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Multimodal Analgesic Alternatives Opioid Minimizing & Opioid Free Strategies

Lois Stewart, PhD, CRNA

Doctor of Nursing Practice

Nurse Anesthesia Program

Assistant Professor, Leighton School of

Nursing

Marian University

lstewart@marian.edu

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Standard 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.

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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

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Opioid Minimization or Elimination?

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The Perioperative Goal (Prevention)

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

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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 beforecortical perception

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Central Neuraxial and Regional Anesthetic Techniques

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Benefits of Neuraxial or Regional Anesthesia

• 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

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Considerations w/ Neuraxial or Regional Anesthesia

• 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

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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 opioid receptor effects

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

• No risk of opioid-induced hyperalgesia (OIH)

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Opioid Induced Hyperalgesia

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

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The Questions…

• Are opioids necessary?

• Are opioids beneficial?

• Are opioids safe?

• Do opioids effectively manage pain?

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At least try for opioid minimization… but how?

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Preventative Analgesic Alternatives

Anti-inflammatory Meds

• Steroids (i.e., Decadron)

• NSAIDS

• Local anesthetics

• Propofol

• Cannabinoids

Anti-glutamatergic Meds

• Ketamine

• Dextromethorphan

• Nitrous oxide

• Magnesium Sulfate

• Gabapentinoids

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Preventative Analgesic Alternatives

Substance P Mitigation

• Dexmedetomidine

• Clonidine

• Tizanidine (Zanaflex)

• Demerol

Unknown MOA

• Acetaminophen

Serotonin/Norepinephrine

• Duloxetine (Cymbalta)

• Trazadone

• Tramadol

• Cyclobenzaprine

• Amitriptyline

• Ketamine

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Multiple Targets with or without Opioid Use

• 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)

• 2 adrenergic agonists: (Clonidine, Precedex)

• Neuroleptics

• Botox

• TENS

• Topical agents

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Multiple Entities Consider Multimodal Analgesia Benefits

• Recommendation • Non-opioids initially for acute

pain including NSAIDs, acetaminophen, nerve blocks, subanesthetic ketamine & IV lidocaine

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Even some doubt with inhalational agents..?

Wanderer & Nathan, 2016

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Alternative Analgesic Modalities/Medications

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Topical Agents/Modalities for Pain and Chronic Pain

• 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

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More Recent References…

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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 - 2mg/kg/hr for 24 - 48 hours postop

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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

• Has anti-inflammatory properties

• Lidocaine dosing = dose over 5-30” for total dose of 1-5 mg/kg*

Draw up 2% 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 (2mg/kg/hr)• Or 1.5 – 2.0 mg/kg bolus q 1 hour

• 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

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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.

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Ketamine

Bell & Nathan, 2017

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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”

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NMDA Receptor

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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

• Due to complementary actions on the NMDA receptor, these co-analgesics have synergistic potential (Mg2+ and ketamine)

Mg2+ assists ketamine to bind longer to NMDA receptors

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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, or those patients 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.

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Methadone Intra-operatively

• An opioid that generally does not incur acute tolerance or OIH

• 4 minutes b/w plasma concentration equilibration and pharmacodynamic effects (similar to fentanyl and sufentanil) = 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

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Esmolol… not just a unique beta blocker

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Esmolol

• Selective 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

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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 as compared to running for hemodynamic control or arrhythmias) Load (if used) up to 0.5 mg/kg

Drip at 5 – 15 (up to 50) cg/kg/min • Versus 50 – 300 cg/kg/min for hemodynamic control

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Precedex

Dexmedetomidine• 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

• 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

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Precedex Dosing – Analgesia & Sedation

• Premedication: 20 cg with small dose of propofol or versed, may repeat X 1 q 10-15” apart

• Bolus 0.5 – 1.0 cg/kg

• Infusion without bolus: 0.4 – 1.0 cg/kg/hr

• Sedation Precedex 10 cg + ketamine 10 mg co-administered

Repeat q 2-4” until

Can also mix 200 cg precedex + 200 mg ketamine in 100 cc NS: run on syringe pump between 15-30 mL/hr

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Don’t forget the Nitrous… !

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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)

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Examples of OFA

• 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

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The Future: The Utility of Functional MRIs

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Use your NMDA Receptors 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

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Future Treatments… Coming Soon?

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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.