Josef Bednařík
Department of Neurology, University Hospital Brno and
Faculty of Medicine, Masaryk University Brno
8.11.2019
Headache and pain
PHYSIOLOGICAL MEANING OF PAIN
 Pain is said to be one of nature´s earliest symptoms of
morbidity.
 Pain is one of the most frequent symptom; only a few
maladies do not have painful phases and in most of them
pain is a characteristic without which diagnosis must always
be in doubt.
 At the very beginning, pain serves as a signal while in the
chronic stage it becomes disease itself.
ACUTE AND CHRONIC PAIN
 Acute pain: it lasts several days or weeks and is usually well localised.
It is a sign of tissue involvement caused by a trauma or disease. In
higher intensity it serves as a great psychic burden to the patient.
Therapy directed against the original cause together with analgesic
therapy leads usually to the diminution or replacement of acute pain.
 Chronic pain: the relation between the cause and the pain is not
usually seen; it lasts longer (more than 3 or 6 months), is unproportional
to the evoked stimulus, badly localised. Social and psychological factors
play important roles. It has no signal meaning but becomes the disease
itself and the therapy is directed exclusively against the pain.
NOCICEPTIVE AND NEUROPATHIC PAIN
 Nociceptive pain: pain arises from actual or
thereatened damage to non-neural tissue. Nervous
system function is normal. The pain tends to be
episodic and poorly localized. It is usually time limited,
meaning when the tissue damage heals, the pain
typically resolves. It tends to respond well to treatment
with opioids. Example is inflammation or trauma.
NOCICEPTIVE AND NEUROPATHIC PAIN
 Neuropathic pain: it is the result of lesion or disease of the
peripheral or central nervous system. The pain may persist for
months or years beyond the apparent healing of any damaged
tissues. In this setting, pain signals no longer represent an alarm
about ongoing or impending injury, instead the alarm system itself is
malfunctioning.
 Neuropathic pain is frequently chronic, and tends to have a less
robust response to treatment with opioids, but may respond well to
other drugs such as anti-seizure and antidepressant medications.
Usually, neuropathic problems are not fully reversible, but partial
improvement is often possible with proper treatment.
DEFINITION AND DIAGNOSIS OF NEUROPATHIC PAIN
Definition (IASP 2012):
“….pain caused by a lesion or disease affecting the somatosensory
system.”
Diagnosis:
1. the pain has a neuroanatomically plausible distribution
(corresponding to a peripheral or central territory of innervation
or representation),
2. the history suggests a lesion or underlying disease that can
damage the somatosensory system, and
3. both (1) and (2) have been securely demonstrated either clinically
or by ancillary testing.
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PHARMACOTHERAPY OF NEUROPATHIC PAIN
8.11.2019
Binder and Baron, 2016
Painful clinical
syndrome
1. Choice drugs 2.Choice drugs 3.Choice drugs
Painful
polyneuropathy
incl. Painful
diabetic
polyneuropathy
Calcium
blocker
modulators
(A)
pregabalin tramadol/opioids:
Independently or
in combination
with
paracetamol/
Drugs of 1.
choice (A)
tramadol
antiepilep-
tics
phenytoin (C)
gabapentin morphin
TCA (A) amitriptylin oxycodon Carbamazepine
(C)
nortriptylin fentanyl
imipramin
NMDA
receptor
inhibitors
dextromethorfane
(B)
klomipramin
SNRI (A) duloxetin
venlafaxin
Thioctic acid (B)
CZECH NATIONAL GUIDELINE FOR
PHARMACOTHERAPY OF NEUROPATHIC PAIN 2011
SPECIFIC PAIN NERVE FIBERS
In terms of peripheral pain mechanisms there is indeed a high degree of
specificity, though not an absolute specificity in the von Frey sense. There
are two types of afferent fibers, i.e. the distal axons of primary sensory
neurons, that respond maximally to noxious stimuli.
One type is the very fine, unmyelinated, so called C fibre and the other is
the thinly myelinated A-delta fiber. The peripheral terminations of these
fibers, or receptors, are the free profusely branched nerve endings in the
skin and other organs.
PAIN RECEPTORS
Receptor characteristics
Histology Type Adequate stimulus Nerve fiber type Sensory quality
Naked
endings
Mechano-
sensitive
Noxious mechanical
stimuli
Small myelinated Sharp fast pain
Naked
endings
Polymodal Noxious stimuli:
1.mechanical
2.thermal-above 43o
C and below 14o
C
3. various
chemicals
Unmyelinated Dull or burning
sloww pain, itch
Naked
endings
Thermal 34-50o
C Unmyelinated Warmth
Naked
endings
Termosensi-
tive
Thermal Small myelinated Cold
PERIPHERAL SENSORY NEURON
The peripheral afferent fibers have
their cell bodies in the dorsal root
ganglia; central extensions of these
nerve cells project, via the dorsal
root, to the dorsal horn of the spinal
cord (or , in the case of cranial nerve
afferents, to the nucleus of the
trigeminal nerve, i.e. the medullary
dorsal horn). The fine myelinated
and unmyeli-nated fibers occupy
mainly the lateral part of the root
entry zone and form the tract of
Lissauer. The lateral division of the
posterior root contains mainly the
small pain fibers.
THE DORSAL HORNThe afferent pain fibers, after traversing Lissauer´s
tract, terminate in the posterior gray matter or dorsal
horn. From the cells of termination (mostly in laminae
I,II and V of Rexed), secondary neurons connect
either with ventral and lateral horn cells in the same
and adjacent spinal segments and subserve both
somatic and autonomic reflexes, or project
contralaterally and to a lesser extend ipsilaterally to
higher levels and subserve pain sensation. A-delta
pain afferents, when stimulated, release several
peptide neuro-transmitters; among them is substance
P. Opiate receptors have been found on both
presynaptic terminal axons and postsynaptic
dendrites. Opiates heave been found to decrease
substance P. Small neurons in lamina II, capable of
releasing enkefalin (i.e. endogenous morphine-like
substance), are presumably inhibitory in nature and
modulate nociceptive input in the spinal segments.
AFFERENT TRACTS FOR PAIN
 lateral spinothalamic tract - a fast conducting pathway
that projects directly to the thalamus; it subserves the
sensory-discriminative aspect of pain, i.e., processes that
underlie the localization and identification, and possibly the
intensity, of the noxious stimuli.
 spinoreticulothalamic or paleospinothalamic pathway
contains a more slowly conducting, medially placed
system of fibers, which projects via short interneuronal
chains to the reticular core of the medulla and the midbrain,
and then to the medial and the intralaminar nuclei of the
thalamus; it subserves the affective-motivational aspects
of pain.
ANTEROLATERAL MEDULLAR FUNICULUS
Unilateral section of the anterolateral funiculus produces a relatively
complete loss of pain and thermal sense on the opposite side of the body,
extending to a level three or four segments below the lesion. After a variable
period of time, pain sensation usually returns, perhaps because of the
presence of pathways, that lie outside the anterolateral quadrants of the
spinal cord and that gradually assume the capacity to conduct pain impulses.
It has been suspected that a longitudinal polysynaptic bundle of small
myelinated fibers in the center of the dorsal horn (the dorsal intracornual
tract) constitutes an ancillary pain conducting pathway.
Unilateral medullar hemisection
syndrome Brown-Sequard
THALAMIC TERMINUS
 The direct spinothalamic fibers segregate into two bundles.
 The lateral division terminates in the ventrobasal and posterior groups of
nuclei;
 The medial contingent terminates mainly in the intralaminar complex of nuclei
and in the nucleus submedius;
 Spinoreticulothalamic fibers (paleospinothalamic tract) project onto the
medial intralaminar thalamic nuclei (the same as the medially projecting
direct spinothalamic pathway);
 Projections from the dorsal column nuclei, which have a modulating
influence on the pain transmission, are mainly ventrobasal and posterior
group of nuclei.
INHIBITORY DESCENDING PAIN PATHWAYS
There are also descending fibers
from the brainstem structures that
have an inhibitory effect on
pain.
 One such pathway emanates from
nuclei in the periaqueductal region
of the midbrain and descends in the
anterolateral columns of the spinal
cord to the posterior horns;
 Other goes from the mesencephalic
reticular formation, dorsal raphe
nucleus, locus coeruleus, and nucleus
reticularis gigantocellularis.
THALAMOCORTICAL PROJECTIONS
The ventrobasal complex and posterior group of nuclei send their
axons to two main cortical areas: the postcentral cortex (S1) and
the upper bank of the sylvian fissure (S2).
These areas are concerned mainly with the reception of tactile and
proprioceptive stimuli and with discriminative sensory function,
including pain. The extend to which either area is activated by thermal
and painful stimuli is uncertain. Stimulation of these cortical areas in a
normal, alert human does not produce pain. Some pain afferents
project to subcortical structures, e.g. amygdaloid nuclei, the
hypothalamus, and the limbic brain.
ENDOGENOUS PAIN CONTROL MECHANISMS
There exists an endogenous neuronal system for analgesia, which
can be activated by the administration of opiates or by naturally
occurring brain substances with the pharmacological properties of
opiates.
This endogenous analgesia system was first demonstrated by
Reynolds in 1969, who found that stimulation of ventrolateral
periaqueductal gray matter produced a profound analgesia without
altering behavior or motor activity. Stimulation produced analgesia
(SPA) produces its effect by inhibiting the neurons of laminae I and
V of the dorsal horn, i.e., the neurons that are activated by noxious
stimuli. Opiates act at several loci in the brainstem, as well as on the
neurons of the dorsal horn, suppressing the input from both the A-delta
and C fibers. It appears that their sites of action correspond with the
sites that produce analgesia when stimulated electrically.
ENDOGENOUS PAIN CONTROL MECHANISMS
The endogenous, morphine-like compounds are generically referred to as
“endorphins”, meaning “the morphine within”. Spinal interneurons
containing enkefalin synapse with the terminals of pain fibers and inhibit
the release of the presumptive transmitter, substance P. A deficiency of
endorphins in a particular region would explain persistent or excessive
pain.
Beta-endorphins not only relieve pain, but suppress withdrawal
symptoms. The mysterious effects of placebos and perhaps of
acupuncture are due to activation of an endogenous system that shuts off
pain through the release of endorphins. The descending pain control
systems probably contain noradrenergic and serotoninergic as well as
endorphin-producing links.
Peripheral and
central
mechanisms of
neuropathic pain
Meacham et al.
2017
8.11.2019
TERMINOLOGY
Pain can be spontaneous or evoked
Evoked pain:
 The term hyperalgesia referrs to an increased sensitivity
and a lowering of the threshold to painful stimuli.
 The term allodynia referrs to pain evoked by a stimulus that
usually doesnot evoke pain (i.e. light touch).
HEADACHE - EPIDEMIOLOGY
 Migraine is one of the most prevalent and disabling medical illnesses in the
world.
 WHO ranks migraine as the third most prevalent medical condition and the
second most disabling neurological disorder in the world.
 The 1-year prevalence of migraine in the general population is 12%.
 The annual and lifetime prevalence are 18% and 33% in women, respectively,
and 6% and 13% in men.
 Migraine affects approximately 10% of school-aged children (5–18 years), and at
prepubertal ages (<13 years) the rate of onset of migraine is slightly higher in
boys than in girls.
 Although, for half of patients with migraine onset occurs before age 20 years,
onset can occur at an early age—eg, infantile colic has emerged as perhaps the
earliest manifestation of migraine.
Migraine is most prevalent
between the ages of 25 and
55 years, and the
prevalence rises through
early adult life
and then falls after midlife
(ie, 55 years).
HEADACHE - EPIDEMIOLOGY
CLASSIFICATION OF HEADACHE
https://ichd-3.org/
3rd INTERNATIONAL CLASSIFICATION OF HEADACHE
DISORDERS (2018)
1. Migraine
2. Tension type headache
3. Trigeminal autonomic cephalalgias (incl. Cluster headache)
4. Other primary headache disorders
5.-12. Secondary headaches
13. Painful lesions of the cranial nerves and other facial pain
(incl. Trigeminal neuralgia)
14. Other headache disorders
CLASSIFICATION
OF MIGRAINE
CLASSIFICATION
OF MIGRAINE
DIAGNOSTIC CRITERIA FOR MIGRAINE
I.1 Migraine without aura I.2 Migraine with aura
VISUAL MIGRENOUS AURA
Positive symptoms:
 Photopsia
 Teichopsia (fortification spectra)
Negative symptoms:
 Scotoma
Combined:
 Scotoma scintillans
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PHASES OF MIGRAINE AND CHANGES OF BRAIN ACTIVITY
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Premonitory:
Fatigue,
Cognitive difficulty,
Heightened sensory
Awareness,
Food craving,
Mood changes,
Anorexia
Aura:
Scotoma,
Fortification spectrum,
Paresthesia,
Weakness,
Vertigo
Headache phase:
Headache,
Nausea and vomiting,
Photophobia,
PhonophobiaPostdrome:
Fatigue,
Cognitive difficulty,
Heightened sensory
awareness,
Food craving
PREMONIOTORY: ACTIVATION OF MENINGEALS
NOCICEPTORS BY INCREASED PARASYMPATHETIC TONE
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Dodick: Headache 2018
8.11.2019MECHANISM OF AURA
Dodick: Headache 2018
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Dodick: Headache 2018
TRIGGERING OF PAIN VIA ACTIVATION OF TRIGEMINOVASCULAR
PATHWAY
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Dodick: Headache 2018
CRGP SIGNALLING IN THE TRIGEMINOVASCULAR SYSTEM
SEROTONINE RECEPTORS AND TRIPTANS
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COMPLEX
PATHOPHYSIOLOGY
OF MIGRAINE
Charles: Lancet
Neurol 2018
PET FINDINGS
Migraine is a brain disease, maybe progressive
OPHTHALMOSCOPIC FINDING IN RETINAL MIGRAINE
TREATMENT OF MIGRAINE
I. Non-pharmacological treatment of migraine
The avoidance of identified aggravating (long-term effect) or triggered (shortterm
< 48 hours) factors:
 stress
 the menstrual cycle
 certain foods
 trauma
 caffeine withdrawal
 If there is a reproducible trigger than its elimination will reduce the
frequency of headaches. Unfortunately, this is often not possible because of
the lack of a single reproducible trigger.
 Other non-pharmacological treatments has been suggested for migraine
patients, including relaxation exercises, biofeedback, massage,
acupuncture, chiropractic, osteopathy, and naturopathy, but their effect is
not proven.
TREATMENT OF MIGRAINE
I. Non-pharmacological treatment of
migraine
Coppola et al.: Cephalalgia 2015
TREATMENT OF MIGRAINE
IIII. Drug treatment
A. Preventive treatment
 beta blockers (propranolol, metoprolol, atenolol
 calcium blockers (verapamil, flunnarizine)
 anticonvulsants (gabapentin, topiramate, valproic acid)
 antidepressants (tricyclic antidepresants, venlafaxin)
 angiotensin converting enzyme inhibitors or angiotensin receptor
blockers (lisinoprin, candesartan, cyproheptadine, ibuprofen,
ketoprofen, naproxen)
 No one drug is superior to the other; the choice of suitable treatment is
often a case of selecting from drugs on the basis of their side effects.
TREATMENT OF MIGRAINE: PREVENTIVE
TREATMENT OF MIGRAINE
II. Drug treatment
B. Treatment of acute attacks
1. Non-specific treatment
 Analgesic drugs
 paracetamol
 codeine phosphate
 Anti-inflammatory drugs
 acetylosalicylic acid
 ibuprofen
 diclofenac
 naproxen
 ketorolac
 Anti-emetics
 metoclopramide
2. Specific antimigraine
treatment
 Ergotamines
 ergotamine
 dihydroergotamine
 Agonists of 5-HT1B and 5-HT1D
 sumatriptan
 zolmitriptan
 naratriptan
 rizatriptan
 eletriptan
 almotriptan
 frovatriptan
TREATMENT OF MIGRAINE: ACUTE
CGRP TREATMENTS
8.11.2019
Gepants: účinné, ale toxické
mABS bindings to CRPR:
 Galcanezumab
 Eptinezumab
 Frenezumab
mAB binding to the CGRP receptor:
 Erenumab
This mABS proved to be efficient in
reduction of both number and severity of
both headache attacks in recurrent
migraine, and in reduction of days with
headache in chronic migraine
8.11.2019
Tension-type headache:
 is not of pulsating quality
 Is not unilateral
 Is not aggravated by physical
activity
 Is not of severe intensity
 Is not accompanied by nausea,
vomitting, photofobia or
phonofobia
Paroxysmal hemikrania: respond
absolutely to indomethacin!!!
3.1 CLUSTER HEADACHE
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4.OTHER PRIMARY HEADACHE
DISORDERS
THE SECONDARY HEADACHES
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Secondary headache
Type Prevalence (%)
Systemic infection 63
Head injury 4
Drug-induced headache 3
Subarachnoid hemorrhage <1
Vascular disorders 1
Brain tumor 0-1
Rasmussen et
al. 1995
TRIGEMINAL NEURALGIA: EPIDEMIOLOGY
Prevalence is 150/milion, women:men = 3:2 (3:1), mostly > 60
years.
Arterial hypertension is established risk factor.
NEW CLASSIFICATION OF TRIGEMINAL NEURALGIA
 Etiology
1. Classical TN (neurovascular conflict – NCV - with morphological
changes of trigeminal nerve due to compression)
2. Idiopathic TN (no NCV or NCV with no morphological changes of
trigeminal nerve)
3. Secondary TN (other pathology or disease as a cause)
 Clinical form (phenotype):
1. Pure paroxysmal form
2. TN with concomitant continuous pain
8.11.2019
CLASSICAL TRIGEMINAL NEURALGIA
 It involves mostly 2. and 3. trigeminal branch, 1. branch is involved in 5% only.
 Pain is sharp, lancinating, like electrique shocks, sometimes continues as
ongoing dull pain.
 Pain is mostly unilateral (bilatera in 3% only).
 Trigger zone is present in 50% of patients. Pain could be triggered by chewing,
cleaning the tooth, speaking, washing, yawning, laughing, blowing one‘s nose.
 There is no motor or sensory deficit in trigeminal zone.
 Remisions could last months or years.
TRIGEMINAL NEURALGIA: DIAGNOSTIC CRITERIA
Diagnostic criteria are based onthe characteristics of pain, normal neurological
findings and the absence of clear cause of pain.
A. Attacks of pain lasting from a fragment of second to 2 minutes in an area of
one or more trigeminal branches and complying with criteria B and C.
B. Pain has to have one of the following characteristics:
 Intense, sharp, superficial, stabbing
 Induced from a trigger zone or triggeering factors
C. Atacks are stereotypic in an individual patient
D. No other pathology or disease as a cause of pain.
CLASSICAL TRIGEMINAL NEURALGIA
Neurovascular confict is a cause – a compression of
trigeminal nerve by a vessel (mostly a. cerebelli superior, less
frequently by a. cerebelli anterior inferior or a. basilaris) 4-6
mm after the exit from the brainstem (transitional zone from
central – oligodendroglia – to peripheral – Schwann cells –
myelin.
NEUROVASCULAR CONFLICT
NEUROVASCULAR CONFLICT
SECONDARY TRIGEMINAL NEURALGIA
It is a symptom of another disease.
 Is is possible to reliably clinically distinguish secondary and classical
TN?
There are samo clues to secondary TN:
 younger age
 worse therapeutical response
 involvement of 1. trigeminal branch
 sensory deficit
 According to last guideline it is NOT possible to clinically differentiate
classical and secondary TN!!!
MRI focused on NCV and other causes of TN should be a part of routine
diagnostic algorithm.
SECONDARY TRIGEMINAL NEURALGIA
 3% of TN is caused by multiples sclerosis (MS), especially between
20-40 years; 1% of MS patients develop TN
 Painful ophthalmoplegia syndrome (Tolosa-Hunt) – granulomatous
inflammation of the cavernous sinus)
 Compression of the trigeminal nerve in the cerebellopontine angle –
schwannoma of n.VIII, V, meningeoma
 Other brainstem lesions – syringobulbia, basilar aneurysm
 Postherpetic neuralgia (herpes zoster ophthalmicus)
THERAPY OF TN
A. Acute treatment
1. I.v. phenytoin or lidocain (low evidence)
B. Chronic treatment
1. Carbamazepine, oxcarbazepine (high evidence)
2. Lamotrigine, baclofen, phenytoin, pregabalin, gabapentin, Botox (low evidence)
3. Microvascular decompression
4. Gamma knife radiosurgery
5. Ablative neurosurgical techniques
C. Causative treatment in secondary TN