#PainMgmt Successful Strategies in Intrathecal Pain Managementneurosciencecme.com/PDF/SP001.pdf ·...

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#PainMgmt

Provided by

Intrathecal Pain Management

Successful Strategies in

Dinner Symposium, Saturday, May 17 7:00 PM: Registration/Buffet Dinner 7:30 PM to 9:30 PM: Symposium

Waldorf Astoria – Central Park Ballroom

#PainMgmt

Supported by: An educational grant from Jazz Pharmaceuticals, Inc.

#PainMgmt

David L. Caraway, MD, PhD Medical Director, Center for Pain Relief, Tri State, PLLC Huntington, WV

David L. Caraway, MD, PhD

● Research: Jazz Pharmaceuticals, Inc.; Mallinckrodt; Medtronic, Inc. ● Speakers Bureau: Jazz Pharmaceuticals,

Inc.; Medtronic, Inc. ● Consultant: Jazz Pharmaceuticals, Inc.;

Medtronic, Inc.

Disclosures

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Agenda 7:00 PM Registration/Buffet 7:30 PM Welcome/Introductions 7:35 PM Patient Selection:

Matching Patients to Treatment Options

8:00 PM Trialing Methods When Initiating Therapy

8:25 PM Titration and Dose Escalation to Optimize Outcomes

8:50 PM Key Clinical Connections and Q&A

9:00 PM Conclusion

#PainMgmt

Learning Objective Apply evidence-based, best practice criteria for appropriate patient selection for intrathecal pain management.

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Learning Objective Integrate established best practice trialing strategies into the decision-making process when developing an individualized treatment approach to pain management.

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Learning Objective Implement an evidence-based titration strategy for the optimal treatment of chronic pain patients who are being managed with IDDS therapy to minimize potential for side effects and in alignment with the goals of the patient.

Challenges in Treating Chronic Pain

●  Illness burden is high: More than 100 million Americans live with disabling chronic pain1

● Treatment choice is complex2

●  Physical therapy (to what extent?) ●  Injections (how many rounds?) ● Oral medication (Choice of drug, dose, long-term issues?) ●  Spinal surgery (Rate of success?) ●  Spinal cord stimulation (Target, frequency?) ●  Targeted drug delivery (Drug, dose, patient selection?)

1.  Institute of Medicine. The National Academies Press, 2011. 2.  Vargas-Schaffer G. Can Fam Physician. 2010;56(6):514-517, e202-515.

PMID: 20547511.

Challenges in Treating Chronic Pain

● Long-term analgesic efficacy with opioids ● May be limited due to dose tolerance1

● May be variable and has led to heightened patient management requirements2

● Diversion of oral opioids is a problem3

● 3 out of 4 people who misuse pain medications use drugs prescribed for someone else

● 14,800 Americans died from prescription pain medication overdoses in 2008

1.  Ballantyne JC, Shin NS. Clin J Pain. 2008;24(6):469-478. PMID: 18574357. 2.  Trescot AM, et al. Pain Physician. 2008;11(2 Suppl):S5-S62. PMID: 18443640. 3.  Drug Enforcement Administration (DEA), 1999-2010.

Patient Reports in Treating Chronic Pain

Chronic pain patient dissatisfaction with opioids

American Pain Foundation. Voiced of Chronic Pain Survey, 2006. http://www.davidmichaelsoncompany.com/Documents/Voices%20of%20Chronic%20Pain%20Report.pdf

No Control

Breakthrough Pain

Enjoyment of Life

Trouble Concentrating

Energy Level Impacted

Feeling Depressed

Limits physical activity

Efficacy of Opioid Therapy

● Short-term efficacy ● Clear efficacy in multiple RCT’s demonstrate

improvement in pain ● Long-term efficacy ● Few RCTs for longer than 12 weeks ● Safety further declines at >50 MED, safety

markedly declines at >100 MED ● No evidence to support dosing of higher than 180 mg

morphine equivalent per day ● Studies mostly look at VAS, little evidence of

improved function

Ballantyne JC, Mao J. N Engl J Med. 2003;349(20):1943-1953. PMID: 14614170.

Opioid Therapy in Chronic Pain

● Consensus: Opioid therapy is first-line for moderate to severe chronic pain related to cancer and advanced medical illness of any type ● There is no consensus on the role of

opioid therapy for chronic non-cancer pain

Martell BA, et al. Ann Intern Med. 2007;146(2):116-127. PMID: 17227935.

Long-Term Opioid Efficacy: Systemic Reviews

Opioid treatment for chronic back pain CONCLUSIONS ● Opioids have limited, if any, short-term

value in chronic low back pain ● Evidence about substance abuse is too

limited to draw any conclusions ● There are insufficient data to judge long-

term outcomes Martell BA, et al. Annals Intern Medicine. 2007;146(2):116-127. PMID: 17227935.

CDC on Opioids

November 1, 2011: Dr. Thomas Frieden Director of the Centers for Disease Control

and Prevention

"For chronic pain, narcotics should be the last resort."

Freedman DW. CBS NEWS. Website http://www.cbsnews.com/news/fatal-painkiller-overdoses-soar-in-us-cdc-says/

Changing the Route of Administration

● Intrathecal drug delivery devices are not a therapy, but are a delivery system for a therapeutic agent ● Opioids (morphine) and ziconotide are

the currently approved therapies for treating chronic pain

Targeted Drug Delivery

● Why consider Targeted Drug Delivery (TDD)? ● What medication choices for TDD are

available? ● What evidence supports such use? ● What is the role of trialing? ● How does the intrathecal route of delivery

compare to systemic in terms of safety, efficacy, side effects and cost?

Why Targeted Drug Delivery?

●  Distributes drug via blood

●  High blood levels of drug ●  Brain receives highest

proportion of drug ●  High dose of drug

required – High elimination load

●  Increase in systemic side effects

●  Intrathecal drug distribution

●  Low blood levels of drug ●  Most drug binds to

TARGET (spinal cord pain receptors)

●  Low dose of drug is effective

●  Low elimination load ●  Minimal effect of genetic

differences in metabolism ●  Minimal systemic effect

on brain and gut Lipp J. Clin Neuropharmacol. 1991;14(2):131-147. PMID: 1849794.

Spinal analgesia Systemic analgesia

Who Is Potential Candidate: Refractory to Oral Analgesics

● Pain History – 14 years severe chronic pain – Lumbar pain with bilateral lower extremity pain – Sedentary but capable of performing activities of daily living

● Pain Etiology and Treatment History – Failed back surgery – Failed spinal cord stimulation – Takes oral opioids, antidepressant, anticonvulsant, sleeping aid, and stool softener

● Assessment – Patient is getting limited pain relief and has become intolerant of treatment as systemic analgesics, including oral opioids

Patient Selection

Redefine Patient Selection

● Elderly axial spinal pain ● Failed Back Surgery Syndrome

not amenable to SCS ● Good analgesia with systemic

opioids but intolerable side effects ● Cancer pain

SCS = spinal cord stimulation TDD = targeted drug delivery Deer TR, et al. Pain Physician. 2010;13(3):E175-E213. PMID: 20495597.

First Choices for Opioid-based TDD

Redefine Patient Selection

Difficult choices for opioid-based TDD ●  High oral opioid use with minimal perceived benefit ●  Poorly defined etiology ●  Poor compliance to previous therapies ●  Young age ●  Psychological issues which have

not been successfully treated ●  Positioning as a salvage therapy

for opioid unresponsive patients ●  Diminished outcomes

Deer TR, et al. Pain Physician. 2010;13(3):E175-E213. PMID: 20495597.

Psychological Evaluation

● Consider recommendations and treat if indicated - prior to trial

● Ability to understand appropriate expectations ● Has patient come to terms with status, expected

life span? ● Major active psychosis, current drug addiction,

some personality disorders, cognitive deficits, progressive organic brain disorders, suicidal, homicidal behavior

Deer TR, et al. Pain Physician. 2010;13(3):E175-E213. PMID: 20495597.

Intrathecal Delivery

● Achieves steady-state, around the clock dosing ● Reduced side effects, use of intermittent dosing

to reduce tolerance ●  Intrathecal Adjuvants (PACC) ● Compliance: Eliminate systemic opioids ● Can provide patient activated rescue dosing (PCA) ● Reduction in longitudinal costs

Advantages

PACC = Polyanalgesic consensus conference

Smith TJ, et al. J Clin Oncol. 2002;20(19):4040-4049. PMID: 12351602.

Treatment Approaches

2012 Polyanalgesic Panel Recommended Concentrations and Doses of Intrathecal Agents

Drug Maximum Concentration

Maximum Dose per Day

Morphine 20 mg/mL 15 mg

Hydromorphone 15 mg/mL 10 mg

Fentanyl 10 mg/mL No known upper limit

Sufentanil 5 mg/mL No known upper limit

Bupivacaine 30 mg/mL 10mg

Clonidine 1000 mcg/ml 40-600 mcg/day

Ziconotide 100 mcg/mL 19.2 mcg/d

Deer TR, et al. Neuromodulation. 2012;15(5):436-464. PMID: 22748024.

2012 Polyanalgesic Panel Recommended Starting Doses of Intrathecal Agents

Drug Recommended Star0ng Dosage

Morphine 0.1 mg/d to 0.5 mg/d

Hydromorphone 0.02mg/d to 0.5 mg/d

Zicono7de 0.1 to 0.5 mcg/d

Fentanyl 25-‐75 mcg/day

Bupivacaine 1 to 4 mg/day

Clonidine 40-‐100 mcg/day

Sufentanil 10 to 20 mcg/day

Intrathecal Opioids

● More invasive ● More difficult to discontinue therapy ● Acquisition costs ● If positioned as a salvage therapy for

patients who have failed but remain on high dose systemic opioids, outcomes are diminished

Disadvantages

Practice of David Caraway, MD. St. Mary’s Regional Medical Center, Huntington, WV. Smith TJ, et al. J Clin Oncol. 2002;20(19):4040-4049. PMID: 12351602.

Pharmacologic Considerations

● Receptors for the agents have to be at the spinal level ● Drug has to get to receptors ● Drug considerations ● Lipid solubility ● Density and baricity ● Kinetics: Bolus vs. continuous

Miljanich G, et al. Pain Pract. 2013;13(2):114-130. PMID: 22631599.

0 1 2 3 4 5 6 7 8 9 10

sity S

VAS Pain Intensity IT Morphine Dose (mg/d)

Discharge/ First Refill Baseline 1 Year 2 Years 3 Years

IT Morphine Efficacy

IT Opioid Doses Increased to Maintain Pain Control

Atli A, et al. Pain Med. 2010;11(7):1010-1016. PMID: 20492572.

Treatment Approaches

Overview of Ziconotide

● Only non-opioid IT therapy approved for severe chronic pain ● N-Type Calcium Channel Blocker

● Earlier introduction for chronic pain patients ● Option for patients with lack of efficacy despite

significant doses of systemic opioids ● Non-narcotic, no respiratory depression ● No tolerance observed ● No withdrawal

Ziconotide prescribing information. Drugs@FDA.gov. Wallace MS, et al. Neuromodulation. 2006;9(2):75-86. PMID: 22151630.

IT Ziconotide Efficacy and Safety (Pooled Studies)

●  Efficacy1

●  Three double-blind, placebo-controlled, multicenter studies ●  N = 457 -  268 ziconotide -  189 placebo

●  Two fast titration studies; one slow titration study ●  Mixed, neuropathic, and nociceptive pain2-4

●  Safety1

●  Evaluated in 1,254 severe chronic pain patients ●  Mean treatment duration = 193 days

1. Ziconotide prescribing information. Drugs@FDA.gov. 2. Wallace MS, et al. Neuromodulation. 2006;9(2):75-86. PMID: 22151630. 3. Staats PS, et al. JAMA. 2004;291(1):63-70. PMID: 14709577. 4. Rauck RL, et al. J Pain Symptom Manage. 2006;31(5):393-406. PMID:

16716870.

Non-malignant

Malignant Myelopathy Neuropathy Radiculopathy Spinal Post-laminectomy

IT Ziconotide Efficacy (Pooled) Results

* From baseline to end of initial titration. Collins R. Poster presented at AAPM Annual Meeting; 2005.

23% 37% 19% 29% 44% 21% 22% 32% 8% 9% 0 9% 4% 7% 7% 1% 0

Ziconotide Placebo

p = .0230

p < .0001 p = .0495

p = .0115

p = .0180

p = .0008 p = .0017

p = .0764

Response in 3 Pooled Placebo Controlled Trials* (N = 453)

Ziconotide Patient Selection

● Ziconotide is effective in a wide range of pain etiologies1

● Patients with a history of psychosis should be excluded from therapy2

● Ziconotide should be used with caution in patients with preexisting depression or cognitive impairment2

1. Ziconotide prescribing information. Drugs@FDA.gov. 2. Wallace MS, et al. Neuromodulation. 2006;9(2):75-86. PMID: 22151630.

Trialing

Does it Matter If and How You Trial?

● What are the goals of therapy? ● Can the trial method help achieve your

clinical goals?

Drug Trial Methods

● Single injection ● One epidural or intrathecal injection

● Multiple injections ● Series of intrathecal or epidural injections ● Epidural injections require a catheter

● Continuous infusion ● Intrathecal or epidural catheter is placed and

connected to external pump

Trialing: Single Shot

Advantages Disadvantages •  Easy, quick •  Do not need to go to

hospital

•  “Failed trial” requires multiple procedures

•  Does not provide patient experience of alternate route of delivery

•  May not be compliant with payor (CMS) guidelines or labeling

Trialing: Continuous Infusion

Advantages Disadvantages •  Best model of the

pharmacodynamics of intended therapy

•  Allows estimation of initial starting dose

•  Compliant •  Hospital and physician

are reimbursed

•  Requires hospital stay and management

Evaluate Trial Results

● Measurement tools ● Subjective: pain diary, pain scores ● Objective: monitor activities, monitor medications

● Assess agreed-upon goals ● Significant pain relief ● Increased functioning ● Reduced side effects ● Decreased use of systemic analgesics

● Trial outcome is positive when goals are met Follett K. and Doleys D. Selection of Candidates for Intrathecal Drug Administration to Treat Chronic Pain: Considerations in Pre-implantation Trials. Medtronic 2002. Website http://professional.medtronic.com/pt/neuro/idd/edu/Pre-implant-patient-education-resources/index.htm#.UxSTLPRdXWY

Titration

Titration Recommendations: PACC

PACC 2012 guidelines concluded that: ●  Intrathecal drug delivery systems may be an

effective pain management option for patients with moderate-to-severe intractable pain.

● The potential for adverse events caused by intrathecal therapies can be diminished with careful dosing and titration.

● And, finally, low doses with slow upward titration is the recommended method of initial dosing, and adjustments are to be made according to patient response.

Ziconotide Slow Titration Trial

Webster LR, et al. J Pain Symptom Manage. 2009;37(3):363-372. PMID: 18715748.

60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020

(0–1

Median VASPI Mean Ziconotide Dose

IT Ziconotide Maintenance of Efficacy

Webster LR, et al. J Pain Symptom Manage. 2009;37(3):363-372. PMID: 18715748.

Dosing

Optimal Dosing Strategies for TDD

● Terminology varies ● Low Dose ● Microdose ● Dosing Strategies

● What are the main components? ● Eliminating systemic opioids ● Starting at low doses, physician control ● Moderating dose escalation ● Providing patient flexibility in dosing ● Applying good clinical skills already in use to manage

dose escalation ● Building evidence

Grider JS, et al. Pain Physician. 2011;14(4):343-351. PMID: 21785477.

Start Low, Go Slow

Ziconotide prescribing information. Drugs@FDA.gov.

What is the Need for Patient-Controlled Dosing?

● Prevalence of “Breakthrough” Pain ● 74% of patients -  The percentage of patients with chronic non-cancer pain who

experienced severe to excruciating intermittent pain (n = 228).1

● 2.4 episodes/day -  The mean number of intermittent pain episodes (defined as

transitory exacerbation of pain that occurs on a background of otherwise controlled pain).1

● 60 minutes/pain episode -  Median duration of intermittent pain episodes.1

Portenoy RK, et al. J Pain. 2006;7(8):583-591. PMID: 16885015.

TDD Requires Same Strategies as Systemic Delivery ● Early titration to achieve

analgesia and therapy goals

● Careful consideration of dose increases

● Maintain moderate doses ● Monitor for side effects,

efficacy ● Physician remains in

control of dosing

Long-Term Follow-up

Clinical Connections

● Patient selection is critical in recommending intrathecal therapy ● Using established trialing strategies can ● Adopting evidence-based dosing

strategies can improve success in intrathecal therapy ● Establish goals of therapy with patient

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