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opioids analgesic

a spinal, as well as supraspinal, analgesic


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

Euphoria or dysphoria
Nausea and vomiting
Cough reflex depression
Respiratory depression


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

Peripheral Effects of Opiates

Decreased gastrointestinal tract motility
Urinary retention
Histamine release
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

- 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


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.


The most common indication for using hydromorphone
appears to be

inadequate pain control or intolerable side
effects with morphine.


Fentanyl and sufentanil

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.


Methadone and Meperidine

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


most widely recognized side effects of intraspinal
narcotics include

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.


Respiratory depression due to

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.


acute cessation of intrathecal opioid administration presents unique potential risk.

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.


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

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


strategies have been advanced to manage such
apparent tolerance

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.


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

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


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

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


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

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



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


Adverse Effects of intrathecal local anesthetics

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


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

transient paresthesias,
motor blockade, and gait impairment.


Alpha-adrenergic agonists

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


receptors exist in the

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


Alpha-adrenergic agonists mechanism of action

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


Alpha-adrenergic agonists have the particular advantage over opiates of

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


Adverse Effects of Clonidine

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


Tizanidine appears to be particularly useful
in the treatment of

opioid insensitive neuropathic pain syndromes.



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.


putative mechanism of
ziconotide induced pain relief is

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


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

neuropathic pain refractory to conventional treatments.


Common causes of neuropathic
pain include

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


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

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


side effects of ziconotide

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.


To prevent the occurrence of these side effects of ziconotide

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


Complications of implanted drug delivery devices



Percutaneous catheters and implanted reservoirs appear
particularly susceptible to infection because

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


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

the use of an in-line bacteriostatic filter


Erosion of the hardware

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.


The most frequently observed complication involves

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


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

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


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

catheter obstruction during surgery


The paraspinous approach limits

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


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

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


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

prevent kinking when the wound is closed.


Patients with drug delivery system
failure usually present with

increased pain or with
subcutaneous fluid accumulation


Initial evaluation includes of delivery system failure

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.


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

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


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

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.


If the intrathecal granuloma becomes
sufficiently large

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


intrathecal granuloma

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.


Granuloma formation
seems to occur more often in the

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


risk of catheter-associated granuloma formation is
highest with

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


Granulomas are more common in patients with

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.


If granulomas are discovered before they are symptomatic

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


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

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


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

surgical decompression and resection is often required


should raise suspicion for the formation of catheter tip granulomas.

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


In addition to following a patient’s pain, experts

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


an increased risk of patient mortality

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.

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