Chapter 63 Implanted Drug Delivery Systems for the Control of Chronic Pain Flashcards
KEY POINTS 1. Intraspinal therapy restricts drug effects to regions associated with the source of the nociceptive input. 2. Morphine and hydromorphone are well suited for intrathecal use in view of their hydrophilicity and slow absorption from the cerebrospinal fluid. Morphine, hydromorphone, and ziconotide are the first-line agents in intrathecal drug therapy. The inclusion of ziconotide as a first line drug is secondary to the randomized, double-blind placebo-controlled studies showing its
opioids analgesic
action
a spinal, as well as supraspinal, analgesic
action
descending system of pain inhibition
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.
At the spinal level of antinociceptive processing, opiates
presynaptically diminish
primary afferent terminal excitability and inhibit substance P release.
Postsynaptically, opiates
act to
suppress excitatory amino acid–evoked excitatory postsynaptic potentials (EPSPs) in dorsal horn neurons.
Intraspinal pharmacotherapy for pain attempts to
largely restrict drug effects to regions associated with the
source of noxious input.
Advantages of Intraspinal opioids
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.
Side Effects from Systemic Administration
of Oral, Parenteral, and Transdermal Narcotics
Central Nervous System Effects of Opiates
Analgesia Mydriasis Euphoria or dysphoria Nausea and vomiting Sedation Confusion Cough reflex depression Respiratory depression
Side Effects from Systemic Administration
of Oral, Parenteral, and Transdermal Narcotics
Peripheral Effects of Opiates
Decreased gastrointestinal tract motility Constipation Urinary retention Histamine release Pruritus Increased biliary duct pressure
Indications for Chronic
Intraspinal Analgesic Administration
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
Contraindications for Chronic
Intraspinal Analgesic Administration
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)
Intraspinally Administered Drugs in the Treatment of Intractable Pain
Opiates
- Morphine
- Hydromorphone
- Fentanyl
- Sufentanil
- Dynorphin
- Beta-endorphin
- D-ala-D-leu-enkephalin
- Methadone
- Meperidine
Alpha-Adrenoceptor Agonists
- Clonidine
- Tizanidine
GABA B Agonists
- Baclofen
Intraspinally Administered Drugs in the Treatment of Intractable Pain
Naturally Occurring Peptides and their Analogues
- Somatostatin
- Octreotide
- Vapreotide
- Calcitonin
Intraspinally Administered Drugs in the Treatment of Intractable Pain
Local Anesthetics
- Bupivacaine
- Ropivacaine
- Tetracaine
NMDA Agonists
- Ketamine
Other Agents
- Ziconotide (SNX I I I)
- Midazolam
- Neostigmine
- Aspirin
- Droperidol
- Gabapentin
Nonallergic reactions to the infused agent, contraindication?
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
Percutaneous epidural catheter attached to
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.
generally regarded as an indicator of long-term efficacy
Pain relief in response to acute intraspinal analgesic agents
approaches to the trial of intrathecal narcotics
single versus multiple
injections, administration via lumbar puncture versus indwelling
catheter, epidural versus intrathecal routes, and bolus versus continuous infusion of the drug
The equianalgesic epidural dose is roughly
10 times that of an intrathecal dose.
epidural administration disadvamtage
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
complication of epidural catheter placement
dural scarring, resulting in catheter failure caused by occlusion, kinking, or displacement.
intrathecal drug
administration carries the disadvantages of
potential CSF leak and postural spinal headaches, respiratory depression caused by supraspinal drug redistribution, and meningeal infection or neural injury.
major advantage of epidural administration
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
advantages of the intrathecal route including
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
different methods to accomplish intraspinal drug delivery
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.
the choice of drug administration
system should be made with careful consideration of
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
continuous versus bolus infusion
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.
subcutaneous reservoirs
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.
type of implanted drug pumps
drug-filled bellows
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.
type of implanted drug pumps
the programmable, peristaltic drug pump
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
Both implanted pump types require at an interval dependent upon
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
costs of these drug
administration systems over time.
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.
usefulness of morphine for intrathecal therapy for chronic pain
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
relative
equianalgesic potency between routes of administration has
been estimated to be
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.
Hydromorphone vs Morphine
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.
