Transcript Pain management at the End of Life

Pain Management at the End
of Life
HPNA 2013 Symposium
Houston
11/2/13
Shalini Dalal, M.D
Associate Professor
Palliative Care & Rehabilitation Medicine
U.T. MD Anderson Cancer Center
Houston
Faculty Disclosure
• No conflicting interests
Objectives
• Imperatives for pain management at the end of life.
• Barriers to effective pain management and how to
overcome them
• Evidence-based approach to pain management near
the end of life, with a focus on:
– Assessment
– Use of opioids
• Appropriate use of opioids
• Managing opioid-related side effects.
• Discuss future trends in pain management.
Case Study 1:
RS, a 65 yr lady with h/o Breast cancer
• s/p mastectomy and radiation, completed 18 mths ago. Now
on Tamoxifen.
• Other relevant history:
– has enjoyed good health, married, 3 adult children. Her widowed
mother with moderate dementia lives with her.
– actively involved in her catering business with her son and is chief
caregiver to her mother.
• Past 2 weeks:
– c/o pain in the lower back, radiating left hip and leg.
– One of her daughters, a radiologist has been giving her mother
acetaminophen-codeine, with mild relief in pain. Quit taking after 3
days
• RS is miserable, still has significant pain and feels that
overall she is worse due to constipation.
Case 2:
JS, 54 yr male with relapsed met sarcoma
• Extensive disease: right pelvis, sacral epidural disease and
pleural metastasis
• Progression despite multiple chemo
• Multiple opioid escalations/ rotations over the past 1½ yrs.
• Social:poor historian. Records indicate: divorced, two
children, lives with significant other, older son is estranged.
History of alcohol abuse in the remote past. Ex smoker.
• Presented to EC with uncontrolled pain
Case 2: JS, 54 yr male with relapsed met sarcoma
Crying and restless
Nausea with vomiting
Intermittent twitching
Poor historian, confused
Pain worse with palpation and
toucing his leg
100
Fentanyl
patches
50
100
100
Pain score: 20/10
50
8 fentanyl patches = 650
micrograms/hr
100
50
100
Definitions
• Pain
“An unpleasant sensory and emotional experience
associated with actual or potential tissue damage, or
described in terms of such damage”.
International Association for the Study of Pain (IASP)
The Imperative For Pain management at EOL
•
•
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•
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Demographic
Financial
Human suffering
Moral and ethical
Legal
Demographic challenges
A SOBERING TRENDLINE
100
Lifetime Risk
of Dying (%)
50
0
Dawn of
Time
Timeline
Today
Demographic challenges contd
• Success of modern medicine…
– ↑ life expectancy (1940s ≈ 50/60 yrs, 2001 ≈ 80s)
– By 2030: 20% of US population will be > 65yrs
• But…
↑ number of people with chronic conditions
• 90 million living with at least 1 chronic Illness
• 7/10 Americans die from chronic disease
• Medicare population :
– 90% deaths occur in the course of chronic illness
– Of the 1.5 million who die of chronic illness each year
» > 70 % admitted to a hospital during the last six months of life.
The Dartmouth Institute for Health Policy and Clinical Practice.
The Dartmouth Atlas of HealthCare Web site. www.dartmouthatlas.org
Financial challenges
Growth in expenditures for health care in the USA, 1970–
2003.
Source: Health Care Financing Administration, Office of the Actuary, National Health
Financial Challenges
~ 30% of Medicare cost sickest 5% of patients.
~ 70% of overall health care sickest 10% of the population.
• Of the ~ 250 billions
medicare spends
• 26% spent last 12
months of life
• 14% in last 2 months
of life
Percent Dying and Percent of Medicare Payments Spent in the Last 12
Months of Life, among Medicare Beneficiaries Aged 65 and Older, 1978–
2006, Health Serv Res. 2010 April; 45(2): 565–576
Financial challenges, contd
• Patient/family
– Personal expenditures on medical care are the major
cause of personal bankruptcy.
– > 50% elderly population has income of <$20,000 and
spends >25% on health care
– The SUPPORT study
• 31 % of patients' families lost most of their life savings.
• Spending more money does not necessarily lead to
improved results. ..
• Human Suffering challenge
Definition
• Suffering
"a state of severe distress associated with events that
threaten the intactness of the person."
Eric Cassell, NEJM, 1982.
Pain and Suffering
• Pain and suffering are related when:
–
–
–
–
The pain is overwhelming
The patient does not believe the pain can be controlled
The source of pain is unknown
The pain is apparently without end
Eric Cassel, 1982
Pain
Physical symptoms
Psychological
Suffering
Spiritual
Cultural
Social
Woodruff, 1999
Experience of being hospitalized
with a serious illness in the US
• > 50% patients  report suboptimal care
• 1 in 4  inadequate treatment of pain & dyspnea
• 1 in 3  receive no education on how to treat their pain/
other symptoms following a hospital stay.
• 1 in 3  not provided with arrangements for follow-up care
after hospital discharge.
• 1 in 3 families inadequate emotional support.
• 30 % families lose most or all of their savings in caring for a
loved one with a serious illness.
Teno. JAMA. 2004; Covinsky. JAMA. 1994 ; SUPPORT. JAMA. 1995
Dartmouth Atlas of Health Care; The Commonweath Fund. Care coordination.Quality Matters 2007
The SUPPORT* study 1995
9000 pts; median survival 6 months
• High Symptom burden
– 60% mod-severe pain at 8 to 12 days of hospitalization.
– > 50% had serious pain in the last 3 days of life.
– 25 % had moderate or severe dyspnea
• Poor communication about goals of care
– HCP not aware of pts preferences re: Advanced Directives
• Substantial emotional suffering –pts/ families & staff
* The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments
(SUPPORT). JAMA. 1995.
Cancer Pain Prevalence
Disease Stage
% pain (95% CI)
After Curative Rx
33% (21-46%)
Undergoing cancer Rx
59% (44-73%)
Advanced/metastatic/
terminal
64% (58-69%)
All disease stages
combined
53% (43-63%).
Cancer Type
% pain (95% CI)
Head/neck
70% (51-88%)
Gyn
60% (50-71%)
Gastro
59% (44-74%)
Lung
55% (44-67%)
52 studies, Systematic Review
Breast
54% (44-64%)
> 1/3 patients with pain, graded their
pain as moderate or severe.
GU
52% (40-60%)
Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol. 2007
Symptoms At The End of Life in Children With
Cancer
Wolfe J. et al, NEJM 2000; 342(5) p 326-333
80
% Successfully
Treated
70
%
60
50
40
30
20
10
27 %
Pain
16 %
Dyspnea
10 %
Nausea And Vomiting
Overall experience of being hospitalized at
the end of life ?
• Not so good…
What is high quality EOL care from
the patient's perspective?
• To have pain and other distressing symptoms
controlled
• To achieve a sense of control
• To avoid burdening family members
• To avoid inappropriate prolongation of the dying
process
• To strengthen relationships with loved ones
(Singer, et. al, JAMA 1999).
Hierarchy of the Dying Person’s Needs
To share and come to terms with the unavoidable future
To perceive meaning in death
To maintain respect in the face of increasing weakness
To maintain independence
To feel like a normal person, a part of life right to the end
To preserve personal identity
To talk
To be listened to with understanding
To be loved and to share love
To be given the opportunity to voice hidden fears
To trust those who care for them
To feel that they are being told the truth
To be secure
To obtain relief from physical symptoms
To conserve energy
To be free from pain
Ebersole, P., & Hess, P. (1994). Toward healthy aging (p. 752). St. Louis, MO: Mosby, Inc.
Moral obligation to relieve pain
• The relief of suffering
– cardinal goal of the ethical and compassionate practice of medicine.
• The obligation of medical providers to relieve pain is a
conditional obligation
– ethical principle of beneficence guides duty to relieve pain
– Unless patient of sound mind rejects such treatment.
• Ethically acceptable to administer drugs in whatever dose is
necessary to relieve a patient's suffering, even if doing so
may cause foreseeable side effects, as long as patients or
their proxies are made aware of this possibility
Legal consequences of pain under
treatment
Public’s attention to under-treatment has peaked
• Little is done about under-treatment under the current system
• No states directly address under-treatment, and by default defer to
medical board
• How do medical boards reprimand physicians for under-treatment?
– CME and counseling
Examples:
• Bilder case, Oregon 1999
– Boards requires CME and counseling
• Whitney case, California 2003
– Board requires CME
Legal consequences, cont’d.
• Stage is set for civil lawsuits of large proportions
– Involved when families dissatisfied with medical board’s response to
complaint
Civil law suit examples
• North Carolina: Estate of Henry James v. Hillhaven (1991)
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–
–
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NH patient who died a painful death from terminal met prostate ca
Nurse did not follow doctor’s orders
$15 million to family
no disciplinary action for either the nurse or the facility.
• California
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Bergman v. Eden Medical Center(1998)
Admitted for 5 days, diagnosed with lung cancer. Pain scores 7-10,
Physician did not properly address patient’s pain
$1.5 million to family
Roadblocks…
Barriers to effective pain relief
• No lack of information about the gap that exists
between evidence and practice
• WHO has formally acknowledged a host of systemwide barriers
– Regulatory/System
– Health care professional: attitudinal/educational
– Patient related: attitudinal/educational
Healthcare provider related barriers
• Lack of education- crucial barrier
– Inadequate understanding of pain mechanisms/ contributors
to pain expression
– Inadequate assessment and treatment
– Misconceptions (opioids)
– Fear of legal sanctions/scrutiny
• Many studies have focused on the attitudes and
knowledge of health care professionals
– acknowledge insufficient training and experience with
prescribing or titrating opioids
– rampant misconceptions regarding opioid use
– unsafe, leads to addiction, best reserved for dying patients
Barriers: patient/family
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•
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•
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Fear of giving up --> signifies disease progression
Misconceptions of opioids --> ‘‘too strong’’
Fear of side effects --> more bothersome than pain
Fear of addiction
Fear of tolerance --> “will not work as disease
progresses”
Overview of Barriers to pain relief
Regulatory/System
Resource limitations
Restrictive drug
control laws and
regulations
Lack of adequate
palliative care services
Health care
professional
Low priority for pain
relief and palliative care
Opioids are unavailable
or too costly
Cultural, political,
and social factors
Lack of education on
cancer pain and opioids
Public unaware of pain relief
options
Social stigma persists
Untrained health
professionals
Physicians with exaggerated
opioid concerns and fear of
legal sanctions
Patient
related
Patient fears opioid effects
Uncontrolled pain in
cancer patients
Dalal S, Tanco KC, Bruera E. State of
art of managing pain in patients
with cancer. Cancer J. 2013
The nociceptive pain pathway
Noxious stimuli
•Thermal
•chemical
•mechanical
Bingham B et al. (2008) Nat Clin Pract Rheumatol doi:10.1038/ncprheum0972
Physiological vs pathological pain
• Physiological pain:
– dissipates when the inciting noxious stimuli is removed.
• Pathological pain:
– no fundamental purpose
– arises whn injury to tissues and/or nerves.
• Neural plasticity:
– changes in the peripheral and central pain-signaling pathways
• increase in neuronal excitability and decreased central inhibition.
• manifest clinically as spontaneous pain, pain hypersensitivity
(e.g. hyperalgesia and allodynia) and increased receptor fields.
• Peripheral and central sensitization
– 2 well recognized mechanisms that contribute to neural
plasticity in the periphery and CNS, respectively.
Peripheral sensitization
refers to the increased excitability and reduced thresholds of primary sensory neurons
at sites of tissue/nerve injury or inflammation.
TUMOR
Nociceptor terminal
PG
Tissue damage,
inflammation and
acidosis
↑ Inflammatory
Mediators
(Eg.cytokines,
PGE2, BK, NGF,
ET, Protons (H+),
ATP
ET
BK
NGF
Cascade of intracellular signaling pathways that alter the function/ kinetic
properties of transducing receptors and sodium channels leading to increased
neuronal sensitivity and excitability
Central Sensitization
Persistent
Stimulation
Dorsal
Horn
Synapse
ACTION
POTENTIAL
↑ excitability of dorsal horn neurons
Primary sensory
Afferent neuron
(pre-synaptic)
SP
SP SP
SP
SP
SP
SP
Ca
Ca
Magnesium
block
SP
SP
SP
Glutamate
SP
SP
SP
Ca
Mg
NMDA
receptor
AMPA
receptor
PKC
Mg
Mg
SP
NK-1
receptor
Ca
Ca
Muopioid
receptor
Ca
Ca
↑PKC
Pain
Amplification
SP
Substance P
Glutamate
carrying
vesicles
SP
SP
Neurons become more responsive and
excitable (spinal windup).
sets the stage for the second or
delayed phase
Second order
dorsal horn neuron
• transcription of pro-nociceptive
terminal ( postsynaptic)
genes that maintains neuronal
excitation even in the absence of
ongoing peripheral signals.
Pain at the end of life
• Subjective, dynamic and multidimensional experience
• Pain expression impacted by the terminal nature of illness
which also results in other sources of distress that impact QoL
•
•
•
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functional decline
Dependence
family disruption
financial burdens
• Presence of concurrent symptoms:
• E.g. dyspnea, nausea, fatigue, and anxiety
• should be simultaneously explored and treated.
• “Total pain:” First coined by Dame Cecily Saunders
Total pain is the sum of four components: the patient’s
physical experience, and psychological, social, and spiritual
components to distress
ex Phy
pe si
rie ca
nc l
e
al
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So
S
p
ir
Em
it
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al
n
io
ot
TOTAL
PAIN
Four components of Total Pain
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Cognitive
Meaning of pain
Coping style
Attitudes, belief, knowledge
Cognition level
Physiological
pain etiology
pathophysiology


Affective
Emotional response
Suffering
Pain
Experience


Sensory
Pain severity, location
Pain quality

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
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

Behavioral
Pain behaviors
Communication of pain
Other concurrent symptoms
( fatigue, sleep)
Socio-cultural
Cultural background
Family dynamics, role
Caregiver perspective
Comprehensive approach to assessment and
management of pain in terminally ill patients.
Multidimensional Pain
Assessment
Reassessment
Decision Making Process
Therapeutic Plan
It takes team work
Palliative Care Interdisciplinary Team
Chaplain
Nurse
Psychiatric CNP
APN
Patient
Social Worker
Physician
PT/OT
Pharmacist
Dietician*
Comprehensive approach to assessment and
management of pain in terminally ill patients.
Multidimensional Pain
Assessment
Reassessment
Decision Making Process
Therapeutic Plan
Multidimensional Assessment
So where do we begin?
“ Be a good listener- you never learn much
from talking”
- Will Rogers
Pain Assessment
• “Pain is what the patient states it is”
– statement highlights the need to listen to the patient and
hear what he/she has to say about the pain.
• A formal systematic assessment of pain
– relays to pt’s/family that their complaints are legitimate
concerns
– are being quantified and documented
– will be used to evaluate treatments
– allows them to become active participants
Screening for Pain, “The Fifth Vital Sign”
• routine and “visible”
• frequent assessment is standard of care.
Medical History and Cognition
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Medical Evaluation
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Extent /stage of disease/cancer, metastatic sites
Prior and planned oncologic treatments
Medical co-morbidities and organ dysfunction
Medications/drug allergies
Impaired cognition can compromise assessment
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Delirium: Majority of patients at end of life
Cognitive impairments may be missed when no objective
testing is performed
screening tests for cognitive impairments
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Nursing Delirium Screening Scale (NuDESC)
•
5-item scale observational scale (disorientation, inappropriate behavior ,
communication, illusions/hallucinations, psychomotor retardation)
Mini Mental State Examination (MMSE)
Memorial Delirium Assessment Scale (MDAS)
implement early, preferably before detailed symptom assessments
Components of Multidimensional Pain Assessment, contd
Pain and its
For each site of pain determine:
Characteristics • Severity: Current; Average, worst, and least scores in last 24 h
• Location and radiation
• Quality
• Temporal Features
• onset: acute, chronic exacerbation of chronic pain
• Continuous, intermittent, breakthrough, incidental pain)
• Exacerbating or relieving factors
• Inferred Pathophysiology
• Nociceptive-somatic or visceral; neuropathic
• Likely etiology or pain syndrome
Impact of pain • Daily functioning
on Qol
• Mood, coping, and related aspects of psychological well-being
domains:
• Social and familial relationships
• Sleep
Components of Multidimensional Pain Assessment, contd
Concurrent
Symptoms
• Fatigue, drowsiness, dyspnea, insomnia, anorexia,
nausea, anxiety, depression
Function
• Ability to ambulate, ADLs, ROM, breathing.
Note restrictions related to pain
Psycho-social,
• patient distress, psychiatric history
spiritual, and cultural • beliefs, attitudes regarding opioids
issues
• Family support, knowledge/beliefs of pain & mgmt.
Alcoholism and
Substance Abuse
• Prior or current
• prescription and non-prescription drug abuse
prior use of opioids
and other analgesics
• Efficacy of analgesics
 Side-effects such as GI and/or CNS related
Risk factors for under-  0pioid fears and concerns about adverse effects
treatment of pain
 financial
Pain Severity
• Pain scores
1-3: mild
4-6: moderate
7-10: severe
• Patients may use these numbers differently !
• Some patients may complain of “severe pain” but rate it as “5”
while others may have “moderate” pain and rate the same.
– Clinical judgment is required
– clarify patient’s sense of the pain (without finding fault with
patient’s choice of number) and its impact on physical
activity, mood, sleep, and social interactions.
Personalized Pain Goal (PPG)
• Assessment of individual goals for pain management
– Pain treatments needs to be personalized, and tailored to patients’
individual needs for comfort and functioning. (NCCN, APS
recommendations for cancer pain)
• PPG : A simple method may be to ask the patient, to describe
on a 0-10 scale, the level/intensity of pain that will allow the
patient to achieve comfort in physical, functional, and
psychosocial domains.
• Use of terms such as “acceptable” or “tolerable” pain may
have a negative connotation, suggesting patient has to
accept/ tolerate the pain.
Edmonton Symptom
Assessment Scale
(ESAS)
Multiple symptoms can
be assessed concurrently
Pain assessment in patients with
cognitive impairments
• Patients with mild-moderate cognitive impairments can
usually respond to a self reported pain scales.
• Severe impairment
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–
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Ask patients few questions
observe behaviors
family/caregivers reports
Behavioral assessment tools ( FLACC)- research setting
Behavioral cues suggestive of pain
Verbal cues
Crying, moaning, groaning, or
grunting
Non-verbal cues
 Facial Expressions
Grimacing, biting lips, blinking or
closing eyes tightly
 Body Movements
Clenching fists, restlessness,
combativeness, or guarding
 Social Interaction and
Withdrawn, silent, wanting to spend
time in bed, irritability, insomnia,
decreased appetite
activities
Pain assessment: family/caregiver as
proxies:
• Not always be in concordance with patient’s report.
Studies:
• Hospitalized seriously ill patients,
– surrogates accurate in estimating pain 73%, severity 53%
• Cancer patients
– caregivers accurate 71% of the time
– female caregivers: higher % agreement with patient’s report.
• Hospice patients
– caregivers more likely overestimated pain.
• Clinicians should use family/caregiver reports in combination with
behavioral observations in severely impaired patients.
– In case of doubt, a trial of analgesics is recommended to avoid
the risk of under-treatment.
Comprehensive approach to assessment and
management of pain in terminally ill patients.
Multidimensional Pain
Assessment
Reassessment
Decision Making Process
Therapeutic Plan
Decision making process
• Formulation of an individualized treatment plan
– Active participation by patient/families
– better able to state preferences, and set their limits of care according
to personal values and goals.
• Clinicians should discuss
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–
–
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–
–
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the overall medical condition, and overall goals of medical care
potential contributors of pain (and other symptoms if present)
identification of achievable objectives.
discuss potential appropriate treatments
benefits/burdens of each option in the setting of advanced illness.
patient/family resources and limitations
reassure that in most instances pain relief is obtainable
• Patient preferences should weigh into final decision making.
– These discussions need to be ongoing.
Comprehensive approach to assessment and
management of pain in terminally ill patients.
Multidimensional Pain
Assessment
Reassessment
Decision Making Process
Therapeutic Plan
Existing Treatments
• Systemic analgesics:
– NSAIDs, acetaminophen, Opioids
• Adjuvant agents
– Anticonvulsants; antidepressants
• Bisphosphonates
• Modification of disease process:
– chemo, surgery or XRT, including radiopharmaceuticals
• Psychological interventions
• Physical therapy
• Integrative approaches
• Interventional techniques
– peripheral nerve blocks, radiofrequency ablation,
neurosurgical procedures
Opioid Use for Pain in Terminally Ill
• Opioids mainstay of cancer pain management.
• General principles of opioid use
– Select right opioid, at the right dose, frequency and route
– Prevent and treat opioid side effects.
• No uniformly preferred agent
• Opioid selection typically based on
– clinical judgment/comfort, formulary, cost, availability, and
patient’s past experience/analgesic response
Many pain guidelines…
• WHO Cancer pain relief. 1986.
• Agency for Health Care and Research
– Management of Cancer Pain. Clinical Practice Guideline
• National Comprehensive Cancer Network
– Adult Cancer Pain.
• American academy of pain medicine
• American pain society
– Guideline for the Management of Cancer Pain in Adults and Children
– Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic
Non-cancer Pain
• EAPC
– Morphine and alternative opioids in cancer pain: the EAPC
recommendations. Br J Cancer.
• Institutional
Table 1 Key WHO guidelines for cancer pain relief and palliative care
Dalal, S. & Bruera, E. (2013) Access to opioid analgesics and pain relief for patients with cancer Nat. Rev.
Clin. Oncol. doi:10.1038/nrclinonc.2012.237
WHO Cancer pain relief. 1986.
By the mouth
By the clock
By the ladder
Morphine
Severe pain
(7-10)
Codeine
Moderate pain
(4-6)
Acetaminophen
Mild pain
(0-3)
3-step “analgesic ladder”
Why recommendations do not always
work in clinical practice
• recommendations based on
– the need to spread out basic information
– simple and reliable
– do not fit many clinical situations
• More complex pain situations (longer survival, more
aggressive oncological treatments)
• Need of flexibility individually-based
Mercadante 2013
Criticism of WHO ladder approach
• Use of non-opioids
– concern in frail terminally ill
– compromised liver or renal functions.
• Usefulness of Step-2 questioned.
– delayed introduction of strong opioids may
result in periods of uncontrolled pain.
• Strong opioids may be safely initiated
at low doses, and are more beneficial
in cancer patients with mild-moderate
pain.
Opioids: two sides of the same coin
Opioid Use for Pain Management
A balancing act…
Analgesia
Adverse-effects
Benefits of analgesia should clearly outweigh
treatment-related adverse effects
Opioid Side-Effects
Commonly recognized side-effects:
• Sedation*
• Nausea
• Constipation*
• Urinary retention*
• Respiratory depression*
• Euphoria*
• Pruritus
• Opioid induced Neurotoxicity
* Attributed to mu-opioid receptor activation; Reversed by opioid antagonists :
Opioid Induced Neurotoxocity (OIN)
A syndrome of neuropsychiatric toxicity
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•
•
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•
•
•
•
•
Cognitive impairment
Delirium
Severe sedation
Hallucinations
Delirium
Myoclonus
Seizures
Hyperalgesia (paradoxical pain)
Each can occur alone, in combination, in any order
Suspect OIN if any present in a patient taking opioids
Hallucinations
• Usually Visual or tactile
• A study found 47% of hospice inpatients had visual
hallucination within the prior month.
– Hallucinators were more likely to be on opioids
– Hallucinations of a person standing by the bedside was the
commonest type
Fountain A. Visual hallucinations: A prevalence study among hospice inpatients.
Palliat Med 2001;15:19–25
Etiology of Delirium in Terminally Ill
 Opioids and other psychoactive medications
 Underlying Brain disease
 Uremic or Hepatic encephalopathy
 Dehydration
 Hypercalcemia,
 Hypernatremia
 Hypoxemia
 Sepsis
 “Terminal Delirium”
Opioids & dehydration top 2 causes of reversible delirium
Morita T, Psychosomatics 2004;45:107–113; Lawlor PG, Arch Intern Med 2000;160:786–794.;
Pereira J, Cancer 1997;79:835–842
Mechanism of Opioid Induced
Neurotoxicity
Not fully understood
• Accumulation of excitatory non-analgesic opioid metabolites
• Accumulation of the parent opioid
• NMDA activation
• Predisposing factors:
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high or prolonged opioid doses
rapid dose escalation
use of psychoactive drugs
dehydration, renal failure, advanced age, or underlying
brain disease or cognitive failure
Opioid Metabolism
• Most opioids metabolized in the liver, and renally
excreted.
– ↑ accumulation of parent opioid and its metabolites
– with high opioid doses; dehydration; renal failure.
– metabolites may cause toxicity via non mu-receptor
actions
Major Morphine Metabolites
Morphine
Liver
Opioid
metabolites
Neuro-excitatory
metabolite
Morphine-3-glucoronide (M3G)
Normorphine
Neuro-excitatory effects
• Hallucinations, delirium, allodynia,
hyperalgesia, myclonus, seizures.
• Is not a mu-agonist
Naloxone does not reverse effects
Renal
Elimination
Analgesic metabolite
Morphine-6-glucoronide (M6G)
 a potent mu-agonist
 ↑ analgesic effects
 ↑ mu-receptor side-effects
Summary of Opioid Metabolites
Opioid
Key Enzyme
UGT2B7
Major metabolites
M3G and M6G
Hydromorphone UGT1A3, 2B7
H3G
Oxycodone
CYP3A4, 2D6
Noroxycodone, oxymorphone
Oxymorphone
UGT2B7
6-OH-oxymorphone,
oxymorphone-3-glucuronide
Fentanyl
CYP3A4
Norfentanyl
Codeine
CYP3A4, 2D6
Morphine, C6G
Hydrocodone
CYP3A4, 2D6
Hydromorphone,
norhydrocodone
Propoxyphene
CYP3A4
Norpropoxyphene
Meperidine
CYP3A4, 2B6,2C19 Normeperidine
Tramadol
CYP2D6Morphine
O-desmethyl tramadol
Prevention of OIN
1. Evaluate and treat risk factors, as appropriate
2. Initiate and titrate opioids cautiously
3. Frequent Re-assessment for analgesic and adverse
effects of opioids
Prevention of OIN:
Evaluate for presence of risk factors
–
Able to maintain hydration?
•
–
–
–
–
? Nausea, bowel obstruction, anorexia, depression
Underlying renal and liver function?
Does patient have underlying brain disease, sepsis, or
hypoxia
Is patient on sedating medications
Screening for cognitive impairment or delirium
•
•
•
Mini-mental State Examination (MMSE)
Memorial Delirium Assessment Scale (MDAS)
Nursing Delirium Screening Scale (NuDESC)
Opioid Therapy
• Two phases:
– Initial phase
• depends on patient’s reports of pain, goals for pain relief, and
whether the patient is currently on opioids or not.
– Titration phase:
• Ongoing: careful opioid titrations and close monitoring of pain
relief outcome (personalized pain goal, side-effects, physical and
psychosocial functioning) is required to achieve an individualized
analgesic response.
Opioid Naïve Patients
• Initial phase:
– immediate release (IR) opioids at starting doses ( such as
7.5-15mg morphine) on PRN or “as needed,” every 2 to 4
hours.
• Titration phase:
– an extended release (ER) opioid could be administered on
a fixed schedule based on the use of prn opioids.
– Continue prn IR opioids for breakthrough pain.
• Fentanyl patches are usually not recommended for
use in opioid-naïve patients.
Back to ……Case Study 1:
RS, a 65 yr lady with h/o Breast cancer
• s/p mastectomy and radiation, completed 18 mths ago. Now
on Tamoxifen.
• Past 2 weeks:
– c/o pain in the lower back, radiating to the left hip and lateral lower
leg.
– One of her daughters, a radiologist has been giving her mother
acetaminophen-codeine, with mild relief in pain
• RS is miserable, still has significant pain and feels that
overall she is worse due to constipation.
Clinic visit with patient RS
• Oncologist saw earlier : bone scan, xrays labs ordered
• Patient is very anxious after above visit.
• RS is hesitant but agrees to start on opioids if her
constipation is manageable.
• However daughter is concerned about her mother
becoming hooked on medications like a junkie.
Myth Busting: Addiction
“A pattern of compulsive drug use characterized by
craving and the need to use a drug for effects other
than pain relief”
• A psychological/ behavioral syndrome with 3
distinguishing characteristics
– Loss of control over drug use
– Compulsive drug use
– Continued use despite harm
Myth Busting: Physical Dependence
• An adaptive physiological response to chronic
presence of a drug
• Normal expected response to chronic opioid Rx
• Not an indicator of addiction
• Evident with opioid withdrawal:
– yawning, sweating, tremor, fever,  HR, insomnia,
muscle/abdominal cramps, dilated pupils
– Occurs when drug is abruptly stopped or antagonist given
– Avoided by  dose 20-30%/day
Myth Busting: Tolerance
• Evident by reduced potency of analgesic effects of
opioids following repeated administration, i.e.,
increasing doses are necessary to produce pain relief
• Related to opioid receptor regulation
• Often reason pts. “save” opioids until terminal phase
Woodruff R, Palliative Medicine, 1999
RS clinic patient continued
• Patient prescribed morphine IR 15mg, to take ½
tablet as needed every 3 hours
• Reglan 10mg PO q 6 hours X 3 days then prn
• And what else?
Patient RS concerns:
Constipation
• Plan on it!
• Tolerance: doesn't happen
• Adjust the dose of laxative/softener with
adjustments in opioid dose
• Need bowel stimulants such as senna, bisacodyl
• Keep asking about their bowels
“The hand that writes the
opioid order shall also
write the laxative order!”
• quote from the Canadian palliative care
curriculum
1 week later, RS returns
• Now confirmed to have metastatic breast cancer to
multiple sites in the bone.
• Plan for chemotherapy after radiation (iliac bone and left
hip)
• She is seen by our team counselor, expresses her fears
about being a burden on her husband and children,
about being able to care for her elderly mother and her
catering business which she runs with one of her sons.
• Pain not well controlled. Transient relief. Took 2 ½ tablets
of 15mg tablets.
• Constipation improved. Senna 2 BID, polyethylene glycol
once daily. No OIN
Opioids: infrequent dosing
Toxicity
Effect
Analgesia
Pain
Time
24hours
Opioids: Adequate dosing
Toxicity
Analgesia
Pain
Time
24hours
For patients already on opioids..
• If there is no evidence of OIN and pain is not adequately
controlled (pain goal not met):
– Increase scheduled opioids by 25 to 50%, or by an amount
equal to the breakthrough opioids used in the previous 24
hours.
=Morphine ER15mg q8hours
– The breakthrough opioid dose should be recalculated as
10-15 % of the new scheduled dose, and prescribed every
2-4 hours as needed.
=Morphine IR 7.5mg q3hours prn pain
Case 2: JS, 54 yr male with relapsed met sarcoma
Crying and restless
Nausea with vomiting
Intermittent twitching
Poor historian, confused
Pain worse with palpation and
toucing his leg
Pain score: 20/10
Opioid induced neurotoxicity?
Delirium
Myoclonus
hyperalgesia
100
Fentanyl
patches
50
100
100
8 fentanyl patches = 650
micrograms/hr
50
100
50
100
Paradoxical Pain with Opioid Use
• Opioids may paradoxically ↑ pain
• Pain is usually
– more severe, diffuse, extends to other areas of distribution
from the preexisting
Pain
 Allodynia: painful response to a stimulus that
is normally not painful (such as light touch)
 Hyperalgesia: severe pain response to a
stimulus that normally produces only mild pain
response.
Opioids
Increased
Opioids
Pain
increases
Opioid-induced hyperalgesia (OIH)
Differentiate from
– ↑ pain due to disease progression
– Opioid tolerance
– Opioids usually increased in above two and associated with
improvement, but would worsen OIH
 Not always easy to distinguish OIH from above two
 If a trial of increasing opioids worsens pain, need to consider
OIH
Potential Contributors for Delirium/OIN
TERMINAL ILLNESS
Pain
Anorexia, Nausea
Vomiting,
Dysphagia,
Bowel
Obstruction,
Depression
↓ FLUID
INTAKE
DEHYDRATION
AND
IMPAIRED
RENAL
FUNCTION
Hypotension
Hypercalcemia
Fatigue, sedation,
postural hypotension
and dizziness, nausea,
constipation
Opioid Titration
Accumulation
of parent opioid
and its
metabolites
Excessive sedation,
myoclonus,
hallucination, opioid
induced hyperalgesia
DELIRIUM
COMA
AND
DEATH
Treatment of opioid induced neurotoxicity
(OIN)
• Treat underlying etiology of OIN
– Stop offending opioid. Hydration to help elimination
• Manage the pain
– Patient still needs opioid for pain management
– Chose alternate opioid
– Alternatives options to decrease need for opioids
• Symptomatic management of OIN
– Such as for agitated delirium
Hydration
• Rationale:
-Facilitates elimination of accumulated opioid and neuroexcitatory metabolites.
• Consider Pros and Cons…
• Subcutaneous route an option if oral not available
–
–
–
–
Simple, low cost, less need for supervision
25 or 27 gauge butterfly needle is used, use 5-7 days
Continuous versus bolus infusions
Can be used to administer other medications, including
opioids
Opioid Rotation
Rationale:
• OIN attributed to accumulation of offending opioid and its
metabolite, so the treatment is stopping offending opioid
• New opioid is used to control pain
*de Stoutz et al. JPSM; 1995
– Retrospective study of 80 patients with OIN (Cognitive
deterioration, hallucinations, myoclonus)
– Opioid rotation significantly improved symptoms and pain
control in vast majority of patients
– New opioid dose was significantly lower than that thought to
be equianalgesic
Opioid Rotation, cont’d.
• Which opioid is best to switch to ?
– OIN is not believed to be a class effect so any alternate opioid
may be chosen
– Dose of new opioid calculated from Equianalgesic Table
– Switch to methadone may have advantages
• No neuro-excitatory or active metabolites
• Good oral bioavailability
• Does not depend on renal excretion, so safer in presence of renal
failure
Opioid Rotation Recommended Steps
Step 1
 Calculate total daily (24 hr) dose of the offending opioid
Step 2:
 Calculate new opioid daily dose using equianalgesic conversion table.
Step 3:
 Decrease above new opioid dose by 25-50% for incomplete tolerance
between opioids
Step 4:
 Divide by number of scheduled doses/day. Breakthrough dose ~ 10-15%
of daily dose every 2-4 hours as needed.
Step 5:
 Titrate new opioid until adequate analgesia is achieved.
Initial Equianalgesic Opioid Dose Conversion
Table
Conversion Factor
Oral
Dose
Parenteral
(IV/SC) Dose
From IV/SC
opioid to oral
opioid
From oral opioid
to oral morphine
Morphine
15 mg
6 mg
2.5
1
Oxycodone
10 mg
NA
NA
1.5
Oxymorphone
5 mg
0.5 mg
10
3
Hydromorphone
3 mg
1.5 mg
2
5
Opioid
•Helps select the initial dose avoiding over- or under-dosing
•Comparative values are approximate. Opioid dose should be further titrated
based on the patient’s response.
Morphine to Methadone Conversion
Oral morphine equivalent
daily dose (MEDD) in
milligrams
< 100
> 100 – 300
> 300 – 600
Conversion
ratio*
3:1
5:1
> 800 – 1000
10:1
12:1
15:1
> 1000
20:1
> 600 – 800
* Dose of methadone is calculated by dividing
the MEDD by the conversion ration. This
dose should be decreased by 25-50% to
accommodate for lack of incomplete
tolerance
Fentanyl patch of 650 mcg/h
=morphine oral 1600mg/day
1600/20=80mg
50% reduce=40mg methadone/d
Patient is started on Methadone
30mg po q 8hours
Dilaudid as prn
Treatment of OIN:Delirium
Neuroleptics:
• Haloperidol most commonly used for agitation or mixed delirium
– Less sedating and fewer anti-cholinergic effects
• olanzapine, risperidone, and quetiapine
• Chlorpromazine
Benzodiazepines: not generally recommended (unless seizures)
due to excessive sedation, increased confusion, and increased
disinhibition with use
Case 2 continues
ex Phy
pe si
rie ca
nc l
e
al
ci
So
• Pain better controlled by day 3, still using frequent
prn hydromorphone (8 times). Methadone dose
increased.
• Delirium and myoclonus resolved.
• Team validated his complains of pain
Em
ua
l
– discussed etiology and plan of care for the 2 pain
syndromes he was experiencing
– possible chemical coping to cope with emotional suffering
Sp
iri
t
l
na
io
ot
TOTAL
PAIN
Four components of Total Pain
• Patient open to counseling. Met with chaplain and
psychologist.
– Counseling allowed him to express profound fear of dying,
his remorse about not having a good relationship with his
son, and becoming a burden on his girlfriend.
Chemical coping
• “the use of medications in non-prescribed ways to
cope with periods of intense physical and emotional
distress.”
• Suspect in patients with h/o alcohol and drug abuse.
– tend to return to their previous maladaptive behaviors
when faced with life stressors, and cope by using opioids
and/or sedatives
• Identification of at-risk patients
– early referral to pain or palliative care specialists
– interdisciplinary efforts to replace maladaptive behaviors
with adaptive ones
• counseling and relaxation techniques
Comprehensive approach to assessment and
management of pain in terminally ill patients.
Multidimensional Pain
Assessment
Reassessment
Decision Making Process
Therapeutic Plan
Reassessment
• Frequent reassessments of the patient’s pain and
related outcomes is crucial, and considered the most
important aspect of pain management.
• Examples of efficacy in pain management include
–
–
–
–
decreases in pain intensity
achievement of pain relief goals
improvements in physical and psychosocial functioning.
These outcomes should not be at the expense of major
opioid induced side-effects.
Monitoring Outcome: The 4 A’s
• Analgesia (pain relief)
• Activities of Daily Living (psychosocial functioning)
• Adverse effects (side effects)
• Aberrant drug taking (addiction-related outcomes)
(Passik and Weinreb, 1998)
Opioid Use for Pain in Terminally Ill
• Upto 30% of pts may not have a successful
outcome
– ↑ adverse effects
– inadequate analgesia
– ↑ adverse effects and inadequate analgesia.
Cherny
N, J Clin Oncol 2001;19: 254-254
New and emerging drugs for treatment for pain
2 broad categories:
Refinement in current
use of opioids
New Drugs
New delivery
systems
Combination
drugs
Development of nonopioid drugs
different mechanisms of action
based on implicated
products/receptors involved in
peripheral and central
sensitization
Inhibiting bone resorption
Development of non-opioid drugs and their targets
Central nervous system
Neuronal
• NMDA receptors
• Glial cell modulators
Peripheral nociceptive neurons
Sensitizing mediators and their
receptors
• NGF, ET
• TRPV1, Na channels
Bone
Osteoclast inhibition:
RANKL inhibitors
Bingham B et al. (2008) Nat Clin Pract Rheumatol doi:10.1038/ncprheum0972
Raising The Bar
Providing high quality care…
how can you improve the care you deliver
• Patient-centered
to our
most vulnerable and sick patients?
respect & respond to pt. preferences/needs/values;
Communication should be clear, honest, respectful
• Skilled providers
in pain and symptom control. Consult
• Effective
based on scientific knowledge to benefit; refrain if futile
• Timely
proactive and preemptive when issues predictable
• Safe
avoid injuries from care intended to help.
Low Expectations…
• Equitable
not vary in quality due to pt. characteristics, status
THANK YOU!
Wishing everyone a safe and happy holiday season!