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SECTION
4
NERVOUS
SYSTEM
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17
Pain
and
analgesics
But
pain
is
perfect
misery,
the
worst
Of
evils, and, excessive,
overturns
All
patience.
(John
Milton,
1608-1674,
Paradise
Lost)
SYNOPSIS
One of the
greatest
services
doctors
can do
their
patients
is to
acquire skill
in the
management
of
pain.
•
Pain:
the
phenomenon
of
pain; clinical
evaluation
of
analgesics; choice
of
analgesics;
treatment
of
pain syndromes; spasm
of
smooth
and
striated
muscle; neuralgias;
migraine
•
Drugs
in
palliative
care:
symptom
control;
pain
•
Narcotic
or
opioid
analgesics: agonists,
partial
agonists, antagonists;
morphine
and
other
opioids;
classification
by
analgesic
efficacy;
opioid
dependence;
opioids
used
during
and
after
surgery;
opioid
antagonists;
•
Non-narcotic
analgesics
(NSAIDs):
see
Ch. 15
tissue
damage,
or
described
in
terms
of
such
damage.
1
It is
mediated
by
specific
nerve
fibres
to
the
brain where
its
conscious
appreciation
may be
modified
by
various
factors.
The
word 'unpleasant' comprises
the
whole range
of
disagreeable feelings
from
being merely inconve-
nienced
to
misery, anguish, anxiety, depression
and
desperation,
to the
ultimate cure
of
suicide.
2,3
•
Analgesic drug:
a
drug that relieves pain
due to
multiple causes, e.g. paracetamol, morphine.
Drugs that relieve pain
due to a
single cause
or
specific
pain syndrome only, e.g. ergotamine
(migraine),
carbamazepine (neuralgias), glyceryl
trinitrate (angina pectoris),
are not
classed
as
analgesics;
nor are
adrenocortical steroids that
suppress
pain
of
inflammation
of any
cause.
•
Analgesics
are
classed
as
narcotic
(which
act in
the
central nervous system
and
cause
drowsiness, i.e. opioids)
and
non-narcotic
(which
act
chiefly
peripherally, e.g.
diclofenac).
•
Adjuvant drugs
are
those used alongside
analgesics
in the
management
of
pain. They
are
not
themselves analgesics, though they
may
modify
the
perception
or the
concomitants
of
pain
that make
it
worse (anxiety,
fear,
Pain
Pain
is an
unpleasant sensory
and
emotional
experience
associated with
actual
or
potential
1
Merskey
H et al
1979 Pain terms:
a
list with definitions
and
notes
on
usage.
Pain
6:
249.
2
Melzack
R,
Wall
P
1982
The
challenge
of
pain. Penguin,
London.
3
Loeser
J D,
Melzack 1999 Pain:
an
overview. Lancet 353:1607.
319
17
PAIN
AND
ANALGESICS
depression),
4
e.g. psychotropic drugs,
or
they
may
modify
underlying causes, e.g. spasm
of
smooth
or of
voluntary muscle.
The
general principle that
the
best treatment
of a
symptom
is
removal
of its
cause applies.
But
this
is
often
impossible
to
achieve
and
symptom
relief
of
pain
by
analgesic drug
is
required.
Pain
is the
most common symptom
for
which
patients
see a
doctor.
The
complaint does
not
mean
that
an
analgesic
is
needed.
To
manage
the
pain,
the
doctor
needs
to
know what
is
happening
to the
patient
in
mind
and
body.
Optimal management
of
pain requires that
the
clinician should have
a
conceptual
framework
for
what
is
happening
to the
patient
in
mind
and
body.
•
Acute
pain
is
managed primarily (but
not
invariably)
by
analgesic
drugs.
•
Chronic
pain
often
requires adjuvant drugs
in
addition
as
well
as
nondrug measures.
Analgesics
are
chosen according
to the
cause
of
pain
and its
severity.
Phenomenon
of
pain
An
understanding
of the
phenomenon
of
pain
ought
to
accommodate
the
following
points:
•
Pain
can
occur without tissue
injury
or
evident
disease
and can
persist
after
injury
has
healed.
•
Serious
tissue
injury
can
occur without pain.
•
Emotion
(anxiety,
fear,
depression)
is an
inseparable concomitant
of
pain
and can
modify
both
its
intensity
and the
victim's
behavioural
response.
•
There
is
important processing
of
afferent
nociceptive (see below)
and
other
impulses
in
the
spinal cord
and
brain.
Appreciation
that pain
is
both
a
sensory
and an
emotional
(affective)
experience
has
allowed clini-
cians
to
realise that
to
meet
a
complaint
of
pain
automatically
with
a
prescription alone
is not an
appropriate response,
for
'There
is
always more
to
analgesia
than analgesics'.
5
Pain that
is not the
subject
of an
analysis
by the
clinician (and explana-
tion
to the
patient)
may be
inadequately relieved
because
of
lack
of
understanding.
It is a
justified
and
shaming
criticism
if
doctors
do not
provide
adequate
relief
of
severe pain (postsurgical, pallia-
tive
care
of
advanced cancer)
by bad
choice
and by
overusing
and, also
important,
underusing
drugs,
and by
defective
relations with their patients.
THE
VARIOUS
ASPECTS
OF
PAIN
Pain
is not
simply
a
perception,
it is a
complex
phenomenon
or
syndrome, only
one
component
of
which
is the
sensation actually reported
as
pain.
Pain
has
four
major
aspects present
to
varying
extent
in any one
case:
Nociception
6
is a
consequence
of
tissue
injury
(trauma,
inflammation)
causing
the
release
of
chemical
mediators which activate
nociceptors,
defined
as
receptors that
are
capable
of
distinguish-
ing
between noxious
and
innocuous stimuli
in the
tissue. That said,
it is
widely assumed that there
is no
specific
single histological structure that
is a
noci-
ceptive
receptor,
but
that
free
unmyelinated termi-
nals
in
skin, muscle, joints
and
viscera
are
activated
by
noxious stimuli
and
transmit information
by
thin myelinated (A-delta)
and
nonmyelinated
(C)
fibres
to the
spinal cord
and
brain. Thus nociception
is
not,
for
example,
due to
overstimulation
of
touch
or
other receptors.
A
number
of
receptors, identified
by
anatomical, electrophysiological
and
pharmaco-
logical
means, have been associated with nocicep-
tors,
and
include acetylcholine, prostaglandin
E,
adrenergic,
5-hydroxytryptamine, glutamine, brady-
kinin, opioid
and
adenosine.
The
ligands
for
these
receptors
may be
released
in the
periphery
from
neurones
or be of
non-neuronal origin.
Pain perception
is a
result
of
nociceptive input
plus
a
pattern
of
impulses
of
different
frequency
and
intensity
from
other peripheral receptors, e.g. heat,
4
Tricyclic
antidepressants
may
reduce
morphine
requirement
in
palliative
care
without
noticeably
altering
mood.
5
Twycross
R G
1984
Journal
of the
Royal
College
of
Physicians
of
London
18: 32.
6
Latin:
noxa:
injury.
320
17
and
mechanoreceptors whose threshold
of
response
is
reduced
by the
chemical mediators. These
are
processed
in the
brain whence modulating inhibi-
tory impulses pass down
to
regulate
the
continuing
afferent
input.
But
pain
can
occur
without
nocicep-
tion (some neuralgias
7
)
and
nociception does
not
invariably
cause pain; pain
is a
psychological state,
though most
pain
has an
immediately antecedent
physical
cause.
Suffering
is a
consequence
of
pain
and of
lack
of
understanding
by
patients
of the
meaning
of the
pain;
it
comprises anxiety
and
fear
(particularly
in
acute
pain)
and
depression (particularly
in
chronic
pain),
which will
be
affected
by
patients' persona-
lities,
and
their
beliefs
about
the
significance
of the
pain,
e.g. whether merely
a
postponed holiday,
or
death,
or a
future
of
disability with loss
of
indepen-
dence. Depression makes
a
major
contribution
to
suffering;
it is
treatable,
as are the
other
affective
concomitants
of
pain.
Pain
behaviour comprises consequences
of the
other three aspects (above);
it
includes behaviour
that
is
interpreted
by
others
as
signifying
pain
in
the
victim, e.g. such immediate
and
obvious aspects
as
facial
expression,
restlessness,
seeking isolation
(or
company), medicine-taking,
as
well
as, in
chronic
pain,
the
development
of
querulousness, depres-
sion, despair
and
social withdrawal.
It
is
thus
useful
to
distinguish between acute
pain
(an
event whose
end can be
predicted)
and
chronic pain
(a
situation whose
end is
commonly
unpredictable,
or
will only
end
with
life
itself).
The
clinician's task
is to
determine
the
signifi-
cance
of
these items
for
each patient
and to
direct
therapy accordingly. Analgesics may,
but not
neces-
sarily will,
be the
mainstay
of
therapy; adjuvant
(nonanalgesic) drugs
may be
needed,
as
well
as
nondrug therapy (radiation, surgery).
TYPES
OF
PAIN
Acute
pain
(defined
as of < 3
months duration)
is
7
Neuralgia
is
pain
felt
in the
distribution
of a
peripheral
nerve.
PHENOMENON
OF
PAIN
transmitted principally
by
fast
conducting A-delta
fibres
(but
to a
lesser extent involves slow conduct-
ing
type
C
fibres)
and has
major
nociceptive input
(physical trauma, pleurisy, myocardial
infarct,
perforated
peptic
ulcer). Patients perceive
it as a
transient, though sometimes severe threat
and
they
react
accordingly.
It is a
symptom that
may be
dealt
with unhesitatingly
and
effectively
with drugs,
by
injection
if
necessary,
at the
same time
as the
causative disease
is
addressed.
The
accompanying
anxiety
will vary according
to the
severity
of the
pain,
and
particularly according
to its
meaning
for
the
patient,
whether
termination
with
recovery will
soon
occur,
major
surgery
is
threatened,
or
there
is
prospect
of
death
or
invalidism.
The
choice
of
drug
will depend
on the
clinician's assessment
of
these
factors.
Morphine
by
injection
has
retained
a
pre-
eminent place
for
over
100
years because
it has
highly
effective
antinociceptive
and
anti-anxiety
effects;
modern opioids have
not
rendered morphine
obsolete.
Neuropathic
pain
follows
damage
to the
nervous
system.
Acute
pain
without
nociceptive
(afferent)
input (some neuralgias)
is
less susceptible
to
drugs
unless consciousness
is
also depressed,
and any
frequently
recurrent acute pain, e.g. trigeminal
neuralgia,
poses
management problems that
are
more akin
to
chronic pain.
Chronic
pain
is
transmitted principally
by
slow
conducting type
C
fibres
(but
to a
lesser extent
by
fast
conducting A-delta
fibres).
It is
better regarded
as
a
syndrome
8
rather than
as a
symptom (see
above)
for it is a
collection
of
disparate pains
of
long
duration,
often
sharing common emotional
and
behavioural aspects.
It
presents
a
depressing
future
to the
victim
who
sees
no
prospect
of
release
from
suffering,
and
poses
for
that reason long-term
management problems that
differ
from
acute pain.
Suffering
and
affective
disorders
can be of
over-
riding importance
and the
consequences
of
poor
management
may be
prolonged
and
serious
for the
patient. Analgesics alone
are
often
insufficient
and
8
A set of
symptoms
and
signs
that
are
characteristic
of a
condition though they
may not
always have
the
same cause
(Greek:
syn: together,
dramein:
to
run).
321
17
PAIN
AND
ANALGESICS
adjuvant
drugs
as
well
as
nondrug therapy gain
increasing importance.
Although
dependence
is
less
of
a
problem than might
be
feared,
continuous
use
of
high
efficacy
opioids, e.g. morphine, pethidine,
is
generally
is
best avoided
in
chronic pain
(except
that
of
palliative care).
But the
lower
efficacy
opioids
(codeine, dextropropoxyphene)
may
often
be
needed
and
used.
Sedation should
be
avoided
and
therapy should
be
oral
if
possible; regimens should
be
planned
to
avoid
breakthrough pain. Antidepressants
can
often
be
useful.
Sedative-hypnotic
drugs,
e.g. benzo-
diazepines,
may be
needed
for
anxiety
but may
induce depression.
Chronic
pain
syndrome
is a
term used
for
persistence
of
pain when detectable disease
has
disappeared,
e.g.
after
an
attack
of low
back pain.
It
characteristically
does
not
respond
to
standard
treatment
with analgesics. Whether the basis is
neurogenic, psychogenic
or
sociocultural
it
should
not be
managed
by
intensifying drug treatment.
Opioid
analgesics, which
may be
producing depen-
dence, should
be
withdrawan
and the use of
psycho-
tropic drugs, e.g. antidepressants
or
neuroleptics,
and
nondrug therapy, including psychotherapy,
should
be
considered.
Transient pain
is
provoked
by
activation
of
noci-
ceptors
in
skin
or
other tissues
in the
absence
of
tissue damage.
It has
evolved
to
protect humans
from
physical damage
from
the
environment
or
excessive
stressing
of
tissues.
It is a
part
of
normal
life
and not a
reason
to
seek medical help. Never-
theless,
it is
partly through
the
production
of
transient pain
in
physiological experiments that
present concepts
of
pain have evolved.
MECHANISMS
OF
ANALGESIA
Endogenous
opioid neurotransmitters
in the
spinal cord
and
brain
constitute
a
pain
inhibitory
system;
they
are
activated
by
nociceptive
and
other
inputs (including treatments such
as
transcuta-
neous nerve stimulation,
and
acupuncuture)
and
mediate their
effects
through
specific
receptors.
Activation
of
opioid receptors prevents
the
release
of
substance
P (a
neurotransmitter
and
local hormone
involved
in
pain transmission) with
the
result that
pain transmission
is
inhibited. Several types
of
receptor have
been
recognised,
principally:
(j,
(mu),
5
(delta)
and
K
(kappa)
receptors
for
which
the
endo-
genous ligands respectively are: endomorphins, met-
encephalin
and
dynorphins.
Synthetic
opioids produce analgesia
by
simulat-
ing the
body's
natural opioids
and the
existence
of
different
types
of
receptor explains their varying
patterns
of
actions.
Definition
of
these receptors
and
their subdivisions
offers
hope
for the
design
of
new
selective
high-efficacy
analgesics
free
from
the
disadvantages
of the
existing
opioids.
Naloxone,
the
competitive opioid antagonist, binds
to and
blocks
all
opioid receptors
but
exerts
no
activating
effect.
Naloxone
has
particularly high
affinity
for the
(0-receptor;
it
worsens (dental) pain,
an
effect
that
may be
explained
by
blocking access
of
endogenous opioids
to
their receptor(s).
9
It
does
not
induce hyperalgesia
or
spontaneous pain because
the
opioid paths
are
quiescent until activated
by
nociceptive
and
other
afferent
input.
In
addition
to
these opioid mechanisms, non-
opioid mediated pathways, e.g. serotonin,
are
important
in
pain. There
is
suggestion that opioid
mechanisms
are
more important
in
acute severe
pain,
and
nonopioid mechanisms
in
chronic pain,
and
that this
may be
relevant
to
choice
of
drugs.
NSAIDs.
When
a
tissue
is
injured
(from
any
cause),
or
even merely stimulated, prostaglandin synthesis
in
that
tissue
increases. Prostaglandins have
two
major
actions: they
are
mediators
of
inflammation
and
they also sensitise nerve endings, lowering
their threshold
of
response
to
stimuli, mechanical
(the
tenderness
of
inflammation)
and
chemical,
allowing
the
other mediators
of
inflammation, e.g.
histamine, serotonin, bradykinin,
to
intensify
the
activation
of the
sensory endings.
Plainly,
a
drug that prevents
the
synthesis
of
prostaglandins
is
likely
to be
effective
in
relieving
pain
due to
inflammation
of any
kind,
and
this
is
indeed
how
aspirin
and
other nonsteroidal anti-
inflammatory
drugs
(NSAIDs)
act. This discovery
was
made
in
1971, aspirin having been extensively
9
Naloxone also appears
to
cause
pyrovats
(practitioners
of
religious
firewalking
ceremonies)
to
quicken their
pace
over
the hot
coals.
322
CLINICAL
EVALUATION
OF
ANALGESICS
17
used
in
medicine since 1899.
10
NSAIDs
act by
inhibiting cyclo-oxygenase (see
p.
280). Thus
it is
evident that NSAIDs will relieve pain when there
is
some tissue
injury
with consequent inflammation,
as
there almost always
is
with pain. They also
act in
the
central
nervous
system
(prostaglandins,
despite
their
name,
are
synthesised
in all
cells except
erythrocytes)
and
there
is
probably some central
component
to the
analgesic
effect
of
NSAIDs.
But,
analgesic
and
anti-inflammatory
effects
are
not
parallel,
e.g.
aspirin relieves pain rapidly
at
doses that
do not
significantly reduce inflammation
and the
onset
of its
anti-inflammatory
effect
at
higher
doses
may be
slow. Paracetamol
is an
effective
anal-
gesic
for
mild pain
but has
little anti-inflammation
effect
in
arthritis, though substantial
effect
on
post-
dental
extraction swelling. Other NSAIDs show
a
different
mix of
action against pain
and
inflamma-
tion (see
Ch.
15).
Corticosteroids
diminish inflammation
of all
kinds
by
preventing prostaglandin synthesis (the phospho-
lipase
A
that releases arachidonic acid
for
such
synthesis
is
inhibited
by
lipocortin-1 which
is
produced
in
response
to
glucosteroids). Short-term
use may be
valuable; long-term
use
poses many
problems (see
Ch.
34);
in
general
the
corticosteroid
should
be
withdrawn
after
one
week
if
there
is no
benefit.
The
pain threshold
is
lowered
by
anxiety,
fear,
depression, anger, sadness, fatigue,
or
insomnia,
and is
raised
by
relief
of
these
(by
drug
or
nondrug
measures)
and by
successful
relief
of
pain. Since
emotion
is
such
an
important
factor
in
pain,
it is no
surprise that placebo tablets
or
injections
alleviate
pain
but
with
the
added disadvantage that they
rapidly lose
effect
with repetition.
The
importance
of the
meaning
of
pain
to its
victim
is
illustrated
by
injuries
of war and of
civilian
life:
10
Propagandists
for
complementary
(alternative)
medicine
allege
that conventional
scientific
medicine will
not
recognise
any
therapy, e.g. complementary medicine, unless
its
mode
of
action
is
known. This
is
untrue.
Validated
empirical
observation, i.e.
scientific
evidence,
is and
always
has
been accepted.
To
the
wounded soldier
who had
been under
unremitting
shell
fire
for
weeks,
his
wound
was a
good
thing
(it
meant
the end of the war for
him)
and was
associated with
far
less
pain than
was the
case
of the
civilians
who
considered
their
need
for
surgery
a
disaster.
11
The
desire
for
analgesics
has
been found
to be
less amongst victims
of
battle injuries than amongst
comparable civilian injuries.
On the
other hand,
morphine
has
been
found
to be
relatively
ineffec-
tive
against experimental pain
in
man,
probably
because
it
acts best against pain that
has
emotional
significance
for the
patient.
New
analgesics have been
successfully
developed
by
animal testing, possibly because
the
emotional
response
to
experimental pain
in an
animal
is
akin
to the
human response
to
disease
or
accidental
injury.
This emotional
response
does
not
generally
occur
in a
subject
who has
volunteered
to
undergo
laboratory
experiments that
can be
stopped
at any
time,
and it
probably accounts
for the
fact
that
a
placebo
gives
relief
in
only
3% of
these
cases.
Clinical
evaluation
of
analgesics
Therapeutic trials
in
acute pain
are
often
conducted
on
patients
who
have undergone abdominal
surgery
or
third
molar
tooth
extraction,
and in
chronic
pain
on
chronic rheumatic conditions. Only
the
patients
can say
what they
feel
and
pain
is
best
measured
by a
questionnaire
or by a
visual analogue
scale;
this
is a
line,
10 cm
long,
one end of
which
represents pain
'as bad as it
could possibly
be'
(which
patients
identify
as
'agonising')
and the
other
end 'no
pain';
patients mark
the
line
at
the
point they
feel
represents their pain between
these
two
extremes. Such techniques
are
highly
reproducible.
Since
what
is
being measured
is how
patients
say
they
feel,
the
trial must
be
double-blind.
11
Beecher
H K
1957
Pharmacological
Review
9: 59.
323
17
PAIN
AND
ANALGESICS
Observers
who
interrogate
the
patients
for
relief
(intensity
and
duration)
and
adverse
effects
must
be
constant
and
trained.
If
asked
by a
personable
young woman,
a
higher proportion
of
patients
(of
both sexes) admit
to
pain
relief
if the
same question
is put by a
man.
Choice
of
analgesics
12
RANKED
BY
CLINICAL
EFFICACY
(see
also ranking
of
opioids,
p.
338)
Mild
pain
•
Non-narcotic (nonopioid) analgesics
or
NSAIDs,
e.g.
paracetamol, ibuprofen, diclofenac.
13
(Ch.
15)
Where
these
fail
after
using
the
full
dose
range,
proceed
to
drugs for:
Moderate
pain
•
Narcotic (opioid)
analgesics,
low-efficacy
opioids,
e.g.
codeine, dihydrocodeine,
dextropropoxyphene, pentazocine.
•
Combined therapy
of
NSAIDs
plus
low-efficacy
opioid, either
as a
fixed-dose formulation, which
is
convenient
for
acute
pain
or
separately
to
find
the
optimum dose
of
each, which
may be
preferable
for
chronic pain though less
convenient.
Where
these
fail
proceed
to
drugs for:
Severe
pain
•
High-efficacy
opioids,
e.g.
morphine,
diamorphine,
pethidine,
buprenorphine.
An
added NSAID
is
useful
if
there
is an
additional
tissue
injury
component,
e.g.
gout, bone
metastasis.
12
Based
on
Twycross
R G
1978
In:
Saunders
Cicely
M
(ed)
The
management
of
terminal disease. Arnold,
London.
The
work
of
this author
contributes
much
to
this chapter.
13
Paracetamol
is
sometimes
not
classed
as an
NSAID
because
its
anti-inflammatory
pattern
differs
substantially
from
most,
i.e.
it is
central rather than peripheral,
as
witness
its
weak
anti-inflammatory
efficacy
in
rheumatoid arthritis.
Where
these
fail
proceed
to
drugs for:
Overwhelming
acute
pain
•
High
efficacy
opioid plus
a
sedative/anxiolytic
(diazepam)
or a
phenothiazine tranquilliser,
e.g.
chlorpromazine, levomepromazine
(methotrimeprazine)
(which also
has
analgesic
effect).
Note:
adjuvant drugs
(p.
331)
may be
useful
in all
grades
of
pain.
COMBINING
ANALGESICS
Simultaneous
use of two
analgesics
of
different
modes
of
action
is
rational,
but two
drugs
of the
same
class/mechanism
of
action
are
unlikely
to
benefit
unless there
is a
difference
in
emphasis,
e.g.
analgesia
and
anti-inflammatory action (paraceta-
mol
plus aspirin),
or in
duration
of
action;
a
patient
taking
an
NSAID with
a
long duration,
e.g.
naproxen (used once
or
twice
a
day),
is
benefited
by
an
additional drug
of
shorter duration
for an
acute
exacerbation,
e.g.
ibuprofen, paracetamol.
A
low-efficacy
opioid
can
reduce
the
effective-
ness
of a
high-efficacy
opioid
by
successfully
com-
peting with
the
latter
for
receptors. Partial agonist
(agonist/antagonist) opioids,
e.g.
pentazocine, will
also antagonise
the
action
of
other opioids,
e.g.
heroin,
and may
even induce
the
withdrawal
syn-
drome
in
dependent subjects.
FIXED-RATIO
(COMPOUND)
COMBINATIONS
Large
numbers
of
these
are
offered
particularly
to
bridge
the
efficacy
gap
between paracetamol
and
morphine. Doctors should consider
the
formulae
of
these preparations
before
using them.
Caffeine
has
been shown
to
enhance
the
analgesic
effect
of
aspirin
and of
paracetamol
and to
accelerate
the
onset
of
effect,
but at
least
30 mg and
probably
60
mg are
needed
(a cup of
coffee
averages about
80
mg and of tea
averages about
30
mg).
Tablets
containing paracetamol (325
mg)
plus
dextropropoxyphene (32.5
mg)
(co-proxamol, Distal-
gesic),
in a
dose
of 1-2
tablets, provide
an
effective
dose
of
both drugs
and
have been extremely
324
PAIN
SYNDROMES
AND
THEIR TREATMENT
17
popular with both prescribers
and
patients;
its
popularity
may be
influenced
by a
mild euphoriant
effect
of the
opioid,
to
which dependence
can
occur.
A
major
concern
is
that
in
(deliberate) overdose
death
may
occur
within
one
hour
due to the
rapid absorption
of the
dextropropoxyphene,
and
combination with alcohol appears seriously
to
add to the
hazard.
We do not
attempt
to
rank
the
many
preparations available because comparative
evidence
is
lacking.
Pain
syndromes
and
their
treatment
In
general, pain (acute
or
chronic)
arising
from
the
somatic
structures
(skin, muscles, bones,
joints)
responds
to
NSAIDs. Acute pain arising
from
viscera,
which
is
poorly localised, unpleasant,
and
associated with nausea
is
best treated
with
mor-
phine
but
this induces dependence with prolonged
use. This distinction
is
not,
of
course, absolute
and a
high-efficacy
opioid
is
needed
for
severe somatic
pain,
e.g.
a
fractured
bone. Mild pain
from
any
source
may
respond
to
NSAIDs
and
these should
always
be
tried
first.
SPASM
OF
VISCERAL
SMOOTH
MUSCLE
Pain
due to
spasm
of
visceral smooth muscle,
e.g.
biliary,
renal colic, when severe, requires
a
substan-
tial
dose
of
morphine, pethidine
or
buprenorphine.
These
drugs themselves cause spasm
of
visceral
smooth muscle
and so
have
a
simultaneous action
tending
to
increase
the
pain. Phenazocine
and
buprenorphine
are
less liable
to
cause spasm.
An
antimuscarinic
drug such
as
atropine
or
hyoscine
may
be
given simultaneously
to
antagonise this
effect.
Prostaglandins
are
involved
in
control
of
smooth
muscle
and
colic
can be
treated with NSAIDs,
e.g.
diclofenac,
indometacin
(i.m.,
suppository
or
oral).
SPASM
OF
STRIATED MUSCLE
This
is
often
a
cause
of
pain,
including chronic
tension headache. Treatment
is
directed
at
reduc-
tion
of the
spasm
in a
variety
of
ways, including
psychotherapy,
sedation
and the use of a
centrally-
acting muscle relaxant
as
well
as
non-narcotic
analgesics, e.g.
baclofen,
diazepam; clinical
efficacy
is
variable
(see
Other muscle relaxants,
p.
357).
Local
infiltration
with lignocaine (lidocaine)
is
sometimes
appropriate. Tizanidine
is an
cc
2
-adrenoreceptor
agonist that
may be
used
to
relieve muscle spasticity
in
multiple sclerosis, spinal cord
injury
or
disease.
NEURALGIAS
(NEUROPATHIC PAIN)
These include postherpetic neuralgia, phantom limb
pain, peripheral neuropathies
of
various causes,
central
pain,
e.g.
following
a
stroke, compression
neuropathies,
and the
complex regional pain
syndromes (comprising causalgia, when there
is
nerve damage,
and
reflex
sympathetic dystrophy,
when there
is
tissue
but no
nerve
injury);
they
present
the
most challenging problems.
A
tricyclic
antidepressant
and/or
an
antiepilepsy
drug
are
commonly used
in
their management;
analgesics play
a
subsidiary part.
•
Amitriptyline
is
most
frequently
used, starting
with
10 mg at
night increasing
to 75 mg.
Nortriptyline
is
better tolerated
by
some
patients. Their general action
is to
inhibit
noradrenaline (norepinephrine) re-uptake
by
nerve terminals
and
benefit
in
neuropathic pain
may
follow
enhanced activity
in
noradrenergic
pain inhibitory paths
in the
spinal cord.
•
Gabapentin
is the
most commonly used
antiepilepsy drug
in
this setting;
phenytoin
(which
raises
the
threshold
of
nerve cells
to
electrical
stimulation)
or
sodium
valproate
are
used
for
resistant neuralgias.
•
Transcutaneous
electrical
nerve
stimulation
(TENS)
helps some
sufferers;
it may act by
promoting
the
release
of
endorphins.
Ketamine
(see
p.
353)
or
lidocaine
(lignocaine)
(by
i.v. infusion)
are
used
in
special circumstances. Pain
due to
nerve
compression
may be
relieved
by a
corticosteroid
injected
loccally.
•
When these measures
fail,
and an
opioid
appears
necessary, methadone, dextroproxyphene,
tramadol
and
oxycodone
are
preferred;
all
possess
NMDA-receptor antagonist activity
as
well
as
being opioid
m-receptor
agonists.
325
17
PAIN
AND
ANALGESICS
Trigeminal neuralgia
differs
from
other peripheral
neuropathies
in its
management.
The
antiepilepsy
drug, carbamazepine
(p.
417),
was
accidentally
dis-
covered
to be
effective,
probably
by
reducing excit-
ability
of the
trigeminal nucleus.
The
initial dose
should
be
low,
and
individuals generally soon
learn
to
alter
it
themselves during remissions
and
exacerbations
(200-1600
mg/d).
It is not
used
for
prophylaxis. Resistant cases
may
obtain
benefit
from
oxcarbazepine, gabapentin
or
lamotrigine.
Postherpetic neuralgia.
The
pain
of
acute herpes
zoster (shingles)
is
mitigated
by
NSAIDs
and
opioids
(as
well
as by
oral aciclovir started within
48
h of the
rash). Whether
the
incidence
of
posther-
petic neuralgia
is
reliably reduced
by
early treatment
with
an
antivirus drug
has yet to be
proved. Amitrip-
tyline
is an
appropriate initial choice,
failing
which
gabapentin
may be
used.
A
topical application
of
capsaicin, derived
from
Capsicum
spp
(pepper
and
chilli),
may be
applied
as a
counter-iritant, although
the
initial intense burning sensation
may
limit
its
use. Conventional analgesics
are
ineffective.
HEADACHE
Headache originating inside
the
skull
may be due
to
traction
on or
distension
of
arteries arising
from
the
circle
of
Willis,
or to
traction
on the
dura mater.
Headache originating outside
the
skull
may be
due to
local striated muscle spasm;
14
an
anatomical
connection, only recently identified, between
an
extracranial
muscle
and the
cervical dura mater
may
help
to
explain headache
of
cervical origin.
Treat-
ment
by
drugs
is
directed
to
relieving
the
muscle
spasm, producing vasoconstriction
or
simply
administering analgesics, beginning,
of
course,
with
the
non-narcotics,
e.g.
paracetamol, ibuprofen.
MIGRAINE
The
acute migraine attack appears
to
begin
in
serotonergic
(5-HT)
and
noradrenergic
neurons
in
the
brain. These monoamines
affect
the
cerebral
and
extracerebral
vasculature
and
also cause
release
of
further
vasoactive substances such
as
histamine,
prostaglandins
and
neuropeptides involved
in
pain,
i.e.
there
is
neurogenic inflammation that
can
be
inhibited
by
specific
antimigraine drugs (below).
The
migraine aura
of
visual
or
sensory disturb-
ance
probably originates
in the
occipital
or
sensory
cortex;
the
throbbing headache
is due to
dilatation
of
pain-sensitive arteries outside
the
brain, including
scalp
arteries.
Identifying
and
avoiding triggering
factors
are
important. These include stress (exertion, excitement,
anxiety,
fatigue,
anger),
food
containing vasoactive
amines (chocolate, cheese),
food
allergy, bright
lights
and
loud noise,
and
also hormonal changes
(menstruation
and
oral contraceptives)
and
hypo-
glycaemia. These precipitants
may
initiate
release
of
vasoactive substances stored
in
nerve endings
and
blood platelets. Many attacks, however, have
no
obvious trigger.
Treatment.
A
stepped approach
to
therapy
is
logical.
15
• The
acute
migraine
attack
should
be
treated
as
early
as
possible with
an
oral dispersible
(soluble)
analgesic formulation
so
that
it may be
absorbed
before
there
is
vomiting
and
accompanying
gastric stasis with slow
and
erratic
drug absorption. Aspirin (600
mg) is
effective
and its
antiplatelet action
may add to its
advantage; paracetamol, ibuprofen
and
naproxen
are
alternatives. Metoclopramide
or
domperidone, dopamine agonists,
are
useful
antiemetics that also promote gastric emptying
and
enhance absorption
of the
analgesic.
Opioids
such
as
codeine, dihydrocodeine
and
dextropropoxyphene
are not
suitable
for
migraine.
•
If
the
oral route
is
unsuccessful,
a
rational
alternative
is to use
suppositories
of
diclofenac
100
mg for
pain
and
domperidone
30 mg for
vomiting, although
the
diarrhoea that
may
accompany migraine would compromise their
efficacy.
Efficient
use of an
analgesic
and an
antiemetic
is
adequate
for the
majority
of
acute
attacks.
14
As in
tension headache
or
frontal
headache
from
'eyestrain'.
15
British
Association
for the
Study
of
Headache
2001.
http://www.bash.org.uk
326
[...]... importance, except in asthmatics in whom morphine should be avoided anyway because of its respiratory depressant effect Urinary tract Any contraction of the ureters is probably clinically unimportant Retention of urine may occur (particularly in prostatic hypertrophy) due to a mix of spasm of the bladder sphincter and to the central sedation causing the patient to ignore afferent messages from a full... transdermally is also available for pain relief in palliative care • • • • ADJUVANT DRUGS Phenothiazines are antiemetic, antianxiety and sedative agents and they may change the affective response to pain (particularly methotrimeprazine) Tricyclic antidepressants (and perhaps others) have a morphine-sparing effect even in the absence of an effect or mood In selected cases the full range of techniques of... and so morphine is unsuitable for use in tetanus and convulsant poisoning; indeed, morphine can itself cause convulsions Morphine causes antidiuresis by releasing antidiuretic hormone, and this can be clinically important Appetite is lost with chronic use Peripheral nervous system The discovery of opioid receptors is sensory nerves and their inhibiting effect on inflammatory mediators may lead to advances... was treated with continuous subcutaneous heroin (diamorphine) infusion Whilst the randomised controlled trial provides a major basis for therapeutic advance, telling us what generally does happen, the clinical anecdote yet has value, telling us what can happen, and providing examples for us to emulate With intelligent use of drugs, which follows from informed analyses of objectives, doctors can enable... action and respiratory depression (the fatal dose becomes higher), but not to some stimulant agonist effects, e.g constipation and miosis, which persist Opioids that have mixed agonist/antagonist actions (partial agonists) induce tolerance to the agonist but not to the antagonist effects; naloxone (a pure antagonist) induces no tolerance to itself There is a cross-tolerance between opioids (for dependence... extensive presystemic metabolism (mainly conjugation in gut wall and liver) and only about 20% of a dose reaches the systemic circulation; the initial oral dose is about twice the injected dose Given s.c (particularly) or i.m., morphine is rapidly absorbed when the circulation is normal, but in circulatory shock absorption will be delayed and morphine is best given i.v Morphine in the systemic circulation... Maurer D W, Vogel V H 1962 Narcotics and narcotic addiction Thomas, Springfield, Illinois Courtesy of the authors and publisher 30 For a general account, see: Drug Misuse and Dependence — Guidelines on Clinical Management HMSO, London, 1999 31 It has x 2.5 the strength of Methadone Linctus, for cough (yellow or brown); they must not be confused 337 17 PAIN AND A N A L G E S I C S Buprenorphine is an . meaning
of the
pain;
it
comprises anxiety
and
fear
(particularly
in
acute
pain)
and
depression (particularly
in
chronic
pain),
which will
be
affected
. Any
contraction
of the
ureters
is
probably clinically unimportant. Retention
of
urine
may
occur (particularly
in
prostatic hypertrophy)
due to