Pain Management

R YA N HA MB L E TO N, DMDOR AL MAX ILLOFACIAL SUR G ER Y

A PR IL 20 1 8

Purpose

• Change the way we approach pain management

• I’m not going to introduce a new or novel medication or pain management technique

• Re-evaluate the use of existing tools

Outline

• Brief history of opioids

• Review of statistics on drug abuse

• Pain pathways: targets for treatment

• Drug review

• Literature review

• Questions

“We know of no other medication routinely used for non-fatal condition that kills patient so

frequently.”

-Tom Frieden, CDC Director

History of Opioids

• Use of opioids dates back to Sumerians of Mesopotamia which was cultivated for recreational and medicinal use in 3400 BC. (Called Joy Plant and spread across trade routes)

• Reintroduced into Europe by Philippus von Hohenheim in the 16th

centure as a laudanum, tincture of opium, for medicinal treatment (why was it lost in the first place?)

• Morhpine was isolated in the 1820’s by Friedrich Serturner

• 1874, Charles R.A Wright set-out to find a less addictive alternative and synthesized dactylmorphine, also known as heroin

History of Opioids

• Soothing Syrup Formula:

• Morphine Sulfate (65mg/oz)

• Sodium Carbonate

• Spirits Foeniculis

• Aqua Ammonia

• 1849 – Brought to market

• 1911 – AMA branded it a ”baby killer”

• 1930 – removed from market

History of Opioids

• It wasn’t until the Civil War that the use and abuse of the opioids spread across the United States

• First addicts were morphine-dependent war veterans

• Soldier’s Disease

History of Opioids

• 1895 – Bayer brought their new “wonder drug” to market

• Stronger than Aspirin

• Excellent cough suppressant

• Safe alternative to morphine for addicts

• 1900 – “It possess many advantages over morphine”Boston Medical and Surgical Journal

History of Opioids• 1914 – Harrison Narcotics Tax Act

• First broad crack-down

• taxed and tightly regulated the sale and distribution of opioids

• Thousands of doctors and pharmacists were arrested (no longer prescribing to maintain addiction)

• 1920 – Doctors very wary of opioid based drugs (Doctors aware of highly addictive nature of opioids)

• 1924 – Heroin considered illegal (at the peak of the crisis, estimated to have 300,000 people addicted)

• For most of the 20th century, physicians avoided use of opioids in treating chronic, non-cancer pain

Opioid Epidemic

“It’s not just the guy who’s never worked a day in his life. It’s airline pilots. It’s teachers. I’m sure

there’s law enforcement, firemen out there hooked on it. It’s Joe Citizen that is dying.”

-Gust Andrew Teague IIDeputy Sheriff

Montgomery County, Ohio

“We know of no other mediation routinely used for a non-fatal condition that kills

patients so frequently.”

-Tom Frieden, CDC Director

• 2000 – 2016: over 600,000 people died from drug overdose

• 2016 – Opioids (prescription, heroine, fentanyl) killed more than 42,000 people

• Deaths in 2016 was 5 greater than 1999

• Approximately 115 American die daily from opioid overdose

• 40% of all opioid deaths involve a prescription

• 66% of all drug overdose deaths involve an opioid

Pathogenesis of Pain

•Acute Pain •Chronic Pain

Initial Stimulus or Injury

Nociceptive pathwayInflammatory Pathway

Pain sensation is closely linked to molecular and cellular interactions between the nervous and immune systems

Mediations that modulate nociceptor neuron activity and pain sensation

Neuropeptides and neurotransmitters thatAct on innate and adaptive immune cells toModulate their function

Inflammatory Pathway

Inflammatory Pathway

L E UKOTR IENES

• Chemotaxis

• Vasoconstriction

• Increased Vascular Permeability

• Bronchospasm

• Activate C –fibers

• Activate A-delta fibers

PR O STAG LA NDINS

• Prostacyclin

• Vasodilation

• Thromboxane

• Vasoconstriction

• Platelet aggregation

• Prostaglandin

• Vasodilation

• Increased permeability

• Sensitizes nociceptor neurons to other painful stimuli

Innate Immune Response

• Macrophages – Pain Sensitization via release of cytokines, growth factors and lipids that act directly on Nociceptor Neurons

• Neutrophils – sustain pain through production of cytokines and prostaglandin

• Mast Cells – Sensitize nociceptors by release of histamine, serotonin, Nerve growth factor and cytokines

• Basophils – Histamine, Serotonin, cytokines

• Platelets – Thromboxane, ADP

Initial Stimulus or Injury

Nociceptive pathwayInflammatory Pathway

Pain sensation is closely linked to molecular and cellular interactions between the nervous and immune systems

Mediations that modulate nociceptor neuron activity and pain sensation

Neuropeptides and neurotransmitters thatAct on innate and adaptive immune cells toModulate their function

Nociceptive Pathway

• 4 processes

• Transduction: noxious stimulus acts on free nerve endings located in various tissues, leading to electrical activity and resulting in generation of nerve impulse

• Transmission: which involves conveying these nerve impulses through the CNS

• Modulation: refers to the central neural activity that dampens and controls the incoming pain signals

• Perception: combination of transduction, transmission, modulation develop into subjective, sensory and emotional experience to pain

Nociceptors• Sensory receptors that directly respond to 3 noxious stimuli:

• Mechanical

• Thermal

• Chemical

• Multiple Nociceptors exist:

• A-beta

• A-delta

• C-polymodial

• Silent Nociceptors

Nociceptive Pathway

• Various Nociceptive Fibers

• A-beta fibers

• A-delta fibers

• C-polymodial fibers

• Silent Nociceptors

• Distributed through out mucosa, skin, periosteum, muscles, dental pulp

Nociceptive Pathway

• A-beta fibers• Large diameter , myelinated• Light Touch, pressure, vibration• Low frequency, non-noxious stimuli

• A-delta fibers• Large diameter, myelinated• High Frequency, painful mechanical

stimuli• Sharp or stabbing pain

• C-Polymodal fibers• Small diameter• Slow, non-myelinated fibers• Burning, aching pain

• Silent Nociceptors• Mechanically insensitive• Active via release of cytokines

Nociceptive Pathway

SubnucleusCaudalisStimulus

ThalamusPrimaryAfferentNeuron

SecondaryNeuron

Third-Order

Neurons

Cerebral Cortex

Limbic Forebrain

Initial Stimulus or Injury

Nociceptive pathwayInflammatory Pathway

Pain sensation is closely linked to molecular and cellular interactions between the nervous and immune systems

Mediations that modulate nociceptor neuron activity and pain sensation

Neuropeptides and neurotransmitters thatAct on innate and adaptive immune cells toModulate their function

Nociceptor Regulation of Inflammation

Pain isn’t a symptom of inflammation, but an active participate in regulating immunity

Neuropeptides/Neurotransmitters

• Calcitonin-gene related peptide (CGRP)

• Substance P (SP)

• Vasoactive intestinal peptide (VIP)

• Pituitary adenylate cyclase-activating peptide (PACAP)

• Galanin (GAL)

• Somatostatin (SST)

Nociceptive Regulation of Pain

• Targets of the neuropeptides/ neurotransmitters

• Vasculature

• Adjacent Nociceptors

• Dendritic Cells

• Neutrophils

• Macrophages

• Mast Cells

• Platelets

• T Cells

Neuropeptides/Neurotransmitters

• Calcitonin-gene related peptide:

• Vasodilation and tissue edema

• Frequency of perfused lymphatic vessels

• Angiogenesis and lymphangiogenesis during skin wound healing

• Subtance P

• Lymphatic vessel contractility

Nociceptive pathwayInflammatory Pathway

Stimulus

Peripherial SensitizationHyperalgesia

AllodyniaPain Spread

Timing of Inflammation/Nociceptive Pain

INFL A MMATO RY PR O CE SS NO CICE PTIVE PA IN

• A – Delta: Instant

• 6 – 30 m/sec

• C- fibers: slow

• 0.5 to 2 m/sec

Strategies: Perioperative Pain Management

Strategies: Perioperative Pain Management

• Reduce or eliminate the proinflammatory mediators

• Blocking nociceptive transmission at the peripheral nerve

• Reducing Nociceptive input from the injury site

• Attenuating the perception of pain

Strategies: Perioperative Pain Management

• Reduce or eliminate the proinflammatory mediators

• Blocking nociceptive transmission at the peripheral nerve

• Reducing Nociceptive input from the injury site

• Attenuating the perception of pain

The effect of steroid on post-operative pain

Strategies: Perioperative Pain Management

• Reduce or eliminate the proinflammatory mediators

• Blocking nociceptive transmission at the peripheral nerve

• Reducing Nociceptive input from the injury site

• Attenuating the perception of pain

Local Anesthetics

• Lidocaine

• Bupivacaine

• Exparel – Bupivacine liposome injectable suspension

Lidocaine

• 2% most commonly used by DDS

• Onset

• Infiltration: < 2 min

• Block: 2-4 min

• Duration

• Infiltration: 60min

• Block: 90 min

Bupivacaine

• Fomulated as 0.25%, 0.5% and 0.75% w or w/o epi 1:200k

• 0.5% is most widely used by DDS

• Onset:

• Infiltration: 2-10min

• Block: 2-10min

• Duration:

• Infiltration: 5-6hrs

• Block: 5-7hrs

EXPAREL• Bupivacaine Liposome Injectable

Suspension

• Microscopic, spherical honey-combed structure with internal chambers filled with encapsulated bupivacaine

• 72 hrs of pain relief

• 13.3 mg/ml

• Max Dose: 266mg

• Route of Administration: infiltration

EXPAREL

• Caution:

• Only administer Exparel 20 min after injecting Lidocaine, or other non-bupivacaine anesthetics. Otherwise, there may be an immediate release of bupivacaine

• Not recommended in patints >18 yo or pregnant pts. Safety has not been established in adolescents or children.

• Avoid additional use of LA within 96 hrs of administration

• Not recommended for epidural, intrathecal or regional nerve blocks

Drug Overview

• NSAID

• Motrin/Ibuprofen/Advil

• Naproxen

• Toradol

• Meloxicam

• Celebrex

• Steroids

• Acetaminophen

• Opioids

• Proteases

• Local Anesthetics

• Exparel

• Topical Anesthetics

NSAID

• Ibuprofen

• Non-selective inhibition of COX-1 and COX-2

• Analgesic and antipyretic effect

• Maximum dose

• Adult:3200mg/24hrs

• Children (6mo – 12yr): 10mg/kg q6-8hr with max dose of 40mg/kg

• Peak concentration 1 to 2 hrs

• T1/2= 2 hrs

• Metabolized by liver

NSAID

• Naproxen

• Non-selective COX-1 and COX-2 inhibitor

• Max Dose: 1500mg/24hr

• Standard Dosing: 250 – 500 mg BID

• T1/2 = 12-15hrs

Toradol• MOA:

• Non-selective COX1 and COX2 inhibitor

• Pharmacokinetics:

• Onset: 30min

• Peak Effect: 45-60min

• T1/2: 4-6hrs (DURATION)

• Dose:

• IV: 30mg over 1 min

• PO: 40mg daily for max of 5 days

• 50x more analgesia than naproxen

• Not indicated for use in pediatric patients or for minor or chronic conditions

Meloxicam

• MOA:

• preferential COX-2 inhibition over COX-1

• Pharmacokinetics:

• Onset: 1 hr

• T1/2: 20hrs

• Dosing:

• Max dose: 15mg/daily

• 7.5mg/BID vs 15mg daily

Steroids

• MOA:

• Inhibit the production of arachidonic acid

Acetaminophen• MOA: central and peripherial

• Inhibits PGE synthesis via COX-1 and COX-2 inhibition• Predominantly targets COX-2• High level of arachidonic acid = ineffective

• Impacts neurotransmitters in CNS • Activation of descending serotonergic (?)

• Weak anti-inflammatory effect compared to NSAID

• Max Dose: 4000mg/day ….3000mg/day

• Leading cause of acute liver failure in adult in USA

• Pregnancy

• associated with hyperkinetic disorders and ADHD-like behaviors

• If taken greater than 20wks in gestation, increased risk of Autism Spectrum Disorder with HKD

Opioids (hydrocodone, oxycodone, codeine)

• MOA:

• Bind opioids receptors (mu, kappa, delta) in CNS to • 1. inhibit the transmission of nociceptive input from the periphery to the spinal cord

• 2. activate the descending inhibitory pathways that modulate transmission in the spinal cord

• 3. alter limibic system activity

• Pharmacokinetics• Onset: 10-30 min

• Time to Peak Effect: 30 – 60 min

• Duration: 4-6 hrs (hydrocodone); 3-4 hrs (oxycodone); 4 hrs (codeine)

• Dosing• Hydrocodone: 5-7.5mg q4-6hr; Oxycodone: 5-15mg q4-6hr; Percocet: 5-10mg q4-6hr

Pain Management Strategies

Strategy

• Ibuprofen vs Naproxen

• A study of naproxen and ibuprofen in patients with osteoarthritis seen in general practice. The Manchester general Practitioner Group

• 226 patients with osteoarthritis

• 500mg BID vs Ibu 400mg TID

• Naproxen superior at relieving resting pain, movement pain, nignt pain and interference with daily activities

• In patients taking ibuprofen, there was significant improvement when crossed over to naproxen

• Overall patient preference was Naproxen

Strategy

• Combination of Acetaminophen with Ibuprofen was as effective as combination of opioid and acetaminophen in managing arm and leg pain in ER’s

• Chang et al., “No Significant Difference in Pain Relief for Opioids vs Non-Opioid Analgesics for Treating Arm or Leg Pain”

• Conclusion:

• “For adults coming to the emergency department for arm or leg pain due to sprain, strain, or fracture, there was no difference in pain reduction after 2 hours with ibuprofen-acetaminophen vs three comparison opioid-acetaminophen (paracetamol) combinations.”

Strategy

• Moore, P.A. et al, “Combining ibuprofen and acetaminophen for acute pain management after third-molar extractions”

• Conclusion:

• Ibu-APAP combination may be more effective analgesic than are many opioid formulations

Closing Remarks

• When a patient complains of pain…the current though paradigm is to escalate opioid therapy. IF patient has pain despite taking hydrocodone, we might consider percocet.

• Consider altering NSAID therapy. If Ibuprofen isn’t effective, consider naproxen.

• Pain prevention has greater benefits than attempts at rescue therapy when pain exacerbations occur

References• Pg 4: An overview of clinical pharmacology of ibuprofen

• Oman Med J. 2010 Jul; 25(3): 155–1661

• A study of naproxen and ibuprofen in patients with osteoarthritis seen in general practice. The Manchester General Practitioner Group.

• The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings.

• Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders.

• Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: A Danish national birth cohort study.

• Optimal management of orthodontic pain.

• Pharmacologic Therapies in Musculoskeletal Conditions

• PERIOPERATIVE USE OF COX-2 AGENTS

References• A study of naproxen and ibuprofen in patients with osteoarthritis seen in

general practice. The Manchester General Practitioner Group.

• Pathogenesis of Postoperative Oral Surgical Pain

• Severity and Impact of Pain after day-surgery

• Basic Anatomy and Physiology of Pain Pathways

• Nociceptor Sensory Neuron-immune Interactions in Pain and Inflammation

• Website: https://www.physio-pedia.com/images/7/7b/Peripheral_sesnitization_1.jpg

• Ricciotti, E., Fitzgerald, GA., “Prostaglandins and Inflammation”, Arterioscler Thromb Vasc Biol. 2011 May, 31(5): 986 - 1000

References• Lawrence, T., Willoughby, D.A., Gilroy, D.W., “Anti-inflammatory lipid

mediators and insights into the resolution of inflammation”, Nature Reviews. Immunology. November 2002

• Giovannitti, J.A., Rosenberg, M.B., Phero J.C., “Pharmacology of Local Anesthetics Used in Oral Surgery.” Oral & Maxillofacial Surgery Clinics, August 2013, 25(3): 453 – 465

• Gordon, S.M, Mischenko, A.V., Dionne, R.A., “Long-Acting Local Anesthetics and Perioperative Pain Management”, Dental Clin N AM 54(2010) 611-620

• Dionne, R.A., Wirdzek, P.R., Fox, P.C., Dubner, R., “Suppression of postoperative pain by the combination of a nonsteroidal anti-inflammatory drug, flurbiprofen, and a long-acting local anesthetic, etidocaine”, JADA, April 1984, 108 (4): 598-601