Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 19) pdf

• 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

SECTION 4

NERVOUS SYSTEM

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 suchdamage.1 It is mediated by specific nerve fibres tothe brain where its conscious appreciation may bemodified by various factors

The word 'unpleasant' comprises the whole range

of disagreeable feelings from being merely nienced to misery, anguish, anxiety, depression anddesperation, to the ultimate cure of suicide.2,3

inconve-• Analgesic drug: a drug that relieves pain due to

multiple causes, e.g paracetamol, morphine.Drugs that relieve pain due to a single cause orspecific pain syndrome only, e.g ergotamine(migraine), carbamazepine (neuralgias), glyceryltrinitrate (angina pectoris), are not classed asanalgesics; nor are adrenocortical steroids thatsuppress 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 arenot themselves analgesics, though they maymodify the perception or the concomitants ofpain 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.

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 toanalgesia than analgesics'.5 Pain that is not thesubject of an analysis by the clinician (and explana-tion to the patient) may be inadequately relievedbecause of lack of understanding It is a justifiedand shaming criticism if doctors do not provideadequate relief of severe pain (postsurgical, pallia-tive care of advanced cancer) by bad choice and byoverusing 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 complexphenomenon or syndrome, only one component ofwhich is the sensation actually reported as pain.Pain has four major aspects present to varyingextent in any one case:

Nociception6 is a consequence of tissue injury(trauma, inflammation) causing the release of

chemical mediators which activate nociceptors,

defined as receptors that are capable of ing between noxious and innocuous stimuli in thetissue That said, it is widely assumed that there is nospecific single histological structure that is a noci-ceptive receptor, but that free unmyelinated termi-nals in skin, muscle, joints and viscera are activated

distinguish-by noxious stimuli and transmit information distinguish-bythin 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 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 thesereceptors may be released in the periphery fromneurones or be of non-neuronal origin

pharmaco-Pain perception is a result of nociceptive input plus

a pattern of impulses of different frequency andintensity from other peripheral receptors, e.g heat,

4 Tricyclic antidepressants may reduce morphine

requirement in palliative care without noticeably altering

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 neuralgias7) 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.

P H E N O M E N O N O F P A I N

transmitted principally by fast conducting A-deltafibres (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 atransient, though sometimes severe threat and theyreact accordingly It is a symptom that may be dealtwith unhesitatingly and effectively with drugs,

by injection if necessary, at the same time as thecausative disease is addressed The accompanyinganxiety will vary according to the severity of thepain, and particularly according to its meaning forthe patient, whether termination with recovery willsoon occur, major surgery is threatened, or there isprospect of death or invalidism The choice of drugwill depend on the clinician's assessment of thesefactors Morphine by injection has retained a pre-eminent place for over 100 years because it hashighly effective antinociceptive and anti-anxietyeffects; modern opioids have not rendered morphineobsolete

Neuropathic pain follows damage to the nervous

system Acute pain without nociceptive (afferent)input (some neuralgias) is less susceptible to drugsunless consciousness is also depressed, and anyfrequently recurrent acute pain, e.g trigeminalneuralgia, poses management problems that aremore akin to chronic pain

Chronic pain is transmitted principally by slow

conducting type C fibres (but to a lesser extent byfast conducting A-delta fibres) It is better regarded

as a syndrome8 rather than as a symptom (seeabove) for it is a collection of disparate pains of longduration, often sharing common emotional andbehavioural aspects It presents a depressing future

to the victim who sees no prospect of release fromsuffering, and poses for that reason long-termmanagement problems that differ from acute pain.Suffering and affective disorders can be of over-riding importance and the consequences of poormanagement may be prolonged and serious for thepatient 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).

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 ofreceptor have been recognised, principally: (j, (mu),

5 (delta) and K (kappa) receptors for which the genous ligands respectively are: endomorphins, met-encephalin and dynorphins

endo-Synthetic opioids produce analgesia by

simulat-ing the body's natural opioids and the existence ofdifferent types of receptor explains their varyingpatterns of actions Definition of these receptorsand their subdivisions offers hope for the design ofnew selective high-efficacy analgesics free from thedisadvantages of the existing opioids

Naloxone, the competitive opioid antagonist, binds

to and blocks all opioid receptors but exerts noactivating effect Naloxone has particularly highaffinity 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 doesnot induce hyperalgesia or spontaneous pain becausethe opioid paths are quiescent until activated bynociceptive and other afferent input

In addition to these opioid mechanisms, opioid mediated pathways, e.g serotonin, areimportant in pain There is suggestion that opioidmechanisms are more important in acute severepain, and nonopioid mechanisms in chronic pain,and that this may be relevant to choice of drugs

non-NSAIDs When a tissue is injured (from any cause),

or even merely stimulated, prostaglandin synthesis

in that tissue increases Prostaglandins have twomajor actions: they are mediators of inflammationand they also sensitise nerve endings, loweringtheir 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 theactivation of the sensory endings

Plainly, a drug that prevents the synthesis ofprostaglandins is likely to be effective in relievingpain due to inflammation of any kind, and this isindeed how aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) act This discoverywas 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.

C L I N I C A L E V A L U A T I O N O F A N A L G E S I C S 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 underunremitting shell fire for weeks, his wound was agood thing (it meant the end of the war for him)and was associated with far less pain than was thecase of the civilians who considered their need forsurgery a disaster.11

The desire for analgesics has been found to beless amongst victims of battle injuries than amongstcomparable civilian injuries On the other hand,morphine has been found to be relatively ineffec-tive against experimental pain in man, probablybecause it acts best against pain that has emotionalsignificance for the patient

New analgesics have been successfully developed

by animal testing, possibly because the emotionalresponse to experimental pain in an animal isakin to the human response to disease or accidentalinjury This emotional response does not generallyoccur in a subject who has volunteered to undergolaboratory experiments that can be stopped at anytime, and it probably accounts for the fact that aplacebo 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 abdominalsurgery or third molar tooth extraction, and inchronic pain on chronic rheumatic conditions Onlythe patients can say what they feel and pain is bestmeasured by a questionnaire or by a visual analoguescale; this is a line, 10 cm long, one end of whichrepresents pain 'as bad as it could possibly be'(which patients identify as 'agonising') and theother end 'no pain'; patients mark the line atthe point they feel represents their pain betweenthese two extremes Such techniques are highlyreproducible

Since what is being measured is how patientssay they feel, the trial must be double-blind

11 Beecher H K 1957 Pharmacological Review 9: 59.

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 analgesiceffect)

Note: adjuvant drugs (p 331) may be useful in allgrades of pain

COMBINING ANALGESICS

Simultaneous use of two analgesics of differentmodes of action is rational, but two drugs of thesame class/mechanism of action are unlikely tobenefit unless there is a difference in emphasis, e.g.analgesia and anti-inflammatory action (paraceta-mol plus aspirin), or in duration of action; a patienttaking 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 acuteexacerbation, e.g ibuprofen, paracetamol

A low-efficacy opioid can reduce the ness of a high-efficacy opioid by successfully com-peting with the latter for receptors Partial agonist(agonist/antagonist) opioids, e.g pentazocine, willalso antagonise the action of other opioids, e.g.heroin, and may even induce the withdrawal syn-drome in dependent subjects

effective-FIXED-RATIO (COMPOUND) COMBINATIONS

Large numbers of these are offered particularly tobridge the efficacy gap between paracetamol andmorphine Doctors should consider the formulae

of these preparations before using them Caffeinehas been shown to enhance the analgesic effect ofaspirin and of paracetamol and to accelerate theonset 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) plusdextropropoxyphene (32.5 mg) (co-proxamol, Distal-gesic), in a dose of 1-2 tablets, provide an effectivedose of both drugs and have been extremely

P A I N S Y N D R O M E S A N D T H E I R T R E A T M E N T 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, includingpsychotherapy, sedation and the use of a centrally-acting muscle relaxant as well as non-narcoticanalgesics, e.g baclofen, diazepam; clinical efficacy isvariable (see Other muscle relaxants, p 357) Localinfiltration with lignocaine (lidocaine) is sometimesappropriate Tizanidine is an cc2-adrenoreceptoragonist that may be used to relieve muscle spasticity

in multiple sclerosis, spinal cord injury or disease

NEURALGIAS (NEUROPATHIC PAIN)

These include postherpetic neuralgia, phantom limbpain, peripheral neuropathies of various causes,central pain, e.g following a stroke, compressionneuropathies, and the complex regional painsyndromes (comprising causalgia, when there isnerve damage, and reflex sympathetic dystrophy,when there is tissue but no nerve injury); theypresent 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 somepatients Their general action is to inhibitnoradrenaline (norepinephrine) re-uptake bynerve terminals and benefit in neuropathic painmay follow enhanced activity in noradrenergicpain 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 nervecompression may be relieved by a corticosteroidinjected loccally

• When these measures fail, and an opioid appears

necessary, methadone, dextroproxyphene,tramadol and oxycodone are preferred; allpossess NMDA-receptor antagonist activity aswell as being opioid m-receptor agonists

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 inpain, 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 sensorycortex; the throbbing headache is due to dilatation

of pain-sensitive arteries outside the brain, includingscalp arteries

Identifying and avoiding triggering factors areimportant These include stress (exertion, excitement,anxiety, fatigue, anger), food containing vasoactiveamines (chocolate, cheese), food allergy, brightlights 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 endingsand blood platelets Many attacks, however, have

no obvious trigger

Treatment A stepped approach to therapy islogical.15

• The acute migraine attack should be treated as

early as possible with an oral dispersible(soluble) analgesic formulation so that it may beabsorbed before there is vomiting and

accompanying gastric stasis with slow anderratic drug absorption Aspirin (600 mg) iseffective and its antiplatelet action may add to itsadvantage; paracetamol, ibuprofen and

naproxen are alternatives Metoclopramide ordomperidone, dopamine agonists, are usefulantiemetics that also promote gastric emptyingand enhance absorption of the analgesic Opioidssuch as codeine, dihydrocodeine and

dextropropoxyphene are not suitable formigraine

• If the oral route is unsuccessful, a rationalalternative is to use suppositories of diclofenac

100 mg for pain and domperidone 30 mg forvomiting, although the diarrhoea that mayaccompany migraine would compromise theirefficacy Efficient use of an analgesic and anantiemetic is adequate for the majority of acuteattacks

14 As in tension headache or frontal headache from

'eyestrain'.

15 British Association for the Study of Headache 2001 http://www.bash.org.uk

P A I N S Y N D R O M E S A N D T H E l R T R E A T M E N T 17

• Severe migraine attacks should be treated with a

triptan, e.g sumatriptan (below) In contrast to

symptomatic treatments, triptans are best used

during the established headache phase of the

acute attack Headache may return in 6-36 h in

about one-third of patients, necessitating a

second dose

• Ergotamine 1-2 mg as a suppository is used if

other treatments have failed, but not within 12 h

of the last dose of a triptan; similarly a triptan

should not be given until 24 h have elapsed after

stopping ergotamine

Sumatriptan

Sumatriptan (Imigran) selectively stimulates a

subtype of 5-hydroxytryptaminej-receptors (called

5-HT1B/]D-receptors) which are found in cranial

blood vessels, causing them to constrict It is rapidly

absorbed after oral administration and undergoes

extensive (84%) presystemic metabolism; but

bio-availability by the s.c route is 96% The t1/, is 2 h

The oral dose is 50-100 mg, the 24 h total not to

exceed 300 mg The oral route may be avoided by

sumatriptan 20 mg given intranasally, repeated

once in not less than 2 h, with not more than 40 mg

in 24 h When a rapid response is required,

suma-triptan 6 mg is given s.c., the dose to be repeated

once if necessary after 1 h but the total should not

exceed 12 mg in 24 h

Sumatriptan is generally well tolerated Malaise,

fatigue, dizziness, vertigo and sedation are

asso-ciated with oral use Nausea and vomiting may

follow oral or s.c administration The most

impor-tant adverse effects are feelings of chest pressure,

tightness and pain in about 5% of cases; these may

be accompanied by cardiac arrhythmia and

myo-cardial infarction and appear to be due to coronary

artery spasm Patients with ischaemic heart disease,

unstable angina or previous myocardial infarction

should not be given sumatriptan; use in relation to

ergotamine (see above)

Almotriptan, naratriptan, rizatriptan and

zol-mitriptan are similar.16

16 Ferrari M D et al 2001 Oral triptans (serotonim 5-HT 1B/1D

agonists) in acute migraine treatment: a meta-analysis of 53

trials Lancet 358:1668-1675.

Ergotamine

Ergotamine is a partial agonist at cc-adrenoceptors(vasoconstrictor) and also a partial agonist at seroto-nergic receptors It must be used with special care.Ergotamine constricts all peripheral arteries (aneffect potentiated by concomitant (3-adrenoceptorblock), not just those affected by the migraineprocess Due to tissue binding, its effect on arteriespersists as long as 24 h and repeated doses lead tocumulative effects long outlasting the migraine attack

It is incompletely absorbed from the tinal tract; rectal administration may be preferred

gastrointes-in the acute attack of migragastrointes-ine Ergotamgastrointes-ine isextensively metabolised in the liver (t1/2 2 h).Tablets, 1 mg, may be crushed before swallowingwith water Initially 1-2 tablets should be taken andthereafter, not more than 4 tablets should be taken

in 24 h, the sequence should not be repeated for

4 days, and not more than 8 tablets should be taken

in a week Suppositories, 2 mg, are now preferred

as part of stepped therapy (above); they are subject

to the same maximum dose restrictions Caffeineenhances both the speed of absorption and peakconcentration of ergotamine and is often combinedwith it (though it may prevent sleep)

Paraesthesiae in hands or feet give warning ofperipheral ischaemia Overdose can cause peripheralgangrene Due to its complex actions on receptors,vasoconstriction is best antagonised by a nonselectivevasodilator such as glyceryl trinitrate, nifedipine orsodium nitroprusside (rather than by an a-adreno-ceptor blocker) Patients with vascular disease,coronary and peripheral, are particularly at risk.Ergotamine is a powerful oxytocic and isdangerous in pregnancy It may precipitate anginapectoris, probably by increasing cardiac pre- andafterload (venous and arterial constriction) ratherthan by constricting coronary arteries

Ergotamine should never be used for prophylaxis

of migraine

Drug prophylaxis of migraine

This should be considered when, after adjustment

of lifestyle, there are still two or more attacks permonth Benefit may be delayed for several weeks.Options (which may help up to 60% of patients)include:

• ft-adrenoceptor block by propranolol(dl); (the

d-isomer, which lacks fl-blocking action though

it has membrane stabilising effect, also prevents

migraine), as do other pure antagonists (atenolol,

metoprolol) but not partial (ant)agomsts, see

page 474 It seems that (3-adrenoceptor block is

not the prime therapeutic action Note that if

ergotamine (for an acute attack) is given to a

patient taking propranolol for prophylaxis there

is risk of additive vasoconstriction (block of

(B-receptor mediated dilatation with added

a-receptor constriction)

• Calcium entry blockers, e.g verapamil, flunarizine,

may provide benefit

• Pizotifen and cyproheptadine block serotonin

(5-HT) receptors as well as having some

Hj-antihistamine action; they can be

effective

• A tricyclic antidepressant, e.g amitriptyline in low

dose; start with 10 mg at night and increase to

50-75 mg

• Methysergide (an ergot derivative) blocks

serotonin receptors but it has a grave rare

adverse effect, an inflammatory fibrosis,

retroperitoneal (causing obstruction to the

ureters), subendocardial, pericardial and pleural

Drug 'holidays', i.e withdrawal for 1-2 months

each 6 months, are a prudent safeguard Because

of this risk, methysergide cannot be a drug of

first choice though it may be justified for a

patient who is experiencing a sequence of severe

attacks

Cluster headaches may be treated with a 5HT1

-receptor agonist, e.g sumatriptan, as for migraine

Since bouts of headache tend to be of limited

dura-tion, e.g a few weeks, short courses of methysergide

are justified in intractable cases

Premenstrual migraine may respond to mefenamic

acid or to a diuretic After six months it is worth

trying slow withdrawal of the prophylactic drug

Headache of raised intracranial pressure (cerebral

oedema) responds to dexamethasone (10 mg i.v.;

4 mg 6-hourly, 2-10 d) which reduces the pressure;

and to nonopioid analgesics (see also Palliative

care)

OTHER PAIN SYNDROMES

• Inflammation responds to NSAIDs but may needsupport from a low-efficacy opioid

• Arthritis: see Chapter 15

• Minor trauma, e.g many sports injuries, iscommonly treated by local skin cooling (spray ofchlorofluoromethanes), counterirritants (see

p 302) and NSAIDs, e.g diclofenac, systemically

vasodilator drugs may, but equally may not,provide benefit

• Malignant disease requires the full range ofanalgesics and adjuvant drugs and procedures(see Palliative care, below)

• Bone pain, including cancer metastases, requiresNSAIDs alone and with opioids

Bisphosphonates, e.g sodium pamidronate,sodium clodronate, relieve pain from osteolyticbone metastases from breast cancer and multiplemyeloma

• Nerve compression can be relieved by localcorticosteroid (prednisolone) or nerve block(local anaesthetic); nerve destruction can beachieved by alcohol, phenol

• Dysmenorrhoea, see page 730

• Mastalgia may benefit from gamolenic acid (inevening primrose oil), danazol and

bromocriptine; or from a combinedcontraceptive pill

In sickle cell anaemia crises avoid pethidine asthe metabolite norpethidine may accumulate; hydro-xyurea reduces the frequency (see p 599)

PATIENT-CONTROLLED ANALGESIA

The attractions of enabling patients to manage theirown analgesics rather than be dependent on othersare obvious In mild and moderate pain it is easy

to provide tablets for this purpose, but in severechronic and acute recurrent pain, e.g terminal ill-ness, postsurgical, obstetric, other routes are needed

to provide speedy relief just when it is needed.Drug delivery systems range from inhalation devices

to patient-controlled pumps for i.v., i.m., s.c and

epidural routes

Despite the obvious problems, e.g training

patients, supervision, preventing overdose, these

can achieve the objectives of satisfying the patient

while reducing demand on nurses' time, especially

when the aim is to allow the patient to die

comfortably at home

Inhalation via a demand valve of nitrous oxide

and oxygen, as in obstetrics, may be used

tempo-rarily in other situations: e.g urinary lithiasis,

trigeminal neuralgia, during postoperative chest

physiotherapy, for changing painful dressings and

in emergency ambulances

Drugs in palliative care

Symptom control

It is a general truth that we are all dying; the

difference between individuals is the length and

quality of the time that remains.17 Terminal illness

means that period (generally weeks) when active

treatment of disease is no longer appropriate and

the emphasis of care is palliative, i.e to provide the

maximum quality of life during these final weeks

This means that symptom control becomes the

priority because,

One cannot adequately help a man to come to

accept his impending death if he remains in severe

pain, one cannot give spiritual counsel to a woman

who is vomiting, or help a wife and children say

their goodbyes to a father who is so drugged that

he cannot respond.18

As the scope of life contracts, so the quality of

what remains becomes more precious Symptoms

should not be allowed to destroy it Drugs are

pre-eminent in symptom control An illustrative instance

of success in palliative care is provided here by:

17 Mack R M 1984 Lessons from living with cancer New

England Journal of Medicine 311:1640 Recommended

reading: a personal account by a surgeon who had lung

cancer with metastases.

18 Dr Mary Baines, St Christopher's Hospice, London.

S Y M P T O M C O N T R O L

An elderly gentleman with obstructing carcinoma

of the oesophagus who was a keen gardener Heremained at home, free from pain, attended agarden show on Saturday, worked in his garden onSunday, and died on Monday.19

He was treated with continuous subcutaneousheroin (diamorphine) infusion Whilst the random-ised controlled trial provides a major basis fortherapeutic advance, telling us what generally doeshappen, the clinical anecdote yet has value, telling

us what can happen, and providing examples for

us to emulate With intelligent use of drugs, whichfollows from informed analyses of objectives,doctors can enable their patients to depart from life

in peace20 and with dignity, i.e true euthanasia.21

Whilst the skilful use of drugs can provideincalculable relief and deserves careful study, thismust not hide the fact that the manner, attentive-ness and human feeling of the attendants are domi-nant factors once drugs have controlled any grosserphysical and mental aberrations.22 The needs of thedying have been summarised as security, companion-ship, symptomatic treatment, and medical nursing

19 Russell P S B 1984 New England Journal of Medicine 311: 1634.

20 ' ; and for many a time

I have been half in love with easeful Death, Call'd him soft names in many a mused rhyme,

To take into the air my quiet breath;

Now more than ever seems it rich to die,

To cease upon the midnight with no pain.' (John Keats: 1795-1821).

21 Euthanasia (Greek: eu: gentle, easy; thanatos: death) is the

objective of all It does not mean deliberately killing people peacefully, which is voluntary euthanasia That giving increasing doses of opioids and sedative drugs may also shorten life (the 'double effect') 'is not in our view a reason for withholding treatment that would give relief, as long as a doctor acts in accordance with responsible medical practice with the objective of relieving pain or distress, and with no intention to kill' Report of the select committee on medical ethics House of Lords, January 1994 HMSO, London.

22 Give me the doctor partridge plump, Short in the leg and broad in the rump,

An endomorph with gentle hands, Who never makes absurd demands That I abandon all my vices, Nor pulls a long face in a crisis, But with a twinkle in his eye Will tell me that I have to die.

(WH Auden 1907-73)