This seminar consists of various Anticonvulsants and antidepressants which are used in chronic pain .iNcludes mechanism and fda recommendations.

1. ANTIDEPRESSENT AND
ANTICONVULANT AS
ANALGESICS
Ravi shankar sharma
Moderator- Dr. Ajit kumar

2. A/T IASP:
• “Nociceptive pain” -- “Pain that arises from actual or threatened
damage to non-neural tissue and is due to the activation of
nociceptors.”
• “Pain caused by a lesion or disease of the somatosensory nervous
system.” “Neuropathic pain”

3. Nociceptive Vs Neuropathic pain

4. Antiepileptic drugs (AEDs)
• Used in the treatment of chronic pain syndromes for more than 50
years.
• Neuropathic syndromes have been treated with AEDs, including:
• Diabetic neuropathy
• Postherpetic neuralgia
• Glossopharyngeal neuralgia
• Postsympathectomy neuralgia
• Postthoracotomy pain syndrome

5. CLSSIFICATION:
First-generation antiepileptics
• Benzodiazepines
• Carbamazepine
• Ethosuximide
• Phenobarbital
• Phenytoin
• Primidone
• valproic acid
Second-generation antiepileptics
• Felbamate
• Gabapentin
• Lacosamide
• Lamotrigine
• Levetiracetam
• Oxcarbazepine
• Pregabalin
• Tiagabine
• Topiramate
• Vigabatrin
• Zonisamide

6. Peripheral nerve damage
• With intact connective tissue
sheath – axons grow in formally
innervated area
• With damage connective tissue
sheath - axon extensions grow in
any direction, become tangled to
form neuroma.

7. • Neuromas generate ectopic electrical impulses at the regenerating
tips.
• Causes disruption in the balance of the excitatory (e.g., glutamate)
and inhibitory (e.g., γ-aminobutyric acid [GABA]) neurotransmitters.
• Leads to hyperexcitability of the neuronal membrane sodium
channels and voltage-dependent calcium channels, causing rapid
ectopic firing.

8. AEDs Mechanism of action

9. VALPROIC ACID
Uses-
• broad-spectrum AED used to treat a number of epileptic syndromes
• preventive treatment of migraine, cluster & tension-type headaches.
• Mood stabilizer

10. Mchanism of action
• Inhibit GABA aminotransferase and succinic semialdehyde dehydrogenase.
• Selectively enhancing postsynaptic GABA responses.
• Direct effects on neuronal membranes.

11. Valproate increases brain GABA levels
suppress events in the cortex, perivascular
parasympathetics or trigeminal nucleus caudalis.
suppresses neurogenic inflammation and directly
attenuates nociceptive neurotransmission
Relief of headache

12. Dose-
• Available as 250-mg capsules and 250 mg/5 mL syrup.
• starting dosage- is usually 250 mg/day.
• Titrated slowly upward to a maximum dosage of 1000 to 2000
mg/day, in divided doses.

13. Metabolism –
• Absorbed rapidly orally
• Peak concentrations in 1 to 4 hours.
• About 90% bound to plasma proteins.
• Hepatic metabolism
• 15-hour half-life.

14. S/E-
• CNS depression
• Hepatotoxicity
• Hematologic toxicity

15. CLONAZEPAM
Uses-
• Chronic malignant and nonmalignant pain syndromes:
• Headaches & Temporomandibular joint dysfunction
• Phantom limb pain & other neuropathic states
• Fibromyalgia

16. Increases frequency of chloride channel opening

17. MOA-
• Enhance GABA receptor–mediated chloride channels opening.
• particularly effective when used in combination with other
neuropathic analgesics

18. Dose-
• Available as 0.5-, 1-, and 2-mg tablets.
• Starting dose 0.5 mg at bedtime, with the dose being slowly increased to
0.5 to 1 mg three times per day.
• Antiepileptic dose - 20 mg/day have been used in epilepsy.
• Headache and pain 1 to 6 mg/day.

19. Metabolism –
• Rapid oral absorption.
• Peak concentrations in 1 to 4 hours.
• 85% bound to plasma proteins.
• Hepatic metabolism
• Half life of about 24 hours.

20. S/E-
• Drowsiness
• Dizziness
• Fatigue
• Sedation
• Physical and psychological dependence
• Abrupt discontinuation is prohibited.

21. Α2δ Ligands
• Gabapentin
• Pregablin

22. • α2δ-1, VGCC subunit, (binding site of GPN ‘s)
• NMDAR activity increased by nerve injury
• α2δ-1 + NMDARs  heteromeric complex in spinal cords
promotes surface trafficking and synaptic targeting of NMDARs
Gabapentin or an α2δ-1 C terminus-interfering peptide normalizes
NMDAR synaptic targeting
↓neuropathic pain by - forward trafficking of α2δ-1-NMDAR complexes
Neuropathic
pain

23. α2δ- is an NMDAR-interacting protein that increases NMDAR synaptic delivery in
neuropathic pain

24. GABAPENTIN
Uses-
• Postherpetic neuralgia
• Diabetic neuropathy
• Refractory CRPS type 1
• Migraine headaches
• Other neuropathic states

25. Dose-
• Available as 100-, 300-, 400-, 600-, and 800-mg capsules and 250
mg/5 mL syrup.
• reported adequate pain relief dose- 900 to 2400 mg/day

26. Metabolism :
• well absorbed orally
• Largely unbound to plasma proteins.
• It is not metabolized and is renally excreted.
• Half-life of 5 to 9 hours.

27. S/E-
• Somnolence,
• Diarrhea
• mood swings
• Ataxia
• Fatigue
• Nausea
• Dizziness

28. PREGABALIN
• Fibromyalgia
• Diabetic neuropathy
• Spinal cord injury nerve pain
• PHN
• Other neuropathic States

29. MOA-
EATT-excitatory a
acid transporter

30. Dose-
• Available in 25, 50, 75, 100, 150, 200 & 300mg capsules & 20 mg/mL oral
solution.
• 75 to 150 mg B.D, or 50 to 100 mg TDS (150–300 mg/day) in patients with C.Cr
of at least 60 mL/min.
• Start at 75 mg od/B.D., or 50 mg TDS (150 mg/day).
• Increase up to 300 mg/day within 1 week based on efficacy and tolerability.

32. Metabolism-
• Eliminated by renal excretion as unchanged drug
• Half-life of 6.3 hours in subjects with normal renal function.

33. S/E-
• Angioedema
• Hypersensitivity
• Peripheral edema
• Dizziness
• Somnolence.

35. FELBAMATE
Uses-
• Trigeminal neuralgia
MOA-
• Inhibition of NMDA and AMPA
• Potentiating GABA receptor–mediated chloride channels
• Inhibiting spontaneous discharges from the voltage dependent sodium
channels.

36. Dose-
• Available as 400- and 600-mg tablets and 600 mg/5 mL suspension.

37. S/E-
• plastic anemia
• Fulminant hepatic failure.
• Frequent monitoring with CBCs and LFTs

38. TOPIRAMATE
Uses-
• Post-thoracotomy pain syndrome
• Intercostal neuralgia and other neuropathic pain states.
• Headaches,

39. Topiramate blocks voltage-dependent sodium and calcium channels.
It also inhibits the excitatory glutamate pathway while enhancing effect of GABA.

40. Dose-
• Available as 25-, 100-, and 200-mg tablets.
• Starting dosage -- 25 to 50 mg/day
• Dosage can be increased to 400 mg/day in two divided doses over 8
weeks.

41. S/E-
• kidney stones because of the inhibition of carbonic anhydrase.

42. Sodium channels:

43. Types of VGSC:

44. PHENYTOIN
Use –
• Diabetic neuropathy
• Trigeminal neuralgia
• Neuropathic cancer pain
• Postherpetic neuralgia
• Complex regional pain syndrome (CRPS) types 1 and 2
• Postsympathectomy neuralgia

45. MOA
• Prolongs inactivated state of VSSC
• Reduction of neuronal hyperexcitability
• Stabilizing the neural membrane.

46. Dose -
• Phenytoin is supplied as 30- and 100-mg capsules.
• The recommended dosage is up-to 300 mg/day.
• An exact dosage needed to achieve adequate analgesia has not been
define

47. Metabolism-
• Absorption orally is slow and variable
• peak concentrations - 3 hours or as long as 12 hours.
• 90% bound to plasma proteins
• Metabolized primarily by the liver.
• Half-life of 20 to 60 hours at therapeutic concentrations.
• Narrow therapeutic window and its short- and long-term side effects
limit use.

48. CBCs, LFTs, and serum drug levels need to be closely monitored

49. CARBAMAZEPINE
Uses
•Trigeminal neuralgia
• Best neuropathic analgesic for lancinating or electric-like pain.
• Other neuropathic pain syndromes such as
• GPN, DPN & pain syndromes A/W multiple sclerosis.
• Migraine headaches in pediatric populations

50. binds to VSSN in their inactive conformation thus prevents repetitive and
sustained firing of an action potential

51. Dose
Available as 100-mg chewable tablets
100-, 200-, and 400-mg extended-release tablets
100 mg/5 mL suspension.
• Starting dosage between 100 and 300 mg/ day
• Dose can be slowly increased over several weeks as needed to a
maximum total dose of 1200 mg/day

52. Metabolism-
• Slow absorbed orally, Active metabolite - 10,11-epoxycarbamazepine
• Peak concentrations -- 4 to 8 hours but may be delayed 24 hours
• 75% bound to plasma proteins.
• Half-life is between 10 and 20 hours.
• Narrow therapeutic window.

53. S/E-
• Agranulocytosis and aplastic anemia ( advised to report episodes of fever)
• Hypersensitivity reactions , Stevens-Johnson syndrome
• liver failure.
• hyponatremia
• A baseline CBC and LFTs should be obtained
• Frequent monitoring thereafter, particularly in the first 6 months.

54. OXCARBAZEPINE
• Chemically similar to carbamazepine
• trigeminal neuralgia.

56. NUMBER NEEDED-TO-TREAT (NNT)
• To obtain a clinically meaningful response to treatment
• Lower NNT suggests better efficacy, higher doses associated with
lower NNTs

58. Antidepressants as Analgesics
TRICYCLIC ANTIDEPRESSANTS
• Amitriptyline
• Clomipramine
• Desipramine
• Dothiepin
• Doxepin
• Imipramine
• Nortriptyline

59. MOA of Antidepressants

60. Site of action of Anti-depressants in pain
TCA’S
SNRI
SSRI

61. Indications :
• Post-herpetic Neuralgia
• Painful Diabetic Neuropathy
• Painful Mononeuropathy and Polyneuropathy
• Pain Associated with Spinal Cord Injury
• Fibromyalgia
• Osteoarthritis
• Low Back Pain
• Cancer-Related Neuropathic Pain
• HIV related Sensory Neuropathy

62. Analgesic effects of TCAs:
• Occur more rapidly (a week or less after initiating TCA therapy),
• At lower serum blood levels
• At lower doses than those used for antidepressive effects.
• Pain-relieving properties can be observed at much lower doses, even
1/10th to 1/30th of their FDA-approved maximum.

63. Mode of Action of Tricyclic Antidepressants
EFFECTS MODE OF ACTION
Serotonergic Interferes with serotonin reuptake Alters serotonin binding to receptors
Noradrenergic Interacts with α2 adrenoreceptors
Opioidergic Modifies opioid receptor densities Increases opioid levels in some brain areas
N-Methyl-D-aspartate
(NMDA) receptor
Binds to the NMDA receptor complex Alters NMDA binding characteristics
Adenosine receptor Inhibits adenosine uptake
Sodium channel Blocks sodium channels
Calcium channel Increases densities of L-type calcium channels
Other receptors Inhibits histaminic, cholinergic, muscarinic, and nicotinic receptors

64. S/E-
• Sedation
• Constipation
• Dry mouth
• Sexual dysfunction
• Weight gain
• Arrhythmogenic and may induce seizures in overdose
• Risk for major fetal malformation.

67. SELECTIVE SEROTONIN REUPTAKE INHIBITORS
• Citalopram
• Escitalopram
• Fluoxetine
• Fluvoxamine
• Paroxetine
• Sertraline

68. Uses-
• Shown little effect on most types of pain
• Painful Diabetic Neuropathy
• Fibromyalgia
• Chronic pelvic pain

69. Dose-
• Sertraline -started at 25 mg/day and increased by 25- to 50-mg increments.
• Citalopram - Initial dose of 20 mg once daily- 40 mg/day
Doses above 40 mg/day are not recommended (risk of QT prolongation).
• Escitalopram- twice as potent. ,,, started at 10 mg
• Trazodone’s - 400 mg in divided doses

71. S/E-
• Dry mouth
• Daytime sedation
• Insomnia
• GI upset (particularly with sertraline)
• Constipation
• Tremors
• Weight gain
• Sexual dysfunction (decreased libido, decreased arousal, anorgasmia)
• increased risk for major fetal malformation

72. Serotonin syndrome –
• SSRIs with monoamine oxidase inhibitors (MAOIs) -serotonin syndrome.
• Hyperserotonemia
• C/f: -agitation or altered mental status,diarrhea, hyperthermia, ataxia,
myoclonus, hyperreflexia, and autonomic instability.
• Rx.-supportive, but cyproheptadine may be used to block further
serotonin production.

73. SEROTONIN–NOREPINEPHRINE REUPTAKE
INHIBITORS
• Duloxetine
• Milnacipran
• Nefazodone
• Venlafaxine
• Duloxetine is the first antidepressant to have a specific pain indication

74. Uses-
• Painful Diabetic Neuropathy (Duloxetine)
• Fibromyalgia (Duloxetine)
• Degenerative arthritis

75. MOA-
• Inhibit reuptake of serotonin but also norepinephrine from the
synaptic cleft.
Dose-
• Duloxetine may be started at 20 or 30 mg and then increased to 60 mg
after 1 week.

76. Adverse effects:
• similar to those of the SSRIs.
• Nausea (particularly with duloxetine in the first week)
• hypertension (particularly with venlafaxine), and diaphoresis.
• Do not combine SNRIs with MAOIs and use caution with tramadol, SSRIs.

78. Pain Treatment Guidelines Regarding
Antidepressant Drugs

80. Prescribing recommendations for antiepileptics and
antidepressants in neuropathic pain management

81. Thank you