What’s New In Acute Pain
Management: Reducing Our
Dependence On Opioids
Trevor D. Schack, MD
University of Michigan
Objectives
•
To review recent developments in the understanding of acute
pain with focus on molecular pathophysiology and the
repercussions of poorly controlled pain
•
To understand the role of opioids in acute pain management
including new insights into their potential negative
consequences
•
To understand current opioid-sparing strategies including
multimodal analgesia and regional techniques
Introduction
Background
•
1996 – WHO Pain
Ladder
•
1996 – APS “fifth vital
sign”
•
2000 – JCAHO Pain
Management Standards
Background
•
2000s – CMS introduces Hospital Consumer Assessment of
Healthcare Providers and Systems (HCAHPS) survey
•
•
•
2/18 questions directly relating to pain
4/18 indirectly relating to pain
2010 – The Patient Protection and Affordable Care Act
includes HCAHPS to calculate value-based incentive
payments
Pain Control Remains
Inadequate
Overall Pain After Surgery
% ADULTS SURVEYED
60
50
40
30
20
10
0
Slight
Moderate
1995
Severe
2003
Warfield CA, Kahn CG. Anesthesiology. 1995;83:1090-1094.
Apfelbaum JL, et al. Anesth Analg. 2003;97:534-540.
Extreme
Effects of Uncontrolled Pain
Opioid Use Increases
Frasco et al (2005)
As Do Side Effects
•
Vila et al (2005) reported a more than two-fold increase in
the incidence of opioid related adverse events involving oversedation
•
•
11->24.5/100,000 patients (p < 0.001)
94% had a documented decrease in level of consciousness
preceding the event
Other Opioid Side Effects
•
•
•
•
•
•
•
•
•
•
Ileus/Constipation
Nausea/Vomiting
Sedation/Resp Depression
Cough suppression
Confusion/Delirium
Pruritus
Dry mouth
Sweats
Urinary retention
Tolerance/Dependence
Cost of Adverse Events
•
In addition to potential mortality risk, opioid-related adverse
events have been associated with an increase in cost and
length of stay (Oderda, 2007)
So, What Has Changed?
Advances in Understanding
Descartes 1664
Today
Molecular Mechanisms
Pain Pathophysiology
Opioid Induced Hyperalgesia
*Koppert (2007)
Anesthesia, Analgesia, and
Cancer
*CDC 2010
93%
84%
78%
49%
3
Epidural Patients 57%
Lower Risk Recurrence
7
Pathogenesis of Tumor
Metastases
Immune Response to Tumor
Cells
• Natural Killer Cells
• Spontaneously recognize and
lyse tumor cells
• Activated by IL-2 and IFN-y
• Patients with low levels of NK
cells have increased risk for
recurrence
• Stress-induced attenuation NK
activity in rat model is
associated with breast tumor
growth and metastasis
• Cytotoxic T-cells
• Dendritic Cells
*Dranoff (2004)
Surgery—A Critical Time
• Surgery is the mainstay treatment for primary tumors
• Can offer best prognosis for patients with solid tumors
• Likely a critical period when metastases are either established
or eradicated
• Can result in minimal residual disease—microscopic deposits
at margins or micrometastases
• Fate of these neoplastic cells likely dependent on the
competence of the host immune response perioperatively
• Studies show the presence of neoplastic cells in circulation 24
hr following tumor resection assoc with increased recurrence
Effect of Surgery on Immune
Function and Metastasis
• Perioperative immunosuppression as a result of the
neuroendocrine stress response and cytokine inflammatory
response
• Disrupting endothelial barriers during surgery releases tumor
cells into circulation—supported by PCR
• Release of growth factors—PGE2, VEGF, TGF-b
• And pro-inflammatory cytokines—IL-1, TNF-a, PGE2
• Decreased levels of anti-angiogenic compounds—endostatin,
angiostatin
Effect of Pain on Immune
Function and Metastasis
NK Cell Activity In Rats
Having Surgery
100
90
89.7
80
LYTIC UNITS
• Pain is a potent stimulant of
the HPA axis and
sympathetic nervous
system, which can lead to
immunosuppression
• Acute pain suppresses NK
cell activity and promotes
tumor development in
animals
• Analgesia has been shown
to attenuate this effect
72.9
70
60
50
52
41.3
40
30
20
10
0
*Page (2001)
4x Tumor
Retention
Levels IL-1 and IL-6 With Different Analgesics
*Beilin (2003)
Opioids and Immune Function
NK Cell Activity In Rats With Various Opioids
NK Cell Activity In Humans
*Beilin 1989
*Beilin 1996
• Both cellular and humoral immunity are suppressed by
perioperative and chronic opioid use
• NK cell activity is reduced by opioids
• Whether this indirectly promotes cancer recurrence and
metastasis is unknown
Opioids—Direct Effect on
Cancer Progression?
Breast Tumor Volume In Mice
control (▪)
morphine (▵)
morphine + naloxone (□)
naloxone (▴)
*Gupta (2002)
*Lennon (2012)
• Breast cancer cells implanted in mice show increased
tumor volume and vascularization when treated with opioid
• Likely through direct stimulation Mu receptor or its
interaction with VEGF receptor
Role For μ-Opioid Receptor?
• NSCLC cells show 5x
increase in MOR expression
• Silencing MOR in animal
model causes reduced tumor
growth (35-50%) and
metastasis (45-70%)
• Similar results are obtained
with a naltrexone infusion
• Lung cancer cells injected into
MOR knockout mice show no
tumor development
• Same cells injected into
controls developed lethal
tumors in 12 days
*Mathew (2011)
MOR With A118G Polymorphism
Survival Probability in Carriers of A118G
• Most common
polymorphism in MOR
• Results in decreased
responsiveness
• 5% African-American
women
• 24% Caucausian
*Borstov (2012)
*Zylla (2013)
15% survival in high MOR
group vs 70% in low MOR
• MOR expression and
long-term requirement
independently
associated with inferior
survival
• For every unit MOR +
area, risk of cancer
progression incr 65%
and death 55%
• For every 5 mg/d MEQ,
risk of progression incr
8% and death 5%
Future Prospective Studies
*Heaney (2012)
“Whenever possible, anesthesiologists should use
multimodal pain management therapy. Central regional
blockade with local anesthetics should be considered.”
Regional
Anesthesia/Analgesia
• Increased patient satisfaction
• Improved analgesia
• Decreased postoperative opioid use
Transversus Abdominal Plane
(TAP) Blocks
External
oblique
Internal
oblique
Transversus
abdominis
Quadratus
lumborum
• First described by Rafi et al
(2001)
• Provides analgesia to the
abdominal wall
• Blocks anterior divisions of lower
thoracic, subcostal and first
lumbar nerves between IO and
TA muscles
• Efficacy established by RCT
• Dye studies show reliable
spread T10-L1 (iliac crest to
costal margin)
TAP Blocks For Donor
Nephrectomy at UM
Donor Nephrectomy Incisions
TAP Indications
• Best for lower abdominal and
pelvic incisions from the umbilicus
and below
•
•
•
•
•
Donor nephrectomy
‘Hand-assist’ lap port
Appendectomy
Hysterectomy
Cesarean Section
• Alternative when epidural is not
possible or ‘overkill’
•
•
•
•
•
Smaller incision/outpatient surgery
Unable to tolerate placement
Coagulopathy
Infection
Spinal abnormalities
TAP Technique
Paravertebral Blocks
• First described in 1905 by
Sellheim, a German physician
• Fell out of practice until 1979
• Efficacy supported by multiple
RCTs
• Complications are reportedly
low with most feared being
pleural puncture and
pneumothorax (0.5%)
• Cochrane Review 2013: may
prevent persistent postsurgical
pain after breast surgery in 1 out
of every 4-5 patients
Paravertebral Indications
• Best for thoracic procedures but
can be performed from cervical to
lumbar region
• Good alternative to epidural
• Single-shot
•
•
•
•
Breast surgery (T2-T6)
VATS (varies)
Small umbilical hernia (T7-T10)
Prostatectomy/hysterectomy (T10-L1)
• Continuous
•
•
•
•
•
•
Breast surgery (T2-3)
Lateral nephrectomy (T6-7)
Thoracotomy/VATS (T4-5)
Rib fractures (varies)
Major abdominal (T7-8)
Pelvic (T10-11)
Paravertebral Anatomy
*usra.ca
Classic Technique
•
•
•
•
Identifty spinous processes
Entry point 2.5 cm lateral
Contact transverse process
Redirect caudally to “walkoff”
• Advance 1 cm
• Inject 5 ml local anesthetic
• Repeat for additional levels
Ultrasound Technique
*Narouze (2010)
Ultrasound Technique
*Narouze (2010)
Thoracic Epidural Analgesia
*Manion (2012)
• Analgesia: lower pain
scores than with systemic
opioids
• CV: reduced risk of MI and
dysrhythmias
• GI: earlier return of bowel
function
• Pulm: reduced risk of
pulmonary complications,
reduced mechanical
ventilation
• Endo: decreased postop
protein catabolism and
hyperglycemia
Thoracic Epidural Analgesia
*Manion (2012)
• Excellent for larger incisions
• Benefit less well established
for minimally invasive
procedures
• Higher systemic side effect
profile than TAP or
paravertebral blocks
• Can be associated with
hypotension, N/V, urinary
retention, numbness,
weakness
• Require personnel to
manage on floor
Opioid-Sparing Medications
Gabapentinoids
General:
• Decrease pain scores and opioid use
• Likely effective at reducing chronic postsurgical pain
• Side effects include sedation, dizziness, visual disturbances
Mechanism:
• Structural analogs of GABA but do not bind to its receptor
• Bind to voltage-gated calcium channels, modulating the release of
excitatory neurotransmitters
Pharmocodynamics:
• Gabapentin absorption is limited to a small portion of the duodenum
while pregabalin is absorbed throughout the small intestine
• Gabapentin absorption can be significantly impaired by antacids
• Both are renally excreted without significant metabolism
Gabapentinoids—What Dose
and When?
Timing of Dosing
• Studies indicate that postop dosing
is just as effective as preop
• Peak plasma level in 1-2hr but peak
CSF level in 6-8 hr
• So, preop dosing may have to occur
earlier for max benefit
Dose
• Studies looking low (300-600 mg) vs
high (900-1200 mg) doses of
gabapentin favor higher dosing
• The same is true for pregabalin
• Continuing medication thru recovery
probably most effective
*Schmidt (2013)
COX Inhibitors
COX Inhibitors
COX Inhibitors
Nonspecific NSAIDs (COX 1
and 2 activity)
• Ketorolac, Ibuprofen
• Use limited perioperatively
due to platelet dysfunction,
GI and renal toxicity
Coxibs (COX 2)
• Celebrex
• Potential cardiac/renal
toxicity
• Reduced GI side effects, no
platelet inhibition
Both
• May lead to dose-dependent increase of cardiovascular
toxicity and impaired osteogenesis
• 15-55% reduction in perioperative opioid use (Elia 2005)
COX Inhibitors and Cancer
• COX-2 inhibitors:
•
•
•
•
Induce apoptosis
Decrease levels of angiogenic factors
Decrease microvascular density in animal models
Attenuate opioid-induced immunosuppression
• COX-2 inhibitiondecreased PGE2direct impact on cancer
cell mutation, proliferation, and survival
• Overexpression of COX-2 is associated with increased cancer
recurrence and is a poor prognostic indicator
• Farooqui et al—mouse model showed chronic morphine use
increases COX-2 expression in tumor cells, and can impair
analgesia while promoting tumor angiogenesis
Tylenol—Now Available By IV
• Effective, well tolerated
• Caution with severe hepatic
impairment
• Safe with renal dysfunction
• Max 3g/day
• 1g IV acetaminophen
reduced morphine use after
orthopedic surgery
approximately 30%
(Sinatra, 2005)
Liposomal Bupivacaine
• Exparel – bupivacaine loaded
in multivesicular liposomes
• FDA approved for local
infiltration
– Hemorrhoidectomy
– Bunionectomy
• No delay in wound healing
after orthopedic surgery
• Acceptable adverse effect
profile
*Chahar (2012)
• Attempted dose response
study for 14 volunteers
having femoral n block
• Tested quad strength and
tolerance to electrical
current
• Found dose response in
opposite direction—higher
the dose, lower the effect
Other Adjuvants
Alpha-2 Agonists
• Clonidine, dexmedetomidine
• Can provide sedation,
hypnosis, anxiolysis,
sympatholysis and analgesia
• Antinociceptive effect due to
action on alpha-2 receptors
in brain and spinal cord
• Can cause profound
hypotension, bradycardia
• Meta-analysis shows 2025% reduction morphine at
12-24 hrs postop
(Blaudszun, 2012)
NMDA R Antagonists
• Ketamine
• At subanesthetic doses (0.5
mg/kg) may exert NMDA
blockade modulating central
sensitization and OIH
• Hallucinations, bad dreams,
dizziness, blurred vision
• Inhibits NK cell activity in
animal models
The Future
PROSPECT (Procedure Specific Postoperative Pain
Management)
• http://www.postoppain.org
The Future
Questions???