PAIN, NEUROPATHIC PAIN, HEADACHE
Josef Bednařík
Neurology – lecture (aVLNE9X1p)
General neurology questions:
3. Pain (anatomy, characteristics, types of pain)
7. Cranial nerve V (anatomy, function, signs and symptoms of
lesion)
Special neurology questions:
37. Headache (definition, classification)
38. Migraine, cluster headache
39. Trigeminal and glossopharyngeal neuralgias
10.9.2021
2015
Pain, neuropathic pain
2020
̶ Google
̶ Pain: 863.000.000 references
Neuropathic pain: 1.200.000 references
̶ Medline
̶ Pain: 6610 articles
̶ Neuropathic pain: 260 articles
̶ 2.020.000.000 references
̶ 5.250.000 references
̶ 185.000 articles
̶ 8507 articles
Pain is probably the most frequent and one of the earliest medical symptoms
at all. There is also increasing awareness of a neuropathic pain as a specific
neurological syndrome with high prevalence in a population (estimated up to
8%)
Neurology - lecture (aVLNE9X1p)
Definition of pain
The revised IASP definition of pain (2020):
“An unpleasant sensory and emotional experience associated
with, or resembling that associated with, actual or potential
tissue damage.”
Neurology - lecture (aVLNE9X1p)
Clinical classification of pain:
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.
Neurology - lecture (aVLNE9X1p)
Neurology - lecture (aVLNE9X1p)
Patophysiological classification of pain:
nociceptive and neuropathic pain
̶ To great extend pathophysiological classification overlaps with a clinical one:
acute pain is mostly nociceptive and most chronic pain cases belongs to
neuropathic pain type or has at least neuropathic component.
̶ Nociceptive pain: pain arises from actual or threatened damage to non-neural
tissue. Nervous system function is normal. 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 a 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
and is frequently chronic. In this setting, pain signals no longer
represent an alarm about ongoing or impending injury, instead the
alarm system itself is malfunctioning.
̶ Usually, neuropathic problems are not fully reversible, but partial
improvement is often possible with proper treatment.
Neurology - lecture (aVLNE9X1p)
Definition of neuropathic pain
Definition (IASP 2012):
“….neuropathic pain is caused by a lesion or disease affecting the
somatosensory system.”
Neuropathic pain is a clinical syndrome with different types of pain
and frequent and important co-morbidities, such as depression,
anxiety and sleep disturbances.
Neurology - lecture (aVLNE9X1p)
Clinical symptoms and signs as a part of a
neuropathic pain
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Terminology
̶ Pain can be spontaneous or evoked
̶ Evoked pain:
̶ The term hyperalgesia refers to an increased sensitivity and a
lowering of the threshold to painful stimuli.
̶ The term allodynia refers to pain evoked by a stimulus that
usually does not evoke pain (i.e. light touch).
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Comorbidities of neuropathic (chronic) pain
Neurology - lecture (aVLNE9X1p)
Epidemiology of neuropathic pain
▪20-24% of diabetics suffer from painful diabetic polyneuropathy
▪25-50% of patients older >50 years with herpes zoster develop chronic
postherpetic neuralgia (≥3 months after healing of skin rush)
▪Up to 20% post-mastectomy patients suffer with post-mastectomic pain
▪1/3 of patients with carcinoma suffer from neuropathic pain (isolated or in
combination with nociceptive pain)
▪7% of patients with low back pain has neuropathic component of pain
Epidemiology of neuropathic pain
According to neuropathic pain prevalece of neuropathic pain in population ranges
between 1.5 - 6-8 % of population and serves as an important socioeconomic problem
Disease or clinical syndrome with neuropathic
pain
Prevalence/incidence of neuropathic pain
Diabetic polyneuropathy 15-25% of diabetic population
HIV polyneuropathy 35 % of HIV-positive individuals
Postherpetic neuralgia 11-40/100 000/year
Trigeminal neuralgia 5-28/100 000/year
Carpal tunnel syndrome 180/100 000/year
Cervical radiculopathy 83/100 000/year
Stroke 8-10%
Multiple sclerosis 28-80% (trigeminal neuralgia 2-6 %) of MS cases
Spinal cord injury 10-80% of spinal cord injury cases
Anatomical correlate of neuropathic pain
Neurology - lecture (aVLNE9X1p)
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 Termosensi-
tive
Thermal 34-50o
C Unmyelinated Warmth
Naked endings Thermal Small myelinated Cold
Specific pain receptors and nerve fibers
̶ Pain receptors (nociceptors) are naked
nerve endings
̶ Pain stimuli are transmitted by
unmyelinated (C) and thinly myelinated (A
delta) afferent sensory fibres.
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Picture taken from: https://faculty.washington.edu/chudler/cv.html
Neurology - lecture (aVLNE9X1p)
Anatomical dissociations of somatosensory
pathways at spinal cord level
̶ There is an anatomical dissociation of two main
afferent somatosensory pathways at spinal cord
level:
̶ spinothalamic pathway, formed by 2nd sensory neuron which
after interpolation in the dorsal horns and crossing via
anterior commisure goes up via contralateral anterolateral
spinal columns (and contributing to the perception of pain
and temperature),
̶ dorsal columns and medial lemniscus system formed by
fibres of the 1st sensory neurons going up via ipsilateral
dorsal columns. Baehr M, Frotscher M. Topical
diagnosis in Neurology. 6th ed.
Thieme 2014
Inhibitory descending pain pathways
̶ There are also descending
fibers from the brainstem
structures that have an
inhibitory effect on pain.
̶ These neurons are opioidergic
and serotoninergic.
De Vrij, E. Acupuncture and pain relief. 2010
Neurology - lecture (aVLNE9X1p)
Pathophysiology of neuropathic pain
̶ Lesion or disease of the somatosensory system is
a prerequisite for development of neuropathic pain,
but different pathophysiological mechanisms may
be involved:
̶ Peripheral sensitization
̶ Hyperexcitability (ectopic discharges)
̶ Central sensitization
̶ Synaptic reorganization
̶ Denervation hypersensitivity
̶ „Wind-up“ phenomenon
̶ Loss of inhibitory control
̶ Such a lesion, however, does not necessarily lead
to neuropathic pain!!!
Meacham et al. Curr Pain Headache Rep 2017
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Pharmacotherapy of neuropathic pain
Neurology - lecture (aVLNE9X1p)
̶ In contrast to nociceptive pain, pharmacoterapy of neuropathic
pain is based on s.c. atypical analgesics (co-analgesics).
̶ They are very often used and known also as antiepileptics
(anticonvulsants) or antidepressant drugs.
Czech national guideline for pharmacotherapy
of neuropathic pain 2011
Neurology - lecture (aVLNE9X1p)
Adopted from: Bednařík J,
Ambler Z, Opavský J, Keller O,
Rokyta R, Mazanec R. Klinický
standard farmakoterapie
neuropatické bolesti. 2011.
Pharmacotherapy of neuropathic pain
10.9.2021
Binder and Baron, 2016
Definition and classification of headaches
̶ Headache, i.e. pain perceived in the head region (or propagated to it), is very
frequent. Almost all individuals experience headache at least in the shortterm.
Headache thus belongs among the most frequent neurological
symptoms or diseases.
̶ The main classification of headaches according to etiology comprises:
̶ Primary headaches (disease)
̶ Secondary headaches (symptom)
̶ Painful cranial neuropathies (i.e. pain in the distribution of a cranial nerve)
and other facial pains.
Neurology – lecture (aVLNE9X1p)
Classification of headache
https://ichd-3.org/
Neurology – lecture (aVLNE9X1p)
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
Neurology – lecture (aVLNE9X1p)
Epidemiology of headaches
̶ Primary headaches form more than 90% of headaches cases.
Acute headaches in pregnancy. Raffaelli et al. J Headache Pain 2017.
Picture taken from: https://www.medscape.org/viewarticle/451273_2
Neurology – lecture (aVLNE9X1p)
Epidemiology of migraine
̶ 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 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.
Neurology – lecture (aVLNE9X1p)
Classification
of migraine
Neurology – lecture (aVLNE9X1p)
Classification
of migraine
Neurology – lecture (aVLNE9X1p)
1.1 Migraine without aura
Diagnostic criteria for migraine
1.2 Migraine with aura
Neurology – lecture (aVLNE9X1p)
Pathophysiology of migraneous aura:
„cortical spreading depression“
Dodick DW. Cephalalgia 2018
Neurology – lecture (aVLNE9X1p)
Migrenous visual aura
Positive symptoms:
̶ Photopsy (flashes)
̶ Teichopsy („fortification spectra“)
Negative symptoms:
̶ Scotomas
Combined symptoms:
̶ Scotoma scintillans
Banyas GT, Review of Optometry, 2015
Chawla J. Drugs and Diseases, 2019
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Dodick: Headache 2018
Triggering of pain via activation of
trigeminovascular pathway
Neurology – lecture (aVLNE9X1p)
Trigeminovascular neurogennic inflammation
model: serotonine receptors and triptans
Pictures taken from: Yolande Knight, UCL Queen Square Institute of Neurology, 1998.
Neurology – lecture (aVLNE9X1p)
The role of CGRP in the pathophysiology of
migraine
Dodick DW. Cephalalgia 2018
Neurology – lecture (aVLNE9X1p)
Non-pharmacological treatment of migraine
̶ The avoidance of identified agravating (long-term effect) or triggered (short-term < 48 hours) factors:
̶ stress
̶ the menstrual cycle
̶ certain foods
̶ trauma
̶ caffeine withdrawal
̶ alcohol
̶ lack of sleep
̶ 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.
Neurology – lecture (aVLNE9X1p)
Non-pharmacological Treatment of Migraine
Coppola et al.: Cephalalgia 2015
Neurology – lecture (aVLNE9X1p)
A. Treatment of acute attacks
Pharmacological treatment of migraine
2. Specific antimigraine treatment
▪ Ergotamines
▪ ergotamine, dihydroergotamine
▪ Agonists of 5-HT1B and 5-HT1D: triptans
▪ sumatriptan
▪ zolmitriptan
▪ naratriptan
▪ rizatriptan
▪ eletriptan
▪ almotriptan
▪ frovatriptan
1. Non-specific treatment
▪ Analgesic drugs
▪ paracetamol
▪ codeine phosphate
▪ Anti-inflammatory drugs
▪ acetylosalicylic acid
▪ ibuprofen
▪ diclofenac
▪ naproxen
▪ ketorolac
▪ Anti-emetics: metoclopramide
Neurology – lecture (aVLNE9X1p)
Pharmacological treatment of migraine
B. 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)
Neurology – lecture (aVLNE9X1p)
Pharmacological treatment of migraine
B. Preventive treatment: blockade of CGRP or CGRP
receptors
̶ mABS bindings to CGPR:
̶ 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
Edvinsson L, Cell 2018
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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
Classification of headache
Paroxysmal hemikrania: respond
absolutely to indomethacin!!!
Classification of headache
3.1 Cluster Headache
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Classification of headache
4.Other primary headache disorders
Classification of headache
Neurology – lecture (aVLNE9X1p)
The secondary headaches
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
New classification of trigeminal neuralgia
̶ Etiology
1. Classical TN (neurovascular conflict – NCV - with
morphological changes of trigeminal nerve due to
compression)
2. Secondary TN (other pathology or disease as a cause)
̶ Clinical form (phenotype):
1. Pure paroxysmal form
2. TN with concomitant continuous pain
10.9.2021
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 (bilateral 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.
Classical 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: etiology
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
Turton M, Malan-Roux, P. Stomatological Dis Sci 2019
Microvascular
decompression
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)
Trigeminal neuralgia: therapy
A. Acute treatment
▪ 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
Lékařská fakulta Masarykovy univerzity
2021