Total pain is the concept that pain due to chronic disease has physical, psychological, social, and spiritual dimensions.

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Total Pain
Michael Aref, MD, PhD, FACP, FHM
Assistant Medical Director of Palliative Medicine

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I
DISCLOSURES

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Disclosures
• None
I work in palliative care…

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II
OBJECTIVES

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Objectives
• Discuss models of pain.
• Understand pain pathways.
• Understand the concept of total pain.
• Discuss how biochemical and neurohormonal
mechanisms are influenced by physical, psychological,
social, and spiritual components of pain.
• Understand uses of opioids in pain management.
• Identify complications of opioid pain management.

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III
PAIN: MODELS

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Central Neuropathic
• Non-dermatomal
• Direct central nervous injury
• Radiating or specific
• Burning, prickling, tingling,
electric, shock-like or lancinating
Peripheral Neuropathic
• Dermatomal
• Direct peripheral nervous injury
• Radiating or specific
• Burning, prickling, tingling,
electric, shock-like or lancinating
Visceral (,)
• C fiber activity
• Distension, ischemia and
inflammation of organs
• Diffuse, deep ache,
pressure, sickening,
squeeze, dull or sharp
Types of Pain
Psychogenic
• Pain that is caused, increased, or prolonged
by mental, emotional, or behavioral factors.
Acute < 3 months
Chronic > 3 months
Malignant pain is due
to a progressive disease
that will lead to death.

Non-malignant pain is due to a
non-threatening cause that may
persist until, but is not the cause of,
death.

1st
2nd
tramadol
oxycodone
methadone
3rd
Never
Opioid?
2nd – 3rd
Somatic (,)
•  fiber activity
• Skin and deep tissue
damage
• Pinprick, stabbing or
sharp
Goldstein and Morrison, Evidenced-Based Practice of Palliative Care: Expert Consult, Ch 1, 2
Mann and Carr, Pain: Creative Approaches to Effective Management

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4-Step Model of Pain
Transduction Transmission Perception Modulation
Acute stimulation in the
form of noxious
thermal, mechanical, or
chemical stimuli is
detected by nociceptive
neurons.
Nerve impulses
transferred via axons of
afferent neurons from
the periphery to the
spinal cord, to the
medial and ventrobasal
thalamus, to the
cerebral cortex.
Cortical and limbic
structures in the brain
are involved in the
awareness and
interpretation of pain.
Pain can be inhibited or
facilitated by
mechanisms affecting
ascending as well as
descending pathways.
Wyatt SA, Adjunct Approaches to Chronic Pain Management for Individuals with Substance Abuse Disorder, July 21, 2016

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Total Pain
Social
Psychological
Physical
•Role
•Relationships
•Occupation
•Financial cost
•Emotional response
•Comorbid mood disorder  anxiety
•Adjustment to new baseline
•Cause?
•Associated symptoms
•Debility and fatigue
Superimposed on Maslow’s Hierarchy of Needs
Spiritual
•Existential coping
•Religious beliefs
•Meaning of life/illness
•Personal value
Interventional Pain Service
Other Specialties
Pharmacy
Physical Therapy
Social Work
Financial Navigator
Occupational Therapy
Chaplaincy
Art & Music Therapy
Social Work
Psychology
Psychiatry
Curr Opin Support Palliat Care. 2008; 2(2):110-3
Maslow AH, A Theory of Human Motivation, 1943

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IV
PAIN: PATHWAYS

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Nocioceptive Nerve Conduction Pathways
J Pain. 2010 Aug;11(8):701-9
nobaproject.com/modules/touch-and-pain

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Neurotransmitters
Substance P
• Central neurotransmitter,
neuromodulator, and immunomodulator.
• Degraded by angiotensin converting
enzyme (ACE).
• Blocking action of substance P, showed
significant activity versus placebo in
outpatients with major depression and
moderate anxiety.
• In rats, stress causes substance P release
in the medial nucleus of the amygdala.
Glutamate
• Glutamate mediates the vast majority of
fast excitatory transmission in the brain.
• Glutamatergic system is a primary
mediator of psychiatric pathology.
• Animal models have shown that
environmental stress enhance glutamate
release, reduce glial mediated glutamate
cycling, and alter synaptic transmission in
limbic/cortical areas.
• Glucocorticoids secreted during stress
affect the basal release of glutamate in
several limbic and cortical areas, including
the hippocampus, amygdala and
prefrontal cortex.
Dialogues Clin Neurosci. 2002 Mar; 4(1): 21–29
PNAS, 2003, vol. 101(12) : 4280–4285
Neuropharmacology. 2012 Jan; 62(1): 63–77
Nat Rev Neurosci. 2011 Nov 30; 13(1): 22–37.

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Neurotransmitters
γ-aminobutyric acid (GABA)
• GABA mediates the majority of
fast inhibitory transmission.
• Wide ranging abnormalities in
GABA content in individuals with
mood disorders.
Glycine
• Amino acid that serves as an
inhibitory neurotransmitter.
• Pain control due to cannabinoids
and endocannabinoids involves
modulation of glycine receptors.
Neuropharmacology. 2012 Jan; 62(1): 63–77
Mol Psychiatry. 2003 Aug; 8(8):721-37, 715.
Neurochemical Research. 2003;28:965–976
CNS Neurol Disord Drug Targets. 2007 Apr; 6(2):127-40
themedicalbiochemistrypage.org/nerves.php

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Neurotransmitters
Serotonin
• 5-hydroxytryptamine; 5-HT
• Pathogenesis of depression and
anxiety is dependent on
serotonergic function, e.g.:
– 5-HT1A agonists for treatment of
certain anxiety disorders
– 5-HT1C and 5-HT2 receptor
antagonists for treatment of
generalized anxiety disorder
– 5-HT1D receptor agonists are used
in the treatment of migraine
Int Clin Psychopharmacol. 1995 Jan;9 Suppl 4:41-5
Neuron. 2012; 76(1): 175-191

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Neurotransmitters
• Norepinephrine projections from the locus coeruleus innervate
the limbic system, which is implicated in the regulation of
emotions.
• Numerous differences have been found in elements of the
norepinephrine system in postmortem brains from depressed
patients and healthy controls.
• Mice with genetically engineered functional enhancement of the
norepinephrine system are protected from stress-induced
depression-like behaviors.
• Serotonin norepinephrine reuptake inhibitors (SNRI) are indicated
for treatment of depression, anxiety, fibromyalgia, and diabetic
neuropathy.
Norepinephrine
Neuropsychiatr Dis Treat. 2011; 7(Suppl 1): 9–13
www.mayoclinic.org/diseases-conditions/depression/in-depth/antidepressants/art-20044970

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Peripheral Nerve and Spinal Neurotransmitters of Pain
Nat Rev Drug Discov. 2014 Jul;13(7):533-48
www.rnceus.com

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Neuronal projections to different brain “centers”
Emotional centers
NE projections from the locus coeruleus to the hypothalamus
NE projections from the locus coeruleus to the amygdala and
prefrontal cortex
5-HT projections from the midbrain raphe to the hypothalamus
5-HT projections from the midbrain raphe to the amygdala and
prefrontal cortex
DA projections from the ventral tegmentum to the nucleus
accumbens
Cognitive centers
NE projections from the locus coeruleus to the dorsolateral
prefrontal cortex
DA projections from the ventral tegmentum to the
dorsolateral prefrontal cortex
Histamine projections from the hypothalamus to the
dorsolateral prefrontal cortex
Somatic centers
NE projections from the locus coeruleus to the hypothalamus
NE projections from the locus coeruleus to the cerebellum
NE projections from the locus coeruleus to the spinal cord
5-HT projections from the midbrain raphe to the
hypothalamus
5-HT projections from the midbrain raphe to the striatum
5-HT projections from the midbrain raphe to the spinal cord
DA projections from the substantia nigra to the striatum
Neuropsychiatr Dis Treat. 2011; 7(Suppl 1): 9–13

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V
OPIATES

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Dose Units Medication Route Real World
15 mg morphine PO
15 mg hydrocodone PO
10 mg oxycodone PO
5 mg morphine IV
4 mg hydromorphone PO
0.75 mg hydromorphone IV
0.05 (50) mg (mcg) fentanyl IV
Dose Equivalents

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Dose Equivalents

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World Health Organization Analgesic Ladder
Strong opioids
• Fentanyl transdermal
• Hydromorphone
• Methadone
Moderate opioids
• Hydrocodone
• Morphine
• Oxycodone
Weak opioids
• Codeine
• Tramadol
Nonopioid analgesics
• Acetaminophen / Salicylates / NSAIDs
• Corticosteroids
Adjuncts
• Anticonvulsants
• Antidepressants (SNRI, TCA)
• Baclofen
• Ketamine
Interventions
• Acupuncture
• Art / Music Therapy
• Massage
• Physical Therapy
• Psychological Treatment
• Transcutaneous electrical nerve stimulation
Procedures
• Nerve blocks
Procedural Interventions
• Patient controlled analgesia pump
• Neurolysis
• Spinal stimulator
• Intrathecal pump
• Neurosurgery
Chronic pain
Non-malignant pain
Cancer pain
Acute pain
Chronic pain without
control
Acute crises of chronic
pain
Canadian Family Physician 2010; 56(6):514-517

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Descending the Ladder
Katrina Disaster Working Group Suggested Tapering
Regimens
• Decrease dose by 10% every day,
• Or decrease dose by 20% every 3-
5 days,
• Or decrease dose by 25% every 7
days.
Veterans Affairs Suggested Tapering Regimens
• Short-Acting Opioids
– Decrease dose by 10% every 3-7 days.
– Or decrease dose by 20-50% every day until lowest available
dosage form is reached then increase the dosing interval,
eliminating one dose every 2-5 days.
• Long-Acting Opioids
– Methadone
• Decrease dose by 20-50% per day to 30 mg daily, then
decrease by 5 mg daily every 3-5 days to 10 mg/day, then
decrease by 2.5 mg daily every 3-5 days.
– Morphine SR
• Decrease dose by 20-50% per day to 45 mg daily, then
decrease by 15 mg daily every 2-5 days.
– Oxycodone CR
• Decrease dose by 20-50% per day to 30 mg daily, then
decrease by 10 mg daily every 2-5 days.
– Fentanyl
• Rotate to another opioid such as morphine SR or
methadone and then taper off that opioid.
paincommunity.org/blog/wp-content/uploads/Safely_Tapering_Opioids.pdf
AAPM 2005
USVA 2003

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Some Considerations
• Opioid-induced nausea = haloperidol PRN (max 2 mg TID) + olanzapine QHS
• Neuropathic pain + muscle spasm = gabapentin
• Neuropathic pain + anxiety - depression = pregabalin
• Post-operative pain + anxiety - depression = pregabalin
• Muscle spasm + fibromylagia = cyclobenzaprine
• Muscle spasm + anxiety = diazepam
• Depression  anxiety + neuropathic pain = duloxetine
• Superficial somatic pain + minimize opioids = lidocaine topical
• Deep somatic pain = orphenadrine
• NSAID + renal impairment = diclofenac topical
• NSAID + bleeding risk = choline magnesium trisalicylate
Two symptoms for the price of one

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VI
CASE #1

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Case
• 23-year-old white female with chronic abdominal pain, nausea, and
food aversion secondary to multiple surgeries for hereditary
pancreatitis and complications thereof.
• Non-malignant abdominal pain managed with progressive increases in
opiates, now on high-dose opiates, 200 mcg/hr fentanyl patch with 4-8
mg of hydromorphone as needed every 2-3 hours
• Mother strong advocate for patient.
• Consulted for pain management.

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How is she NOT dead?

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CDC Grand Rounds, January 13, 2012 / 61(01);10-13
Dose and Overdose

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Course
• Basal opiates increased and discharged home
• Patient seen on subsequent hospitalizations for other
complications, e.g. line infection, portal vein thrombosis.
Abdominal pain continues to worsen without change in
pathology.
• Having built a relationship with patient, discussed
concerns that opiates were worsening her pain.
Agreeable to weaning off opiates.

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Narcotic Bowel Syndrome
Chronic or frequently recurring abdominal pain that is treated with acute high dose or
chronic narcotics and all of the following:
• The pain worsens or incompletely resolves with continued or escalating dosages of
narcotics.
• There is marked worsening of pain when the narcotic dose wanes and improvement
when narcotics are reinstituted (“Soar and Crash”).
• There is a progression of the frequency, duration and intensity of pain episodes.
• The nature and intensity of the pain is not explained by a current or previous
gastrointestinal diagnosis*
*A patient may have a structural diagnosis (e.g., inflammatory bowel disease, “chronic
pancreatitis”) but the character or activity of the disease process is not sufficient to
explain the pain.
Clin Gastroenterol Hepatol. Oct 2007; 5(10): 1126–1122.

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VII
CASE #2

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Case
• 72-year-old white male with metastatic pancreatic
cancer, admitted for pain control.
• Patient has been on rapidly escalating doses of
morphine. Delirious, in his lucid moments he weeps,
morphine has been aggressively increased. In the past 24
hours he developed intermittent jerking of his limbs.
• Consulted for pain management.

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Opiate-Induced Hyperalgesia
• Increasing sensitivity to pain stimuli (hyperalgesia). Pain
elicited from ordinarily non-painful stimuli, such as stroking
skin with cotton (allodynia).
• Worsening pain despite increasing doses of opioids.
• Pain that becomes more diffuse, extending beyond the
distribution of pre-existing pain.
• Presence of other opioid hyperexcitability effects: myoclonus,
delirium or seizures.
• Can occur at any dose of opioid, but more commonly with
high parenteral doses of morphine or hydromorphone and/or
in the setting of renal failure.
www.mypcnow.org/blank-h5muh

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Course
• Patient was switched to fentanyl, but at 75%
equianalgesic dose.
• Pain controlled, delirium improved, myoclonic jerks
resolved.
• Patient died on in-patient hospice.

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QUESTIONS? COMMENTS? CONCERNS?
THANK YOU