C7.Pain and its treatment

Pain is a common presenting symptom in primary care and an important cause of morbidity. Patients with mild to moderate pain self-medicate initially, using familiar analgesics or following pharmacist or lay advice. Those with severe pain normally present to GPs or hospitals. GP referrals to area hospital Pain Clinics are common.

The large psychological and cultural components may cause stoics to ignore a pain until the

condition is difficult to salvage: doctors have dismissed the pain of their own myocardial infarc-

tion as ‘indigestion’! Despite its universality and the existence of effective remedies, journal arti-

cles frequently discuss the poor management of post-operative, chronic and terminal disease

pain.

This chapter discusses the characteristics and pharmacotherapy of various types of pain, to guide best practice. Morphine-like drugs are referred to here as ‘opioids’, although this term strictly describes only synthetic compounds, ‘opiates’ being of natural origin. The term ‘narcotic’ is not synonymous with ‘opioid’: it describes central nervous system depressants that relieve pain, producing narcosis (sedation and unconsciousness) in sufficiently high doses. It is widely used legally for addictive drugs of abuse.

Introduction

Although pain is a universal experience, it is

difficult to define. One possible definition is:

An unpleasant sensory and emotional experi-

ence associated with actual or potential tissue

damage or described in terms of such damage. It

serves biological functions, warning of external

danger, e.g. excessive heat or physical trauma,

and internal pathology, e.g. inflammation or

blockage of a ureter by a kidney stone, enabling

avoidance or treatment. It is inherently self-

limiting when the provoking source is removed

or cured.

This indicates that pain is not simply a phys-

ical sensation. Pain perception also depends on

the patient’s emotional reaction to the stimulus

(see below).

Types of pain

Acute pain usually has a readily definable cause.

Its biological function is protective, acting as a

warning that an external threat is noxious, or

signalling  organ  malfunction.  It  has  a  well-

defined  time  of  onset,  often  associated  with

signs of hyperactivity of the autonomic nervous

system,   e.g.   tachycardia,   hypertension   and

pallor, depending on the severity of the symp-

toms and how the patient interprets them. The

best way of managing acute pain is to diagnose

and treat the cause, though this is often clear,

e.g. following any kind of trauma. Temporary

relief with analgesics is valuable while healing and recovery proceed.

Chronic pain is usually considered to be pain

that has lasted for longer than 6 months. It does

not signify a danger that requires immediate

avoidance and a patient may not interpret such

pain as indicating serious disease. Further, adap-

tation by the autonomic nervous system over

time may lead to the absence of objective physical

signs. However, there is often progressive phys-

ical  deterioration,  with  sleep  disturbance  and

weight  loss.  In  severe  cases,  patients  undergo

serious affective and behavioural changes, e.g.

major depression (see Chapter 6).

Essential  components  in  the  treatment  of chronic pain are the identification of any organic problem, i.e. accurate diagnosis, and the recogni-

tion and management of significant affective and environmental factors.

Pain threshold and assessment

The patient’s mood, morale and the meaning of

the pain for that patient affect their pain percep-

tion. Thus if a patient has chest pain and a

relative or close friend has recently had an MI,

the patient may interpret his or her pain as a

life-threatening event. This results in the pain

threshold being lowered, i.e. anxiety is algesic,

resulting in less tolerance of the pain or greater

awareness of it. Conversely, if another friend

with a similar pain interprets it as indigestion,

or it is diagnosed as such, this would not be

very stressful, the pain threshold would not be

lowered,   and   the   pain   may   be   tolerated.

However, this may not be a rational response

(see  Chapter 3).  Although  it  is  possible  to

measure an individual’s pain threshold, e.g. by

applying a defined stimulus, usually a constant

heat source at a defined distance and recording

the time from application to withdrawal, this is

purely a research tool, e.g. when assessing the

effectiveness of a new analgesic or for comparing

analgesics. However, this does not help when

assessing  a  patient’s  pain.  Further,  attention

must always be paid to factors that modulate the

pain threshold (Table 7.1).

Introduction      457

Assessment

Pain is a subjective experience, so only the indi-

vidual affected knows its nature and severity: the

individual patient’s assessment and description

are vital. Useful clues can be gained from a

patient’s response to a particular analgesic, e.g. if

pain is described as ‘severe’ but relief is obtained

from   modest   doses   of   paracetamol            (aceta-

minophen), it is probable that there is a sig-

nificant  emotional  component  to  the  pain

perception. Careful, empathetic exploration of

this aspect may be more rewarding than the use

of  increasingly  potent  analgesics.  Also,  the extent  to  which  a  condition  interferes  with

social and pleasure activities may be a better

guide to severity than absence from work or

school. Other clues are obtained from what a

patient reports and their observable behaviour

(Table 7.2).

The origin of acute pain is usually easy to diag-

nose, unlike that of chronic pain, which is often

of obscure origin, particularly when it is due to

tment

non-malignant  disease.  A  careful  assessment

should be carried out before treatment is started

and patients should be re-assessed regularly. The

salient features to be elucidated are given in

Table 7.3.

Figure 7.1 gives some examples of pain assess-

ment tools. The visual analogue scales are rapid

and enable immediate feedback, e.g. advice on

the use of medication or a decision to change

medication.  Patients  should  be  given  a  fresh

tool  sheet  on  each  occasion:  if  they  see  the

previous sheet it prejudices how they respond.

There are other ways, e.g. a pictorial scale of

faces  expressing  response  to  different  pain

levels.  The  Short  Form  McGill  pain  question-

naire (see  References  and  further  reading,  p.

511)  can  be  completed  within  5 min  and  is

well-validated. It is important to document the

results  of  the  assessment,  to  provide  a  clear

history  of  the  progression  of  pain  and  the progress  of  analgesia  for  use  by  all  personnel involved with a patient’s care.

Pathophysiology of pain

An understanding of how the sensation of pain

is generated is essential to an appreciation of

how modification of these pain pathways can

ameliorate the pain.

Gate theory

Various  theories  have  tried  to  integrate  the

anatomical pain pathways and the psychological

and neurological components that contribute to

the perception of pain. The generally accepted

model is the ‘gate control theory’, illustrated

diagrammatically in Figure 7.2. This was first

proposed by Melzack and Wall in 1965, and has

since been modified as knowledge has increased.

The  theory  proposes  that  neuronal  impulses

generated by noxious stimuli are modified in the

dorsal horn of the spinal cord by a specialized

mechanism  (‘gate’),  which  can  tend  to  either

inhibit  or  facilitate  transmission  of  the  pain

impulse  from  peripheral  organs  to  the  brain.

The  gate  is  not  an ‘all-or-none’  mechanism,

and a balance between opposing factors deter-

mines how much of the initial nerve impulse

is transmitted through it.

It has been shown recently that the SNC9A

gene determines the structure of the voltage-

gated sodium channels that are responsible for the transmission of signals along afferent pain fibres. Mutations in the gene may result in an inability to sense pain or excessive pain sensi-

tivity (hyperalgesia). This discovery points the way to a new type of analgesic.

tment

Pain receptors and fibres

Two main groups of skin receptors have been identified:

•  High-threshold   mechanoreceptors  (HTMs),

which detect local deformation, e.g. touch.

•  Polymodal nociceptors, which detect a variety

of types of injury  (e.g. heat) and noxious

(harmful) stimulation. These do not have a specialized  structure  and  are  simply  bare nerve endings in the periphery.

Stretch receptors also occur in muscles, the wall

of the gut and the capsules of internal organs.

Three types of nerve fibres are involved in pain

transmission. The A-beta fibres are large, myeli-

nated and fast-conducting (30-100 m/s). They

have a low stimulation threshold and respond to

light touch. The A-delta fibres are small, lightly

myelinated and slower-conducting (5-15 m/s).

They respond to pressure, heat, chemicals and

cooling, and give rise to the sensation of sharp

pain,  producing  reflex  withdrawal  and  other

prompt  action.  The  C  fibres  are  small  and

unmyelinated  and  therefore  slow-conducting

(0.5-2 m/s); they respond to all types of noxious

stimuli and transmit more prolonged, dull pain

signals. The last two of these types of fibres

usually require high-intensity stimuli to trigger a

response.

According to the gate control theory, A-delta

and C fibres transmit pain signals to the dorsal

horns of the spinal cord. Impulses in these fibres

can be modulated by A-beta activity that can

selectively  block  impulses  from  being  trans-

mitted   to   the   transmission   cells   in   the

substantia gelatinosa of the spinal cord. Such

blockage prevents upward transmission to the

CNS, and no pain sensation is perceived. This

explains   why   rubbing   an   injured   area,   or

applying a ‘counter-irritant’ such as capsaicin,

which stimulates the A-beta fibres, can relieve

the pain caused by an injury to that area, which

stimulates the smaller C-fibres.

The gate control mechanism is believed to

operate continuously, even in absence of an

apparent trigger, because there is a continuous

barrage of impulses from, principally, the C-

fibres, whose receptors are continually active

and react only slowly to stimuli. The effect is to

set a threshold below which there is no effector

response.   Action   subsequent   to   stimulation

depends on the numbers of fibres involved, their

firing rate, the proportion of large and small

fibres, and the effect of central control mecha-

nisms. The latter may over-ride the gate control,

as occurs under hypnosis. When the complexi-

ties of this mechanism have been elucidated,

new drugs or techniques of pain control may

emerge.

Pathological pain

It  has  been  suggested  that  peripheral  tissue

damage (e.g. from trauma, surgery or cancer)

causes   central   sensitization,   i.e.   neuronal

changes occur that make the spinal neurones

hyper-responsive for a long period to afferent

signals  that  would  not  normally  trigger  the

gating  mechanism.  One  consequence  of  this

theory is that prophylactic (‘pre-emptive’) local,

regional or opioid analgesia should be given

before surgery or any predictable moderate to

severe  pain,  to  prevent  central  sensitization

occurring. The concept also accords well with

our experience of treating severe chronic pain:

for effective control it is essential that the pain

should not be allowed to recur (see below).

New classes of analgesics are emerging, e.g.

compounds that block spinal cord receptors for

excitatory  amino  acids  such  as  N-methyl-D-

aspartate (NMDA). One such drug is dizocilpine,

Pathophysiology of pain            461

which blocks the NMDA ion channel and resem-

bles ketamine, but has a much greater potency

and is more selective for the receptor. Dizocilpine

has  been  shown  to  prevent  and  eliminate

central   sensitization   in   animals.   Further,

Swedish research indicates that ketamine, which

was introduced as an IV anaesthetic, is an effec-

tive analgesic at concentrations lower than those

required to produce anaesthesia, or at which

central nervous side-effects (hallucinations and

other transient psychotic effects) are trouble-

some. Ketamine  is being used increasingly in

palliative care for difficult-to-control cases and

may give dramatic improvement that is main-

tained for several months. Other general anaes-

thetics are widely used for the relief of obstetric

pain (p. 507).

Neurotransmitters involved in pain

Opioid receptors and endogenous opioids

The important discoveries of stereospecific opioid

receptors (of which several subtypes are known)

and endogenous opioids further increased our

understanding of the biochemical mechanisms

involved in pain transmission and perception.

Several families of endogenous opioids have

been   identified   including   the   endorphins,

enkephalins  and  dynorphins  (p. 468). Each

family  is  derived  from  a  distinct  precursor

polypeptide and has a characteristic anatomical

distribution.

Other transmitters and mediators

Physical or chemical insult can stimulate noci-

ceptors. Inflammation, ischaemia or other pain-

inducing stimuli cause the release of noxious

chemicals (e.g. bradykinin, histamine and 5-HT)

in    injured    tissues.    Prostaglandins   (PGs),

although not directly producing pain, appear to

sensitize nociceptors to various chemical and

pressure  stimuli.  This  explains  why  NSAIDs,

which block PG synthesis, are effective analgesics

in some situations.

Substance  P  (neurokinin-1),  a  polypeptide

probably released by the small-diameter C-fibres,

is believed to be involved in pain transmission in the dorsal horns of the spinal cord. It is probably

not the actual transmitter, but initiates a series

of events leading to the recruitment of pro-

inflammatory agents. The latter release media-

tors, e.g. PGs, LTs, 5-HT and histamine, which

stimulate the nerve endings and cause sensitiza-

tion. Sensitization involves a lowering of the

trigger threshold, producing hyperalgesia. Exci-

tatory amino acid transmitters, e.g. glutamate

and aspartate, may also be involved.

Pain transmission may be blocked if opioid

receptors have already been occupied by endor-

phins at the spinal level. If successful in passing

through the gating mechanisms, and several are

probably involved in the total pathway, the pain

impulse is transmitted via the reticular activating

system of the pons and midbrain to the thalamus.

From there, they are directed to the appropriate

part of the cerebral cortex where the impulses are

perceived as pain. The limbic system, which is

anatomically close to these areas, is thought to

be responsible for the emotional component of

pain (see Chapter 6). Transmission of the pain

impulse may be modified in the CNS by the

presence of 5-HT and other chemical mediators.

It has been shown recently that pain signalling

is amplified by certain ion channels in neuron

membranes.  There  are  ten  isoforms  of  the

sodium channel protein that share a common

structure but have different amino acid composi-

tions.  Gene  SCN9A  encodes  for  the  Nav  1.7

sodium channel that is expressed preferentially

at high levels in dorsal root ganglion and sympa-

thetic ganglion neurons. It is deployed at the

endings of nociceptive neurons close to the site

of pain initiation and loss of the SNC9A gene

causes inability to experience pain. This opens a

new avenue for analgesia, by blocking either

Principles of analgesic use         463

SNC9A transcription or translation or the Nav

1.7  protein.  Preliminary  work  suggests  that this  can  be  done  without  interfering  with

sympathetic nerve signalling.

The   exact   pathophysiology   of   pain   is

extremely complex and is still not fully under-

stood. Figure 7.3 shows a simplified concept of the pain pathways and ways in which current

treatments are thought to interrupt it.

Principles of analgesic use

The WHO recommendation on how to achieve

effective  analgesia  is: “Dose  patients  by  the

mouth, by the clock and by the ladder.” These

points, and the general principles that should be

employed when using analgesics, are outlined

below.

Type and characteristics of pain

Because various types of treatment are available

to  manage  pain  (Figure  7.4),  it  is  important

to  determine  whether  the  pain  is  acute  or

chronic, to diagnose the cause, and to ascertain

if  any  psychogenic  component  is  present

before deciding on the appropriate approach to

treatment.

Acute pain generally responds well to anal-

gesics, but chronic pain presents a far more

complex problem. It often requires a multidisci-

plinary approach, employing several different

modes of therapy. While the main emphasis in

this chapter is on analgesics, alternative methods

of pain control will also be discussed briefly, to

place them in context.

Choice of analgesic

The type and severity of the pain will usually

determine the specific drug or regimen to be

used. Initiation of analgesia should be at the step

appropriate to pain severity on the WHO ‘anal-

gesic ladder’ (Table 7.3) and the appropriate dose

and potency of analgesic is found by titrating the

dose upwards, or down, until pain control is

achieved at minimal dosage. Table 7.3 provides

only an outline of the analgesics used, a more

comprehensive listing being given in Table 7.4.

The use of many of these drugs may be a matter

of  personal  preference  or  convenience:  it  is

always preferable to learn to use a few drugs well,

rather than a wide range indifferently. TheUK

Department of Health document “Building a

Safer NHS for Patients ” recommends

using a limited range of opioids.

Individualization of dosage

Dose requirements are affected by many vari-

ables including the severity of the pain, the

patient’s pain threshold, age, weight and the

presence of concurrent disease. Each analgesic

should be given an adequate trial by dose titra-

tion, i.e. modifying the dose until pain control is

adequate   or   until   dose-limiting   side-effects

occur, before switching to another drug (see, for

example,  Chapter  12  and  the  BNF,  Section

10.1.1).

When using opioids in terminal disease, the

only upper limit is that dose which successfully

relieves the patient’s pain without causing unac-

tment

ceptable side-effects. For example, sedation is

only a problem if it becomes unacceptable to

the patient, but respiratory depression may be

important, especially if respiratory function is

already compromised, or unimportant. A recent

research paper concluded that: “Properly titrated

opioids have no respiratory depressant effect in

adults who are awake”.

The American Pain Society has recently recom-

mended that patients and their families should

be   fully   involved   in   pain   assessment   and

management, including changes in dosage or

routes of administration, and measurement of

outcomes. However, it is common for patients to

tolerate a lower analgesic dose when managed in

a professional environment. This is due partly

to  better  analgesic  management  and  partly

because, in the home environment, the anxiety

of  their  families  or  carers  that  the  patient

should  obtain  complete  relief  leads  to  over-

dosing. Sometimes the patient seeks an exces-

sive dose to spare their families from distress at

seeing them suffer. The anxiety of families and

carers is readily transmitted to patients, either

overtly  or  inadvertently, and exacerbates the

problem.

Dosage schedule

Traditionally, pain relief has been given on a

‘when required’ basis, so that the patient was

expected to experience a return of pain before

requesting more analgesic. Such an approach

may sometimes be useful in acute pain, to see

whether the symptoms are regressing, but is

inappropriate in treating chronic pain because

pain itself is a potent algesic (pain promoter): if

pain is allowed to recur, a higher dose of anal-

gesic will be required to re-establish pain control.

Thus, regular administration of analgesics is

essential in chronic pain so that the patient’s

memory of the pain is reduced and, hopefully,

gradually obliterated. This controls the psycho-

logical component and associated fear. When

the patient has confidence in prescriber and

treatment, the pain threshold may be raised,

making it possible to reduce the analgesic dose.

The drugs, and their dose level, frequency and

routes  of  administration,  must  be  reviewed

frequently to ensure not only that analgesia is     Routes of administration

adequate  but  also  that  doses  of  concurrent

drugs are appropriate and that side-effects are   In selecting the most appropriate route of drug

minimized and managed suitably.           administration  for  a  patient,  factors  such  as ‘nil-by-mouth’,    gastrointestinal    obstruction,

persistent vomiting, limited venous access or

reduced  muscle  mass  have  to  be  taken  into

account.

Oral and sublingual

The oral route (per os, PO) is preferred if it is avail-

able although some opioids, e.g. pethidine (meperi-

dine),  are  poorly  absorbed  from  the  gut  and

bioavailability can vary widely between patients.

The peak effect usually occurs 30-60 min after

dosing with normal oral formulations. Because

peak  activity  occurs  much  later  with  most

modified-release preparations, it is inappropriate

to  initiate  pain  control  with  these  products.

Ideally,  the  total  daily  requirement  should  be

determined using a standard-release formulation,

i.e. one with rapid release of the drug, preferably a

solution. However, tablets may be used (e.g. with

morphine) if the solution is disliked. When stable

pain control has been achieved, this dose is then

translated to the equivalent dose of a modified-

release preparation to reduce the dose frequency.

The sublingual route is particularly attractive, because it provides a rapid onset of action and avoids  the  losses  from  first-pass  metabolism, but  may  be  unsuitable  for  very  ill  patients who produce little saliva. However, the Expert Working Group of the European Association for Palliative Care advises against the buccal and sublingual routes because there is no evidence for their clinical superiority over other routes

and absorption may be unreliable.

Parenteral

The  intramuscular  (IM)  route  is  commonly used post-operatively. It has the disadvantages of wide fluctuations in absorption, a 30- to 60-min lag time to peak effect, and a more rapid decline in activity than after oral administration.

In cancer patients, who are often cachectic (i.e.

profoundly  ill  and  malnourished)  and  have

reduced muscle mass, IM administration can be

painful and normal doses can give abnormally

high peak concentrations. Because many cancer

patients have low platelet counts, IM injection

may cause severe bruising. Further, IM injection

tment

causes some muscle damage and the release of

creatinine kinase, so this route must not be used

within 48 h of a suspected MI (see Chapter 4)

because this enzyme is used as one marker for MI.

The  gluteal (buttock)  muscles  are  often  used

because of their large mass and it is less likely that

a major blood vessel will be entered accidentally.

IM injections are preferably avoided in children because they may give rise to complications.

A  bolus  intravenous  (IV)  dose  obviously

provides the most rapid pain relief and avoids

first-pass metabolism. However, rapid action also

means rapid adverse reactions. This is particu-

larly important with the opioids, which cause

respiratory depression. The main determinant of

the time taken to achieve a therapeutic effect

with a centrally acting drug is its lipid solubility,

which determines how quickly the drug leaves

the plasma and is distributed into the CNS.

The IV route does not appear to confer any

advantage for maintenance dosing, and opioid

tolerance may occur more rapidly. However, it

enables rapid titration of the analgesic dose in

patients  with  acute,  severe  pain  or  an  acute

exacerbation of chronic pain. The IV infusion

of  analgesics  after  major  surgery  gives  good

post-operative pain control and has been shown

to  decrease  the  recovery  period  and  reduce

post-operative complications.

The oral route is equally effective for treating stable chronic pain, unless the patient is unable to absorb oral medications because of vomiting, dysphagia or bowel disease. In such cases, SC infusion is the preferred parenteral route.

Spinal  anaesthesia  is  used  routinely  in

obstetrics  and  increasingly  for  surgery  on

patients who are unsuitable for a general anaes-

thetic, post-surgically and for palliative care in a few terminally ill patients (p. 487).

The continuous SC infusion of opioids is used widely and achieves virtually constant blood

levels (see below).

Rectal

The rectal route  (per rectum, PR) is another

alternative  to  oral  administration  in  patients

who   are   vomiting   or   on   a ‘nil-by-mouth’

regimen, provided that it is not precluded by

bowel disease. Several analgesics are available as

suppositories (Table 7.4). This route also avoids

loss of available drug by first-pass metabolism.

Rectal administration should be avoided in

patients with a low platelet count due to cancer

chemotherapy  or  to  disease  because  it  may

provoke bleeding which is difficult to control.

Transdermal

This route is used currently only with fentanyl

and buprenorphine. It is useful if the oral route

cannot be used and continuous parenteral infu-

sion is either unavailable or unsuitable. Fentanyl

has a short duration of action if given orally or

by  parenteral  bolus  injection,  due  to  rapid

metabolism and tissue redistribution, whereas

the   transdermal   patches   provide   prolonged

dosing.

However, skin reactions may occur with the patches and the BNF advises application to dry, non-irritated, non-irradiated, non-hairy skin of the torso or upper arm, rotation of application sites when a patch is changed and avoidance of the same area for several days.

Guidelines for analgesic use

Accurate diagnosis of the cause of the pain is

very important. However, there may be many

underlying causes, especially in palliative care,

so it may not be possible to identify a specific

cause. The following guidelines are generally

applicable.

•  Use the oral route whenever possible.

•  Only the patient knows if relief is adequate.

However, treatment goals should be realistic: complete freedom from pain may be difficult to achieve. It may be helpful to set realistic stepwise goals, e.g. freedom from pain, in

collaboration   with   the   patient   in   the

following ascending order:

-  At night.

-  At rest.

-  On movement.

•  If an analgesic fails after a trial at adequate

            dose and frequency, move up the ‘analgesic

Principles of analgesic use         467

ladder’ (Table 7.3): a substitute from the same class is unlikely to be more effective. If the patient is not supervised, e.g. in the commu-

nity, it is worth checking that the patient is taking their analgesic(s) and any adjuvant

medicines  regularly  and  at  the  prescribed dose. Fear of addiction is common.

•           If increased analgesia is required, the dose

should be increased but the dosage interval

should   remain   unchanged.   Reducing   the

dosage  interval  below  that  appropriate  for

the drug merely makes life more difficult for

the patient.

•           Pain should not be allowed to recur. Drugs

with a short duration of action, e.g. pethidine

(meperidine), are unsuitable for the manage-

ment of sustained severe pain.

•           Opioids are not a panacea: due weight must

be given to the use of adjuvants (p. 479), the

management  of  psychosocial  aspects  and intercurrent disease, and the control of adverse reactions.

•           Tolerance  to  opioids,  and  dependence  on

them, is not usually a practical problem when

treating severe pain. Many patients receiving

palliative  care  remain  on  a  uniform  dose

throughout much of their illness. Opioid use

should not be dictated by a short or poor

prognosis, but by the needs of the patient.

Physical dependence does not preclude dose

reduction. If the patient’s condition improves

or if other treatments relieve the pain, dose

reduction may be essential to avoid toxicity.

•           There is some evidence that a state of hyper-

algesia may occur with high IV or intrathecal

doses of opioids but it is not clear to what

extent  this  is  relevant  to  clinical  practice.

The  effect  may  be  due  to  altered  hepatic

metabolism, i.e. a shift from the production

of morphine-6-glucuronide (M6G), a potent

analgesic, to M3G, an opioid antagonist.

•           Always keep an open mind and review the

treatment frequently. It may be possible to

reduce the dose following a period of stable, good control. Conversely, a requirement for increasing doses is probably not due to drug tolerance or dependence but may indicate a deterioration in the underlying disease or the onset of another condition.

Analgesic drugs and techniques

Opioid analgesics

Mode of action

Opioid receptor sites

As mentioned earlier, receptor sites exist in the

brain, spinal cord and elsewhere where opioids

such as morphine bind to produce analgesia (and

other   pharmacological   effects).   The   body’s

natural ligands for these receptors are the endor-

phin,   enkephalin   and   dynorphin   peptides.

Receptor-binding studies have identified at least

three major types of opioid receptors, designated

mu  (l;  two  subtypes,  l1,  l2),  delta (d,  two

subtypes) and kappa (j; three subtypes), each

with distinct roles so that the type of pharmaco-

logical effect associated with each receptor is

different. These effects are summarized in Table

7.5. About 65% of the amino acid composition

of the three receptor types in animals are iden-

tical or very similar, as are most of their trans-

membrane regions and intracellular loops, but

most of their extracellular loops differ. A further

sigma (r) receptor has been described, but its

role is uncertain because opioid activity there is

not antagonized by naloxone, a specific opioid

antagonist.

Most of the research in this field has been

carried out in rats and mice, but the evidence

from them is not directly relevant to humans. A

complication is that some of the receptors and

their subtypes have been proposed based on

drug-binding studies, but their pharmacological

properties are ill defined or unknown. Because of

these uncertainties and because further receptors

and  subtypes  may  exist,  it  is  not  currently

possible to allocate the actions of drugs with

certainty to specific subtypes in man. However,

this is an active research field and drugs are likely

to emerge that act at specific receptors to achieve analgesia without the unwanted effects.

Morphine  and  related  plant  alkaloids  have

molecular  structures  similar  to  those  of  the

endogenous peptides, and so activate the same

receptors. Methadone, although chemically unre-

lated, can adopt a similar configuration. Natu-

rally  occurring and synthetic opioid drugs are

classified according to the subtypes of receptors

to which they bind, and the type of response

that they thus evoke (Table 7.5). The available

drugs   include   pure   opioid   agonists,   partial

agonists, agonists-antagonists, and pure antago-

nists. The affinity with which a drug binds to a

receptor is important: analgesics with a high

receptor  affinity,  e.g.  buprenorphine,  exert  an

analgesic  action  for  much  longer  than  their

plasma half-life would suggest.

Opioid agonists and antagonists

Pure agonists (e.g. morphine) elicit a maximum

response  if  given  in  sufficient  concentration.

However, a partial agonist (e.g. buprenorphine)

can only produce a partial response irrespective

of the concentration, and there may even be a

decreased response if the optimum concentra-

tion is exceeded. The morphine-like opioids are

thought to exert their agonist effects primarily

at the mu receptor and to a lesser degree at the

kappa receptor (Table 7.5). Partial agonists (Table

7.6) bind with the mu receptor and compete

with the agonists, both naturally occurring and

exogenous. If they are used in combination with a complete agonist, they may act as competitive

antagonists and the level of analgesia may be

reduced,  or  as  partial  agonists,  so  that  they

show  only  limited  activity.  Mixed  agonists-

antagonists, e.g. pentazocine, are antagonists at

the mu receptor but are still effective as anal-

gesics  through  agonist  effects  at  the  kappa

receptor, the agonist effect being either complete

or partial.

At the other end of the spectrum are the pure

antagonists, which are used to reverse respira-

tory depression post-operatively, to treat opioid

poisoning (e.g. naloxone), and to prevent relapse

in detoxified opioid addicts (e.g. naltrexone).

Opioid-sensitive and opioid-insensitive pain

Virtually all acute pain, with the possible excep-

tion of labour pain, falls into the opioid-sensitive

category, the analgesic effect being related both

to the type of agent used (weak or strong opioid)

and the dose. The WHO defines ‘weak opioids’

as those used to control mild to moderate pain

and ‘strong opioids’ are those used for moderate

to severe pain.

Neuropathic pain (e.g. post-herpetic neuralgia

and pain resulting from a stroke), includes de-

afferentation  pain,  i.e.  pain  resulting  from

damage  or  interruption  of  afferent (sensory)

nerve fibres, is partially opioid-sensitive and an

adjuvant, e.g. a tricyclic antidepressant, usually

amitriptyline or nortriptyline, an anticonvulsant,

e.g. gabapentin or pregabalin (see Chapter 6) or

nerve blocks may be required. Opioid-insensitive

pains include most headaches. Pain arising from

muscle spasm is best dealt with using muscle

relaxants, e.g. diazepam and baclofen.

The management of post-herpetic neuralgia is discussed on p. 505.

Other  types  of  pain  may  also  be  partially

opioid-sensitive, e.g. that resulting from bone

metastases is best treated with a combination of

NSAIDs and opioids. NSAIDs may be adequate

on their own, e.g. diclofenac in palliative care or

as suppositories post-operatively when patients

are ‘nil-by-mouth’, or possibly in combination

with  paracetamol (acetaminophen),.  However,

opioids may be needed initially or for continuing

support. Some other types of cancer pain (e.g.

that  arising  from  nerve  compression,  raised

intracranial  pressure  and  extensive  tumour

infiltration of tissues) may require an opioid plus

an  adjuvant,  e.g.  a  potent  anti-inflammatory

glucocorticoid   with   minimal   mineralocorti-

coid activity (betamethasone or dexamethasone).

Psychogenic pain must always be addressed by

identifying the underlying causes as well as by

drug management, e.g. anxiolytics, antidepres-

sants or other psychotropic agents in addition to

analgesics. Analgesic adjuvants are discussed on

p. 479.

Therapeutic use

Morphine

This has become the standard against which

other opioid analgesics are judged and is gener-

ally the treatment of choice for chronic severe pain in advanced cancer. No other strong opioid, given orally, is consistently superior.

In  addition  to  its  central  analgesic  action,

morphine causes euphoria and a sense of detach-

ment. It also causes drowsiness for up to the first

7 days of treatment. This profile is clinically

useful as it reduces the anxiety and anguish that

are commonly associated with severe pain from

whatever cause, e.g. MI and terminal disease.

However, morphine should not be used primarily

as a sedative. Occasional patients remain drowsy,

in which case a dose reduction and a slower dose

titration can be tried, and coexisting problems

should be sought, e.g. the concurrent use of

other sedatives. Liver impairment has little effect

on the hepatic metabolism of morphine until it is

severe, but renal damage prolongs the duration

of action because 90% is renally excreted, mostly

as  glucuronides,  and  morphine-6-glucuronide

(M6G)  has  twice  the  analgesic  potency  of

morphine.

Morphine    aggravates    functional    gastro-

intestinal  pain (e.g.  from  colonic  spasm  or constipation), so it is unsuitable in patients with these  problems,  although  the  latter  can  be

managed with stimulant laxatives.

One of the most important advances in the

management of chronic pain has been the intro-

duction of modified-release oral formulations of

morphine, which usually give excellent control

tment

with once- or twice-daily dosing. These contain

morphine bound to an ion exchange resin from

which it is released by inward diffusion of sodium

and potassium ions. Because of their slow onset of

action, the appropriate dose must be established

using quick-release dosage forms, e.g. solutions or

normal tablets, and the first dose of a modified-

release product should be given with the last

dose(s)  of  quick-release  product  to  cover  the

period until the new steady state is achieved.

Adjustment of the doses of both types of product

may be necessary to prevent breakthrough pain

occurring. If breakthrough pain should occur in

the early stages of modified-release medication, it

is controlled with solution or injections (occa-

sionally normal-release tablets) and the dosage

regimen reassessed.

Suppositories are a useful alternative to injec-

tions if vomiting is a problem or if patients are unable to swallow. They are also convenient if a patient’s carer cannot give injections.

The potential hazard of respiratory depression

due to morphine  may be increased because it

appears to reduce the sensation of breathless-

ness, so the patient should be in a supervised

environment when large doses are needed.

Papaveretum  is   a   preparation   of   morphine

hydrochloride (85%),   papaverine  and   codeine,

which is now rarely used in the UK. It no longer

contains  noscapine,  a  centrally  acting  cough

suppressant,   and   the   reformulated   product

contains a lower weight of papaverine but the

same dose of morphine. This has created prob-

lems   when   dispensing   and   special   care   is

required. Papaveretum  has also been confused

with papaverine, which is used to treat male

impotence.

Morphine is the antitussive of choice for the

treatment of the distressing cough of terminal

lung cancer, with methadone as an alternative.

Many former traditional morphine  mixtures, e.g. the ‘Brompton Cocktail’, opium tincture and camphorated opium tincture (paregoric), are no longer used in the UK because they confer no benefit over morphine alone.

Morphine is sometimes used for topical anal-

gesia   when   local   anaesthetics   do   not   give adequate relief (unlicensed indication).

A  guideline  to  the  equi-analgesic  doses  of opioids is given in Table 7.7.

Other pure agonist drugs

Diamorphine (heroin, 3,6-diacetylmorphine)

Opinions differ over the choice between heroin

and morphine. Because of its abuse potential and

its disputed benefit, diamorphine is not available

(often illegal) in most countries outside the UK.

Diamorphine itself is not an opioid agonist, but

is rapidly metabolized to 6-monoacetylmorphine

(6-MAM) and morphine, which are. Because both

diamorphine and 6-MAM are more lipid-soluble

than morphine they penetrate the blood-brain

barrier more rapidly and so have a faster onset of

action, though the final activity is due to the

morphine produced on hydrolysis. Diamorphine is

generally regarded as more potent than morphine

on injection, both as a euphoriant and analgesic,

and may cause less nausea and hypotension.

However,  the  oral  potencies  of  the  two  are

similar  because,  when  given  orally,  heroin  is

completely   hydrolysed   to   morphine   before

absorption from the gut.

Diamorphine  is   unstable   in   solution,   so

morphine is preferred for oral solutions. However,

diamorphine is very soluble in water and so is

preferred in the UK for IM and SC administra-

tion as the injection volume is small. This may be important in very emaciated patients. Solutions are prepared from the sterile powder as required and are not stored.

Pethidine (meperidine)

This  moderately  potent  analgesic  is  most

commonly used peri-operatively and in obstetric

analgesia. Because it is unpredictably absorbed

and undergoes significant first-pass metabolism,

oral  bioavailability  is  poor  and  variable,  with

some trials showing equivalence with paracetamol

(acetaminophen). However, some patients obtain

satisfactory  relief  with  oral  pethidine,  and  sat-

uration  of  metabolic  pathways  may  increase

bioavailability with chronic use (but see below).

Given parenterally, it has a swift onset of action as

it is highly lipophilic and crosses the blood-brain

barrier  readily.  This  property  makes  it  useful

for preoperative medication and treating acute

pain.  The  short  duration  of  action (1-3 h)

normally  makes  it  unsuitable  for  treating

chronic pain, as approximately 2-hourly dosing

would be required.

Further, pethidine is unsuitable for chronic use

because  its  toxic  metabolite  norpethidine  accu-

mulates, causing anxiety, agitation, tremors and

seizures. The latter is cleared renally and also

accumulates  in  renal  impairment.  Pethidine

probably  causes  more  nausea,  vomiting  and

hypotension than other opioids, and is said to

have less effect on smooth muscle, so it is some-

times  used  for  renal  or  biliary  colic,  though

there is no good evidence to support this: IM

or rectal diclofenac is usually preferred for this

indication.

Although pethidine may produce less euphoria

and sedation than morphine, this is disputed, and

respiratory depression and postural hypotension

are common at effective doses. Most of these

side-effects can be corrected by using it with the

antipsychotic agent haloperidol, which potenti-

ates the analgesia, permitting lower doses to be

used, and is anti-emetic, sedative and possibly

euphoric. However, the toxicity of haloperidol

limits the maximum dose that can be used (see

Chapter 6).

Pethidine interacts with MAOIs to cause either

severe hypertension or hypotension, depending

tment

on the patient and the relative doses of each,

and so should not be used in patients taking

hypotensive  drugs  or  MAOI  antidepressants, except under very close supervision.

Methadone

This agent is well absorbed and well tolerated by

mouth and has been used with some success in

pain control, particularly in the USA. However,

its metabolism and excretion are complex, so the

patient’s physical, mental and emotional condi-

tion needs to be monitored closely. Its medicinal

use in the UK is primarily for those intolerant of

morphine and it is used widely to manage opioid

dependence.

Pharmacokinetics.   Methadone has a very long

elimination  half-life  on  multiple  oral  dosing

(about 25 h) and is very highly bound to plasma

and CNS proteins, so that accumulation can

occur with chronic use. This leads to drowsiness

and confusion, which may occasionally be life-

threatening.   The   half-life   is   extended   con-

siderably by renal or hepatic impairment, so

methadone  must be used with special care in

elderly or debilitated patients and in alcohol

abusers.   Steady-state   blood   levels   are   not

achieved until at least 4-5 days after the initia-

tion of therapy or a change in dose, so loading

doses  are  sometimes  used  to  achieve  rapid

control. Despite the long half-life, the duration

of action is about 6-8 h initially, increasing to

6-12 h with chronic dosing, so several daily

doses must be given initially. Once- or twice-

daily dosing is used when steady-state blood

levels have been achieved, because of the risk of

accumulation and toxicity.

Although the degree of sedation and respira-

tory depression reflect the absolute amount of methadone in the body, the total body load does not   influence   the   magnitude   of   analgesic response, possibly owing to different affinities for the different receptor subtypes.

Use   in   opioid   dependence.   Methadone  is

widely used in drug abuse clinics as a replacement

for heroin, to help recreational drug users main-

tain a stable lifestyle. When a drug user has

learned alternative strategies to heroin  use for

coping with stressful situations, the methadone

may    be    withdrawn    gradually.    However,

methadone  may  itself  lead  to  a  morphine-like

dependence and the potential for abuse is similar

to that for morphine. Although withdrawal symp-

toms are less intense than those with morphine,

and  it  may  relieve  the  physical  withdrawal

symptoms without giving ‘highs’ for the same

length of time, the onset of withdrawal symp-

toms is slower (24-48 h) and they are more

prolonged. Opioid misusers are usually given a

very   gradually   reducing   methadone   dosage

regimen, the level of which is carefully titrated

to the patient’s needs.

However, buprenorphine  is now more widely

used  to  manage  opioid  detoxification (with-

drawal).  Further,  the  value  of  methadone  in

treating opioid withdrawal has been challenged:

it is not a cure and is often regarded more as a

method of social control, to minimize the crim-

inal activities often associated with drug misuse,

rather than as therapy.

In  these  days  of  opioid-addicted  mothers, neonatal  opioid  dependence  should  not  be

overlooked.

Hydromorphone

This potent analgesic, about 7.5 times as potent as morphine, is used in the UK when patients are intolerant of other opioids. It has a rapid onset of action but a relatively short half-life. Oral

dosing is required 4-hourly, or twice daily with the modified-release preparation.

It is more widely used in the USA and Europe,

probably because diamorphine  is not available

there. Like the latter it is very soluble in water

and injection volumes are small, so it may be

useful in syringe drivers (see below). However,

the injectable preparation is not licensed in the

UK.

Dipipanone

This agent is usually given orally only. Although it has been given by SC or IM injection in the past, it should not be given by the IV route

because this may produce a dramatic fall in

blood pressure.

The only available tablet in the UK is formu-

lated  with  cyclizine (an  antihistamine)  as  an anti-emetic. This makes the product unsuitable for chronic use, e.g. in palliative care.

Opioid analgesics          473

Oxycodone

This is effective orally and is used widely in

North America and elsewhere as a modified-

release oral product and, combined with aspirin

or paracetamol (acetaminophen), for moderately

severe pain. In the UK it is available as normal-

release capsules, modified-release tablets and as

an injection for slow IV injection or SC use. It is

sometimes used in syringe drivers for patients

intolerant of other opioids, but the low concen-

tration of the existing formulation limits the

dose volume that can be given by this route.

Fentanyl and its congeners

These  agents  are  used  primarily  for  intra-

operative analgesia. Opioids are widely used in

low doses to supplement general anaesthesia

with nitrous oxide-oxygen and a neuromuscular

blocking   agent.   The   muscle   relaxants,   e.g.

suxamethonium,   pancuronium  and   atracurium

(there are many others), relax the diaphragm

and abdominal muscles and may permit light

anaesthesia to be used. In addition, they relax

the vocal cords and so facilitate the passage of an

endotracheal tube to assist in passing anaesthetic

gases or oxygen. Patients who have received a

muscle relaxant must always have assisted or

controlled respiration when fentanyl is used.

Alfentanil,  fentanyl  and  remifentanil  have  a rapid onset of action (1-2 min) and are used to reduce the induction dose of an anaesthetic,

especially in poor-risk patients.

Remifentanil can be used intra-operatively as an

IV infusion in adults and young children. Because

it is rapidly metabolized by blood enzymes it has

a very short duration of action and does not accu-

mulate, so post-operative respiratory depression

is unlikely. Because of its very short duration of

action,  additional  analgesia  is  usually  needed

post-operatively.

Alfentanil and fentanyl may also be used intra-

operatively  as  an  IV  infusion  or  as  IV  bolus

injections. These may cause severe respiratory

depression   and   cardiovascular   side-effects,

especially   with   fentanyl.   Because   respiratory

depression may occur for the first time post-

operatively, patients who have received either

drug need to be observed carefully for some

hours after recovery. Sufentanil (not licensed in

the UK) is used similarly in the USA.

The side-effect of respiratory depression with alfentanil and fentanyl is used to advantage in intensive care patients on assisted respiration to manage respiration without interference from their endogenous respiratory drive. The opioid effect is reversed with naloxone when respiratory depression is no longer required.

Fentanyl is used widely as transdermal patches

(Chapter 13), each of which lasts for 72 h, for the

control of stable chronic pain when the oral

route is unavailable or unsuitable. Because it

takes  about 12 h  for  the  patch  to  produce

adequate analgesia, it should be applied at an

appropriate time, e.g. simultaneously with the

last modified-release morphine dose when trans-

ferring from morphine. The equivalence between

the fentanyl patches and morphine is that fentanyl

25 lg/h  for  72 h  is  equivalent  to  morphine

hydrochloride 90 mg daily.

Unfortunately,  the  patches  are  often  used

poorly in the community. Because of the lag time

in  reaching  an  effective  concentration  after  a

change in dose there may be too rapid titration;

titration by increments that are too large; or inap-

propriate use in unstable pain, all of which may

cause toxicity.

There is a buccal formulation, supplied with a

special applicator, for breakthrough pain, but

many  patients  find  it  difficult  to  use.  An

intranasal formulation is under trial for break-

through pain when using patches, as a more

convenient  alternative  to  the  buccal  and  IV

formulations.

Fentanyl is used by SC infusion in palliative care,  mainly  for  patients  with  renal  failure because its metabolites are inactive.

Opioid rotation

Although oral morphine is the potent analgesic of

choice, there is a minority of patients in whom

their  pain  is  inadequately  controlled  despite

large doses. It is unclear why this situation occurs.

Postulated mechanisms are the complex metabo-

lism  and  pharmacokinetics  of  morphine,  with

active  metabolites  that  may  accumulate,  and

down-regulation of receptors or other receptor

change.

These  patients  may  benefit  from  a  change

in the route or method of administration, e.g.

SC  injection,  patient-controlled  analgesia (p.

tment

489)  or  epidural  anaesthesia  (p.  508).  Nerve

blocks (Figure 7.3 and  p.  487)  may  also  be

appropriate.

However, a satisfactory result may be achieved

by a change of opioid, i.e. opioid rotation (also

known as opioid switching). It is preferable to

use a pure agonist, e.g. hydromorphone, methadone

or oxycodone. Transdermal fentanyl or buprenor-

phine  is unlikely to be useful in this context

because of the pharmacokinetics of the patches.

An initial dose reduction is often advocated, and

is safe practice, with access to medication for

breakthrough pain, taken when necessary. The

dose can then be titrated according to patient

response.

The  reasons  for  benefit  from  rotation  are not  clear,  but  include  differing  metabolism, different   receptor   subtype   responses   and variable  sensitivity  to  side-effects.

Opioid rotation is not a universal panacea, and

frequent changes are undesirable. It is important

to  evaluate  possible  reasons  for  loss  of  pain

control,  e.g.  new  symptoms  or  intercurrent

disease, and to consider alternative approaches

to pain control.

Codeine and its congeners

Codeine phosphate itself is a relatively weak anal-

gesic, but is converted to morphine and norcodeine in the liver. Although 10% of Caucasians cannot carry out this change the relevance of this to

clinical practice is not known.

It is used for mild to moderate pain. It has a

‘ceiling’ effect, i.e. if the normal maximal dose of

60 mg fails to control the pain, further dose

increases do not produce more analgesia. The

side-effects of drowsiness, nausea and constipa-

tion  often  become  intolerable  at  the  ceiling

dose. It is appropriate to co-prescribe a laxative

(e.g. lactulose) in patients taking regular doses.

It is widely used as a cough suppressant and as

a component of compound mild analgesics, e.g.

with  aspirin  or  paracetamol (acetaminophen).

There is little evidence for the efficacy of these

compound products, because the codeine doses

are usually sub-therapeutic, i.e. 30 mg, and

there is a considerable increase in side-effects.

However, they are firmly entrenched in clinical

practice.

Codeine formulations are best avoided in all

children under 12 and should not be used in

infants: the common belief that codeine is an

effective sedative and hypnotic has resulted in

fatalities.

It has the potential to cause dependence and pharmacists  need  to  be  vigilant  when  clients are  using  regular  supplies  of  OTC  products containing it.

Dihydrocodeine  tartrate  is  possibly  a  more potent  analgesic  than  codeine  and  is  used  for moderate to severe pain. However, both drugs are on Step 2 of the WHO ladder. Like codeine it is used in compound analgesic products and has similar disadvantages, including dependence. It is sometimes prescribed for dental pain.

Partial agonist and agonist-antagonist drugs

These  were  developed  in  an  attempt  to  over-

come opioid dependence problems. Although

not totally devoid of abuse potential, they have

less than that of morphine  and other similar

agonists.

Nalorphine  was  the  prototype  of  this  group but is no longer used owing to an unacceptably high incidence of psychotomimetic side-effects. Subsequently, two types of agonist-antagonist drugs have been developed that are classified

according to their activity relative to morphine or nalorphine (Table 7.6).

Agents of the nalorphine type characteristically act only as competitive antagonists at the mu-

receptor but have varying affinities and intrinsic activities  at  all  receptor  types.  The  mixed

agonist-antagonists of the morphine type have a high  affinity  for  mu-receptors,  but  a  low intrinsic activity there.

Morphine-like opioids

Buprenorphine is a partial agonist that has a 6- to

8-h duration of action and is effective in the

relief of moderate to severe pain unresponsive to

non-opioid analgesics. Its potency is similar to

that of pethidine. It is available in a sublingual

formulation (but see above) and is sometimes

used for premedication and peri-operative anal-

gesia. For acute pain, the onset of analgesia of

the sublingual tablets is about 30 min. However,

the use of buprenorphine in chronic severe pain is

Opioid analgesics          475

problematic. It has a ‘ceiling effect’, like pethidine

(meperidine) and codeine, and a low therapeutic

index, like pentazocine, so increasing the daily

dose above about 3 mg is unlikely to be benefi-

cial. It is used to manage opioid withdrawal (see

‘methadone’ above). The sublingual tablets are

popular among drug abusers and some health

authorities have introduced a voluntary ban on

prescribing these.

The transdermal patches have a lower inci-

dence of side-effects than the sublingual formu-

lation and are suitable for controlling moderate

to severe chronic pain in palliative care and

other patients. It takes about 24 h to reach a

steady-state plasma level with the patches that

are replaced after 72 h. Patches for replacement

after 7 days are also available, the steady-state

plasma  level  being  achieved  during  the  first

application. However, the dose should be deter-

mined with the 72-h patches before switching

to the 7-day formulation. Because buprenorphine

is  a  partial  agonist-antagonist,  breakthrough

pain can only be managed appropriately using

the buprenorphine sublingual tablets: the use of

other opioids gives unpredictable effects. The

analgesic response should not be assessed before

24 h, but any dose adjustments should be made when the patches are changed. Due to its long terminal half-life of about 30 h, patients who

suffer  side-effects  necessitating  removal  of  a patch  need  to  be  monitored  for  a  further

24-30 h. Unlike the pure opioid agonists, the

effects, and side-effects, of buprenorphine are only partially reversed by naloxone.

Side-effects.   Because   of   its   high   receptor

affinity, large doses of other opioids may be

required  to  displace  buprenorphine  from  the

receptor. This may lead, in those patients who do

not obtain adequate pain relief with buprenor-

phine, to a confused situation of inadequate anal-

gesia, despite a large opioid dose, but enhanced

toxicity. If given to a patient receiving other

opioids chronically, buprenorphine may precipi-

tate  pain  and  withdrawal  symptoms.  Thus  it

should be used alone. In common with most other

opioids, buprenorphine causes dose-related respira-

tory  depression.  Because  of  its  high  receptor

affinity  its  effect  is  not  readily  reversed  by

naloxone, making it more hazardous in overdose.

Buprenorphine  is  highly  emetogenic  in  some patients but appears to be less likely than other opioids to cause constipation.

Meptazinol has about one-tenth of the anal-

gesic potency of morphine. It is unusual in that it

is thought to have two central mechanisms of

action:  a  partial  agonist-antagonist  effect  at

opioid receptors, plus effects on central cholin-

ergic receptors. It has a variable onset of action

(0.25-3 h orally, 0.5 h rectally), and its duration

of action is also variable (2-7 h). Thus dosing

is required every 3-6 h, depending on patient

response. It undergoes extensive first-pass metab-

olism, so blood levels after oral dosing are low

and this route is better suited to the short-term

relief of moderate pain, e.g. peri-operatively. For

moderate  to  severe  pain,  meptazinol  is  best

given by IM or slow IV injection. It is likely to

cause nausea and vomiting.

Meptazinol is claimed to cause less respiratory

depression than other opioids, possibly because

of  its  cholinergic  effects  or  its  preferential

action at the mu-receptor, and may be a useful

analgesic to consider in patients with compro-

mised respiratory function, but there is a diver-

gence of opinion on this point. Some clinicians

advocate the cautious use of morphine, despite

its  respiratory  depressant  effects,  in  patients

with  compromised  lung  function,  believing

that pain itself acts as a respiratory stimulant

and reduces the risk of administering a known

respiratory depressant. Further, should respira-

tory   depression   occur   following   morphine

administration,  this  can  readily  be  reversed

by  administering  naloxone,  whereas  complete

reversal  of  the  effects  of  a  mixed  agonist-

antagonist   such   as   meptazinol   cannot   be

achieved readily with naloxone and additional

measures are needed, e.g. assisted respiration

with  oxygen (see  Chapter 5)  and  possibly  a

respiratory stimulant.

The potential for abuse is probably less than that  of  morphine  because  its  euphoric  effects disappear with increasing dose.

Nalorphine-like opioids

Pentazocine  is  a  moderately  potent  analgesic

that is used infrequently nowadays in the UK

as  it  shares  the  hallucinogenic  potential  of

nalorphine  and  causes  a  high  incidence  of

tment

confusion  and  hallucinations.  Like  buprenor-

phine, pentazocine may precipitate a withdrawal

reaction in patients who are opioid-dependent.

It  is  unsuitable  for  pain  associated  with  MI

because,  unlike  morphine,  it  can  increase  the

cardiac workload.

The oral efficacy of pentazocine is poor (slightly

less potent than codeine) and, due to its low ther-

apeutic index, doses cannot be increased greatly

to  treat  severe  pain  without  also  markedly

increasing the incidence and severity of side-

effects. However, it is more potent when admin-

istered by any parenteral route than both codeine

and dihydrocodeine.

Tramadol

This has both opioid and non-opioid modes of

action, enhancing adrenergic and serotonergic

actions. It is a metabolite of the antidepressant

trazodone, so it is not surprising that it inhibits

noradrenaline (norepinephrine)  re-uptake  and

the stimulation of serotonin release at synapses.

These secondary effects are responsible for the

psychiatric  side-effects  seen  in  some  patients,

but  they  are  also  believed  to  facilitate  the

pathways that inhibit pain perception.

Tramadol is a weaker analgesic than most other

opioids and appears to cause less respiratory

depression. Because it causes less constipation it

is often used when toileting difficulties create

post-operative problems. There may also be a

reduced potential for dependence, but tramadol

should not be used if there is a history of drug

dependence or convulsions. It has been used for

obstetric and peri-operative pain and in MI, but

is unsuitable for intra-operative analgesia during

light anaesthesia.

Side-effects.   Apart  from  those  referred  to

above, it may also cause occasional hyperten-

sion,  anaphylaxis,  hallucinations  and  confu-

sion, particularly in elderly patients. Because it

is not classed as a controlled drug in the UK,

it  is  probably  used  more  frequently  than  is

justified.

Summary of opioid side-effects

Actions of morphine other than those described

above are usually considered to be side-effects Nausea and vomiting

Morphine and its derivatives stimulate the CTZ

(Chapter 3) and may cause nausea and vomiting,

although this tends to be transient, wearing off a

few days after initiating therapy or an increased

dose. These effects may be avoided by prophy-

lactic co-administration of an anti-emetic (see

Chapter 3) over this period. Anti-emetics are also

appropriate in patients who are already vomiting

owing to drug use or who have a history of

vomiting  with  opioids,  and  may  be  given

initially either rectally or parenterally to bring

existing vomiting under control.

Anti-emetics are not indicated in patients who

are not currently nauseated and so should not be

used routinely: good practice is not to prescribe

a  drug  unless  there  is  a  positive  indication.

However, it is appropriate to prescribe a small

quantity of an anti-emetic for use ‘as required’,

in anticipation of possible need. Because dipi-

panone  is  only  available  combined  with  an

anti-emetic  (cyclizine),  it  is  not  recommended

for use in palliative care.

Because the incidence of nausea and vomiting is higher in ambulatory patients, it is thought

that a vestibular component is also involved. It is often helpful for the patient to lie quietly if

this problem occurs.

Constipation

Opioids  cause  an  increase  in  gastrointestinal

sphincter tone and a decrease in propulsive peri-

stalsis. This causes delayed gastric emptying and,

almost inevitably, constipation. The regular co-

administration of a stimulant laxative plus a

stool softener is nearly always used in anticipa-

tion of the problem. Dantron, as co-danthrusate

(dantron plus docusate) or co-danthramer (dantron

plus poloxamer ‘188’), is probably the most effec-

tive agent. Dantron is specifically licensed in the

UK only for the treatment of constipation in

terminal care, but it has also been used for

patients with cardiac failure or MI, to avoid

cardiac stress due to bowel strain. The licence is

restricted because studies in rats have indicated a

potential carcinogenic risk. Products containing

dantron may colour the urine red, and patients

should be warned of this apparently alarming

effect. Dantron  may also cause a rash in the

buttock area in incontinent patients, so it should

Opioid analgesics          477

be reserved for use when other laxatives are

ineffective.

The equivalent product in the USA is a combi-

nation of casanthranol (a natural anthracene)

and docusate (dioctyl sodium sulphosuccinate).

Other smooth muscle effects.   Morphine also

increases the tone in the sphincter of Oddi,

which leads to increased pressure in the biliary

system   and   occasional   biliary   colic.   Other

actions  on  smooth  muscle  include  increased

urethral tone, causing difficulties in micturition,

and very rarely bronchoconstriction after large

doses.

Respiratory depression

Morphine  and  other  opioids  can  significantly

depress respiration, and this is usually the cause

of death from overdose. Respiratory rate, tidal

volume and response to hypercapnia or hypox-

aemia are all reduced. However, like many of its

other side-effects, respiratory depression is not

usually a limiting factor in patients who are

experiencing  severe  pain,  because  pain  is  a

potent arousal mechanism. Nevertheless, opioids

must be used with great care in patients with

advanced   respiratory   disease   or   otherwise

depressed  respiratory  function.  Opioid  doses

should be reduced if other procedures, e.g. nerve

block (Figure 7.2 and p. 487) or radiotherapy,

reduce pain successfully.

Effects on the eye

Stimulation  of  the  oculomotor  nerve  causes

constriction of the pupil, which is often a diag-

nostic  aid  in  cases  of  morphine  overdose  and

addiction. Thus, opioid analgesics are generally

avoided in patients with head injury, because

the opioid-induced pupillary changes, nausea

and general CNS clouding may mask the signs

induced by trauma and confuse the neurological

examination.

Cardiovascular effects

The usual doses of opioid analgesics generally do

not have major cardiovascular effects in patients

with normal cardiac function. However, mor-

phine may cause venous pooling and postural

hypotension, through its venodilator action. The

consequent reduction in cardiac preload (see

Chapter 4) is an additional benefit to analgesia,

and its euphoric action may help immediately following MI, to relieve severe anxiety.

Hypersensitivity

Occasionally, allergic-type reactions occur with

opioid agents, and both local reactions at the site

of injection and systemic allergic symptoms have

been reported. If a patient is hypersensitive to

morphine, both codeine and diamorphine (heroin)

are also contra-indicated as they are structurally

similar.   However,   methadone   and   pethidine

(meperidine)  are  suitable  alternatives,  being

chemically unrelated.

Dependence

Opioid analgesics can produce both physical and

psychological dependence, although the latter

appears to be a rare event when opioid analgesics

are used to relieve pain. If a patient asks for

increased  dosages  of  analgesics  because  their

pain has worsened or not been controlled, this

should not be perceived automatically as drug-

seeking behaviour or evidence of dependence.

Physical dependence does occur, and can be

managed by reducing the dose of opioid slowly

when it is no longer needed for pain, rather than

stopping  abruptly,  which  causes  unnecessary

withdrawal symptoms.

Naloxone.   Adequate doses of this antagonist

will reverse completely all the actions of pure

opioid agonists, so it is a complete antidote for

both the actions and side-effects of morphine-like

drugs.  However,  care  should  be  taken  when

using naloxone to reverse opioid-induced respira-

tory depression, as patients who have been using

opioid agents chronically are extremely sensitive

to antagonists and too high a dose of naloxone

can precipitate a withdrawal reaction and recur-

rence of severe pain. Further, it will not fully

antagonize  the  action  of  partial  agonist  and

agonist-antagonist drugs (see above).

Because the duration of action of naloxone is

shorter than that of morphine and other opioids,

repeated  injections  or  IV  infusion  may  be

required. The naloxone dose varies widely, being

dictated by the patient’s condition and response.

Oxygen and the respiratory stimulant doxapram

(hospital use) may be needed to spare the naloxone

dose and so maintain adequate analgesia.

tment

Less potent analgesics

These are mainly used for the treatment of acute or chronic pain resulting from trauma, surgery and chronic systemic diseases such as arthritis. They   include   low-potency,   centrally-acting morphine-like compounds (‘weak opioids’), e.g. codeine and dihydrocodeine, and drugs that act on peripheral pain pathways, e.g. aspirin, salicylates and NSAIDs (see Chapter 12). Paracetamol (aceta-

minophen)  also  has  central  effects,  but  at

different  receptors  from  the  opioids,  and  its toxicity is discussed in Chapter 3.

Weak opioids

These  drugs  have  a  ceiling  to  their  analgesic

effect, usually because of dose-limiting adverse

reactions, and therefore have a limited efficacy

relative   to   the   strong   opioids.   Therefore

combinations  of  these  drugs  with  paracetamol

(acetaminophen),   provided   that   it   is   not

contra-indicated (i.e. liver function is not compro-

mised), or aspirin (if tolerated), may be expected

to have an additive, possibly synergistic, anal-

gesic   effect.   However,   the   BNF   states   that

“Compound analgesics  are commonly

used, but the advantages have not been substan-

tiated”. Despite this, they are prescribed very

widely. Their continuing popularity, with both

patients  and  prescribers,  may  represent  the

triumph  of  experience  over  theoretical  good

practice.

Codeine is chemically related to morphine and is

metabolized to morphine in the liver, so it shares

its pharmacological actions. It is thought to have

less abuse potential but is too constipating for

long-term use.

Dihydrocodeine  is mainly used for moderate

pain. It has a flat dose-response curve, so there is

no advantage in increasing the dose above that

normally recommended: if analgesia with dihy-

drocodeine is inadequate, a change to a strong

opioid is indicated.

Dextropropoxyphene (propoxyphene) resembles

methadone structurally, and is less potent than

codeine.  There  has  been  considerable  contro-

versy over its widespread use owing to serious problems if taken in overdose. In the UK, dextro-

propoxyphene has been used principally in combi-

nation  with  paracetamol (acetaminophen)  as

co-proxamol, which is unfortunately commonly

used as a agent for suicide. It has been suggested

that as little as 15-20 tablets of this combination

can prove fatal, especially if alcohol is impli-

cated. The main cause of death in overdose with

dextropropoxyphene  alone is respiratory depres-

sion, but in overdose with co-proxamol this is

compounded with the hepatotoxicity of parac-

etamol (acetaminophen; see Chapter 3). Acute

over-dosage with co-proxamol  requires prompt

administration of naloxone, to antagonize the

dextropropoxyphene, resuscitation treatment and

management of paracetamol overdose. If naloxone

is not used, patients may die of cardiovascular

collapse before reaching hospital.

Because of these serious toxic effects in over-

dose, and the fact that it is one of the most

common suicide agents in the UK, co-proxamol is

regarded as unsuitable for prescibing in the NHS

and is being withdrawn from use in the UK.

Like other opioid analgesics, dextropropoxyphene can lead to dependence, the likelihood being

about the same as with codeine.

Nefopam  is   structurally   unrelated   to   the

opioids and is sometimes useful when the pain

has not responded to other analgesics. Its main

advantage is that it does not cause respiratory

depression,   but   its   sympathomimetic   and

antimuscarinic side-effects, notably restlessness,

dry mouth, urinary retention and, less often,

blurred vision, tachycardia, insomnia, headache

and  confusion,  may  be  troublesome.  Thus,

nefopam must be used with caution in the elderly

and  if  there  is  evidence  of  renal  or  hepatic

impairment, because it is extensively metabo-

lized in the liver and largely excreted in the

urine. Because of its adverse cardiovascular and

CNS effects, nefopam is contra-indicated in MI

and if the patient is liable to convulsions.

Non-steroidal anti-inflammatory drugs

NSAIDs appear to act peripherally at the pain

receptor level, and so do not produce the phys-

ical dependence often associated with opioid

analgesia. They are particularly useful in treating

Analgesic adjuvants      479

patients with chronic disease accompanied by both pain and inflammation, e.g. RA (see Chapter 12) and for the short-term treatment of mild to moderate acute pain, including musculoskeletal injuries  and  bone  pain.  Particular  indications include the relief of pain accompanying dysmen-

orrhoea, and that associated with neoplastic bone metastases. In the latter case, combinations of an opioid with an NSAID are likely to be considerably more effective than an opioid alone.

The  topical  and  other  uses  of  NSAIDs  are discussed in Chapter 12.

Analgesic adjuvants

These include three types of agent:

•  Co-analgesics           (secondary   analgesics),   for

example an anticonvulsant, e.g. clonazepam, gabapentin or pregabalin, or a low-dose tricyclic antidepressant, e.g. amitriptyline.

•  Other psychotropic agents, e.g. normal dose

            antidepressants, to treat the depression that

frequently accompanies moderate to severe chronic pain.

•  Corticosteroids, e.g. dexamethasone, to reduce

            oedema  around  a  tumour  and  so  prevent

pressure on adjacent nerves or other tissues.

Other drugs that are used to prevent or treat

the adverse effects of the primary analgesic, e.g.

antiemetics or laxatives, are not discussed here.

Analgesic adjuvants tend to be used primarily

in treating the chronic pain of neoplastic disease

(Table 7.8). Their inclusion in a drug regimen

may enhance pain relief, or it may be possible to

reduce the dose of opioid, and consequently its

side-effects. Other categories of drugs are also

used, e.g. antispasmodics, neuroleptics and anxi-

olytics. The mechanisms by which these agents

exert their effects are not clearly established, but

are unrelated to the opioid receptor system.

First-generation    antihistamines,    e.g.    ali-

memazine, chlorphenamine and promethazine are

used primarily for their sedative properties and

may also help to relieve nausea and skin irrita-

tion.  However,  many  of  these  are  markedly

hypnotic, notably alimemazine and promethazine,

and the latter has a long duration of action

(about 12 h). Great care is needed when using

the    sedative    antihistamines    with    other

psychotropic drugs, especially opioids, because

profound sedation may result. They also have

marked antimuscarinic activity and may cause

urinary  retention,  glaucoma  and  pyloroduo-

denal obstruction. Patients vary considerably in

their  response  to  antihistamines  and  children

and  the  elderly  are  very  susceptible  to  their

side-effects.

Stabbing or shooting pains (neuralgia) caused

by  nerve  inflammation  or  damage  appear  to

respond  particularly  well  to  anticonvulsant

drugs, which are thought to act by suppressing

abnormal  spontaneous  activity  in  traumatized

nerve fibres. Carbamazepine is generally the most

successful  agent,  although  side-effects  can  be

troublesome, especially in the elderly. If carba-

mazepine is ineffective, it is worth trying phenytoin

or  another  anticonvulsant  before  abandoning

this line of treatment. Therapy should be initiated

gradually, increasing the dose carefully until relief

is  obtained  or  unacceptable  side-effects  are

encountered (see Chapter 6).

Tolerance to the side-effects of all adjuvants is  improved  by  starting  with  low  doses  and titrating the dose slowly, especially in frail or elderly patients.

The best results with analgesic adjuvants are

often obtained if they are introduced early on in

the disease process, before demyelination (loss

of the myelin sheath of nerves) has occurred.

Demyelination may result from infiltration or

sustained pressure by a tumour, producing nerve

block, slowing of nerve conduction or nerve irri-

tability and inflammation. It also makes nerves

more liable to viral infection. The end result of

these  processes  may  be  paraesthesias,  partial

paralysis, painful spasm, etc.

Damage to central or peripheral nerves, either

as the prime cause of neuropathic pain  (see

above)  or  due  to  the  secondary  effects  from

a tumour is recognized by abnormal sensitivity

in  an  area  of  autonomic,  sensory  or  motor

dysfunction.

Psychotropic drugs

Drugs  from  disparate  therapeutic  groups  are

used, and their modes of action in the treat-

tment

ment of pain is controversial. It is postulated

that they block the re-uptake of certain neuro-

transmitters in the pain pathway, e.g. 5-HT and

noradrenaline    (norepinephrine),   thus   inter-

fering  with  pain  impulse  transmission  or  its

modulation. However, their pro-analgesic effect

does not simply result from their psychotropic

actions  because  they  are  effective  at  much

lower doses, and act more rapidly, than in the

treatment  of  depression (see  Chapter 6).  If

depression needs to be treated, full antidepres-

sant  doses  should  be  used.  They  may  raise  a

pain threshold that had been lowered by the

understandable anxiety and depression associ-

ated  with  chronic  pain.  Some  studies  have

suggested that tricyclic antidepressants with an

intact  tertiary  amine  group (e.g.  amitriptyline

and  imipramine)  are  the  most  effective.  Anti-

depressants  are  thought  to  be  most  effective

against  the       ‘burning’,  deafferentation  pain

associated with sensory nerve damage, which is unresponsive to opioids.

The  benefits  of  an  antidepressant  may  be

further increased by combination with a small

dose  of  a  neuroleptic  drug,  such  as  a  buty-

rophenone (e.g. haloperidol) or a phenothiazine

(most commonly perphenazine). However, these

are rarely used in palliative care and such combi-

nations  should  only  be  used  by  prescribers

experienced   in   their   use,   because   cardiac

arrhythmias,  postural  hypotension,  excessive

sedation, dyskinesias (e.g. TD, p. 420), dystonias

(abnormalities of muscle tone), myelosuppres-

sion and enhanced antimuscarinic side-effects

may be a problem. Therefore neuroleptics are

best avoided.

Anxiolytics.   Diazepam,  is  especially  useful because  it  has  muscle  relaxant  properties  in addition to its anxiolytic effect, and so is used frequently.  If  anxiety  is  not  a  problem  and diazepam  is  too  sedating,  then  baclofen  is  a suitable alternative for muscle spasm.

Cholecystokinin            (CCK),    the    hormone

involved in food digestion that is released by

enteroendocrine cells in the gut (see Chapter 3),

is also produced in the brain where it acts as a

neurotransmitter involved in feelings of anxiety.

It has recently been shown that CCK antago-

nists, e.g. devazepide and proglumide, reduce the

sensation  of  anticipated  pain.  Although  this points to a novel mode of analgesia, no product of this type has been marketed.

Glucocorticosteroids

These  have  a  wide  application  in  advanced

neoplastic   disease   because   they   reduce   the

inflammatory  swelling  around  tumours,  and

hence the pressure on nerves and in bones, thus

alleviating the pain. These actions are additional

to any growth-suppressant action on tumour

cells, but the effect may be only temporary.

Glucocorticoids  also  suppress  the  release  of

mediators such as histamine and kinins and are

euphoric, thus raising the pain threshold. It is

usual to start with a high dose to bring the symp-

toms under control and then reduce it as quickly

as possible to the lowest effective dose, or to zero

if  the  corticosteroid  is  ineffective (see  also

Chapters 5, 12 and 13). Slow dose reduction is

not necessary if treatment has been less than

3 weeks.

Dexamethasone,   and   to   a   lesser   extent

betamethasone,  lowers  intracranial  pressure  in

cerebral  oedema  and  is  especially  useful  for

relieving the headache and associated symptoms.

Low-dose corticosteroids (e.g. 2 mg dexametha-

sone) also improve mood and, possibly, appetite,

but co-analgesia requires higher doses - about ten

times that dose.

Anabolic  steroids  have  been  advocated  to

improve food utilization and increase muscle

bulk and strength in patients with oesophageal,

gastric and small bowel tumours who have prob-

lems with swallowing and nutrient absorption.

An increase in muscle bulk would also reduce the

discomfort   of   repeated   injections.   However,

there is no good evidence for clinical benefit.

Feeding by a nasogastric tube or percutaenous

endoscopic gastrostomy (PEG), with a cannula

giving direct access to the stomach to bypass

swallowing problems, is preferred.

Analgesic adjuvants      481

Cannabis and cannabinoids

The use of cannabis as monotherapy or as an

adjunct  to  other  analgesics  is  hotly  debated

because of its current rescheduling in the UK as

a Class  C  Controlled  Drug,  to  which  special

licensing  conditions  apply.  Marijuana  is  the

most  widely  used,  or  abused,  psychoactive

substance. It is regarded by most governments

as having no therapeutic uses, although there

are numerous anecdotal reports of its benefit,

e.g. in relieving spasticity in multiple sclerosis.

The  UK  Medicines  and  Healthcare  Products

Regulatory Agency (MHRA) has recently stated

that it has “not objected to importing Sativex

oromucosal spray for use in multiple sclerosis

patients”.  Clearly,  further  research  is  needed,

but  this  seems  to  imply  that  a  UK  licence  is

likely.

Only one cannabinoid, nabilone, is currently used in the UK, for the management of nausea and vomiting caused by cytotoxic chemotherapy uncontrolled  by  other  drugs,  and  this  has

numerous side-effects.

The use of cannabis, especially at a young age, is a definite risk factor for the development of schizophrenia (see Chapter 6).

A major barrier to progress is that cannabis

smoke  contains  more  than 60 cannabinoids

and   no   standardized   product   exists.   One

component,   D-9-tetrahydrocannabinol            (D-9-

THC), seems largely to reproduce effects similar

to  smoking  cannabis.  However,  it  would  be

rash  to  assume  that  other  cannabis  compo-

nents  are  not  adjuncts  or  that  they  do  not

have  potential  value  as  co-analgesics.  The

precise effects of D-9-THC vary with the imme-

diate  environment,  dose  and  route,  and  the

psychological attributes of the user, similarly to

alcohol.

Cannabinoid receptors are widely distributed in the brain. Why this is so, and the functions of endogenous ligands, are unknown but are of

considerable interest.

sensation  of  anticipated  pain.  Although  this points to a novel mode of analgesia, no product of this type has been marketed.

Glucocorticosteroids

These  have  a  wide  application  in  advanced

neoplastic   disease   because   they   reduce   the

inflammatory  swelling  around  tumours,  and

hence the pressure on nerves and in bones, thus

alleviating the pain. These actions are additional

to any growth-suppressant action on tumour

cells, but the effect may be only temporary.

Glucocorticoids  also  suppress  the  release  of

mediators such as histamine and kinins and are

euphoric, thus raising the pain threshold. It is

usual to start with a high dose to bring the symp-

toms under control and then reduce it as quickly

as possible to the lowest effective dose, or to zero

if  the  corticosteroid  is  ineffective (see  also

Chapters 5, 12 and 13). Slow dose reduction is

not necessary if treatment has been less than

3 weeks.

Dexamethasone,   and   to   a   lesser   extent

betamethasone,  lowers  intracranial  pressure  in

cerebral  oedema  and  is  especially  useful  for

relieving the headache and associated symptoms.

Low-dose corticosteroids (e.g. 2 mg dexametha-

sone) also improve mood and, possibly, appetite,

but co-analgesia requires higher doses - about ten

times that dose.

Anabolic  steroids  have  been  advocated  to

improve food utilization and increase muscle

bulk and strength in patients with oesophageal,

gastric and small bowel tumours who have prob-

lems with swallowing and nutrient absorption.

An increase in muscle bulk would also reduce the

discomfort   of   repeated   injections.   However,

there is no good evidence for clinical benefit.

Feeding by a nasogastric tube or percutaenous

endoscopic gastrostomy (PEG), with a cannula

giving direct access to the stomach to bypass

swallowing problems, is preferred.

Analgesic adjuvants      481

Cannabis and cannabinoids

The use of cannabis as monotherapy or as an

adjunct  to  other  analgesics  is  hotly  debated

because of its current rescheduling in the UK as

a Class  C  Controlled  Drug,  to  which  special

licensing  conditions  apply.  Marijuana  is  the

most  widely  used,  or  abused,  psychoactive

substance. It is regarded by most governments

as having no therapeutic uses, although there

are numerous anecdotal reports of its benefit,

e.g. in relieving spasticity in multiple sclerosis.

The  UK  Medicines  and  Healthcare  Products

Regulatory Agency (MHRA) has recently stated

that it has “not objected to importing Sativex

oromucosal spray for use in multiple sclerosis

patients”.  Clearly,  further  research  is  needed,

but  this  seems  to  imply  that  a  UK  licence  is

likely.

Only one cannabinoid, nabilone, is currently used in the UK, for the management of nausea and vomiting caused by cytotoxic chemotherapy uncontrolled  by  other  drugs,  and  this  has

numerous side-effects.

The use of cannabis, especially at a young age, is a definite risk factor for the development of schizophrenia (see Chapter 6).

A major barrier to progress is that cannabis

smoke  contains  more  than 60 cannabinoids

and   no   standardized   product   exists.   One

component,   D-9-tetrahydrocannabinol            (D-9-

THC), seems largely to reproduce effects similar

to  smoking  cannabis.  However,  it  would  be

rash  to  assume  that  other  cannabis  compo-

nents  are  not  adjuncts  or  that  they  do  not

have  potential  value  as  co-analgesics.  The

precise effects of D-9-THC vary with the imme-

diate  environment,  dose  and  route,  and  the

psychological attributes of the user, similarly to

alcohol.

Cannabinoid receptors are widely distributed in the brain. Why this is so, and the functions of endogenous ligands, are unknown but are of

considerable interest.

Mode of action

These  agents  depend  on  the  ability  of  the

lipophilic aromatic moiety of their molecules to

dissolve in and attach to Na÷ channels and pene-

trate the lipoid nerve membrane. They prevent

the  large  transient  Na÷   flux  across  excitable

nerve membranes by interacting directly with

the intracellular components of voltage-gated

sodium   channels.   The   result   is   that   the

excitability threshold rises and nerve conduction

slows and eventually fails. Although the drugs

also bind to potassium channels and inhibit

them  at  higher  concentrations,  this  is  not

thought to contribute to their action.

The smaller the nerve fibre, the more sensi-

tive it is to the action of these agents, so there is some selectivity at the concentrations used: they block transmission by small pain fibres but leave inhibitory (large) pain fibres, touch and

movement relatively unimpaired.

Local anaesthetics also have important effects

on calcium flux across cell membranes, so lido-

caine (lignocaine) is the drug of choice for treating

the ventricular arrhythmias that may accompany

MI, heart surgery and digitalis intoxication. This

effect also contributes to their systemic toxicity.

Use

Except  for  procaine,  the  penetration  of  local

anaesthetic  agents  through  ophthalmic  and

mucous membranes is greater than through the

skin, permitting effective local anaesthesia in the

eye, nostrils, throat, urethra and rectum. This

property is used to facilitate the passage of endo-

scopes, catheters, etc. into body cavities and

enables even relatively major operations (e.g. for

cataract) to be carried out with minimal trauma

as day-care procedures.

Local anaesthetics are not normally injected

intravenously, except for the use of IV lidocaine

(lignocaine) for treating ventricular tachycardias.

However, IV regional anaesthesia (Bier’s block) is

used to anaesthetize a limb, intravascular spread

being prevented by using a tourniquet. The use

of local anaesthetics by IV infusion to produce

general anaesthesia is hazardous and requires

Local anaesthetics         483

expert  advice,  so  this  route  is  rarely  used. Regional anaesthesia can also be achieved by spinal use (see below).

Skin anaesthesia

This  is  difficult  to  achieve  through  intact

skin,  owing  to  poor  penetration,  though  a

lidocaine-prilocaine cream may be used under an

occlusive dressing (to increase penetration) for

1 h before painful procedures. This is a eutectic mixture that has a low melting point and is an oil that is able to penetrate intact skin at normal temperatures. It has been used before injecting very nervous children.

A  tetracaine  gel  can  also  be  used  similarly

before  venepuncture  or  venous  cannulation.

These must not be used on wounds, abrasions or

inflamed skin because absorption may be rapid

and extensive and lead to systemic side-effects.

Ophthalmic procedures

Oxybuprocaine and tetracaine are used extensively.

Because tetracaine produces deeper anaesthesia, it

can be used for minor surgery. Proxymetacaine

and lidocaine-fluorescein eye drops are used for

conventional tonometry (measuring the intraoc-

ular pressure by pressing a membrane against the

cornea) as one of the procedures for diagnosing

glaucoma. However, non-contact methods, e.g.

firing a jet of compressed air at the cornea, are

used increasingly. Oxybuprocaine  has a similar

activity to tetracaine, but is less irritant.

Otolaryngology

Lidocaine (lignocaine) is the preferred agent.

            Nose, throat, eye and ear procedures are the

only  ones  in  which  cocaine  is  still  used.  It  is

preferably avoided because of its powerful CNS

stimulant  action  and  potential  for  abuse.

Because  of its  sympathomimetic  effects,  due

to  blocking of noradrenaline (norepinephrine)

at  synapses,  cocaine  should  not  normally  be

used  with adrenaline (epinephrine) and similar

drugs, but some surgeons believe that combi-

nation  with  adrenaline reduces  cocaine  absorp-

tion  and  is  operatively  beneficial.  Cocaine

rapidly produces effective surface analgesia that persists for at least 30 min, depending on the

concentration used.

Spinal anaesthesia

Bupivacaine, levobupivacaine and ropivacaine are

used to block nerve transmission at any point up

to spinal cord level (see Figure 7.3), providing

temporary pain relief. This topic is dealt with on

p. 487. It is likely that levobupivacaine will replace bupivacaine because the L-isomer is the biologi-

cally active form and can be given at higher

doses with fewer side-effects.

Prolongation and enhancement of effect

Prolongation and enhancement of local anaes-

thesia  is  usually  done  by  combination  with

vasoconstrictors. Most local anaesthetics cause

vasodilatation  and  so  are  often  formulated

with adrenaline (epinephrine), which produces

local  vasoconstriction  and  so  prevents  rapid

distribution  into  the  surrounding  tissues  and

the circulation.

This effect prolongs the duration of action and

potentiates the anaesthetic effect, owing to the

increased local concentration of agent. Also, the

reduced rate of systemic absorption enables drug

metabolism to keep pace with administration,

thus  reducing  the  peak  plasma  level  and  so

systemic toxicity. Peak plasma concentrations

occur after about 10-25 min, so patients should

be monitored carefully for 30 min after injection

to ensure that no serious side-effects arise.

However,  adrenaline  (epinephrine)  is  contra-

indicated if the anaesthetic is to be used in or near the fingers, toes or other appendages, because the intense  vasoconstriction  of  their  small  blood vessels may result in ischaemic necrosis.

Felypressin, a synthetic derivative of the ADH

vasopressin,  may  be  a  suitable  alternative  to

adrenaline (epinephrine) and is used for dental

procedures if the latter is contra-indicated in a

particular patient. However, vasoconstrictors are

themselves toxic and the same considerations

apply as with adrenaline. Further, they must not

tment

normally  be  used  with  cocaine,  which  has intrinsic vasoconstrictor and mydriatic proper-

ties. An alternative is to use a viscous vehicle,

usually   containing   dextran      110,   and   this approach has been used to prolong the local

action of lidocaine (lignocaine) for up to 10 h, though the effect is very variable.

Bupivacaine has a long duration of effect (up to

10 h), and may be useful if adrenaline or fely-

pressin are contra-indicated. However, it has a

slow onset of action (30 min), so lidocaine  is

usually used initially, followed by bupivacaine or

levobupivacaine. The time of onset of action of

bupivacaine depends on the concentration, dose

and route used. It is used for peripheral nerve

blocks and infiltration nerve blockade, and is the

principal drug used for spinal anaesthesia in the

UK (Figure 7.3). Bupivacaine is contra-indicated

for use in IV regional anaesthesia, because of

the risks of its long action, cardiovascular and

central nervous toxicity, and because prolonged

restriction   of   the   blood   supply   would   be

required. Although bupivacaine is used widely for

spinal obstetric anaesthesia, the concentration

and circumstances of use in this setting require

expert advice.

Side-effects of local anaesthetics

As  usual,  inflammation  and  trauma  increase

penetration  markedly,  so  significant  systemic

absorption may then occur. On occasion, this

may lead to toxicity, especially with tetracaine

(amethocaine). This drug must never be used on

mucous membranes, e.g. before bronchoscopy

and cystoscopy: lidocaine is safer. The lidocaine-

prilocaine cream used on the skin is irritant to the

eyes and is ototoxic, and so should not be used

on or near these organs.

Local anaesthetics are generally very safe, and

adverse  events  are  rare  when  they  are  used

properly. However, apart from the use of the

lidocaine-prilocaine  cream   and   tetracaine  gel

mentioned  above,  they  should  generally  be

avoided  for  topical  application  to  the  skin

because   sensitization   may   occur.   Systemic

complications  may  also  occur,  usually  when

large doses are used to produce spinal nerve

blocks. This is usually from accidental intravas-  Physical methods

cular injection, which is particularly hazardous if

injections contain adrenaline (epinephrine).

Traction, to relieve pressure on spinal nerve roots

Hypersensitivity   occurs   occasionally:   com-

pounds of the same chemical type tend to give cross-reactions, but these do not occur between the ester and amide groups (Table 7.8).

Topical agents

Liniments and rubs have a long medical history

and were once the only available treatments for

localized  joint  and  soft  tissue  damage.  The

active ingredients are mostly essential oil prod-

ucts, e.g. camphor, menthol, methyl salicylate,

turpentine, sometimes with capsicum oleoresin

or nicotinates.

More  recently,  several  NSAIDs  have  been

presented as gels or creams. These have the

advantage that if only one or two joints are

affected they can be applied to those localized

areas.  This  avoids  the  need  to  take  larger

amounts of drug orally and some of the associ-

ated side-effects. Because of this, and possibly

because patients are involved in the treatment,

topical NSAIDs are popular. Although penetra-

tion of the drug into joints and soft tissues has

been demonstrated, there is little localized effect

and the therapeutic benefit is debatable.

The modes of action of most topical agents, apart  from  any  specific  NSAID  activity,  are alleged to be:

•  Increased blood flow to the area, induced by

            the massage and vasodilatation.

•  Counter-irritation,   i.e.   stimulation   of   C

            neurons inhibits local release of substance P

and so attenuates the transmission of pain

impulses.  This  mode  of  action  has  been demonstrated for capsaicin cream, which is used for the alleviation of osteoarthritis and pos-herpetic neuralgia (PHN; p. 505).

A 5% lidocaine (lignocaine) patch is licensed in the  USA  for  the  treatment  of  post-herpetic neuralgia and is occasionally imported into the UK on a named-patient basis.

(see Chapter 12), and manipulation and mobi-

lization of muscles and joints are the traditional

approaches of physiotherapy (PT), osteopathy

(OT) and chiropractic, and are of undoubted

value in some patients. PT also uses the applica-

tion of heat (including short-wave diathermy),

cold, ultrasound, electrical muscle stimulation

and laser therapy. Ultrasound has been advo-

cated for soft tissue injuries, PHN, facial neuritis

and phantom limb pain, i.e. that apparently felt

in an amputated limb.

Ice packs are widely used in the early treatment

of soft tissue injuries, especially sport and similar

traumas.  The  mnemonic  ‘RICE’,  i.e.  Rest,  Ice,

Compression, Elevation, is used by first-aiders.

Care is needed not to cause ‘ice burns’ by using

a cloth between the skin and the cold pack.

Techniques recruiting endogenous inhibitory mechanisms

In addition to increasing the understanding of

how conventional analgesics act, the gate theory

has stimulated interest in alternative methods of

pain relief. The emphasis has shifted from nerve

destruction or blocking of pain conduction to

the recruitment of the body’s own inhibitory

systems. This is the principle underlying the use

of vibration, percussion, massage, and counter-

irritation   with   rubefacients.   The   cooling

produced by pain-relieving sprays may also stim-

ulate pain trigger points (see below) or, if the

cooling is sufficiently intense and prolonged, a

degree of local anaesthesia may be produced.

However, skin ‘burns’, or even frost-bite, must be

avoided.

These techniques are not always successful,

but they may provide acceptable pain relief to

some patients with otherwise intractable condi-

tions. Some authorities insist that these simple

methods should be used first, and persevered

with for several weeks, before either a maximum

effect is achieved or the approach is abandoned.

Table 7.9 lists the principal alternative methods of pain control.

Neuromodulation by electrical stimulation

The most commonly used method in this cate-

gory is transcutaneous electrical nerve stimula-

tion (TENS). This is normally used for the relief of

chronic peripheral pain, though it has also been

used to relieve acute pain, e.g. of operative inci-

sions. Electrodes are placed over the painful area,

or at the periphery of a very sensitive area, though

the optimum placing needs to be found by careful

trial  by  the  patients  themselves.  Acupuncture

sites are occasionally used (see below).

Patients wear a battery-driven pulse generator and vary the frequency, pulse width and power, normally  to  produce  a  pleasant  non-painful tingling   sensation.   Patients   usually   know whether the method is going to be successful

within 5-15 min. The pulse characteristics can be adjusted and the frequency of use may vary from three 1-h sessions daily upwards.

The conditions most likely to respond are post-

herpetic neuralgia, low back pain, phantom limb

pain and post-operative scar pain. The mode of

action is believed to be stimulation of the large,

inhibitory A-beta nerve fibres, closing the pain

gate in the dorsal horn of the spinal cord and

reducing or abolishing upward transmission of

the stimulus.

Invasive  techniques  have  also  been  used

occasionally. Electrodes connected to a minia-

ture   radio   receiver   have   been   implanted

around  peripheral  nerves,  near  the  posterior

columns  of  the  spinal  cord,  or  even  in  the

brain,  and  stimulated  by  a  patient-controlled

radio transmitter.

Although  complications  are  rare,  electrical neuromodulation is contra-indicated for psycho-

neurotic or emotionally unstable patients, and for opioid addicts. The most common problem is contact dermatitis from the electrodes.

Acupuncture

Therapeutic acupuncture, i.e. for the relief of

chronic pain rather than as an operative anaes-

thetic, is used both by practitioners who follow

the traditional Chinese system, with its over 300

sites  for  insertion  of  the  needles,  and  some

Western doctors, who may follow an empirical

system. Needles are inserted to a precise depth

and may be left in place for up to 30 min, or

rotated,  moved  up  and  down,  or  electrically

stimulated.  Western  practitioners  sometimes

insert the needles into sensitive trigger points,

i.e.  sensitive  sites  in  muscles  associated  with

fibromyalgia or myofascial pain that cause acute

pain or muscular spasm when touched.

The mode of action is hotly disputed, but may

involve interference with nerve depolarization,

stimulation of inhibitory nerve fibres, release of endorphins, enkephalins or 5-HT, or hypnotic suggestion.  The  success  of  the  treatment  is certainly influenced profoundly by cultural and psychological factors. One estimate is that about 10% of patients are responders, a further 10% are non-responders, and the remainder experience varying degrees of benefit.

Chemical nerve blocks

Regional nerve blocks

These may be:

•  Field blocks, i.e. SC injections at various sites

            around sensory nerves in the area of the

procedure.

•  Peripheral blocks involve a similar procedure,

            but  the  local  anaesthetic  is  often  injected

around  a  nerve  plexus,  e.g.  the  brachial

plexus,  an  intricate  network  of  nerves

emerging from the spinal cord at the base of

the  neck (between  the  lower  cervical  and

uppermost thoracic vertebrae) which supply

the whole arm, or the lumbosacral plexus,

which supplies the lower back and limbs.

•  Central blocks can be:

-  Epidural  (extradural,  peridural),  outside

the spinal cord between the dura mater

and the inner wall of the vertebral canal.

-  Caudal, in the lumbar or sacral regions of

the spinal cord, where it divides to form

the cauda equina.

-  Intrathecal (subarachnoid), into the CSF

            between the pia mater and the arachnoid.

With intrathecal anaesthesia the level of the

nerve block, and so the area and organs affected,

depends on the position of the patient and the

specific gravity (SG) of the anaesthetic solution.

Isobaric solutions have the same SG as the CSF

and exert their effect at the level of injection.

Hypobaric solutions are lighter than CSF and

act higher than the injection site, depending on

the positioning of the patient. Hyperbaric solu-

tions are heavier than CSF and flow towards the

bottom  of  the  spinal  cord.  They  are  used

Chemical ner ve blocks 487

primarily for operations in the genital area and on the legs.

Central and other anaesthetic blocks

Local anaesthetics

These agents (see above) may be used to produce

a reversible block of afferent nerves  at any

point up to spinal cord level (see Figure 7.3),

including the local segment of the spinal cord.

This provides temporary pain relief or anaes-

thesia  for  operations  on  patients  in  whom

general anaesthesia is unsuitable, e.g. due to

cardiac and respiratory problems or when central

nervous sedation is undesirable. However, local

anaesthetics also block other types of sensation

and motor impulses, though usually to a lesser

extent. The degree and extent of the anaes-

thetized area depends on the concentration and

volume of solution injected.

Epidural (extradural) and intrathecal opioids

are sometimes used for the relief of post-operative

and chronic pain. Injections are usually given

via a catheter located at the correct segment of

the spinal cord. The effect is on the sensory,

dorsal horn nerves. The release of substance P

and   other   neurotransmitters   from   primary

afferent  nerves  is  inhibited  by  pre-synaptic

opioid receptors, and effects on post-synaptic

receptors  reduce  activity  in  ascending  spinal

tracts. However, conduction in motor and auto-

nomic nerves is unaffected by opioids, so motor

functions and blood pressure are generally not

affected by the spinal use of opioids. The anal-

gesia produced is normally insufficient for intra-

operative  pain  so  spinal  opioids  are  used  as

adjuncts to general anaesthetics. Spinal morphine

(often  diamorphine  in  the  UK)  may  provide

8-16 h of analgesia and can give months of low-

dose analgesia in cancer patients without the

side-effects  of  oral  or  other  parenteral  use.

However, continuous infusions of morphine are

safer and technically simpler and are widely

used. Alfentanil infusions have also been used.

Such reversible nerve blocks are also used in

diagnosis and to determine which nerves are

involved in a particular pain process and the

probable result of a permanent nerve block because the production of the latter by nerve

ablation with neurolytic agents can often be

inaccurate  and  may  not  achieve  the  desired result. Levobupivacaine is used intrathecally for this purpose and is the agent of choice in the UK. The use of morphine with a low concentration of bupivacaine is synergistic.

Permanent nerve blocks

Once the correct site has been identified, an

irreversible block produced by the injection of

such  agents  as  alcohol,  phenol,  chlorocresol

or urethane may provide much longer-lasting

relief. Unfortunately, this procedure may be too

lengthy for patients who have severe intractable

pain.

Alcohol  produces  total  neurolysis,  but  the

extent  of  blockage  produced  may  be  varied

by  using  an  appropriate  concentration  of  a

phenolic   agent.   These   injections   may   be

subarachnoid, extradural, subdural, autonomic

or peripheral depending on the site of ablation

that provides satisfactory relief. Surgery or heat

(radiofrequency ablation) may also be used.

These  are  most  useful  in  treating  patients

with  well-defined  localized  pain.  As  expertise

and  knowledge  increases,  a  wider  range  of

destructive  methods,  peripheral,  central  or

autonomic, is becoming available. Because the

peripheral nerves are easily accessible, they are

often chosen as sites for destruction, although

nerve regeneration can occur with consequent

return  of  the  pain.  Alternatively,  the  sensory

root can be destroyed. This should theoretically

result  in  permanent  pain  relief,  as  axonal

regeneration  should  not  occur  if  the  nerve

fibres are interrupted proximal to the sensory

ganglion.  Unfortunately,  this  is  not  always

successful.

The procedures are potentially hazardous, and

partial loss of sensation and function, throm-

bosis, spinal cord infarction, and even death

have occurred: a skilled and experienced anaes-

thetist or neurosurgeon is required to conduct

such procedures successfully. Because of these

hazards, permanent nerve blocks are procedures

of last resort.

Injection of alcohol has sometimes been used

to destroy the pituitary gland, and so prevent

tment

hormone  release,  in  patients  who  have  wide-

spread bilateral  cancer  pain,  especially  if  the

tumour  is  hormone-dependent.  Because  the

alcohol spreads around the floor of the third

ventricle and into its cavity, it is possible that part

of the success of this technique is from direct

hypothalamic  injury.  About 70%  of  patients

benefit, more than half obtaining complete relief.

However, nerve blocks do not usually give

complete   pain   relief,   so   adjuvant   oral   or

parenteral  opioids  are  usually  still  required,

although it may be possible to use lower doses.

Neurosurgical approaches

The most common surgical procedures for pain

relief are cordotomy (see below) and insertion

of   epidural,   intrathecal   and   intraventricular

catheters for opioid or local anaesthetic delivery

directly to specific areas of the CNS. Subarach-

noid   catheter   injection   can   sometimes   be

successful in cases where conventional opioid

administration has failed to reach central opioid

receptors.

Whereas drug therapy may not completely

remove pain, an effective surgical nerve block

can do so. The main problem is that it may not

be possible to block the appropriate pathway

without impairing other nerve pathways. It is

usual to identify the nerve to be treated using

low-power radiofrequency stimulation and to

follow this with high-power pulses to ablate the

nerve.

Cordotomy involves the interruption of the

anterolateral  quadrant  of  the  spinal  cord  in

the  cervical  or  thoracic  region.  This  may  be

done percutaneously using a diathermy probe,

or  sometimes  by  open  surgery,  and  is  most

useful  in  treating  unilateral  pain  below  the

shoulders.  The  method  is  used  primarily  in

patients  who  have  a  limited  life  expectancy

(about 2 years),  because  the  development  of

alternative  nerve  pathways  often  allows  pain

to return after some time. Thus, cordotomy is

used primarily in patients with advanced, irre-

versible disease and severe intractable pain, of

whom  over  80%  obtain  complete  relief  with

such treatment.

Psychotherapy and hypnosis     intravenously, though the epidural route may

also  be  used.  When  the  patient  experiences

unacceptable pain, they press a button on the

The role of psychotherapeutic drugs has already been mentioned (see above). These behavioural approaches may be effective if there is no organic basis for the pain (i.e. it is psychogenic), if there is a minor cause but the pain is grossly aggravated by  psychological  factors  and  if  anxiety  and depression exacerbate pain significantly.

Meditation  and  relaxation  training  help

patients divert their attention away from pain

and facilitate their tolerance of it. Hypnosis

sufficient to induce a light trance is a recognized

form of treatment and some patients are able to

self-hypnotize. It may relieve pain completely in

the (highly suggestible) 20% of responders, and

be a useful adjunct to other forms of treatment

in  many  more.  Hypnosis  is  unsuitable  for

patients with psychiatric illnesses who may be

impossible to hypnotize or who behave in a

bizarre fashion under hypnosis.

Biofeedback  involves  linking  a  patient  to

equipment that monitors and displays parame-

ters such as heart rate or blood pressure (which

are increased by pain) or muscle tension (which

may cause pain). The patient is taught relaxation

techniques  and  sees  how  this  modifies  their

physiological responses and reduces their pain

level; thus they learn to control their symptoms

appropriately.

Syringe drivers and patient-controlled analgesia

Definition

This is a technique for continuous, regular or

intermittent dosing with opioids, and occasion-

ally with epidural local anaesthetics, according to the patient’s perception of their own needs

and  pain  severity.  The  method  is  used  for controlling  acute  pain,  e.g.  post-operatively, following trauma and in burns patients.

The equipment usually comprises a micro-

processor-driven  syringe  containing  the  drug

solution, which is administered parenterally via

a catheter. This may be done subcutaneously or

control unit and a predetermined dose of drug is administered.

Advantages

The advantages of PCA are:

•           Patients are in control of their pain, not vice

versa,  and  feel  more  secure.  This  alone

improves the quality of analgesia obtained.

•           The blood level is maintained more closely

within the therapeutic range than can be

achieved with injections given on demand.

This should improve analgesia and minimize

side-effects, but PCA has to be stopped some-

times due to severe nausea and other side-

effects. Unacceptable side-effects may be due

to overdosing by the patient (see below).

•           Doses can readily be titrated to cope with

wide variations in pain severity and patient

needs.

•           There is minimal delay between the percep-

tion of intolerable pain and obtaining a dose

of analgesic. There is also less demand on

nursing time and pharmacy provision.

•           The system is very versatile and can some-

times   be   used   in   a   domiciliary   setting.

However, some patients tend to overdose and

a syringe driver delivering a SC opioid at a

constant rate, which is not patient-controlled,

may occasionally be used in palliative care.

Disadvantages and limitations

The following points are additional to those

usually associated with opioid or local anaes-

thetic use:

•  Highly trained staff are required to set up the

            equipment and supervise the patient.

•  The method is only suitable for maintenance

analgesia, not for dose titration. The patient’s needs should be stable and established clearly, or readily estimated, and a suitable loading dose given before starting PCA.

•  Some patients reject the technique.

•  A patient’s understanding of how to use the

            equipment may be limited by:

-  Extreme age.

-  Language or comprehension problems.

-  Sedation or confusion.

•  Poorly   controlled   blood   pressure   may

            compromise perfusion of a SC injection site

and the IV route has to be used.

•  Changes  in  renal  or  hepatic  function  may

            cause  significant  variation  in  the  plasma

concentrations of drug, as for all routes of

administration.

Modes of use

Two PCA arrangements are possible:

•  Patient-controlled analgesia only.

•  Continuous   background   infusion   plus   a

            patient-controlled bolus analgesic.

PCA only

This technique is best suited to acute analgesia. If excessive demand is made and the patient

becomes sedated, this is a self-regulating situa-

tion, because the patient then makes less demand for analgesia until the sedation wears off.

Continuous background infusion plus PCA

This is particularly appropriate for chronic pain relief, e.g. severely burned patients, who often need opioids for long periods. It can be given as 30-50% of their predetermined hourly dose as a background infusion, the PCA function being used for breakthrough pain.

Continuous background infusion only

Strictly, this is not PCA, because there is no

control  by  the  patient.  It  is  more  useful  in

managing chronic pain, especially in patients

who have stable analgesic needs. Further, they

may  be  unable  to  manage  the  equipment

correctly because they are confused or have little

understanding of the equipment and the princi-

ples  of  use.  It  is  less  suitable  for  acute  pain

because  of  the  inability  to  manage  break-

through pain, the risk of excessive sedation and

other adverse reactions.

tment

Technical and clinical aspects

Technical   and   clinical   points   include   the following:

•           The  bolus  dose  delivered  on  demand  in

PCA must be adequate, but must not cause

unacceptable side-effects.

•           The time over which the dose is injected

following   patient   triggering   is   adjusted

according to the route used. Thus, for IM or

IV injections the time may need to be length-

ened to 5 min to avoid stinging or inadequate

clearance from the site. Also the ‘lock-out

interval’,  i.e.  the  time  after  the  end  of  a

dose during which another bolus cannot be

obtained, may need to be lengthened. Alter-

natively, the solution concentration may be

increased so that a smaller volume is injected.

•           The lock-out interval should be long enough

to avoid adverse drug reactions. It is usually

5-8 min.

•           The  maximum  dose  allowed  in  a  given

period   should   be   controlled,   e.g.  30 mg

morphine in 4 h.

•           Inadequate analgesia. If usage is:

-  Two or less doses/hour, counsel the patient

about fears of opioid use, etc. and advise more frequent use.

-  More than three bolus doses/hour, increase

            bolus concentration.

-  Review other possibilities, e.g. pain is not

            opioid-responsive or may be a new com-

plication  of  the  disease  and/or  surgery.

•           Nausea and vomiting:

-  Use anti-emetics (see Chapter 3, p. 107),

            e.g. rectal prochlorperazine or a 5-HT3 antag-

onist. Transdermal hyoscine (scopolamine)

may be used occasionally in patients under

60 years if injections are undesirable. This is not suitable in the elderly because it may cause urinary retention and confusion.

-  Decrease  bolus  volume  or  increase  the

duration of delivery of each bolus, to give lower peak plasma concentrations.

-  Change the route, for example to IM, or

possibly the opioid.

•           Urinary retention: relieve with indwelling or

intermittent catheterization.

•           Pruritus: this is not usually a problem with  IV PCA, but may be with spinal or epidural dosing.

-  Change the route or opioid.

-  Use a non-sedating antihistamine.

ches, migraine and facial pain    491

-  Use  low-dose  naloxone  if  the  pruritis  is

            intractable, but care is required because the

analgesia may be reversed if the naloxone dose is too large.

Some common pain situations

The application of the principles discussed above is illustrated by discussing the management of some common pain situations.

Headache, migraine and facial pain

Epidemiology and aetiology

Headache is probably the most common of all

the pain syndromes, and about 80-90% of the

population have at least one headache each year.

Of   these,   about 15%   experience   recurrent

episodes of all kinds that interfere with their

normal daily activities, and it is estimated that headaches  cause  an  annual  loss  of  about  70 million working days in the UK.

Peak GP consulting rates occur in the 10- to 40-year age group, the female : male ratio being about 2.5 : 1 overall. The principal causes of

chronic daily headache are given in Table 7.10. There  are  estimated  to  be  over 5   million

migraine sufferers in the UK, though at least half have mild to moderate pain and do not consult their doctors. Pure tension-type headache is an unusual cause for a visit to a GP.

Analgesic  abuse  is  an  important  cause  of headache, recognition of which requires a high index of suspicion.

The  main  concern  of  pharmacists  when  a

client requests advice is to distinguish between

benign headaches and those requiring medical

intervention (Table 7.11). Headache accompa-

nied by the following features requires referral to

the patient’s GP.

•  New pain of sudden onset, especially in those

            aged 60 or over.

•  A marked change in the character or timing of

            recurrent headaches.

•  Fever

•  Neck stiffness.

•  Impairment of cognition, motor function or

            vision lasting for more than 24 hours, e.g.

-  Understanding or reasoning.

-  Abnormality of gait, posture or writing.

-  Limb weakness or clumsiness.

tment

-  Eye problems, e.g. flashing lights, jagged

            lines, blurred vision, loss of part of the

visual field (scotoma).

-  Disturbance lasting    24 h is defined as a

transient   ischaemic   attack  (TIA;   see

Chapter 4) and still requires referral, espe-

cially  in  those  already  taking  low-dose

aspirin.

-  Sensitivity to touch in the area of the pain

            (may be temporal arteritis; see Chapter 12).

-  A family history of migraine.

Classification

The International Headache Society has issued

modified guidelines for classifying chronic daily

headache (Table 7.11). Despite this formidable

list, most headaches are benign. Only the four    tion (provided that this has been confirmed

most common types are discussed below, the

pain patterns associated with these and other

types being illustrated in Figure 7.5.

Tension-type headache

Clinical features

This common form of headache may arise from

sustained  muscle  contraction  in  the  cervical

(neck) region or scalp, or be psychogenic in

origin (e.g.  caused  by  stress  or  depression).

Headaches may be episodic, i.e. occurring on less

than 15 days/month and having no persistent

symptoms. However, they are often chronic, e.g.

on more than 15 days/month for more than

6 months, present at similar times each day,

every morning or evening, or on the same days each week (Table 7.12). The pain is:

•  Mild to moderate.

•  Typically has a bilateral ‘hatband’ or more

            generalized distribution (Figure 7.5(a)).

•  Non-throbbing,   no   burning   or   pressure

sensations.

•  Not aggravated by head movement.

There are few abnormal signs, but the scalp and neck muscles may be tender. Bilateral pain, absence of vomiting and tendency to be chronic distinguish it from migraine (see Table 7.12), which is episodic by definition.

Management and pharmacotherapy

Treatment of this condition is often unsatisfac-

tory because no specific pathology can be iden-

tified and it may be difficult or impossible to

modify  employment,  social  and  personality trigger  factors.  Management  and  symptomatic treatment involve:

•  Possible extensive investigations to eliminate

            serious  pathology (e.g.  cerebral  abscess  or

cancer, stroke), to reassure the patient.

•  Avoidance   of   any   identifiable   causes,   if

possible.

•  Physical and psychological treatments may

            help, e.g. relaxation therapy, psychotherapy,

            hypnotherapy, ice packs or cervical manipula-

as a safe procedure in that patient).

•           Analgesics appropriate to severity, e.g. para-

cetamol (acetaminophen), aspirin (in the over-

16s, if tolerated) or combinations of these

            with  codeine  or  dihydrocodeine,  but  these

            may be abused. Combinations with dextro-

            propoxyphene are no longer used in the UK.

• NSAIDs. Diclofenac, ibuprofen  and naproxen,

sometimes   flurbiprofen  or   tolfenamic   acid (unlicensed indication).

•           Antidepressants (see Chapter 6) if indicated.

Low-dose   amitriptyline,  10-25 mg   nightly,

increasing up to 75 mg daily if required is

widely  used (unlicensed  indication).  Anxi-

olytics  are  undesirable  because  they  may

lead to habituation. Treatment is more effec-

tive if patients present soon after the onset of

symptoms.  Antidepressants  are  withdrawn

gradually  after  about 6  months’  sustained

improvement.

•           It has recently been shown that performing a

brain scan in people who suffer chronic daily

headache relieved anxiety in the short term

and  reduced  the  use  of  medical  resources

significantly, with an associated reduction in

costs.

Analgesic abuse headache

This  may  accompany  any  other  form  of

headache. Because it occurs daily it is frequently

associated with tension headaches. The normal

pattern is that a patient complaining of headache

will manage well initially by self-medicating with

simple analgesics as the need arises. There may

then  be  a  progression  to  regular  daily  simple

analgesic  use,  seeking  advice  for ‘something

stronger’, consulting their doctor and regular use

of a compound analgesic (e.g. co-codamol or co-

dydramol  in  the  UK),  even  a  potent  opioid,

without obtaining satisfactory relief. This adds

the side-effects of the analgesic, i.e. any of the

side-effects of opioids (see above), to the effects

of the headache. Misuse of antimigraine drugs

can cause similar problems. Opioids should not

be required in tension-type headache.

The correct course of action is to stop the daily

analgesic medication. This may cause rebound

exacerbation  of  headache  for 1-2 weeks  and            •           Migraine without aura (common migraine).

withdrawal symptoms may need to be treated with   anti-emetics   and   sedatives.   Cognitive therapy (see Chapter 6) usually helps, but failure to   improve   subsequently   should   prompt   a neurological or psychiatric investigation.

Migraine

Definitions

The International Headache Society has devel-

oped the following criteria (ICHD-II; 2004) with

the intention of simplifying the diagnosis of

migraine and defining those patients who are

likely to respond to different treatments. The

character of the headache should not be explic-

able by possible CNS damage. Two main types of

migraine are defined:

Repeated headache attacks, lasting for 4-72 h, with   the   following   features:   recurrent

moderate   to   severe,   throbbing   headache, usually  unilateral  but  sometimes  bilateral, accompanied by intolerance of light or noise, nausea, and sometimes vomiting. The pain should comply with at least two of:

(a)        Normal physical examination.

(b)        No   other   reasonable   cause   for   the

headache.

(c)        At least two of:

-  Unilateral pain.

-  Throbbing pain.

-  Aggravation   of   pain   with   head

            movement.

-  Moderate to severe intensity of pain.

(d)        At least one of:

-  Nausea or vomiting.

-  Photophobia and sonophobia.

•  Migraine with aura (classical migraine). Two

            or more headache attacks that comply with

three of the following characteristics:

(e)  One   or   more   fully   reversible   aura

symptoms indicating cerebral cortical or brainstem dysfunction.

(f)  At least one aura symptom developing

            over more than 4 min, or two or more

symptoms occurring in succession.

(g)  No aura symptom should last for more

than 1 h.

(h)  Headache follows aura with a pain-free

            interval of less than 1 h.

‘Borderline migraine’ is often diagnosed when one of the criteria is not met.

The pain scale for migraine (migraine index)

is a product of duration and intensity, where

intensity is graded from 0 (none) to 3 (severe).

The aura consists of warning of an impending

attack, usually with visual symptoms, but audi-

tory,  smell  and  motor  limb  disturbances  may

also  occur,  lasting 4-60 min  (see  below).  The

headache usually follows within 60 min, or may

accompany these symptoms.

Epidemiology

For epidemiological purposes, migraine patients (migraineurs) are defined as having had at least five attacks without aura, or two with aura.

Migraine  is  common  worldwide,  reported

variously  as  affecting 5-25%  of  women  and

2-20% of men. This spread is due to different

definitions and trial methods. The highest inci-

dence  of  migraine  without  aura  is  at 10-11

years  of  age  in  males  and 14-17 years  in

females. That of migraine with aura is at about

5 years  in  males  and  about  12-13  years  in

females. There is then a slow increase in preva-

lence  in  women  up  to  age  40  years,  but  the

prevalence of all forms declines after the age of

45-50. Onset after age 60 of an exceptionally

severe  headache  unlike  any  in  a  patient’s

previous experience is very unusual: this should

raise the possibility of significant pathology, e.g.

subarachnoid haemorrhage or temporal arteritis

(see Chapter 12). There is a genetic predisposi-

tion in some patients, but no simple Mendelian

inheritance.

tment

Some  10%  of  the  population  are  ‘active

migraineurs’, 5% have 18 or more migraine days annually; 1% have one each day or week. The average duration of an attack is about 24 h, but may be 2-3 days in 20% of patients.

Aetiology and pathology

The aetiology has yet to be elucidated in humans.

The traditional view that symptoms are simply

the result of alterations in cerebral blood flow is

probably incorrect. The haemodynamic changes

observed during all phases of the attack cannot

alone account for the symptoms. Rather, the

vascular changes reflect cranial disturbance, e.g.

vasodilatation  of  cranial  or  meningeal  blood

vessels, or oedema.

The anatomy of the cerebral circulation is

complex  with  a  high  degree  of  redundancy, probably because:

•  There is an absolute requirement for a contin-

            uous supply of glucose and oxygen.

•  The  brain  is  highly  active  metabolically,

            consuming about 20% of total blood oxygen at

rest.

•  Even a brief interruption of the blood supply

            may cause unconsciousness; 1-2 min depriva-

tion impairs brain cell activity and 4-5 min causes permanent damage.

There is a complete circle of interconnecting

arteries at the base of the brain (the circle of

Willis), derived from the four main ascending

arteries, two vertebral, two internal carotid. This

minimizes the risk of ischaemia, e.g. due to a

small clot, because the circle can be supplied by

any of its ascending arteries. The cerebral veins

have no valves, have very thin walls, and no

muscle  layer.  Thus  they  cannot  be  causal  in

migraine  but  can  account  for  the  pounding

nature of the headache, reflecting systolic heart-

beats. There are also large venous sinuses that

drain  pooled  venous  blood  from  the  brain

and skull. Numerous anastomoses connect the

arterial circle and this venous system.

There are several pathophysiological theories

of migraine symptomatology, reflecting current

uncertainties.   Migraineurs   probably   have   a

genetically determined, or congenital, reduced

CNS excitation threshold, i.e. they fall into an

intermediate   group   between   epilepsy   and   familial hemiplegic migraine), and paralysis of

normality, but a genetic origin for this has not

been demonstrated. However, mutations have

been identified in genes for the voltage-gated

calcium and sodium channels and for the alpha2

subunit of the Na÷/K÷  pump in some types of

familial migraine.

Thus the concept that vascular changes may

account for the prodrome (see below), and that

the subsequent headache is caused by vasodi-

latation is no longer tenable. However, opening

of arteriovenous anastomoses may be expected

to expose the cerebral veins to arterial pressures

for which they are not designed, and this could

explain the pounding nature of the headache,

because the thin-walled veins would be exposed

to the systolic pressure with every heartbeat.

They would then expand, putting pressure on

the brain, and relax during diastole. Further, it is

known that stimulation of cranial nerves, espe-

cially the trigeminal, causes neurogenic plasma

extravasation in the dura mater and the release

of pro-inflammatory mediators.

Dilatation  of  the  carotid  arterial  circulation

causes  stretching  of  arterial  walls  and  so

thickening of the meninges, producing pain.

Serotonin (5-HT), released by vascular nerves or platelets, is clearly implicated in the patho-

genesis  of  migraine.  The  recent  advances  in treatment have been derived from the observa-

tion that injection of 5-HT can abort migraine attacks, but causes substantial side-effects. Addi-

tionally, the introduction of an NSAID that is a potent inhibitor of PG and LT B4  synthesis has also  focused  attention  on  the  pathogenetic

role of these eicosanoids. Nitric oxide is also

implicated in CNS vasodilatation.

Clinical features

Different patterns occur in individual sufferers,

ranging  from  occasional  headaches  that  are

almost indistinguishable from tension headache

to frequent disabling episodes (Figure 7.4(d-j)).

Symptoms may mimic those of TIAs (which

resemble a stroke, but the patient recovers within

24 h)  and  are  clearly  associated  with  cerebral ischaemia. There may be dizziness or partial or complete blindness (basilar migraine), partial or

complete   hemiparesis (one-sided   paralysis,

the eye muscles (ophthalmoplegic migraine) or

facial muscles. It is important to distinguish these

symptoms,  which  arise  gradually,  from  those

of thromboembolic TIAs, which are usually of

sudden onset, because both treatment and prog-

nosis are very different for the two conditions.

These atypical migraines are uncommon but are

important  because  they  are  associated  with

ischaemia; the 5-HT1  agonists, because they are

potent vasoconstrictors, are contra-indicated for

their treatment. These forms of migraine are now

believed  to  be  due  to  genetically  determined

abnormalities of the cerebral calcium channels

and will not be discussed further here. However,

the possibility is raised that this is the inherited

basis of some forms of migraine.

Migraine is known to be associated with an increased risk of ischaemic stroke, and a large European  study  has  found  that  this  risk  is increased   threefold   in   young   women   with migraine. Up to 40% of strokes in this study

developed from a migraine attack, and factors such as oral contraceptive use, hypertension and smoking further increased the risk.

Common migraine

This is the usual form of migraine, affecting

about 75% of sufferers. The symptoms resemble

those of classical migraine, but tend to comprise

only headache, malaise and nausea. Occasion-

ally, aura occurs without other symptoms. There

may  be  considerable  difficulty  in  distinguish-

ing  between  common  migraine  and  tension

headache. Both syndromes are very common

and so may be concurrent, or tension headache

may exacerbate common migraine at some stage.

Migraine with aura

Triggers for attacks are listed in Table 7.12. There may be three distinct phases to an attack:

•  Feelings of well-being, yawning, food rejec-

            tions or cravings, etc., which may last for up

to 24 h (the prodrome).

•  These are followed by an aura; and

•  Finally the headache and associated features

occur (Table 7.13).

The aura develops over 5-20 min and lasts for

4-60 min. The aura is usually visual, including

spots (scotomas), blurred vision, flashing lights and  jagged  lines. ‘Pins  and  needles’,  facial tingling, speech difficulties and unusual smells may also occur, and there may be nausea.

This is followed by a severe throbbing headache

that may start unilaterally and be localized, but

may later become more general. Nausea increases

and vomiting usually follows. Sufferers are irri-

table, photophobic and sonophobic and usually

retreat to a dark, quiet bedroom. The attack lasts

from hours to days and often terminates with

sleep, often followed by a longish, variable pain-

free period. Because attacks are associated with

smooth muscle inhibition there is often urinary

retention followed by a delayed diuresis towards

the end of an attack.

Investigation

A  typical  history  and  a  normal  neurological examination are usually conclusive. The pres-

ence of atypical features should prompt further examination to exclude meningitis, subarach-

noid haemorrhage, TIAs, partial epilepsy, stroke, a  brain  tumour  or  other  serious  pathology. Patients are normal between attacks.

tment

The possible involvement of all of the factors listed in Table 7.12 should be assessed, possibly with a patient diary.

Management

Apart   from   the   mildest   form   of   common

migraine,  this  requires  pharmacotherapy,  but

some general measures are important, as follows:

•  Effective identification and treatment of any

            associated diseases.

•  Counselling:

-  For   identification   and   avoidance   of

            possible trigger factors (Table 7.12), espe-

cially changing or stopping a combined

oral contraceptive in young women.

-  Strong reassurance that the condition is

benign, because many patients think that

they have a brain tumour or are going

‘mad’.

-  The importance of prompt treatment at

            the first sign of an impending attack.

-  Rest, usually in a quiet, darkened room.

The principles of treatment of are outlined in

Table 7.13.

Acute attacks   icantly, not least because patients may regard it

as treatment failure. Recurrence occurs in about

General considerations

35% of responders, for unknown reasons.

Gastric stasis and generally poor gut peristalsis

develops during an attack, so drug absorption

from the gut may be compromized with all drugs

in migraine, especially with conventional tablets

and capsules. Absorption is improved by using

effervescent oral formulations and by using an

anti-emetic and prokinetic drug, e.g. metoclo-

pramide or domperidone, 30 min before an anal-

gesic if possible, or simultaneously. Routes of

administration that avoid first-pass metabolism,

e.g. buccal dosage forms (sublingual tablets and

oral aerosols), nasal sprays and injections, are

pharmacokinetically  preferable,  because  many

of the drugs used undergo extensive first-pass

metabolism.   Suppositories   are   useful   if   the

patient   is   nauseated   and   vomiting.   Patient

dislike of suppositories and repeated injections

may be outweighed by the rapidity and extent of

benefit derived from a product.

It may take experimentation over a few attacks

to establish the optimum drug, dosage and route

of administration. Patients do not always require

the same treatment: mild attacks may respond to

simple analgesics, while severe ones in the same

patient may require specific treatment. The rela-

tive responses to different drugs may be different

in different attacks, but the response to specific

treatment seems to be more consistent than that

to simple analgesics.

Opioid analgesics should be avoided, because they  are  ineffective,  exacerbate  nausea  and vomiting and, if taken regularly for attacks, may cause analgesic overuse headache.

Drugs should not be used during the aura,

which is unresponsive to treatment and may not

always be followed by headache. However, if it is

known that headache always supervenes, simple

analgesics should be taken before the headache

is established.

Specific anti-migraine drugs, the 5-HT1 agonists (triptans),  should  be  reserved  for  established headache, on grounds of toxicity, in patients who find simple analgesics and anti-emetics ineffec-

tive.  Although  all  triptans  are  effective,  the response  varies  between  patients,  as  do  the incidence and severity of side-effects.

Headache  recurrence  following  response  to

treatment limits the benefits of treatment signif-

The ‘therapeutic gain’ (TG) is the response rate to treatment minus the response to placebo or comparator, and is used below. However, trial results are difficult to compare due to different end-points, time of measurement of the response, use of ‘escape medication’ and comparison in only one attack or over several attacks.

There are two approaches to management: the

traditional  stepped-care  model (ladder),  i.e.

simple analgesic to compound analgesic to a

triptan (see below) or ergotamine, or to decide on

the appropriate treatment for a particular patient

depending on their symptoms, the stratified-

care model. The latter is gaining ground with

the  introduction  of  the  triptans,  which  are

effective and less toxic than ergotamine.

Simple and compound analgesics

These have been discussed above and in Chapter

12. Adequate doses should be used, i.e. aspirin

600-900 mg  every  4-6 h,  provided  that  it  is

tolerated and not contra-indicated, or paracet-

amol (acetaminophen) 1000 mg every 4-6 h (to a

maximum of 4 g daily). Effervescent aspirin is pre-

ferred and is sometimes as effective as sumatriptan.

Non-steroidal anti-inflammatory drugs

Tolfenamic acid is an NSAID that is specifically

licensed for the treatment of acute migraine

attacks. It has the general properties and side-

effects of NSAIDs and may also cause dysuria

(mostly in men), tremor, euphoria and fatigue,

but it seems to be well tolerated. Tolfenamic acid

is reported to be as effective as the 5-HT1 agonists

and is formulated as a tablet that disintegrates

rapidly  and  has  good  bioavailability.  Other

NSAIDs that are licensed for migraine treatment

are ibuprofen (1.2-1.8 g daily in divided doses),

diclofenac, flurbiprofen and naproxen, at equiva-

lent dosage. Flurbiprofen and diclofenac are also

available as suppositories, which are useful if the

patient is vomiting.

Serotonin agonists (5-HT1 agonists, ‘triptans’)

All of these are effective in relieving migraine

headaches, but they are not suitable for prophy-

laxis. Unlike simple analgesics and NSAIDs, there

is evidence that they are most effective when

used at the first signs of the headache and not during the aura.

The 5-HT1B/1D-receptor agonists licensed in the

UK are sumatriptan and the newer almotriptan,

eletriptan, frovatriptan, naratriptan, rizatriptan and

zolmitriptan. These drugs act highly selectively

on specific subsets of 5-HT1  receptors, 5-HT1D

and, to a lesser extent, 5-HT1B. They have a much

lower affinity for other 5-HT1  receptors and are

inactive at 5-HT2, 5-HT3, adrenergic, dopamin-

ergic, muscarinic and benzodiazepine receptors.

The role of 5-HT1D  and 5-HT1B  receptors is uncertain. They are believed to be pre-synaptic ‘autoreceptors’  that  control  the  release  of

neurotransmitters at the nerve terminal.

Because of their vasoconstrictor action, 5-HT1

agonists are likely to aggravate any condition

caused by arterial blockage, spasm or inflamma-

tion and are contra-indicated in such situations,

e.g. IHD, previous MI, atypical angina, uncon-

trolled or severe hypertension and intermittent

claudication (see Chapter 4), temporal arteritis

and Raynaud’s disease (see Chapter 12).

Non-responders.   Zolmitriptan   is   the   only

antimigraine drug that can be repeated for the

same attack by those who fail to respond to a first

dose; this should be not less than 2 h after the

first dose. For all other triptans non-responders

should not repeat the dose. This also minimizes

the risk of analgesic-induced headache. Non-

responders will not gain any benefit from a

second dose of the same or any other triptan,

because this will increase or prolong vasocon-

striction and the risk of ischaemia and throm-

boembolic stroke, without relieving the migraine.

Further, the maximum dose of all triptans that

may be used within 24 h is limited.

However, the same drug, given by a different

route or in a higher dose, may be successful in

another attack. Non-responders are more likely

to benefit from a change to a different drug class.

If a small dose has proved to be inadequate, a

larger dose may help in a subsequent attack.

Partial responders.   If an attack responds to a

first dose only one repeat dose of a triptan should

be used for the same attack if there is inadequate

relief or in those in whom the headache remits

tment

and  recurs.  The  precise  details  vary  with  the drug  and  dosage  form:  the  BNF  and  patient information leaflets should be consulted.

Although more expensive than previous treat-

ments, the cost-benefit ratio for triptans is prob-

ably no worse than for older drugs. There is less time off work and a better quality of life.

Sumatriptan is poorly absorbed from the tablets

(14% bioavailability), taking 2 h to reach a peak

plasma  concentration  which  is 75%  of  that

obtained  by  SC  injection.  The  latter  is  the

preferred mode of use, which avoids first-pass

metabolism. An autoinjector device has been

produced (peak plasma concentration at 12 min,

97%  bioavailability;  TG  in 51%  of  patients

initially, 71% at 1 h).

The oral route is not suitable if there is nausea

and vomiting, and it clearly gives slower relief

than the injection. However, some patients who

do not wish to inject find it adequately effective

(TG 33%, 58% of patients, 100-mg dose). Alter-

natively, a nasal spray is available for those not

wishing to inject or who are vomiting and gives

rapid absorption, but the peak plasma concen-

tration (at 1-1.5 h) is only about 20% of that

from the injection, partly due to pre-systemic

metabolism. Some patients find the nasal spray

inconvenient and irritant: it is also expensive.

The terminal elimination half-life is about 2 h.

Sumatriptan may also help in the management of cluster headache (see below).

Side-effects  include  drowsiness,  a  transient

increase or reduction in blood pressure, brady-

cardia  or  tachycardia  and,  occasionally,  fits.

However, these side-effects are usually mild and

fairly brief. Caution is required in renal impair-

ment and, following reports of chest pain and

coronary  vasoconstriction,  they  are  contra-

indicated in patients with ischaemic syndromes

(see above).

Interactions.   Because of the similar modes of

action, sumatriptan must not be used with ergot-

amine: nor within 24 h of stopping ergotamine,

which must not be used within 6 h of taking

sumatriptan. Use with MAOIs, SSRIs and lithium

increases the risk of CNS toxicity, and use of

sumatriptan with these must be avoided.

Second-generation triptans have better bio-

availability, greater potency at active receptor sites  and  longer  half-lives  than  sumatriptan.      of ergotamine, despite its complex actions and

Because they are more lipophilic, CNS penetra-

tion is also improved and they reduce neuroex-

citability, especially in the trigeminal ganglion.

Naratriptan is similarly effective to sumatriptan, and is available as tablets. Used at the lower dose (2.5 mg)  it  may  have  fewer  side-effects  than sumatriptan and has similar interactions, but the TG is also lower. At the higher dose (5 mg) it resembles sumatriptan. Because it has a longer duration of action it may be useful in patients who regularly suffer from relapses.

Zolmitriptan is another recent introduction in

tablet form, designed to be a potent 5-HT1 partial

agonist  and  more  lipophilic than  sumatriptan,

giving better CNS penetration. It has a slightly

higher TG than sumatriptan but a higher inci-

dence of adverse reactions. It is also available as

orodispersible tablets and as a nasal spray. It is not

clear whether the orodispersible tablets are supe-

rior to normal ones and are clearly unsuitable if

they cause a dry mouth.

Rizatriptan  is  available  as  tablets  and  ‘melt’

wafers that are dissolved on the tongue and swal-

lowed. It is consistently effective and well toler-

ated, and is cost-effective. Rizatriptan metabolism

is reduced by propranolol. Patients taking propra-

nolol must not take rizatriptan within 2 h of a dose

of propranolol and should take only the minimum

dose of rizatriptan.

Frovatriptan has the longest half-life of the 5-

HT1  agonists and may be particularly useful in menstrual migraine. It is somewhat less effective, and cheaper, than other triptans.

Possible  side-effects  with  all  these  agents include drowsiness and transient hypertension; dry mouth, unpleasant sensations in any part of the body, and muscle pain and weakness may also occur. Absolute contra-indications for this entire group are given above.

Arrhythmias   due   to   accessory   cardiac

conduction pathways are an additional contra-

indication  for  zolmitriptan.  It  is  also  contra-

indicated in those who have had a TIA or a stroke.

There is inadequate information on their use in the elderly.

Second-line drugs

These   include   ergotamine  and   isometheptene

mucate. Low cost has ensured the continued use

long list of side-effects. The BNF states that both of these are “less suitable for prescribing”, and their use is declining.

Ergotamine tartrate is the oldest antimigraine

drug,  with  ergot  preparations  having  been  in

use for at least 2000 years. The isolation and

pharmacological characterization of the ergot

alkaloids in the mid-20th century (pure ergota-

mine was isolated by Stoll in 1920) was a major

event in the development of modern pharma-

cology. It is an amino acid alkaloid derived from

the lysergic acid nucleus. Preparations contain

about 40% of the relatively inactive ergotami-

nine, due to spontaneous epimerization. Because

of its long history, well-conducted controlled

trials have not been carried out, so there is no

objective evidence for its level of benefit. Actions

of ergotamine include:

•  At 5-HT1 and 5-HT2 receptors:

-  Partial agonist in many blood vessels (it is

            a powerful vasoconstrictor).

-  Mixed agonist/antagonist actions in the

            CNS.

-  A non-selective 5-HT antagonist in many

            smooth muscles.

•  At alpha-adrenergic receptors:

-  Partial agonist/antagonist in blood vessels

            and smooth muscles, promoting uterine

contraction and vasoconstriction.

-  Antagonist in the central and peripheral

            nervous systems.

•  At dopaminergic D2 receptors:

-  Powerful  stimulation  of  the  CTZ,  espe-

            cially with injections, causes nausea and

vomiting.

While the vasoconstrictive effects of ergotamine

contribute to its benefit in migraine, these non-

selective, wide-ranging actions mean that it also

has a formidable array of side-effects. These, and

the risk of habituation, which limits its use to not

more than twice per month, have contributed to

its increasingly rare use. It is less effective than

sumatriptan  and  probably  also  less  so  than

naproxen.

Ergotamine  is available as compound tablets

with  cyclizine,  as  an  anti-emetic,  and  with

caffeine, allegedly to promote absorption. The

benefit from caffeine is debatable and it may even cause analgesic headache (see above). Oral

bioavailability is poor, about 1-3%, with exten-

sive   first-pass   metabolism   and   large   inter-

individual variations in absorption. The use of a

buccal aerosol or sublingual tablets may provide

improved absorption, but the aerosol has a very

nauseating  taste.  Suppositories  give  about  a

20-fold increase in peak plasma concentration,

and this is probably the preferred route. Phar-

macokinetic  data  are  rather  imprecise  due  to

assay  difficulties (peak  plasma  concentrations

are only about 10-500 pg/mL).

Because ergotamine binds irreversibly to recep-

tors it has a longer duration of action than the

triptans. This may be beneficial in patients with

lengthy  attacks  or  those  in  whom  headache

recurs frequently after triptans. However, there are

restrictions on dose frequency because of its strong

peripheral vasoconstricting action, i.e. not more

than four tablets in 24 h, not to be repeated within

4 days, and not more than eight tablets/week.

Patients have lost fingers because of failure by GPs and pharmacists to adhere to these dosage restrictions,  or  to  recognize  inappropriate

prescribed dosage.

Although injections of ergotamine have been

used, they usually contain a mixture of ergot alka-

loids. They therefore have numerous side-effects

and, in addition, are highly emetogenic (20% of

tment

patients) and are often poorly tolerated. The side-

effects, contra-indications, etc. of ergotamine are given in Table 7.14.

Dihydroergotamine  preparations   have   been

withdrawn in theUKbut the nasal spray is

widely used inNorth Americaand continental

Europe.

Isometheptene, an indirect sympathomimetic

agent, is marketed in theUKcombined with

paracetamol (acetaminophen). It may cause circu-

latory disturbances, dizziness, rashes and, rarely,

blood   dyscrasias.   Its   numerous   side-effects,

cautions, contra-indications and interactions are

considered to outweigh its clinical usefulness.

Prophylactic pharmacotherapy

This may not be necessary if attacks are infre-

quent or of mild to moderate severity and if this

situation is well tolerated by the patient and is

well controlled by acute drug usage. However,

opinion differs as to when prophylaxis should be

considered. In theUK, it is often recommended if

there is more than two moderate to severe attacks

a month,  if  they  suffer  increasing  headache

frequency or significant disability despite suitable

treatment and if they cannot take appropriate

migraine treatment. In theUSAthe borderline is

drawn at three or more attacks per month. Much

depends on what level of pain and disruption to marked  drowsiness  initially,  so  the  minimum

their lives, balanced against side-effects, patients are able to tolerate.

The drugs used comprise:

•  Beta-blockers: propranolol, metoprolol (possibly

            atenolol, nadolol, timolol).

•           5-HT   antagonists:   pizotifen    (pizotyline),

methysergide.

•  Tricyclic   antidepressants:   e.g.   amitriptyline

            (whether   the   patient   shows   depressive

symptoms or not; unlicensed indication).

•  Sodium   valproate   and   CCBs       (unlicensed

indication).

The modes of action of these drugs in migraine are  unclear,  especially  because  the  effects  of other   beta-blockers   and   anticonvulsants   are similar to those of placebo.

The use of methysergide for resistant cases is

restricted  to  hospital  consultants  in  the UK,

because of its toxicity, especially retroperitoneal

fibrosis.

All of these drugs are, at most, 50% effective in

only about half of the patients, but one can

usually  be  found  useful  by  trial  and  error.

Further, it is difficult to be sure of the true

benefit because there is a large placebo effect, up

to about 40%. Each of the drugs needs to be tried

for at least 2-3 months before it is discarded as

ineffective. If the patient responds, treatment

should continue, with 6-monthly medication

reviews: complete remission is common.

It has also been suggested that trials of high-

dose riboflavin or NSAIDs might be worthwhile.

If NSAIDs are used (this is an unlicensed indica-

tion), the drug selected would have to be rela-

tively free of side-effects (e.g. ibuprofen) because

long-term use is involved. As usual, there needs

to be a balance between benefit and harms.

Beta-blockers, usually propranolol, are usually regarded as the drugs of choice for migraine

prophylaxis. Their utility is limited by their side-

effects (see Chapter 4) and, in the past, by their interaction with ergotamine, because both drugs cause peripheral vasoconstriction. This interac-

tion is less of a problem if one of the newer 5-HT1 agonists is being used to treat attacks.

Pizotifen  (pizotyline)  is  probably  the  second

choice, but good evidence of benefit is lacking.

This also has antihistaminic properties and causes

dose should be taken at night and increased grad-

ually, as tolerance is achieved, to the minimum dose  that  gives  satisfactory  control.  Increased appetite and weight gain often make it unaccept-

able,  especially  to  women.  Its  weak  antimus-

carinic properties may cause urinary retention and closed angle glaucoma, so it may not be suit-

able in middle-aged to elderly patients. Another 5-HT1  agonist/antihistamine,  cyproheptadine,  is sometimes used in refractory cases.

Clonidine  has been used but is regarded as

unsuitable in theUKbecause it may cause or

aggravate severe depression, with an increased risk of suicide. Migraine sufferers may often be depressed due to the condition

The  highly  desirable  introduction  of  more

effective            prophylactic    drugs    presumably awaits  a  better  understanding  of  migraine

pathophysiology.

Cluster headache (migrainous neuralgia)

This name derives from the fact that episodes

tend  to  occur  in  clusters  of  attacks,  lasting

several  weeks,  interspersed  by  remissions  of

months to years. Despite its synonym, it is unre-

lated to migraine, though many of the same

drugs are used.

Clinical features

There are abrupt episodes of excruciating, unilat-

eral pain (‘suicide headache’) which affect the

eye, temple or forehead and increase over about

30 min  and  may  last  for  several  hours.  The

affected eye waters copiously and there is often

flushing of the same side of the face (Figure

7.5(k)), though this may vary. Attack frequency is between eight per day and one on alternate

days, usually once or twice a day for a few weeks or months, often at night and at predictable

times. The prodromal signs of classical migraine and the aura do not occur, and the attacks do not usually cause vomiting.

Sufferers are mostly men aged 30-50 (male :

female ratio, 10 : 1), but remission tends to occur

by the age of 60. There is no persistent major

deficit. The cause is unknown, but alcohol may provoke attacks, especially during a cluster. The fact that high-dose oxygen may abort an attack points to the possibility of oxygen starvation in part of the CNS.

Pharmacotherapy

Sumatriptan, by SC injection, is the only drug

licensed for cluster headache. It may be taken in

anticipation of an imminent attack (unlicensed

indication), because the timing is usually consis-

tent once a cluster has started. High-flow (100%)

oxygen often provides relief within minutes.

Pizotifen  and   verapamil  (also   methysergide,

hospital-only; see above) are used for prophy-

laxis throughout a cluster. Regular oral lithium

(see Chapter 6) may help chronic sufferers.

Trigeminal neuralgia

Definition

This is a neuropathy of the fifth cranial (trigem-

inal) nerve that causes episodes of agonising,

lancinating (stabbing or ‘electric shock’) pain, usually on one side of the face. Each episode lasts for a few seconds.

Clinical features

The trigeminal  (Vth cranial) nerve is mostly

sensory and has three branches:

•  Ophthalmic; carrying sensory fibres from the

            anterior half of the scalp, forehead, the eye

and surrounding structures, the nasal cavity and side of the nose.

•  Maxillary; contains fibres serving the lower

            eyelid, nose, palate, upper teeth and lip, and

parts of the pharynx.

•  Mandibular; serving the anterior tongue (not

            taste), lower teeth and jaw, cheek and side of

the head in front of the ear.

Trigeminal  neuralgia  is  usually  of  unknown

cause, but it can also occur in multiple sclerosis

and due to a fifth nerve tumour. It may also be

a  form  of  post-herpetic  neuralgia,  when  it

usually affects the ophthalmic branch. Other

tment

neuropathies can affect the trigeminal nerve, but these  are  usually  chronic  and  distinct  from trigeminal neuralgia.

The severe spasms of pain usually affect the

mandibular division and may spread upwards to

involve the other branches. The characteristics

and   localized   distribution   of   the   pain   are

diagnostic: no neurological abnormality can be

detected.

Spasms may occur several times a day, usually

in response to trivial triggers, e.g. cold wind,

touching, shaving or washing the face, chewing

or tooth brushing. Episodes remit spontaneously

for anything from months to years, but always

recur.  Middle-aged  and  elderly  patients  are

mostly affected.

Management

Most patients respond to pharmacotherapy with carbamazepine, taken at the commencement of an  attack.  This  usually  reduces  the  severity, duration and frequency of attacks and is not

beneficial in other forms of headache.

Carbamazepine is a rather toxic antiepileptic

drug with a long list of side-effects and interac-

tions, being a liver enzyme inducer (see Chapter

3). Consequently, it is usual to start with a low

dose in a first attack and build up slowly (fort-

nightly)  until  symptoms  are  controlled.  This

is especially necessary if dizziness occurs. Like

phenytoin and some other anticonvulsants, carba-

mazepine has a narrow therapeutic window, so

plasma-level monitoring should be instituted if

high doses are used.

Phenytoin  may   be   effective   in   those   not responding to carbamazepine. If the side-effects of high-dose carbamazepine are not tolerated, a combination with phenytoin is sometimes used, the doses of each being reduced appropriately. However, these interact (both are liver enzyme inducers)  and  such  combinations  are  rarely justified (see Chapter 6).

The dose and build-up in subsequent attacks depend on the patient’s reaction and tolerance to the drugs.

Tricyclic  antidepressants  are  more  useful  in

post-herpetic facial neuralgia and in non-specific

facial and jaw pain associated with depression

(see below).

Surgery or nerve ablation with alcohol injec-

tions may be required in those not responding to pharmacotherapy.

Post-herpetic neuralgia

Definition

This  is  a  chronic  pain  syndrome  in  the

dermatome  (the  skin  area  served  by  a  single

sensory nerve) affected by herpes zoster, an acute

skin infection (shingles) due to reactivation of

varicella-zoster provirus (VZV, see Chapter 8).

Clinical features

VZV causes chickenpox, a common acute skin

infection. Most patients (90%) are children under

the age of 10. Infections in older people are gener-

ally severe and occasionally fatal, and are usually

associated  with  immunosuppression,  e.g.  drug

treatment (transplant, autoimmune and cancer

patients), radiotherapy, some neoplastic diseases

(especially  lymphomas),  and  AIDS,  or  waning

immunity in old age.

During recovery from chickenpox the virus

tracks up sensory nerve axons to the local dorsal

root ganglia and becomes incorporated in the

nuclear DNA there as a provirus. This location is

protected from immunological defence mecha-

nisms, so the provirus persists until it is reacti-

vated by a reduction in host immunity. The virus

then tracks back down the nerve axon to cause a

skin infection in the dermatome innervated by

that   sensory   nerve.   This   pattern   may   be

repeated. There are usually three distinct phases:

•  Prodromal,  with  malaise,  unilateral  nerve

            pain or paraesthesia lasting 3-5 days (range

1-14 days), the skin being very sensitive to touch, and sometimes mild fever.

•  Active, vesicles appear over 3-5 days and crust

            over during several days to 3 weeks, accompa-

nied  by  nerve  and  skin  pain  which  seems excessive relative to the skin involvement.

•  Chronic   post-herpetic   neuralgia     (PHN)

lasting months to years.

Post-herpetic neuralgia  505

Occasionally,   the   nerve   may   be   affected without any skin eruption. The affected area is unilateral, sharply demarcated at the mid-line front and back, and may involve a few adjacent dermatomes. The principal sites are the thorax (50%  of  cases),  head  and  neck (20%)  and lumbosacral area (15%). Involvement of the eye or ear requires specialist advice.

Management and pharmacotherapy

Shingles

Mild cases

Only   simple   or   compound   analgesics   and soothing and drying lotions (see Chapter 13) are required.

Moderate to severe cases

These require prompt treatment, especially if the patient is immunocompromised:

•           Early antiviral treatment, to minimize the risk

of PHN and complications, e.g. eye or ear

involvement.  However,  diagnosis  may  be difficult  because  the  prodromal  symptoms may mimic migraine, heart disease or acute abdominal problems. The antivirals (see also Chapter 8) used include:

-  Aciclovir orally, or by IV infusion in the

            immunocompromised, plus topical appli-

cation to the eye or ear if these are affected.

Alternatives are famciclovir and valaciclovir,

oral prodrugs of penciclovir  and aciclovir

respectively, with superior bioavailability.

-  Foscarnet, occasionally amantadine, for resis-

tant strains of VZV (unlicensed indications in theUK).

•           Antibacterials   for   bacterial   opportunistic

infections of the rash (see Chapter 8).

•           Pain control with:

-  Analgesics, including opioids (see below) if

            needed,   though   most   have   not   been

assessed. Side-effects may become unac-

ceptable   before   effective   analgesia   is achieved.

-  Local   anaesthetics  (p.         482),   especially

topical lidocaine, or nerve block (p. 487) if pain is severe.

-  A  sedative  tricyclic  antidepressant,  e.g.

            amitriptyline  or  trimipramine,  at  night,  as

an analgesic adjunct, hypnotic and anti-

depressant.

-  Anticonvulsants, i.e. gabapentin  or prega-

            balin, reduce the pain.

-  There   is   conflicting   evidence   for   the

            benefit of capsaicin, and this may cause

skin reactions (see below).

-  TENS (see p. 486).

•  Soothing soaks to the affected skin.

Chronic post-herpetic neuralgia

Severe  pain  in  the  prodromal  or  early  active

phases indicates the likelihood of severe PHN,

so early aggressive antiviral treatment is indi-

cated. Prolonged PHN requires any of the anal-

gesic  treatments  listed  above (depression  is  a

feature of moderate to severe PHN). There is no

evidence  for  most  opioid  analgesics  in  PHN,

but tramadol and  oral  oxycodone  are  effective

and  the  risk of dependence must be weighed

against the possible benefit for this condition,

which  is  not  life-threatening  although  very

debilitating.

Capsaicin cream, a counter-irritant, is also used

after the rash has healed. This is very irritant

and must not be applied until the lesions have

healed completely. It should be applied not less

than three, nor more than four times daily. If

applied  less  frequently  the  transient  burning

sensation may be more severe and prolonged;

the  skin  needs  to  become  habituated.  More

frequent application also causes skin irritation.

Application sites must not be occluded and the

hands must be washed thoroughly immediately

after application. The area around the eyes must

be avoided.

Corticosteroids  are  contra-indicated  in  the acute phase because they may promote wide-

spread viral dissemination across the skin. They may help when the rash has healed and a short trial   course   of   prednisolone  is   worthwhile. Intrathecal methylprednisolone is also helpful, but its safety has not been established.

Non-drug measures (e.g. TENS, p. 486) may help to minimize the dose of analgesic and the risk of opioid dependence.

tment

Prophylaxis

A varicella vaccine is available. Use of the vaccine in non-immune individuals, especially those at risk of varicella infection, may prevent an attack of shingles in later life.

Shingles   is   not   contagious,   because   the

syndrome develops only after a previous chick-

enpox infection and reactivation of dormant

provirus. However, chickenpox may occur in a

non-immune patient due to contact with a case

of shingles.

Some special pain situations

Certain categories of patient present particular problems in pain control. This can be from the type   of   pain   itself   or   may   relate   to   the constraints that their disease state may impose on any choice of therapy.

Opioids and other sedatives in surgery

Premedication

The objectives of pre-anaesthetic medication are

to:

•  Relieve  anxiety  without  excessive  drowsi-

            ness, so that the patient remains cooperative

and the various preparative procedures can proceed smoothly.

•  Give   an   amnesic   effect   and   so   avoid

            unpleasant memories.

•  Relieve any preoperative pain. •  Minimize:

-  the dose of the general anaesthetic, usually

            inhalational.

-  the  undesirable  effects  of  anaesthesia,

            e.g.  vomiting,  headache,  coughing  and

excessive secretions.

-  post-operative stress.

Several  agents  may  be  required  to  achieve these ends.

Surgery  is  often  preceded  by  organic  or

traumatic  pain,  and  itself  obviously  causes

moderate to severe pain. Even mild preopera-

tive pain interferes with the smooth induction of general anaesthesia and increases the amount of anaesthetic required.

Oral benzodiazepines are widely used. They are

sedative, anxiolytic and amnesic, but have no

analgesic effect. Short-acting ones are preferred,

e.g.  lorazepam,  midazolam  or  temazepam,  but

diazepam, which is long-acting, is also used in

adults.

Diazepam is used to provide mild sedation, but

it is unsuitable for children because its effects in

them are unreliable and it may cause paradoxical

excitation.  Alimemazine,  a  sedative  antihista-

mine, may be used in children, but this may cause

post-operative restlessness. It is unsuitable for use

in elderly patients because of its antimuscarinic

effects, e.g. urinary retention and blurred vision.

Opioids  are  no  longer  widely  used  for

premedication.  The  choice  of  opioid  is  deter-

mined by their duration of action and the inci-

dence of side-effects. Morphine, and sometimes

pethidine in obstetrics, are used occasionally, but

their side-effects are particularly undesirable in

surgical patients, e.g. prolonged recovery time,

nausea and vomiting, constipation and urinary

retention,  bradycardia  causing  hypotension,

respiratory   depression             (especially   in   those

patients with an asthmatic tendency or frank

asthma) and spasm of the bile duct and ureters.

However,  premedication  with  an  opioid  may

minimize  the  occurrence  of  agitation  during

recovery. They are more usually used at induc-

tion and to reduce the dose of a general anaes-

thetic required by about 15%. They also enhance

analgesia during general anaesthesia. Drugs with

a rapid onset and short duration of action are

now preferred because any side-effects resolve

rapidly. Alfentanil and fentanyl can be adminis-

tered by IV injection or infusion. Remifentanil is

given by IV infusion only. They are also used as

analgesics to prevent the pain due to procedures,

e.g. dressing changes. Their side-effect of respira-

tory   depression   is   beneficial   in   ventilated

patients,  to  prevent  spontaneous  respiration

interfering with the ventilation provided by the

equipment.

Patients with severe adrenal suppression due

to corticosteroid use may have a dramatic fall in

blood pressure due to operative stress, so a high-

dose   glucocorticoid   with   mineralocorticoid

properties,   e.g.   hydrocortisone  and   especially

Some special pain situations      507

fludrocortisone, may be used in anticipation of intra-operative shock.

Antimuscarinic  drugs,  e.g.  hyoscine  (scopo-

lamine) hydrobromide, are now rarely used for

premedication, whether alone or in combination

with  an  opioid.  They  reduce  the  excessive

bronchial and salivary secretions that occur with

some inhaled anaesthetics, due to airway intuba-

tion.  Hyoscine  produces  some  sedation  and

amnesia and reduces vomiting, but may cause

undesirable  bradycardia  and  CNS  side-effects,

e.g. excitement, hallucinations and drowsiness,

especially in the elderly.

However, modern anaesthetic techniques and

the increasing use of day-case surgery largely

avoid  the  need  for  traditional  premedication

routines.

Induction agents

Propofol provides rapid recovery without hang-

over and causes little undesirable muscle activity.

It is an oil at room temperature: 1% injections

are given intravenously, but 2% injections are

emulsions and are given by IV infusion. Propofol

is also used as a sedative for short surgical and

diagnostic procedures, but there is a significant

incidence of bradycardia, allergic reactions and

convulsions.

Obstetric pain

The use of analgesics to control the pain of

labour presents several problems and poses risks to both mother and fetus. The ideal agent should meet the following criteria:

•  Provide adequate pain relief.

•  Interfere  minimally  with  the  course  and

            duration of labour.

•  Have little effect on fetal vital signs during

            labour and after birth.

Pethidine  (meperidine)  is  the  most  common

obstetric  analgesic  as  it  is  short-acting  and

generally  meets  these  criteria.  However,  prob-

lems still occur, notably respiratory depression

in the neonate, the incidence of which can be

reduced by giving the drug early in the course

of labour and using the IM route, the IV route being associated with more neonatal respiratory depression.

Common   alternative   forms   of   analgesia

include  the  epidural  administration  of  local

anaesthetics,   and   the   inhalation   of   sub-

anaesthetic doses of 50% nitrous oxide in oxygen.

Palliative treatment of cancer pain

Great advances have been made in this field, and

most patients can be maintained virtually free of

pain  by  application  of  the  principles  of  the

WHO ‘analgesic ladder’ (Table 7.3). It isessen-

tial to appreciate that pain is not an invariable

accompaniment to cancer, and about one-third

of  cancer  patients  remain  pain-free.  A  clear

understanding of the common pain syndromes

associated with neoplasms and their pathophys-

iological mechanisms, the psychological state of

the patient, and the indications and limitations

of the available therapeutic approaches, is vital

to effective management. Short-acting drugs, e.g.

pethidine  (meperidine), are unsuitable because

they require frequent dosing, without additional

benefit.

tment

Several different types of pain may be associ-

ated with cancer (see Table 7.15), and these often

co-exist: some 80% of patients who are experi-

encing pain have two or more types and about

20% four or more types. The pain may be due to

the disease itself or to the debility it causes, and to

coexisting disease or treatment, and so a com-

bination  of  therapeutic  approaches  is  often

required.  Thus  a  multidisciplinary  approach,

including specialist ‘Macmillan’ pharmacists, has

been adopted increasingly to form pain teams,

which take a holistic approach to the patient’s

needs.  The  clinical  aspects  of  cancer  and  its

overall management are discussed in detail in

Chapter 10.

Types of pain

Because pain can have many causes, some of

which  are  not  directly  related  to  neoplastic

activity, especially careful assessment and diag-

nosis of the pain is essential in cancer patients.

Regular reassessment is required to take account

of disease progression and the occurrence of

unrelated intercurrent disease. Depending on its

aetiology, the pain in terminal disease may only

be partially responsive to opioid analgesics, so a

combination of analgesics with different phar-

macological actions is often necessary. Adjunc-

tive agents, radiotherapy or surgical approaches

may be appropriate in special circumstances.

Tumour infiltration of tissues

Visceral organs

Tumour invasion of the stomach, biliary tract,

intestine,   uterus   or   bladder   causes   intense

contraction of the local smooth muscle with

increased pressure and local ischaemia. Visceral

pain is characteristically increasing in intensity,

diffuse,  unlocalized  and  continuous.  Opioid

drugs are the most effective in these circum-

stances, but treatment must be started on the

appropriate step of the WHO ‘analgesic ladder’

and must be given in adequate doses. A simple

analgesic, usually paracetamol (acetaminophen),

added to the opioid is often helpful. A regular

laxative, combining both a stimulant and a stool

softener (see  Chapter 3),  is  also  needed  to

prevent constipation that would otherwise add

to the pain and complicate the picture.

Nerves

Infiltration or compression of local nerves by a

tumour  may  cause  a  variety  of  symptoms

according  to  the  site  of  involvement.  These

include  hyperaesthesia (increased  sensitivity),

dysaesthesia     (painful   sensation),   neuralgia

(paroxysmal nerve pain), allodynia (pain elici-

tated by light touch). Motor disturbances and

sensory loss may also occur. The tumour may

cause persistent mechanical stimulation of high-

threshold nociceptors, i.e. those not readily stim-

ulated, and partial damage to axons and nerve

membranes, resulting in increased sensitivity to

sympathetic  stimulation  and  pressure.  Nerve

pain may respond to standard opioid analgesics,

at least partially, but unacceptable side-effects

often   occur   before   adequate   analgesia   is

achieved,  so  a  combined  approach  is  often

required. Analgesic adjuvants, nerve blocks or

neurosurgical  procedures (see  above)  may  be

more successful, but the last two of these may

not always be achievable (see above), or desirable

in very frail patients, and may add their own

problems.

Some special pain situations      509

Bones

Bone pain is common in cancer and may be due

either  to  a  primary  tumour (e.g.  multiple

myeloma) or to metastases (e.g. from breast, lung

or prostate cancer). Bone tumours stimulate local

pain receptors directly and induce the production

of PGs that may cause osteolysis (solution of the

mineral component of bone), sensitize free nerve

endings and augment pain perception. Inhibitors

of PG release, e.g. NSAIDs (see Chapter 12), are

thus  the  logical  choice  to  treat  bone  pain.

Although  NSAIDs  exert  their  main  analgesic

action at peripheral sites, there is also a central

component. It is worth maximizing the dosage of

individual  agents  and  changing  drugs  if  side-

effects  are  excessive  or  the  response  is  poor,

because individuals vary considerably, both in

their response to different NSAIDs and in the

occurrence of side-effects. Bisphosphonates, e.g.

alendronic acid, disodium pamidronate, ibandronic

acid, sodium clodronate and zoledronic acid, can

also  help  by  inhibiting  osteolysis.  Strontium

ranelate  both  inhibits  osteolysis  and  stimu-

lates  mineralization  and  may  also  be  helpful

(unlicensed   indication).   However,   cytotoxic

chemotherapy  or  single-dose  local  palliative

radiotherapy, if appropriate (see Chapter 10), may

have a dramatic, if temporary, analgesic effect.

Opioids  are  generally  not  very  effective  in relieving  bone  pain  and  can  sometimes  be reduced in dose or withdrawn totally after the introduction of an NSAID, though many patients use the combined therapy.

Morphine in palliative care

Optimal use follows the guidelines given on pp.

470  and  490.  Oral  morphine  is  the  first-line

opioid in palliative care. Initially, the oral dose of

plain tablets or liquid is given 4-hourly, with

rescue  medication  as  required.  Doubling  the

bedtime dose usually enables the patient to sleep

throughout the night. With a 4-h duration of

action, morphine takes about 24 h to reach steady

state, so patients need re-evaluation daily. Once

stabilized, the change is made to modified-release

tablets (not to be crushed), usually formulated

for 12-hourly dosing. If pain increases, the dose

should  be  increased  but  the  dose  interval

retained.

If oral dosing is not possible or not tolerated,

rectal (dose  equals  oral  dose)  or  SC  routes

(potency relative to oral is 2, as a bolus or contin-

uous infusion) can be used. The choice may

depend on the availability of the desired dosage

form (see Table 7.4) and its suitability, e.g. the IM

route gives more pain with morphine and should

not  be  used.  The  IV  route  is  uncommon  in

palliative care because pharmacological tolerance

develops, leading to escalating doses.

A change to diamorphine (heroin) or hydromor-

phone (in North  America  or  elsewhere  that

heroin is not licensed) may be needed if high

doses are required, because morphine is not very

soluble and only small volumes can be injected

by the SC route. Also, if the SC route is unsuit-

able  due  to  generalized  oedema,  coagulation

problems, poor peripheral circulation or local

adverse drug reactions, the IV route may be used

(potencies relative to oral morphine: diamorphine

(heroin), about 3; hydromorphone, about 15).

About 20% of patients fail to respond to these

measures. These will need spinal opioids, with

local anaesthetics and other adjuncts (see above).

Patients with liver failure

These   patients   often   present   a   therapeutic

dilemma because most of the commonly used

analgesics are contra-indicated. In particular, the

effect of liver failure on the pharmacokinetics

and pharmacodynamics of the analgesic has to

be  considered (see  Chapters 2  and  3).  Most

opioids are significantly metabolized by the liver

and will accumulate in liver disease if dosing

intervals  are  not  adjusted.  Further,  the  oral

bioavailability  of  opioids  may  be  increased

owing to reduced first-pass metabolism.

Patients with liver failure are particularly sensi-

tive to the effects of opioids, as to other seda-

tives, because they are metabolized hepatically

and   relatively   small   doses   can   precipitate

encephalopathy (see  Chapter 3).  Those  with

cirrhosis   are   liable   to   develop   oesophageal

varices (see Chapter 3), and NSAIDs should be

used cautiously as the gastrointestinal irritation

caused may precipitate catastrophic bleeding.

Chronic administration of large doses of hepato-

toxic drugs, e.g. paracetamol  (acetaminophen),

tment

can further exacerbate the liver failure. Fortu-

nately,   the   severity   of   liver   failure   usually encountered in cancer patients does not require large dosage changes.

In practice, an estimate of the dosage interval

required to prevent accumulation occurring is

obtained by giving a cautious dose of opioid, the

subsequent dose being withheld until the pain

reappears. It is particularly important in this

situation to use drugs in which the analgesic

half-life is similar to the plasma half-life, e.g.

morphine (plus its active metabolite, morphine-6-

glucuronide), because the risk of accumulation is

then minimized, as the loss of analgesic effect

should correlate with drug clearance.

Patients with renal failure

Choosing an appropriate analgesic in this group

of patients does not usually present a problem

(but see Chapter 14). Some analgesics however

(e.g. the NSAIDs) can cause nephropathy, so

taking a medication history is important, to

determine whether the renal failure may initially

have  been  due  to  analgesic  over-dosage  or

misuse. NSAIDs may also be contra-indicated

because they may exacerbate fluid retention and

precipitate decompensation in developing heart

failure (see Chapter 4).

Opioid analgesics may present a significant

problem   in   renal   failure.   Morphine  and   its

glucuronide metabolites accumulate, requiring

an increased dosing interval or dose reduction.

Fentanyl is said to be safer in renal impairment

and can be given intravenously. If injections are

not tolerated, then transdermal patches can be

used. However, it takes about 24 h after applica-

tion of the first patch to reach an adequate

fentanyl plasma concentration. Further, the long

half-life of fentanyl (about 17 h) creates problems

if the drug accumulates, and replacement with

an alternative must be started at a low dose

concurrently with the removal of a patch, and

increased gradually thereafter. Alfentanil is being

used increasingly in palliative care for patients in

renal failure.

Pethidine  (meperidine)   should   be   avoided

because the toxic metabolite norpethidine accu-

mulates in renal failure and can lead to seizures.