multimodal perioperative analgesia: a pharmacologic review · 2019-12-16 · a pharmacologic review...
TRANSCRIPT
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Multimodal Perioperative Analgesia: A Pharmacologic Review
Reza Salajegheh MD
Assistant Professor Anesthesiology/Pain Medicine
Yet…But I’m working on it!
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Learning Objectives
• Review the classes of non‐opioid medications utilized perioperatively
• Understand how each pharmacologic option contributes to managing pain and reducing opioid consumption
• Discuss the differences between perioperative opioid options (specifically oral)
Brief Recap of Shortage Protocol
• Non‐opioid cocktail:
– Celecoxib (NSAID)
– Acetaminophen
– Gabapentin
Pre‐operative phase
• Opioid options:– Short Acting:
• Hydromorphone
• Oxycodone
– Long Acting:• Methadone
• MS Contin
• Oxycontin
• ERAS*:
– Intrathecal Duramorph
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Brief Recap of Shortage Protocol
• Non‐opioid options:– Lidocaine
– Ketamine
– Dexmedetomidine
– Esmolol
– Volatile Anesthetics
– IV Acetaminophen (redose)
– Rectal Acetaminophen (redose)
Intra‐operative phase
• Opioid options:
– Rectal Morphine
– Rectal Hydromorphone
Brief Recap of Shortage Protocol
• Non‐opioid options:– IV/Rectal Acetaminophen
– Ketamine Rescue
– Lidocaine gttcontinuation
– Ketamine gttcontinuation
– Redose NSAID where appropriate
Post‐operative phase
• Opioid options:
– Rectal Morphine
– Rectal Hydromorphone
– Oral Oxycodone
– Oral Hydromorphone
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Brief Recap of Shortage Protocol
• Neuraxial:
– Epidural
– Local anesthetic spinal
Miscellaneous
• Regional:
– Significantly increased the number of TAP blocks
– Consideration of regional approach in operative cases where not routine
• Surgeon:
– Intercostal blocks
– Local infiltration
NSAIDs
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NSAIDs‐ Mechanism
So why not COX2 selective all the time?
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So why not COX2 selective all the time?
NSAIDs
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NSAIDs
• Multiple studies that demonstrate opioid sparing effect of both mixed and COX2 selective.
• Must balance benefit with potential risks:– GI injury
– Renal injury
– Hepatic injury
– Increased risk of CVA/MI higher with greater COX2 activity (maybe)
– Can worsen bleeding or can inhibit blood thinning effect of ASA
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PRECISION TRIAL
• Randomized, double blinded, prospective evaluating Celecoxib, Ibuprofen, Naproxen in patients at “increased cardiovascular risk”.
• Compared 600mg TID Ibuprofen, 375 mg BID Naproxen, and 100mg BID Celecoxib
• Found Celecoxib to be non‐inferior from a CV event perspective
• Caveats‐ company sponsored, lower dose of Celebrex than in previous studies, consideration of time with ASA
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Acetaminophen (NSAID?)
Acetaminophen‐ Mechanism
• NSAID?Only very weak (if any) peripheral COX inhibition.
Older studies demonstrated reduction in swelling post injury when compared with placebo.
• Central COX inhibitor?Thought until recently to exert primary effect through
some degree of central COX inhibition.
• Maybe modulation of serotonin?
• More recently: Indirect activation of Cannabinoid (CB1) receptor
• Probably some combination
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Acetaminophen
• Multiple studies demonstrate either opioid reduction, or decreased pain scores without change in opioid consumption.
• Hepatic toxicity in overdose.
• Can cause elevation of liver enzymes in patients if taken 4000mg per day chronically. Grain of salt…
• Can cause renal injury in overdose.
Acetaminophen
• Rarely effective as monotherapy (not never though…)
• However… primary role to be used as an adjunct and has shown synergism.
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Acetaminophen
• Bet you didn’t know (or maybe you did)…– More than 25 billion doses used per year in the United States alone
– Increases risk of GI bleed in combination with NSAIDs therapy (higher risk than NSAIDs administered alone)
– Can cause GI irritation even as monotherapy– Safe in patients with chronic stable liver disease… probably
– Safe in patients with hepatitis (without cirrhosis) – Median lethal dose of 400mg/kg, 1977 panel determined hepatotoxic dose to be 15000mg
Gabapentinoids
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• Class within anticonvulsants which are structural analogs of GABA
• Two drugs within the class are:
– Gabapentin (Neurontin)
– Pregabalin (Lyrica)
• Likely the most commonly prescribed anticonvulsants for treating pain
What are the Gabapentinoids?
Gabapentin
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• Synthesized in 1977 as drug for treatment of spasticity and in mid 1990s for treatment of epilepsy
• Primarily used in the U.S. for neuropathic pain
• Non‐linear kinetics and absorption is dose dependent
• Absorption is 80% at 100 mg and 27% at 1600 mg
• Excreted unchanged in the urine
Gabapentin (Neurontin)
• Side effects:– Dizziness (27‐46%) – Somnolence (15‐25%) – Peripheral edema – Indigestion – Dry mouth– Itching – Impotence – Tingling in hands/feet – Weight gain– Tremor
Gabapentin (Neurontin)
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Pregabalin
• Studies demonstrate anticonvulsant, analgesic, and anxiolytic activity
• 98% excreted unchanged in urine
• Linear absorption kinetics (absorbed throughout small intestine) >90% over dose range of 10‐ 300 mg
Pregabalin (Lyrica)
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• Side Effects:
– Dizziness (22‐38%)
– Somnolence (15‐28%)
– Peripheral edema (10‐15%)
–Weight gain 2‐3 kg (4‐14%)
– Euphoria (5%) led to Schedule V listing
Pregabalin (Lyrica)
Renal Impairment
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• Gabapentin‐
– FDA approved only for postherpetic neuralgia and treatment of partial seizures
– Used off label for diabetic neuropathy, CRPS, phantom limb pain, spinal stenosis, MS related pain, migraine prophylaxis, as an adjuvant for cancer related pain, fibromyalgia
Current indications
• Pregabalin‐
– FDA approved for diabetic neuropathy, post herpetic neuralgia, seizures, and more recently fibromyalgia.
– Used off label for generalized anxiety disorder, CRPS, phantom limb pain, migraine prophylaxis, spinal stenosis, panic disorders
Current indications
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• Modulate the α‐2δ subunit of presynaptic P/Q‐type voltage‐gated calcium channels
• Which is thought to effect the subsequent release of excitatory neurotransmitters from activated nociceptors, such as glutamate
• Other mechanisms may include activation of noradrenergic pathways
Mechanism of Action
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• The principal difference is in their bioavailability…
What’s the Difference?
• Both drugs are absorbed by amino acid carriers, but absorption of gabapentin is limited to a small part of the duodenum.
• Conversely, Pregabalin is absorbed throughout the entire small intestine.
• Thus differences in theoretical side effects, saturation, etc.
What’s the Difference?
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Perioperative Use?
• Over 100 trials evaluating the use of perioperative Gabapentin to reduce post operative pain.
• Smaller but still growing number of trials evaluating the efficacy of Pregabalin to this same end.
• The consensus appears to be that the perioperative use of gabapentinoids does reduce post operative pain and opioid use.
Perioperative Utility
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• In a meta‐analysis that included 12 RCTs of high quality (6‐7/7 Cochrane Quality Score) indicated statistically significant reduction in pain at 20‐24 hours
Perioperative Utility
• Same analysis indicated a statistically significant reduction of post operative analgesic consumption but also a statistically significant increase in sedation
Perioperative Utility
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• Another meta‐analysis with more liberal inclusion criteria demonstrated a 35% reduction in total opioid consumption over the first 24 h following surgery, a significant reduction in postoperative pain at rest (in the first 24 h) and with movement (at 2 h, 4 h and 12 h).
Perioperative Utility
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• Studies comparing timing of dosing are somewhat limited. Two studies in particular compared administration of Gabapentin 2 hours preoperatively and immediately post incision via NG tube‐ with no statistically significant difference in total opioid consumption or pain scores.
How to dose? Timing…
How to dose? Timing…
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• Another small study involving two stage molar surgery utilizing post op and pre op Pregabalinshowed a small advantage for post op dosing… but only for pain at rest in the first twenty four hours.
• A study examining preoperative gabapentin versus a combination regimen of preoperative and postoperative dosing found less PCA morphine use at 24, 36, and 48 h in the combination regimen.
How to dose? Timing…
• A Cochrane review utilizing data from unpublished studies indicated that post operative first dose administration of Gabapentin showed efficacy in treatment of acute post operative pain.
How to dose? Timing…
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• Studies are too few with number of patients enrolled also too few to make a definitive recommendation… However there are solid trends…
Optimal Dosing
Optimal Dosing
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• Level of evidence for Gabapentin far outweighs that of Pregabalin...
• But appears to be primarily a function of the fact that Gabapentin has been studied to a much greater degree as opposed to a true performance difference.
• Indeed it appears as though their performance is comparable.
• Gabapentin is generic, and thus less expensive.
Gabapentin versus Pregabalin
What about Chronic Postsurgical Pain?
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What about Chronic Postsurgical Pain?
• Meta analysis combining trials evaluating the effect of gabapentin and pregabalin on chronic post surgical pain determined that though better designed and more appropriately powered trials were necessary, both gabapentin and pregabalin were effective in reducing chronic postsurgical pain.
What about Chronic Postsurgical Pain?
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Lidocaine infusion
Lidocaine infusion
• Thought to reduce pain scores, opioid consumption, PONV, time to flatus, time to bowel movement.
• Moderate evidence for open abdominal surgery.
• Cumulatively , very low evidence: 2018 cochrane update.
• Total joint (hip specifically)‐ found to offer no benefit
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Lidocaine infusion
• Local anesthetic mechanism of action via blockade of fast voltage gated Na+ Channels‐preventing generation of an action potential.
• However this mechanism does not explain benefit with levels achieved during systemic administration
• It is therefore thought that the benefit is via anti‐inflammatory properties.
Lidocaine infusion
• Local anesthetics have been found:
– to reduce polymorphonuclear granulocyte (PMN) adherance, migration, and accumulation at the site of inflammation.
– to interfere with macrophage and monocyte function.
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Lidocaine infusion
• Concern therefore becomes‐ what about infection?
– Local anesthetics have inherent antibiotic and antiviral properties (e coli, s aureus)
– However this is at higher concentrations‐ what about systemic use?
– Hasn’t been an issue so far.
Lidocaine infusion
• MAC sparing
– As high as 60% in certain animal models
– Between 10 and 30% reduction in humans
– Does have a reduced hemodynamic response and reduction in BIS increase, but only when exposed to surgical stimulus
–Would need to be an anti‐nociceptive mechanism? Possibly due to blockade of spinal cord WDR neurons?
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Exparel
Exparel
‐ 1.3% Bupivacaine in multivesicular liposomes.
‐ 285 dollars wholesale price‐ now even higher per 20 ml vial (previously 14 dollars)
‐ Traditional bupivacaine hcl 1 to 3 dollars for similar dose.
‐ Cost is higher yes‐ but can it save money by minimizing other resources? Reduce LOS?
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Exparel
‐ 1.3% Bupivacaine in multivesicular liposomes.
‐ 285 dollars wholesale price‐ now even higher per 20 ml vial (previously 14 dollars)
‐ Traditional bupivacaine hcl 1 to 3 dollars for similar dose.
‐ Cost is higher yes‐ but can it save money by minimizing other resources? Reduce LOS?
Exparel
• Meta‐analysis comprised of 17 studies that met strict inclusion criteria involving 779 patients
• Compared with local anesthetic infiltration (of the long acting variety…)
• No effect on pain at rest 24h after surgery
• No effect on opioid consumption 24h following surgery
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Exparel
• No effect on pain at rest 48h after surgery
• No effect on opioid consumption 48h after surgery
• No effect on post operative opioid consumption 72 hours after surgery
• No effect on LOS
• No difference between ortho vs non orthosurgery
Exparel
BUT….
Did show a decrease in post‐
operative nausea. Mechanism??
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Exparel
Caveat‐
Thoracic data not included (studies did not meet inclusion criteria), but infiltration technique does generate interesting discussion…
Ketamine
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Ketamine
• Reduces opioid consumption perioperatively‐particularly with thoracic, upper abdominal, and major orthopedic surgical patients
• Particularly useful in patients who are opioid tolerant
• Unique in that it is an analgesic, anesthetic, and amnestic in one drug
• Does not cause respiratory depression as monotherapy
Ketamine
• Primary mechanism is via NMDA antagonism (non‐competitive), though full mechanism is not fully understood.
• Multiple additional sites of action being studied:– Opioid activity
– Voltage gated Na and Ca activity
– SNRI and SSRI effect
– Several more…
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Ketamine
• Causes increase in sympathetic tone‐ which makes it an ideal drug from a hemodynamic standpoint‐ with the caveat that it is a direct cardiac depressant…
• Can cause reversal of opioid tolerance… caution respiratory depression in patients on high dose opioid medications.
Ketamine
• Most well known adverse effect is agitation and hallucinations
• Most common side effect likely nausea/vomiting
• Can prolong QT, elevate BP, elevate liver enzymes, cause nystagmus, predispose to arrhythmias (likely catecholamine related), increase secretions, etc.
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Ketamine
Meta‐analysis suggested a modest but statistically significant reduction in the incidence of chronic pain after surgery following treatment with ketamine. However, small trials.
Ketamine
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Esmolol
Esmolol
• Often used to rapidly blunt physiologic response to surgery or laryngoscopy or for rapid reduction in heart rate
• Beta1 receptor blocker
• Rapid onset‐ short acting with elimination half time of 9 minutes
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Esmolol
• May have pain relieving properties as well
• Meta‐analysis showed patients treated with an perioperative esmolol infusion had lower pain scores, reduced opioid rescue requirement, and less PONV. Esmolol also had a MAC sparing effect. There was no impact on the emergence time.
• Caveat is that the studies were small, low powered, and heterogeneous. Currently 79 registered trials looking at further study, however.
Esmolol
• Difficult to say whether the anti‐nociceptive trend is due to the opioid sparing effect (and thus reduced hyperalgesia) or frank analgesic properties.
• Proposed analgesic mechanisms include:– by blocking β‐adrenoceptors within the brainstem and decrease neuronal inflow traffic into the central nervous system rather than acting within the brain directly
– Decreased hepatic blood flow prolonging the duration of other anesthetic/analgesic medications?
– Anti‐inflammatory?
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Dexmedetomidine
Dexmedetomidine
• Sedative and analgesic
• α2 receptor agonist, with 8 times greater receptor affinity than clonidine
• Does not cause respiratory depression as monotherapy
• Biphasic effect on blood pressure‐ lower BP with lower doses (central activation) and higher BP with higher doses (peripheral activation)
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Dexmedetomidine
• Other reported side effects include: nausea, vomiting, dry mouth, bradycardia, atrial fibrillation, pyrexia, chills, pleural effusion, atelectasis, pulmonary edema, hyperglycemia, hypocalcaemia, acidosis…
• However, no absolute contraindication to it’s use
Dexmedetomidine
• As with all other adjuvant drugs…
Cochran Review for abdominal pain‐
“compared with no treatment ‐ seemed to reduce the need for opioids without worsening the experience of postoperative pain after abdominal surgery in adults. However, the quality of evidence was very low because studies were poorly conducted and because results were not similar across studies”
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Dexmedetomidine
• And our very own Dr. Naik:
Conclusion:
No difference in post operative opioid consumption and pain scores (24, 48, and 72 hours).
Dexmedetomidine
The question becomes whether the method of usage bears an impact (probably yes).
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Long acting and Sustained release Opioids
• Rule of thumb (true in MOST cases‐ but not all):Any “Contin” or “ER” opioid dose can be determined by the
following method:
Expected daily equivalent dose of the short acting = Total daily dose of long acting
Example: 10mg of Oxycodone (IR) q4hours = 60mg of Oxycodone (IR) a day
Therefore this patient would get 60mg of Oxycontin a day, BUT split over 2 (sometimes 3) doses.
Thus 30mg BID Oxycontin = 10mg q4hours Oxycodone
Long acting and Sustained release Opioids
• So what does this mean? In theory…
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Long acting and Sustained release Opioids
• So what does this mean? In theory…
Long acting and Sustained release Opioids
• However in a study for osteoarthritis pain…
Patients receiving short‐ and long acting opioids reported no significantly different scores for pain levels (P =.201 and P =.296, respectively). Though patients taking short‐acting opioids had numerically higher average pain scores than patients receiving combination or extended release therapies (5.67 vs 5.35, respectively), the analgesic effects between short‐ and long‐acting opioids were not considered significant (P =.201).
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Long acting and Sustained release Opioids
With that said…
– Shorter acting, quicker onset opioids have a stronger association with hyperalgesia… (though occurs with all opioids with prolonged exposure…)
– Shorter acting, quicker onset opioids tend to have a greater dopamine surge…
– Utilization as single dose “priming” method as opposed to repeated dosing requires further study...
Methadone
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Methadone
• Exists in a racemic mixture where one enantiomer (Levomethadone) binds to the µ receptor and the other enantiomer (Dextromethadone) binds to the NMDA receptor.
• Single dose lasts 4‐8 hours (analgesic time), which is extended with larger dosing or repeated dosing.
• Elimination half‐life ranges widely but generally 15‐55 hours. (traditionally taught as 24 hour halflife)
Methadone
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Methadone
• Only opioid shown to reduce post operative opioid consumption (complex spine surgery)
• Advantages:
– Less Tolerance
– Less Hyperalgesia
– Neuropathic properties
– Less addictive?
Methadone
• Disadvantages:
–Management gets dicey at higher doses
– In untrained hands‐ potentially higher risk of respiratory depression
– Can prolong QT at higher doses
– Repeated dosing significantly prolongs duration (maybe not a bad thing)
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Methadone
Methadone
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Oral? But this is surgery…
JAMA Internal Medicine study demonstrated a 31% reduction in total opioid consumption with nochange in pain scores by transitioning from IV use to oral/subcutaneous use where possible on an inpatient unit.
20mcg of Fentanyl IV = 0.4mg hydromorphone IV = 2mg oral hydromorphone or 5mg oral oxycodone
Think about the analgesic impact per MME when choosing your opioid…
Our Outcomes
To reiterate: goal was to generate an analgesic bridge to PACU while minimizing IV consumption…
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Opioid consumption in MMEs
0
20
40
60
80
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120
2017 Jul 2017 Aug2017 Sep 2017 Oct 2017Nov
2017 Dec 2018 Jan 2018 Feb 2018Mar
2018 Apr 2018May
2018 Jun 2018 Jul 2018 Aug2018 Sep
Before group Post‐Intervention
AvgOralMMEsPerLog
AvgParenteralMMEsPerLog
AvgMMEsPerLog
Opioid MME per patient by phase of care
0
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20
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70
Before group Post‐Intervention
(blank)
Intra‐op
Post‐op
Pre‐op
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PACU pain scores per patient
0.00
1.00
2.00
3.00
4.00
5.00
6.00
2017 Jul 2017 Aug 2017 Sep 2017 Oct 2017 Nov 2017 Dec 2018 Jan 2018 Feb 2018 Mar 2018 Apr 2018May
2018 Jun 2018 Jul 2018 Aug 2018 Sep
Before group Post‐Intervention
AveragePainScore
AveragePainScorebyPLC
Future
• Endocannabinoid system
• Resiniferatoxin‐ champion of Scoville Scale
• MAGNETS!! How do they work?? (Transcranial Magnetic Stimulation)
• Peripheral Stimulator
• Detox? We’ll find out….
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Questions?
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