Chapter 16 Membrane Stabilizers Flashcards
1. In neuropathic pain, there is altered processing and changes in central modulation. These include pathologic activity in injured nerves (resulting in hyperexcitability, spontaneous and evoked pain), loss of C-fibers, sprouting of the large fibers in the outer laminas of the dorsal horn where the nociceptive-specific neurons are located (resulting in allodynia), and increased activity in the sympathetic nervous system. 2. Some of the molecular changes in neuropathic pain include the accumulat
conditions resulting in chronic neuropathic pain include
diabetic polyneuropathy, postherpetic neuralgia,
central neuropathic pain, traumatic/surgical nerve
injury, incomplete spinal cord injury, trigeminal neuralgia, multiple sclerosis, radiculopathy, complex regional pain
syndrome (CRPS), and HIV-associated peripheral neuropathy
neuropathic pain
Defined as pain initiated or caused by a primary
lesion or dysfunction in the nervous system, neuropathic pain is often described as burning, lancinating, or tingling
in nature
The source of neuropathic
pain may be related to
damage of a peripheral nerve, with or without associated autonomic changes or CNS dysfunction. Examples of these changes include prolonged central sensitization, damage to neuronal inhibitory functions, and alteration of the effects of pain on the sympathetic nervous system.
Following tissue injury, the threshold of A-d and
C-fiber activation
decreases, and an augmented response
to a given stimulus occurs
What channels has alterations in ion at the site of injury?
Sodium and calcium channels play a fundamental role in the
propagation of hyperexcitability in central and peripheral
neurons.
After nerve injury, the number of ion channels
accumulates in excess, and leads to
ectopic, spontaneous firing of sensory nerves and dorsal root ganglion cell bodies. The result of neuronal membrane hyperexcitability is the chronic perception of pain
membrane stabilizer
classification
sodium-channel blocking
agents (antiepileptics, anticonvulsants, local anesthetics, tricyclic antidepressants, and antiarrhythmics) and calcium channel blocking agents
When evaluating the effectiveness of medications for neuropathic pain, outcome measures most commonly include
changes in the average daily pain score by a 10-cm (100-mm) visual analog scale (VAS) and on an 11-point Likert scale (0, no pain; 10, worst possible pain) numeric rating scale (NRS); patient-reported pain relief of 30% or greater (moderate benefit); patient-reported pain relief of 50% or greater (substantial benefit).
“Numbers needed to
treat” (NNT)
The NNT is the number of patients treated with a particular drug in order to obtain one patient with a defined degree of relief.
The “numbers needed to harm” (NNH)
is the number needed to treat with a certain drug before a patient can experience a significant side effect
NNT/NNH ratio
The drugs with a low NNT/NNH ratio are superior to the drugs with high NNT/NNH ratio
SODIUM-CHANNEL BLOCKERS
These agents include the antiepileptic/ anticonvulsants, local anesthetics, tricyclic antidepressants, and antiarrhythmics. As a group, they inhibit the development and propagation of ectopic discharges
The primary agents used
for neuropathic pain that are sodium channel blockers
antiepileptics/ anticonvulsants and local anesthetic
The primary agents used
for neuropathic pain that are calcium channel blockers
Gabapentin and pregabalin,
Sodium-channel blockers are used for primary therapy or adjunctive treatment for processes such as
trigeminal neuralgia, CRPS, diabetic neuropathy, radicular extremity pain, chemotherapy-induced peripheral neuropathy, and postherpetic neuralgia
The initial dosage of phenytoin
100 mg BID to TID
phenytoin is primarily used for the treatment of
diabetic neuropathy
Phenytoin provides pain
relief by
blocking sodium channels, thereby preventing the release of excitatory glutamate and inhibiting ectopic discharges
Phenytoin Side Effects
Sedation, motor disturbances, slowing of mentation and somnolence, with
nystagmus and ataxia seen in some patients. development of facial alterations, including gum hyperplasia and a coarsening of facial feature
Fosphenytoin
an intravenously
administered pro-drug that converts to phenytoin, is used
by some to avoid a long dosing interval or initial burning at the injection site
Phenytoin effect on cytochrome P450 enzyme
Phenytoin activates the cytochrome P450 enzyme system in the liver, and, hence, careful assessment of co-therapy is warranted. For example, phenytoin decreases the efficacy of
methadone, fentanyl, tramadol, mexiletine, lamotrigine, and
carbamazepine
Co-administration with
antidepressants and valproic acid could lead to
increased blood concentration of phenytoin, lowering the subsequent
doses required for effect in patient
CARBAMAZEPINE (TEGRETOL) mechanism of action
Na channel blockade
Dosage of Carbamazepine
initial dosage of carbamazepine is 100 to 200 mg BID, titrated to effect, with typical dose ranges of 300 to 1200 mg/day, administered in two divided doses. Common maintenance doses are 600 to 800 mg
The chemical structure
of this Carbamazepine is similar to that of the
tricyclic antidepressants
Carbamazepine is thought to inhibit pain via
peripheral and central mechanisms. Carbamazepine
selectively blocks active fibers, having no effect
on normally functioning A-d and C-fiber nociceptors
Major uses of Carbamazepine include
primary therapy for trigeminal neuralgia (tic doloreux), thalamic-mediated post-stroke pain, postherpetic neuralgia, and diabetic neuropathy.
Side Effects of Carbamazepine
Drowsiness, dizziness, and nausea and vomiting
are common side effects
Carbamazepine is associated with very deleterious side effects, including
pancytopenia (necessitating a complete blood count and monitoring while on this
therapy), Stevens Johnson syndrome, and toxic epidermal necrolysis
Trigeminal Neuralgia
a sharp severe facial pain in one or more of the distributions supplied by the trigeminal nerve. It is caused by compression of the trigeminal nerve at the pontine origin of the nerve by an aberrant loop
of an artery or vein
Patients on carbamazepine therapy should have blood
tests done every 2 to 4 months because
there is an increased risk of developing agranulocytosis and aplastic anemia with
this agent
OXCARBAZEPINE (TRILEPTAL)
the keto-analog of carbamazepine, was
developed to preserve carbamazepine’s membrane-stabilizing
effects while minimizing minor adverse effects, such as sedation and serious, life-threatening reactions
Major Advantage of Oxcarbazepine
monitoring of drug
plasma levels and hematologic profiles is generally not necessary
Oxcarbazepine Mechanism of Action
oxcarbazepine blocks
sodium channels; it does not affect gamma-aminobutyric acid (GABA) receptors
Oxcarbazepine Side Effect
Hyponatremia (Na < 125 mmol/L) somnolence, dizziness, nausea and vomiting
Oxcarbazepine Dosages
Initial Dosage: 600 mg twice daily
Titration: Increase by 300 mg daily
Max dose: 1200–1800 mg every 3 days
Institution of oxcarbazepine therapy requires
Monitoring of sodium levels should be performed
VALPROIC ACID (DEPAKOTE)
Na channel blockade;
acts at the GABA-A receptor–> increase GABA
VALPROIC ACID indications
agent was effective in migraine therapy at dosages of 800 mg/day for a period of 8 week
VALPROIC ACID Side Effects
Side effects include
gastrointestinal upset, somnolence, and dizziness
VALPROIC ACID Dosage
Initial Dosage: 250 mg twice daily
Titration: Increase by 250 mg weekly
Maximum Dosage: 500 mg twice daily
LAMOTRIGINE (LAMICTAL) mechanism of action
Stabilize slow Na channel; suppress release of glutamate from presynaptic neurons
LAMOTRIGINE (LAMICTAL) Dosage
initial dosage is 25 to 50 mg at bedtime, and can be increased to 50 mg twice daily after 2 weeks. Subsequently, it may be increased by 50 mg increments every 1 to 2 weeks as tolerated, to a dose of 300 to 500 mg/day in two divided
doses
How should LAMOTRIGINE be discontinued?
Upon discontinuation, drug administration should be slowly tapered over a 2-week time period
Lamotrigine Side Effects
Rash (especially when lamotrigine is combined with valproic acid), dizziness, somnolence, Stevens-Johnson syndrome
Lamotrigine Indication
A major use for carbamazepine-resistant neuralgia. carbamazepine is the first-line therapy. diabetic neuropathy
Prescribing physicians should also be aware that when lamotrigine is combined with the CYP450 inhibitor
valproate, the initial dose should be reduced to
12.5 mg daily, and titration should be done cautiously
TOPIRAMATE (TOPAMAX)
mechanism of action
Na channel blockade; potentiate GABA inhibition and inhibits the AMPA- type glutamate (excitatory) receptor
Topiramate Dosage
Initial Dosage: 50 mg daily at bedtime increasing to an
upper limit of 200 mg
BID
Maximum Dosage: 1500 mg twice daily
Topiramate Side Effects
Sedation (primary side effect), kidney stones, glaucoma (as topiramate is an inhibitor of the enzyme, carbonic anhydrase)
Topiramate Indications
diabetic neuropathy, postherpetic neuralgia,
intercostal neuralgia, and CRPS
LEVETIRACETAM (KEPPRA) dosage
A starting dose for levetiracetam is 500 mg
twice daily, and may be increased to a recommended
3000 mg/day in divided doses. Dosages up to 5000 mg/ day have been assessed in the treatment of neuropathic pain
Why does Levetiracetam not have significant drug interactions?
Levetiracetam is
not metabolized by the cytochrome P450 system
Levetiracetam was found to be ineffective in the treatment of neuropathic pain secondary to
a spinal cord injury and postmastectomy pain
Levetiracetam Adverse effects
include asthenia, dizziness, somnolence, and headache
Local anesthetics are used in neuropathic pain states to block
the aberrant firing of abnormal nerves, although they also block normally conducting (non-nociceptive) nerves
Local anesthetics Indications
they are effective in the treatment of postherpetic neuralgia, trigeminal neuralgia, radiculopathies,
and peripheral neuropathies
LIDOCAINE typical dose
is 1 to 5 mg/kg IV
Lidocaine Side effects
dizziness, blurred vision, and seizure, typically presenting at a plasma level of 10 mg/ml
Potential Cardiac Risks of Lidocaine
Given that lidocaine is an
antiarrhythmic, bradycardia and cardiac depression (present at 20 to 25 mg/ml plasma concentration) are potential risks of this agent; therefore, obtaining ECG Indicated for long-term or high-dosage use of lidocaine
A formulation of 5% lidocaine is available in
transdermal application
Lidocaine patch(Lidoderm) benefit in patients with various types of neuropathic pain, including
postherpetic neuralgia, post-thoracotomy pain, intercostal neuralgia, and meralgia parasthetica
Eutectic Mixture of Local Anesthetics (EMLA)—
comprised of prilocaine and lidocaine
Prilocaine is readily metabolized to
o-toluidine, which can lead to methemoglobinemia.However, if dosages of prilocaine are kept below 600 mg, clinical methemoglobinemia is less likely to develop
MEXILETINE
This agent is an antiarrhythmic,
and, for pain relief, can be considered an oral analog
of lidocaine
MEXILETINE dosage
The standard starting dose is 75 to 150 mg/day, with a
target of 300 to 450 mg/day.
Mexiletine Indications
diabetic neuropathy, thalamic stroke pain, spasticity, and myotonia, although its effects are minimal.
Mexiletine Side Effect
somnolence, irritability, blurred vision, and nausea and vomiting,
severely limit the utility of this medication
Patients taking Mexiletine are at risk for developing
blood dyscrasias, and should have blood tests on a regular basis
Six different types of Calcium Channel Blockers found in nervous tissue
L, N, P, Q, R, and T.
Calcium-channel blockers used for treatment of neuropathic pain mechanism of action
They bind to the alpha2-delta subunit of L-type voltage-gated calcium channels, and result in decreased release of glutamate, norepinephrine, and substance P
Calcium-channel blockers relation to GABA
While structurally derived from the inhibitory neurotransmitter, GABA, neither gabapentin nor pregabalin bind to or have activity at the GABA receptor. They also have no effect on uptake or metabolism of GABA
GABAPENTIN (NEURONTIN) mechanism of action
Binds to alpha-2-delta subunit of voltage-gated
Ca channel
GABAPENTIN (NEURONTIN)
Dosage
initial dose is 100 to 300 mg at bedtime; with a gradual increase to a maximum of 3600 mg/day in TID divided doses. After 2 to 5 days, the dose is increased to 300 mg twice daily, and after another 2 to 5 days to 300 mg 3 times daily thereafter. Subsequently,
the dose can be increased by 300 to 600 mg every other week as tolerated until an effective dosage is obtained or the maximum daily dose is reached.
GABAPENTIN (NEURONTIN) Side Effect
The main dose limiting
side effects are fatigue, somnolence, and dizziness, which are often attenuated by gradual dose titration
Gabapentin dosage reduction is necessary in patients with
renal insufficiency
GABAPENTIN (NEURONTIN) Indications
postherpetic neuralgia,
CRPS, painful diabetic neuropathy, adjunctive therapy for symptomatic spinal stenosis.
PREGABALIN (LYRICA)
Dosage
Initial pregabalin dosing is 150 mg/day, given in two or three divided doses, or 75 mg given at bedtime in elderly
patients. Upward dose titration can be completed after
3 to 7 days to 300 mg/day, and subsequently increased
to a maximum dose of 600 mg/day within 2 weeks of
initiatio
PREGABALIN (LYRICA) mechanism of action
Pregabalin is an alpha2-delta ligand structurally related
to gabapentin. It similarly binds to calcium channels and
modulates calcium influx into hyperexcited neurons, leading
to its antinociceptive and antiseizure effects.
Pregabalin advantages over gabapentin include
a more rapid onset of pain relief, linear pharmacokinetics with low intersubject variability, fewer dose-related side
effects allowing for faster dosage upward titrations, and
twice daily versus 3 times daily dosing. Additionally,maximum benefit often occurs after 2 weeks of treatment at target doses of 300 to 600 mg/day compared with up to 2 months in gabapentin-treated patient
Pregabalin relation to GABA
While it
is structurally derived from the inhibitory neurotransmitter
GABA, it does not bind to GABA or benzodiazepine receptors
PREGABALIN (LYRICA) indications
Pregabalin is approved for the treatment of peripheral and central neuropathic pain, including postherpetic
neuralgia and painful diabetic neuropathy
PREGABALIN (LYRICA) side effects
Most common adverse effects
include somnolence and dizziness,
How should Pregabalin be discontinued?
When discontinuing pregabalin,
it should be gradually tapered down over at least 1 week to minimize symptoms, including insomnia, nausea, headache, and diarrhea
ZONISAMIDE (ZONEGRAN)
mechanism of action
This agent acts by blocking T-type calcium channels and sodium channels; its action also increases GABA release
ZONISAMIDE (ZONEGRAN) dosage
The initial dose is 100 mg QD for 2 weeks, increasing by
200 mg/week, for a target of 600 mg/day
ZONISAMIDE (ZONEGRAN) indications
It has uses in various
types of neuropathic pain.
ZONISAMIDE (ZONEGRAN) side effects
Side effects include ataxia,
decreased appetite, rash, and renal calculi (due to the
carbonic anhydrase inhibitor effect). In children, there is
an increased risk of oligohydrosis and susceptibility to hyperthermia
ZICONOTIDE (PRIALT)
Ziconotide is a v-conopeptide (previously known as SNX-111) that is administered intrathecally due to its peptidic structure. It is derived from the venom of a marine snail (genus Conus)
ZICONOTIDE (PRIALT) mechanism of action
Ziconotide blocks calcium
influx into N-type calcium channels that are present in
the dorsal horn lamina of the spinal cord, thus preventing
the afferent conduction of nerve signals
ZICONOTIDE (PRIALT) dosage and form of administration
Administration occurred via an intrathecal infusion pump, and dosing should be started low, at a recommended dose of
2.4 mg/day (0.1 mg/hr). Due to a lag time, it should be
titrated up slowly, at intervals of no more than two to
three times per week, to a recommended maximum of
19.2 mg/day
ZICONOTIDE (PRIALT) Adverse Effects
Ziconotide does not cause tolerance, dependence,
or respiratory depression, and adverse effects
primarily involve the CNS, including dizziness, ataxia,
confusion, and headache
ZICONOTIDE (PRIALT) indications
ziconotide is approved
for the management of severe chronic pain in patients for
whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatments, including intrathecal opiates
MAGNESIUM
antagonists of the N-methyl-d-aspartate (NMDA) receptor,
membrane-stabilizing effect
