#PainMgmt Successful Strategies in Intrathecal Pain Managementneurosciencecme.com/PDF/SP001.pdf ·...
Transcript of #PainMgmt Successful Strategies in Intrathecal Pain Managementneurosciencecme.com/PDF/SP001.pdf ·...
#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
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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
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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.
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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
51%
60%
No Control
Breakthrough Pain
59%
70%
74%
77%
81%
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
Deer TR, et al. Neuromodulation. 2012;15(5):436-464. PMID: 22748024.
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
0
2
4
6
8
10
12
14
16
Mean
VAS
Pain
Inten
sity S
core
Mean
IT M
orph
ine D
ose (
mg/d)
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. [email protected]. 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. [email protected]. 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
Bone
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
10
20
30
40
50
Dec
reas
e in
VA
SPI (
%)
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. [email protected]. 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
Deer TR, et al. Neuromodulation. 2012;15(5):420-435. PMID: 22494357.
Trialing: Single Shot
Deer TR, et al. Neuromodulation. 2012;15(5):420-435. PMID: 22494357.
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
Deer TR, et al. Neuromodulation. 2012;15(5):420-435. PMID: 22494357.
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.
Deer TR, et al. Neuromodulation. 2012;15(5):436-464. PMID: 22748024.
Ziconotide Slow Titration Trial
Webster LR, et al. J Pain Symptom Manage. 2009;37(3):363-372. PMID: 18715748.
Zico
notid
e M
ean
Dos
e (m
cg/d
ay)
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
0
20
40
60
80
100
60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020
Mea
n Zi
cono
tide
Dos
e (m
cg/d
)
Med
ian
Pain
Inte
nsity
(0–1
00)
Days
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. [email protected].
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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