Side Effects and Drug Abuse:
Managing Opioid Risk
Russell K Portenoy MD
Executive Director
MJHS Institute for Innovation in Palliative Care

Chief Medical Officer
MJHS Hospice and Palliative Care
Professor of Neurology and Family and Social Medicine
Albert Einstein College of Medicine

Side Effects and Drug Abuse:
Managing Opioid Risk


Safe and effective opioid prescribing
requires

Skills to optimize pain reliefSkills to minimize risk
 Risk of side effects and toxicities
 Risk of abuse-related outcomesSide Effects and Drug Abuse:
Managing Opioid Risk


Safe and effective opioid prescribing
requires

Skills to optimize pain reliefSkills to minimize risk
 Risk of side effects and toxicities
 Risk of abuse related outcomesOpioid Side Effects
 Most common side effects
 Gastrointestinal effects
 Neurological effects
 Neurocognitive effects
 Neuroendocrine effects

 Other concerns





Itch
Urinary retention
Sleep-disordered breathing
QTc prolongation

Opioid-Induced
ConstipationPrevalence of OIC is uncertain because
multiple causes often co-existEstimates vary

23% to 63% of cancer patients receiving opioids



15% to 90% of non-cancer patients receiving
opioids

OIC may cause distress, increase cost ofcare, and lead to discontinuation ofanalgesics
Nelson AD, Camilleri M. Ther Adv Chronic Dis 2016;7:121134; Bell TJ, et al, Pain Med 2009;10:35-42.

Opioid-Induced
Constipation
Contributing factors







Advanced age
Dietary change
Poor hydration status
Decreased physical activity
Premorbid gastrointestinal disease, e.g., IBS
Comorbid gastrointestinal disease







Structural pathology
Autonomic neuropathy

Comorbid systemic disease, e.g., hypercalcemia
Drugs with constipating effects
Psychosocial factors, e.g., loss of privacy

Opioid-Induced
Constipation
 Mechanisms
 Central effects mediated by multiple brainstem
receptors

 But peripheral effects predominate Mediated by mu and other receptors in gut wall

 Effects
 Increased non-propulsive motility Decreased peristalsis

 Decreased secretions
Mori T, et al. J Pharmacolo Exp Ther 2013;347:91-99

Opioid-Induced
Constipation
 Management
 Consider treatment of contributing factors
 Consider opioid rotation
 Oral to transdermal route may be useful Non-pharmacologic interventions
 Improve hydration
 Dietary changes

Opioid-Induced
Constipation
 Management
 “Routine” use of laxative therapy recommended
in most cases

 No data on dose finding, combination therapy,
laxative rotation

Nelson AD, Camilleri M. Ther Adv Chronic Dis
2016;7:121-134

Opioid-Induced Constipation:
First-line Therapy
Type

Effects

ExamplesBulk laxatives

Dietary fiber; causes water retention
in the colon and increase stool bulk

Psyllium husk, methylcellulose

Osmotic laxatives

Salt content retains fluid retention andincreased intestinal secretion

Polyethylene glycol, lactulose,
sorbitol, magnesium citrate

Stool softeners

Decrease surface tension to lubricate
and soften fecal matter

Docusate

Stimulants

Increased colonic motility andelectrolyte transport; stimulate fluid
secretion

Senna, bisacodyl, cascara

Wald A. JAMA 2016;315:185-191; Candy B, et al. Cochrane
Database Syst Rev. 2011 Jan 19;(1):CD003448

Opioid-Induced Constipation:
New Treatments
Probiotics
 Peripherally-acting mu opioid antagonists








Oral and injectable methylnaltrexone
Oral naloxegol
Oral naloxone, alone or in opioid combination drug

Chloride channel stimulants
Linaclotide acts via agonism at guanylate cyclase C Lubiprostone acts via activation of a prostaglandin receptorProkinetics


Metoclopramide used occasionally

Others—5HT4 modulators and bile acid transport
inhibitors—in development

Davis M, Gamier P. Curr Oncol Rep 2015;17(12):55.
doi:10.1007/s11912-015-0481-x; Wald A. JAMA 2016;315:185-191

Opioid-Induced
Somnolence/Mental Clouding
Prevalence is uncertain because multiplecauses often co-exist
 Management


Psychostimulants

Methylphenidate most studied

10 mg/day resulted in 35% improvement insedation compared to 8% in placebo

15 mg/day resulted in 61% reduction in sedation
versus 21% in placebo
Byas-Smith MG, et al. Clin J Pain. 21:345-352 2005; Wilwerding MB, et al.
Support Care Cancer 1995;3:135-138; Bruera E, et al. JPSM
2003;26;5:1049-54; Webster L. et al. Pain Med 2003;2:135-40 Kurita GP, etal. J Clin Oncol 2011;29:1297-1303

Opioid-Induced
Somnolence/Mental CloudingManagement


Other psychostimulants

Modafinil has limited dataRetrospective trial data resulted in a 40%
reduction in sedation scores

Dextroamphetamine, amphetamine, others

Cholinesterase inhibitors


Donepezil 5 mg daily for 1 week improved sedationand fatigue in cancer patients in a small open-label
trial
Byas-Smith MG, et al. Clin J Pain. 21:345-352 2005; Wilwerding MB, et al.
Support Care Cancer 1995;3:135-138; Bruera E, et al. JPSM
2003;26;5:1049-54; Webster L. et al. Pain Med 2003;2:135-40.

Opioid-Induced
Neuroendocrine Effects
 Opioids inhibit GnRH, LHRH, FSH and LH
 Reduce testosterone and estrogen by inhibiting
GnRH, LHRH, FSH, and LH
 Reduce testosterone production by stimulating
prolactin release Potential effects
 Sexual dysfunction, infertility, galactorrhea, fatigue,
depressed mood, hot flashes, night sweats
 May worsen osteoporosis or sarcopenia
Smith HS, et al. Pain Physician 2012;15:ES145-ES156; De Maddalena C,
et al.. Pain Physician 2012;15:ES111-ES118

Opioid-Induced
Neuroendocrine Effects
 Management
 Depends on analysis of risk-to-benefit Assess symptoms—depressed mood, weakness,fatigue, sexual dysfunction—and other risks
 If benefits possible, measure testosterone andconsider treating male hypogonadism withreplacement therapy
 If benefits possible, measure estradiol andconsider treating premenopausal women withestrogen therapy
Smith HS, et al. Pain Physician 2012;15:ES145-ES156; De
Maddalena C, et al.. Pain Physician 2012;15:ES111-ES118

Opioid-Induced Itch
 Prevalence: 2%-10%
 May worsen itch from other factors

 Management Skin care and treatment of contributing factors

 Consider opioid rotation
 Drugs for opioid-related itch
 Opioid antagonists effective but difficult to use Others tried based on limited evidence and use inother forms of itch
Ko MC, et al. J Pharmacol Exp Ther. 2004; 310:169-76;
Siemens W et al. Dtsch Arztebl Int 2014;111:863-870;
Reich A, Szepietowski JC. Clin Exp Dermatol 2010;35:2-6

Opioid-Induced Itch
 Drug therapy for itch
 H1 antagonists, e.g. diphenhydramine H2 antagonists, e.g. ranitidine
 5-HT3 antagonists, e.g. ondansetron SSRI antidepressant, e.g. paroxetine or sertraline Atypical antidepressant: mirtazapine
 Gabapentinoid, e.g. gabapentin or pregabalin
Siemens W et al. Dtsch Arztebl Int 2014;111:863-870; Reich
A, Szepietowski JC. Clin Exp Dermatol 2010;35:2-6

Opioid-Induced
Urinary Retention
 Prevalence unknown Mechanisms poorly understood Decreased detrusor muscle tone and contraction
 Sensation of fullness
 Voiding reflex diminished Management
 Consider opioid rotation
 Opioid antagonists work but difficult to use Consider alpha-1 adrenergic blocker, e.g., tamsulosin
Rawal N. An experimental study of urodynamic effects of epidural morphineand of naloxone reversal. Anesthesia & Analgesia. 62;7:641-7. 1983

Opioid-Induced
Sleep-Disordered Breathing
Opioids may worsen pre-existing obstructive or
central sleep apnea
 Opioids may precipitate a new sleep apnea
synodrome—central or both central andobstructive
 Risk may be higher with methadone and whenbenzodiazepines are co-administered

Cheatle M. Pain Medicine 2015;16, Suppl 1:S22-S26

Opioid-Induced
Sleep-Disordered BreathingManagement
Assess for existing sleep apnea syndrome or
its risk factors
 Avoid methadone in those at high risk
 Avoid benzodiazepines in those at high risk
 Use co-analgesic approaches to reduce
needed opioid dose
 Consider primary treatment of sleep disorder if
risk vs. benefit warrantCheatle M. Pain Medicine 2015;16, Suppl 1:S22-S26

Opioid-Induced
QTc ProlongationDose-dependent effect of methadone
Management
Assess and manage other risk factors, e.g., hypokalemia
 Review baseline ECG should be reviewed in most casesWith rare exceptions, do not use methadone if QTc >500 ms

Consider alternatives if the QTc >450 ms and <500 ms

Repeat the ECG after 2 weeks or after increasing thedose, at least once or twice Consider repeat ECG if dose goes above 100 mg/dayKrantz M, et al. Ann Intern Med. 2009;150(6):387-395.

Side Effects and Drug Abuse:
Managing Opioid Risk


Safe and effective opioid prescribing
requires

Skills to optimize pharmacological outcomesSkills to minimize risk
 Risk of side effects and toxicities
 Risk of abuse related outcomesDrug Abuse: Importancein Palliative Care

Drug abuse is associated with serious illnesses







HIV/AIDs, some cancers, cirrhosis, heart failure, others
Smoking co-exists with drug abuse and independently
increases risk of serious illness

Palliative care specialists frequently prescribe
drugs that may be abused or diverted
Clinicians have an obligation to help address apublic health problem

Drug Abuse: Importancein Palliative Care

Prescription drug abuse has increased sharply
in the US and is increasing in other countries
Adverse consequences include rise in heroin
addiction and opioid mortality
Patients with pain due to serious illness can beharmedDirectly, by the development of abuse or addiction
Indirectly, by the unintended impact of regulations
that target abuse and diversion

Drug Abuse in Palliative
Care: ManagementAll clinicians should be able to recognize, assess,diagnose, and manage the phenomena related todrug abuseDefinitions must be understoodPhysical dependence Tolerance Drug abuse Addiction Aberrant drug-related behavior
 Pseudoaddiction
 Diversion
Definitions of Substance
Abuse PhenomenaPhysical dependence

Abstinence on abrupt discontinuation or dose
reduction, or administration of an antagonistNot an overt problem if abstinence is avoidedMay or may not be present in drug abusersShould never be labeled “addiction”

Dependence

Meanings varyTerm should not be usedDefinitions of Substance
Abuse PhenomenaToleranceDeclining drug effect induced by exposure to thedrugTolerance to a side effect is desirable



Tolerance to a favorable effect is problematicMay or may not be present in drug abusers or thosewith addiction

Should never be labeled “addiction”

Definitions of Substance
Abuse Phenomena


Abuse


Any drug use outside of socially accepted normsUse of an illicit drug OR significant non-adherence
during the use of a controlled prescription drug

Caution: Norms vary, reflecting culture and laws
Caution: Imprecise term—“drug abuse” may becalled “misuse”, “nonadherence” or“aberrant drug-related behavior”

Definitions of Substance
Abuse PhenomenaAddiction

A disease whose manifestations are best understoodas a complex interaction between biological,
psychological, and psychosocial phenomena
DSM-V now includes a group of “Substance Relatedand Addictive Disorders”, e.g., opioid use disorderA problematic pattern of use leading to clinicallysignificant impairment or distress, as manifested by atleast two of 11 characteristics during a 12-month period

American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 5th Edition, 2013

Definitions of Substance
Abuse PhenomenaAddiction


Another definition: A primary, chronic, neurobiologic
disease with genetic, psychosocial, and environmental
factors influencing its development andmanifestations
Characterized by the “4C’s”--Craving--Compulsive use--Loss of Control--Continued use despite harm

1997 joint statement of APS, AAPM and ASAN: Savage SR, et al: J Pain
Symptom Manage 2003;26(1):655-67

Definitions of Substance
Abuse Phenomena

Aberrant Drug-Related Behavior
Behaviors during treatment that raise concerns about
abuse, addiction, or diversion


Caution: Reflects culture and laws

Caution: Imprecise term—“aberrant drug-related
behavior” may be called “drug abuse”, “misuse”,“nonadherence”, “problematic drug-related behavior,”or “red flag behavior”

Aberrant Drug-Related
Behavior: Examples• More serious– Selling prescription drugs– Prescription forgery– “Doctor shopping”– Stealing or borrowing
another patient’s drugs– Injecting oral formulation– Obtaining prescription drugs
from nonmedical sources– Concurrent abuse of related
illicit drugs– Multiple dose escalations• Less serious– Repeated asking for higher
doses– Drug hoarding– Requesting specific drugs– Occasional temporary dose
escalation without permission– Use of the drug to treat
another symptom– Reporting euphoria or otherpsychic effects
Passik SD, Portenoy RK: In Holland J, et al:
Handbook of Psycho-oncology, 2nd ed, 1998, pp 576-586

Definitions of Substance
Abuse Phenomena

Pseudoaddiction

Aberrant drug-related behavior driven byuncontrolled symptoms, which resolve when
symptoms are better controlled

Originally used in a case report of an inpatient withcancer who became difficult to manage

Should not be used to avoid a primary diagnosis of
addiction, or avoid the label of drug abuse
Can co-exist with addiction—reminder that abuse andaddiction are worsened by unrelieved symptoms andother stressors
Weissman DE, Haddox JD, Pain 1989;36:363-366;
Passik SD et al, Pain Manag 2011;1:239-248

Definitions of Substance
Abuse PhenomenaDiversionUnlawful channeling of controlled drugs to theillicit marketplace due to theft or unlawful activityof physicians, pharmacists, or patients

If clinician behavior is perceived as facilitating
diversion, an individual may be prosecuted

Inciardi JA, et al. Subst Use Misuse 2006;41:1–10

Drug Abuse in Palliative
Care: Management


Universal Precautions


A set of practices intended to assess and minimize
the risk of abuse, addiction, or diversionModel developed for opioid treatment of chronic painCan be applied to all patients receiving any controlled

substance

Gourlay DL, Heit HA, Almahrezi A: Pain Med 2005;6(2):107–12

“Universal Precautions”
in Palliative Care

5-step approachAssess and stratify risk



Choose to prescribe or not to prescribe

Monitor adherence to minimize risk

Monitor drug-related behaviors over timeRespond to aberrant drug-related behaviors

At all steps, document and communicate
Portenoy RK, Ahmed E: 2014;32(16):1662-70

Step 1:
Assess and Stratify Risk

Assess and stratify riskVery low or negligible

A bedbound patient residing in a controlledenvironment
A patient with advanced dementia

Step 1:
Assess and Stratify Risk

Assess and stratify risk

Lower or higher based on historyPersonal history of alcohol abuse or drug abuseFamily history of alcohol or drug abuse

Any significant psychiatric history

Michna E, et al. J Pain Symptom Manage 2004;28:250-258

Step 1:
Assess and Stratify Risk

Assess and stratify risk

Other relevant history
Smoking historyYounger age



Better performance status

Some medical conditions



Poor social adjustment



History of physical/sexual abuseHistory of incarceration



Prior involvement in drug abuse culture

Findings on examination, e.g. needle marks,
sometimes helpful
Michna E, et al. J Pain Symptom Manage 2004;28:250-258

Step 1:
Assess and Stratify Risk

Assess and stratify risk
Some tools may be helpfulComputerized prescription drug monitoring

Laboratory tests, e.g., urine drug screening
 Simple tool, e.g., CAGE-AIDHave you felt you ought to Cut down on your alcohol or drug use?
Have people Annoyed you by criticizing your alcohol or drug use?
Have you felt bad or Guilty about your alcohol or drug use?
Have you had a drink or used drugs first thing in the morning to steady yournerves, treat a hangover, or get the day started? (Eye-opener)
Passik S, et al, Pain Med 2008;suppl s2:s145-s166; Ewing JA. JAMA.1984;252:1905-1907;
Kwon JH, et al. Oncologist 2015;20:692-697

Step 1:
Assess and Stratify Risk


Questionnaires are seldom used

Screening tool for Addiction Risk (STAR)(Friedman et al, Pain Med, 2003)



Screener and Opioid Assessment for Patients with Pain
(SOAPP) (Butler et al, Pain, 2004)
Pain Medicine Questionnaire(Adams et al, J Pain Symptom Manage, 2004)




Screening Instrument for Substance Abuse Potential(SISAP) (Coambs et al, Pain Res Manage, 1996)
Substance Abuse Subtle Screening Inventory (SASSI)(www.sassi.com)

Step 2:To Prescribe or Not

In palliative care, the usual response is toprescribe
However, some scenarios require caution

If risk of diversion is high, do not prescribe unlessthe risk can be eliminatedIf risk of drug abuse is high, consider reasonable
alternatives, proceed only with appropriate
adherence monitoring in place

Step 3: Monitor Adherence
to Minimize Risk
 If the decision is made to prescribe,

implement adherence monitoring as necessary
to reduce risk and help some patients
maintain control

If the risk is negligible, no specific approach may beneededIf the risk is not neglible, implement strategies
appropriate to the level of risk

Step 3: Monitor Adherence
to Minimize Risk
 Options

Use an opioid with a low street value

Do not use short-acting opioids

Prescribe small quantities



Require consultations



Require use of one pharmacy

Perform pill counts when the patient is seen

Use a written agreement

Implement biofluid drug concentration monitoring

Step 3: Monitor Adherence
to Minimize Risk
 Role of drug concentration monitoring Usually urine or saliva; hair testing also used
 If appropriately interpreted, can be used to verify
that a prescribed medication is taken and that
other drugs are not Interpretation requires understanding of potential
for false positives and false negatives

Step 4: Monitor
Drug-Related Behaviors
Drug-related behavior should be monitored
like any other effectFrom history obtained from patient or familyFrom findings on examination



From objective evidence, e.g. result of pillcounts,drug screening, etc.

Step 4: Monitor
Drug-Related Behaviors
 Differential diagnosis of aberrant behavior
 Addiction
 Pseudo-addiction
 Other psychiatric diagnosis
 Organic brain syndrome Personality disorder Chemical coping Depression/anxiety/situational Family issues
 Criminal intent

Step 5: Respond
To Aberrant Behaviors
Management depends on the seriousness of the
behavior and the diagnosis








If diversion is occurring, it must be stopped orprescribing must stop
Consider whether stopping the controlled drug is an
option in managing other types of abuse
If treatment is continuing, consider increasing
adherence monitoring
If behavior is very serious, consider inpatient stay toachieve control and decide on next steps, if possible

“Universal Precautions”
in Palliative Care

At all steps of a “Universal Precautions”
approachDocument and communicate

Portenoy RK, Ahmed E, J Clin Oncol 2014;32(16):1662-70

Side Effects and Drug Abuse:
Managing Opioid Risk


Conclusion

Safe and effective prescribing of controlled drugs
requires the skills to assess and manage risk
Managing risk involves assessing and reducing theharm potentially caused bySide effects and toxicities



Abuse-related outcomes