This document provides information on understanding pain management and daily practice management. It discusses types of pain such as acute vs chronic pain and nociceptive, nocioplastic, and neuropathic pain. It also covers topics like pain physiology, receptors, assessment, goals of pain management, pharmacology of specific drugs like morphine, oxycodone, hydromorphone, fentanyl, hydrocodone, buprenorphine, and tramadol. The role of an interdisciplinary team in pain management is emphasized.

1. Understanding Pain
Management and
Daily Practice Management
Agron Ismaili MD | Regional Medical Director
VITAS®
Healthcare | agron.ismaili@vitas.com

2. CME Provider Information
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You must participate in the entire activity as partial credit is not available. If you are
seeking continuing education credit for a specialty not listed below, it is your responsibility
to contact your licensing/certification board to determine course eligibility for your
licensing/certification requirement.
Physicians
In support of improving patient care, this activity has been planned and implemented by
Amedco LLC and VITAS
®
Healthcare. Amedco LLC is jointly accredited by the Accreditation
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continuing education for the healthcare team. Credit Designation Statement – Amedco LLC
designates this live activity for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians
should claim only the credit commensurate with the extent of their participation in the activity.

3. CE Provider Information
VITAS Healthcare programs are provided CE credits for their Nurses/Social Workers and Nursing Home
Administrators through: VITAS Healthcare Corporation of Florida, Inc./CE Broker Number: 50-2135. Approved
By: Florida Board of Nursing/Florida Board of Nursing Home Administrators/Florida Board of Clinical Social Workers,
Marriage and Family Therapy & Mental Health Counseling.
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as ACE providers. State and provincial regulatory boards have the final authority to determine whether an individual
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ACE provider approval period: 06/06/2021 – 06/06/2024. Social workers completing this course receive 1.0 ethics
continuing education credits.
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NJ: No NHAs, OH: No NHAs, PA: No NHAs, TX: No NHAs, VA: No NHAs, WI: No NHAs and Nurses are not
required – RT only receive CE Credit in Illinois.

4. Objective
• Describe, define, and differentiate
aspects of pain:
– Acute vs. chronic, nociceptive,
nociplastic, neuropathic
• Discuss the importance of
identifying pain:
– Receptor sensing
– Mechanism of transmission
– Complex interaction of the
elements of the peripheral and
central nervous systems
• Enhance assessment and
management of both
medication and non-medication
measures used to treat total pain
After this presentation, learners should be able to:

5. Goal
To achieve an appropriate understanding of pain
management’s multifaceted applications in the
context of palliative and hospice care

6. Pain Definition
• An unpleasant sensory and emotional experience
associated with actual or potential tissue damage
Merskey, H. et al. (1979). Pain terms: a list with definitions and notes on usage.
Recommended by the IASP Subcommittee on Taxonomy. Pain, 6, 249-252.

7. Acute vs. Chronic Pain (Practice, Reality)
• Acute pain is the most common
reason for ED visits
• Chronic pain comprises around
20% of physician office visits
• $60 billion/year in lost productivity
Zelaya, et al. (2020). Chronic Pain and High-impact Chronic Pain Among U.S. Adults, 2019. NCHS Data Brief No. 390. Available at: https://www.cdc.gov/nchs/products/databriefs/db390.htm
Stewart, et al. (2003). Lost Productive Time and Cost Due to Common Pain Conditions in the US workforce. JAMA, 290(18), 2443-54.
Van den Beuken-van Everdingen, et al. (2007). Prevalence of Pain in Patients With Cancer: A Systematic Review of the Past 40 Years. Annals of Oncology, 18(9), 1437-1449.

8. The Importance of Goals of Care
• Patients’ values are honored
• Symptoms are attended to
quickly and effectively
• Patient and family maintain
control of treatment plan
• Poorly defined goals can lead to:
– Unwanted treatments
– Inappropriate use of resources
– Undue suffering
– Miscommunication
• Emergency clinicians establish
GOC with patients daily
• Any team member can
assess GOC

9. Pain in response to
an injury or stimuli;
typically acute
Nocioplastic Pain that arises from
nocioceptive function,
typically chronic
Neuropathic Pain that develops
when nervous symptom
is damaged
Fibromyalgia, irritable bowl
syndrome, non-specific
low back pain
Post-operative pain, sports
injuries, arthritis, sickle cell
disease, mechanical low
back pain
Post-herpetic neuralgia,
trigeneuralgia, distal
polyneuropathy, CRPS,
neuropathic low back pain
Types of Pain
Nociceptive Pain

10. Acute and Chronic Pain
• Acute pain:
– Usually hours to weeks, most likely responsive
to multimodal therapies
– Noted physiological changes and notable
pain behaviors
• Chronic pain:
– > 3 months (persistent, with long-term conditions,
can be expressed as anxiety, depression, irritability;
may not respond easily to drug therapies; essentially
to correlate with function)
Source for Acute/chronic pain statistics (FSMB USA Model guidelines for the use of controlled
substances for the treatment of pain, Euless, TX 1998 source 1/2/3.

11. Nociceptive, Nocioplastic, and Neuropathic Pain
• Nociceptive:
– Bone (aching, gnawing, localized)
– Visceral (cramping, regionally
localized or referred)
– Somatic (easy to localize and
describe)
• Nocioplastic:
– Central SENSITIZATION –
Increased response to stimulation
mediated by amplification of
CNS (e.g., fibromyalgia, chronic
back pain, etc.)
• Neuropathic:
– Damage or injury to the nerves
that transfer information between
the brain and spinal cord from
the skin, muscles and other parts
of the body
– Burning sensation and affected
areas are often sensitive to
the touch
Federation of State Medical Boards of the United States, Inc. (2005). Model Policy for the Use of Controlled
Substances for the Treatment of Pain. Journal of Pain & Palliative Care Pharmacotherapy, 19(2), 73-8.

12. Types of Pain
Antihistamine
Acetaminophen
Opioids and NMDA blockers
Nerve blocks
NSAIDs
Topical/transdermal
treatments
Nocioplastic Anticholinergic
Anticonvulsants
TCAs and SNRIs
Other serotonin agents
Neuropathic Anticonvulsants
Opioids and NMDA blockers
Nerve blocks
TCAs and SNRIs
Generally not opioid
responsive
Nociceptive Pain

13. Prevalence in Older Adults, Barriers
• Pain is in patients with and
without cancer (present in
75% institutionalized and
50% community elderly) and
about 25% of elderly do not
receive adequate analgesia
• Barriers
• Patient
• Prescribers
• Pharmacy
• System
• Legal
• Common: racial, elderly,
lack of educational skills,
fear of addiction, etc.
J. Med.2007,120(4) 306-315 JAMA 1998; 279; (23)1877-1882 J.Am. Ger. Soc.,1999 47 (8) 936-942 Source 1, 2, 3

14. Pain Statistics: Emphasizing Multifactorial Nature,
Importance in Daily Practice
• Single or multifocal
• Cancer (treatment vs. malignant
process, direct and indirect effects)
vs. non-cancer (pressure ulcers,
RA, OA, sickle cell, osteomyelitis,
back pain, headaches)
• Pain is a serious problem for as
much as 40% of the US population
Resources 1/2/3

15. Integrated Pain Model
Dame Cicely Saunders devised a new paradigm of the
concept of pain beyond the confines of the physical
body responses.
• Total pain is characterized as the multidimensional
nature of the pain experience and includes these
domains of pain:
– Physical
– Psychological
– Social
– Spiritual
Resources 1/2/3

16. Comprehensive Symptom Evaluation
• Symptom ascertainment
(PQRST tool, etc.)
• Past medical and treatment
history (pharmacologic/non-
pharmacologic, comorbid, hx
of opioid use-PDMP, the
effectiveness of treatment)
• Social, psychological, and
family history (mental health,
personal and family hx of
polysubstance abuse, cultural
background, social network,
other behavioral patterns)
• Opioid Risk Assessment
(identifies persons at higher risk
for SUD, possibly necessitates
additional monitoring; ># high
risk, mitigation, misuse, abuse,
diversion, periodic UDS)
• Physical exam and assessment
(integrates hx with observation
for corroboration of symptoms)
• Pharmacologic and
non-pharmacologic
management plan
Resources 1/2/3

17. Pain Physiology Half-Life
• An important aspect in the management
of pain issues
• To determine dosage times by knowing
how long the drug will continue to do
its job
• What is it?
– How much time it takes for blood levels
of a drug to decrease to half of what
they were when the drug was at peak
performance in the body
Resources 1/2/3

18. Pain Physiology, Mechanisms & Receptors
• Transduction: Noxious stimuli—to
action potentials—peripheral nociceptor
sensory fibers
• Some of the substances produced can
affect the pain: nociceptors, tissue
damage, and inflammatory cells
(bradykinin, prostaglandins, etc.)
Resource: 1/2/3

19. Pain Physiology, Mechanisms & Receptors
• Transmission: peripheral, central
transmission by many pathways,
such as: stomato-sensory thalamus,
thalamic-cortical fasciculus, lateral
spinothalamic funiculus, ventral
spinothalamic tract
• Complex interaction of glial cells,
nociceceptors, neurons, biogenic
amines, etc.
Resource: 1/2/3

20. Pain Management Goals
• Optimize patient comfort
• Enhance FUNCTION, physical
well-being, psychological well-being,
spiritual well-being
• Minimize side effects
• Enhance quality of life
Resource: 1/2/3

21. Role and Importance of Hospice IDT in
Pain Management
• Paint the picture, narrative
subjective process,
REASSESSMENT is
very important
• VITAS for many years has
been the leader in effective
pain management for patients
with terminal diseases
• Teamwork is vital for effective
pain management
• We as members of IDT have a
responsibility to manage pain:
– Team manager
– Nurse
– Hospice aide
– Chaplain
– Team physician
– Volunteer
Resource: 1/2/3

22. Pain Physiology, Receptors
• Example of types of pain:
– BONE/VISCERLA/SOMATIC-Nociceptive
– Peripheral, Central-Neuropathic
• Multiple mechanisms, multiple sites, consider
chronic medical problems (esp. mental health
issues) and how they affect patient’s perception
of pain, etc.
Resource: 1/2/3

23. Pain Assessment
Tolerance: Physiologic
phenomenon resulting from regular
use of a drug in which increased use
is needed to produce same effect
• Common concern but
uncommon phenomenon
• E.g., N/V/fatigue (with opioids),
developing tolerance leading
to diminished side effects
• ATTENTION: Tolerance does not
develop for opioid constipation
• Managing opioid tolerance
• Rotation (uncontrolled pain,
neurotoxicity)
Physiologic Dependence:
• Adaption manifested by drug class
specific WITHDRAWAL syndrome –
after abrupt cessation, rapid dose
reduction, decreased blood levels,
administration of antagonist; common
after 1-2 weeks of continuous weeks
of use. Treatment: reintroduction of
opioid, clonidine, BZD, Imodium
Resources 1/2/3

24. Pain Assessment (cont.)
• Addiction: Impaired control, compulsive use, continued
use despite harm, cravings
• Pseudo-addiction: Inadequate pain management,
disease progression, can creates mistrust with patient?
inadequate prescriptions
• Pain is a subjective process, narrative story; validate
the experience
Resources 1/2/3

25. Opioid Therapy: Pharmacology Morphine
• Most frequent indications in
the daily practice:
– Pain/dyspnea/cough/
anesthesia, diarrhea
• Few important steps in the
mechanism of action:
– Bind to opioid receptors,
activate descending
inhibitory pathway, prevent
neurotransmitter release,
reduce formation of
action potentials
• Receptors:
– Mu: brain stem, medical
thalamus, peripheral
– Mu1-analgesia
– Mu2-analgesia GI tract,
respiratory depression, pruritus
– Kappa:
• Limbic system, brain stem,
spinal cord, spinal analgesia,
sedation, dysphoria
• Delta: brain, periphery spinal
analgesia, decreased GI motility,
respiratory depression
Resources 1/2/3

26. Morphine
• Opioid like receptor (ORL-1):
Affects stress, feeding, learning,
memory? opioid tolerance
• Sigma: It is not considered true
opioid receptor, potential for
psych mimetic effects, dysphoria
• DEA class II
• Strong MU and weak kappa and
delta; metabolized in the liver,
excreted by kidneys
• Morphine-3-glucuronide and
morphine-6-glucuronide toxicity
concerns; generally not used
in patients with end-stage
renal disease
• Management of side effects
• Forms: Injectable, oral, rectal
Resources 1/2/3

27. Pharmacology of Specific Drugs
• Oxycodone: agonist MU/Kappa, metabolized with conjugation
in the liver by CYP 450 to active/inactive metabolites
• ATTENTION: Prolonged elimination in renal impairment/failure
• It is combined with acetaminophen/aspirin
• Hydromorphone
• Main mechanisms
• Mu agonist
• Hepatic metabolism via glucouronidation to
Hydromorphone 3G; excreted by kidneys
Resources 1/2/3

28. Pharmacology of Specific Drugs (cont.)
• Fentanyl
– MU agonist
• Has lipophilic effect
• Hepatic metabolism to inactive
metabolites-not dialyzed
• ATTENTION: reduce dose in
severe renal impairment
• Oxymorphone preparation IR/ER
• ATTENTION: can take 2 hours
before or after as taking with
meals can increase serum levels
Resources 1/2/3

29. Pharmacology of Specific Drugs (cont.)
Hydrocodone Derived from codeine
• Can be combined with acetaminophen; DEA II
Buprenorphine
• MU partial agonist (high affinity, low potency), Kappa
antagonist, lipophilic, first-pass metabolism, CYP 450,
may cause QT prolongation; MAT (medication-assisted
treatment-use in opioid use disorder; low ceiling effect;
high doses lead to the same level of analgesia with more
side effects)
• Option for patient use with serious illness and opioids
use disorder (used with or without naloxone)
Resources 1/2/3

30. Pharmacology
Tramadol Weak opiate agonist;
SNRI effect like; CAUTION with SSRI
use (can cause serotonin syndrome)
MU agonist inhibits 5-HT/NE
reuptake (similar to SNRI); NMDA
antagonist; can use in treatment
of neuropathic pain-central pain,
opioid induced hyperalgesia
METHADONE Synthetic DEA II;
for pain any provider; for MAT needs
special license/certification
Methadone Pharmacology: Primary
hepatic with some renal clearance;
no active metabolites (IT IS
CONSIDERED safe in renal impairment)
• Takes time to build stores; Analgesic
half life 9-59h
• Special CAUTION in elderly, rapid
dose titration; HIGHLY VARIABLE
RESPONSE RATES; CYP450
inhibitor, drug-drug interactions,
PROLONG QT, not a good choice
for rapid titration
Resources 1/2/3

31. Dosing and Management
• Choosing an opioid:
– ATTENTION: Review
specific patient/diseases
characteristics-ASSESSMENT
• Short- vs long-acting
– Short-acting: Intermittent/
breakthrough/incident
dose frequency per time
to peak effect
– Long-acting: Continuous pain
• Converting short-acting
to long-acting
– Assess and and determine
total daily dose of opioid
– Convert to oral morphine
equivalents (MME) adjust and
individualize new dosing;
follow up in no more than
1 week
Resources 1/2/3

32. Practical Example of Opioid Rotation
• Morphine ER 80 mg po BID and oxycodone
10 mg po q4h prn pain
• Inpatient/outpatient practice; pain not well
controlled and reported side effects
from morphine
• Because of worsening side effects, decision
to change/rotate opioids

33. Practical Example of Opioid Rotation
• Morphine 80 mg po BID = 160mg/d
– 160 mg/d-OME for above
• Oxycodone is 1.5 times stronger
than morphine
• Oxycodone IR total 60mg = 90 mg
po Morphine
• Total OME 250mg
• Conversion to Oxycodone 160 mg
• Therefore Oxycodone 80 mg po
bid ER form
• Incomplete cross tolerance 40mg po bid

34. Management / Side Effects Specifics
• Opioid rotation:
– Dose-limiting side effects change in route CAUTIOUS
OPIOID NAÏVE start low dose and individualize
• APPRORIATE DOSING
– reduces side effects; balances between side effects,
rotations, multiple barriers etc.

35. Management / Side Effects Specifics
Adverse effects:
Sedation (often tolerance,
modulate dose, non-opioid
options, rotations, psychostimulants)
Respiratory Depression brain
system MU receptors activation,
sedation occurs first pruritus
(dose limiting, NOT TRUE
hypersensitivity-tx MU antagonist,
naloxone antihistamine,
rotations, naloxone)
Concomitant use of benzodiazepines
anticholinergics, Neurontin, alcohol,
sleeping medicines, and muscle relaxants
is dangerous for respiratory depression
Nausea/vomiting (GI slowing
CTZ, vestibular; tolerance
in 3-7 days; antiemetics, rotations)
Tolerance anticipate constipation,
schedule Methylnaltrexone,
laxative, etc.

36. Opioid Management
• Opioid selection variables: medication, patient, EBM
• Initiation - consider following factors: Opioid Naïve, half-life
• IR forms: Mild/moderate pain increase 25-50%
– Severe/uncontrolled increase by 50-100%,
dose frequency per time to peak effect
• Re-ASSESSMENT FREQUENT and important (side effects,
function, dose adjustments, temporal pattern
• ER forms: Total of IR /daily dose (adjust for severity)
– E.g., Oxycodone 5 mg po x 4 doses/d=20 mg ; 50-75% of
above and convert to long-acting oxycodone CR 5 mg po bid
Resources 1/2/3

37. Opioid Management (cont.)
• Fentanyl transdermal; not effective for acute pain; lasts 48-72hrs,
depending on patient metabolism; direct heat can increase drug
absorption, still distributed after patch removed; 70% bound to albumin,
so hypoalbuminemia decreases plasma levels (EOL frequently low
albumin). Must be opioid tolerant to initiate this therapy. VITAS pharmacy
can help manage these medications for patients on VITAS service.
• Extended-release forms: improve adherence, CANNOT CRUSH or chew
• Fentanyl transdermal every 48h-72h
• Methadone 4-7 days
Resources 1/2/3

38. Opioid Management Challenges
• Challenges: with increasing dose escalations-increasing side effects
– Incomplete cross-tolerance
– Drug-receptor interactions
• Safe to reduce equianalgesic dose by 25-50% to compensate
• EXCEPTION:
– Rotating to methadone, reduce more than 75%-90%
– In EOL care
• VERY IMPORTANT use of VITAS Pharmacy counselling to help
physicians/other caregivers that prescribe pain meds, in managing
complexities of pain. VITAS pharmacist significant assist in patient-
centric and safe care.
Resources 1/2/3

39. Opioid Management (cont.)
• Opioid Controlled Analgesia
(PCA) challenges:
– Sedation precedes
respiratory depression
– Loading dose (initial dose
administered by RN); Bolus
(demand), Lockout 10-15 min
based on peak effect), basal rate
(hourly rate-not in opioid naïve)
– Some control (alleviates
anxiety, individualized)
– Loading dose (initial dose
administered by RN);
Bolus (demand), Lockout
(10-15 min based on peak effect),
basal rate (hourly rate-not in
“opioid naïve)
• Please be aware a national
shortage of parenteral opioids
exists and is not available
outside of the hospital
Resources 1/2/3

40. Continue Non-Opioid Pain Management
• NSAIDS: anti-inflammatory, periphery-acting, bind to plasma albumin,
do not cross blood brain barrier, metabolized by the liver, low renal
clearance (<10%)
• Used in bone pain, soft tissue, visceral pain
• Multiple negative side effects (GI, renal etc.)
• Steroids:
– Dexamethasone decreases inflammation; tumor shrinkage, anti-tumor
effects, enhances appetite weight gain, improved sense of well being
– Side effects:
• Immunosuppression
• Psychosis
• Proximal muscle wasting
Resource: 1/2/3

41. Non-Opioid Analgesia
• PoorDrugs with additional
analgesic properties
• Some indications:
– Response to opioid, marked
predisposition to opioids, opioids
side effects to increasing
opioids dose
• Different pain syndromes
• Neuropathic pain
• Bone pain
• Myofascial pain
• Safe use:
– One adjuvant at a time
– Increase dose until limiting
side effects or analgesia
– Can add another analgesic
if partial analgesia and
maximal dose
Resources 1/2/3

42. Non-Opioid Pain Management
• Neuropathic pain
• Few meds that can be used:
– TCAs (AVOID IN GERIATRIC populations mostly
due to ANTICHOLINERGIC effects)
– SNRI can be used: painful, neuropathy, post
mastectomy, fibromyalgia
– SSRI paroxetine painful neuropathy, Fluoxetine
(if comorbid depression), avoid in geriatric population
Resources 1/2/3

43. Non-Opioid Pain Management
• Gabapentin can be used in
neuropathic pain, pregabalin
(faster titration)
• Ketamine* NMDA antagonist
can be used as neuropathic pain
• OPIOID RESISTANT EMPASIZE
role of VITAS Pharmacy
education/assistance
• OPIOID SPARRING effect
(important with worsening shortage
of opioids especially IV forms)
• Post-op pain: much lower dose
analgesic effect than anesthetic
Resources 1/2/3

44. Non-Pharmacologic Pain Management
• CBT (improving mental health,
thoughts, beliefs and behaviors,
QOL; anxiety, bereavement ,
insomnia
• Acupuncture
• Music therapy
• Hypnotherapy
• Massage
• PT/OT
• Heat therapy:
– Increases circulation to
affected tissues
– Relieves joint stiffness and
muscle spasm
– Decreases sensitivity to pain
– Chronic swelling may be reduced
– Simple, easy to do, inexpensive
and possibly effective in
the short-term
– Caution: prolonged use which
may lead to irritation and actual
burn of the over lying skin.
Resources 1/2/3

45. Liver Failure
• Liver responsible for metabolism
of most drugs through CYP450
• Opioids in the liver failure
• Oxycodone: oxymorphone by
liver, increased half life,
unpredictable levels
• Morphine: first pass metabolism
(no CYP450), less hepatic
flow-increased bioavailability
• Methadone (CYP 450), clearance
not altered
• Hydromorphone (first pass
metabolism, GOOD CHOICE
FOR LIVER DYSFUNCTION)
• Patients frequently experience
fatigue, mental and mood disorders
• Patients, family and care
providers may experience guilt,
anger, sadness, fear, anxiety, and
depressed mood
• Additionally, there are effects on
the health of care providers, family
social interactions, and finances

46. Liver Failure (cont.)
• All these responses may
affect patient pain perception
• Reduced response
to medications
• Loss of muscle and body
mass through atrophy
• Tissues become more ridged
• The brain and spinal cord
deteriorate which effects
perception of pain and location
• Wound healing is reduced and
time to heal is longer
• Scaring or incomplete healing
occurs more often
• Methadone (CYP, decreased
hepatic flow–increased blood
levels, avoid in severe liver
dysfunction
• NSAIDS (CYP450;
inhibits prostaglandins
• Acetaminophen-CYP
450-NAPQI-hepatotoxic;<2g /d

47. Renal Failure
• Renal Failure
• Responsible for clearance
of many pain meds;
• Accumulation (in renal failure)
can cause:
• Neurotoxicity, Hepatotoxicity
• Codeine and its metabolites
(morphine, hydrocodone) are
excreted by kidney
• M3G neurotoxic, MSG
analgesic effects
• Oxycodone can accumulate
in renal failure
• Hydromorphone/fentanyl
considered Safe
• Acetaminophen <3g/d; no
significant changes observed
in renal failure

48. Summary Ideas/Thoughts
• It is important to note that increased
social and spiritual interactions may
well have a positive influence upon
pain perception and are too often
under-used as therapy.
• Selected therapies based upon
a thorough evaluation of the
patient’s pain and ability to
tolerate additional treatments
is required of the practitioner.
• Reevaluation to assess responses
to these added therapies needs
to occur as often as reassessment
of analgesic therapy does.
• It is far too easy to simply have
tunnel vison and provide analgesia
for pain and not consider the total
pain concept, which is part of the
benefit to a team approach to
care management

49. Questions?

50. References
1. Hospice and Palliative Medicine Board Review-American Physician institute
2. Medical Knowledge
3. VITAS Resource Library
4. Merskey, H., et al. (1979). Pain terms: a list with definitions and notes on usage.
Recommended by the IASP Subcommittee on Taxonomy. Pain, 6, 249-252.
5. JAMA 2003, 290(18)2443-24454
6. National Academy Press US 1997
7. Annal Oncology 2007;18(9) 1437-1449
8. Stewart, et al. (2003). Lost Productive Time and Cost Due to Common Pain Conditions
in the US workforce. JAMA, 290(18), 2443-54.
9. Zelaya, et al. (2020). Chronic Pain and High-impact Chronic Pain Among U.S. Adults, 2019.
NCHS Data Brief No. 390. Available at: https://www.cdc.gov/nchs/products/databriefs/db390.htm
10.Van den Beuken-van Everdingen, et al. (2007). Prevalence of Pain in Patients With Cancer:
A Systematic Review of the Past 40 Years. Annals of Oncology, 18(9), 1437-1449.