication-Assistance Treatment

65Volkow ND, et al. N Engl J Med. 2014;370(22):2063-6.SAMHSA: https://store.samhsa.gov/shin/content/SMA09-4443/SMA09-4443.pdf

https://store.samhsa.gov/shin/content/SMA09-4443/SMA09-4443.pdf

Tapering & DiscontinuingMedication-Assistance Treatment

66Schuckit MA. N Engl J Med. 2016;375(16):1596-97.

Treatment for Symptoms of Opioid Withdrawal*

Medication-Assistance TreatmentClinical Pearls

Methadone

• A long-acting full µ-opioid receptor agonist that can be safely taken at the start of recovery

• It has a long & variable half-life (i.e., 15 to 40 hours)

• If initiated during withdrawal (i.e., added to opioid therapy during taper), need to be vigilant about dosing • Risk for respiratory depression and/or sedation• Risk of OD if the dose is increased too quickly

• A baseline ECG should be obtained before prescribing • Risk of QT interval prolongation, especially at doses > 100 mg/day and/or • Also keep in mind DRUG INTERACTIONS

67Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42.Volkow ND, et al. N Engl J Med. 2014;370(22):2063-6.

Pharmacodynamic drug interaction


Buprenorphine +/- naloxone

• A µ-opioid receptor partial agonist • Competitively antagonizes concomitantly administered full opioid agonists

• Introduced to patients in mild to moderate withdrawalbecause adding buprenorphine to a full opioid agonist can precipitate withdrawal• Initiate 12-18 hours after last short-acting opioid; 48 hours after long-acting

• Naloxone becomes available only if the medication is dissolved & injected, blocking the effect of buprenorphine• In which case, the withdrawal symptoms can be sudden & severe


Pharmacokinetic drug interaction


Naltrexone

• A µ-opioid receptor antagonist • Blocks opioid effects helps maintain abstinence

• Cannot be taken until opioids are completely out of the body, usually 7 to 10 days after withdrawal begins / abstinence

• A good choice for preventing relapse because it takes away the “high” if the problem opioid(s) is used again


Safe & Appropriate Use of OpiatesClosing

Summary

• The CYP2D6 enzyme is responsible for metabolizing many commonly used opioids to more active metabolites• These opioids are weak substrates and, therefore, can be competitively

inhibited by moderate to strong substrates (e.g., antidepressants)

• This will result in reduced analgesic effect and potentially side effects

• Clinically, we tend to increase the opioid dosage to improve analgesic effect, which may result in opioid addiction, abuse, and/or misuse

• The CYP2D6 enzyme also is highly polymorphic• Genetic variations and drug-gene interactions resulting in

phenoconversion can significantly alter opioid response as well 71

Summary

• Inappropriate prescribing of opioids, entailing drug interactions, is a key upstream driver of the opioid epidemic

• Mitigating strategies are multifaceted and require careful consideration of the nature & extent of drug interactions involving the patient’s complete drug regimen

72

Summary

• Efforts to address the opioid epidemic need to simultaneously reduce opioid abuse & safeguard legitimate & appropriate access to opioids

• Expanding access to addiction-treatment services & MATs is a crucial component of the effort to help patients recover

73

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