Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2817_Библиотеки_им_академика_М_И_Перельмана.pdf
5
Tolerance and dependence
Tolerance (i.e. the necessity to increase the dose in order
to achieve the same effect) may develop during chronic
administration of drugs, and it may be due to both
pharmacokinetic and pharmacodynamic changes. Tolerance to opioids can develop rapidly, especially under
experimental conditions, when doses are increased
steeply. Physical and psychological dependence may
also develop. Physical dependence is associated with a
withdrawal syndrome when the administration of the
drug is stopped abruptly. Psychological dependence
leads to craving for the drug. However, it is very
important to note that the real risk of tolerance to and
dependence on opioids should be assessed during use
of opioid drugs in a clinical context. The concept of tolerance can often be misused in pain management, to
simply mean the requirement for a higher dose. This
only reflects tolerance if the pain has not increased! For
example, in pain associated with cancer, the reason for
increasing the dose is usually an increase in the pain.
Patients can often be maintained on the same oral morphine dosage for months, with no obvious signs of tolerance. Therefore when opioid analgesics are used in
appropriate doses to treat pain that is sensitive to such
drugs, tolerance is not a prevalent problem associated
with chronic opioid drugs. The risk of development of
addiction when opioids are used judiciously for the
relief of pain is low. However, it is important to note
that massively increasing the opioid prescription in the
United States led to 30,000 deaths due to opioid overdoses in 2015 alone, therefore there is new concern
worldwide about the consequences of misuse of opioids.
Risks associated with the unwanted
effects of opioids
The under- use of opioids is sometimes justified by the
fear of inducing life- threatening respiratory depression.
However, the respiratory depression induced by opioids
tends to be short- lived and is often antagonized by the
pain. Other unwanted effects of opiates, such as nausea
and sedation, may dissipate with prolonged use. If
strong opioids are required in a patient, the acceptability
of the medication and the patient’s response may be
much improved by the concomitant management of side
effects. For example, if tolerance to nausea and vomiting
does not develop after a few days, administration of antiemetic compounds is required (sometimes a combination
of such drugs). Pharmacological management may thus
become more complex but ultimately provide the patient
with a pain- free state.
Mode of administration of opioids
Analgesic drugs are available in a variety of formulations, and the versatility of modes of administration is
well illustrated by opioids. As discussed below, each
mode of administration has its advantages and
drawbacks.
• Oraladministration.Thisisawidelyusedroute
and one that most patients prefer. However, it may
not always be available (e.g. immediately after
surgery), or it can be made difficult by swallowing
problems. The occurrence of vomiting will limit
the absorption of drugs administered via this
route. Furthermore, delays in gastric emptying
may also decrease absorption of an orally
administered opioid. Even if the drug is absorbed,
the metabolism in the gut and liver (first pass
metabolism effect) may lead to reduced
bioavailability of the drug using this route.
• Sublingualadministration.Thisavoidsthefirst
pass metabolism, as absorption of the drug occurs
directly into the circulation.
• Rectaladministration.Firstpassmetabolismcan
also be avoided using the rectal route, if acceptable
to the patient. Absorption of the drug is slow, but
bioavailability is improved overall. It is a mode of
administration that can be considered for
maintenance of analgesia.
• Intravenousadministration.Theadministrationof
a bolus of opioids by this route leads to immediate
analgesia. However, this route has a higher risk of
over- dosage, and the patients must not be left
unsupervised for a long time.
• Intramuscularadministration.Intermittent
intramuscular administration of opioids (e.g. on a
4- hourly basis) is still a standard procedure used
worldwide. Pain relief can be achieved
satisfactorily but its maintenance at an optimum
level requires regular assessment. In addition,
repeated injections are painful and the control and
adjustment of the doses may not be easy.
• Intrathecalandepiduraladministration.These
techniques allow the use of much lower doses of
opioids through spinal catheters. However, side
effects do still occur, such as nausea, vomiting and
urinary retention, as well as a risk of respiratory
depression. Furthermore, local infection or
displacement of the catheter may occur.
• Transdermalpatchadministration.Thisisanon-
invasive mode of administration of the drug and is
particularly suitable for lipophilic and potent
compounds (e.g. fentanyl).
Clinical experience clearly shows that the patient’s
response to opioids varies significantly. Ideally, these
individual requirements should be taken into account,
and this is what the procedure called patient-controlled
analgesia (PCA) is achieving today in many centres. PCA
relies on a system whereby the patient can administer
their own analgesic according to their needs and to the
PAIN AND ANALGESIA
109THE NERVOUS SYSTEM
5
severity of their pain. The patient can administer intermittent boluses of the drug, which is delivered through a
catheter, from a lockable programmable pump. The
placement of the catheter can be intravenous, intramuscular, subcutaneous, or even epidural. A minimum time
period between doses (the ‘lock- out’ period), as well as a
maximum dose of the chosen opioid can be programmed
into the PCA device, thus preventing overdose.
Experience shows that patients using PCA titrate their
analgesia to the point where they are comfortable, with-
PAIN AND ANALGESIA
out excess demands. The feeling of control over their
pain significantly improves the patient’s outlook on their
condition. Children may use a PCA device with the help
of a parent or nurse.
Pain sensitivity to opioids
Different types of pain are differentially sensitive to opioid treatments. Some, such as deafferentation pain or
muscle spasms, are insensitive to opioid drugs; nerve or
CNS compression injury or bone cancer are partially sensitive to opioids, while acute pain, post surgical pain and
pain associated with myocardial infarction or other types
of cancers can be readily treated with opioids. Lastly,
there are some conditions such as irritable bowel syndrome that are opioid sensitive, but opioid consumption
is associated with many problems, for example, vomiting, constipation and increased gastrointestinal symptom
severity, and a decreased quality of life.
Non-opioid analgesics
NSAIDs represent the most commonly used group of
drugs worldwide, most of which are available without
prescription. There is significant variability in patient tolerance and response to these drugs. They are mainly used
to treat mild or moderate pain, in general associated with
inflammatory processes (e.g. rheumatoid arthritis and
osteoarthritis). NSAIDs can also be used to treat the severe
pain associated with bone metastasis in cancer. The analgesic/antipyretic/anti-inflammatory effects of NSAIDs
are largely due to inhibition of COX enzymes and the
resulting inhibition of the synthesis of prostaglandins,
which are pro- inflammatory. COX has two isoforms:
COX- 1 and COX- 2. COX- 1 is a constitutive enzyme,
whereas COX- 2 is induced at sites of inflammation.
Aspirin, paracetamol, ibuprofen and diclofenac are nonselective COX inhibitors. It is the inhibition of COX- 1 that
underlies the majority of unwanted effects of NSAIDs,
such as dizziness, drowsiness and gastrointestinal irritation and bleeding. Nephrotoxicity is due to actions on the
constitutively expressed COX- 2 enzyme in the kidney. In
the stomach, the prostaglandins PGE2 and PGI2 inhibit
acid secretion and have a gastroprotective action, whereas
in the kidney PGE2 and PGI2 act as local vasodilators.
Therefore, inhibition of their synthesis reduces renal blood
flow and may precipitate acute renal failure. In addition,
the prolonged use of non-selective NSAIDs is associated
with risk of chronic renal failure due to development of
interstitial nephritis. All NSAIDs also have antiplatelet
activity, leading to increased bleeding time. More recently,
selective COX- 2 inhibitors such as rofecoxib and celecoxib
have become available. These compounds have similar
analgesic efficacy to non-selective COX inhibitors but lack
their risk of inducing ulceration and could be used in the
treatment of osteo- and rheumatoid arthritis and dental
pain. However, following their development it soon
became apparent that their use is associated with a very
high risk of heart attacks and stroke.
Commonly used NSAIDs include:
• Aspirin(acetylsalicyclicacid)isanalgesic,anti-
inflammatory and antipyretic. This is due to the
irreversible inhibition of the COX enzyme. COX is
required for prostaglandin and thromboxane
synthesis, peripherally at the site of injury. Aspirin
acts as an acetylating agent, that is, an acetyl group
is covalently attached to a serine residue in the
active site of the COX enzyme. This makes aspirin
different from other NSAIDs (such as diclofenac
and ibuprofen), which are reversible inhibitors. It
is unclear whether the effect of aspirin also has a
central component. Aspirin- containing
preparations should not be given to children under
12 years because of the risk of development of
Reye’s syndrome.
• Paracetamol(acetaminophen)isantipyreticand
analgesic but with negligible anti-inflammatory
effects (so, technically, it is not a NSAID). It is well
absorbed after oral administration and does not
irritate the gastric mucosa. It was suggested that
paracetamol may act as inhibitor of COX- 3, a
splice- variant of COX- 1, but this is now rejected.
There is considerable evidence that its analgesic
effects are due to activation of descending
serotonergic pathways but its primary site of
action may still be inhibition of PG synthesis,
although this is not associated with an antiinflammatory action. Its mode of action remains
unclear but recent evidence indicates that
paracetamol inhibits prostaglandin synthesis in
cells with low levels and production of peroxide.
At peripheral sites of inflammation with a high
peroxide level, its effect may be inhibited. Another
suggested mechanism involves the paracetamol
metabolite AM404, which is a weak agonist of the
cannabinoid receptors CB1 and CB2 and a potent
activator of the TRPV1 receptor. This suggests that
the cannabinoid and TRPV1 signalling pathways
play important roles in the analgesic effects of
paracetamol. The prolonged use of paracetamol
and the ingestion of high doses are associated with
significant risk of hepatotoxicity. Paracetamol
overdose is treated with N- acetylcysteine.
110 SYSTEMS OF THE BODY
5
• Ibuprofenhasanalgesicandanti-inflammatory
properties. Among the non-selective NSAIDs, it is
one of the drugs of choice because it is effective
and has a relatively low side effect profile. Like
other NSAIDs, its mechanism of action is
principally through COX- 2 inhibition. Alternatives
to ibuprofen are: diclofenac, naproxen, piroxicam,
ketorolac, indomethacin and mefenamic acid.
Other approaches to pain management
Some types of pain do not respond to either opioid analgesics or NSAIDs, nor can they be managed based only on
the principles underlying the World Health Organization
Analgesic Ladder. Examples of such types of pain are given
below, including their pharmacological management.
Neuropathic pain
Neuropathic pain appears relatively insensitive to opioids. It can be significantly relieved with tricyclic antidepressants (e.g. amitriptyline), anticonvulsant agents (e.g.
carbamazepine) or local anaesthetics (Box 5.7). The reason for this diversity of treatment is the pathophysiology
of neuropathic pain, which is complex and still incompletely defined (see above). It is well established that
neuropathic pain involves changes in the phenotype of
the neurons that are part of nociception pathways and
also morphological changes within the grey matter of the
dorsal horn.
Three commonly prescribed drugs for chronic neuropathic pain associated with diseases such as peripheral
(e.g. diabetic) neuropathy, post herpetic neuralgia and
fibromyalgia are gabapentin, its analogue pregabalin and
duloxetine. Gabapentin was initially developed as a
GABA agonist but its mechanism of action is still not fully
defined. Research indicates that it binds with high affinity
to the α2δ- 1 subunit of voltage- dependent calcium channels and therefore inhibits calcium influx through L and
P/Q channels. It also reduces potassium evoked glutamate release and is an agonist at GABAB receptors.
Pregabalin is related in structure to gabapentin and is
more potent. It also binds to the α2δ-2 subunit of the
voltage- dependent calcium channel. Pregabalin decreases
the release of neurotransmitters such as glutamate, noradrenaline and substance P. Common adverse effects of
both include diarrhoea, dizziness, drowsiness and peripheral oedema. Duloxetine is an antidepressant drug that is
a selective serotonin and noradrenaline reuptake inhibitor,
approved for use in diabetic neuropathy.
Migraine
Pain can affect specifically the craniofacial area. The most
common form of this type of pain is generically termed
Box
Local anaesthetics and sodium
5.7
channels
Local anaesthetics (e.g. lidocaine, bupivacaine, prilocaine,
ropivacaine, tetracaine) are agents which block the initiation and propagation of nerve action potentials by blocking Na+ channels. Their mode of administration varies with
surface anaesthesia, infiltration, spinal or epidural anaesthesia. They are generally used for pain associated with
localized surgery, childbirth or in dentistry. A problem associated with local anaesthetics is the risk of systemic toxicity
(e.g. hypotension, bradycardia and respiratory depression).
The addition of a vasoconstrictor such as adrenaline to the
local anaesthetic decreases local blood flow, slowing the
rate of absorption and thus prolonging the anaesthetic
effect.
The molecular targets of local anaesthetics are voltagegated Na+ channels. These channels are present in both
nerve and muscle cells. These channels are also the target of the anticonvulsants phenytoin and carbamazepine
and some anti-arrhythmic drugs. The main component of
Na+ channels is the α- subunit which forms the ion pore.
In mammalian channels the α- subunit is associated with
one or two smaller auxiliary subunits designated β1 and
β2. Na+ channels have three distinct conformational states.
The transition between these states is voltage- dependent.
When the membrane depolarizes the channels revert to an
open state that conducts ions. This is followed by a nonconducting, inactivated state. When the membrane is in a
hyperpolarized state, most Na+ channels are in closed, resting states, which represent the third conformational state.
The selectivity of local anaesthetics for depolarized Na+
channels is a consequence of the binding of these drugs to
the open and inactivated states that predominate at depolarized membrane potentials. These states may be associated with the highest affinity for these drugs. In contrast,
the blockade of the channels by tetrodotoxin (TTX)—a
powerful toxin extracted from the puffer fish—is independent of the conformational state of the channel.
‘headache’. This simple term is deceptive and does not
reflect the complexity of this type of pain disorder. The
International Headache Society has developed a detailed
classification of these conditions, in the form of the
International Classification of Headache Disorders, the
latest version being ICHD- 3. ICHD- 3 classifies headache
disorders into: (1) primary headaches; (2) secondary
headaches; and (3) neuropathies, facial pains and other
headaches.
Migraine is a form of primary headache and is the second most prevalent neurological disorder worldwide. In
the Global Burden of Disease assessment of 2015, it
ranked as the third highest cause of disability worldwide
in adults under the age of 50 years. It affects women
more than men. Migraine has a significant prevalence in
the young (around 9% of children and adolescents) and
PAIN AND ANALGESIA
111THE NERVOUS SYSTEM
5
is associated with missed school days, poorer performance in education and a negative impact on peer interaction and socialization. Migraine can be episodic
(affecting the patient on <15 days per month) or chronic
(at least 15 days per month and with the characteristics
of a migraine on at least 8 days per month, for longer
than 3 months). Misdiagnosis and poor management of
migraine are significant public health problems
worldwide.
Migraine is a disorder that consists of recurrent
PAIN AND ANALGESIA
attacks of severe headache, autonomic nervous system
dysfunction, and in some 20% of patients, an aura
involving complex neurological symptoms. The aura
symptoms develop over 10–30 min and usually last less
than an hour. Symptoms can be visual, sensory, or motor
but may also involve language disturbances. When a
headache follows, it most often occurs within an hour of
the end of the aura. Isolated auras without headache
(previously called ‘acephalgic migraine’ or ‘silent
migraine’) may also occur. The most common aura is
visual and may consist of visual distortions. Sensory disturbances involve one side of the body and are characterized by descriptions of numbness or tingling on the face
and in the hand. The aura often resolves before the onset
of the headache. Some patients may experience a combination of migraine attacks: some attacks associated with
an aura, and others without aura. Patients may also
experience a prodromal phase, hours or days before the
headache. Premonitory phenomena may occur in
approximately 60% of migraineurs in this phase. These
phenomena include psychological, neurological, constitutional and autonomic features. Psychological symptoms include depression, euphoria, irritability,
restlessness, mental slowness, hyperactivity, fatigue and
drowsiness. Neurological phenomena include photophobia, phonophobia and hyperosmia. The generalized or
constitutional symptoms include a stiff neck, a cold feeling, sluggishness, increased thirst, increased urination,
anorexia, diarrhoea, constipation, fluid retention and
food cravings. Some patients just report a poorly characterized feeling that they know a migraine attack is
coming.
The typical migraine headache is unilateral and throbbing. It may be bilateral and constant at first, and later
become throbbing. Nausea occurs in up to 90% of
patients, and vomiting occurs in about one- third of
migraineurs. During the attack many patients experience
intense photophobia, phonophobia and osmophobia and
seek seclusion in a dark, quiet room. Other symptoms
include blurry vision, diarrhoea, abdominal cramps,
polyuria (followed by decreased urinary output after the
attack), facial sensations of heat or cold, and sweating.
Large population studies have shown that 65%–70% of
patients have migraine without aura, approximately 18%
have migraine with aura, 13% have both types and the
remaining minority can have aura without migraine.
Migraine attacks may last 4–72 h. Different combinations of features may occur between patients or even
between attacks in the same patient. It is important to
note that tension- type headache (the most common form
of primary headache) may sometimes present as a throbbing pain but is devoid of the associated features of
migraine. It also presents in general bilaterally. and the
pain has in most cases a pressing or tightening quality.
These differences are important in terms of diagnosis
and treatment of the two conditions.
Migraine attacks are triggered by a variety of factors:
endocrine changes (e.g. during pregnancy or the menstrual cycle), sleep excess or deprivation, physical exercise, stress or tiredness. Paradoxically, migraine may
emerge at a time when the patient feels relaxed.
Intriguingly, even in the same patient, it is impossible to
predict the sensitivity to common triggers. It is recommended that migraineurs should have regular habits and
a balanced lifestyle.
Migraine is a neurovascular disorder, and its pathophysiology is still incompletely characterized; it is
viewed as a condition that is associated with an individual’s propensity towards brain hyperexcitability.
Migraine may involve a primary dysregulation in primary sensory processing in the nervous system. There is
a strong polygenic component and susceptibility loci
have been found on several chromosomes, for example,
chromosomes 1, 2 and 19, and genes associated with
migraine include examples such as CACNA1A, SCN1A
and KCNK18/TRESK, which are linked to the function of
calcium, sodium and potassium channels. Imaging studies have detected activation of the brain stem during
migraine attacks. Migraine is associated with a wave of
vasoconstriction followed by reactive vasodilatation. The
main elements involved in the generation of pain are: the
cranial blood vessels, trigeminal innervation of the vessels, and reflex connections of the trigeminal system with
the cranial parasympathetic outflow. Convincing mechanistic explanations have recently been proposed for some
of the symptoms of migraine (Box 5.8).
As shown in Fig. 5.13, the input from the trigeminal
afferents that innervate the meningeal vessels passes
through the trigeminal ganglion and synapses with
second- order neurons in the trigeminocervical complex.
Second- order neurons project to the thalamus. In the
pons there is a connection with neurons in the superior
salivatory nucleus, which results in a parasympathetic
outflow and is mediated through the pterygopalatine,
otic, and carotid ganglia. This trigeminal- autonomic
reflex exists in normal individuals and is increased in
migraine.
Pain is mainly generated at the level of the cranial vessels or in the dura mater. The innervation involved originates from branches of the ophthalmic division of the
trigeminal nerve and also branches of the C2 nerve roots
(for structures in the posterior fossa). This explains the
distribution of pain over the frontal, temporal, parietal,
occipital and high cervical (neck) regions. The pain may
involve peripheral or central sensitization processes of
craniovascular afferents and the activation of vasodilator
mechanism. However, migraine is not primarily caused
by a vascular event. It is associated with abnormal neu-
112 SYSTEMS OF THE BODY
5
Meninges
Stimulation of
trigeminal afferents
Spinal trigeminal
nuclei and trigeminal
afferents have
IB/ID/IF receptors
5HT
Activation of trigeminal
spinal neurons
VPM thalamus
Facial
somatosensory cortex
Fig. 5.13 Pathways involved in trigeminovascular activation and pain
modulation by serotonin. Ach, Acetylcholine; NO, nitric oxide; NRM,
nucleus raphe magnus; PAG, periaqueductal grey; VIP, vasoactive
intestinal polypeptide; VPM, ventroposteromedial thalamic nucleus;
5HT, serotonin; +, excitation.
Inflammation
or vasodilatation
Release of
NO, VIP, ACh
Activation of superior
Hypothalamus
Sphenopalatine
ganglion
(parasympathetic
efferents)
salivatory nucleus
NRM
PAG
ronal activity in diencephalic or brain stem nuclei (see
Box 5.8).
Evidence accumulated over the last three decades
indicates that the neuropeptide calcitonin gene- related
peptide (CGRP) has a key role in the pathophysiology of
migraine. It is the most abundant neuropeptide in the trigeminal nerve and is expressed in 35%–50% of trigeminal ganglion neurons. Trigeminal activation is associated
with CGRP release, which is enhanced during a migraine
attack. Very early observations showed that during the
attack CGRP serum levels are elevated in the cranial, but
not peripheral, circulation indicating an important local
effect for this peptide. Successful treatment of a migraine
attack concomitantly aborts the pain and the increase in
CGRP. The peptide may exert its effects through several
different receptors, including the CGRP receptor, calcitonin receptor, amylin receptors, and adrenomedullin
receptors. CGRP is expressed in neurons of the cerebral
cortex, hippocampus, cerebellum, thalamic and hypothalamic nuclei, and also in brainstem nuclei. At several of
these sites there is high expression of the CGRP receptor.
The understanding of the crucial role of this peptide has
led to the development of new therapeutic agents, as discussed below. Furthermore, recent research suggests that
another peptide of interest is the pituitary adenylate
cyclase activating polypeptide (PACAP). This peptide
exists in two forms—PACAP- 27 and PCAP- 38—is pres-
ent in the trigeminovascular system and the cranial parasympathetic system, and is co- localized with CGRP. Its
release is increased during migraine attacks. The administration of PACAP can trigger the premonitory symptoms of migraine.
Treatment of migraine attacks
The treatment of migraine consists of non-pharmacological and pharmacological approaches. The non-pharmacological strategy consists of the maintenance of a daily
routine, which avoids changes in lifestyle and also identifies triggering factors. Pharmacological treatment consists of two strategies: non-specific and migraine- specific
treatments.
Non-specific drugs that can be used include aspirin,
paracetamol, ibuprofen, diclofenac potassium or other
NSAIDs, mild opioids or combination analgesics. These
analgesic drugs are also used to treat other types of pain,
including tension- type headache—the other major type
of primary headache. The administration of drugs that
prevent nausea and vomiting (e.g. metoclopramide or
prochlorperazine) and are prokinetic, that is, increase
gastric motility, increases the efficacy of these drugs.
Many migraineurs report a reasonable relief of pain
using a combination of mild analgesics. Such combinations may vary, for the same patient, according to the
severity of the attack.
Migraine- specific drugs include those that modulate serotonin (5- HT) transmission, that is, the triptan family of drugs
and also ergot derivatives. There is ample evidence that
5- HT has a clear link with migraine: very early observations
indicated that migraine attacks are associated with increases
in the level of the 5- HT metabolite 5- hydroxyindole acetic
acid (5- HIAA) and showed that infusion of 5- HT could
abort both pharmacologically- induced or spontaneous
headaches. The role of 5- HT and some of its receptors is
shown in Fig. 5.13.
Ergotamine and dihydroergotamine are ergot derivatives. They bind to at least two receptor classes (adrenergic and 5- HT receptors) and to combinations of different
subtypes within these types (e.g. ergotamine binds to
5- HT1A, 5- HT1B and 5- HT1D subtypes), and they have
complex pharmacodynamics. They induce generalized
vasoconstriction, and their use may lead to ergotism—an
overuse syndrome—which may include rebound headaches when attempting to stop the drug. These drugs
should not be used for the treatment of tension- type
headache.
The triptans are a large family of related compounds
with a less complex pharmacodynamic profile than the
ergot derivatives. Examples of triptans are sumatriptan,
almotriptan, eletriptan, frovatriptan, zolmitriptan, naratriptan and rizatriptan. Sumatriptan was the first drug in
this category and remains the first choice; it is on the
World Health Organisation’s List of Essential Medicines.
All the triptans have a very similar pharmacodynamic
profile. They are 5- HT
receptor agonists. They can be
1B/1D
PAIN AND ANALGESIA
113THE NERVOUS SYSTEM
5
Headache
Box
PAIN AND ANALGESIA
Neurobiological mechanisms involved in migraine
5.8
Activation of the trigeminovascular system is thought
to be responsible for the pain of migraine. The aura symptoms are considered to reflect the onset of cortical spreading
depression (CSD). CSD can be triggered by focal activation
of the cortex and is more readily seen in the occipital cortex than elsewhere. It is characterized by a slowly propagating wave of strong neuronal depolarization that generates
intense neuronal activity, followed by suppressed activity lasting many minutes. This has been confirmed in migraineurs
experiencing aura, using blood oxygen level- dependent
functional magnetic resonance imaging. CSD produces many
changes in the extracellular fluid environment by increasing
levels of potassium ions, protons, arachidonic acid (and its
prostaglandin metabolites), which can sensitize the meningeal vascular afferents. CSD has also been observed using
imaging methods in migraineurs who do not experience aura,
but the mechanisms for initiation and propagation of the
CSD remain incompletely understood.
An alternative view is that migraine occurs due to dysfunction in brainstem nociceptive circuits such that a defect in
pain modulation could result in increased activity in trigeminal neurons making them more susceptible to sensitization
(Fig. 5.14).
Identification of mutations in genes that result in defects in
ion channels indicates that migraine may be a channelopathy.
Most channelopathies are disorders of neuronal excitability,
highlighting the importance of activity in the pathogenesis
of migraine. In familial hemiplegic migraine there is a defect
in the α1 subunit of P/Q type voltage- gated calcium channels.
This channel is expressed in all structures that play an important role in the pathogenesis of migraine. They are known to
regulate cortical neuron firing and in mutant mice that are
deficient in this gene cortical neurons become hyperactive
and may thus contribute to CSD. This channel is also found
on cells that regulate the descending inhibitory pain system,
and blocking P/Q channels facilitates pain, adding further evi-
dence to dysfunction of brainstem activity being involved in
migraine.
Abnormal
cortical activity
Cortical spreading
depression
SSN
activation
Release of
H+, K+, NO,
adenosine,
arachidonic acid
Peripheral sensitization
of pial afferents of
the trigeminal nerve
Fig. 5.14 Pathophysiological mechanisms involved in migraine.
Abnormal cortical activity leads to cortical spreading depression (CSD)
that is the most likely initiating event in stimulating the trigeminal
vascular system afferents in migraine. Abnormal activity in trigeminal
brainstem neurons involved in the control of facial pain may also
contribute to central sensitization of spinal trigeminal neurons (STN)
leading to hyperexcitability. When CSD occurs in conjunction with
migraine trigger factors, migraine occurs. SSN, Superior salivatory
nucleus. (Adapted from Pietrobon D, Striessnig J. (2003) Neurobiology
of migraine. Nature Reviews Neuroscience 4:386.)
activation
Abnormal
brainstem activity
Central sensitization
of trigeminal
brainstem cells
Dura
pain
and aura
administered non-orally (nasal sprays, suppositories,
inhalers, injections). For example, sumatriptan is available
in oral, subcutaneous, rectal and intranasal formulations.
The oral bioavailability ranges from 14% (sumatriptan) to
69% (almotriptan) or 74% (naratriptan). Triptans have at
least three possible sites of action: cranial vasoconstriction
(the 5- HT1B component), peripheral neuronal inhibition
(the 5- HT1D component) and inhibition of transmission
through second- order neurons of the trigeminocervical
complex (5- HT1B, 5- HT1D and possibly 5- HT1F component). Triptans remain the ‘gold standard’ of migraine
attack treatment, although their vasoconstrictor profile
leads to restricted use in patients with cardiovascular disease. More recently, a 5- HT1F agonist—lasmiditan, a firstin- class drug—has also been introduced for the acute
treatment of migraine, but it is associated with a high incidence of adverse events.
114 SYSTEMS OF THE BODY
The side effects of triptans are tingling, paraesthesias, dizziness, flushing, neck pain, or stiffness. They
can constrict coronary arteries, leading to symptoms
similar to angina pectoris. Contraindications to use are
ischaemic heart disease, hypertension and cerebrovascular disease.
More recently, the extensive characterization of the
crucial role of CGRP in migraine pathophysiology has
led to the development of the gepants—a new class of
drug—which are small molecule antagonists of the
CGRP receptor. Ubrogepant and rimegepant were
approved in 2019 and 2020, respectively, for the acute
treatment of migraine. They prevent vasodilation and
can be prescribed especially when the use of triptans is
problematic. Gepants are being considered for the prophylaxis of migraine. In parallel, monoclonal antibodies
against CGRP (e.g. eptinezumab, fremanezumab) and
Trigeminal nerve fibre
Blockade of CGRP receptor
1B/1D
1
Monoclonal
antibody
Gepants
Erenumab
Atogepant
Rimegepant
Ubrogepant
5
PAIN AND ANALGESIA
Blockade of CGRP
2
Monoclonal
4
antibody
Eptinezumab
Fremanezumab
Galcanezumab
Middle meningeal
artery
Vasodilation
CGRP receptor 5-HT
Fig 5.15 Overview of pharmacological treatment of migraine based on modulation of 5- HT and calcitonin gene-related peptide (CGRP) signalling.
(From de Vries T, Villalón CM, MaassenVanDenBrink A. (2020) Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans.
Pharmacology and Therapeutics 211:107528.)
the CGRP receptor (erenumab) have been developed.
These are alternatives for the prophylaxis of migraine
attacks, but they need to be administered parenterally
and their costs are prohibitive for large- scale use, at
present.
An overview of treatments focused on 5- HT and
CGRP targeting is shown in Fig. 5.15.
3
1
4
3
2
Vasoconstriction
receptor 5-HT1F receptor CGRP
3
Stimulation of 5-HT
Triptans Almotriptan
4 Stimulation of 5-HT
Ditans Lasmiditan
1B/1D(/1F)
Eletriptan
Frovatriptan
Naratriptan
Rizatriptan
Sumatriptan
Zolmitriptan
receptor
1F
receptor
• calcium-channelblockers—flunarizine(depression,
weight gain, tiredness)
• 5-HTreceptorantagonists—pizotifen(drowsiness,
weight gain)
• angiotensinIIreceptorantagonists—candesartan
cilexetil (abdominal pain, cough, hypotension)
Overall, novel and better therapeutic targets for the
Preventive treatment of migraine
treatment of migraine (acute and chronic) are continu-
ing to emerge from a better understanding of the pathoIf attacks occur at least twice a month, or if there is a
clear trend toward an increasing frequency of attacks,
preventive treatment may be considered. A variety of
drugs belonging to different pharmacological classes can
be used as prophylactic treatment. The choice of drug
depends on the patient’s choice, tolerability and possible
interactions with other co- morbidities. All such prophylactic therapies are relatively non-specific and have moderate efficacy and substantial side effects, as illustrated in
the examples given below (some of the unwanted effects
of the different classes are indicated in parentheses):
• beta-adrenergicreceptoragonists—propranolol,
metoprolol, atenolol, bisoprolol (tiredness, postural
hypotension)
• tricyclicantidepressants—amitriptyline
(drowsiness, dry mouth, postural hypotension)
• anticonvulsants—sodiumvalproate,topiramate
(weight gain, hair loss, tremor, hepatotoxicity,
teratogenic effects)
physiology of migraine, as exemplified by the advent of
CGRP- focused interventions and the emergence of
PACAP as a new target. PACAP antibodies and anti-
bodies against the PAC1 receptor for PACAP are in
development and already being tested in clinical trials.
Finally, it is important to note that there are also nonpharmacological approaches in migraine management,
for example, the use of neuromodulation devices. This
includes invasive approaches such as deep brain stimulation and occipital nerve stimulation. Other approaches
include non-invasive vagus stimulation (e.g. the gammaCore Saphire is a handheld device which uses set doses
of non-invasive stimulation when held onto the skin to
either the right or the left branches of the vagus nerve in
the neck) or external trigeminal nerve stimulation (e.g.
the Cefaly device placed on the forehead) and sphenopalatine neurostimulation. More recently, a remote electrical neuromodulation (REN) device, which involves
two surface electrodes set in an armband that stimulate
the upper arm peripheral nerves (with the power source
being controlled by the patient’s smartphone), can trig-
115THE NERVOUS SYSTEM
5
ger a form of central conditioned pain modulation
involving the descending pain inhibitory pathways, and
has shown promise for the acute treatment of migraine.
Trigeminal neuralgia
Trigeminal neuralgia is characterized by sudden attacks
of excruciating pain in the distribution of the trigeminal
nerve. It is a condition that has a major impact on the
PAIN AND ANALGESIA
quality of life and ageing increases the risk of developing
it. In most cases it affects just one side of the face, mostly
the lower part. The pain can be initiated by stimulation
of ‘trigger zones’ (e.g. the cheek, chin or lips), and the
attacks can last from seconds to a few minutes. The
attacks of pain can be initiated by very ordinary activities, such as washing or brushing the teeth, or eating—
mechanical allodynia—such that sufferers do not
perform these activities. Attacks may occur many times a
day and may last many weeks or months. Some remission may occur but with unpredictable return of the
attacks. It is suggested that the cause of this neuralgia is
vascular compression (by arteries but also occasionally
veins) of the axons of the trigeminal root in the pons.
This may be caused by a tumour or an arteriovenous
malformation. This may lead to partial focal demyelination, which may alter the electrical activity of trigeminal
neurons through ephaptic connections and spontaneous
activity.
The first line of treatment of trigeminal neuralgia is
pharmacological. The anticonvulsant drug carbamazepine can be used to treat the paroxysmal pain experienced by patients and effectiveness is reported in
60%–80% of cases. Baclofen (a GABAB receptor agonist)
or the anticonvulsants lamotrigine, topiramate, or levetiracetam could also be considered, as well as drugs such
as gabapentin or pregabalin. Botulinum toxin injections
may be beneficial in some cases. If there is no response or
gradual loss of efficacy, surgical procedures could be
attempted, such as decompression of the trigeminal
nerve root or neuro- ablation via rhizotomy with radiofrequency thermocoagulation. However, there may be
recurrence of the pain several years after surgery. Further
research is needed to optimize treatment options in trigeminal neuralgia.
Box
Development of pain pathways
5.9
The question of whether babies, premature or newborn,
feel pain is an important one, as studies show that invasive procedures that would be painful to children or adults
are frequently performed on infants admitted to neonatal
intensive care units. Premature babies do not ‘feel’ pain in
the truest sense, as pain is a learned experience. However,
nociceptive stimuli can have a profound effect on the
development of pain pathways.
The newborn nervous system is not a miniature replica of
the adult version. Pain- related systems in particular develop
during the last trimester and after birth. Much of what we
now know about the development of nociceptive systems is
based on rodent models, as data from the rat and human
post- mortems or abortions are very similar. A newborn rat
is similar to a 24- week- old foetus and a week- old rat pup is
equivalent to a newborn baby.
Nociceptive afferents are physiologically mature before
birth but the nociceptive pathways are not. Thus, the neonatal spinal cord is hyperexcitable due to lack of inhibitory control from spinal cord interneurons and descending
pathways. Neurotransmitter receptors are also widely distributed throughout the spinal cord and undergo postnatal
refinement, so drugs cannot be given simply scaled down
to size. In addition, there are age-related differences in
various other systems such as the kidneys and the hepatic
enzyme systems, so that dosing intervals are not the same
as in adults.
Damage to the newborn nervous system causes profound changes that subsequently alter the development
of the pain pathways. For example, neonatal skin damage such as repeated heal lancing for blood can induce
skin wounding that produces peripheral sensitization. This
can cause release of inflammatory mediators and growth
factors that cause skin hyperinnervation on healing and
changes in the transmitter phenotype of primary afferents.
This change leads to central changes in the spinal cord,
such as inappropriate growth or cell death, which may
have a permanent effect on neural development. Studies
have shown that children who underwent traumatic procedures early in life have lowered pain thresholds compared
to those that did not.
Pain in children and in the elderly
A long- held misperception claimed that neonates and
young children perceive much less pain than adults because
of the immaturity of their central nervous system. This view
has been disproven (Box 5.9), and it is clear that the management of pain in children can and should follow the same
general principles as those used in adult patients. Young
children pose a problem in terms of accurate assessment
and rating of their pain, especially when presenting at accident and emergency departments. The use of paediatric rating scales (see Fig. 5.7) can be helpful in categorizing the
116 SYSTEMS OF THE BODY
intensity of pain. Furthermore, children may not be able to
articulately ask for pain relief, therefore analgesia maintenance regimes should be considered in order to provide
maximum comfort. Once the pain severity has been
assessed, treatment can be administered in several ways
(Table 5.12). Indirect indices of pain relief can be used: the
child could appear less tense and anxious, cry less and sleep
better. Oral administration of drugs is a preferred route but
the rectal route can be used, as well as use of local
anaesthetic- containing creams or intranasal administration
of diamorphine. Aspirin should be avoided in
children below the age of 12 years, but all other NSAIDs can
Table 5.12 Pain management in the Emergency department
Mild pain (VAS 1–3) Moderate pain (4–6) Severe pain (7–10)
5
PAIN AND ANALGESIA
Oral/rectal paracetamol 20 mg/kg loading
dose, then 15 mg/kg 4–6- hourly or
Oral ibuprofen 10 mg/kg 6–8- hourly
*The Medicines and Healthcare products Regulatory Agency has restricted the use of codeine to those over 12 years of age.
Adapted from the National Institute for Clinical Excellence guidelines from the Royal College of Emergency Medicine 2013 document on
management of pain in children.
be used, as well as mild or strong opioids, after adequate
dose adjustment. Children can also be taught how to use
PCA devices. Additionally, it is important to use other nonpharmacological techniques to achieve analgesia. These
may include play and distraction, cuddles, or other measures such as attending to the presenting wound/condition.
The provision of analgesia in the elderly also presents
specific challenges, especially as we undergo many pharmacokinetic changes as we age. For example, aged adults
may have increased body fat and decreased lean body
mass, total body water and serum albumin levels that
impact the distribution of medications. Additionally,
elderly patients may have communication problems and
may under- or over- report pain. Careful assessment using
observational techniques may be required. The absorption
of drugs and their metabolism in the liver may also
change in the elderly, in particular as a consequence of
decreased hepatic function. A decrease in renal function
may also be dangerous, as metabolites (e.g. those of morphine and pethidine) may accumulate. Therefore a reduction in adult doses is often mandatory. Furthermore, the
medication taken by the elderly for other diseases may
lead to complex drug interactions when analgesics are
prescribed. Patients may be particularly vulnerable to side
effects such as confusion, sedation and respiratory depression. Smaller, frequently repeated doses of opioids are
preferable to larger doses. It is generally accepted that
mild pain can be managed by non-pharmacologic methods, for example, heat or ice, or massage; moderate pain
with all of these modalities plus over- the- counter (OTC)
medications and/or non-opioids; and that severe pain
may require intermittent or regular use of opioids, that is,
scaling the analgesic ladder.
As for mild pain plus oral/rectal diclofenac
1 mg/kg 8- hourly (unless already had
ibuprofen) and/or oral codeine phosphate*
1 mg/kg 4–6- hourly (over 12 years old)
OR Oral morphine 0.2–0.5 mg/kg stat
is opioid- insensitive, additional drugs can be considered,
as well as non-pharmacological strategies. Examples of
surgical strategies that can be used to control pain are: cordotomy (i.e. lesion of the spinal pathways that mediate
nociception and are located in the anterolateral quadrant
of the spinal cord), lesioning of the dorsal root entry zone,
spinal cord stimulation and motor cortex stimulation.
These are important therapeutic alternatives for intractable pain that is resistant to medication.
The complexity of pain management is illustrated by
the case presented at the beginning of this chapter (see
Box 5.1). Therefore, there is a need for new agents and
new therapeutic concepts. For example, research using
venomous marine snail toxins has uncovered conotoxins
as new drugs for neuropathic pain. Conotoxins comprise
a large family of peptides that typically contain 12–30
amino acids. α- Conotoxin Vc1.1 targets nicotinic cholinergic receptors as an antagonist and is effective against
peripheral neuropathic pain; it also accelerates functional
recovery of injured neurons. Success has already been
achieved in the clinic with ziconotide (a synthetic equivalent of ω- conotoxin MVIIA), which suppresses pain
through negative modulation of N- type calcium channels. Ziconotide is now a therapeutic option for the treatment of severe chronic pain in patients who have gone
through all other forms of treatment, including strong
opioids such as morphine. Finally, there has also been
much progress in the advanced pharmacological characterization of targets such as the mu opioid receptors,
which are G- protein coupled receptors that can support
the molecular mechanism of ‘biased activation’; this
reflects the fact that different agonists at such receptors
can stabilize different conformations of the receptor and
Consider entonox (50% nitrous oxide and 50%
oxygen) as holding measure then
Intranasal diamorphine 0.2 mL (0.1 mg/kg)
followed by/or IV morphine 0.1–0.2 mg/kg
Supplemented by oral analgesics as required
activate preferentially different pathways. This means
that new ligands for this receptor could be synthesized
General comments on pain management
so that they induce exclusive G- protein activation- linked
signalling (associated with analgesia) but avoid activa-
Mild- to- moderate pain can be successfully managed with
non-opioid analgesics or opioids with moderate efficacy.
Severe pain, acute or chronic, is generally responsive to
opioids with higher efficacy. When the latter drugs are
used judiciously, they can offer pain relief and significantly improve the quality of life of patients without significant tolerance or dependence. In the case of pain which
tion of alternative signalling pathways (such as coupling
of the receptor to the intracellular protein β- arrestin),
which are responsible for adverse effects such as respiratory depression or tolerance. This could result in drugs
with a much- improved profile compared to morphine:
high efficacy as analgesics and elimination of risk of
major side effects.
117THE NERVOUS SYSTEM
5
Recently, a phase 1 trial was initiated for a non-opioid
drug called KCP- 506, developed for the treatment of
chronic neuropathic pain. KCP- 506 is a potent α9α10 nicotinic cholinergic receptor (nAChR) antagonist that has
demonstrated robust analgesic, anti- inflammatory and
neuroprotective effects across several animal chronic
pain models. It offers the potential of a disease modifying therapy that may slow or halt the progression of
chronic pain. The α9α10 nAChR drug target is not
expressed in the CNS (it is expressed in the dorsal root
PAIN AND ANALGESIA
ganglia and non-excitable tissues) and offers a safer therapy with no centrally mediated toxicities. Unlike other
chronic pain therapies, this nAChR antagonist was nonaddictive and non-tolerance- inducing in preclinical studies. It may be an effective treatment for many types of
chronic pain, including radiculopathy, chemotherapyinduced peripheral neuropathy (CIPN), and diabetic
neuropathy.
Self- assessment case study
Mary is a 22- year- old trainee in a City bank in London.
She is very fit and rows in one of the top female teams in
England. On most weekends, she has training sessions or
competitions. One day, as she came home after an
intense training session, she developed a severe headache, which seemed to affect only the left side of her
head. She had nausea and felt very tired, and went to
bed after taking some soluble aspirin. After 3–4 h, the
pain had not fully abated, and Mary thought that she
was developing a bad cold or influenza. A few weeks
after this incident, Mary returned home late in the evening after a long meeting. She felt a tingling sensation in
her fingers and sudden nausea, followed after a short
while by the same type of severe headache experienced
previously. She took paracetamol and tried to relax
watching television, but she found the light and the
sound unbearable. In the morning she felt tired. Finally,
less than a month after this episode, she had a similar
throbbing headache and became very sick on a Sunday
while she was visiting friends. She decided to consult her
general practitioner about these recurring attacks of
headache that were disrupting her life.
After studying this chapter, you should be able to
answer the following questions:
1. What is the likely diagnosis of Mary’s problem?
Considering the described episodes of headache, their
characteristics and frequency, Mary is likely to suffer
from episodic migraine.
2. What is the optimum treatment for her attacks?
Mary has already tried the first line medication: overthe counter analgesics such as aspirin and paracetamol,
but neither helped. So, it is likely that she would have to
transition to use of triptans to manage her migraine
attacks.
3 What is likely to have caused Mary’s condition, and
can prophylactic treatment be envisaged?
The migraine attacks may be linked to times of intense
effort and fatigue (e.g. sports training or long working
hours at the office), which are acknowledged triggers of
this type of primary headache. It is likely that the GP or a
specialist will continue to monitor Mary, and if the frequency of the episodes increases, a prophylactic treatment will be discussed.
118 SYSTEMS OF THE BODY