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Inrathecal Drug Delivery What have we learned ?. David L. Caraway, M.D., Ph.D. CEO, Medical Director Center for Pain Relief, Tri-State St. Mary’s Regional Medical Center Huntington, WV. Disclosure. I make my living providing medical services to patients

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Inrathecal drug delivery what have we learned
Inrathecal Drug DeliveryWhat have we learned?

David L. Caraway, M.D., Ph.D.

CEO, Medical Director

Center for Pain Relief, Tri-State

St. Mary’s Regional Medical Center

Huntington, WV


Disclosure
Disclosure

I make my living providing medical services to patients

Industry: Consulting, speaking, research

Medtronic, Inc., Boston Scientific Inc., Spinal Modulation, Inc., Vertos Inc.

Leadership

NANS

ASIPP


Intrathecal pumps
Intrathecal Pumps

Intrathecal drug delivery systems are not a “therapy.”

They are a delivery system for a therapy.

Opioids are the most commonly used intrathecal therapy.

Three questions to explore:

Is there any good evidence that opioids - regardless of the route of delivery – are safe and effective?

What are the advantages and disadvantages of the intrathecal route of delivery?

How can we improve outcomes?


Short term efficacy

Clear efficacy in multiple RCT’s (up to 8 months) demonstrate improvement in pain

No evidence to support dosing of higher than 180 mg morphine equivalent per day

Long term efficacy

No PCRTs for longer than 8 months

None for pump vs oral

Overall evidence is weak

Studies mostly look at VAS, little evidence of improved function

Is Opioid Therapy Effective?

Ballantyne JC, Mao J.

Opioid therapy for chronic pain. N Engl J Med November 13, 2003;349:1943-53


Dose escalation
Dose Escalation

Tolerance

Physiological

Opioid Induced Hyperalgesia

Solid evidence in animal models

Emerging clinical data

Disease progression

Perception

Goals of therapy

Comorbid psychological/behavioral pathology


Side effects

Dysphoria, constipation, urinary retention, somnolence, cognitive changes

Immune and hormonal function

Testosterone, estrogen, cortisol suppression, decreased libido, infertility (1)

Addiction

Social, psychological, physical and financial consequences

Is Opioid Therapy Safe?

1. Lee C, et al. Low serum cortisol associated with opioid use: Case report and review of the literature. Endocrinologist 2002;12:5-8.


U.S. with 4.6% of world’s population

  • Produces 80% of Lawyers

  • Consumes almost 30% of Global Oil supply (CIA)

  • Consumes 80% of Global Opioid supply Patricia Good, Divisionof Drug Diversion Control, DEA

  • Consumes 99% of Global Hydrocodone supply JAMA, 2007

  • Fatal opioid overdoses tripled to nearly 14,000 deaths from 1999 to 2006 (CDC)

  • 2008 alone 305,885 ER visits related to opioids

7


Intrathecal opioids
Intrathecal Opioids

Advantages:

Achieves steady-state, around the clock dosing

Reduced side effects (1), Use of intermittent dosing to reduce tolerance

Intrathecal Adjuvants

Compliance

Eliminate systemic opioids

Can provide patient activated rescue dosing

Reduction in longitudinal costs, diversion

1. Smith, T. J Clin Oncology, 2002


Intrathecal opioids1
Intrathecal Opioids

Disadvantages:

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

Practice of David Caraway, MD. St. Mary’s Regional Medical Center

Huntington, WV.


Intrathecal opioids2
Intrathecal Opioids

Requires same strategies as systemic delivery

Early titration to achieve analgesia and goals of therapy

Careful consideration of dose increases

Maintain moderate doses

Monitor for side effects, efficacy

IT adjuvants

Physician remains in control of dosing

Practice of David Caraway, MD. St. Mary’s Regional Medical Center

Huntington, WV.


Quality of pain
QUALITY OF PAIN

  • Easy first choices for PUMP

    • Cancer

    • Diffuse pain, eg Rh. Arthritis

    • Elderly axial spinal pain

    • Good analgesia with systemic opioids but intolerable side effects

Practice of David Caraway, MD. St. Mary’s Regional Medical Center

Huntington, WV.


Quality of pain1
QUALITY OF PAIN

  • Difficult choices for PUMP

    Minimal baseline pain with intermittent severe pain (PCA?)

    Poorly defined etiology

    Poor compliance to previous therapies

    Poor response to escalating doses of opioids

    Young age

Practice of David Caraway, MD. St. Mary’s Regional Medical Center

Huntington, WV.


Goals of therapy
Goals of Therapy

Create a treatment plan with specific goals eg:

Manageable constipation

Gardening, shopping, holding grandchildren

Increased range of motion, ambulation

Reduced hospital, ER visits


Psychological evaluation
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

Is this someone you are willing to “marry”?

Major active psychosis, current drug addiction, some personality disorders, cognitive deficits, progressive organic brain disorders, suicidal, homicidal behavior


Dr. Caraway

Know When

To Quit


And…

When never to start!


What are the goals of trialing
What are the goals of trialing?

To increase the odds that the goals of therapy are met


Continuous vs single shot and intermittent bolus
Continuous vs single shot and intermittent bolus

Consistent with standard of care, however:

Titration

Interpreting adverse events

Multiple procedures

Does not model steady-state characteristics of intended therapy


Continuous epidural vs continuous intrathecal screening
Continuous Epidural vs Continuous Intrathecal Screening

Advantages Disadvantages

Intrathecal More closely approximates Increased risk of:l

pharmacodynamics of PDPH system to be implanted CSF leak

Does not require epidural Serious infection

space (fusion, mets) Overdose

Neurological complication

during placement

Epidural May allow outpatient Less predictive? Management Risk of migration to SAS

Extended trials Increased systemic uptake

Less risks


Use of systemic pain medications with idds clbp
Use of Systemic Pain Medications with IDDS: CLBP

Key Findings: While at 12 months 42% decreased or discontinued systemic opioids 58% had no change or increased

n=136

Deer T, Chapple I, Classen A, et al., Intrathecal drug delivery for treatment of chronic low back pain: report from the National Outcomes Registry for Low Back Pain. Pain Med. 2004;5(1):6-13.


Are supplemental systemic opioids necessary
Are supplemental systemic opioids necessary?

Methylnaltrexone data in treatment of opioid induced constipation (OIC)1

Blockade of peripheral mu receptors does not:

change pain scores

induce withdrawal

increase opioid requirements

1. Slatkin N, Thomas J, Lipman AG. Methylnaltrexone for treatment of opiod-induced constipation in advanced illness patients. J Support Oncol. 2009 Jan-Feb;7(1):39-46


Do we need oral opioids after pump implant
Do we need oral opioids after pump implant?

Vertebral Compression Fractures, N=24

Failed systemic opioids

Compare before implant to one year follow up

VAS, DW, ambulation, PHS

Results

None required systemic opioids

All showed significant improvement and reduced side effects

Neuromodulation

Volume 10 Issue 2 Page 167-176, April 2007


Intrathecal opioid safety
Intrathecal Opioid Safety

“Mortality associated with implantation and management of intrathecal opioid drug infusion systems to treat noncancer pain.” Anesthesiology 2009

“…higher mortality than after spinal cord stimulation implants or after lumbar diskectomy in community hospitals.”

Is this an appropriate comparator?

Coffey R, Owens M, Broste S, et al. Mortality Associated with Implantation and Management of Intrathecal Opioid Drug Infusion Systems to Treat Noncancer Pain. Anasthesiology. 2009; 111:881-91


Intrathecal opioid safety1
Intrathecal Opioid Safety

Excess morbidity/mortality not due to surgical complications

No reports of device malfunctioning to cause overdose

Respiratory arrest caused or contributed to cause of death in all cases

Management issues

Continued self-administered medications

Lack of monitoring when initiating dose

Coffey R, Owens M, Broste S, et al. Mortality Associated with Implantation and Management of Intrathecal Opioid Drug Infusion Systems to Treat Noncancer Pain. Anasthesiology. 2009; 111:881-91


Compounding and polypharmacy
Compounding and polypharmacy

“…clinical reports of inflammatory mass lesions and direct spinal cord toxicity that appear to have been caused by compounded and/or impure drugs, or the long-term administration of drug formulations not specifically tested and approved for chronic intrathecal use”

  • ↵Jones TF, Feler CA, Simmons BP, et al. Neurological complications including paralysis after a medication error involving implanted intrathecal catheters. ;:–6.

  • Levin GZ, Tabor DR. Paraplegia secondary to progressive necrotic myelopathy in a patient with an implantable morphine pump. ;:–6.

  • Knox S, Atkinson RP, Stephens R, et al. Myelopathy as a complication of intrathecal drug infusion systems. ;:–7.


Polyanalgesia consensus conference 2007
Polyanalgesia Consensus Conference 2007

Neuromodulation Vol 10 Issue 4 page 300 – 328 October 2007


Recommended maximum intrathecal dosages and concentrations
Recommended Maximum Intrathecal Dosages and Concentrations*

* These represent general recommendations and are dependent upon the specific patient and the clinical experience of the physician and thus, maximum dosage and/or concentrations may vary from these.

Neuromodulation Vol 10 Issue 4 page 300 – 328 October 2007



An approach
An Approach

Continuous infusion trial

Consider an overnight observation for implant

Start with lower than anticipated analgesic dose

Discontinue systemic opioids

Titrate to achieve goals within 6- 8 weeks of initiation of opioid therapy

20 – 30% dose increases

Document attainment of goals


An approach1
An Approach

Failure to achieve moderate stable dose warrants re-examination of treatment plan

Trial of IT adjuvant while holding opioid dose steady

Episodic pain and “rescue dosing”

Reduction or discontinuation

Surveillance

Progression of disease

Complications eg: IG, catheter failure


Dosing
Dosing

“Micro Dosing”

Discontinuation of oral opioids prior to trial

Initiate opioid at low dose

Maybe useful for highly opioid tolerant patients


Where to place the catheter tip

Drug target

Posterior for pain drugs

Several spinal segments sensitized

Anatomical barriers to distribution

Dorsal septum

Dentate ligaments

CSF effects

Thoracic higher CSF velocities

Lumbar less CSF movement

Where to Place the Catheter Tip?

Atlas of Human Anatomy 3rd ed.

By Frank H. Netter, M.D.ICON Learning Systems, Tereboro, NJ


Drug targets chronic pain

Afferents enter into local dorsal horn and project rostral / caudal 4-6 segments

Normal - Modest drive on neurons in distal segments

Sensitization > Recruitment of adjacent afferent neurons and spinal segments

Result> Often not a single pain or spasticity generator

Ideally the drug would spread out over several vertebral segments.

Drug targets: Chronic Pain

Hydrophilic

Drug

Cervical

Desired

profile

Thoracic

Lipophilic

Drug

Lumbar

_

_

_

_

_

Drug Concentration

Sacrum


Anatomy compartmentalization
Anatomy: Compartmentalization caudal 4-6 segments

Dura

Arachnoid

Dorsal Septum

Nerve Roots

Dentate Ligaments

Davson & Segal, Physiology of the CSF and Blood-Brain Barriers, 1996


Csf flow
CSF Flow caudal 4-6 segments

Does NOT simply flow rostral to caudal

Does NOT flow down posterior and up anterior surface

Protein, ionic and drug concentrations DO vary along spine and CSF – nonhomogeneous

Atlas of Human Anatomy 3rd ed.

By Frank H. Netter, M.D.ICON Learning Systems, Tereboro, NJ


Csf oscillates with cardiac cycle
CSF Oscillates with Cardiac Cycle caudal 4-6 segments

Davson & Segal, Physiology of the CSF and Blood-Brain Barriers, 1996


Visualization of csf flow
Visualization of CSF Flow caudal 4-6 segments

Cine MRI

CSF oscillates more at high (rostral) vertebral levels compared to caudal levels

Complex flow patterns

C2

T1

T6

T10

T12

L2

Unpublished data; Hai Ying Liu, University of Minnesota


Spinal drug distribution cm bernards
Spinal Drug Distribution: CM Bernards caudal 4-6 segments

Posterior T12 catheter

8 Hour infusion

Infusion rates: 21ml/hr or 1ml/hr

3H-bupivacaine

14C-baclofen

Baclofen – more hydrophilic;bupivicaine – more lipophilic

CSF - Microdialysis probes

Anterior and posterior

T12 (0 cm), 5 cm caudal, 5 and 10 cm cephalad, cerebral (parietal lobe)

Tissue - Spinal cord sections

1 cm segments

Anterior and posterior

Bernards CM, Anesthesiology, 105, Jul 2006, 169-178.


CSF Bupivacaine Concentrations vs Flow Rate caudal 4-6 segments

.

  • 21 ml/hr: 120-240 min to steady state (posterior vs anterior)

  • Regardless of flow – large difference in posterior vs anterior concentrations

  • High flow – drug distributes 5 cm from tip with less difference between posterior anterior

Data also published in Bernards C.M. Anesthesiology. 2006 Jul;105(1):169-78.


Spinal tissue drug levels
Spinal Tissue Drug Levels caudal 4-6 segments

Cephalad

N=8

  • Low flow – narrow longitudinal distribution pattern vs. high flow – greater distribution (yellow bars)

  • Low flow – posterior to anterior ratio is large vs high flow narrow (blue arrows)

Bernards CM, Anesthesiology, 105, Jul 2006, 169-178.


Lack of distribution with slow infusion
Lack of Distribution with Slow Infusion caudal 4-6 segments

Posterior catheter

Methylene Blue

20 µl/hour

8 hours

No anterior distribution

Catheter Tip

1 cm

Bernards CM, Anesthesiology, 105, Jul 2006, 169-178.

Rostral


Chronic infusion in ambulatory pigs
Chronic Infusion in Ambulatory Pigs caudal 4-6 segments

Does duration of infusion and normal movement and position changes make a difference in spinal drug distribution?

  • 14-day infusion of morphine

  • (1 mg/mL) at 20 μl/h

  • Rostral distribution ~ caudal distribution

  • Catheter tip ~ 9000 ng/g

  • vs. 10 cm 500 ng/g ~ 6% of tip levels

  • Qualitatively similar to 8-hr model:

  • Drug is highly concentrated near catheter tip (log scale)

  • Drug levels fall off rapidly with distance from tip

  • 8 hours vs 14 days

  • Drug levels are detectable 15 cm beyond catheter tip in spinal tissue after 14 days

9000

500

Flack SH, Anderson CM, Bernards CM: Anesthesia and Analgesia (In Press) 2010.


Normalized: caudal 4-6 segmentsSlow vs. Fast Infusion vs. Bolus – Tissue Content

Data published also in: Bernards C.M. Anesthesiology. 2006 Jul;105(1):169-78.


Effect of it bolus volume on drug efficacy
Effect of IT Bolus Volume caudal 4-6 segmentson Drug Efficacy

Rat hind paw on heat source; measure latency of withdrawal

Bolus equal dose of morphine as

High volume / Low concentration (A)

Low volume / High concentration (B)

Place intrathecal catheter with tip at L6 (sciatic nerve entry zone)

Low volume / High concentration had greatest effect

Move catheter tip from L6

High volume /Low concentration had greatest effect

A

B

_

_

_

_

_

Drug Concentration

Frank H. Netter, M.D. et al., Nervous System vol 1, (1972), pp.49

Tony Yaksh, UCSD, unpublished data


Conclusions
Conclusions caudal 4-6 segments

CSF flow patterns vary along spinal canal

CSF volume and local anatomy may be important

CSF oscillations due to cardiac cycle

Limited tissue distribution with slow infusion

Flexible dosing using high-flow intermittent boluses may provide improved drug distribution


Summary clinical considerations
Summary: Clinical Considerations caudal 4-6 segments

  • Catheter tip near level of pathology

  • Use higher flow rates and lower concentrations

  • Bolus dosing

  • Eliminate or reduce systemic opioids

  • Failure to achieve moderate stable dose warrants re- examination of treatment plan

    • Trial of adjuvant medications

    • Episodic pain and “bolus dosing”

    • Reduction or discontinuation

    • Surveillance

      • Progression of disease

      • Complications eg: IG, catheter failure



The end
THE END caudal 4-6 segments

THANK

YOU


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