Kelly Martin CRNA, MSN

Objectives

1. Persistent Post-Surgical Pain (PPP)

2. A review of pain [patho]physiology

3. MMA following APS’ 2016 Guidelines

(1) 80% of surgical pts note pain in first 2 wks after surgery

(2) 75% of those report pain as mod, severe, or extreme

(3) ~40% of pts have mod-to-severe pain immediately post-op

(4) ~25% note significant SE’s from opioids

• Adverse outcomes from under-treatment of peri-op pain:

(1) Splinting/hypoxia; (2) atelectasis; (3) increased r/o PNA; (4) HTN/tachycardia

(risk of cardiac ischemia/stroke); (5) N/V from pain; (6) ileus; (7) urinary

retention; (8) immunologic depression; (9) anxiety/depression; (10)

development of PTSD; (11) increased hospital LOS; (12) hospital readmission; (13)

decreased pt satisfaction; (14) development of chronic pain

Why Care?

Anes./Analgesia Effects Cancer Recurrence…??

Persistent Post-Surgical Pain

• “The development of chronic pain after surgery is not an uncommon event.”

• ~22.5% of all chronic pain is surgically related

• Preemptive analgesia used to help reduce acute, surgical pain

• New concept of preventative analgesic used not only to reduce acute pain, but also PPP

– i.e. preventing peripheral/central sensitization (more to come)

Persistent Post-Surgical Pain – Risk Factors

Fibromyalgia, migraines, IBS,

Raynauds

Persistent Post-Surgical Pain – What Procedure?

Surgical Procedure

PPP (% of surgeries)

Severe Pain (% of surgeries)

1. Limb Amputation 50-85% 5-10%

2. Breast Surgery (esp. radical, reconstruction,

radiation/chemo)

20-50% 5-10%

3. Thoracotomy 30-65% 10%

4. Herniorrhaphy 10-35% 2-4%

5. Cardiac Surgery 30-55% 5-10%

6. Cholecystectomy 5-50%

7. Hip Replacement 12%

8. C-Section 6%

What is pain??

• Pain (def) – “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”

- American Pain Society

• Key Points:

– Pain is an emotional experience

– Pain is both a physiologic and a behavioral phenomenon (i.e. there is a psychological component to pain)

– All factors must be addressed for successful Rx of pain

(N/P – p. 1240)

Things to keep in mind: Pain is complex…

…& the nervous system is plastic

• CNS is extremely ‘plastic’ (i.e. changeable) - synapses & neuronal pools can change quickly for short periods or for long periods of time

• How we manage each patient will impact the plasticity of their CNS – some will inevitably develop CPSP

Neuro[plastic]ity

Let’s dissect pain:

A. 3 broad categories:

1. Neuropathic

2. Psychogenic

3. Nociceptive (the focus today)

B. Nociceptive Pain is either…

1. Visceral (c-fiber)– described as diffuse, dull, vague, referred (ex. bowel obstruction)

2. Somatic (Aδ-) – localized, well-defined, sharp (ex. TKR)

C. All [nociceptive] pain is induced by ONE of THREE things:

1. Mechanically-induced

2. Chemically-induced (we call this the ‘inflammatory soup’)

3. Thermally-induced (temp. extremes)

All activate specific receptors and travel in specific pain pathways

The Classic 4-step Pain Pathway

Chemical

Thermal

Mechanical

Inflammatory Soup

VEMI-CSF

Inflammatory Soup…the ingredients!

Algogenic Mediator: Substrate (receptor): Effect:

Bradykinin Bradykinin Receptor GqP (IP3/DAG/Ca2+)

PGE2/PGI2 EP/IP Receptor GsP (cAMP/PKA)

Histamine H1 Receptor GqP (IP3/DAG/Ca2+)

Serotonin (from plts) 5-HT3 Receptor Ionotropic (Na+) NK-1 rec. sensitization

H+ Ion VR-1 Receptor Ionotropic (Na+/Ca2+)

ATP P2X Receptor Ionotropic (Na+)

Adenosine A2 Purinergic Receptor GsP (cAMP/PKA)

Cytokines (TNFα & IL-1β) Increase expression of NGF (neurotropic peptide – modulates nerve growth)

*Exponentially contributes to peripheral sensitization (NGF) - acts on TrkA Rec

Noxioius Heat (> 43° C) & capsaicin

VR-1, VRL-1 Ionotropic (Na+/Ca2+/K+)

Noxiouis Cold (8-25° C) & menthol

CMR-1 Ionotropic (Na+/Ca2+/K+)

Mechanical Distortion Non-selective cation channel Na+/Ca2+/K+ flux

Nerve Growth Factor

• Causes ‘trophic’ changes to PAN’s– changes the composition of the nerve fiber

• (1) Nerve “sprouting”; and (2) Upregulation of VR-1, adrenoreceptors, & VOSC – leading to spontaneous discharge [ENA])

Symp. Maintained Pain (NGF, NE, PG, etc)

(Both centrally & peripherally)

Neurogenic Inflammation

• Primary afferent nociceptors also release neuropeptides at nerve terminals – process called antidromic stimulation • sP, CGRP, & NKA bind to their respective receptors to produce further vasodilation, edema, and hyperalgesia (FYI – increased plasma levels in CRPS pts) • This is the process of ‘peripheral sensitization’ OR ‘primary hyperalgesia’

Peripheral Sensitization

• Chemicals ‘sensitize’ [normally] high-threshold nociceptors • Low-intensity stimuli that would not normally cause much pain are now perceived as being extremely painful

Transmission: Neospinothalamic (Fast Pain -Aδ)

Transmission: Paleospinothalamic – (Slow/Chronic Pain – C fiber)

‘Wind Up’ / Central Sensitization / 2nd Hyperalgesia

“Chronic Pain is associated with neuroplastic changes in the P&CNS in response to nociceptive input” – EJP 2011

1. Acute: Aberrant activation of PAN’s leads to neuronal hyper-excitability in the DH of the SC (i.e. resting Vm moves closer to

threshold potential)

2. Receptive Field Expansion in SC: adjacent neurons (noxious/innocuous – WDRN) increase firing rate – leading to hyperalgesia and allodynia

3. Later phase/LTP: gene expression facilitated through NMDA & NGF activation leads to ‘sprouting’, channelopathies, etc

4. Loss/death of inhibitory neurons: including interneurons & the descending inhibitory pathway

5. These changes can be permanent

Sympathetic-Afferent Coupling

• DRG ‘basket’ formation: sprouting of post-ganglioninc noradrenergic fibers into DRG causes gene expression for adrenoreceptors that travel to site of injury and contribute to pain channelopathies seen with certain chronic pain syndromes

• α-adrenoreceptors here are excitatory – process of SMP

3 - Perception of pain

• Pain is subjective – everybody perceives pain differently

• Psychogenic Pain – The “Catastrophizing” Patient

– Physical pain caused by mental, emotional, and/or behavioral factors

– Common pain: HA, back pain, stomach pain

– Accompanies: mental disorders, anxiety/depression, social rejection, grieving, other emotional events

– No aggravating factors, yet pain is perceived

– Stigmatized: “both medical professionals and the public tend to think that pain from psychological source is not ‘real’”

4 - Modulation of pain

Descending Pathways OR

‘The Brain Opioid System’

• Purpose is to reduce nociceptive impulses entering the SC from being transmitted to the brain – less pain made conscious

Perioperative Multimodal Analgesia

“Three intertwined processes may serve as targets for the prevention of

chronic pain, and include: (1) peripheral sensitization,

(2) central sensitization & (3) descending modulation.”

- EJP, 2011

Multimodal Approach to Pain Management

• The etiology of pain is multimodal so it only makes sense that the treatment be multimodal as well

Multimodal Analgesia (MMA) – administration of 2 or more drugs that act by different mechanisms for providing analgesia

– Optimize analgesia efficacy while minimizing the SE’s 2/2 lower doses (a balanced anesthetic)

• We now know that opioid monotherapy is not an adequate or appropriate strategy to improve pain management in perioperative pts.

Perioperative Pain Management – Pharmacologic Options:

1. PCA & analgesic adjuncts

– Opioids/non-opioids used for multimodal analgesia

– **The focus of this pharmacology section

2. Neuraxial Techniques (SAB/Epidural/CSE)

– LA +/- opioids/clonidine

3. Peripheral Nerve Blocks

4. Topical/Local Agents

Recent advances in MMA, Anesthesiology (2012)

1-4: Pre-operative teaching and Peri-op APM planning

5: Methods for assessing pain

6: Principles regarding the use of multimodal therapies

7-8: Use of physical modalities

9: Use of cognitive-behavioral modalities

10-19: Systemic Pharmacological Therapies

20-22: Use of Local/Topical Pharm. Therapies

23-25: Use of peripheral RA

26-28: Use of Neuraxial Techniques

29-32: Organization structure/policies & transition to outpatient

Multimodal Pain Management - agents

1. Opioids *‡

2. Non-opioids: IV acetaminophen & COX inhibitors *‡

3. Gabapentinoids *‡

4. Lidocaine (IVLI) *‡

5. Beta Blockers (Esmolol infusion – discussed further in Jon’s lecture)*

6. Ketamine (Discussed in Ryan’s lecture) ‡

7. Mg Sulfate *

8. Alpha-2 agonists (Dexmedetomidine & Clonidine) *

9. Dexamethasone *

10. Nitrous Oxide *

11. Topical Capsaicin & Menthol (not discussed today)

* Agents that will be discussed today

‡ Agents addressed in APS 2016 Guidelines

Opioids (very briefly..)

• Recommendation highlights:

1. *Preop oral opioids to decrease postop pain/opioid consumption is not recommended b/c studies show no clear benefit from this practice

2. Use PCA (vs intermittent healthcare provider boluses) is more effective and has > pt satisfaction

3. Avoid basal PCA infusion for opioid naïve patients – pain control is not improved but S/E profile increased

Non-Opioids

1. Acetaminophen (not considered NSAID)

• PO route – surgical stress & opioids may reduce gastric absorption

• IV route:

– OFIRMEV FDA (2010) approved for: (1) treatment of mild/moderate pain; (2) treatment of moderate/severe pain with opioids; & (3) for fever reduction

• Devoid of SE’s commonly associated with NSAIDs

• MOA (remains unclear):

1. Central COX II-inhibition (SC specifically)

2. Cannabinoid &/or Vanilloid Receptor

3. NMDA Rec?

Non-Opioids

– Takes 15 mins to reach max plasma conc. (i.e. end of infusion) VS 45-75 mins OR 3-4 hrs for oral or rectal routes, respectively

– Mean peak conc. is ~70% higher than oral route (i.e. > bioavailability of drug to have an effect)

– Clinical Analgesia Peaks (~ 1 hour)DOA (4-6 hours)

Same dose for all 3 routes (1 gm)

• Acetaminophen readily penetrates the BBB – notice IV form results in a > CSF conc

• Early/high peak plasma conc. + rapid BBB penetration =

(1) rapid onset & (2) higher peak efficacy

Non-Opioids

Non-Opioids

• However…

• …so, most will get oral/rectal tylenol (cost efficient)

(APS Guidelines, 2016)

Non-Opioids

• What about the pt with liver disease??

1. With ofirmev, plasma conc. is well below threshold for hepatotoxicity (150 mcg/mL)

2. IV route avoids first-pass: avoids overwhelming a compromised liver with high acetaminophen exposure “all at once.”

• However, acetaminophen (via any route) is contraindicated in pts with severe liver disease (b/c compromised glutathione stores)

Non-Opioids

• Why use tylenol??

• Study after study shows (1) reduction in pain scores; (2) reduction in opioid consumption (~30%); (3) reduced PONV; & (4) greater pt satisfaction during the first 24 hours postop (when compared to placebo)

• Surgeries studied: laparoscopic, orthopedic, spine, open abdominal/pelvic, gynecologic, cardiac, and thyroid surgeries…

…so pretty much all surgeries!

Non-Opioids

Non-Opioids

• Inhibit the action of cyclo-oxygenase which prevents the conversion of arachidonic acid to prostaglandins

• Thus, the nociceptive response to endogenous mediators of inflammation is attenuated

(Phosphatidylcholine)

2. NSAIDS

Non-Opioids

Prostanoids: Receptor: Rec. Type: Actions:

a. Thromboxane (TXA2)

b. Prostacyclin (PGI2) c. Prostaglandin D2 (PGD2) d. *Prostaglandin E2 (PGE2) e. Prostaglandin F2 (PGF2)

TP receptor IP receptor DP receptor EP receptor FP receptor

Gq Gs Gs Gs/Gi/Gq Gq

Platelet aggregation; vasoconstriction Inhibit platelet aggregation; vasodilation Inhibit platelet aggregation; vasodilation Vasodilation, uterine contraction, hyperalgesia Uterine contraction

Non-Opioids

2 Important Isoforms:

1. COX-1:

a) Body has a “constitutive” amount

b) Location: kidneys, gastric mucosa, platelets, and endothelium

c) Involved in: renal function, gastric protection, and hemostasis

2. COX-2:

a) Synthesis is “inducible” in the presence of inflammation

b) Location: (1) inflammatory cells; & (2) central nervous system

c) Involved in: pain, inflammation, and fever

Non-Opioids

• Advantages of using NSAIDs in MMA:

1. ↓ inflammatory process

2. *Opioid-sparing effect by ~30%

3. *↓ peripheral/central sensitization

COX-2 in the SC may play an important role in central sensitization – wind up! (success with epidural NSAIDS in animal models)

4. Cover some pain types better than opioids

• Non-selective NSAIDs – deleterious effects:

1. Microvasculature constriction (contraindicated for cardiac surgery)

2. Gastric mucosa irritation (disrupt protective barrier)

3. Platelet inhibition (only lasts ~24 --- is reversible; unlike aspirin)

4. Bronchoconstriction – more leukotriene production

Non-Opioids

• Animal studies suggest a link between bone nonunion after orthopedic & spinal fusion procedures and NSAID use

• Also, NSAID use might be associated with increased r/o anastomotic leakage after colorectal surgery

• APS Guidelines: “The panel found insufficient evidence to recommend against use of NSAIDs in patients who undergo surgery for orthopedic, or colorectal surgery.”

Non-Opioid

Non-Opioid

• Most common periop NSAIDs:

1. Ketorolac IV:

1. 15-30 mg (dose reduction in the elderly)

2. usually given ~30 minutes prior to skin closure

3. Tourniquet use – when to give??

2. Celecoxib (Celebrex):

1. 200 mg given preemptively, 30 mins – 1 hr pre-op

2. Followed by 100-200 mg BID in post-op for 3 days

Agent Potency Dose DOA

1. Aspirin 1 PO: 325-650 mg Q 4 hours

4-6 hours

2. *Celecoxib 1-2 PO: 100-200 mg 4-6 hours

3. Diclofenac Sodium (Voltaren)

15 PO: 100-200 mg Q 4-6 hours

4-6 hours

4. Ibuprofen (Advil, Motrin)

Min PO: 200-800 Q 6 hours

4-6 hours

5. Indomethacin (Indocin) 20 PO: 25-50 mg Q 6-12 hours

4-6 hours

6. *Ketorolac (Toradol) 60 IV: 15-60 mg PO: 10 mg

4-6 hours

7. Naproxen (Naprosyn, Aleve)

3 250-500 mg Q 6 hours

4-6 hours

Non-Opioids

Gabapentinoids

• Class: α2δ-containing VOCC-blockers

• Drugs in clinical use:

(1) Gabapentin (Neurontin)

(2) Pregabalin (Lyrica)

• Structurally similar to GABA yet do not interact with GABA receptors

• Uses: epilepsy, restless leg syndrome, fibromyalgia, neuropathy, & treatment of acute surgical pain (off label use)

Gabapentinoids

MOA – (1) *block presynaptic VOCC; (2) enhance desc. noradrenergic inhibition

Gabapentinoids

-Systematic review of 22 randomized, controlled trials

-Results:

1. Pain relief superior in the gabapentinoid groups (compared to placebo)

2. Opioid-sparing effect during first 24-h ranged from 20-62% after a single-dose of 300-1200 mg gabapentin 1-2 hrs preop

1. Reduction of opioid-consumption equivalent to 30 mg morphine during first 24-h

3. PONV and urinary retention reduced

4. Most common S/E was sedation and/or dizziness (dose reduction)

Gabapentinoids

1. APS Guidelines recommend gabapentinoids as a part of MMA

2. Optimal dose:

A. Gabapentin (P-kinetics highly variable):

• Range from 600 – 1200 mg; 1-2 hrs preoperatively

• Continue for 72 hrs postop – 600 mg/day

B. Pregabalin (P-kinetics stable):

• 150 mg 1-2 hrs preoperatively

• Continue for 72 hrs postop; 75-150 mg/day

Non-Opioids

Gabapentinoids

• P-Kinetics

1. Absorption:

– Gabapentin absorbed by small part in the duodenum – efficacy/plasma conc. plateaus b/c of GI transporter saturation despite increases in dose

– Pregabalin absorbed throughout the small intestine – transporters are not saturated – provides more reliable plasma conc./efficacy

2. Distribution – minimal protein binding

3. Metabolism – minimal

4. Elimination – via the kidneys (98% unchanged)

• Elimination ½ t = 5-6 hrs for both

Lidocaine (IVLI)

MOA (N&P pg 145)

1. Na+ channel blockade

2. New research suggests inhibition of sP (when administered IV)

– Blocks the binding of sP to NK1

– This may explain why IVLI is effective in attenuating post-op pain

– Literature suggests a place with neuropathic pain as well –prevent spontaneous impulse generation from injured nerve fibers

Lidocaine (IVLI)

• Lidocaine has: (1) analgesic; (2) antihyperalgesic; & (3) anti-inflammatory properties

Lidocaine (IVLI)

• Saline group (control) VS IVLI group (experiment); n = 20 in both groups • Pts randomized to 1 of the 2 groups – double blind – pts in IVLI received: 1.5 mg/kg lidocaine at induction; 2 mg/kg/hr intraop; & 1.33 mg/kg/hr for 24 hours postop

• Pts in the control group received equal volume of saline

• Anesthesia maintained with Sevo; opioid intraop was sufentanil • All pts received tylenol, NSAIDS, and rescue narcotics postop

Lidocaine (IVLI)

Findings: Intra-Op:

1. IVLI resulted in a 35% reduction in et-SEVO concentration to maintain HD stability (image)

2. IVLI group received significantly less sufentanil during GA (13.0 ± 3.7 mcg VS 16.3 ± 3.6 mcg; (~20% reduction)

3. HR/MAP slightly lower in the IVLI group (despite receiving less sufenta/SEVO)

Lidocaine (IVLI)

Post-Op: (4) IVLI group required less opioids in first 24 hours postop; (5) IVLI group had less pain during mobilization, and

when coughing; & less abdominal discomfort (image); (6) IVLI group had less fatigue (image)

Lidocaine (IVLI)

Bowel Function/Hospital LOS: (7) Post-op recovery of bowel function was significantly accelerated in IVLI group; & (8) hospital LOS was significantly shortened

Improved bowel function may result from: (a) reduced opioid consumption; (b) LA’s anti-inflammatory properties

Lidocaine (IVLI)

• Plasma conc. of lidocaine drawn (a) after bolus; (b) at the end of surgery; & (c) after 24 hrs – plasma concentrations ranged from 2.1-4.6 mcg/ml (PERFECT!)

Lidocaine (IVLI)

What they found:

1. Perioperative IVLI reduced postop pain and opioid requirement

2. Improved bowel/ileus recovery time

3. Reduced total hospital LOS (BY 1 DAY!)

4. Reduced PONV

IVLI effective mainly in abdominal surgery & spine surgery

Less effective (not ineffective) in GYN and orthopedic cases

Lidocaine (IVLI)

Esmolol Infusion

• Esmolol infusion in the absence of opioids to facilitate the fast-tracking in pts undergoing outpatient surgery

• Most common complications are PONV, pain, and urinary retention which lead to unanticipated admission rate of ~ 5%

• Purpose: compare the standard technique of using fentanyl boluses to the newer, ‘fast track’ approaches of using either esmolol OR remifentanil infusions

(Vol. 105, No. 5, November, 2007)

Esmolol Infusion

Results

1. Post-op fentanyl was significantly lower in the esmolol group (was most in the remi group)

2. The # of pts who received zofran (and the dose administered) for PONV was less in the esmolol group

3. The time from PACU arrival and discharge home was significantly shorter in the esmolol group

3 Groups

Esmolol Infusion

4. There was no difference in the amt of tylenol, naproxen or opioid consumed postdischarge

All of this with ONLY intra-op esmolol (no narcotics!)

IM Ketamine… real quick!

(APS 2016 Perioperative Pain Management Guidelines)

Magnesium Sulfate

• NMDA receptor is both ligand- & voltage-gated

• Requires EPSP of -30 mV before the ‘mag gate’ is displaced and allows glutamate to have an effect at it’s binding site

• Mag Sulfate acts as a non-competitive NMDA antagonist (*unlike competitive antagonists, a max pain response cannot be achieved)

Magnesium Sulfate

• Considerations:

1. Relaxes ASM and VSM:

2. Potentiates the effects of NMBA (pre-junctional)

• Lower dose of muscle relaxation may be needed

3. Eliminated by kidney – avoid in CRI

4. Dosing: 3-4 gm bolus; followed by 1-2 gm/hr infusion

Magnesium Sulfate

• Groups:

1. Group M (mag sulfate; n=25) received a 50 mg/kg bolus of mag prior to induction followed by an infusion at 15 mg/kg/h

2. Group S (saline; n=25) received equal volume of saline

• All patient/surgical/anesthesia variables comparable between groups

• TIVA with propofol/remi

Magnesium Sulfate

Results

1. No difference in remi/propofol consumption

– Group M received significantly less rocuronium

2. Group M had significantly lower MAP

3. Group M had significantly greater satisfaction scores

4. Group M had significantly less PONV and post-op shivering

Magnesium Sulfate

Results

5. Cumulative post-op opioid consumption was significantly less in group M

Results

6. VAS scores were significantly lower in group M at 24- & 48-hrs post-op (while at rest & with movement)

Magnesium Sulfate

• Groups: (1) Group M (n=20): Received 50 mg/kg bolus 15 minutes prior to induction; (2) Group C (n=20): Received 100 mL NaCl 15 minutes prior to induction

• Anesthesia maintained with 50/50 O2/N2O mix, 0.5% ISO, and PRN fentanyl

Magnesium Sulfate

Results:

1. Pain scores with significantly less in the mag. sulfate group at 6, 12 & 24 hrs

2. Opioid consumption (pethidine/demerol) was significantly reduced during the first 24 hours (by a mean of 51.25 mg OR a 3-fold reduction)

α-2 Agonists

MOA - binds to pre-/post-synaptic α2-receptors

(Act a supraspinal, spinal, and peripheral sites)

α-2 Agonists: Coupled with GiP

α-2 Agonists

• Clonidine & Dexmedetomidine (IV/Regional)

Dexmedetomidine is 8 Xs more specific to α-2 receptor (1600:1 compared to 200:1)

• Reduces MAC value by ~ 25% (up to 90% in one study)

Dexmedetomidine

• Dosing: (1) Bolus with 0.5-1.0 mcg/kg over 10 minutes; with/without (2) Infusion at 0.2 – 1.o mcg/kg/hr

– One study using DMET as sole anesthetic titrated to as high as 10 mcg/kg/hr w/o SE’s

Maximum analgesic dose thought to be 0.5 mcg/kg/hr

• Elimination ½ t = 2-3 hrs

• May help reduce opioid-consumption in opioid-tolerant pts

• Minimal respiratory depression

α-2 Agonists

• Meta-analysis of (1) 30 studies, including (2) 1792 patients

• Results:

1. Opioid consumption was less during first 24 hrs (DEX >> Clonidine); after serum levels are undetectable

2. Pain scores were lower during first 24 hrs

3. PONV was reduced (efficacy = to zofran)

4. Clonidine lead to more postop HoTN; and DEX lead to more postop bradycardia

α-2 Agonists

• Groups: (1) PRD Group: Received 50-80 mcg/kg/min propofol, 0.15-2 mcg/kg/min remi & 0.4 mcg/kg/hr DMET; (2) PRS Group: Received same doses of propofol/remi but got saline instead of DMET

• Results: DMET group had

(1) lower BIS values indicating deeper plane of anesthesia

(2) decreased morphine PCA consumption in first 24 hours…

α-2 Agonists

…and had (3) decreased pain scores both while at rest and after coughing in the first 24 hours post-op

- MOA: thought to be r/t

anti-inflammatory properties

- Steroids block the activity of PLA2

- ½ life = 36-72 hours

Dexamethasone

Dexamethasone

• Groups: (1) control/saline (n=59); and (2) experimental/8 mg decadron (n=56)

• All patients received (1) sevoflurane-anesthesia + fentanyl infusion at 1 mcg/kg/hr; & (2) 4 mg zofran 30 mins before end of procedure

[Anesthesiology 114(4) April, 2011]

Dexamethasone

• Results: Nausea, resting/dynamic pain scores, and amount of post-op narcotics were all reduced in the decadron group

• QoR (Quality of Recovery) scores on POD1 were higher in the decadron group (i.e. emotional state, physical comfort, less fatigue)

Dexamethasone

• Meta-analysis included (1) 24 randomized clinical trials with (2) 2,751 pts

• Studies were divided into 3 dosage groups: Low (< 0.1 mg/kg), Intermediate (0.1-0.2 mg/kg); or High (> 0.2 mg/kg)

• Results:

1. Pain scores & opioid consumption were reduced by ~30% with doses > 0.1 mg/kg

2. There were no added benefits with the high-doses

3. Opioid consumption was not decreases with low-doses

Nitrous Oxide

• Analgesic properties -

1. Triggers the release of endogenous opioids in the descending opioid system (antagonized by nalaxone)

2. NMDA-antagonist

Major widespread harm in using N2O has not been clarified!!

• Clearly safe for most patients

Nitrous Oxide

N2O Benefits:

1. Inexpensive

2. Low B:G solubility (rapid on/off)

3. Low O:G solubility (minimal accumulation)

4. Almost no metabolism (0.004%)

5. Decrease amt of primary agent used (may help HD stability)

6. Prevention of OIH

7. *Attenuate neuropathic pain following injury

8. Easier LMA placement: preload with N2O for propofol induction

9. Second Gas Effect

N2O Risks:

1. Emetogenic (time dependent)

2. Expands air containing spaces

3. Diffusion hypoxia

4. Elevates PVR

5. Potential adverse CV outcomes

6. Cell apoptosis to developing nervous system (theoretical) – avoid 1st trimester

7. *Anti-metabolic effects (irreversibly oxidizes vitamin B12)

Nitrous Oxide

1. Neuropathic Pain:

• Rat model – rats subjected to neuropathic pain (damaged SN)

• Experimental Group: 50% N2O x 1 hr VS Control Group: 50% N2O x 1 hr + naloxone (blocks N2O effects)

• 2 significant results:

1. Experimental group can tolerate significant noxious stimuli while receiving N2O (less well tolerated in control group)

2. **BOTH groups: Neuropathic pain ameliorated for ≤ 40 days

Interesting…

Nitrous Oxide

2. Opioid-Induced Hyperalgesia:

• Pts undergoing rhinoseptoplasty with high-dose remi (> 0.3 mcg/kg/min) – a dose likely to induce hyperalgesia

• Experimental: 70% N2O VS Control: 100% O2

• Significantly reduced incidence of hyperalgesia in the N2O group

3. Chronic Pain:

• A retrospective study of pts receiving ESI for chronic back pain concomitantly received N2O for 2 hrs during their treatment

• Found that pts who had received N2O during Rx began requiring lower amounts of opioids to treat their chronic pain

• Again, very interesting…

Nitrous Oxide

4. Acute Pain:

• In the ENIGMA trial, pts use of PCA was decreased in immediate post-op period

• The author suggests, “…there’s smoke here. Something interesting is happening with N2O.”

Nitrous Oxide

Concerns with N2O:

1. N2O irreversibly oxidizes vitamin B12 – which deactivates its fcn as a coenzyme with methionine synthase

2. Methionine Pathway:

a) Dietary folic acid converted to tetrahydrofolate (THF)

b) THF picks up methyl group to become methyltetrahydrofolate (MTHF)

c) 5-MTHF donates methyl group to homocysteine - which forms methionine with the help of methionine synthase and vitamin B12

d) Methionine involved in DNA synthesis, myelin formation, etc

Nitrous Oxide

• Couple things happen when MS (i.e. SAM) stops working:

1. Folate cycle slows/haults = reduced THF = reduced purine & thymidine (DNA synthesis)

2. Methyl group no longer able to be donated to homocysteine to make methionine: leads to hyperhomocysteinemia

• 50% reduction of methionine at 45 minutes; regenerated to normal in 2 hours post-N2O

Nitrous Oxide

• Usually not a problem unless the patient has frequent exposure to N2O (e.g. staged procedures over weeks-to-months)

• Some at risk patients:

1. Bone marrow suppression (avoid in pts receiving chemo)

2. Poor wound healing (DM, PVD, etc)

3. Hyperhomocysteinemia (CAD, PVD, etc)

1. ENIGMA trial found that N2O group had elevated homocysteine levels

2.This had no effect on short-term cardiac outcomes

3.But, when looking 3-4 yrs post-surgery, the N2O group had increased incidence of MI

4.Something to consider…

Bibliography

Blanco-Davila, R., Iglesia, G., Lopez-Alvarez, S., Mayo-Moldes, M. & Zaballos, M. (2012). Esmolol versus ketamine-remifentanil combination for early post-operative analgesia after laparoscopic cholecystectomy: A randomize controlled trial. Canadian Journal of Anesthesia (59), 442-448. doi: 10.1007/s12630-012-9684-x

Bottros, M., McGreevy, K. & Raja, S. (2011). Preventing chronic pain following acute pain: Risk factors, preventative strategies, and the efficacy. European Journal of Pain, 5(2), 365-372. doi: 10.1016/j.eujps.2011.08.013

Buggy, D. J. & Heaney, A. (2012). Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis? British Journal of Anaesthesia 109(S1), i17-i28. doi: 10.1093/bja/aes421

Chan, M. H., Chia, Y. Y., Ko, N. H. & Liu, K. (2004). Role of beta-blockade in anaesthesia and postoperative pain management after hysterectomy. British Journal of Anaesthesia 93(6), 799-805. doi: 10.1093/bja/aeh268

Cho, S., Hwang, W. & Moon, Y. (2013). The effect of a continuous infusion of low-dose esmolol on the requirement for remifentanil during laparoscopic gynecologic surgery. Journal of Clinical Anesthesia (25), 36-41

Chou, Roger et al. (2016). Guidelines on the management of postoperative pain. The Journal of Pain, 17(2), 131-157

Clark, N., Grady, P., Hawkins, R., Lenahan, J., Nezat, G., Oudekerk, C. & Pellegrini, J. (2012). Effect of intraoperative intravenous lidocaine on postoperative pain and return of bowel function after laparoscopic abdominal gynecologic procedures. AANA Journal 80(4), 282-288.

Collins, S., Depp, C., Harless, M. & Hewer, I. (2015). Role of esmolol in perioperative analgesia and anesthesia: A literature review. AANA Journal 83(3), 167-177.

Cote, D., Fergusson, D., Lauzier, F., Moore, L., Nicole, P. & Zarychanski, R. (2011). Perioperative intravenous lidocaine infusion for postoperative pain control: A meta-analysis of randomized controlled trials. Canadian Journal of Anesthesiology, 58. 22-37. doi: 10.1007/sI2630-010-9407

Detroz, B., Durieux, M., Joris, J., Lamy, M., Kaba, A. & Sessler, D. (2010). Intravenous lidocaine infusion facilitates rehabilitation after laparoscopic colectomy. Anesthesiology 106(1), 11-19

Bibliography

Gajraj, N. M. (2003). Cyclooxygenase-2 inhibitors. Anesthesia & Analgesia 96, 1720-1738.

Ge. D., Li, J., Qi, B. & Tang, G. (2015). Intraoperative dexmedetomidine promotes postoperative analgesia and recovery in patients after abdominal colectomy. Medicine 94(43), 1-6

Giordano, J. (2005). The neurobiology of nociceptive and anti-nociceptive systems. Pain Physician 8, 277-290.

Grosu, I. & Lavand’homme, P. (2010). Use of dexmedetomidine for pain control. F1000 Medicine Reports.

Hall J E 2011 Guyton and Hall textbook of medical physiologyHall, J. E. (2011). Guyton and Hall textbook of medical physiology (pp. 303 - 321). Philadelphia, PA: Saunders Elsevier.

Hemmings, H. C., & Hopkins, P. M. (2006). Foundations of anesthesia: Basic sciences for clinical practice (pp. 687 - 697). Philadelphia, PA: Mosby Elsevier.

Kang, M., Park, K. & Ryu, J. (2008). Effects of magnesium sulphate on intraoperative anaesthetic requirements and postoperative analgesia in gynaecology patients receiving total intravenous anesthesia. British Journal of Anesthesia, 100(3), 397-405, doi: 10.1093/bja/aem407

Maihofner, C., Marinus, J., Moseley, G. & van Hilten, J. (2011). Clinical features and pathophysiology of complex regional pain syndrome. Lancet Neurology, 10, 637-48.

Nagelhout & Plaus. (2011). Nurse Anesthesia 4th Edition. Philadelphia, PA: Saunders Elsevier

Reuben, S. (2007). Chronic pain after surgery: What can we do the prevent it? Current Pain and Headaches Reports (11), 5-13

Shnider, M. (2014). Acute Pain. Audio Digest – Anesthesiology, 56(29)

Tiippana, E. (2007). Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anesthesia Anal, 104(6), 1545-56.

Vasconcellos, K. (2013). Nitrous oxide: Are we still in equipose? A qualitative review of current controversies. British Journal of Anesthesia, 111(6), 877-85. doi: 10.1093/bja/aet215

Viscusi, E. (2012). IV acetaminophen improves pain management and reduces opioid requirements in surgical patients. Anesthesiology.

Visser, E. (2005). Complex regional pain syndrome. Australian Anaesthesia, 147-161.

Woolf, C. (2007). Central Sensitization. Anesthesiology, 106, 864-867.