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Pain Management: Interventional Strategies 101

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Objectives

¨  Pharmacist ¤  Identify patients that may benefit from interventional management

¤  Evaluate the role of intrathecal pumps and nerve blocks for pain management

¤  Examine the considerations required when a patient with an intrathecal pump is hospitalized.

¨  Pharmacy technician ¤  Recognize agents that can be utilized for a nerve block ¤  List drugs used to prepare intrathecal nerve blocks

¤  Describe the preparation of a intrathecal pain pumps

Pain Management: Why Care?

¨  Pain is one of the most common reasons for seeking care

¨  In the United States, 20 to 30% of the general population experience chronic or recurring pain (3). ¤ Approximately, 2/3 of these people have had pain for

more than 5 years (4).

¨  67% of patients with metastatic cancer report pain (5)

¨  “War on Opioids”

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Pain Assessment Is Complex

¨  No single approach to pain assessment is appropriate for all patients or in all settings.

¨  Pain is subjective, so no satisfactory objective measures of pain exist.

¨  Pain is multidimensional, the clinician must consider multiple aspects (sensory, affective, cognitive) of the pain experience.

¨  Pain assessments may vary with respect to purpose, setting, patient population.

Pain History

¨  Significant previous and/or ongoing instances of pain and its effect on the patient. ¨  Previously used methods for pain control that have been either helpful or unhelpful. ¨  The patient's attitude toward use of opioids or other medications, including any history of

substance abuse. ¨  The patient's typical coping response for stress or pain, including the presence or absence of

psychiatric disorders such as depression, anxiety, or psychosis. ¨  Family expectations and beliefs concerning pain, stress, and postoperative course. ¨  Ways the patient describes or shows pain. ¨  The patient's knowledge of, expectations about, and preferences for pain management methods

and for receiving information about pain management.

Acute vs. chronic pain

¨  Acute pain might be mild and last just a moment, or it might be severe and last for weeks or months. ¤  In most cases, acute pain does not last longer than six

months ¤ Underlying cause of pain has been treated or has

healed.

¨  Chronic pain persists despite the fact that the injury has healed. Pain signals remain active in the nervous system for weeks, months, or years.

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Pathophysiology of Pain

K+ = Potassium; PG = Prostaglandins; H+ = Hydrogen ions; BK = bradykinin; H= Histamine; SP= Substance P; 5HT = Serotonin

Harrison’s Principles of Internal Medicine, 2008

Noxius Stimuli Activate Pain Pathway 8

Impulse transmitted to

Peripheral Nerve

Synapse with Spinothalamic

tract

Travels to anterior

cingulate, frontal insular,

& somatosensory

cortex in thalamus

Activation of spinal pain transmission

Harrison’s Principles of Internal Medicine, 2008

Management Modalities

¨  Non-pharmacological ¤ Acupuncture, massage, aromatherapy, physical therapy,

etc.

¨  Pharmacological ¤ Topical, transdermal ¤ Oral, rectal ¤  Intramuscular, intravenous

¨  Interventional ¤ Procedure +/- pharmacologic

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Interventional Management

¨  Surgery ¨  Radiation ¨  Radiofrequency ablation

¤  Electrical Stimulation directed towards a tumor ¨  Peripheral Nerve Blocks

¨  Intraspinal drug therapy ¤  Relieve pain by instilling small doses of morphine or

other drugs directly to cerebrospinal fluid

Brogan S, Junkins S. Interventional therapies for the management of cancer pain. J Support Oncol. 2010 Mar-Apr;8(2):52-9.

Neuraxial Pain Management

¨  Encompasses both spinal and epidural anesthesia ¨  performed as the sole anesthetic (with or without

sedation) ¨  combined with general anesthesia to decrease

anesthetic requirements ¨  postoperative analgesia

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Nerve Blocks: Indications

¨  No specific indications for nerve blocks ¨  Typically used to avoid the effects of alternative

methods ¤ Side effects and complications of general anesthesia ¤ Minimizing opioid use

¨  Widely-used for surgical anesthesia ¨  Post-operative pain management ¨  Chronic pain management

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Common Locations for Nerve Blocks 13

Sympathetic Nerve Block

¨  sympathetic nerves come together outside your spine area in thick networks of nerves called ganglions.

¨  Targets a series of nerves that spread out from your spine to your body to help control several involuntary body functions ¤ Blood flow, digestion, and sweating

¨  stellate ganglion block: pain in the upper part of your body.

¨  Lumbar sympathetic block: pain in the lower part of your body, a ganglion near the lower spine

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Facet Joint Block

¨  Facet joints are the small joints located between each vertebra that provide the spine with both stability and flexibility

¨  Facet syndrome occurs when one or more of these joints become inflamed or irritated

¨  Combines a local anesthetic and a corticosteroid anti-inflammatory medication

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Splanchnic/Celiac/Hypogastric Plexus Blocks

¨  Dense cluster of nerve cells and supporting tissue, located behind the stomach, in the region of the celiac artery just below the diaphragm.

¨  Nerve signals to the majority of abdominal organs flow through the celiac plexus and the splanchnic nerves. ¤  Pancreas, liver, gallbladder, stomach, small intestine, and the parts of

the colon.

¨  Abdominal pain that may be caused by irritation, compression or entrapment of the nerve bundles within various abdominal organs ¤  Tumor invasion, fibrosis, or chronic inflammation

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Splanchnic/Celiac/Hypogastric Plexus Blocks

¨  A local anesthetic, steroid or ethyl-alcohol administered ¨  The use of alcohol, called a neurolytic block, because it

destroys the nerves, can provide sustained pain relief in conditions where medications alone are not effective.

¨  A trial block is initially done with local anesthetic as a test to ensure there is pain relief. If substantial pain relief is acquired, a neurolytic block is performed.

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Regional Anesthesia: Adverse Effects

¨  Toxicity of local anesthetics (with epidural techniques)

¨  Transient or chronic paresthesia ¨  Nerve damage ¨  Intra-arterial injection, seizures, or cardiac arrest ¨  Block failure and the need to supplement or convert

to general anesthesia ¨  Intra-arterial injection, seizures, or cardiac arrest ¨  Infection

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Pharmacologic Agents

¨  Local Anesthetics

¨  Opiates ¤  Opioids can enhance analgesia, with the degree of side effects largely

related to lipid solubility. n  Morphine (hydrophilic/lipophobic) injected epidurally stay in place or spread

rostrally

n  Fentanyl (hydrophobic/liphophilic) rapidly absorbed

¨  Adjuncts ¤  Epinephrine (1:200,000 i.e., 5 ucg/mL) can prolong an epidural,

especially if chlorprocaine or lidocaine is used ¤  Sodium bicarbonate favors the non-ionized form of local anesthetics and

promotes more rapid onset of epidural anesthesia.

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Local Anesthetics 20

Intrathecal Pain Management 21

Background

¨  Used in the control of pain and spasticity ¨  Allows for reduced medication doses that can

decrease the side effects typically associated with oral or parenteral drug delivery

¨  Data for pain relief, adverse effect reduction, and cost-effectiveness with cancer pain control are compelling

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Implantable Drug Delivery Systems (IDDS)

http://www.spinesurgeon.co.uk/media/intrathecal-pump-implant.jpg

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Implantable Drug Delivery Systems (IDDS)

Potential Candidates for IDDS

¨  Chronic pain ¨  Recalcitrant pain despite aggressive titration on

standard treatment modalities ¨  Patients unable to tolerate adverse effects of

standard treatment modalities

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Where is therapy administered?

http://www.mayfieldclinic.com/PE-PUMP.htm

IDDS Trial Period

¨  Screening period which determines whether a patient will benefit from an IDDS ¤ Determine the response ¤ Prevention of ineffective pump

n About 95% of patients have a successful treatment of pain

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Knight et al. Implantable intrathecal pumps for chronic pain: highlights and updates. Croat Med J. 2007

IDDS Trial Procedure 28

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Intrathecal Pain Pumps: Benefits

¨  Provides effective pain control for patients who have failed other treatment modalities

¨  Less Systemic Side Effects

Ghafoor, Intrathecal drug therapy for long-term pain management. Am J Health-Syst Pharm 2007

-  Postoperative subarachnoid hemorrhage -  Back Pain, Loss of sensation, Lower extremity weakness

-  Catheter tip inflammatory masses -  Loss of drug effect with long-term therapy -  New-onset radicular pain & spinal cord neurologic

deficits

-  Invasive Infections: Bacterial Meningitis

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Intrathecal Pain Pumps: Adverse Effects

IDDS Medications

Types of Medications Used

Opioids Morphine Hydromorphone

Fentanyl Local Anesthetic Bupivacaine

Adjunct Medications Ziconotide Clonidine Baclofen

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Agents Utilized for IDDS

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Recommended Starting Doses for Intrathecal Therapy

Comparison of Opioid Characteristics

Characteristic Morphine Sulfate

Hydromoprhone Hydrochloride

Fentanyl

Solubility Hydrophilic Hydrophilic Lipophilic

Degree of spread in cerebrospinal fluid

High Intermediate Low

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Ghafoor, Intrathecal drug therapy for long-term pain management. Am J Health-Syst Pharm 2007

Comparison of Opioid Equianalgesic Potency

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Equianalgesic Potency (mg)

Morphine Sulfate

Hydromoprhone Hydrochloride

Fentanyl

Oral 300 60 2

Parenteral 100 20 1

Epidural 10 2 0.1

Intrathecal 1 0.25 0.01

Ghafoor, Intrathecal drug therapy for long-term pain management. Am J Health-Syst Pharm 2007

Evidence Supporting Use IT Opioids in Non-Cancer Pain

¨  Morphine effeciacy has been documented in case studies, retrospective studies, and prospective studies since 1980 ¤  Efficacy Stuides documented

at least a 30- 50% improvement in Visual analog scores

¨  Hydromorphone IT infusions offer therapeutic alternative to IT morphine for patients with intractable pain not alleviated by morphine

¨  Retrospective studies and case reports have documented improvement in pain scores with minimum increase in adverse side effects

Morphine Hydromorphone

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Njee et al. Neuromodulation 2004;7:249–259

Local Anesthetics - Bupivacaine

¨  Co-administration of bupivacaine and morphine has been shown to provide synergistic pain relief, resulting in reduction in morphine dosage

¨  Common Adverse Effects: ¤ Parasthesia, motor and sensory blockade, arterial

hypotension, diarrhea, and urinary retention

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Adjunct Analgesic: Ziconotide

¨  Only administered intrathecally to maximize antinoceptive effectiveness and minimize sympatholysis

¨  Patients with chronic pain received an average reduction of 43% in their Visual Analog Scale of Pain Intensity (VASPI) score.

¨  Common Adverse Effects: ¤ Dizziness, nystagmus, confusion, abnormal gait,

somnolence

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Adjunct Analgesic: Clonidine

¨  Antinoceptive effects of clonidine are mediated via inhibitory interactions with pre-synaptic and postsynaptic afferent fibers in the dorsal horn of the spinal cord

¨  Combination of clonidine and morphine has been shown to be more effective than morphine alone

¨  Common Adverse Effects: ¤  Sedation, hypotension, dry mouth, and bradycardia

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Adjunct Analgesic: Baclofen

¨  Used to treat spinal cord spasticity ¨  Combination therapy with an opioid has been

studied in chronic nociceptive or sympathetic pain syndromes

¨  Common Adverse Effects: ¤ Weakness, hypotonia, sedation, constipation,

respiratory depression

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PUBLISHED LITERATURE REVIEW

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EFFICACY RESULTS AFTER 1 MONTH OF EPIDURAL MORPHINE INFUSION

Measure Baseline At One Month P

Avg Oral Equalanalgesic Morphine Use

77.7± 19.1 mg/day 16.1 ± 3.6 mg/day <0.001

Pain Analog Scale 8.6 ± 0.3 3.8 ± 0.4 <0.001

Hassenbusch, J Neurosurg 73: 405-409, 1990

STUDY DESIGN Observational Study

PATIENT POPULATION

69 Patients Enrolled with 41 being studied

OBJECTIVE • Demonstrate that the epidural route is effective with minimal complications • Screening with temporary epidural catheter infusions results in high rate of subsequent pain relief

COMMON COMPLICATIONS & SIDE EFFECTS EXPERIENCED INCIDENCE

Superficial Wound Infections 3

Skin necrosis 1

Catheter Migration 4

Voiding Disturabances 3

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Randomized Clinical Trial of an Implantable Drug Delivery System Compared with

Comprehensive Medical Management for Refractory Cancer Pain: Impact on Pain, Drug-

Related Toxicity, and Survival

J Clin Oncology. 2002 Oct; 20(19):4040-4049

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The Cancer Pain Trial J Clin Oncology. 2002 Oct; 20(19):4040-4049

Purpose Evaluate the clinical success of intraspinal IDDS in patients with intractable cancer-associated pain.

Design Prospective, Multicenter, Randomized, Concealed, Clinical Trial

Objectives

Primary Objective: Evaluate the clinical success of each study arm at 4weeks •  At least 20% reduction in Pain using Visual Analog Scores (VAS) •  Equal pain scores with at least 20% reduction in symptom control based on National Cancer Institute’s common toxicity criteria Secondary Objective: •  Differences in individual drug toxicities measured using the National Cancer Institute Common Toxicity Criteria (NCI CTC)

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Patient Selection

Patient Inclusion Criteria

•  Documented Cancer •  VAS pain scores consistently ≥5/10 •  Opiate doses ≥ 200 mg of oral morphine or equivalent •  Opiate doses ≤ 200 mg with unacceptable side effects •  Life expectancy ≥ 3 months

Study Design

•  Patients were Randomized to CMM or IDDS •  Data Recorded: Every other week (2-12 weeks) then Monthly until 6 months •  Data collected at visits included

•  Comparison of VAS •  Composite Drug Toxicity score

•  Sum of 15 individual drug toxicity scores (0-4) Of Note: Patients assigned to intrathecal morphine group needed to undergo a trial of intraspinal morphine

202 Randomized

99 CMM

15 Died 6 Withdrew consent

1 Lost to Follow-Up

5 Implanted

70 Not Implanted

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4- week Follow- Up

101 IDDS

8 Died 8 Withdrew Consent

12 Missed Visits

22 Not Implanted

51 Implanted

73

4-week Follow-Up

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Results: Baseline Characteristics of Patients

Characteristic CMM Group (n = 99)

IDDS Group (n = 101)

Age, years 57.8 ± 13.7 56.2 ± 13.2

Type of Pain, %

Neuropathic 14.3 12.9

Nociceptive 25.5 25.7

Mixed 60.2 61.4

Baseline Medication Use, %

Opioids alone 39.8 41.6

Nonopiod adjunctive alone 2.0 2.0

Both 58.2 56.4

Morphine Oral Equivalent dose, mg/d 280 260

Baseline VAS 7.57 ± 1.97 7.44 ± 1.97

Baseline Composite Toxicity Score 6.65 ± 5.58 6.95 ± 4.91

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Reduction in Pain and Drug Toxicity from Baseline to 4 Weeks CMM Group IDDS Group

Variabe n Baseline 4 Weeks n Baseline 4 Weeks P

Median Daily MOEDs

272 mg 290 mg 250 mg 50 mg

VAS Pain Score 72 7.81±1.63 -3.05 ± 3.16 71 7.57 ± 1.79 -3.90 ± 3.42 .055

Common Toxicity Criteria

75 6.36 ± 5.65 -1.09 ± 5.57 73 7.22 ± 5.00 -3.63 ± 5.43 .004

Results: VAS and Toxicity Scores

MOEDs = Morphine Oral Equivalent Doses

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Results: Clinical Success Results

Clinical Success and Failure

CMM Group IDDS Group

Criteria n % n % P

VAS Pain Reduced by ≥ 20% regardless of increseased toxicity, or

equal VAS with ≥ 20% reduction in toxicity

51/72 70.8 60/71 84.5 .05

Both pain and toxicity reduced by ≥ 20% 27/72 37.5 41/71 57.5 .02

Neither pain nor toxicity reduced by ≥ 20% 17/72 23.6 8/71 11.3 .05

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Results: Drug Side Effects

KEY

██ CMM ██ IDDS

Results: Adverse Events seen in IDDS

Event CMM N= 98

IDDS N=101

Total

IDDS-related SAE 5 22 27

Lumbar Site _ 5 5

Catheter Problems _ 5 5

Infections 1 1 2

Hematoma _ 2 2

Inflammation _ 2 2

Wound dehiscence _ 2 2

CSF leak _ 1 1

Nerve irritation _ 1 1

¨  Total Serious Adverse Events = 194 ¤ CMM = 95 (49%) ¤  IDDS = 99 (51%)

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Discussion

¨  Patients with refractory cancer pain are more effectively treated with IDDS than CMM ¤  Increase pain relief ¤ Fewer side effects due to opioids ¤  Improved survival

¨  Limitations: ¤ Did not mention how medication was titrated to effect ¤ Survival analysis was not powered

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Who would benefit?

¨  Patients with estimated life expectancy ≥ 3 months ¨  Patients with Moderate – Severe Pain Scores despite:

¤ Using ≥ 200 mg morphine/day without any symptomatic relief

¤ Using ≤ 200 mg morphine/day suffering from opioid related side effects

¨  Patients with no contraindications to intraspinal or epidural use ¤ Active infection, spinal cord obstruction, coagulopathy,

anticoagulants due to hematoma risk

Smith TJ, et al. Curr Oncol Rep. 2004 Jul;6(4):291-6.

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Conclusions

¨  Intrathecal drug delivery systems have been shown to effectively decrease pain and drug toxicity

¨  Intrathecal drug delivery systems have many serious

adverse side effects that will need to be considered prior to treatment

Pumps: Practical Considerations for Hospitalized Patients

¨  Identifying patients with implanted pump devices ¨  Interrogating the pump

¤  Verification of contents and pump settings

¤  Typically limited to specialty services

¨  Communication ¤  Medication administration record

¨  Refilling pumps ¤  Double check process

¤  Products prepared externally can have a variety of different formulations, concentrations, etc.

¨  Accounting for patients’ complete pain needs

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Refilling IDDS

¨  Review pump contains with provider refilling pump ¨  Ensure double check process in place at critical

points ¤ Calculations for preparation ¤ Review of product selection prior to compounding

initiation n REMEMBER: PRESERVATIVE FREE PRODUCTS ONLY

¤ Real-time verification of compounding

¨  Complete preparation in clean room

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Role of Pharmacists

¨  Medication Safety ¤ Standard concentrations and preparations ¤ Preservative free products ¤ Product sterility

¨  Optimize the use of opioids ¨  Transitioning patients to hospice

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References

¨  Brull R, MacFarlane AJR, Chan VWS. Spinal, epidural, and caudal anesthesia. In: Miller RD, ed. Miller's Anesthesia. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015:chap 56.

¨  Sherwood ER, Williams CG, Prough DS. Anesthesiology principles, pain management, and conscious sedation. In: Townsend CM, Beauchamp RD, Evers BM, Mattox KL, eds. Sabiston Textbook of Surgery. 19th ed. Philadelphia, PA: Elsevier Saunders; 2012:chap 16.

¨  Kleinman, W. & Mikhail, M. (2006). Spinal, epidural, & caudal blocks. In G.E. Morgan et al Clinical Anesthesiology, 4th edition. New York: Lange Medical Books.

¨  Morgan, G.E., Mikhail, M.S., Murray, M.J. (2006). Peripheral nerve blocks. In G.E. Morgan et al Clinical Anesthesiology, 4th edition. New York: Lange Medical Books.

¨  Warren, D.T. & Liu, S.S. (2008). Neuraxial anesthesia. In D.E. Longnecker et al (eds) Anesthesiology. New York: McGraw-Hill Medical.

¨  Staal C, Arends A, Ho S.A self-report of quality of life of patients receiving intrathecal baclofen therapy. Rehabil Nurs. 2003 Sep-Oct;28(5):159-63.

¨  Ackerman LL, Follett KA, Rosenquist RW. Long-term outcomes during treatment of chronic pain with intrathecal clonidine or clonidine/opioid combinations. J Pain Symptom Manage. 2003 Jul;26 (1):668-77.

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References

¨  Angel IF, Gould HJ Jr, Carey ME. Intrathecal morphine pump as a treatment option in chronic pain of nonmalignant origin. Surg Neurol. 1998;49:92-98.

¨  Paice JA, Penn RD, Shott S. Intraspinal morphine for chronic pain: a retrospective, multicenter study. J Pain Symptom Manage. 1996;11:71-80.

¨  Winkelmuller M, Winkelmuller W. Long-term effects of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology. J Neurosurg. 1996;85:458-467.

¨  Bedder MD. Epidural opioid therapy for chronic nonmalignant pain: critique of current experience. J Pain Symptom Manage. 1996;11:353-356.

¨  Brown J, Klapow J, Doleys D, et al. Disease-specific and generic health outcomes: a model for the evaluation of long-term intrathecal opioid therapy in noncancer low back pain patients. Clin J Pain. 1999;15:122-131

¨  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;14:4-16.

¨  Valentino L, Pillay KV, Walker J. Managing chronic nonmalignant pain with continuous intrathecal morphine. J Neurosci Nurs. 1998;30:233-239.

¨  Anderson VC, Burchiel KJ. A prospective study of long term intrathecal morphine in the management of chronic nonmalignant pain. Neurosurgery. 1999;44:289 - 300.

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