Today morphine therapy
for pain is generally restricted to two groups of patients. It is prescribed over relatively short periods for hospitalized
individuals who have discomfort caused by surgical incisions, and it is given over potentially longer periods to ameliorate
the pain suffered by burn victims or people who have incurable cancer. In many
hospitals the standard prescription order says "PRN" (pro re nata, or "as needed"). This order essentially means that
the drug is given only after pain returns. Typically, it is delivered by injection into a muscle or under the skin. The result of the PRN approach is often a confrontation between the patient and the care giver, who
expects morphine analgesia to last for four to six hours. The patient, whose pain has returned earlier than expected, is in
agony and pleads to have the next injection. The health-care worker, fearful of causing addiction, refuses to comply.
When the pain is finally treated, it may be so severe that a large dose has to be given, which increases the likelihood
of side effects, such as mental clouding and nausea. Particularly when a patient has a terminal illness, the issue of
addiction is meaningless, and delaying relief is cruel.
There is another,
more humane way to treat pain, one that is slowly gaining acceptance. In this approach doses are given regularly, according
to a schedule that has been actually tailored to prevent recurrence of the individual's pain. Thus, pain is controlled
continuously; a patient does not wait for discomfort to return before receiving the next dose. This enlightened, preventive approach evolved from pioneering work first undertaken some 20 years
ago by Cicely M. .Saunders, an English physician who established the first modern center devoted to caring for people who
are dying of cancer or other diseases: St. Christopher's Hospice in London. Saunders urged physicians caring for terminally
ill patients to face reality and palliate—to relieve pain, nausea and other discomforts— instead of making futile
attempts to cure disease. The final days or weeks of a person's life, she believed, should be a time of peace and comfort,
spent as pleasurably as possible in the company of family and friends.
To achieve this aim,
Saunders prescribed the Brompton mixture, a version of a liquid analgesic that had been used for advanced cancer
by several London hospitals, including the Brompton Chest Hospital, since the late 19th century. The mixture (made of
morphine, cocaine, chloroform water, alcohol and flavoring syrup) had been eclipsed by injectable morphine, but Saunders
realized that an orally delivered compound would allow many patients to spend a number of their last days at home; a
visiting nurse would simply monitor them, making sure their pain was controlled. Morphine
has since been found to be the only important ingredient in the Brompton mixture, and so today patients who are treated with
the preventive approach to pain take morphine alone, either as a tablet or mixed into a beverage. An initial dose
of 10 milligrams is typically given and repeated every four hours. Then, over the course of perhaps several days or weeks, the dose and timing are
adjusted until a maintenance regimen is established that controls pain around the clock without producing mental
clouding and other side effects.
For patients who have cancer, an approach emphasizing
pain prevention is particularly wise. Pain and the fear of pain are perhaps their greatest source of suffering. In the
early stages of the disease, some 50 percent of people have pain resulting from the cancer itself or from the procedures
designed to arrest its spread. By the time the cancer has reached its final stages, about 70 percent of people report pain,
which tends to be intense and persistent. About 80 to 90 percent of cancer patients
treated with the preventive approach obtain satisfactory relief, reporting that their discomfort is consistently
bearable or, more frequently, gone. Roughly half of the remainder obtain relief with the addition of other therapies. This
success rate is remarkable in view of the destructiveness of cancer and the severity of the pain associated with it.
Enough evidence has now been collected to demonstrate
that the traditional, PRN approach, based as it is on the fear of addiction, makes little sense. Study after study of patients
whose pain is most often treated with narcotics— namely, cancer patients, burn victims and those hospitalized for
surgery— has shown that the patients who develop rapid and marked tolerance to, and dependence on, the narcotics
are usually those who already have a history of psychological disturbance or substance abuse.
Let us first consider
the problem of marked tolerance, which not only is a sign of possible addiction but is also a medical concern in its own right
because the risk of side effects increases as the dose increases. For instance, delivery' of extremely large amounts
of morphine can induce coma and seriously impair respiration. Robert G. Twycross, now at the Churchill Hospital
in Oxford, England, has shown that relatively little tolerance develops in patients with cancer who take individually
adjusted doses of heroin several times a day over long periods. The patients developed some tolerance to the drug initially,
so that the doses had to be gradually raised over the first 12 weeks, but pain relief was achieved without producing serious
side effects. Then
the doses held fairly stable for months.
Balfour M. Mount, one of my colleagues at
McGill University, and I recently found similar results when we studied tolerance to morphine in patients who spent
more than a month in the Palliative Care Unit at the Royal Victoria Hospital in Montreal. (This unit, established by
Mount, was the first service for palliative care at a large general hospital.) The patients in our study, who took the drug
by mouth, answered a pain-evaluating questionnaire that I developed with Warren S. Torgerson of Johns Hopkins University.
The overall intensity of the pain was ranked on a scale ranging from no pain (0) to pain that is mild (1), discomforting (2),
distressing (3), horrible (4) or excruciating (5). About 5 percent of
the patients had persistently high pain levels (3 or higher). The remaining 95 percent had excellent pain control without requiring rapidly
escalating amounts of morphine. Increase in pain, usually a sign of disease progression after a maintenance program has been established, was
the most common reason for a rise in dose. Patients who found that their discomfort had decreased— either spontaneously
or because of treatment, such as reduction of a tumor by radiation—usually required less medication.
John F. Scott of
the Elizabeth Bruyere Health Center in Ottawa also uncovered little evidence of addiction when he analyzed many studies
examining withdrawal symptoms in patients at cancer-treatment clinics. He reports that "if a cancer patient no longer
requires a narcotic for pain control, a gradual reduction in dose will prevent any withdrawal symptoms, although these
are usually mild or absent even after abrupt discontinuance." Any physical dependence is generally overcome without difficulty
when doses are reduced over a period of days. Studies of patients who received
narcotics while they were hospitalized have also uncovered little evidence of addiction. In an extensive study Jane B. Porter
and Hershel Jick of the J Boston University Medical Center followed up on 11,882 patients who were given narcotics
to relieve pain stemming from various medical problems; none of the subjects had a history of drug dependence. The team
found that only four of the patients subsequently abused drugs, and in only one case was the abuse considered major.
are the results of a survey of more than 10,000 burn victims. These individuals, who were studied by Samuel W. Perry of New
York Hospital and George Heidrich of the University of Wisconsin at Madison, underwent debridement, an extremely painful procedure
in which the dead tissue is removed from burned skin. Most of the patients received injections of narcotics for weeks or even
months. Yet not a single case of later addiction could be attributed to the narcotics given for pain relief during the
hospital stay. Although 22 patients abused drugs after they were discharged, all of them had a history of drug abuse.
that narcotic drugs can he administered for pain without causing addiction comes from studies of "patient-controlled
analgesia" in surgical patients and those hospitalized for burns. In such studies patients push a button on an electronically
controlled pump at the bedside to give themselves small doses of morphine (through an intravenous tube). When these devices
were introduced, there was considerable fear that patients would abuse the drug. Instead it soon became clear that patients
maintain their doses at a reasonable level and decrease them when their pain diminishes.
TWO TYPES OF PAIN (SHARP & CHRONIC).
OPIOIDS BLOCK CHRONIC WITHOUT REQUIRING INCREASING DOSES--jk.
Studies that explore
how morphine produces analgesia are h^ helping to explain why patients
who take the drug solely to relieve pain are unlikely to develop rapid tolerance and become addicted. On the basis of
such studies, my former student Frances V. Abbott and I proposed in 1981 that morphine probably has an effect on two
distinct pain-signaling systems in the central nervous system and that one of these—which gives rise to the kind
of pain typically treated with morphine—does not develop much tolerance to the drug.
Our proposal grew out of my efforts to develop
a test in animals that would accurately determine the effectiveness of analgesic drugs on the kind of pain most often
requiring narcotics in human patients: the prolonged, or ''tonic” kind that persists long after an injury is suffered.
This is the sort of* pain that chronically bedevils cancer patients. When an injury first occurs, it gives rise to what is
called phasic pain, which is brief and rapidly rises and falls in intensity. (The pain felt the instant a finger is cut would
be called phasic.) Such phasic pain is usually followed by the tonic kind.
For many years investigators
interested in measuring the analgesic effects of drugs subjected rats to what is called the tail-flick test. After
a rat is injected with a test drug, its tail is immersed in hot water; the time between immersion and when the rat flicks
its tail out of the water is measured as an index of pain. When morphine's effectiveness was examined with this
test, investigators repeatedly found evidence of marked tolerance: the animals required ever-increasing doses in order to
keep the tail in the water for a given time. Such results were interpreted to mean that human patients in pain would readily
become tolerant to morphine and so would become addicted to the drug.
There is a major
problem with the tail-flick test, however. It gives rise to suddenly rising, phasic pain, which is not the kind for which
morphine is usually prescribed. To gain more information about the effects of analgesics on persistent, tonic pain
in humans. John O'Keefe, David Dubuisson and Stephen G. Dennis, who were then my students, developed what is called the
formalin test. A small amount of formalin—formaldehyde diluted in saline—is injected under the skin of a
rat's forepaw. When the animal is not given an analgesic, the formalin produces moderate pain that lasts for about 90
minutes, as evinced by the animal's tendency to lick the paw and a reluctance to put weight on it. If a drug soothes the hurt,
the animal puts weight on the paw more quickly. With the formalin (tonic-pain)
test, Abbott and I (later joined at Me Gill by our colleague Keith B. J. Franklin) discovered that rats developed relatively
little tolerance to the analgesia produced by successive injections of morphine. The most logical explanation for the
different degrees of tolerance found in the tail-flick and formalin tests was that phasic and tonic pain are invoked
by two distinct neural systems that have differing tolerance to morphine.
Other lines of evidence
added support to this idea. For instance, Dennis and I examined the effect on pain of several drugs that interact with
morphine (or that alter pain in their own right) in both the tail-flick and the formalin tests. The results were striking.
Drug effects that we found in one test were absent or even reversed in the other. For example, drugs that reduced morphine
analgesia in one test either had no effect or enhanced the analgesic effect in the other test. If the neural systems that
respond to phasic and tonic pain were one and the same, the effects of the drugs on morphine's activity should have been identical
in both tests.
My colleagues and I think we now knew which of the many neural
pathways in the spinal cord and brain constitute the two pain-signaling systems that are sensitive to morphine.
We also know something about their functioning and how they are affected by morphine. In both systems, information about
pain is delivered to the dorsal horns (wing-shaped regions) of the spinal cord by peripheral neurons emanating from the skin
and other body tissues. Ascending neurons originating in the dorsal
horns then relay the pain signals upward through the spinal cord to various parts of the brain.
system that my colleagues and I think is most associated with sudden, phasic pain is called the lateral system. The name
derives from the simple fact that the system's tracts, which project to the sensory cortex, pass through the brain stem a:
a position to the side of the brain stem's central core. The system that is probably responsible for persistent, tonic pain
is called the medial system; its tracts pass through the central core of the brain stem.
Among the more salient properties of the lateral system are the rapid conduction of impulses and an organization
that maps the relative position of body sites. These properties would enable the system to give rise to sudden, sharp
pain in a readily identified spot in the body. Kenneth L. Cassy of the University of Michigan at Ann Arbor and I have
proposed that the lateral tracts also account to a great extent for the sensory qualities of pain, such as throbbing
The activity of
the lateral system is apparently dampened rather quickly, which would explain why phasic pain often subsides promptly. The
inhibition is accomplished by a system of neurons that originates in what is called the periaqueductal gray matter in
the part of the brain stem known as the midbrain. This descending system sends signals downward to the dorsal horns, where
it inhibits the transmission of pain signals from the peripheral nerves to ascending tracts. After an injury, it is apparently
activated by the Dody's own opioids (endorphins and enkephalins).
If, as we suggest, the lateral system carries
the signals that give rise to sudden, phasic pain, then it is not surprising that the system is naturally subject to powerful
inhibition. Sudden pain from a newly acquired injury opioid will overwhelm an animal, presenting it from fighting, running
for rover or burrowing to escape a predator during an emergency.
The other pain-signaling
system— the medial system—differs from the lateral system in many ways. For example, a number of its tracts send
impulses to the limbic system, which comprises the subcortical regions of the brain involved in motivation and effect. Hence,
we think the medial system controls the emotional component of pain, producing qualities one night describe as wretched, terrifying,
vicious and the like. The system also influences the actions one takes in response to such feelings.
Because the medial
system conducts signals relatively slowly through many small neurons, it is not well suited for providing precise information
during emergencies. Instead it is more suited for producing diffuse, unpleasant feelings for some time after an injury has occurred. Such feelings would help
ensure that, having survived an immediate threat, a wounded individual would feel miserable and so remain inactive long
enough to heal.
Where does morphine
exert its effects? In both the lateral (phasic-pain) and the medial (tonic-pain) systems, morphine clearly has some direct
effect at the dorsal horns. It is also well known that morphine can activate the descending inhibitory system originating
in the periaqueductal gray matter. Abbott and others in my laboratory have found that this descending system has a greater impact on
the lateral system than on the medial system, which suggests that much of morphine's power over sudden, phasic pain
is mediated by the descending neural tracts. Morphine's analgesic activity certainly
is not confined to the dorsal horns and the mid-brain. For instance, strong evidence indicates that morphine acts on the limbic
system, which is known to play a major role in both pain and pleasure. Such activity could well dampen the pain sensations
produced by the medial (tonic-pain) system, which sends a great many impulses to the limbic system.
A recent study by
S. Robin Cohen, my student, and myself lends additional support to the idea that morphine's influence over the medial
system derives in part from activity above the midbrain. We injected morphine into the habenula, a small region of the
brain (just behind the thalamus) that has strong links with the limbic system and a part of the medial system in the
midbrain. The injections produced analgesia 'in the formalin test but not in the foot-flick test (similar to the tail-flick
test), which suggests that morphine acts at the habenula and that, when it does, it inhibits the medial but not
the lateral system. This finding and others indicate that more research should be devoted to areas above the midbrain
if investigators are to gain a fuller understanding of how morphine eases persistent, tonic pain without inducing tolerance
to repeated doses of the drug. In view of the complexity of the neural
mechanisms of pain, it is not surprising that morphine's ability to produce analgesia has been found to vary greatly from
person to person. An important message emerging from studies of such variation is that the need for a high dose is not necessarily
a sign of addiction.
In one such study
involving cancer patients, Robert Kaiko, now at the Purdue Frederick Company in Norwalk, Conn., and his colleagues at the
Memorial Sloan-Kettering Cancer Center found that to achieve a given level of analgesia, less morphine was needed by
older patients than by younger patients, and less was needed by blacks than by whites. Similarly, patients with dull
pain needed lass morphine than did those with sharp pain, and patients with stomach pain needed less morphine than did
patients with pain in the chest or arm.
Genetic factors might
also influence an individual's response to the analgesic power of narcotics, as Anthony L. Vaccarino (my student), R.
Andrew R. Tasker, now at the University of Prince Edward Island, and I learned recently when we examined the effects of morphine
and its antagonist naloxone in a strain of mice specially bred for studies of immunologic function. We unexpectedly found
that the "antagonist" actually enhanced morphine analgesia and produced analgesia on its own in rats subjected to
the formalin test. These surprising findings, which so far have been documented only for this strain of mice, are clearly
the result of a genetic anomaly. The discovery of a genetic influence on morphine's
actions raises the possibility that susceptibility to addict on might also have a genetic component in some people. Evidence
collected by other groups is consistent with that idea, although little work addresses the problem directly.
There is no way to
identify patients who might be genetically predisposed to morphine addiction, but I must emphasize again that a person's
psyche^-logical history is indicative of risk. More than 50 percent of
narcotics I abusers have had bouts of major depression, and 87 percent have a history of psychiatric disorder.
Society's failure to distinguish between the emotionally
impaired addict and the psychologically healthy pain sufferer has affected every segment of the population. Perhaps the
most distressing example is unnecessary pain in children. Many health-care workers
under-treat pain in youngsters, not only because of fear of addiction but also because of the mistaken belief that young
children do not feel pain as intensely as adults. In a classic study, Joann M. Eland and Jane E. Anderson of the University
of Iowa found in 1977 that more than half of the children from four to eight years old who underwent major surgery—including
limb amputation, excision of a cancerous neck mass and heart repair—were given no medication for relief of their postoperative pain; the remainder received
inadequate doses. When 18 of the children were matched with adults who underwent similar procedures, the children
as a group were found to have been given a total of 24 doses of analgesic drugs, whereas the adults were given a total of 671 doses.
The elderly also pay the penalty of
ignorance. In a
study of post-surgical pain my colleagues and I found that surgical wards contain two basic populations: a young and
middle-aged group that recovers quickly and an older group whose pain remains severe and lingers for many days beyond
the normal three- to four-day recovery period. Despite the persistent, high level of pain in these older patients (presumably
because of complications that arise after surgery) and despite the longer recovery period, they do not receive larger doses
or a higher daily amount of medication. About 30 percent of the patients on a surgical ward at any time fall into this older
category; they thus represent a substantial number of people who suffer needlessly high levels of pain.
The pain suffered by burn victims is known to be agonizing, and
yet it, too, tends to be poorly controlled. Manon Choiniere of the Burn Center at the Hotel Dieu in Montreal and I found that
even in the best burn facilities—those with highly capable, compassionate physicians, nurses, physiotherapists
and others—pain levels are high. Our study of 30 consecutive patients who underwent debridement and physiotherapy
(exercise to prevent loss of joint flexibility) classified the seventy of pain on the basis of the pain questionnaire
I developed with Torgerson. We discovered that during treatment in the first two weeks, 23 percent had severe ("horrible") pain, and 30 percent
had extremely severe ("excruciating") pain. Even when the patients were at rest, 13 percent of
them reported having severe pain, and another 20
percent said they had extremely severe pain. These data, by the way, were obtained from patients who were already medicated
according to standard textbook recommendations (that is, the drug order said "PRN").
For many patients
who are hospitalized for surgery or burns or who have terminal cancer, the prescription is clear: a preventive approach
to pain should be instituted to maximize the effectiveness of narcotics therapy. What, though, should be done for people
who suffer from debilitating" chronic pain but who do not have a fatal illness? These people have traditionally been
excluded from long-term therapy with narcotics, again for fear they would become addicts.
Consider the case of a 26-year-old athlete who sustained a major spinal injury that caused him to suffer from excruciating
pain in the back and legs. The pain rendered him unable to work, and he became a burden to himself, his family and society,
which pays his medical bills. His physician discovered that small doses of morphine taken orally each day (the way cancer
patients receive them) obliterated the pain. With the help of the medication, the young man resumed working and made
plans to marry his childhood sweetheart, who was accepting of his injury. One
day, however, the physician was accused by his regional medical association of prescribing narcotics for a purpose unapproved
by the association and of turning the patient into an addict. Fearful of losing his medical license, the physician
stopped prescribing the drug. (Where morphine administration is allowed by law, physicians can technically prescribe
it at will, but they are in fact restricted by the regulations of medical societies, which control licensing.) Of course, the young man's pain returned. In desperation, he turned to other physicians and was rebuffed.
He then sank rapidly into depression and again became mired in helplessness and hopelessness.
It was once unthinkable to give narcotics indefinitely
to patients who were not terminally ill. Yet studies designed to examine addiction specifically in such patients
are beginning to show that for them, as for the standard candidates for narcotics therapy, these drugs can be helpful without producing addiction.
In one recent study
Russell K. Portenoy and Kathleen M. Foley of Sloan-Kettering maintained 38 patients on narcotics for severe, chronic non-cancer
pain; half of the patients received opioids
for four or more years, and six of these were treated for more than seven years. About 60 percent of the 38 patients reported
that their pain was eliminated or at least reduced to a tolerable level. The therapy became problematic in only two patients,
both of whom had a history of drug abuse. With cautious optimism, Portenoy and
Foley suggest that morphine might be a reasonable treatment for chronic pain in many patients who are not terminally ill.
They point out the problems that may accompany narcotics maintenance therapy, and they provide careful guidelines for
monitoring patients. Studies such as theirs are doing something in medicine that is akin in aeronautics to breaking the
sound barrier. They represent a breakthrough to a reasoned, unbiased examination of the effectiveness of narcotics
In patients who have rarely been considered for such therapy.
Among the critics
of long-term narcotics therapy for such patients are physicians and others who fear that people will simply be given
a prescription for a drug and will never receive the advantages of a multidisciplinary approach to the care of pain.
Yet both approaches are compatible; in fact, they complement each other. For
the future, many more well-controlled studies are needed to provide data on the long-term effects of narcotics on
chronic non-cancer pain. At the same time, medical and government agencies must provide the authorization and funds
for such studies to take place. The goal is nothing short of rescuing people whose lives are now being ruined by pain.
narcotic analgesics in clinical practice. R. G. Twycross in Advances in Pain Research and Therapy, Vol. 5. Edited by John
J. Bonica et al. Raven Press, 1983.
chronic use of opioid analgesics in non-maugnant pain: report of 38 cases. R. K. Portenoy and K. M. Foley in Pain, Vol. 25, pages
the challenge of pain. Revised edition. Ronald Melzack and Patrick Wall. Penguin USA, 1989.
textbook of pain. Second edition. Edited by Patrick D. Wall and Ronald Melzack. Churchill Livingstone, Inc., 1989.
influence of the pain and symptom
control team (PSCT)
on the patterns of treatment of pain and other symptoms in a cancer center.
Eduardo Bruera, Carleen Brenneis, Mary Michaud and R. Neil MacDona'd in Journal of Pain and Symptom Management,
Vol. 4, No. 3, pages 112-116; September, 1989.