Exam 3 CNS

Migraine headaches clinical presentation

POUND

• pulsating with photophoia Phonophobia, osmophobia

• Onset gradual

• Unilateral

• Nasuea

• Disabling intensity

4–72 hours

Tension type headaches clinical presentation

• mild to moderate pain intensity

• Dull nonpulsatile tightness/pressure

• bilateral

• hatband pattern

• Associated symptoms uncommon

  • Mild photophobia or phonophobia

  • may have tender spots on pericranial or cervical muscles

• No premonitory symptoms or aura

• disability minor compared to migraines

30 minutes–7 days for typical episodic attacks

Cluster headache Clinical presentation

• Excruciating penetrating pain

• Unilateral in orbital ,supraorbital or temporal locations

• Deep, non pulsating behind the eye

• sudden onset with short duration

• Circadian rhythm

• lasts weeks to months

• more common at night in spring and fall

Restless/pacing/agitated

Acute treatment Serotonin Receptor Agonists Triptans Mechanism

Selective aginsits if 5-HT1b and 5-HT1d receptors

• Vasoconstriction of intercranial blood vessels

• inhibition of vsoacative peptide

• inhibition of transmission of oain signaks to thalamus

Acute treatment: Serotonin Receptor Agonists Triptans AE’s

• Parasthesias (tingling/numbness) Fatigue, Dizziness, Flushing, somnolence

• Risk of increased BP

• Taste perversion and nasal discomfort

• Triptan sensations

-tightness pressure heaviness or poain in chest neck or throat

Triptans Containdications

• Ischemic Heart disease

• Uncontrolled HTN

• Stroke/TIA

• Peripheral vascular disease

• Hemiplegic migrain/basilar migraine

Triptan drug interactions

DO NOT GIVE within 24 hrs of ergotamine or another triptan.

Risk of serotonin syndrome woth other serotonergic agents

Triptan Oral tablets

Sumatriptan        Almotriptan

Zolmitriptan        Frovatriptan

 Naratriptan         Eletriptan

        Rizatriptan

Triptan Oral Disintegrating tablets ODT

Zolmitriptan

Rizatriptan

Triptan Nasal sprays

Sumatriptan

Zolmitriptan

Triptan Nasal powder / Sub Q

Sumatriptan

Acute treatment: Ergot alkaloids and derivatives (Ergots) mechanism

Non selective seratonin agonist of 5-HT1 receptors

vasoconstriction of intracranial blood vessels

considered for those who do not benefit from triptans

Acute treatment: Ergot alkaloids and derivatives (Ergots) AE’s

• Nasuea and vomiting most common

  • pretreatment with antiemetic

• Abdominal pain, weakness, fatigue, paresthesias, muscle pain, diarrhea, chest tightness

• Rhinitis and taste disturbance with nasal formulations

• Ergotism (rare)

  • Severe peripheral ischemia due to intense vasoconstrictor effects

  • Cold, numb, painful extremities; continued paresthesias; diminished peripheral pulses; claudication; gangrenous extremities

• MI, bowel ischemia, brain ischemia (rare)

Ergots contraindications

• Severe renal/hepatic impairment

• coronary,cerebral or peripheral vascular disease

• Uncontrolled HTN

• sepsis/ vasopressor

• Pregnancy

• DO NOT USE within 24 hrs of triptans

• BBW → life threatening peripheral ischemia of extrmeties with CYP3A4 inhibitors

Ergots dosage forms

Ergotamine -

• Sublingual Monotherapy

• Oral tablet/Rectal supp w caffeine

Dihydroergotamine -

• SubQ

• IM

• IV

Acute treatment: Seratonin receptor agonists (ditans) Mechanism

• Serotonin 5-HT_1F receptor agonist

• Decreased stimulation of trigeminal system without causing vasoconstriction → useful for patients with contraindications to triptans/ergots (

Acute treatment: Seratonin receptor agonists (ditans) AE’s

• Dizziness, drowsiness, fatigue, paresthesias, sedation, nausea, vomiting

• CNS depression 

  • Do not administer unless patient can wait at least 8 hours between dose & operating heavy machinery or driving

• Risk of medication overuse headache

Ditans drug interactions

• Risk of serotonin syndrome with other serotonergic meds

• caution with alcohol and CNS depressants

• decreased heart rate with other heart rate lowering meds

• P-gp inhibitor

Lasmiditan dosage formulations

Oral tablet only

Acute treatment: CGRP receptor agonists (gepants) mechanism

• Calcitonin gene-related peptide (CGRP) receptor antagonist

• Antagonize/blocks CGRP induced neurogenic vasodilation to block pain signals from the trigeminal nerve

• Works without causing vasoconstriction of blood vessels → useful for patients with contraindications to triptans/ergots 

Acute treatment: CGRP receptor agonists (gepants) AE’s

• Nausea, drowsiness

• Warning for hypersensitivity reactions, including delayed serious reactions

• Taste disturbances with zavegepant

CGRP receptor agonists (gepants) dose formulations

Ubrogepant	Oral tablet
Rimegepant	ODT
Zavegepant	Intranasal spray

When starting prevention in migraine plan

KEEP ACUTE TREATMENT

Initiating, Reassessing, and Discontinuing Migraine Therapy

Start	Frequent/disabling attacks, poor acute options, overuse risk, or patient preference
Titrate	Start traditional oral agents low and increase as tolerated
Assess	Track headache days, severity, disability, rescue use, and adverse effects
Adequate trial	About 3 months at an effective/tolerated oral dose before calling it ineffective; maximal benefit may take longer
Successful therapy	A meaningful target is often roughly 50% fewer migraine days, plus better function

Consider taper

After sustained good control, often 6–12 months, with an individualized plan

Menstrual Migraines

• Acute treatment: NSAIDs or triptans

• Short-term preventative treatment if regular menstrual periods & acute treatment unsuccessful: naproxen or frovatriptan

  • Start 2-3 days prior to the first day of menses and continued during menstruation

• If all above ineffective: continuous treatment with combined hormonal contraceptives or progesterone-only contraceptives 

Headache Alarm Symptoms

• Acute onset of first or worst headache ever

• Accelerating pattern of headache following subacute onset

• Onset of headache after age 50

• Headache associated with systemic illness

  • Fever, nausea, vomiting, stiff neck, rash

• Headache with focal neurologic symptoms or papilledema

• New onset headache in a patient with cancer or HIV

• Thunderclap headache

  • Severe headache that peaks within 60 seconds

Migraine prophylactic treatment CV meds

Beta blockers

• Metoprolol

• Propanalol

• Timolol

Useful in comorbid HTN tachycardia or angina

Beta blocker AE’s

• Bradycardia, hypotension, fatigue, impotence, drowsiness, sleep disturbances, vivid dreams, depression, memory impairment

• Hyperkalemia, AKI, hypotension

Migraine prophylactic treatment Antidepressants

TCA - Amitriptyline

SNRI - Venlafaxine

useful in comorbid depression anxiety/ neuropathic pain

Amitryptyline Adverse effects

• Anticholinergic adverse effects

  • Dry mouth, constipation, urinary retention, blurred vision

  • Caution in benign prostatic hyperplasia and glaucoma

• Administer in the evening or at bedtime due to sedation

• Weight gain, orthostatic hypotension, cardiac conduction abnormalities

Venlafaxien AE

• Nausea and vomiting

• Drowsiness, dizziness

• Monitor for serotonin syndrome if used with triptans or other serotonergic agents

Migraine prophylactic treatment Antiepileptics

Topiramate

Valproic acid

• May be useful in comorbid seizures

• Topiramate may be useful in obesity

• Topiramate is the most extensively studied medication for migraine prophylaxis

Topiramate AE’s

• Paresthesias (50% of patients)

• Dizziness, drowsiness, fatigue

• Caution in cognitive impairment due to disturbances in attention, memory impairment, and language problems

• Diarrhea, taste perversion

• Weight loss 

• Metabolic acidosis

• Caution in a history of kidney stones due to nephrolithiasis

• Warning for fetal harm

Divalproex Sodium/Sodium Valproate/Valproic Acid AE’s

• BBW: 

  • Pancreatitis

  • Hepatotoxicity (baseline LFTs)

  • Fetal risk

• Nausea and vomiting 

  • Common, early side effect

  • Lower incidence with gradual titration of dose

• Weight gain, tremor, hair loss, somnolence

• Thrombocytopenia

Migraine prophylactic treatment Onabotulinumtoxin A (Botox)

• if > 15 headache days per month (chronic migraine)

Hormonal contraception with migraine

• Combination hormonal contraception (estrogen/progestin) not recommended for use in migraine with aura

• Two-fold increased risk of stroke in those taking estrogen-containing contraceptives

Lasmiditan Safety

Sedation/dizziness, serotonin syndrome, additive CNS depression; no driving for at least 8 hours; one dose maximum per 24 hours

Oral gepants safety

Agent-specific CYP3A/P-gp interactions, hypersensitivity, renal/hepatic restrictions

Nasal zavegepant safety

Taste disturbance and nasal effects; interaction rules differ from oral gepants

CGRP antibodies safety

Hypersensitivity and injection/infusion effects; current product warnings include vascular concerns and, for several products, severe constipation

TTH Pharmacologic Therapy

• Mainstay of acute therapy: simple analgesics and NSAIDs (alone or in combination with caffeine)

• Preventive treatment appropriate for chronic TTH and can consider in frequent episodic TTH if > 2 days per week, lasts more than 3-4 hours, or if substantial disability

  • Tricyclic antidepressants most often used

TTH Non-Pharmacologic Therapy

Stress management, relaxation, CBT, biofeedback; address posture and musculoskeletal contributors

nociceptive pain

Pain. arising from tissue damage

(regular injury/inflammation)

peripheral and nervous system

Neuropathic pain

pain arising from damage to damage reporting system - nervous system

neural damage,pinching,irritation

peripheral and nervous system

Central sensitization/ nociplastic pain

Altered pain processing in the Central nervous system

non-nociceptor receptors

low pain threshold

9fibromyalgia,IBS, chronic low back pain

Nociceptive pain types

Somatic

Visceral

Somatic pain profile

Localized

pinprick, stabbing, sharp pain

A-delta fiber activity located in periphery

Visceral pain profile

generalized

Ache, pressure, or sharp pain

C fiber activity involved deeper innervation

Visceral organs

Neuropathic pain profile

Radiating or specific

Burnign, prickling, tingling, electric shock like, lancinating

Dermatomal (periphery) or non dermatomal (central)

damage to nerve itself causes pain

Nociplastic Pain

Altered nociceptive processing without tissue injury or nerve lesion fully explaining the pain

• Often widespread pain, hypersensitivity, poor sleep, and fatigue

nociception

sensory processes that leaf to processing painful stimuli

Allodynia

pain due to stimulus that normally dont cause pain (tactile, cold)

Analgesia

Pain relief

Hyperalgesia

Exaggerated pain from a stimulus that causes pain

Nociceptive Circuit

1. Depolarization of primary sensory neurons

2. Action potential communicated from

periphery → dorsal root →brainstem/thalamus → cortex and limbic system

3. Modulation at all levels by remote and local excitatory/inhibitory internuerons

peripheral transduction

Chemical , mechanical, thermal stimuli

voltage gated sodium channels convert depolarization to an action potential

Speeds of peripheral transduction

• Aβ: A-beta

  • Rapidly conducting, respond to mechanical stimuli (light touch, vibration, movement of hair)

• Aδ: A-delta

  • Conduct with intermediate velocity (respond to cold, heat & high-intensity mechanical stimuli

  • Thinly myelinated; faster, sharp, localized “first pain”

• C-fibers:

  • conduct slowly. Multimodal (heat, warmth, intense mechanical stimuli, chemical irritants)

Neurotransmission in the Spinal Cord Dorsal Horn

• AP reaches dorsal horn, neurotransmitter released

• Role of calcium channels

• Sodium/ Calcium influx

Inhibitory Regulation of Neurotransmission

Local inhibitory interneurons & projections from brainstem to spinal cord

↓presynaptic Ca2+ conductance

↑post synaptic K+ conductance

↓adenylyl cyclase activity

Peripheral sensitization

contributes to allodynia & hyperalgesia

Sensitizing agents

• PGE2,

• IL1-beta

• NGF

• Histamine

Increased likelihood of action potential initiation and propagation

Central sensitization

also contributes to allodyniua and hyperalgesia

BDNF substance P

kinase activation

Enhanced short-term and long term synpatic excitability

MoA of anti inflammatory drugs

a. Inhibit formation of Prostaglandins

b. Inhibit immune functions

c. Antagonists of chemicals released by the immune system (i.e. histamine)

How inflammation causes pain

1. Activation of Pain Receptors

2. Swelling and Pressure

3. Release of Immune Cells

4. Alterations in Nerve Function

5. Psychological Factors

Activation of Pain Receptors

Inflammation triggers the release of prostaglandins, bradykinin, and other chemicals that sensitize pain receptors (nociceptors).

Swelling and Pressure

Inflammation causes swelling due to the accumulation of fluid in the injured area. This swelling can put pressure on nerves, causing pain.

Release of Immune Cells

Immune cells, such as neutrophils and macrophages, infiltrate the inflamed area and release substances that contribute to pain. For example, neutrophils release enzymes that damage tissue, while macrophages release cytokines that activate pain receptors

Alterations in Nerve Function:

Chronic inflammation can lead to changes in nerve structure and function. This can result in persistent pain, even after the initial injury has healed.

prostaglandins

Potent chemical messengers, call in immune system, regulate inflammation, body temperature, analgesia, platelet aggregation.

Synthesized and released on demand.

Short half life: seconds to minutes

COX-1 gene process

regular process gene → mRNA → Arachidonic acid → prostaglandins

COX-2 gene process

Induced by

• Oxidative stress

• Injury

• Ischemia

• Seizures

• ND

Anticonvulsants in pain Gabapentinoids

Primarily for neuropathic pain

Gabapentin/pregablin

• Used for postherpetic neuralgia/ diabetic peripheral neuropathy

• Pregablin used in fibromyalgia

• Renally dose adjusted

Trigeminal neuralgia first line treatment

Anticonvulsants- Carbamazepine or oxcarbazepine

Antidepressants

TCA - Amitriptyline / SNRI’s

First line for neuropathic pain

• also used in low back pain/fibromyalgia

mechanism of action of how opiates can lead to euphoria.

Opioids activate mu receptors on inhibitory GABA neurons in reward circuitry, including the ventral tegmental area.

– Mu receptors are Gi/o-coupled: activation reduces adenylyl cyclase activity, reduces presynaptic calcium entry, and increases potassium conductance.

– Inhibiting a GABA neuron means less inhibition of a dopamine neuron. This is disinhibition, not direct stimulation of dopamine receptors.

Mu activation → less GABA release → dopamine neurons become more active → increased dopamine signaling in the nucleus accumbens → reward/euphoria.

The Pharmacist’s Role in Acute and Chronic Opioid Therapy

• Identify patients at risk for abuse/misuse and intervene when possible

• Educate patients on goals of therapy, realistic expectations, opioid safety, appropriate follow up and reassessment, and opioid discontinuation when necessary

• Use non-pharmacologic and adjunct therapies whenever possible

• Utilize the state PDMP

• Provide naloxone per PA Act 139

Lidocaine 5% patch MoA

• Voltage-gated sodium-channel blockade; localized neuropathic pain, especially PHN

Typically up to 3 patches for 12 hours in 24, then off;

Topical diclofenac MoA

• COX inhibition for localized musculoskeletal/OA pain

Measure with the dosing device; avoid damaged skin and unnecessary duplicate NSAIDs

Low-dose capsaicin MoA

• TRPV1 activation followed by reduced nociceptor function

Burning is common initially; regular use is needed, not occasional rescue application

Capsaicin 8% system MoA

Clinician-applied treatment for selected peripheral neuropathic pain

60 minutes for PHN; 30 minutes on feet for diabetic neuropathy; generally no more often than every 3 months

Fentanyl patch MoA

Systemic mu-opioid agonism

Delayed onset, opioid tolerance required, heat/transfer precautions

Buprenorphine patch

Systemic partial mu agonism

Chronic-pain product with formulation-specific dosing and heat precautions

Oxycodone BBW

CYP3A4 interactions can cause fatal overdose/respiratory depression

Codeine and tramadol BBW

Life-threatening respiratory depression/death in children; risk related in part to variable CYP2D6 metabolism

Methadone BBW

QT prolongation/torsades plus respiratory-depression and interaction risks

Transdermal fentanyl BBW

Serious/fatal respiratory depression; accidental exposure and increased absorption with heat

Nonaspirin prescription NSAIDs BBW

Serious cardiovascular thrombotic events and GI bleeding/ulceration/perforation; contraindicated in the CABG setting

ketorolac BBW

Major GI, renal, bleeding, and cardiovascular risks; 5-day total systemic-treatment limit

Carbamazepine BBW

SJS/TEN; aplastic anemia/agranulocytosi

Lamotrigine

Serious skin rash, including SJS/TEN; greater risk with rapid titration or valproate

Oral dantrolene BBW

Hepatotoxicity

Intrathecal Baclofen BBW

Potentially fatal abrupt withdrawal

TCA adverse effects

anticholinergic effects, orthostasis, sedation, and cardiac-conduction problems;

Chronic opioid use Adverse effects

Tolerance

Hyperalgesia

• increased sensitivity to pain

Physical dependence

Constipation

• does not subside with tolerance

Opioid adverse effects

• Constipation

• Naseau/vomiting

• Sedation

• Resp depression

• Pruritis

• Mood changes

• Sexual dysfunction

opioid induced constipation management

best management = prevention

• counsel on proper fluid/fiber intake

• Stimulant laxative ± stool softerner (senna + docusate)

opioid induced nasuea/vomiting management

• Dose reduction

• Switchig opioids

• change route of administration

• atiemetic if needed

• take with food (except oxymorphone)

• other causes

Opioid-Induced Sedation & Respiratory Depression prevention/treatment

Prevention

• Appropriate patient selection (caution in pulmonary dysfunction, sleep disordered breathing, head injury, elderly)

• Minimize polypharmacy with other CNS depressants (eg. benzodiazepines, gabapentin, pregabalin, muscle relaxants, etc), sedating medications, or alcohol

• Titrate dose cautiously

Treatment

• Dose reduction, switch opioids, change route of administration

• Naloxone if minimally responsive, breathing rate low for respiratory depression

• Consider adding a stimulant for sedation

Opioid-Induced Pruritus management

• Dose reduction, switch opioids, change route of administration

• Antihistamines

  • Caution in older adults

  • Dry mouth, constipation, blurred vision, confusion

• Nonpharmacologic management

  • Topical lotions

Opioid tapering

Taper opioids when harm outweighs benefit to reduce dose or discontinue

Should be done slow enough to minimize withdrawal

Gradual taper of 5% to 20% every 4 weeks

○ Allows for neurobiological and psychological adaptations

○ May be faster or slower

How a Painful Stimulus Reaches Conscious Perception

• Transduction: tissue injury/heat/pressure/chemicals activate sensory endings and depolarize the nociceptor.

• Propagation: voltage-gated sodium channels generate and carry an action potential along the primary afferent.

• Spinal synapse: the signal reaches the dorsal horn; calcium entry triggers release of glutamate and neuropeptides such as substance P.

• Ascending transmission: second-order pathways cross and ascend toward brainstem/thalamic structures, with onward processing in cortical and limbic regions.

• Perception: the brain assigns sensory location/intensity and emotional meaning.