MULTIMODAL ANALGESIC ALTERNATIVES LOIS STEWART, PHD, CRNA COMMUNITY HEALTH NETWORK - INDIANAPOLIS

DISCLAIMER

I HAVE NO FINANCIAL

RELATIONSHIPS WITH ANY

COMMERCIAL INTEREST RELATED TO THE CONTENT OF THIS ACTIVITY.

I WILL LIKELY DISCUSS OFF-

LABEL USE DURING MY PRESENTATION

MOUNT AIRY CASINO RESORT

SESSION OBJECTIVES

In this session, multimodal analgesic therapies will be reviewed. This review will focus on multimodal pharmacological interventions, rather than regional anesthetic techniques

Briefly review the history of ‘pre-emptive’ analgesia

Briefly describe the importance of regional and neuraxial anesthetic techniques in opioid-sparing analgesic regimens

Provide an overview of available non-opioid analgesic pharmacological interventions

Describe the pharmacologic actions of selected non-opioid analgesic medications

WHITHER SHALL WE GO FROM HERE??

Opioid Minimization versus Opioid Elimination??

THE PERIOPERATIVE GOAL

http://www.aafp.org/afp/2001/0515/p1979.html

BALANCED MULTIMODAL PRE-EMPTIVE ANALGESIA

Balanced & Multimodal

Analgesics that act on distinct and varied pain pathway components, to increase efficacy and decrease side effects

Goal of preemptive analgesia is to prevent the induction of CNS plasticity

Initiated prior to procedural trauma

Modalities or their effects outlive the continued generation of noxious stimuli, or at least the most intense period of the same

Best pre-emptive modalities modify

noxious afferent input before cortical

perception

CENTRAL NEURAXIAL AND REGIONAL TECHNIQUES

BENEFITS OF NEURAXIAL AND REGIONAL

TECHNIQUES

Avoidance of large doses of multiple IV medications

Possible avoidance of general anesthesia and its inherent potential complications throughout the perioperative period

Less hemodynamic compromise if no general anesthetic

Less PONV

Attenuated neuroendocrine stress response

Decreased thromboembolic complications

Less time for ambulation and/or discharge, dependent on block utilized

Less use or no use of opioid agents

CONSIDERATIONS WITH NEURAXIAL AND REGIONAL TECHNIQUES

Potential longer pre-operative time period

Limitations due to proper equipment

Limitations due to proper training or experience

Complications inherent to each type of blockade

Risk of systemic local anesthetic toxicity

BETTER LIVING THROUGH CHEMISTRY…

BENEFITS OF NON-OPIOID PARENTERAL ANALGESICS

No unwanted opioid receptor side effects

Reduced risk of respiratory depression for patients diagnosed with obesity or OSA

Reduce risk of immunosuppression and metastatic disease with intraoperative administration of opioids via the ζ-opioid receptor effects

Avoidance of opioid exposure for both naïve and patients with substance abuse history

No risk of opioid-induced hyperalgesia (OIH)

AVOIDANCE OF OPIOID INDUCED HYPERALGESIA (OIH)

Felt to be related to acute dose escalation or

agent potency

Increased sensitivity to noxious stimuli

Known in chronic opioid use for more than

100 years

Same pathophysiology as neuropathic pain

! central/peripheral sensitization

Recent evidence implies it can occur acutely

THE QUESTIONS FOR YOU, FOR EACH PATIENT

Are opioids necessary?

Are opioids beneficial?

Are opioids safe?

Do opioids effectively manage pain?

Just as with any other therapeutic decision you make… you are the judge of what the patient needs and what works best in your hands

CONSENSUS = AT LEAST TRY FOR OPIOID MINIMIZATION… BUT HOW?

ANALGESIC ALTERNATIVES

Anti-inflammatory MedsSteroids (i.e., Decadron)

NSAIDS

Local anesthetics

Propofol

Cannabinoids

Anti-glutamatergic Meds Ketamine

Dextromethorphan

Nitrous oxide

Magnesium Sulfate

Gabapentinoids

ANALGESIC ALTERNATIVES

Substance P MitigationDexmedetomidine

Clonidine

Tizanidine (Zanaflex)

Demerol

Unknown MOA Acetaminophen

Serotonin/NorepinephrineDuloxetine (Cymbalta)

Trazadone

Tramadol

Cyclobenzaprine

Amitriptyline

Ketamine

MULTIPLE TARGETS OF ACTION Anticonvulsants: (Lyrica, Neurontin, Tegretol) *

Antidepressants: (TCAs, SSRIs, SNRIs) * NSAIDS: (PO, IV, IM), acetaminophen, Toradol, corticosteroids* Opioids (PO, Intrathecal, transdermal)

New combos: Tapentadol (MOR-NRI), Suboxone

Tramadol

BZD, anti-anxiety & skeletal muscle relaxants

NMDA antagonists: (N2O, ketamine, methadone, DMT)

Systemic LAs: (IV, PO) α2 adrenergic agonists: (Clonidine, Precedex)

Neuroleptics

Botox

TENS Topical agents

LITERATURE CONSIDERING MULTIMODAL ANALGESIA BENEFITS

EVEN SOME RE-THINKING ABOUT INHALATIONAL AGENT USE

ALTERNATIVE ANALGESIC

MODALITIES/MEDICATIONS

TOPICAL MODALITIES

Lidoderm patches

Flector patches (NSAID)

Voltaren gel

Capsaicin patches

Newer [high] patches

Fentanyl patches

Buprenorphine patches

Iontophoresis (PT modality)

E-stim and ionically charged medications

LOCAL ANESTHETICS

Lidocaine, procaine and chloroprocaine are the most commonly used for this

Given slow bolus or continuous infusion, or both

Component of ERAS protocols

Modulates neurotransmission via voltage-gated sodium channels and has anti-inflammatory properties

If good results consider adding oral antiarrhythmic therapy to the CP regimen

Often used in PACU for acute exacerbation of pain in CP patient

Can be used intra-operatively in patients with history of CP or with high risk surgery

Can be combined with ketamine and/or magnesium gtt in a controlled infusion for additive effects

LIDOCAINE

Amide local anesthetic with analgesic, anti-hyperalgesic, and anti-inflammatory properties

Mediated by sodium channel blockade (VGSCs) Inhibition of G-protein coupled receptors and limited NMDA blockade

Significant reduction in postoperative pain and opioid consumption after abdominal surgery with…

Decreased ileus and length of stay

Dosages: 1.5mg/kg at induction + 1 – 2 mg/kg/hr for 24 - 48 hours postop

Alternative schemes

Draw up 2% lidocaine and run it at 0.1ml/kg/hr (70 kg = 7 ml/hr): M & M 2015

Colorectal Dis. 2013 Feb;15(2):146-55

Practitioner Consensus: 1.5 mg/kg bolus with 2mg/min gtt = 30cc/hr with 4:1 drip (2mg/kg/hr)

1.0 – 2.0 mg/kg bolus q 1 hour

TARGET: NMDA RECEPTOR

KETAMINE

FDA approved in 1970 for General Anesthesia

Unacceptable toxicity including hallucinations and dysphoric reactions at induction doses

Subanesthetic doses (0.5mg/kg or less) provide analgesia for neuropathic pain

Subanesthetic doses provide relief from treatment-resistant depression

Subanesthetic doses lead to improved response to subsequent opioid therapy leading to reduced postoperative pain and opioid requirements.

KETAMINE

Bell & Nathan, 2017

• Now felt to have neuro-protective effects

• This does not extend to the same

situations in children with neuro injury as it can promote neuronal cell apoptosis

MAGNESIUM

FDA approved for prevention of seizures (pre-eclampsia) and replacement of magnesium deficiency

Off-label use in ER includes treatment of: acute migraine headache, cardiac arrhythmias including Torsade de pointes, atrial fibrillation, cardiac arrest, bronchospasm, seizures, and alcohol withdrawal

Desirable effects include: smooth muscle relaxation, decreased sympathetic release, decreased heart rate, decreased blood pressure, NMDA blocking effect decreases postoperative opioids

“Nature’s calcium channel blocker”

KETAMINE + MAGNESIUM

NMDA receptor activation is a key component to nociception and especially to central sensitization

Ketamine has been shown in controlled trials to reverse central sensitization even after establishment

Ketamine’s affinity for the NMDA receptor is 20X stronger than for any other binding site; a non-competitive antagonist

The NMDA receptor cannot activate until magnesium plug is out of the way in the central ion pore of the receptor

D/t complementary actions these co-analgesics have synergistic potential at the NMDA R

(Mg2+ and ketamine)

Mg2+ assists ketamine to bind longer to NMDA receptors

KETAMINE + MAGNESIUM

Ketamine should be co-administered with Versed or propofol

Will spare the usual needed opioid dose by approximately 50%

Should be discontinued in the last 30 minutes prior to surgery end for outpatients, without a history of CP

Magnesium 2 - 3 gm, or 30mg/kg

Ketamine 0.25 - .50 mg/kg bolus

Drip rates: 10-15mg/hr or achieve the same by timed bolus

Drip rates: 0.05 – 0.3 mg/kg/hr

Alternative Scheme: Bolus with 25 mg ketamine on induction the hang a drip: 100 mg ketamine plus 3 gm MgSO4 in 250cc NS and run at 50cc/hr. If inpatient CP patient, run drip until 4-5 hours prior to discharge. If CP patient in for elective outpatient surgery, discontinue 30 minutes prior to surgery end.

METHADONE

An opioid that generally does not incur acute tolerance or OIH Effects at opioid and NMDA receptors

4 minutes b/w plasma concentration equilibration and pharmacodynamic effects

similar to fentanyl and sufentanil in so far as rapid onset

Hepatic metabolism and clearance

Dose-dependent elimination half-life

Distributive elimination for small doses

Metabolic elimination for large doses (15-60 hours)

20mg, or 0.2 – 0.3 mg/kg as a single induction dose is recommended

ESMOLOL… A UNIQUE BETA BLOCKER

ESMOLOL

Selective B1 adrenoreceptor antagonist

Distribution T1/2 = 2”

Elimination T1/2 = 9”

Organ-independent metabolism by plasma esterases

Provides hemodynamic stability

Reduced anesthetic requirements (additive to MAC)

Reduced opioid consumption: Less PONV

Earlier discharge: Increased patient satisfaction

ESMOLOL

Antinociceptive/opioid-sparing effects

Decreased hepatic metabolism of opioids

??? Increased permeability of the BBB ! opioids

Decreased activation of the hippocampus, decreased neuroendocrine stress response therefore less NMDA receptor activation

Facilitates nociception inhibitory pathways, perhaps via SC neurotransmitter release using GABA or glycine pathways

Dosing schemes for analgesia (reduced dose compared to running for hemodynamic control or arrhythmias)

Load (if used) up to 0.5 mg/kg

Drip at 5 – 15 (up to 50) µcg/kg/min

Versus 50 – 300 µcg/kg/min for hemodynamic control

PRECEDEX

Dexmedetomidine

α2 adrenergic agonist on presynaptic autoregulation receptors

Dose-dependent sedation, anxiolytic, and analgesic without respiratory depression

Pliable and cooperative patient if used for sedation

Less amnestic qualities to sedation vs. other agents Decreased activity of noradrenergic neurons in the locus ceruleus ! increases GABA-ergic neuronal activity Decreases/eliminates opioid requirements of patients in pain

Especially if used with other non-opioid medications Monitor for hypotension and bradycardia, especially if using bolus

PRECEDEX DOSING FOR ANALGESIA & SEDATION

Premedication: 20 µcg with small dose of propofol or versed, may repeat X 1 q 10-15” apart Bolus 0.5 – 1.0 µcg/kg

Infusion without bolus: 0.4 – 1.0 µcg/kg/hr Sedation

Precedex 10 µcg + ketamine 10 mg co-administered

Repeat q 2- 4” until desired effect Can also mix 200 µcg precedex + 200 mg ketamine in 100 cc NS: run on syringe pump between 15-30 mL/hr

DON’T FORGET TO CONSIDER THE NITROUS…

EXAMPLES OF OFA – TIVA

Example # 1: (DLP) OFA

Dexmedetomidine (0.6 mg/kg loading dose, then 0.3 mg/kg/h infusion)

Lidocaine (1.5 mg/kg loading, 2 mg/kg/h infusion)

Propofol (50 – 200 mcg/kg/min)

EXAMPLES OF OFA - WITH VOLATILE AGENT

Example # 2: (MLK) OFA

Induce GA with propofol and esmolol (20-40 mg) and maintain with volatile agent

Combine in a 100 mL bag of 0.9% NS:

Magnesium 30 - 60 mg/kg (max 6 g)

Lidocaine 1 – 1.5 mg/kg

Infuse over 30– 60 minutes

Consider second infusion if case is two hours or longer

Ketamine 5 mg/mL in a 10-mL syringe

5 – 10 mg q 30 minutes

THE MCLOTT MIX

http://mclottmix.com/mclott-mix-3/

SUMMARY ARTICLE

WHAT NEW MODALITIES DOES THE FUTURE HOLD?

USE YOUR NMDA RECEPTORS IN THE HIPPOCAMPUS TO RECALL…

Multiple regions of the brain are linked to, or process, nociceptor activity

The descending inhibitory system is intricately linked to emotional, cognitive and motivational cortical & subcortical centers

• Limbic, PFC, insular, basal nuclei

New research ! these higher centers can influence the activity of the pontomedullary DI centers

More intense research into the exact mechanisms of the DI system

RVM ON cells

RVM OFF cells

COULD THIS BE IN OUR NEAR FUTURE…?

REFERENCES

Bell, J.D. & Nathan, N. (2017). Ketamine for neuroprotection in acute neurologic injury. Anesthesia & Analgesia, 124(4), 1237-1243.

Brandal, D., Keller, M.S., Lee, C., Grogan, T., Fujimoto, Y., … Cannesson, M. (2017). Impact of enhanced recovery after surgery and opioid-free anesthesia on opioid prescriptions at discharge from the hospital: A historical-prospective study. Anesthesia & Analgesia, 125(5), 1784-1792.

Do, S. (2013). Magnesium: a versatile drug for anesthesiologists. Korean Journal of Anesthesiology, 65(1), 4–8.

Dunn, L. & Durieux, M. (2017). Perioperative use of intravenous lidocaine. Anesthes, 126(4):729-737.

Glass, P.S., Collard, A., Vincent, M.D., Mistraletti, G., …Franco, M.P. (2007). Intraoperative esmolol infusion in the absence of opioids spares postoperative fentanyl in patients undergoing ambulatory laparoscopic cholecystectomy. Anesthesia & Analgesia, 105(5), 1255-1262.

Gorlin, A., Rosenfeld, D., & Ramakrishna, H. (2016). Intravenous sub-anesthetic ketamine for perioperative analgesia. Journal of Anaesthesiology, Clinical Pharmacology, 32(2), 160–167.

Herroeder, S., Schönherr, M., De Hert, S., & Hollmann, M. (2011). Magnesium: essentials for anesthesiologists. Anesthes, 114(4):971-993.

International Anesthesia Research Society, (2014). Esmolol. Retrieved from https://www.openanesthesia.org/esmolol/

Kandil, E., Melikman, E., & Adinoff, B. (2017). Lidocaine infusion: a promising therapeutic approach for chronic pain. Journal of Anesthesia & Clinical Research, 8(1), 697.

Kurdi, M., Theerth, K., & Deva, R. (2014). Ketamine: current applications in anesthesia, pain, and critical care. Anesthesia, Essays and Researches, 8(3), 283–290.

Sammour, T., Zargar-Shoshtari, K., Bhat, A., Kahokehr, A., & Hill, A.G. (2010). A programme of Enhanced Recovery After Surgery (ERAS) is a cost-effective intervention in elective colonic surgery. N Z Med J, 123(1319), 61-70.

Sleigh, J., Harvey, M., Voss, L. & Denny, B. (2014) Ketamine – more mechanisms of action than just NMDA blockade. Trends in Anesthesia and Critical Care, 4, 76 – 81.

Surana, A. (2016) Role of magnesium: a step ahead in anaesthesia. J Anesth Crit Care Open Access, 6(1): 00218.

Wanderer, J.P. & Nathan, N. (2016). Anesthetizing patients and their immune systems: Volatile anesthetics at work. Anesthesia & Analgesia, 123(2), 263.

QUESTIONS??