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The report published in 1990 by the Royal College of Surgeons and the
College of Anaesthetists did not mince words. ‘The treatment of pain after
surgery in British hospitals has been inadequate,’ it said. ‘Traditional
antiquated attitudes (to pain) should be changed.’ Surveys performed in
hospitals in the 1980s revealed that as many as three quarters of patients
wake from surgery in moderate or severe pain – a figure which has changed
little for almost forty years. In the world of neuroscience, meanwhile,
revolutions have come and gone, and research into the mechanisms underlying
acute pain has blossomed, bringing forth new methods of treatment. So why
the lack of progress on the wards?

The short answer is tradition. In the British health service, outdated
attitudes live on as bedfellows with high technology. Few hospitals in Britain
have a coherent policy on how best to treat pain after surgery. Doctors
and nurses, for instance, do not routinely assess and record pain as they
do heart rate and blood pressure. And the people who are best equipped to
tackle the problem, anaesthetists, are often confined to operating theatres.
According to a 1990 study of attitudes to pain in British hospitals, staff
often choose drugs randomly and with little regard for the nature or severity
of the pain, and only one in five ward staff aim to relieve pain completely.
Morphine remains the standard prescription for postoperative pain, as it
was in the last century.

All this stands in stark contrast to progress in academic quarters.
It has long been clear to neurophysiologists that the chain of physiological
and psychological events which causes pain offers many opportunities for
treatment that avoid the stupor of morphine. A standard injection of morphine
has a blanket effect on the nervous system. The drug acts centrally, desensitising
clusters of neurons that process much of the information that passes through
the spinal cord – information that is essential for life. The side effects
are unpleasant, and occasionally dangerous: nausea, dizziness and impaired
breathing, to name but three. In most cases, the dose required for good
pain relief approaches half the dose which may stop a patient breathing
altogether – not a reassuring safety margin.

The quest for alternatives has been dominated by the search for ways
of blocking pain at specific sites in its transmission pathway, rather than
by befuddling the entire central nervous system. And herein lie the questions
that have both dogged and inspired pain researchers for more than three
decades. To what extent is pain initiated and sustained by physiological
processes near to the damaged tissue – local events, as opposed to events
in the brain and spinal cord? Why do many amputees feel pain in the limb,
or limbs, they have lost? Moreover, why does our mental and emotional state
influence so strongly our perception of pain?

Neuroscientists still disagree over how to account for many aspects
of pain. Yet much of their current thinking builds on one unifying idea,
the so-called gate theory of pain, proposed in the 1960s by Patrick Wall
of University College London and Ronald Melzack of McGill University in
Montreal. It argues that the nerve impulses which cause pain must pass through
a number of gates on their way to the brain and that these gates are controlled
both by messages descending from the brain and by messages travelling towards
the brain on other sensory fibres.

Most of the gates take the form of circuits of interconnecting neurons
in the spinal cord. Together they act like the editor in a television studio,
fading between different views and generally modulating the flow of sensory
information. The final ‘broadcast’ – our perception of pain – results from
the brain projecting the unpleasant sensation to a point on our internal
image of our body that is usually, but not always, the site of injury. Signals
generated anywhere on the sensory circuit can relay false messages: hence
the pain that amputees sometimes feel in a phantom limb.

Research inspired by the gate theory has shown that acute pain originates
not just in nerve terminals close to damaged tissue but in the sensory system
as a whole. The theory has thus done much to demolish the traditional, naive
view of pain as the simple product of messages sent from specialised pain
receptors (nociceptors) embedded in skin and a ‘pain centre’ in the brain.
The theory has also given neuroscientists the conceptual tools with which
to tackle some awkward phenomena. It helps to explain, for example, why
nerve signals produced by touch or mild mechanical stimulation often inhibit
the transmission of pain messages. Such signals, says the theory, travel
along large, fast-conducting nerve fibres and into the spinal cord, where
they block pain messages travelling along smaller, slow-conducting fibres.

More recently, researchers have been trying to unravel the cellular
events that govern the mixing of ‘local’ and ‘central’ inputs to our perception
of pain. Clifford Woolf and his colleagues at University College London
and others are examining a phenomenon called central sensitisation. Here
nerve fibres that normally carry perfectly innocuous sensory information
– of the kind resulting from everyday pressure on muscles and joints, for
example – start driving the nervous system to produce pain. As a result,
we respond in an exaggerated way to what should be a painless flow of nerve
impulses. The phenomenon is thought to play a key part in sustaining the
acute pain that often results from surgical damage to tissue.

Woolf and his team believe that the problem originates in the capacity
of certain neurons in the spinal cord to undergo prolonged changes in sensitivity.
Damage to tissue triggers a constant flow of pain impulses from nociceptors.
These not only cause immediate pain, argue the researchers, but over time
boost the sensitivities of spinal cord neurons to impulses from normal sensory
fibres. In a sense, the pain the patient eventually feels is out of proportion
to the scale of the injury – an unhappy outcome which raises the question
of why the phenomenon has evolved. The likely answer is that it is an adaptation
which encourages us to rest while our injury heals. Like most types of pain
it is probably a protective device.

An intriguing aspect of central sensitisation is that it has features
in common with certain cellular processes that have been proposed to account
for memory. The more the nervous system uses its spinal cord neurons to
process pain signals, the more acutely the neurons seem to respond to stimulation.
It is almost as if the neurons are ‘learning’ from experience, as if they
are inherently ‘plastic’. Current thinking about how the brain learns from
sensory inputs in general runs along similar lines.

Many neuroscientists believe that the key to understanding plasticity
in the spinal cord – and perhaps how the brain learns – lies in a molecule
known as the NMDA receptor. This complex of proteins straddles the membranes
of neurons, where it is kicked into action by the simple chemical glutamate,
one of the body’s fleet of neurotransmitters. The receptor derives its name
from the fact that it responds specifically to the chemical N-methyl-d-aspartate
acid.

What is special about the NMDA receptor is that it seems to act as a
trigger for strengthening neural synapses. When activated, it sets in motion
a cascade of powerful cellular events: calcium ions flow into the neuron,
metabolic enzymes swing into action and genes are switched on. The end result
is that the neuron becomes more responsive to incoming electrical signals;
it behaves as though the synapses through which it communicates with the
world have suddenly gained in strength. In experiments on tissue slices
and on rats, the increased sensitivity can last for many minutes.

Yet the NMDA receptor is more than an academic curiosity. The neural
plasticity it causes may have profound implications for treating pain after
surgery. The object, say those investigating the phenomenon, should be to
prevent the spinal cord from becoming sensitised in the first place. This
means blocking the initial barrage of pain impulses that flow from the site
of tissue injury to prevent them from reaching the spinal cord.

The best tactic here is to apply an anaesthetic block to the nerve tissues
closest to the site of the operation before the surgeon touches the patient
with a scalpel. Local nerve blocks of this kind (such as arm blocks and
epidurals) which can render parts of the body numb, are growing in popularity
among anaesthetists. Woolf reports that in a recent trial comparing a nerve
block with conventional general anaesthetic, patients who received the block
requested lower levels of painkillers after surgery, even when the numbing
effect of the block had worn off.

Another way of reducing central sensitisation would be to administer
anti-inflammatory drugs such as aspirin. Most injuries trigger the release
of substances that provoke inflammation in the damaged tissue. As the inflammatory
response stimulates nociceptors, it may add to the barrage of impulses that
sensitise the spinal cord. A recent study done in the Ulster Hospital in
Belfast tested this notion on postoperative pain caused by the extraction
of wisdom teeth. Patients who were given an anti-inflammatory drug called
diclofenac before surgery felt less pain afterwards than patients who received
the same dose during surgery.

On a completely different tack, researchers elsewhere are exploring
the possibility of using drugs that disable the NMDA receptor to block sensitisation
of the spinal cord. This is not the first time that research on a receptor
has inspired methods of blocking pain selectively. Hopes were raised in
the 1970s when Solomon Snyder, of the Johns Hopkins University, Maryland,
and others discovered that spinal cord neurons possess morphine receptors.
These had previously been considered the exclusive property of neurons buried
deep in the brain. Moreover, the spinal cord’s morphine receptors were closely
associated with neurons thought to be involved in the gate mechanism.

The implication was obvious: morphine injected into the spine might
well produce powerful regional pain relief without the dangerous side effects
caused by giving the drug to the whole body. Over the past few years this
promise has been partly fulfilled. The discovery has been a boon, in particular,
to one of the best known painkilling procedures, the epidural anaesthesia
that is used both for the relief of labour pains and postoperative pain.
The epidural space is a cylindrical area close to the spinal cord but separated
from it by a tough membrane called the dura. If morphine is injected into
the epidural space, close to the spinal gate circuits, only a tenth of the
normal dose of the drug is required. The result is powerful pain relief
without any of the usual side effects.

Even so, epidural morphine is not completely problem-free. One concern
is the rare but unpredictable spread of morphine up through the spinal fluid
to the brain stem, where its activity can bring breathing to a virtual standstill
– the equivalent of a massive overdose. Synthetic opioids that are more
soluble in lipids, such as fentanyl, are cleared from the spinal fluid more
rapidly and so have fewer side effects. The best results come from a cocktail
comprising a weak local anaesthetic and an opioid. This minimises the side
effects of each component and compounds the analgesic effect. When such
a cocktail is administered before surgery, only a light general anaesthetic
is required to keep the patient asleep and free of any discomfort. The patient
can be awake, alert and free of pain within five minutes of surgery, even
after a major operation.

Perhaps the greatest difficulty doctors and nurses face in treating
pain is that it is a wholly subjective experience: it is a phenomenon that
cannot be measured. This makes it hard not to be judgmental and label the
patient who cries out after a simple injection as having ‘a low pain threshold’.
Are we being unkind, or do such people genuinely feel more pain? The conventional
view of pain is that it is a one-dimensional variable, a number between
one and a hundred. Indeed the commonest scoring system for pain is the visual
analogue scale, in which the patient is presented with a line marked ‘no
pain’ at one end and ‘the worst pain imaginable’ at the other and invited
to mark the line at the position that best represents the pain they are
feeling.

Yet pain has several dimensions. For instance, there is the sudden and
spontaneous reflex response to injury that originates wholly in the spinal
cord. Without such protective reflexes we are doomed to injure and mutilate
ourselves without being aware of it – the fate of lepers. Then there is
the first sensation of discomfort – usually a sharp pain resulting from
impulses sent along fast-conducting fibres – followed by a second wave of
duller burning discomfort. Even more intriguing are periodic pains that
come and go in a regular cycle. Such phenomena may prove useful to neuroscientists
investigating gate mechanisms and pain pathways, but to clinicians they
only complicate the task of diagnosis.

For internal pain the problems of diagnosis are greater still. Compared
with the skin, internal organs have few nociceptors, and the sensory cortex
possesses relatively few neurons devoted to receiving signals from them.
The consequences of this are twofold. First, the pain threshold is higher.
The gut, for example, can be handled, cut, burnt and crushed without pain,
so long as the lumen that surrounds it is not distended. Secondly, when
internal pain does occur, it is usually projected onto the mind’s image
of the body surface and is poorly localised. Hence, we indicate gut ache
with the flat of our hand because we can’t locate the pain precisely. When
an internal pain can be pinpointed, it is a sure sign that the abdominal
wall, with its better nerve connections to the sensory cortex, is becoming
inflamed.

The unpredictability of a patient’s perception of pain is compounded
by wide variations in responses to morphine. Judging the right dose may
be difficult, and accidental overdoses are not uncommon, particularly among
elderly patients. Inadequate staffing of surgical wards, combined with the
strict accounting required for every dose, means that morphine may not be
given frequently enough to provide continuous pain relief. Patients are
often unwilling to bother the nurse even if they are in pain.

These problems inspired the development in the early 1980s of a neat
technological fix, the patient-controlled analgesia (PCA) pump. Patients
press a button when they feel pain, and in response morphine is injected
into the bloodstream by a computer-controlled pump. Repeated small doses
keep the patient comfortable and each individual can choose their own compromise
between pain relief and side effects. The computer monitors the dosage,
and sets limits on the rate or maximum dose. Like the train driver’s dead
man’s handle, the system has a built-in safety factor: large doses will
send the patient to sleep, so they will stop pressing the button. Perhaps
the main advantage of PCA is the psychological one that pain is easier to
bear if you know it can be relieved. Yet despite its popularity with patients,
PCA does not avoid the disadvantages of morphine, and some doubt its cost-effectiveness.

Yet selective painkilling procedures, such as arm blocks and epidurals,
need not add to the costs of the overburdened health service because good
pain relief allows patients to recover more quickly. In my own area, patients
for gall bladder surgery who are given epidural anaesthesia have been shown
to recover and leave hospital two days earlier than those who have conventional
anaesthetics.

But equally important, attitudes need to change. Pain should not be
neglected, or thought of as being simply a diagnostic tool. We need an acute
pain service in all hospitals, not only to implement the sophisticated methods
of pain relief now available, but also to make sure the simple things are
done well. The patient who wakes from surgery pain-free can easily be kept
comfortable – agony is harder to treat.

Robin Youngson is an anaesthetist who until recently practised in Britain.
He now works at the Acute Pain Service of Auckland Public Hospital, Auckland,
New Zealand.

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HOW ANAESTHETISTS FIND THE RIGHT SPOT

Almost all sensory information from the trunk and limbs passes through
the spinal cord. The surface of the body can be divided into bands called
dermatomes. A nerve impulse originating in a particular dermatome will arrive
at a specific segment of the spinal cord, where it will stimulate spinal
neurons. For example, signals from the middle finger of each hand are invariably
transmitted through the seventh cervical segment of the spinal cord (abbreviated
to C7).

Pain signals, once generated, can still be interrupted before they reach
the sensory cortex and activate neurons. When local anaesthetic drugs, such
as lignocaine, are injected near to peripheral nerves or the spinal cord,
they cause a regional ‘news blackout’, preventing the brain from registering
any pain or injury.

These drugs also block a stress response to surgery, which may be hazardous.
Even when anaesthetised, the body can react to surgery with dramatic increases
in pulse rate, blood pressure and hormone production. Blood sugar rises,
levels of steroid hormones increase and proteins are released that cannibalise
healthy tissue in order to mend tissue that has been injured. This response
to injury is an adaptation which increased survival in primitive humans.
But to the patient lying in a hospital be after surgery it is more likely
to be harmful.

The distinctive anatomy of peripheral nerves allows the distribution
of an anaesthetic to be tailored to the area undergoing surgery. Local anaesthetic
applied close to the spinal cord produces a block which has a distribution
conforming to the pattern of dermatomes. Further out, individual nerves
can be blocked.

Nerves to neighbouring segments of the spinal cord may combine to form
cables that serve whole limbs. The whole arm can be numbed by an injection
into the armpit, for example.

If the tip of a needle is introduced into the fibrous sheath which extends
under the collarbone up into the neck, a local anaesthetic can be injected
which will surround the nerves that run into the arm. Even after major surgery,
the arm can in this way be kept completely pain-free, for many days if required.

What nerve connections there are between the sensory cortex and the
internal organs pass through segments of the spinal cord, too. For instance,
the pain of uterine contraction in labour is abolished by targeting an epidural
anaesthetic to block nerve signals in two specific segments (T11 and T12).