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J E R E M Y A . A D L E R , M S , P A - CP A C I F I C P A I N M E D I C I N E C O N S U L T A N T S

UPDATE: CHRONIC PAIN

Consultant• Depomed• Endo Pharmaceuticals• Pfizer• Janssen Pharmaceuticals• Jazz Pharma• St. Jude Neuromodulation

As part of this presentation, off-label uses of pharmaceuticals and devices may be discussed.

Products mentioned do not include full prescribing information, please refer to FDA approved information

DISCLOSURES

National Institutes of Health

Funding 2010

http://report.nih.gov/categorical_spending.aspx

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AGENDA

• Burden of Chronic Pain • Pathophysiology - Disease Model• Pain Assessment• Multi-disciplinary Approach• Updates in Management

• Pharmacotherapeutic• Technological Updates• Interventional Updates

• Monitoring Updates

FROM THE NEW ENGLAND JOURNAL OF MEDICINE:

• “the relief of suffering, it would appear, is considered one of the primary ends of medicine by patients and lay persons, but not by the medical profession.”

Cassel E. The nature of suffering and the goals of medicine N Eng J Med. 1982; 306: 639-645.

BURDEN OF CHRONIC PAIN

• Institutes of Medicine 2011• “Pain as a Public Health Problem”• Prevalence: ~100 Million Americans• “Given the burden of pain in human lives, dollars, and social

consequences, relieving pain should be a national priority”• Leading Cause of Disability• Primary reason patients seek healthcare

• 80% of visits have pain complaint• Tremendous Costs

• Total U.S. Expenditures: $560 - $630 Billion• Lost Productivity

• Missed Work• Less Productive Workforce

http://www.iom.edu/Reports/2011/Relieving-Pain-in-America-A-Blueprint-for-Transforming-Prevention-Care-Education-Research.aspx

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GOALS OF MANAGEMENT

• Improve Quality of Life

• Reduce Loss of Functioning/Disability• Lessen Pain Intensity• Address Co-morbidities• Improve Patient Satisfaction• Minimize Treatment Related Adverse Events• Empower Self-management• Cost-effective Care/Reduced Utilization

ACUTE PAIN

• Signal of Disease/Injury/Surgery Within the Body• Proportional to Stimulus• Goal: Treat Illness, Restore Function, Prevent Chronic

• Pain lasting 3-6 months• Pain no longer serves purpose

CHRONIC PAIN

• Peripheral Nervous System• Gathers information from surroundings• Primary afferent neurons (Aδ / C-fiber)• Cell bodies located in dorsal root ganglia

• Central Nervous System• Secondary interneurons• Synapse in dorsal horn• Information ascends to cerebral cortex• Modulating pathways descend caudally

• Autonomic Nervous System• Carries sensory information from viscera

ANATOMY

• Pain information transmitted from injured tissue (skin, muscle, or viscera) to cerebral cortex

• Protection from tissuedamage

NOCICEPTIVE PAIN

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• Dysfunction within the nervous system• Not proportional to intensity of stimulus• Spontaneous• Quality: Burning, electrical, shooting

• Both Nociceptive and Neuropathic components

NEUROPATHIC PAIN

MIXED PAIN PATHOPHYSIOLOGY

DISEASE MODEL EVIDENCE

• Neuroplasticity• Structural Neuronal Changes• Facilitate Pain Transmission• May Explain Ongoing Pain after “Pain Generator” Removal

• Ascending Changes• Aβ-fiber Sprouting at C-fiber Synapse

• Descending Changes• Reduced Density of Spinal Inhibitory Interneurons

• Current Treatment Model: Symptomatic Management

• Herpes Zoster Virus activation• C-fiber Damage• Reduced Neuronal Density• Loss of Superficial Dorsal Horn Terminals• Aβ fibers Sprout into Superficial Terminals

• Express glutamate (depolarizes) and creates allodynia• Start expressing Substance P

• Not sensitization Neuralplasticity• Anti-NGF may be future treatment

MODEL: POST-HERPETIC NEURALGIA

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GLIAL CELL ACTIVATION

• Glia have role in initiating and maintaining pain in peripheral nerve injury (neuroexcitatory substances)

• Glia activation has been demonstrated in multiple pain states (nerve injury, bone cancer, MS, radiculopathy, etc.)

• Suppressing Glia (or it’s proinflammatory cytokines) returns pain to normal• Suppress tolerance, dependence, reward, respiratory

depression and constipation• Enhance analgeisa

FIBROMYALGIA (STANFORD LDN STUDY)

• Glia cell antagonist: naltrexone• Low dose <5 mg (study used 4.5mg daily)

http://snapl.stanford.edu/research/ldn.html

PAIN ASSESSMENT

PAIN ASSESSMENT

• Inherently SUBJECTIVE• Acute Pain

• Vital Sign Changes• Pain Behaviors

• Chronic Pain• Vital Signs Stable• Possibly No Pain Behaviors

• Verbal Analog Scale (0-10 with 10/10 worse)• Visual Analog Scale (100mm None to Severe Pain)• Wong-Baker Faces• Multidimensional Scales (McGill, SF-36, etc.)

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APPROACHES

• Multidimensional Approaches are Superior

Physical Behavioral

Interventions Pharmacotherapy

Optimal Outcome

CHRONIC PAIN MANAGEMENT CONTINUUM

• Exercise programs• Meditation and Relaxation• Over-the-Counter Medications• Adjunctive Medications• Physical Rehabilitation• Somatic and Sympathetic Nerve Blocking• Cognitive and Behavioral Therapies• Oral Opioid Medications• Spinal Cord Stimulation• Spinally Administered Opioids• Neurodestructive Procedures

PHYSICAL APPROACHES

• Physical Therapy• Exercise• Lifestyle Changes• Achieve Ideal Body Weight• Massage• Activity Pacing• Chiropractic• Yoga• Tai Chi

BEHAVIORAL APPROACHES

• Cognitive Behavioral Therapy• Biofeedback• Hypnosis• Stress Reduction / Relaxation Training• Activity Pacing• Coping Skills Training• Mood Management / Counseling

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INTERVENTIONAL / NON-PHARMACOLOGICAL

• Injection Treatments• Somatic/Sympathetic Blockade• Targeted Medication Delivery

• Corticosteroid• Botulinum Toxin

• Neuromodulation• TENS• Implantable Devices

• Drug Delivery Systems• Neurodestruction

• Radiofrequency Neurotomy• Surgery

• Non-Pharmacological• Heat/Cool Therapy• Acupuncture• CAM• Counter-irritants

PHARMACOLOGIC

• Self-Management• Oral OTC (NSAIDs / Acetaminophen)• Capsaicin Topical• Supplements

• Prescription Therapies• NSAIDs• Muscle Relaxers / Antispasmotics• Adjuvant Therapies• Topical Medications• Opioids

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Step 1Nonopioid analgesic with or without adjuvant medication

Step 2Combination opioid product (opioid plus nonopioidanalgesic) and adjuvant medication

Step 3Single-entity opioid with nonopioid analgesic and adjuvant medication

Moderate to moderately-severe pain

Moderate to severe pain

Mild to moderate pain

OTC / NSAIDS to Opioids

Cutson TM. Prim Care. 1998;25:407-421. Glajchen M. J Am Board Fam Pract. 2001;14:211-218. Adapted from Reid C, Davies A. Palliat Med. 2004;18:175-176.

WORLD HEALTH ORGANIZATIONSTEP LADDER OUTCOME BASED MONITORING

• Functional Goals:• More objective and correlate best with Quality of Life

• ADLs• Work• Recreation

• Pain Severity Reductions:• Target typically 30-50%

• Treatment Related Adverse Events• Aberrant Drug Taking Behaviors

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NSAIDS UPDATE

• NSAIDs have peripheral anti-inflammatory effects• Topical preparations as patch, gel or drops• Repetitive c-fiber activation spinal prostaglandin release• Acetaminophen inhibits COX-3 centrally

CYCLOOXYGENASE (COX) INHIBITORS

NSAIDS UPDATE

• Intranasal Ketorolac (Sprix) • Combination NSAIDs

• Naproxen / Esomeprazole (Vimovo)• Naproxen / Famotidine (Duexis)

• Technology• Intestinal Protective Drug Absorption System

• Naproxen Sodium(Naprelan)• ProSorb Dispersion Technology

• Diclofenac (Zipsor)• Topical Dicofenac

• Pennsaid 1.5%• Voltaren Gel 1%• Flector Patch 1.3%

ADJUVANT UPDATE

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• Modulators• Gabapentinoids• Bind α2δ subunit of Ca2+

• No GABA effects• Gabapentin, Pregabalin

• Blockers• Physically Block Channel• Ziconotide

• Reduce Neurotransmitter Release

CA2+ CHANNEL (N-TYPE) DRUGS CA2+ CHANNEL MODULATORS

• Pregabalin (Lyrica)• New indication:

• Management of Neuropathic Pain Associated with Spinal Cord Injury

• Fibromyalgia• Post-herpetic neuralgia• Painful Diabetic Nerve Pain

• Gastroretentive Gabapentin (Gralise)• Once-daily for post-herpetic neuralgia

• Gabapentin enacarbil (Horizant)• New indication:

• Management of post-herpetic neuralgia in adults• Prodrug of gabapentin

CONOPEPTIDES

• N-type Ca2+ Channel Blocker• Ziconotide (Prialt)

• Conus Magus Snail• For management of severe chronic pain

when IT therapy warranted and intolerant or refractory to other treatment, such as systemic analgesics, adjunctive therapies or IT morphine

• 1000x more potent than morphine• Other conopeptides in development

• 1000s small stable proteins in venom

SEROTONIN / NOREPINEPHRINE REUPTAKE INHIBITOR

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SNRI

• Duloxetine (Cymbalta)• Expanded Indications

• Chronic Musculoskeletal Pain• Chronic Low Back Pain• Chronic Osteoarthritis Pain

• Diabetic Peripheral Neuropathic Pain• Fibromyalgia

• Many SNRIs in pipeline for pain conditions

DULOXETINE –CHRONIC LOW BACK PAIN / OA

• Exclusion: Major Depressive Disorder

• Inclusion: VAS ≥4/10

• CLBP:• Adults ≥18, non-radicular, present >6 months

• OA:• Adults ≥40, knee involvement, pain ≥14 days/month for 3

months

DULOXETINE RESULTS

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndLifeSupportDrugsAdvisoryCommittee/UCM225311.pdf

TOPICAL CAPSAICIN

• Capsaicin 8% (Qutenza Patch)

• Indicated for Post-herpetic Neuralgia• Binds Peripheral Vanilloid Receptor

• Stimulated by heat, abrasion• Ongoing receptor binding results in Sp Depletion• Sp results in C-fiber Functionality = Pain• Neurodegeneration with high potency

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• Blocks binding of Acetylcholine containing vesicle and subsequent release

• New Indication for Botox:• Migraine Headache

• Prevent headache in adults with 15 or more days of headache and lasting more than 4 hours

BOTULINUM TOXIN TRIPTANS

• Needleless SC Sumatriptan (Sumavel Dosepro)• Tmax = 12 minutes (Oral sumatriptan Tmax = 2.5 hrs)• Can be used 1 hr after oral sumatriptan if relief not

obtained• No sharps

CANNABINOIDS

• Sativex• Delta-9-THC and Cannabidiol Mouth Spray• Available in many countries• Pending FDA approval• Use includes management of muscle spasms in multiple

sclerosis• Seeking approval for cancer pain OPIOID UPDATE

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• Presynaptic Binding • Ca2+ channel

inhibition• G-protein linked

• Postsynaptic Binding • Membrane Hyper-

polarization by opening K+ channels

• Suppress Peripheral Inflammatory Cells

• Central Actions

OPIOID PHARMACOLOGY UPDATE

• Expanded Indication• Tapentadol ER (Nucynta ER)

• Opioid Agonist / NE Reuptake Inhibitor• Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

• Transdermal• Buprenorphine (Butrans)• Only Schedule III sustained-release opioid for around the clock pain• Partial μ & δ agonist, κ antagonist

• Tablet Technology• Oxycodone CR (OxyContin)• Oxymorphone ER (Opana ER)• Hydromorphone ER (Exalgo)• Tapentadol ER (Nucynta ER)• Morphine ER (Embeda) – Approved, but voluntary recall

TABLET TECHNOLOGY

• Drug Delivery• Oros – Hydromorphone ER (Exalgo)

• Uses osmotic pressure through laser drilled hole• Pelleted Capsule – Morphine ER (Kadian/Embeda)

• Rate limiting membrane over morphine with core• SODAS – Morphine ER (Avinza)

• Polymer coated morphine• Contin – Morphine ER (MSContin), Oxycodone ER

(OxyContin)• Intac – Oxymorphone ER (Opana ER)

• Polymer matrix controlled drug delivery

TABLET TECHNOLOGY

• Tamper Resistant (Crush Resistant)• Intac Technology (Opana ER, Nucynta ER?)• OxyContin• Exalgo?

• Sequestered Antagonist• Morphine/naltrexone (Embeda)

• To early to determine if technology will reduce abuse

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RAPID ONSET FENTANYL

• Multiple New Delivery Technologies• Gum Mucosa (Fentora)• Buccal Mucosa via stick (Actiq)• Sublingual Spray (Subsys)• Nasal Spray (Lazanda)• Sublingual Tablet (Abstral)• Buccal Film (Onsolis)

• All have FDA Labeling for Breakthrough Cancer Pain in opioid tolerant patients

REMS: RISK EVALUATION AND MINIMIZATION STRATEGY

• Transmucosal Immediate Release Fentanyl (TIRF)• Approved 2011by FDA• Implemented March 2012

• Extended Release and Long Acting Opioids (ERLA)• Approved July 9, 2012 by FDA• Expect implementation by March 2013

TIRF GOALS

• Prescribing and dispensing TIRF medicines only to appropriate patients, including use only in opioid-tolerant patients

• Preventing inappropriate conversion between fentanyl products

• Preventing accidental exposure to children and others for whom TIRF medicines were not prescribed

• Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose

TIRF REQUIREMENTS

• Provider Education Required • “Knowledge Assessment”

• Pharmacy Certification Required • “Knowledge Assessment”

• Patient Education• Sign “Patient-prescriber agreement”• Medication Guides

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ERLA REMS

• Extended-Release and Long-Acting Opioids• Mandatory elements for manufactures, voluntary for

prescribers• Provider Education – Voluntary• Expect education programs by March 1, 2013

• Anticipate Industry grants to CE programs• AAPM – Safe Opioid Prescribing Course

• Patient Education via REMS approved Patient Counseling Document is recommended in interim

• All Brand and Generic Medications• Immediate-release medications not effected

MONITORING UPDATES

URINE DRUG TESTING

• Supported by multiple Clinical Practice Guidelines• Need working relationship with lab/toxicologist• Cut-offs (Negative = below cut off)• Metabolism / Contaminants• Parent/Child Drugs• Immunoassay

• Qualitative• Many false positive / false negative

• Confirmatory (GC/LC/MS)• Quantitative

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PRESCRIPTION DRUG DATABASE MONITORING (CURES)

• California has oldest PDMP in country• Threatened to be dissolved (budget)• Indexes Millions of Controlled Substance Rx• Online Access• Recommended as part of Comprehensive

Approach to Prescription Drug Abuse/Diversion:• Published Guidelines for Opioid Management• Centers for Disease Control• White House

REGISTER FOR CURES

• Sign up in Cyber Café• Need:

• Government Issued ID (Drivers License)• DEA Certificate• PA Medical License

• Documents must be NOTARIZED : Notary onsite

• NO COST to conference participants for notary

SEARCHING CURES

• https://pmp.doj.ca.gov

SEARCHING CURES

Select “Patient Activity Report”

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SEARCHING CURES

• Use only initials in search

• Less information is better

• i.e. Jane Doe• Change

months to 12

D JXX/XX/XXXX

12

X

SEARCHING CURES

• Select all appropriate profiles

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INTERVENTIONAL UPDATE

ADVANCED PAIN THERAPIES

• Spinal Cord Stimulation• Medtronic RestoreSensor

• Accelerometer to address uncomfortable positional stimulaltion• St. Jude Epiducer

• Allows percutaneous placement of surgical lead

• Boston Scientific 16-contact lead

MINIMALLY INVASIVESURGICAL UPDATE

• MILD (Minimally Invasive Lumbar Decompression)• Percutaneous pencil-sized portal (5.1mm)• Removes bone/tissue to decompress lumbar spinal stenosis

• Percutaneous Facet Fusion (TruFuse)

• Percutaneous Sacroiliac Joint Fusion (MIS- iFuse)CONCLUSIONS

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CONCLUSIONS

• IOM Report Pain as a “National Priority”• Advancement:

• Pain Classification• Pathophysiology• Medication Targets• Engineering of Technology (Efficacy & Safety)• Device and Invasive Approaches• Monitoring for improved Safety of Therapeutics

• Future:• Prevention and Disease Modifying?• Greater efficacy & safety?• Cost effective?

Jeremy A. Adler, MS, PA-Cjadler@simplyweb.net

477 N. El Camino Real #B301 3998 Vista Way #108Encinitas, CA 92024 Oceanside, CA 92056760-753-1104 760-753-1104

THANK YOU AND Q&A