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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
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
Slight Moderate Severe Extreme0
10
20
30
40
50
60
Overall Pain After Surgery
1995 2003
% A
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Warfield CA, Kahn CG. Anesthesiology. 1995;83:1090-1094.Apfelbaum JL, et al. Anesth Analg. 2003;97:534-540.
As Do Side Effects• Vila et al (2005) reported a more than two-fold increase in
the incidence of opioid related adverse events involving over-sedation• 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)
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
• 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 GA O
nly
GA/Fen
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10089.7
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NK Cell Activity In Rats Hav-ing Surgery
Lyt
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nits
*Page (2001) 4x Tumor Retention
Opioids and Immune Function
*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
NK Cell Activity In Rats With Various Opioids NK Cell Activity In Humans
Opioids—Direct Effect on Cancer Progression?
*Gupta (2002)
control (▪)morphine ( )▵morphine + naloxone (□)naloxone ( ) ▴
• 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
*Lennon (2012)
Breast Tumor Volume In Mice
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)
*Borstov (2012)
MOR With A118G Polymorphism
• Most common polymorphism in MOR
• Results in decreased responsiveness
• 5% African-American women
• 24% Caucausian
Survival Probability in Carriers of A118G
*Zylla (2013)
• 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%
15% survival in high MOR group vs 70% in low MOR
“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
• 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)
External oblique
Internal oblique
Transversus abdominis
Quadratus lumborum
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
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)
Classic Technique• Identifty spinous processes• Entry point 2.5 cm lateral• Contact transverse process• Redirect caudally to “walk-
off”• Advance 1 cm• Inject 5 ml local anesthetic• Repeat for additional levels
Thoracic Epidural Analgesia• 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*Manion (2012)
Thoracic Epidural Analgesia• 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*Manion (2012)
GabapentinoidsGeneral:
• 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 InhibitorsNonspecific 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 inhibitiondecreased PGE2direct 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 AdjuvantsAlpha-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 20-25% 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