Chapter 63 Implanted Drug Delivery Systems for the Control of Chronic Pain

Question 1

opioids analgesic

action

Answer 1

a spinal, as well as supraspinal, analgesic

action

Question 2

descending system of pain inhibition

Answer 2

This pathway begins with projections from the frontal cortex and hypothalamus to the periaqueductal gray (PAG) of the midbrain. PAG fibers then project to the dorsal pons and the
posteroventral medulla, where projections then travel via the dorsolateral funiculus to terminate in the substantia gelatinosa of the spinal cord dorsal horn. These efferent
projections inhibit the second order ascending nociceptive neurons and thus inhibit pain transmission.

Question 3

At the spinal level of antinociceptive processing, opiates

presynaptically diminish

Answer 3

primary afferent terminal excitability and inhibit substance P release.

Question 4

Postsynaptically, opiates

act to

Answer 4

suppress excitatory amino acid–evoked excitatory postsynaptic potentials (EPSPs) in dorsal horn neurons.

Question 5

Intraspinal pharmacotherapy for pain attempts to

Answer 5

largely restrict drug effects to regions associated with the

source of noxious input.

Question 6

Advantages of Intraspinal opioids

Answer 6

Systemic side effects are minimized, and a much higher local analgesic concentration is achieved at its site of action, even at comparatively lower doses. Morphine and hydromorphone are particularly well suited for this application, because of their hydrophilicity and resulting slow absorption from the cerebrospinal fluid. As a result, analgesia from intrathecal morphine or hydromorphone not uncommonly lasts up to 24 hours.

Question 7

Side Effects from Systemic Administration
of Oral, Parenteral, and Transdermal Narcotics

Central Nervous System Effects of Opiates

Answer 7

Analgesia
Mydriasis
Euphoria or dysphoria
Nausea and vomiting
Sedation
Confusion
Cough reflex depression
Respiratory depression

Question 8

Side Effects from Systemic Administration
of Oral, Parenteral, and Transdermal Narcotics

Peripheral Effects of Opiates

Answer 8

Decreased gastrointestinal tract motility
Constipation
Urinary retention
Histamine release
Pruritus
Increased biliary duct pressure

Question 9

Indications for Chronic

Intraspinal Analgesic Administration

Answer 9

Chronic pain with known pathophysiology
Sensitivity of the pain to the agent to be infused
Failure of maximal medical therapy (antiinflammatory
agents, antidepressants, nonnarcotic analgesics, and systemic narcotics.)
Favorable psychosocial evaluation
Favorable response to trial of intraspinal analgesic agents

Question 10

Contraindications for Chronic

Intraspinal Analgesic Administration

Answer 10

Intercurrent systemic infection,
Uncorrectable bleeding diathesis,
Allergy to agent to be infused,
Failure of a trail of intraspinal analgesic agents,
acute psychotic illnesses and severe, untreated depression or anxiety
Obstruction of cerebrospinal fluid flow (relative)

Question 11

Intraspinally Administered Drugs in the Treatment of Intractable Pain

Answer 11

Opiates

• Morphine
• Hydromorphone
• Fentanyl
• Sufentanil
• Dynorphin
• Beta-endorphin
• D-ala-D-leu-enkephalin
• Methadone
• Meperidine

Alpha-Adrenoceptor Agonists

• Clonidine
• Tizanidine

GABA B Agonists
- Baclofen

Question 12

Intraspinally Administered Drugs in the Treatment of Intractable Pain

Answer 12

Naturally Occurring Peptides and their Analogues

• Somatostatin
• Octreotide
• Vapreotide
• Calcitonin

Question 13

Intraspinally Administered Drugs in the Treatment of Intractable Pain

Answer 13

Local Anesthetics

• Bupivacaine
• Ropivacaine
• Tetracaine

NMDA Agonists
- Ketamine

Other Agents

• Ziconotide (SNX I I I)
• Midazolam
• Neostigmine
• Aspirin
• Droperidol
• Gabapentin

Question 14

Nonallergic reactions to the infused agent, contraindication?

Answer 14

such as urinary retention or pruritus, most often occur only acutely after initial intrathecal exposure to the drug and
often resolve with time or respond to specific treatment. These reactions therefore do not represent absolute contraindications
to chronic intrathecal drug infusion

Question 15

Percutaneous epidural catheter attached to

Answer 15

external pumps,
internalized passive catheters with reservoirs requiring percutaneous bolus drug administration, patient activated
mechanical systems, constant rate infusion pumps, and
programmable infusion pumps are all viable options.

Question 16

generally regarded as an indicator of long-term efficacy

Answer 16

Pain relief in response to acute intraspinal analgesic agents

Question 17

approaches to the trial of intrathecal narcotics

Answer 17

single versus multiple
injections, administration via lumbar puncture versus indwelling
catheter, epidural versus intrathecal routes, and bolus versus continuous infusion of the drug

Question 18

The equianalgesic epidural dose is roughly

Answer 18

10 times that of an intrathecal dose.

Question 19

epidural administration disadvamtage

Answer 19

may lead to greater systemic side effects, including constipation and urinary retention. These higher doses further increase the probability of developing tolerance. Also, the higher dose requirement with epidural infusion to reach equivalent subarachnoid concentration necessitates refilling pump reservoirs on a more frequent basis. Dural fibrosis possible
Question of increased tolerance

Question 20

complication of epidural catheter placement

Answer 20

dural scarring, resulting in catheter failure caused by occlusion, kinking, or displacement.

Question 21

intrathecal drug

administration carries the disadvantages of

Answer 21

potential CSF leak and postural spinal headaches, respiratory depression caused by supraspinal drug redistribution, and meningeal infection or neural injury.

Question 22

major advantage of epidural administration

Answer 22

the theoretically lower risk of serious complication. epidural catheters can be placed at virtually any level, making it potentially
more useful for the treatment of upper body pain, Reduced risk of respiratory depression, spinal headache, neural injury

Question 23

advantages of the intrathecal route including

Answer 23

the lower drug dosage requirements leading to increased intervals
between pump refills, the lower risk of catheter failure, and the infrequent occurrence of potential complications, suggest
this is the preferred route for intraspinal drug delivery, Less systemic effect, No dural fibrosis at tip of catheter, Possible to sample spinal fluid for culture diagnosis and drug levels

Question 24

different methods to accomplish intraspinal drug delivery

Answer 24

percutaneous epidural catheters attached to external pumps,
internalized passive catheters and reservoirs requiring percutaneous
drug administration, patient activated mechanical systems, constant rate infusion pumps, and programmable infusion pumps.

Question 25

the choice of drug administration | system should be made with careful consideration of

Answer 25

the individual benefits of programmability, bolus versus continuous drug infusion, the patient’s general medical and ambulatory status and his or her estimated life expectancy

Question 26

continuous versus bolus infusion

Answer 26

Continuous spinal infusion results in lower peak CSF morphine concentrations and corresponding lower plasma levels than bolus administration, while providing stable steady state levels at the spinal site of action. It has been suggested that continuous infusion may result in a reduced rate of opioid receptor tachyphylaxis and decrease the risk of producing delayed respiratory depression. intermittent bolus intrathecal administration may decrease the risk of intrathecal granuloma formation and may increase the long term efficacy of intrathecal delivery.

Question 27

subcutaneous reservoirs

Answer 27

require daily percutaneous access and are associated with discomfort and increased risk of infection. They do, however, allow the patient unencumbered activity during the day and can be accessed for either bolus administration or for continuous infusion by attachment to an external pump.

Question 28

type of implanted drug pumps drug-filled bellows

Answer 28

compressed by pressurized gas with its outflow regulated by a high resistance valve. The infused solution is then delivered at a fixed rate; dose changes are made by changing the solution concentration.

Question 29

type of implanted drug pumps the programmable, peristaltic drug pump

Answer 29

This pump can be programmed transcutaneously and sophisticated drug dose regimens can be instituted. Dose changes can be made with noninvasive reprogramming. Because these pumps are battery operated, they require surgical replacement when the batteries expire

Question 30

Both implanted pump types require at an interval dependent upon

Answer 30

the size of the drug reservoir, the concentration of the drug to be infused and the rate of drug delivery. The maximum interval between refills of the pump is six months, as drug stability within the pump has been confirmed for up to six months

Question 31

costs of these drug | administration systems over time.

Answer 31

In general, it appears that for patients whose life expectancy and intraspinal drug use will exceed three months, it is cost effective to choose a fully implanted drug pump, whereas for patients with shorter life expectancy, a percutaneous catheter or implanted reservoir may be more reasonable.

Question 32

usefulness of morphine for intrathecal therapy for chronic pain

Answer 32

usefulness lies in the ability to achieve excellent pain control over a long duration at a fraction of the dose required for systemic opioids while avoiding many of the commonly seen side effects of systemic administration

Question 33

relative equianalgesic potency between routes of administration has been estimated to be

Answer 33

300 for oral administration, 100 for IV administration to 1 for intrathecal (IT) administration. Doses at the initiation of therapy are almost always below one milligram per day.

Question 34

Hydromorphone vs Morphine

Answer 34

Hydromorphone is approximately five times more potent, has fewer active metabolites and a smaller supraspinal distribution than morphine; this could account for reports of fewer side effects when compared to morphine.

Question 35

The most common indication for using hydromorphone | appears to be

Answer 35

inadequate pain control or intolerable side | effects with morphine.

Question 36

Fentanyl and sufentanil

Answer 36

are two potent opioids that diffuse rapidly across the blood-brain barrier because of their strong lipophilicity. Fentanyl produces a functionally equivalent effect on pain compared to morphine while binding to fewer, highly potent mu agonist, receptors. Sufentanil may be more useful for segmental rather than diffuse analgesia and may elicit less drug tolerance than morphine.

Question 37

Methadone and Meperidine

Answer 37

Methadone is a racemic mixture of D- and L-opioid isomers and meperidine is a synthetic opioid.

Question 38

most widely recognized side effects of intraspinal | narcotics include

Answer 38

fatigue, somnolence, nausea, vomiting, urinary retention, pruritus, decreased sexual libido and decreased testosterone levels in men, noncardiac pedal edema, and, rarely, delayed respiratory depression. These side effects appear to be more prevalent with intrathecal morphine use as compared to other opioids. Fentanyl and hydromorphone have apparently better side effect profiles.

Question 39

Respiratory depression due to

Answer 39

most often seen in opioid-naive patients and results from supraspinal redistribution of the drug. This side effect is both dose dependent and naloxone reversible.

Question 40

acute cessation of intrathecal opioid administration presents unique potential risk.

Answer 40

Spinal morphine withdrawal syndrome results in hyperalgesia after cessation of morphine and is caused by the release of excitatory neurotransmitters and neuromodulators from primary afferents after long-term exposure to morphine, a type of “rebound” effect.

Question 41

Reasons for the development of increasing narcotic requirement to maintain a similar degree of pain control in a significant fraction of patients over time

Answer 41

1. may reflect the development of tolerance at the receptor level 2. may also result from a change in the status of the patient’s disease. 3. changes in the patient’s psychosocial status may result in the decreased ability to cope, resulting in perceived increase in the degree of pain. 4. malfunction of the pump and catheter system or the development of a catheter tip inflammatory mass

Question 42

strategies have been advanced to manage such | apparent tolerance

Answer 42

First, one must carefully evaluate for the presence of pump system malfunction or the presence of a catheter tip inflammatory mass. If this is not the case, then simply increasing the drug dose may restore excellent pain control. When this fails, or when the drug dose is escalated to levels that are felt to be potentially problematic, temporarily using systemic analgesics while the pump is turned off for a period of several days to a few weeks, a so-called drug holiday.

Question 43

If the decreased efficacy of intraspinal narcotics is caused by receptor tolerance, this “drug holiday” often results in

Answer 43

receptor down regulation and a return of efficacy when intraspinal opioids are reinstituted

Question 44

Another strategy to deal with tolerance involves the use of narcotics active at other opioid receptor subclasses.

Answer 44

Like mu receptor agonists, delta receptor agonists appear to work through a G-protein system to hyperpolarize the neuronal membrane through an increase in potassium conductance and thus inhibit neuronal activity. Kappa receptor agonists appear to function differently than mu or delta receptor agonists. These agents appear to activate a different G-protein mechanism, which blocks calcium entry through a voltagedependent calcium channel

Question 45

A final strategy to deal with tolearnce is the concomitant administration of

Answer 45

another intrathecal pharmacologic agent such as a local anesthetic. The combination of opioids and local anesthetics, alpha-adrenergic agents or ziconotide has been used successfully in patients failing intrathecal opioid monotherapy.

Question 46

Bupivacaine

Answer 46

``` an amide class local anesthetic. opioids plus bupivacaine resulted in significantly better pain control, less oral opioid use, fewer clinic visits, and better patient satisfaction than intrathecal opioids alone ```

Question 47

Adverse Effects of intrathecal local anesthetics

Answer 47

At high doses of local anesthetics, particularly lidocaine, permanent injury can result because local anesthetics injure dorsal and ventral roots by increasing glutamate concentration in the cerebrospinal fluid and produce chromolytic deterioration of motor neurons in the lumbar spinal cord with resultant vacuolation of the dorsal funiculus. In clinically applicable intrathecal doses, however, such side effects are not seen with bupivacaine.

Question 48

Clinically apparent side effects of bupivacaine, | seen rarely and at high doses, include

Answer 48

transient paresthesias, | motor blockade, and gait impairment.

Question 49

Alpha-adrenergic agonists

Answer 49

frequently used second line adjuvant agents in intraspinal pain pharmacotherapy. Ex: clonidine and tizanidine

Question 50

Alphaadrenergic | receptors exist in the

Answer 50

substantia gelatinosa of the spinal cord, situated on both pre- and postsynaptic terminals of small primary afferents

Question 51

Alpha-adrenergic agonists mechanism of action

Answer 51

They appear to mediate antinociception by indirectly decreasing the release of substance P

Question 52

Alpha-adrenergic agonists have the particular advantage over opiates of

Answer 52

little or no effect on respiratory centers, largely eliminating the possibility of respiratory depression. Another potential advantage of adrenergic agents is their specific efficacy in the management of neuropathic pain states

Question 53

Adverse Effects of Clonidine

Answer 53

Hypotension, Bradycardia, transient sedation. There were no opioid-like side effects of respiratory depression, pruritus, or nausea

Question 54

Tizanidine appears to be particularly useful | in the treatment of

Answer 54

opioid insensitive neuropathic pain syndromes.

Question 55

Ziconotide

Answer 55

now marketed as Prialt, is a novel 25 amino acid peptide isolated from marine snail venom. It is a highly selective N-typevoltage-sensitive calcium channel antagonist; these channels are found at the presynaptic nerve terminals in the spinal dorsal horn.

Question 56

putative mechanism of | ziconotide induced pain relief is

Answer 56

the blockade of neurotransmitter | release at the primary afferent nerve terminal.

Question 57

FDA approved the | use of ziconotide as a nonopioid intrathecal analgesic option for patients with

Answer 57

neuropathic pain refractory to conventional treatments.

Question 58

Common causes of neuropathic | pain include

Answer 58

complex regional pain syndrome (CRPS), HIV-associated neuropathy, postherpetic neuralgia, diabetic peripheral neuropathy, and central neuropathic pain syndromes related to multiple sclerosis, poststroke pain, and spinal cord injury

Question 59

a relatively high risk | of side effects with ziconotide use due to

Answer 59

a relatively narrow therapeutic window, with a small difference between the dose required for analgesia and the dose required to produce side effects

Question 60

side effects of ziconotide

Answer 60

dizziness, confusion, gait ataxia, memory impairment, nystagmus, dysmetria, sedation, agitation, hallucinations, nausea, vomiting, urinary retention, somnolence, and coma. They seem to occur most often when high doses are used at the initiation of therapy or when dose is increased quickly.

Question 61

To prevent the occurrence of these side effects of ziconotide

Answer 61

it is recommended that infusion start with the lowest possible dose and then is titrated slowly to effect. Ziconotide should not be offered to patients with complicated psychiatric profiles or a history of psychotic episodes

Question 62

Complications of implanted drug delivery devices

Answer 62

infection

Question 63

Percutaneous catheters and implanted reservoirs appear | particularly susceptible to infection because

Answer 63

their communication with the skin or frequent access through the skin. Infection may involve the surgical wound or the subcutaneous region surrounding the hardware. This is effectively treated by removal of all implanted hardware and the administration of appropriate intravenous antibiotics. Re-implantation of the drug delivery system is usually delayed for at least three months after completion of antibiotic therapy

Question 64

Infusion of contaminated drug solution is of great concern as this may lead to potentially life-threatening meningitis. The risk of this complication can be limited by

Answer 64

the use of an in-line bacteriostatic filter

Question 65

Erosion of the hardware

Answer 65

through the skin is a less common complication, and may occur especially in cachectic, poorly nourished patients. This risk can be limited by placing the implant in a deep pocket, by ensuring the hardware does not lie directly under the incision, and by performing a meticulous multilayer closure.

Question 66

The most frequently observed complication involves

Answer 66

failure of the system itself. Catheter problems, however, are most common. These complications include kinking, obstruction, disconnection, or shearing of the catheter.

Question 67

There are several techniques to limit the risk of catheter | failure and include the

Answer 67

use of fluoroscopy during catheter | placement to confirm the absence of loops, partial kinks, or malposition in a dural nerve root sheath.

Question 68

Observation of cerebrospinal fluid flow during each stage of implantation helps detect

Answer 68

catheter obstruction during surgery

Question 69

The paraspinous approach limits

Answer 69

the sharp angle of the catheter as it enters and exits the interspinous ligament and guards against shearing at these sites.

Question 70

Securing the catheter with a purse string suture as it exits the interspinous ligament and again with a silastic fixation device also helps

Answer 70

prevent cerebrospinal fluid leak and migration of the catheter out of the subarachnoid space.

Question 71

dissection of a small space above the fascia in which the catheter comfortably rests will help

Answer 71

prevent kinking when the wound is closed.

Question 72

Patients with drug delivery system | failure usually present with

Answer 72

increased pain or with | subcutaneous fluid accumulation

Question 73

Initial evaluation includes of delivery system failure

Answer 73

the comparison of the expected and true residual volume in the pump reservoir; a significant disparity warrants further investigation. Plain radiologic evaluation of the entire system may reveal catheter disconnection and may also demonstrate kinking or migration of the catheter from the subarachnoid space. the instillation and attempted intrathecal delivery of iodinated contrast material via the pump may be helpful in differentiating between catheter or pump failure.

Question 74

Quantitative nuclear | medicine studies may also be helpful in evaluation of delivery system failure

Answer 74

the pump can be | filled with dilute solutions of radioactive material and the delivery of these materials can be followed over time

Question 75

common to all implanted drug delivery systems is the potential for overdose. With an externalized system, this may result from

Answer 75

improper setting of the external drug pump or improper dilution of the infusate by the pharmacy. Far more insidious can be the incorrect reprogramming of indwelling drug pumps or injection of the refill volume into the subcutaneous space, as these errors are potentially subtle and not immediately recognized.

Question 76

If the intrathecal granuloma becomes | sufficiently large

Answer 76

spinal cord and nerve root compression may occur and result in new or worsening neuropathic pain, weakness, numbness, loss of bowel and bladder function, and even paralysis

Question 77

intrathecal granuloma

Answer 77

they are local, chronic inflammatory reactions related to dural based mast cell degranulation in response to the very drug infused. They occur where drug is most concentrated at its exit from the catheter lumen before it can disperse throughout the CSF.

Question 78

Granuloma formation | seems to occur more often in the

Answer 78

longest and narrowest portion of the spinal canal, the thoracic spinal cistern. This region has the most stagnant CSF flow during the cardiac cycle and it tends to be the target for the catheter tip in most current pump placement operations. What results is the infusion of drug into the intrathecal space where the highest relative concentration is possible: a tight space with poor flow

Question 79

risk of catheter-associated granuloma formation is | highest with

Answer 79

opioids, with the exception of fentanyl. There seems to be a direct relationship between both the concentration of opioid in the infused solution and the rate at which it is infused with the likelihood that a granuloma will form

Question 80

Granulomas are more common in patients with

Answer 80

nonmalignant pain as opposed to those being treated for cancer pain. They are more often seen in younger patients as well. It could be deduced that because these groups have longer life expectancies, they are exposed to greater concentrations of opioids and subsequently are more likely to develop granulomas.

Question 81

If granulomas are discovered before they are symptomatic

Answer 81

discontinuation of drug infusion is often all that is necessary. Stabilization and even regression of granulomas has been shown after drug infusion ceases. Another suggested strategy is the infusion of hypertonic saline after discontinuing opioid infusion

Question 82

the most common strategy for the treatment of | asymptomatic catheter tip granulomas is

Answer 82

the withdrawal of the catheter one to two spinal levels. The granuloma frequently resolves and allows for continued analgesic infusion, although at a lesser dose and rate or with another agent less likely to produce catheter tip granulomas

Question 83

When catheter tip granulomas enlarge to the size where frank spinal cord compression occurs and when patients have become symptomatic

Answer 83

surgical decompression and resection is often required

Question 84

should raise suspicion for the formation of catheter tip granulomas.

Answer 84

requirement for increasing opioid doses. The appearance of new or altered pain sensations in a dermatomal distribution near the known location of the catheter tip, or new radicular pain or numbness is also suspect

Question 85

In addition to following a patient’s pain, experts | recommend

Answer 85

close neurological follow up of all patients treated with intrathecal drug administration. Motor examination should be a routine part of every clinic visit. As catheter tip granulomas develop slowly, attention to subtle changes in physical examination may be an indication for MRI imaging or CT myelography

Question 86

carry | an increased risk of patient mortality

Answer 86

data has very recently been published that has demonstrated that both the initial implantation and the routine maintenance of intrathecal drug delivery systems for the treatment of chronic nonmalignant pain. The cause of death in all causes was likely the respiratory depressant effect of opioids on the central nervous system.