Evolving Best Practices With Intrathecal Analgesics

EVOLVING BEST PRACTICES with

INTRATHECAL ANALGESICS

Improving the Care of Patients With Severe Chronic Pain TIMOTHY R. Deer, MD, DABPM JASON E. Pope, MD, DABPM, FIPP

This activity is jointly provided by Global Education Group and Integritas Communications.

This activity is supported by an educational grant from Jazz Pharmaceuticals, Inc.

EVOLVING BEST PRACTICES with

INTRATHECAL ANALGESICS Improving the Care of Patients With Severe Chronic Pain

Date of Release: November 17, 2016 Date of Credit Expiration: November 16, 2017

This activity is jointly provided by Global Education Group and Integritas Communications.

This activity is supported by an educational grant from Jazz Pharmaceuticals, Inc.

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Table of Contents Faculty iv Preamble vi Chapter 1 Overview of Intrathecal Therapy for Chronic Pain

1

Timothy R. Deer, MD, DABPM

Chapter 2 Patient Selection for Intrathecal Drug Delivery

9

Jason E. Pope, MD, DABPM, FIPP

Chapter 3 Initiating Intrathecal Therapy for Severe Chronic Pain

15

Timothy R. Deer, MD, DABPM

Chapter 4 Longitudinal Management of Patients on Intrathecal Therapy

23

Jason E. Pope, MD, DABPM, FIPP

Intrathecal Analgesics 31 Clinical Resource Center™ Intrathecal Analgesics 35 Supplemental Video Library

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FACULTY Timothy R. Deer, MD, DABPM President and Chief Executive Officer Center for Pain Relief, Inc. Charleston, West Virginia

Dr. Timothy Deer was born and raised in Chesapeake, West Virginia. During the last decade, he has originated many ideas that have been incorporated into the mainstream of present day theory and practice of interventional pain management.

Dr. Deer completed his medical school education at West Virginia University, where he was an Alpha Omega Alpha honor student at the top of his class. After medical school, Dr. Deer attended the University of Virginia School of Medicine, where he trained in Internal Medicine, Anesthesiology, and Pain Medicine.

Over the past 13 years, Dr. Deer has held numerous appointments, including that of the Chairman of the American Society of Anesthesiologists’ committee on Pain Medicine. This 42,000–member group represents more pain clinicians than any other organized body. Dr. Deer has also been President of the West Virginia Society of Anesthesiologists, President of the West Virginia Society of Interventional Pain Physicians, and Representative to the Carrier Advisory Committee to Medicare for Ohio and West Virginia.

In addition to those positions, Dr. Deer is on the Board of Directors for the North American Neuromodulation Society. He is also on the editorial committees for the journals Neuromodulation, Pain Medicine, and Pain Physician.

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FACULTY

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Jason E. Pope, MD, DABPM, FIPP President Summit Pain Alliance Santa Rosa, California

Dr. Jason Pope is the President of Summit Pain Alliance in Santa Rosa, California.

He serves the North American Neuromodulation Society (NANS) as a Director-atLarge, Membership Committee Chair, Advocacy and Policy Committee Co-chair, and Annual Meeting Co-chair for the upcoming 2017 meeting. He is also a Co-chair for the Special Interest Group in Neuromodulation for the American Society of Regional Anesthesia (ASRA). Further, he is the Committee Chair for CME and Education for the International Neuromodulation Society (INS), working on efforts to improve global exposure to pain treatment and neuromodulation techniques.

Dr. Pope completed his doctor of medicine at Indiana University School of Medicine in Indianapolis, his anesthesiology residency at Vanderbilt University Medical Center in Nashville, Tennessee, and his fellowship in pain medicine at the Cleveland Clinic in Ohio. Following fellowship, he advocated for pain care access and therapy as a congressional fellow to a member of the House of Representatives Energy and Commerce Subcommittee on Health.

Focused on education, Dr. Pope is centered on improving outcomes and safety. He is extensively published in peer-reviewed journals, has authored many chapters, textbooks and atlases, and has presented at regional, national, and international meetings. Working foundationally on comprehensive workshops for fellows, residents, and physicians in practice, both domestically and internationally, Dr. Pope and his colleagues are working toward an improved neuromodulation space.

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PREAMBLE Target Audience The educational design of this activity addresses the needs of pain specialists and other clinicians who manage patients with severe chronic pain.

Statement of Need/Program Overview Complexities in the underlying pathophysiologic mechanisms and clinical manifestations of chronic pain result in a large number of patients for whom conventional management strategies fail to produce adequate pain relief or functional gains.1,2 For some of these individuals, medications delivered directly to the intrathecal space can be a safe and effective treatment option.3, 4 The US Food and Drug Administration (FDA) has approved 2 analgesics—ziconotide and morphine— for intrathecal delivery in patients with severe chronic pain.5,6 However, intrathecal therapy remains underutilized for chronic pain, in part owing to historically suboptimal outcomes stemming from poor patient selection, systemic barriers, and safety concerns (eg, opioid-induced respiratory depression).7 Available in multiple formats, this multimedia eHealth Source™ will cover the latest published evidence and practical guidance on evaluating candidates for intrathecal drug delivery, initiating this treatment strategy using FDA-approved intrathecal analgesics, longitudinally monitoring patients with implanted pumps, and tailoring therapy based on analgesia, functional outcomes, and treatment-emergent adverse effects.

References

1. National Research Council. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Institute of Medicine. Washington, DC: The National Academies Press; 2011.

2. Gatchel RJ, Peng YB, Peters ML, Fuchs PN, Turk DC. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol Bull. 2007;133(4):581-624.

3. Onofrio BM, Yaksh TL, Arnold PG. Continuous low-dose intrathecal morphine administration in the treatment of chronic pain of malignant origin. Mayo Clin Proc. 1981;56(8):516-520.

4. Prager J, Deer T, Levy R, et al. Best practices for intrathecal drug delivery for pain.

Neuromodulation. 2014;17(4):354-372.

5. Ver Donck A, Vranken JH, Puylaert M, et al. Intrathecal drug administration in chronic pain syndromes. Pain Pract. 2014;14(5):461-476.

6. Kim P, Grigsby E, Deer T, et al. Effectiveness and safety of intrathecal ziconotide as the first agent in pump for adult patients with severe chronic pain. Presented at the 22nd Annual Napa Pain Conference; August 27-29, 2015; Napa, CA. 7. Coffey RJ, Owens ML, Broste SK, et al. Mortality associated with implantation and management of intrathecal opioid drug infusion systems to treat noncancer pain.

Anesthesiology. 2009;111(4):881-891.

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PREAMBLE

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Educational Objectives After completing this activity, the participant should be better able to: • Describe key anatomic and neurologic issues related to the practical use of intrathecal analgesics for the treatment of severe chronic pain • Perform comprehensive preimplantation workups of candidates for intrathecal analgesic therapy • Discuss the clinical profiles, dosing strategies, and other prescribing considerations for FDA-approved analgesics that have been approved for intrathecal use • Utilize intrathecal therapy for patients with severe chronic pain to reflect the benefits and risks of available medications, trial results, the latest guideline recommendations, and other recently published evidence • Tailor intrathecal therapy for severe chronic pain based on ongoing monitoring of analgesia, functional outcomes, and treatment-emergent adverse events

Physician Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Integritas Communications. Global is accredited by the ACCME to provide continuing medical education for physicians.

This CME/CE activity complies with all requirements of the federal Physician Payment Sunshine Act. If a reportable event is associated with this activity, the accredited provider managing the program will provide the appropriate physician data to the Open Payments database.

Physician Credit Designation Global Education Group designates this activity for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Global Contact Information For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.

Nurse Practitioner Continuing Education Global Education Group is accredited by the American Association of Nurse Practitioners as an approved provider of nurse practitioner continuing education. Provider number: 110121. This activity is accredited for 1.5 contact hour(s) which includes 0.2 hour(s) of pharmacology.

Activity ID #2148E. This activity was planned in accordance with AANP CE Standards and Policies.

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Instructions to Receive Credit In order to receive credit for this activity, participants must score 70% or better on the posttest and complete the program evaluation at www.ExchangeCME.com/ITehealth.

System Requirements PC: Microsoft Windows 2000 SE or above.

Flash Player Plugin (v7.0.1.9 or greater) Internet Explorer (v5.5 or greater), or Firefox Adobe Acrobat Reader• MAC: M AC OS 10.2.8 Flash Player Plugin (v7.0.1.9 or greater) Safari Adobe Acrobat Reader* Internet Explorer is not supported on the Macintosh. *Required to view printable (PDF) version of the lesson.

Fee Information & Refund/Cancellation Policy There is no fee for this educational activity.

Disclosure of Conflicts of Interest Global Education Group (Global) requires instructors, planners, managers and other individuals and their spouses/life partners who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

The faculty reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Timothy R. Deer, MD, DABPM Consultant – Axonics Modulation Technologies, Inc., Bioness Inc., Ethos Pharmaceuticals, Inc., Flowonix Medical, Inc., Medtronic, Nevro Corp., Nuvectra Corp., Saluda Medical Pty Ltd., SpineThera, Inc., St. Jude Medical, Inc., Vertos Medical Inc.; Grant/Research Support – Bioness Inc., Jazz Pharmaceuticals plc, Medtronic, St. Jude Medical, Inc.; Stock Options – Axonics Modulation Technologies, Inc., Bioness Inc., Ethos Pharmaceuticals, Inc., Nuvectra Corp., Saluda Medical Pty Ltd., SpineThera, Inc., Vertos Medical Inc. Jason E. Pope, MD, DABPM, FIPP Consultant/Independent Contractor– Flowonix Medical, Inc., Jazz Pharmaceuticals plc, Medtronic, Nuvectra Corp., St. Jude Medical, Inc.; Grant Research Support–Flowonix Medical, Inc., Jazz Pharmaceuticals plc, St. Jude Medical, Inc.; Royalties– Elsevier, Springer Nature

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PREAMBLE

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Kristen Delisi

Nothing to disclose

Andrea Funk

Nothing to disclose

Amanda Glazar, PhD

Nothing to disclose

Laura Gilsdorf

Nothing to disclose

Jim Kappler, PhD

Nothing to disclose

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global Education Group (Global) and Integritas do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity.

Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

eReader version available at

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EVOLVING BEST PRACTICES WITH INTRATHECAL ANALGESICS

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CHAPTER 1

Overview of Intrathecal Therapy for Chronic Pain Timothy R. Deer, MD, DABPM

C

hronic pain is a complex disease state unto itself, characterized by pathologic changes in the nervous system and clinical manifestations that are markedly shaped by psychosocial and potentially iatrogenic factors.1 When the nociceptive system is persistently activated, peripheral and central neural pathways that normally transduce noxious environmental stimuli into perceived pain in the brain can become aberrantly sensitized.2-4 For example, heightened release of neurotransmitters at connections between peripheral nociceptors and secondary neurons in the dorsal horn of the spinal cord strengthens these synapses, causing increased sensitivity to noxious stimuli, or hyperalgesia.2,3 Additionally, ongoing signaling along nociceptive neural pathways can recruit low-threshold peripheral mechanoreceptors, which normally respond to touch.2,3 Adding these primary neurons to pain-sensing circuits increases dorsal horn activity and causes allodynia, defined as pain caused by normally non-noxious stimuli (see link to supplementary VIDEO 1 on page 35).2,3 These and other neural processes can manifest clinically as severe, persistent, and functionally disabling pain, which is often difficult to manage despite individualized care with oral medications and psychosocial modalities. Achieving good outcomes for patients with severe chronic pain has recently become even more difficult because of the serious safety concerns and public health issues associated with oral prescription opioids.5 When patients fail to reach their analgesic and functional goals with more conventional therapies, their clinicians should consider advanced pain management options. One interventional modality involves delivering analgesics directly into the intrathecal cerebrospinal fluid (CSF) via a catheter.6,7 In 1981, a group from the Mayo Clinic in Minnesota published a paper describing substantial and sustained pain relief with an implanted pump delivering intrathecal low-dose morphine in a patient with cancer-related pain.8 Since that Download this activity and additional tools at

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EVOLVING BEST PRACTICES WITH INTRATHECAL ANALGESICS

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time, a number of systematic reviews have found intrathecal therapy to be effective and safe for cancer-related and chronic noncancer pain.9,10 Systematic reviews using the United States Preventative Services Task Force criteria have reported a strength of evidence of level II-2 for cancer-related pain with at least 3 months of follow-up, and level II-3 for chronic noncancer pain with at least 12 months of follow-up.10 Real-world results, however, have at times been somewhat disappointing. In many practices, clinical outcomes with intrathecal analgesics have been hurt by poor patient selection, the perception that this route of delivery should be considered a “last resort” salvage therapy, safety concerns (eg, opioid-induced respiratory depression), and other systemic barriers.11,12 The consequence has been an overall underutilization of a potentially valuable treatment strategy for patients with severe chronic pain.

ANATOMIC and CLINICAL OVERVIEW of INTRATHECAL DRUG DELIVERY Intrathecal therapy for chronic pain relies on a pump implanted under the subcutaneous tissue in the abdomen to deliver an analgesic directly into the intrathecal space of the spinal cord via a catheter.6 In general, the catheter tip is placed at the level of the spinal cord that innervates the body region containing the primary pain generator.6 Once in the CSF, intrathecally delivered medications diffuse across the pia-arachnoid and white matter of the spinal cord to reach the target dorsal horn receptors and ion channels involved in nociceptive processing and transmission.13 Drugs infused into the CSF do not show signs of significant bulk directional flow.14,15 Instead, they are subject to bidirectional craniocaudal oscillatory movement, facilitated by fluctuating intrathoracic pressure from respiration, and expansion and relaxation of the brain owing to the cardiac cycle.14,15 Thus, there is some pulsatile movement toward the brainstem and other supraspinal neural centers, which can allow the agent to induce additional effects—both beneficial and potentially deleterious—at higher brain levels.15 Intrathecal drug delivery produces better analgesia and fewer treatment failures and technical issues compared with epidural administration of the medication.16 Importantly, as a consequence of both the targeted delivery and CSF dynamics, intrathecal administration offers the advantage of using relatively low daily dosages to achieve the desired analgesia.17 This translates to a lower drug elimination load for the patient

CHAPTER 1 Overview of Intrathecal Therapy for Chronic Pain

and reduced systemic side effects compared with oral or intravenous administration of the same agent. Moreover, the programmed pump controls the infusion rate throughout the day to eliminate the peaks and troughs in drug plasma levels observed with oral dosing.14

FDA-APPROVED INTRATHECAL ANALGESICS: MECHANISMS of ACTION To date, two analgesic medications have been specifically approved by the US Food and Drug Administration (FDA) for intrathecal delivery (see link to supplementary VIDEO 2 on page 35). Morphine is a µ-opioid receptor agonist that primarily exerts its spinal effects by binding to receptors in the substantia gelatinosa, a dorsal column of gray matter that extends the full length of the spinal cord into the medulla oblongata.18 Opioid receptors are located both presynaptically and postsynaptically at the central connections between first-order nociceptors and secondorder spinal neurons.18 Presynaptic activation of µ-opioid receptors inhibits the release of excitatory neurotransmitters, whereas postsynaptic ligand binding hyperpolarizes the second-order neurons, reducing their ability to fire in response to excitatory inputs.19 Therefore, the net effect of morphine is a dampening of ascending pain-related neural activity.19 Because morphine is a relatively hydrophilic molecule, it remains largely in the CSF and can move with the local pulsatile motion to reach supraspinal brain areas.15 A small amount of morphine can also diffuse slowly out of the intrathecal space to enter the circulation.15 This spread of morphine can cause a number of side effects that are commonly observed with systemic opioids, including constipation, nausea, urinary retention, sedation, and endocrine issues.6,15 The most catastrophic potential complication of intrathecal morphine is respiratory depression, which is related to the activation of µ-opioid receptors in the brain’s respiratory centers, including the brainstem.15 The risk of respiratory depression may increase when opioids are delivered through intrathecal catheters placed at higher spinal levels—especially cervical locations—given their closer proximity to the brainstem and the greater cardiopulmonary-induced CSF movement in this region.20 Other risks of intrathecal morphine include the development of granulomas—ie, inflammatory masses at the catheter tip that can cause potentially serious neurologic complications (see Chapter 4).21 Additionally, as with systemic opioid dosing, tolerance to the analgesic effects of intrathecal morphine may develop, although most longitudinal reviews suggest that the necessary increases in morphine doses are often, but not always, moderate.22

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The other FDA-approved intrathecal analgesic is ziconotide, a synthetic equivalent of a naturally occurring conopeptide found in the piscivorous marine snail Conus magus.23 Ziconotide is thought to exert its analgesic effect by reversibly antagonizing presynaptic N-type voltage-gated calcium channels expressed by primary nociceptive neurons in the dorsal horn.23 Blocking these channels prevents presynaptic calcium influx, which is essential for synaptic vesicle fusion and the release of pronociceptive neurotransmitters (eg, glutamate and substance P). Ziconotide is a relatively large hydrophilic molecule that does not readily cross the blood-brain barrier and, therefore, must be administered directly in the spinal cord to achieve its analgesic effects.15 Moreover, because of its size and high affinity for N-type voltage-gated calcium channels, ziconotide does not markedly diffuse out of the CSF or reach clinically relevant levels in the peripheral circulation.15 The pulsatile motion of the CSF allows the medication to spread rostrally to supraspinal areas.15 Higher concentrations of intrathecal ziconotide may spread to cortical areas, where it may cause the neuropsychiatric adverse events observed in some patients (eg, hallucinations, cognitive impairment). However, it does not affect the brainstem’s respiratory drive and therefore does not cause respiratory depression, and no cases of granuloma have been associated with the use of intrathecal ziconotide.23

CLINICAL TRIAL EVIDENCE for FDA-APPROVED INTRATHECAL ANALGESICS The use of both FDA-approved intrathecal analgesics is supported by a number of clinical trials.22 Much of this evidence is summarized in the Polyanalgesic Consensus Conference (PACC) recommendations.22 Last published in 2012, these practice guidelines have been updated by an interdisciplinary expert panel organized by the International Neuromodulation Society (new guidelines are expected to be published in late 2016).22,24,25 The goal is to create algorithmic processes for various aspects of intrathecal analgesic therapy based on evidence for efficacy and safety, and when necessary, the expert panel’s consensus opinion. Among opioids, morphine has the largest evidence base supporting its use as an intrathecal monotherapy. Most published studies have been open-label or retrospective, examining patients with cancer-related pain or various types of chronic noncancer pain.26,27 A more recent randomized controlled trial for chronic noncancer pain confirmed the efficacy intrathecal morphine by comparing a group

CHAPTER 1 Overview of Intrathecal Therapy for Chronic Pain

of patients who received a stable drug dose for 10 weeks with a group in whom the morphine dose was reduced by 20% each week.28 Significant increases from baseline to the last observation were noted for pain levels and disability in the dose-reduction group, but not in the control group.28 The other FDA-approved intrathecal analgesic, ziconotide, can be used with the Medtronic SynchroMed® II Infusion System or a CADDMicro® Ambulatory Infusion Pump.29 The efficacy and safety of ziconotide is supported by 3 randomized placebo-controlled trials in patients with cancer-related or chronic noncancer pain.30-32 Overall the studies comprised 457 patients, 268 of whom received ziconotide.33 The drug showed robust efficacy across a range of malignant and chronic nonmalignant pain types, including myelopathy, neuropathy, radiculopathy, and postlaminectomy pain, among other conditions.33 A 3-year, open-label extension of 78 patients with chronic pain who completed one of the randomized clinical trials showed sustained efficacy with relatively stable dosing and no evidence of analgesic tolerance.34 Additional insights can be gained from a national registry of patients treated with intrathecal ziconotide—the Patient Registry of Intrathecal Ziconotide Management (PRIZM).35,36 For example, data obtained over 12 months from patients ≥18 years old with severe chronic pain show that the analgesic benefits of ziconotide are initially and longitudinally more robust when it is the first rather than the second-or-later drug used in the intrathecal pump (Figure 1).36 A number of other intrathecal agents have been used off-label as monotherapy or in combination regimens for patients with severe chronic pain. Other commonly used intrathecal opioids include hydromorphone, fentanyl, and sufentanil.22 At times, bupivacaine is delivered with an intrathecal opioid, which is thought to enhance treatment efficacy and reduce the risk of opioid dose escalation.37 Overall, the evidence for efficacy and safety with these approaches is not as strong as the data supporting intrathecal ziconotide and morphine, and the new PACC guidelines recommend considering off-label monotherapy or combination regimens only if the FDA-approved intrathecal agents have failed or are contraindicated. Of note, hydromorphone is currently being evaluated in 2 clinical trials with the goal of obtaining FDA approval as an intrathecal product.

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EVOLVING BEST PRACTICES WITH INTRATHECAL ANALGESICS

n=22 n=22

8

12

n=35 n=26

2

n=28 n=22

1

Week 4

Month 6 9 12

n=14 n=9

n=18 n=12

n=26 n=17

n=22

0

n=29

10

2.4 µg/d

-20

2.7 µg/d

-10

-30

-50

1.5 µg/d

-40

1.8 µg/d

Mean Change From Baseline on the NPRS, % ± SEM

20

n=27 n=17

6

Ziconotide first in pump (n=51; mean [SD] baseline score, 7.4 [1.9]) Ziconotide not first in pump (n=42; mean [SD] baseline score, 7.9 [1.6])

FIGURE 1. PRIZM registry: Outcomes with ziconotide as first drug in pump36 Data from the PRIZM registry of adults with severe chronic pain (life expectancy >6 months) treated with intrathecal therapy. Lower scores indicate improvement, and mean dosing values are shown for Week 1 and Month 12 timepoints.

NPRS, numerical pain rating scale; PRIZM, Patient Registry of Intrathecal Ziconotide Management; SD, standard deviation; SEM, standard error of the mean.

CHAPTER 1 Overview of Intrathecal Therapy for Chronic Pain

REFERENCES 1. Gatchel RJ, Peng YB, Peters ML, Fuchs PN, Turk DC. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol Bull. 2007;133(4):581-624.

2. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain.

2011;152(suppl 3):S2-S15.

3. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895-926.

4. Whitten CE, Donovan M, Cristobal K. Treating chronic pain: new knowledge, more choices.

Perm J. 2005;9(4):9-18.

5. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49.

6. Prager J, Deer T, Levy R, et al. Best practices for intrathecal drug delivery for pain.

Neuromodulation. 2014;17(4):354-372; discussion 372.

7. Pope JE, Deer TR, Bruel BM, Falowski S. Clinical uses of intrathecal therapy and its placement in the pain care algorithm. Pain Pract. 2016. [Epub ahead of print].

8. Onofrio BM, Yaksh TL, Arnold PG. Continuous low-dose intrathecal morphine administration in the treatment of chronic pain of malignant origin. Mayo Clin Proc. 1981;56(8):516-520.

9. Falco FJ, Patel VB, Hayek SM, et al. Intrathecal infusion systems for long-term management of chronic non-cancer pain: an update of assessment of evidence. Pain Physician.

2013;16(suppl 2):SE185-SE216.

10. Hayek SM, Deer TR, Pope JE, Panchal SJ, Patel VB. Intrathecal therapy for cancer and noncancer pain. Pain Physician. 2011;14(3):219-248.

11. Pope JE, Deer TR, McRoberts WP. Intrathecal therapy: the burden of being positioned as a salvage therapy. Pain Med. 2015;16(10):2036-2038.

12. Coffey RJ, Owens ML, Broste SK, et al. Mortality associated with implantation and management of intrathecal opioid drug infusion systems to treat noncancer pain.

Anesthesiology. 2009;111(4): 881-891.

13. Kroin JS. Intrathecal drug administration. Present use and future trends. Clin Pharmacokinet.

1992;22(5):319-326.

14. Deer TR, Smith HS, Cousins M, et al. Consensus guidelines for the selection and implantation of patients with noncancer pain for intrathecal drug delivery. Pain Physician.

2010;13(3):E175-E213.

15. Webster LR. The relationship between the mechanisms of action and safety profiles of intrathecal morphine and ziconotide: a review of the literature. Pain Med. 2015;16(7):1265-1277.

16. Dahm P, Nitescu P, Appelgren L, Curelaru I. Efficacy and technical complications of long-term continuous intraspinal infusions of opioid and/or bupivacaine in refractory nonmalignant pain: a comparison between the epidural and the intrathecal approach with externalized or implanted catheters and infusion pumps. Clin J Pain. 1998;14(1):4-16.

17. Bottros MM, Christo PJ. Current perspectives on intrathecal drug delivery. J Pain Res. 2014;7:615-626.

18. Arvidsson U, Riedl M, Chakrabarti S, et al. Distribution and targeting of a mu-opioid receptor (MOR1) in brain and spinal cord. J Neurosci. 1995;15(5 Pt 1):3328-3341.

19. Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia. 2nd ed. New York: Vendome Group, LLC; 2007.

20. De Andres J, Asensio-Samper JM, Fabregat-Cid G. Intrathecal delivery of analgesics.

Methods Mol Biol. 2014;1141:249-278.

21. Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference 2012: consensus on diagnosis, detection, and treatment of catheter-tip granulomas (inflammatory masses).

Neuromodulation. 2012;15(5):483-495; discussion 496.

22. Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15(5):436-464; discussion 464-466.

23. Pope JE, Deer TR. Ziconotide: a clinical update and pharmacologic review. Expert Opin Pharmacother. 2013;14(7):957-966.

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24. Deer TR, Hayek S, et al. The Polyanalgesic Consensus Conference (PACC) recommendations on intrathecal drug infusion systems: best practices and guidelines. Neuromodulation. 2016.

[In Press] 25. Deer TR, Hayek S, et al. The Polyanalgesic Consensus Conference guidelines for intrathecal drug delivery infusion system trialing. Neuromodulation. 2016. [In Press].

26. Reig E, Abejon D. Continuous morphine infusion: a retrospective study of efficacy, safety, and demographic variables. Neuromodulation. 2009;12(2):122-129.

27. Shaladi A, Saltari MR, Piva B, et al. Continuous intrathecal morphine infusion in patients with vertebral fractures due to osteoporosis. Clin J Pain. 2007;23(6):511-517.

28. Raphael JH, Duarte RV, Southall JL, Nightingale P, Kitas GD. Randomised, double-blind controlled trial by dose reduction of implanted intrathecal morphine delivery in chronic noncancer pain. BMJ Open. 2013; 3(7). pii:e003061.

29. Prialt [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals Inc.; revised 2/2013.

30. Rauck RL, Wallace MS, Leong MS, et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage.

2006;31(5):393-406.

31. Staats PS, Yearwood T, Charapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA. 2004;291(1):63-70.

32. Wallace MS, Charapata SG, Fisher R, et al. Intrathecal ziconotide in the treatment of chronic nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial.

Neuromodulation. 2006;9(2):75-86.

33. Collins R. Effectiveness of intrathecal ziconotide in multiple pain etiologies: a meta-analysis of three controlled trials. Presented at the 21st Annual Meeting of the American Academy of Pain Medicine. February 23-27, 2005; Palm Springs, CA. 34. Webster LR, Fisher R, Charapata S, Wallace MS. Long-term intrathecal ziconotide for chronic pain: an open-label study. J Pain Symptom Manage. 2009;37(3):363-372.

35. Deer T, McDowell G, Rauck RL, et al. Correlation of patient-reported outcomes in patients with severe chronic pain treated with intrathecal ziconotide. Presented at: 19th Annual Meeting of the North American Neuromodulation Society; December 10-13, 2015; Las Vegas, NV. 36. Saulino MF, Deer T, Rauck RL, et al. Effectiveness and safety of intrathecal ziconotide as the first agent in pump for adult patients with severe chronic pain. Presented at: 70th Postgraduate Assembly of the New York State Society of Anesthesiologists; December 9-13, 2016; New York, NY. 37. Veizi IE, Hayek SM, Narouze S, Pope JE, Mekhail N. Combination of intrathecal opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer pain patients. Pain Med. 2011;12(10):1481-1489.

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CHAPTER 2

Patient Selection for Intrathecal Drug Delivery Jason E. Pope, MD, DABPM, FIPP

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reatment algorithms for chronic pain are evolving. These changes are partly a consequence of growing evidence for efficacy and safety with some more advanced pain management options based on better technologies, improved patient selection, and increased provider vigilance around key therapeutic challenges.1-3 For example, intrathecal drug delivery should no longer be positioned only after high-dose systemic opioids have failed to produce adequate results.2 Morbidity and mortality data suggest that intrathecal opioids administered for chronic pain by a qualified pain specialist are safer than high systemic doses.4-6 Further, because the pump is filled during an office appointment under the control of the implanting physician, intrathecal therapy likely reduces the well-documented risks of abuse and diversion associated with oral opioid formulations.7 Moreover, some nonopioid options delivered into the intrathecal space at relatively low doses can provide sustained pain relief with few systemic side effects and no risk of respiratory depression.8,9 Within the context of other interventional strategies, intrathecal drug delivery can now generally be considered alongside neurostimulation.2 Because lack of well-controlled data makes it difficult to directly compare these 2 options in any given disease state, a number of factors should guide clinical decision making—eg, type of pain, likelihood the pain source will spread, age, previous treatments, patient prognosis, need for titratability, treatment history, and overall safety considerations.10,11 Most importantly, as with any medical intervention, accurate diagnosis and identification of appropriate candidates for these advanced pain care modalities are critical to maximizing the chances of clinical benefit.

CLINICAL INDICATIONS for INTRATHECAL ANALGESIC THERAPY The regulatory approvals for intrathecal morphine and ziconotide do not include specific pain diagnoses, but rather state that these analgesics

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and this route of delivery can be considered in any patient with severe chronic pain in whom conventional approaches are insufficient or not tolerated.12 Empirical evidence and clinical experience, however, have shown that favorable outcomes are more likely with certain chronic pain disorders—notably those with a well-localized source of pain and clear diagnosis.12 Examples include axial pain following failed back surgery and complex regional pain syndrome (Table 1). On the other hand, there is a relative paucity of positive evidence to support intrathecal drug delivery as a treatment strategy for more global chronic pain conditions, such as fibromyalgia. Furthermore, medical comorbidities that preclude device implantation and chronic drug infusion include severe coagulopathies and conditions that markedly obstruct the flow of cerebrospinal fluid.12

TABLE 1. Chronic Pain Conditions That May Respond Positively to Intrathecally Delivered Analgesics11,12 Axial pain (not addressable with surgery)

Vertebral compression fractures Refractory facet arthropathy Multilevel spondylosis or spondylolisthesis

Failed back surgery syndrome Extremity pain (not addressable with surgery)

Radiculopathy

Neuropathies of the trunk

Postherpetic neuralgia

Joint pain Post-thoracotomy pain syndromes

Complex regional pain syndrome Visceral pelvic or abdominal pain Cancer pain

Direct tumor invasion Chemotherapy-induced

End-of-life pain Systemic opioids limited by intolerable side effects despite otherwise effective analgesia

CHAPTER 2 Patient Selection for Intrathecal Drug Delivery

Regardless of the pain diagnosis, selected patients should have failed to respond adequately to several evidence-based pharmacologic and nonpharmacologic modalities. A comprehensive inventory of previous medications and interventions is required, including routes of administration, dosage, duration of use, perceived efficacy, and adverse effects. Each patient’s pain management history not only helps determine whether intrathecal drug delivery is appropriate, but also guides subsequent clinical decisions with this modality. For example, if the patient failed to achieve adequate pain relief from systemic opioids, changing only the route of administration within the same analgesic class is unlikely to produce a better outcome.2

COMPONENTS of the PREIMPLANTATION PATIENT WORKUP The high degree of variability in responses to intrathecal analgesics highlights the importance of multifactorial patient assessment and risk stratification strategies before a pump is implanted. Published guidelines on the use of intrathecal therapy for chronic pain lay out a number of tasks that should be performed prior to deciding to move forward.7,11,12 Essential information must be collected from the patient’s medical history, physical exams, ancillary testing, and ongoing clinical interviews. The overall goals of the preimplantation workup are to confirm the pain diagnosis, address potential complicating factors, document inadequate responses to more conventional therapies, and ensure that the patient is providing fully informed consent. Additionally, characterizing the pain type and location provides important information regarding appropriate drug options and the spinal target when positioning the catheter tip.11 Although there are very few absolute contraindications to the use of intrathecal therapy for severe chronic pain, clinicians should be on the lookout for a number of clinical scenarios that increase risks with this modality. Clearly, candidates should be fit for surgery; knowledgeable about achievable therapeutic goals and potential hazards relative to other treatment options; and able to comply with the ongoing requirements of care (eg, returning to scheduled follow-up appointments for outcome evaluations and pump refills).12,13 Here, establishing an effective patientprovider partnership early in the treatment process is essential. This requires open communication, longitudinal patient education, and reasonable outcomes expectations among all parties. Documented

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informed consent from the patient is also critical, potentially including agreement to supervision by the prescribing physician, treatment risks and goals, scheduled refill appointments, screening for illicit drugs or alcohol abuse, and actions to be taken if therapeutic responses are inadequate or intolerable.12 The goal is to encourage shared decisionmaking, which in turn is likely to enhance satisfaction with treatment, improve functional and psychological status, and foster adherence to the care plan.7,11,12 Patients should also be screened for relevant comorbidities and other potentially complicating factors. Pulmonary disorders, sleep apnea, obesity, and cardiac disease need to be recognized as increasing the risk of respiratory depression if opioids are introduced.14 Medications and substances that depress activity in the central nervous system can also potentiate opioid-induced inhibition of respiratory drive.11 Thus, concomitant use of such agents—eg, benzodiazepines—should be avoided, or at least the doses should be minimized as much as possible.

Similarly, for most patients being treated with systemic opioids, daily doses should be reduced as much as possible.11,15 In addition to attenuating respiratory risks, this strategy may reduce the eventual intrathecal dose required, uncover potential contributions of opioidinduced hyperalgesia to pain levels, and increase the likelihood of successful outcomes with intrathecal monotherapy.16-18 Before any invasive intervention, disorders that deleteriously affect wound healing or increase the risk of surgical site infection, such as uncontrolled diabetes, should be optimally managed.14,19 Patients should be queried about conditions associated with immunosuppression to ensure that affected individuals are offered the most appropriate antibiotic coverage.11 Coagulopathies or anticoagulant therapy should also be identified and appropriately addressed or temporarily discontinued, respectively.11,19,20 If intrathecal opioids are being considered, a baseline endocrine evaluation can provide values for comparison with subsequent periodic test results to assess potential suppressive effects in the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes.12 On the other hand, if ziconotide is going to be introduced, creatinine kinase levels should be checked initially and compared with later values because in some clinical trial patients, these values increased to well above normal.14

CHAPTER 2 Patient Selection for Intrathecal Drug Delivery

PSYCHOLOGICAL EVALUATIONS of CANDIDATE PATIENTS Guidelines have also recommended that the psychological status of each candidate be assessed to identify characteristics that may positively (eg, proper expectations, coping skills) or negatively (eg, drug abuse, severe depression) affect treatment responses.12,21 Of note, however, no highlevel evidence has shown that these particular patient traits or the results of psychological evaluations accurately predict long-term outcomes with intrathecal analgesics. Nevertheless, psychological comorbidities—eg, mood disorders, substance abuse, or cognitive issues—are common in chronic pain cohorts, potentially interfering with patients’ ability to make medical decisions, adhere to treatment plans, and derive analgesic and functional benefits after a pump has been implanted.20 Implementing a semistructured approach to psychological testing can help identify patients in need of additional support, although the precise goals of the assessment differ depending on the overall health status of the patient. For instance, patients facing imminent death from terminal disease usually do not require a full psychological evaluation, but may benefit from counseling efforts aimed at reducing any distress associated with end of life. All other patients should be examined for underlying mental disorders, psychosocial support networks, and expectations for outcomes if intrathecal therapy is pursued (see link to supplementary VIDEO 3 on page 35).12 Some experts recommend including psychological testing instruments that have been standardized in patients with chronic medical illnesses (eg, Millon® Behavioral Medicine Diagnostic) as well as in psychiatric cohorts (eg, Minnesota Multiphasic Personality Inventory®-2).12 If previously unidentified or inappropriately managed issues are uncovered, tailored mental health treatment can reduce distress, improve functioning, and put patients in a better overall position to benefit from intrathecally delivered analgesics.12 Early psychological evaluations are particularly important if intrathecal ziconotide is being considered, given the risks of neuropsychiatric adverse events (eg, hallucinations, cognitive disturbances) and its contraindication in patients with a preexisting history of psychosis.11

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REFERENCES 1. Lamer TJ, Deer TR, Hayek SM. Advanced innovations for pain. Mayo Clin Proc.2016;91(2):246-258.

2. Pope JE, Deer TR, Bruel BM, Falowski S. Clinical uses of intrathecal therapy and its placement in the pain care algorithm. Pain Pract. 2016. [Epub ahead of print].

3. Prager J, Jacobs M. Evaluation of patients for implantable pain modalities: medical and behavioral assessment. Clin J Pain. 2001;17(3):206-214.

4. Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers --- United States, 1999-2008. MMWR Morb Mortal Wkly Rep. 2011;60(43):1487-1492.

5. Coffey RJ, Owens ML, Broste SK, et al. Mortality associated with implantation and management of intrathecal opioid drug infusion systems to treat noncancer pain.

Anesthesiology. 2009;111(4):881-891.

6. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305(13):1315-1321.

7. Deer TR, Smith HS, Cousins M, et al. Consensus guidelines for the selection and implantation of patients with noncancer pain for intrathecal drug delivery. Pain Physician.

2010;13(3):E175-E213.

8. Pope JE, Deer TR. Intrathecal pharmacology update: novel dosing strategy for intrathecal monotherapy ziconotide on efficacy and sustainability. Neuromodulation. 2015;18(5):414-420.

9. Webster LR, Fisher R, Charapata S, Wallace MS. Long-term intrathecal ziconotide for chronic pain: an open-label study. J Pain Symptom Manage. 2009;37(3):363-372.

10. Coffey RJ, Owens ML, Broste SK, et al. Medical practice perspective: identification and mitigation of risk factors for mortality associated with intrathecal opioids for non-cancer pain.

Pain Med. 2010;11(7):1001-1009.

11. Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: Report of an interdisciplinary expert panel. Neuromodulation. 2012;15(5):436-464.

12. Prager J, Deer T, Levy R, et al. Best practices for intrathecal drug delivery for pain.

Neuromodulation. 2014;17(4):354-372.

13. Deer TR, Pope JE. Factors to consider in the choice of intrathecal drug in the treatment of neuropathic pain. Expert Rev Clin Pharmacol. 2015;8(5):507-510.

14. Deer TR, Levy R, Prager J, et al. Polyanalgesic Consensus Conference—2012: recommendations to reduce morbidity and mortality in intrathecal drug delivery in the treatment of chronic pain. Neuromodulation. 2012;15(5):467-482.

15. Grider JS, Etscheidt MA, Harned ME, et al. Trialing and maintenance dosing using a low-dose intrathecal opioid method for chronic nonmalignant pain: a prospective 36-month study.

Neuromodulation. 2016;19(2):206-219.

16. Grider JS, Harned ME, Etscheidt MA. Patient selection and outcomes using a lowdose intrathecal opioid trialing method for chronic nonmalignant pain. Pain Physician.

2011;14(4):343-351.

17. Kim D, Saidov A, Mandhare V, Shuster A. Role of pretrial systemic opioid requirements, intrathecal trial dose, and non-psychological factors as predictors of outcome for intrathecal pump therapy: one clinician’s experience with lumbar postlaminectomy pain.

Neuromodulation. 2011;14(2):165-175.

18. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review.

Anesthesiology. 2006;104(3):570-587.

19. Deer TR, Mekhail N, Provenzano D, et al, for the Neuromodulation Appropriateness Consensus Committee. The appropriate use of neurostimulation: avoidance and treatment of complications of neurostimulation therapies for the treatment of chronic pain.

Neuromodulation. 2014;17(6):571-597.

20. Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference—2012: recommendations on trialing for intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15(5):420-435.

21. Deer TR, Smith HS, Burton AW, et al. Comprehensive consensus based guidelines on intrathecal drug delivery systems in the treatment of pain caused by cancer pain. Pain Physician. 2011;14(3):E283-E312.

CHAPTER 3

Initiating Intrathecal Therapy for Severe Chronic Pain Timothy R. Deer, MD, DABPM

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ntrathecal therapy should be initiated and longitudinally supervised by a physician specialist who is trained and skilled in the use of intrathecal drug delivery systems (IDDSs) and knowledgeable about the pharmacologic characteristics and prescribing considerations for intrathecal analgesics.1 The experience level of the lead physician has been tied to both the risk of immediate postoperative complications and the probability of long-term system integrity.2 At times, the implanting physician will also be responsible for coordinating ongoing management of the patient and the pump. Alternatively, these tasks may be performed by different people, in which case the 2 physicians should be in close communication well before the pump is introduced to share relevant information from the preimplantation workup, select the IDDS and initial intrathecal analgesic, perform an appropriate trial (when necessary), and plan for intraoperative and immediate postoperative patient care.

RECOMMENDATIONS on INTRATHECAL ANALGESICS The previous iteration of the Polyanalgesic Consensus Conference (PACC) guidelines contained 2 evidence-based algorithms designed to guide intrathecal medication choices for nociceptive or neuropathic pain.3 Within each algorithm, monotherapies and potential drug combinations were placed on 5 tiers, with Line 1 containing the PACC panel’s recommendations for initiating intrathecal therapy.3 The intrathecal analgesics approved by the US Food and Drug Administration (FDA), ziconotide and morphine, were listed on Line 1 in the neuropathic and nociceptive pain algorithms.3 Additional first-line agents for nociceptive pain included 2 other opioids (fentanyl and hydromorphone), whereas the combination of morphine + bupivacaine was placed on Line 1 for neuropathic pain.3 Beyond these recommended medications,

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supervising physicians could move down the algorithms from Line 2 to Line 5, selecting analgesics from the tiered options to fit the particular clinical situation.3 In the updated PACC guidelines, recommendations on selecting intrathecal medications have been somewhat restructured. The underlying cause of pain (ie, cancer/other terminal disorders vs chronic noncancer conditions) and affected area (ie, localized vs diffuse) have been used as a framework for 4 algorithms, each of which covers both nociceptive and neuropathic pain types.4 Examples cited as localized pain include axial back pain from vertebral compression fractures and specific dermatomal manifestations of postherpetic neuralgia, whereas diffuse is used to describe pain in an entire extremity, discomfort throughout the back or a leg, or abdominal pain encompassing more than one quadrant.4 In each algorithm, the first tier has been split into Lines 1A and 1B, with ziconotide and morphine listed as the only Line 1A agents.4 Thus, in the absence of contraindications, the PACC has recommended using (or at least trialing) the FDA-approved intrathecal monotherapies with Level-I evidence before moving to other singleagent or combination regimens. Subsequent tiers have been created to reflect evidence for efficacy and safety, the experience of the expert panel, and the relationship between the size of the pain source and drug properties that affect diffusion from the catheter tip (eg, relatively hydrophilic molecules that spread farther for diffuse pain).4 The choice between first-line morphine and ziconotide (or among potential options on subsequent tiers in the PACC algorithms) should be individualized based on a number of factors—most importantly safety, but also patient age, pain type, prognosis, anticipated treatment duration, and previous responses to systemic and intrathecal analgesics.4 In chronic noncancer pain, the absence of risks for overdose or granuloma formation led the PACC to recommend ziconotide as the first choice unless it is contraindicated.4 Indeed, the presence of risk factors associated with respiratory depression should weigh heavily in clinical decision-making each time a new intrathecal regimen is selected.

Furthermore, as stated earlier, patients who did not derive significant pain relief from high-dose oral opioids are unlikely to experience better analgesia if only the route of administration has changed. On the other hand, in patients with quickly progressing cancer, the wide dosing range and titratability of opioids may be attractive.

CHAPTER 3 Initiating Intrathecal Therapy for Severe Chronic Pain

RECOMMENDATIONS on TREATMENT TRIALING Before an IDDS is permanently implanted, patients are usually administered a provisional neuroaxial infusion of the selected medication.

This therapeutic trialing can provide important clinical information, such as the responsiveness of the pain to the analgesic, identification of unacceptable or unmanageable adverse events, and initial insights into long-term dosing needs.1,5,6 It should be noted that there is little consensus on the potential benefits and drawbacks of trials, and no well-designed studies have shown the superiority of any specific trialing technique or duration in predicting long-term outcomes.6-8 Additionally, there are circumstances in which it may be desirable to skip the trialing step—for instance, in the setting of uncontrolled pain at the end of life, where expeditious intervention is needed.5,9 For most cases, however, consensus guidelines recommend documenting a successful trial (often historically defined as at least a 50% reduction in pain scores) before moving forward, and certain payors require a positive trial before covering the IDDS implantation.1,5,6,10 The trial should be structured to account for a number of factors, including selected drug, complexity of the painful condition, treatment history, practice setting, and patient’s overall medical status.5 The drug can be administered via single injection, intermittent boluses, or continuous infusion, with either an intrathecal or epidural site of delivery.6 Conceptually, the results of an intrathecal trial would best predict responses to an implanted IDDS if the trialing method matches the long-term treatment strategy as much as possible. Yet the published literature does not currently show that continuous infusion through an intrathecal catheter results in better outcomes, and this trialing method may be impractical or inappropriate for some patients.6 Many experts feel that bolus trialing can provide sufficient information with reduced costs, patient burdens, and infection risk compared with infusions.

This may be particularly true with ziconotide, due to its relatively slow clearance from the cerebrospinal fluid and long duration of action.5 However, because of the drug’s narrow therapeutic window, bolus ziconotide dosing may cause adverse events that would not manifest with the standard slow titration approach to initiating continuous intrathecal ziconotide (see link to supplementary VIDEO 4 on page 35).4 In the PACC update, the guidelines and a companion paper cover current best practices in patient-centric trialing strategies, including

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updates to previous recommendations (eg, recommended trialing doses and individualizing observation protocols for intrathecal opioid trialing) (Table 2).4,10

TABLE 2. Recommended Doses for Intrathecal Bolus Trialing4,10 Drug Morphine Hydromorphone Ziconotide Fentanyl Bupivacaine Clonidine Sufentanil

Recommended Dosea 0.1 to 0.5 mg 0.025 to 0.1 mg 1 to 5 mg 15 to 75 mg 0.5 to 2.5 mg 5 to 20 mg 5 to 20 mg

Starting doses of medication in the opioid-naive patient for outpatient bolus delivery should not exceed 0.15 mg morphine, 0.04 mg hydromorphine, or 25 mg fentanyl. a

PUMP IMPLANTATION Pump selection and implantation are shaped by the patient’s clinical status, IDDS characteristics (eg, the desire for continuous vs variable flow), pain source, selected medication, and supervising physician’s comfort level with the devices, although evidence-based literature addressing several aspects of these systems is limited.11-13 Detailed surgical recommendations are beyond the scope of this CME activity, but it is essential for implanting physicians to be vigilant about surgical technique, wound healing, and strategies to prevent infection, including antimicrobial prophylaxis.1,13-15 Intrathecal medications can be delivered via an external pump with a tunneled or nontunneled percutaneous catheter, or from fully implantable devices. Implantable systems are appropriate for most patients outside of those nearing end of life.16 Fully implanted, fixed-rate systems offer the advantages of lower cost, larger reservoir volumes, and less frequent refills, whereas fully implanted programmable IDDSs allow for intermittent or continuous drug delivery, adjustable

CHAPTER 3 Initiating Intrathecal Therapy for Severe Chronic Pain

dosage, and in some cases patient-directed features, such as selfadministered doses for breakthrough pain and longitudinal logging of predose and postdose pain levels. The accuracy of IDDSs is determined by the ratio of delivered-to-programmed drug volume calculated at the time of reservoir refill.17 Available data regarding FDA-approved IDDS accuracies are generally favorable. For example, the Prometra® programmable infusion system—approved for delivery of intrathecal morphine—was shown to have a mean accuracy of 97.1%, while the SynchroMed® II programmable system—approved for delivery of intrathecal ziconotide—demonstrated a mean accuracy of 97.5% in clinical testing.17,18 Despite little formal supportive data, implanting physicians generally strive to place the catheter tip under fluoroscopic guidance at the spinal level corresponding to the dermatome associated with the pain source.4 Of note, however, the catheter tip must be placed with consideration for the “spinal environment” (eg, previous surgeries, proximity to higher brain regions).19-21 Also, afferent neurons entering a given spinal level can make additional synapses with rostral and caudal secondary neurons, such that optimal efficacy may require infused medications to reach the dorsal horn in multiple spinal segments.19-21 A number of catheter-anchoring techniques can be employed to reduce the risk of dislodgement and other complications.13 The overall goals are to prevent tension at the site of entry and kinks in the catheter, while securing the catheter to the anchor, and the anchor to the connective tissue beneath the skin.1

INITIAL DOSING with INTRATHECAL ANALGESICS Starting dosages and drug-titration strategies are directed in part by trialing outcomes, with a generally conservative mindset to minimize adverse events.1 Recommended dosage ranges when beginning the continuous infusion of intrathecal analgesics are unchanged in the most recent PACC guideline update (Table 3).3,4 The best initial opioid dosage depends on the patient’s use of systemic opioids at the time of implant, but converting daily systemic opioid use into intrathecal dosages is problematic due to variability in patient responses, pharmacologic changes introduced by the different routes of delivery, and the recommended weaning or reducing of systemic opioid use prior to initiating intrathecal therapy.4 Additionally, the prescriber should consider risk factors for respiratory depression and the

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TABLE 3. Recommended Starting Dosage Ranges of Intrathecal Medications for Long-Term Therapy3,4 Drug Morphine Hydromorphone Ziconotide Fentanyl Bupivacaine Clonidine Sufentanil

Recommended Starting Dosea 0.1–0.5 mg/day 0.01–0.15 mg/day 0.5–1.2 mg/day (product labeling allows up to 2.4 mg/day) 25–75 mg/day 1–4 mg/day 20–100 mg/day 10–20 mg/day

Starting dosages for continuous intrathecal delivery of opioid medications should be half of the trial dose. a

resources available in the health care setting in which the drug is being introduced.4 As a general rule, the PACC panel suggests using 50% or less of the efficacious intrathecal trial dose as an initial daily intrathecal dose for opioids or ziconotide.4 One change in the new PACC guidelines is a shortening of the recommended postinitiation observation period for ziconotide from 12 hours to 6 hours if the patient had no signs of neurologic dysfunction before intrathecal therapy was started.4 The optimal approach to intrathecal medication infusion has not been characterized. Most published studies have relied on continuous infusion. However, many IDDSs now offer the possibility of bolus dosing potentially in combination with continuous flow. Compared with continuous infusion, the spread of intrathecal medications may be greater with serial boluses, which would allow for more flexibility in catheter placement and greater antinociceptive coverage along the spine.21 An open-label registry of patients with chronic pain and uncontrolled pain episodes found that allowing patient-controlled medication boluses decreased average pain scores, increased patient satisfaction, and reduced the use of supplemental oral medications.22 Additionally, a recent preliminary case series examining the effects of ziconotide found that a nocturnally weighted flex dosing strategy

CHAPTER 3 Initiating Intrathecal Therapy for Severe Chronic Pain

improved the efficacy and tolerability of intrathecal therapy, while greatly reducing the use of systemic opioids (see link to supplementary VIDEO 5 on page 35).23 Although larger randomized studies are needed before definitive recommendations can be made, these data suggest that intrathecal therapy may be best delivered with tailored dosing strategies that reflect the characteristics of the medication and the needs of the patient.

REFERENCES 1. Prager J, Deer T, Levy R, et al. Best practices for intrathecal drug delivery for pain.

Neuromodulation. 2014;17(4):354-372.

2. Ridley B, Rawlins PK. Intrathecal baclofen therapy: ten steps toward best practice. J Neuroscience Nursing. 2006;38(2):72-82.

3. Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15(5):436-464.

4. Deer TR, Hayek S, et al. The Polyanalgesic Consensus Conference (PACC) recommendations on intrathecal drug infusion systems: Best practices and guidelines Neuromodulation. 2016.

[In Press].

5. Pope JE, Deer TR, Bruel BM, Falowski S. Clinical uses of intrathecal therapy and its placement in the pain care algorithm. Pain Pract. 2016. [Epub ahead of print].

6. Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference—2012: recommendations on trialing for intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15(5):420-435.

7. Burton AW, Deer TR, Wallace MS, Rauck RL, Grigsby E. Considerations and methodology for trialing ziconotide. Pain Physician. 2010;13(1):23-33.

8. Hamza M, Doleys DM, Saleh IA, Medvedovsky A, Verdolin MH, Hamza M. A prospective, randomized, single-blinded, head-to-head long-term outcome study, comparing intrathecal (IT) boluses with continuous infusion trialing techniques prior to implantation of drug delivery systems (DDS) for the treatment of severe intractable chronic nonmalignant pain.

Neuromodulation. 2015;18(7):636-649.

9. Deer TR, Smith HS, Burton AW, et al. Comprehensive consensus based guidelines on intrathecal drug delivery systems in the treatment of pain caused by cancer pain. Pain Physician. 2011;14(3):E283-E312.

10. Deer TR, Hayek S, et al. The Polyanalgesic Consensus Conference guidelines for intrathecal drug delivery infusion system trialing. Neuromodulation. 2016. [In Press].

11. Falco FJ, Patel VB, Hayek SM, et al. Intrathecal infusion systems for long-term management of chronic non-cancer pain: an update of assessment of evidence. Pain Physician.

2013;16(suppl 2):SE185-SE216.

12. Pope JE, Deer TR. Intrathecal drug delivery for pain: a clinical guide and future directions. Pain Manag. 2015;5(3):175-183.

13. Follett KA, Burchiel K, Deer T, et al. Prevention of intrathecal drug delivery catheter-related complications. Neuromodulation. 2003;6(1):32-41.

14. Bowater RJ, Stirling SA, Lilford RJ. Is antibiotic prophylaxis in surgery a generally effective intervention? Testing a generic hypothesis over a set of meta-analyses. Ann Surg.

2009;249(4):551-556.

15. Deer TR, Mekhail N, Provenzano D, et al, for the Neuromodulation Appropriateness Consensus Committee.. The appropriate use of neurostimulation: avoidance and treatment of complications of neurostimulation therapies for the treatment of chronic pain.

Neuromodulation. 2014;17(6):571-597.

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16. Belverud S, Mogilner A, Schulder M. Intrathecal pumps. Neurotherapeutics. 2008;5(1):114-122.

17. Wesemann K, Coffey RJ, Wallace MS, Tan Y, Broste S, Buvanendran A. Clinical accuracy and safety using the SynchroMed II intrathecal drug infusion pump. Reg Anesth Pain Med. 2014;39(4):341-346.

18. Rauck R, Deer T, Rosen S, et al. Long-term follow-up of a novel implantable programmable infusion pump. Neuromodulation. 2013;16(2):163-167.

19. Bottros MM, Christo PJ. Current perspectives on intrathecal drug delivery. J Pain Res. 2014;7:615-626.

20. De Andres J, Asensio-Samper JM, Fabregat-Cid G. Intrathecal delivery of analgesics.

Methods Mol Biol. 2014;1141:249-278.

21. Yaksh TL, Fisher C, Hockman T, Wiese A. Current and future issues in the development of spinal agents for the management of pain. Curr Neuropharmacol. 2016. [Epub ahead of print].

22. Ilias W, le Polain B, Buchser E, Demartini L, oPTiMa study group. Patient-controlled analgesia in chronic pain patients: experience with a new device designed to be used with implanted programmable pumps. Pain Pract. 2008;8(3):164-170.

23. Pope JE, Deer TR. Intrathecal pharmacology update: Novel dosing strategy for intrathecal monotherapy ziconotide on efficacy and sustainability. Neuromodulation. 2015;18(5):414-420.

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CHAPTER 4

Longitudinal Management of Patients on Intrathecal Therapy Jason E. Pope, MD, DABPM, FIPP

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ong-term success with analgesics delivered intrathecally for chronic pain requires diligent patient monitoring to identify emergent adverse events and compare treatment goals with the degree of analgesia.1 To aid this process, patients should be educated to relay promptly any changes in pain intensity, pattern, disability, or associated symptoms, and to recognize potential side effects of the intrathecal medications.2 Ongoing psychosocial education—an extension of the pretrialing psychological assessment—is also needed to reinforce the patient’s understanding of treatment goals and limitations, and to identify new and evolving factors that may interfere with reasonable treatment expectations and good therapeutic outcomes.3 Initial monitoring steps in the early postoperative period focus on potential complications from intrathecal drug delivery system (IDDS) implantation, such as superficial or deep surgical site infection, other wound-healing complications, postdural-puncture headache, and cerebrospinal fluid (CSF) leakage, although many of these risks can be mitigated by adequate training of the implanting physician.2 During the early observation period, it is also critical to detect medication dosing complications and side effects, and to manage the most serious potential adverse events associated with first-line intrathecal medications—most notably respiratory depression with opioids.4

MONITORING of PATIENT OUTCOMES As treatment progresses, intrathecal therapy should be tailored to reflect repeated measures of beneficial responses (documentation of self-reported pain levels and functional outcomes), the emergence of side effects, the goal of markedly reducing or eliminating systemic opioid supplementation, and the progression of the painful disorder or other comorbidities.4 There is evidence to support the potential durability of intrathecal drug delivery in chronic pain management,

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which may provide an advantage in some cases over traditional spinal cord stimulation strategies.5,6 As with any pharmacologic approach to pain management, providers should strive for the lowest effective intrathecal medication dosage, identified by starting conservatively and then titrating up to the desired effect in the absence of intolerable side effects. Upward drug titration should proceed cautiously, taking into account the patient’s age, general medical status, and clinical indicators of tolerance. It is important to adjust the dosing with an appropriate interval between titration encounters to avoid dose stacking and overdose.

Although the therapeutic window of opioids can be relatively large, patient selection and catheter location can help mitigate dose escalation with opioid monotherapy, as can supplementation with Tier 2 medications.4 High intrathecal opioid dosages or infused concentrations can contribute to opioid-related side effects, including opioid-induced hyperalgesia, opioid-induced hormone suppression, and granuloma formation.2,4 Based on ongoing assessment of outcomes after systemic supplementation with opioids has been eliminated, intrathecal opioid dosages can be increased by no more than 30% every 7 days as long as notable benefits continue to be documented.2 However, intrathecal opioid dose escalation due to analgesic tolerance can be problematic over time in some patients, particularly in younger individuals.7 Thus, alternative agents, such as ziconotide, may be preferred in this cohort, or prescribers can consider evidence that the off-label addition of bupivacaine to the intrathecal opioid may allow synergistic analgesia and reduce the risk of opioid dose escalation.8 Patients should be counseled on potential adverse events with intrathecal medications and vigilance is recommended.2 Specifically, patient education on intrathecal opioids must highlight respiratory depression, which has been identified as the most critical treatment-related safety issue associated with intrathecal drug delivery.2 One review of mortality found that the risk of death associated with intrathecal opioids was greater than those with spinal cord stimulation or spine surgery, with the largest imbalance observed during the first few days after device implantation.9 Of the 557 deaths during the 9-year review of patients treated with intrathecal opioids for chronic noncancer pain, 88 (16%) occurred within 3 days of a device-related procedure, such as implantation, pump refill, or change to the IDDS or catheter, and all seemed to be iatrogenic and related

CHAPTER 4 Longitudinal Management of Patients on Intrathecal Therapy

to opioid dosing.9 That said, intrathecal opioid therapy contributes to far fewer mortalities than systemic opioids, which are involved in nearly 16,000 deaths annually in the United States.10 Nevertheless, it is absolutely critical that steps are taken to increase monitoring vigilance and introduce redundancies in checking intrathecal dosing and pump programming each time a device-related procedure is performed. All clinicians involved in monitoring patients on intrathecal opioids should be alert for signs and symptoms of respiratory depression, which, in the setting of neuraxially administered opioids, has been defined as reduced respiratory rate (<10 breaths per minute), decreased oxygen saturation (arterial oxygen saturation <90%), or hypercapnia/hypercarbia (arterial carbon dioxide tension <50 mm Hg).11 Patients and other coordinating prescribers must also understand that full disclosure of the use of additional central nervous system depressants is essential, and periodic urine drug screens may be desirable in some patients to confirm selfreports and rule out illicit substances.2 Ziconotide should be titrated slowly (eg, at 0.5 to 1.0 µg increments once during each week).4 The maximum recommended dose in the prescribing information is 19.2 µg/day, although the vast majority of patients will never approach this level and are commonly treated with less than 6.9 µg/day. There are no risks of granulomas or overdose causing respiratory depression, but patients should be monitored for neuropsychiatric reactions, such as hallucinations and serious cognitive impairment.4 Based on the clinical trials with ziconotide, patients should also be aware of dizziness, nausea, headache, and nystagmus as potential adverse effects.12 When first-line intrathecal agents are contraindicated, or prove ineffective or intolerable, supervising physicians can turn to medications on higher tiers in the new 2016 Polyanalgesic Consensus Conference (PACC) algorithms covering medication selection based on underlying disease and size of the painful area (see Chapter 3).4 It should be noted, however, that beyond Line 2 in each algorithm, the recommendations reflect clinical experience–based observations and expert consensus from the PACC committee (with an emphasis on safety), and there is a lack of published supportive clinical trials or case series.4 Additionally, caution is required when combining intrathecal medications in the pump delivery systems; although common practice, this is off-label and can introduce concerns regarding pump longevity and stability of the drug admixtures.13 The PACC guidelines provide maximum concentrations

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and daily dosages for a number of potential intrathecal agents, which should be considered as providers titrate up to improve analgesia or functional gains (Table 4).3

TABLE 4. Maximum Concentrations and Daily Doses of Intrathecal Agents Recommended by the PACC3 Drug Morphine Hydromorphone Fentanyl Sufentanil Bupivacaine Clonidine Ziconotide

Maximum Concentration 20 mg/mL 15 mg/mL 10 mg/mL 5 mg/mL 30 mg/mL 1000 mg/mL 100 mg/mL

Maximum Dose per Day 15 mg 10 mg 1000 mg 500 mg 10 mg 600 mg 19.2 mg

IDENTIFYING and ADDRESSING INTRATHECAL GRANULOMAS One potentially serious adverse outcome from intrathecal opioids is the formation of a granuloma.14 These noninfectious masses of fibroblasts, collagen, and a few inflammatory cells usually arise from the arachnoid layer of the meninges as a result of an inflammatory reaction near the site of the catheter tip, and are thought to be influenced by the local medication concentration.15 Among the medications recommended early in the PACC algorithms, all but ziconotide and fentanyl are granulomagenic agents.14 Case reports with baclofen and sufentanil have also been described, although the accuracy of those findings is somewhat unclear.14 The reported incidence of granulomas in the literature markedly variesâ&#x20AC;&#x201D;eg, 0.49% among patients implanted with an IDDS for pain management to 3% in a 20-year retrospective survey of patients treated with intrathecal morphine.14-16 Moreover, because these data rely on reports of complications that present with neurologic symptoms, the actual incidence of granuloma formation, including asymptomatic cases, may be even higher. The risk of granuloma

CHAPTER 4 Longitudinal Management of Patients on Intrathecal Therapy

development appears to correlate directly with the daily opioid dose, the rate of drug titration, and duration of intrathecal therapy.14,15 There is a growing body of evidence that suggests high concentration and sustained presence of medication surrounding the catheter tip, for whatever reason, may also increase the likelihood of a granuloma formation.14 A recently described experimental animal model suggests that bolus delivery may improve the local drug concentration around the catheter, limiting granuloma development.17 Patients presenting with a change in their neuralgic function, new neurologic complaint, or change/loss of analgesic efficacy should be critically evaluated for integrity of the device, medication dosing accuracy, progression of disease, and granuloma formation. A granuloma should be on the differential diagnosis if clinically patients present with new or altered sensory symptoms, new motor weakness, or changes in neurologic symptoms (eg, reflex testing) compared with baseline.2,14 Other signs and symptoms include new bowel or bladder dysfunction, the sudden need for large opioid dose escalations, or new radicular pain.14 As described, some of these symptoms appear as dose-related titration challenges, suggesting targeted evaluations are needed to distinguish among granulomas, progression of the painful disease, opioid tolerance, and such catheter-related complications as dislodgement or migration from intrathecal space, fracture, kink, or other occlusion.14 Outside of selecting alternative intrathecal medications, providers can decrease the risk of granulomas primarily by using the lowest effective concentration and dose of the intrathecal opioid.2,14 Additional evidence suggests alternative dosing strategies can be helpful.2,14 Although granulomas are relatively rare, the potential neurologic sequelae from spinal cord or nerve-root impingement can be devastating if they are misdiagnosed or not addressed. Therefore, all patients being treated with granulomagenic medications should be evaluated for signs and symptoms of granuloma via periodic physical exams that include neurologic testing.14 If a granuloma is suspected, the diagnosis should be confirmed using magnetic resonance imaging (MRI) with or without gadolinium around the location of the catheter (Figure 2); computed tomography myelogram can be substituted if MRI is not available or cost-prohibitive.14,18 If a granuloma is detected, the causative medication should be eliminated or at least greatly reduced, with care to avoid severe withdrawal symptoms, and a neurosurgeon can be consulted, as appropriate (see link to supplementary VIDEO 6 on page 35).14

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FIGURE 2. Granuloma MRI18 A postcontrast T1-weighted image shows an extradural intramedullary lesion affecting the spinal cord.

CONCLUDING COMMENTS on MULTIDISCIPLINARY LONG-TERM MANAGEMENT It is important to remember that chronic pain conditions for which intrathecal drug delivery is appropriate are almost universally best managed by a well-coordinated health care team. Intrathecal therapy initiation and ongoing management can significantly reduce health care costs compared with conventional pain management, especially when there is full elimination of systemic opioids.19 To achieve good multidisciplinary and patient-centric care, the supervising clinician will oversee pump refills and intrathecal medication adjustments after integrating information from various providers.2 The new iteration of the

CHAPTER 4 Longitudinal Management of Patients on Intrathecal Therapy

PACC guidelines highlight the need for provider education across health care settings and specialties to address the growing evidence pool related to intrathecal drug delivery for chronic pain and the expanding access.4 Protocols for patient and IDDS management should be built around collaborative team-based care, ongoing education for patients and caregivers, and appropriate use of psychosocial support services. A patient-focused approach at each stage in the continuum of intrathecal therapy—from initial evaluation to long-term drug delivery—can contribute to favorable outcomes among patients with severe refractory chronic pain (see link to supplementary VIDEO 7 on page 35).

REFERENCES 1. Pope JE, Deer TR, Bruel BM, Falowski S. Clinical uses of intrathecal therapy and its placement in the pain care algorithm. Pain Pract. 2016. [Epub ahead of print].

2. Prager J, Deer T, Levy R, et al. Best practices for intrathecal drug delivery for pain.

Neuromodulation. 2014;17(4):354-372.

3. Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15(5):436-464.

4. Deer TR, Hayek S, et al. The Polyanalgesic Consensus Conference (PACC) recommendations on intrathecal drug infusion systems: Best practices and guidelines Neuromodulation. 2016.

[In Press].

5. Duarte RV, Raphael JH, Sparkes E, Southall JL, LeMarchand K, Ashford RL. Long-term intrathecal drug administration for chronic nonmalignant pain. J Neurosurg Anesthesiol.

2012;24(1):63-70.

6. Hayek SM, Veizi E, Hanes M. Treatment-limiting complications of percutaneous spinal cord stimulator implants: A review of eight years of experience From an academic center database. Neuromodulation. 2015;18(7):603-608.

7. Hayek SM, Veizi IE, Narouze SN, Mekhail N. Age-dependent intrathecal opioid escalation in chronic noncancer pain patients. Pain Med. 2011;12(8):1179-1189.

8. Veizi IE, Hayek SM, Narouze S, Pope JE, Mekhail N. Combination of intrathecal opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer pain patients. Pain Med. 2011;12(10):1481-1489.

9. Coffey RJ, Owens ML, Broste SK, et al. Mortality associated with implantation and management of intrathecal opioid drug infusion systems to treat noncancer pain.

Anesthesiology. 2009;111(4):881-891.

10. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49.

11. American Society of Anesthesiologists. Practice guidelines for the prevention, detection, and management of respiratory depression associated with neuraxial opioid administration: an updated report by the American Society of Anesthesiologists Task Force on Neuraxial Opioids and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology.

2016;124(3):535-552.

12. Prialt (Ziconotide) Prescribing Information. Jazz Pharmaceuticals Inc. Palo Alto, CA; Revised 02/2013.

13. Shields DE, Aclan JB, Szatkowski AB. Chemical stability of admixtures containing ziconotide 25 mcg/mL and morphine sulfate 10 mg/mL or 20 mg/mL during simulated intrathecal administration. Int J Pharm Compd, 2008;12(6):553-557.

14. Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference—2012: consensus on diagnosis, detection, and treatment of catheter-tip granulomas (inflammatory masses).

Neuromodulation. 2012; 15(5): 483-95.

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30 15. Duarte RV, Raphael JH, Southall JL, Baker C, Ashford RL. Intrathecal granuloma formation as result of opioid delivery: systematic literature review of case reports and analysis against a control group. Clin Neurol Neurosurg. 2012;114(6):577-584.

16. Reig E, Abejรณn D. Continuous morphine infusion: a retrospective study of efficacy, safety, and demographic variables. Neuromodulation. 2009;12(2):122-129.

17. Eddinger KA, Rondon ES, Shubayev VI, et al. Intrathecal catheterization and drug delivery in guinea pigs: a small-animal model for morphine-evoked granuloma formation. Anesthesiology.

2016;125(2):378-394.

18. Varghese T, Bemporad J, Camici S, Mortazavi S. Recurrent intrathecal catheter-tip granuloma in a patient receiving high dose hydromorphone: a case report. Adv Biosci Biotechnol.

2013;4(1):147-152.

19. Hatheway JA, Caraway D, David G, et al. Systemic opioid elimination after implantation of an intrathecal drug delivery system significantly reduced health-care expenditures.

Neuromodulation. 2015;18(3):207-213.

In order to receive credit, participants must complete the preactivity questionnaire, posttest, and program evaluation at

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INTRATHECAL ANALGESICS

CLINICAL RESOURCE CENTER™

GUIDELINE UPDATES (IN PRESS) The Polyanalgesic Consensus Conference (PACC) recommendations on intrathecal drug infusion systems: best practices and guidelines.

Deer TR, Hayek S, et al. Neuromodulation. 2016. [In Press]

The Polyanalgesic Consensus Conference guidelines for intrathecal drug delivery infusion system trialing.

Deer TR, Hayek S, et al. Neuromodulation. 2016. [In Press].

GUIDELINES Polyanalgesic Consensus Conference—2012: Recommendations on Trialing for Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel Deer TR, et al. Neuromodulation. 2012;15(5):420-435. }}http://www.ncbi.nlm.nih.gov/pubmed/22494357

Polyanalgesic Consensus Conference—2012: Recommendations for the Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel Deer TR, et al. Neuromodulation. 2012;15(5):436-464. }}http://www.ncbi.nlm.nih.gov/pubmed/22748024 Download this activity and additional tools at

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Polyanalgesic Consensus Conference—2012: Recommendations to Reduce Morbidity and Mortality in Intrathecal Drug Delivery in the Treatment of Chronic Pain Deer TR, et al. Neuromodulation. 2012;15(5):467-482. }}http://www.ncbi.nlm.nih.gov/pubmed/22849581

Polyanalgesic Consensus Conference—2012: Consensus on Diagnosis, Detection, and Treatment of Catheter-Tip Granulomas (Inflammatory Masses) Deer TR, et al. Neuromodulation. 2012;15(5):483-495. }}http://www.ncbi.nlm.nih.gov/pubmed/22494332

Best Practices for Intrathecal Drug Delivery for Pain Prager J, et al. Neuromodulation. 2014;17(4):354-372. }}http://www.ncbi.nlm.nih.gov/pubmed/24446870

SUGGESTED READING Mortality Associated With Implantation and Management of Intrathecal Opioid Drug Infusion Systems to Treat Noncancer Pain Coffey RJ, et al. Anesthesiology. 2009;111(4):881-891. }}http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1932483

Intrathecal Ziconotide and Opioid Combination Therapy for Noncancer Pain: an Observational Study Deer TR, et al. Pain Physician. 2009;12(4):E291-E296. }}http://www.ncbi.nlm.nih.gov/pubmed/19668287

Download this activity and additional tools at

Intrathecal Analgesics CLINICAL RESOURCE CENTERâ&#x201E;˘

A Predictive Model for Intrathecal Opioid Dose Escalation for Chronic Non-Cancer Pain Duarte RV, et al. Pain Physician. 2012;15(5):363-369. }}http://www.ncbi.nlm.nih.gov/pubmed/22996848

Care and management of intrathecal and epidural catheters.

Du Pen A. J Infus Nurs. 2005;28(6):377-381. }}www.ncbi.nlm.nih.gov/pubmed/16304495

Prospective Study of 3-Year Follow-up of Low-Dose Intrathecal Opioids in the Management of Chronic Nonmalignant Pain Hamza M, et al. Pain Med. 2012;13(10):1304-1313. }}http://www.ncbi.nlm.nih.gov/pubmed/22845187

Androgen Deficiency in Long-term Intrathecal Opioid Administration Kim CH, et al. Pain Physician. 2014;17(4):E543-E548. }}http://www.ncbi.nlm.nih.gov/pubmed/25054405

Practical Considerations and Patient Selection for Intrathecal Drug Delivery in the Management of Chronic Pain Saulino M, et al. J Pain Res. 2014;7:627-638. }}http://www.dovepress.com/practical-considerations-and-patient-selectionfor-intrathecal-drug-de-peer-reviewed-article-JPR

Safety and Efficacy of Intrathecal Ziconotide in the Management of Severe Chronic Pain Smith HS, Deer TR. Ther Clin Risk Manag. 2009;5(3):521-534. }}http://www.dovepress.com/safety-and-efficacy-of-intrathecal-ziconotidein-the-management-of-sev-peer-reviewed-article-TCRM

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Long-term Intrathecal Ziconotide for Chronic Pain: an Open-Label Study Webster LR, et al. J Pain Symptom Manage. 2009;37(3):363-372. }}http://www.sciencedirect.com/science/article/pii/S088539240800376X

Clinical Accuracy and Safety Using the SynchroMed II Intrathecal Drug Infusion Pump Wesemann K, et al. Reg Anesth Pain Med. 2014;39(4):341-346. }}http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218763/pdf/aap-39-341.pdf

Programmable Intrathecal Pumps for the Management of Chronic Pain: Recommendations for Improved Efficiency Wilkes D. J Pain Res. 2014;7:571-577. }}http://www.dovepress.com/programmable-intrathecal-pumps-for-themanagement-of-chronic-pain-reco-peer-reviewed-article-JPR

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INTRATHECAL ANALGESICS

SUPPLEMENTAL VIDEO LIBRARY VIDEO 1. Overview of Chronic Pain Pathophysiologic Mechanisms Timothy R. Deer, MD, DABPM }}www.exchangecme.com/project/itvideos

VIDEO 2. FDA-Approved Intrathecal Analgesics Timothy R. Deer, MD, DABPM }}www.exchangecme.com/project/itvideos

VIDEO 3. Psychological Evaluations of Candidates for Intrathecal Drug Delivery Jason E. Pope, MD, DABPM, FIPP }}www.exchangecme.com/project/itvideos

VIDEO 4. Trialing With Intrathecal Analgesics Timothy R. Deer, MD, DABPM }}www.exchangecme.com/project/itvideos

VIDEO 5. Intrathecal Dosing Strategies with Ziconotide Timothy R. Deer, MD, DABPM }}www.exchangecme.com/project/itvideos

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VIDEO 6. Addressing Granulomas Associated With Intrathecal Drug Delivery Jason E. Pope, MD, DABPM, FIPP }}www.exchangecme.com/project/itvideos

VIDEO 7. Patient Perspectives on Intrathecal Therapy for Chronic Pain }}www.exchangecme.com/project/itvideos

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Please visit the CLINICAL RESOURCE CENTER™ for additional information and resources

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