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

Outline

• Brief history of opioids

• Review of statistics on drug abuse

• Pain pathways: targets for treatment

• Drug review

• Literature review

• Questions

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

History of Opioids

• 1874 – Heroin synthesized

• 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

• Doctors could no longer prescribe opiate-based drugs

• 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

Changing of the Tide….

• 1980 - Porter and Jick: Editorial in NEJM pushing back on risk profile of opioids for treatment of chronic pain

• 1981, 1986 - Foley and Portenoy : Published two articles indicating that there was little risk of addiction using opioids to treat chronic pain

• “opioid maintenance therapy can be safe, salutary, and more humane alternative” – Portenoy

• 1990 - James Campbell: Pain considered the 5th vital sign (president of american pain society and American pain foundation)

Changing of the Tide….

• 2001 - Joint Commission

• Scathing report released about under treatment of pain by doctors

• New Standard: pain must be assessed in all patients

• Demarcation and need for improvement if patients suffering from pain

• “there is no evidence that addiction is a significant issue when persons are given opioids for pain control.”

Joint CommissionAuthority Figures:

James CampbellPortenoy

Pharmaceutical Companies

0

50

100

150

200

250

300

90's 96 99 2012

Prescriptions Filled By US Pharmacies

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 medication routinely used for a non-fatal condition that kills

patients so frequently.”

-Tom Frieden, CDC Director

• Roughly 21 -29 % of patients prescribed opioids for chronic pain misuse them

• Between 8 and 12 % develop an opioid use disorder

• Treatment as short as 10 days can lead to dependency

• An estimated 4-6 % who misuse prescription opioids transition to heroin

• About 80 % of people who use heroin first misused prescription opioids

15% of surgical patients may become dependent following perioperative use of opioids

• Most people who use opioids obtain them for free from their friends and family

• Those who are are highest risk of overdose get them in ways different from those who use them less frequently

• The amount of opioids sold to pharmacies, hospitals, doctor’s offices nearly quadrupled between 1999 to 2010. Prescriptions also quadrupled.

• Deaths from prescription opioids (oxycodon, hydrocodone, methadone) has more than quadrupled since 1999.

• In 2013, providers wrote nearly a quarter billion opioid prescriptions (nearly 1 prescription for every person living in the USA)

• 1999 – 2016: over 630,000 people died from drug overdose

• Deaths in 2016 was 5x 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

Adolescents

• 276, 000 teens were current, non-medical users of pain relievers

• 122,000 teens were addicted to pain reliever

• 21,000 teens had used heroine in past 12 months

• 5,ooo teens were current users of heroin

• Most obtain their pain relievers from family and friends

• Prescribing rates among teens doubled between 2004 to 2007

Opioid Epidemic - Colorado

• Since 1999, Colorado has seen 100% increase in opioid prescriptions (7.9/100,000 to 15.8/100,000)

• Age-adjusted death rate for non-heroin opioid overdose rose from 2.0/100,000 to 6.1/100,000 in 2014 (205% increase)

• 25% of users admit to using pain medications in non-prescribed ways

• 29% have used pain medication belonging to others

• Prescription drug arrests increased 27% between 2011 and 2015

According to a study that examined medical marijuana laws and opioids analgesic overdose rates from 1999 to 2010, “States with medical cannabis laws had a 24.8% lower mean annual opioid overdose

mortality rate compared with states without medical cannabis laws”

Who Prescribes the Most Opioids?

• Highest Odds of Prescribing an Opioid:

• Orthopedics

• Dentists

• Emergency Medicine

• Opioid Prescriptions by Specialty:

• Family Medicine

• Dentistry

• Emergency Medicine

As dentists, write approximately 12% of opioid prescriptions

Pathogenesis of 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 U KOTR IEN ES

• 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

• 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

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

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

Nociceptive pathwayInflammatory Pathway

Stimulus

Peripheral SensitizationHyperalgesia

AllodyniaPain Spread

Perioperative Pain Management

Ideal Strategy for Pain Management?

Drug Overview

• NSAID

• Ibuprofen

• Naproxen

• Ketorolac

• Meloxicam

• Caldolor

• Ofirmev

• Steroids

• Acetaminophen and Ovirmef

• Opioids

• Gabapentin

• Local Anesthetics

• Exparel

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

Naproxen

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

• Max Dose: 1500mg/24hr

• Standard Dosing: 250 – 500 mg BID

• T1/2 = 12-15hrs

Ketorolac• 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

Ketorolac

• Indications:

• moderate to severe pain

• Usage:

• Can spray 1 or 2 nostrils

• Re-dose every 6-8 hrs

• Do not use for more than 5 days

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

Caldolor ( IV ibuprofen)

• MOA:

• Non-selectieve cox1 and cox2 inhibitor

• Pharmacokinetics

• Onset: immediate

• Cmax: 6.5min

• Dosing:

• IV only

• Must dilute in NS, LR

• Max dose: 3200mg/24hr

Steroids - Dexamethasone• MOA:

• Inhibit the conversation of phospholipids to arachidonic acid

• Direct Inhibition of leukocyte infiltration to inflammatory site

• Mitigates capillary permeability

• Pharmacokinetics

• Onset: • IV: prompt• PO: 1-2hr

• Duration 72 hrs

• T1/2 = 190min

• Dosing

• IV: 8 – 12 mg preoperatively

• PO: 4mg q8 hrs x 4 doses

Steroid - Methylprednisolone• MOA

• Modify transcirption and protein synthesis

• Interfere with leukocyte infiltration

• Suppress humoral immune response

• Inhibit phospholipase A2

• Pharmacokinetics

• T1/2 = 1.8-5.2hrs

• Peak Concentration: 1.1 – 2.2 hrs

• Dosing

• See Dose pack

Acetaminophen• MOA: central and peripheral

• 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

Ofirmev

• MOA

• Similar to APAP

• Pharmacokinetics

• Onset: immediate

• Cmax: 15min

• Dosing

• IV only

• 1000mg

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

Gabapentin• MOA

• No Direct GABAergic action; increases [GABA]

• Decreases [Glutamate]

• High-affinity binding sites through-out brain

• Interferes with voltage-gated Ca2+ channels

• Pharmacokinetics

• T1/2 = 4.8 – 8.7 hrs

• Tmax: 8 hrs

• Dosing:

• 300-1200mg PO night before surgery, 1 -2 hrs before surgery or immediately after.

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

Ideal Strategy for Pain Management?

The effects of NSAID’s on peri-operative pain

First 8 drugs are NSAIDS

The 2nd drug is OTC

• 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

• 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.”

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

• Decoteau, C., et al, ”Assessment of pre-emptive analgesics effect of Caldolor vs Ofirmev on 3rd molar surgery : A prospective, randomized, double-blinded pilot study.”

• Results:• A total of 53 patients have participated in this ongoing clinical trial. 50 patients

(Female: 36 Male: 14) have completed this study. The overall pain rating in the Caldolor group was significantly lower than Ofirmev group. The average amount of narcotic medications taken in the Caldolor! group was 2 in comparison to 6 in the Ofirmev group.

• Conclusion:• The average number of narcotic medications taken during 7 day post-operative

period with no preemptive analgesia is about eight. There was significant reduction of narcotic consumption in subjects who received preemptive Ibuprofen. Preemptive analgesia should be incorporated in routine clinical practice

Acetaminophen

• Weil, K. et al., “Paracetamol for pain relief after surgical removal of lower wisdom teeth”, Cochrane Database of Systemic Reviews

• Objective:

• To assess the beneficial and harmful effects… at different doses and administered postoperatively.

• Conclusion:

• Paracetamol provided a statistically significant benefit when compared with placebo for pain relief at both 4 and 6 hours after taking the drug. It is most effective at 1000 mg dose, and can be taken at six hourly intervals without compromising safety.

The effects of steroid on post-operative pain

The effects of local anesthetic on post-operative pain

The effects of Gabapentin and Pregabalin on post-operative pain

Conclusion:

“The single small study using gabapentin 500 mg in dental pain did not demonstrate any analgesic efficacy over placebo, but the number of participants was too small to draw any conclusions”

Pain Management Strategies

Preoperative NSAIDS, Corticosteroids or

Gabapentin

Long-acting local anesthetic

Ibuprofen 600mg QIDAPAP 500mg QID

SpirxNasal Spray

Decadron 4mg TID x 3 tabs

Breakthrough PainHydrocodone/APAP 5/325 – QID

OROxycodon

ORAPAP 1000mg q6-8hrs

OR

• Discuss the expectation of pain with the patient and family

• Change the patient’s paradigm for pain management

• Administer NSAIDs pre-operatively

• Administer corticosteroid pre-operatively

• Consider using long-acting local anesthetics

• Treat pain pre-emptively during the first 24 hrs following surgery

Document, Document, Document!

Laws, Lawyers and Guidelines

Colorado Policy

• Colorado Medicaid Program

• 7 day supply to be filled initially

• Two additional 7-day refills

• If there is a 4th refill request, it will require prior authorization from the dept

• 4th refill could also require a consultation with a pain management physician from the department’s Drug Utilization Review Board

• Goal of new policy: reduce Medicaid members who might develop an addiction to opioids and to reduce the excess opioid pills in the community

Lawsuit Settlements

• Mallinckrodt Plc — $35 million — April 3, 2017

• Costco Wholesale — $11.75 million — January 19, 2017

• McKesson Corporation — $150 million — January 17, 2017

• Cardinal Health Inc.— $20 million — January 9, 2017

• Cardinal Health — $40 million — December 23, 2016

• Purdue Pharma — $24 million — December 23, 2015

Physicians

• Dr. Edita Milan

• Dr. Yee C. Ho, Allegany County Hospital

• Lake Hospital System, Dr. Nancy Rodway

• Dr. Michael Belfiore

• Insys Therapeutics, Linden Care (pharmacy), and Dr. Vivienne Matalon

OPIOIDS LAWSUITS ARE GROUNDBREAKING: There is no exact precedent for these opioid lawsuits, but that

doesn’t make them any less legitimate.

Wilbert Hatcher v Physician, Pharmacies, Pain Clinics

• West Virginia:

• Wilbert Hatcher

• History of criminal behavior to obtain and use drugs

• West Virginia Supreme Court upheld right to sue

• Senator Joe Manchin (D-WV) endorsed the lawsuit: “Prescription painkillers are handed out in his home state “like M&M’s.””

Closing Remarks

• Opioids are not the best option for pain relief

• Optimal pain relief is a function of multi-modal therapy

• Consider altering NSAID therapy should be first line treatment

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

• Do not prescribe more than 7 days worth of opioids.

• Document, document, document

Closing Remarks

Questions?

References• Bushra, R., Aslam, A. An overview of clinical pharmacology of ibuprofen. Oman Med J.

2010. Jul 25 (3): 155 – 166.

• The Manchester General Practitioner Group. A study of naproxen and ibuprofen in patients with osteoarthritis seen in general practice. Current Medical Research and Opinion. 1984. (1): 41 – 46.

• Graham, G.G., Davies, M.J., Day, R.O., Mohamudally, A., Scott, K.F. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology. 2013. June 21 (3): 201-32.

• Liew, Z., Ritz, B., Rebordosa, C., Lee, P.C., Olsen, J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr. 2014. April 168(4):313-20.

• Loveless., M.S., Fry, A.L. Pharmacologic Therapies in Musculoskeletal Conditions. Med Clin North Am. 2016. July 100(4): 869-90.

• Zemmel, M.H. The Role of cox-2 inhibitors in the perioperative setting: efficacy and safety—a systematic review. AANA J. 2006. Feb 74(74):49-60

References• Ong C.K.S., Seymour, R.A., Pathogenesis of Postoperative Oral Surgical Pain. Anesth

Prog. 2003. Winter 50(1):5-17.

• Beauregard, L., Pomp, A., Choiniere, M. Severity and Impact of Pain after day-surgery. Can J Anaesth. 1998. Apr 45(4):304-11.

• Bourne, S., Machado, A.,G., Nagel, S., J. Basic Anatomy and Physiology of Pain Pathways. Neurosurg. Clin. N. Am. 2014. Oct 25 (4):629-38.

• Pinho-Ribeiro, F.,A., Verri W.,A., Chiu, I.M. Nociceptor Sensory Neuron-immune Interactions in Pain and Inflammation. Trends Immunol. 2017. Jan 38(1):5-19.

• https://www.physio-pedia.com/images/7/7b/Peripheral_sensitization_1.jpg

• Ricciotti, E., Fitzgerald, GA. Prostaglandins and Inflammation. Artherioscler. 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. 2013. August 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. 2010. 54: 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. 1984. April 108 (4): 598-601

• Stader, D., E. (ED). 2017 Opioid Prescribing and Treatment Guidelines. Colorado Chapter, American College Emergency Physicians

References• Tsurufuji, S. Mechanisms of anti-inflammatory action of dexamethasone: blockade by

hydrocortisone mesylate and actinomycin D of the inhibitory effect of dexamethasone on leukocyte infiltration in inflammatory sites. Journal of Pharmacology and Experimental Therapeutics. 1984. April 229(1): 237 -243.

The real kicker…..Prescriber Checkup• https://projects.propublica.org/checkup/