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.

Equally persuasive 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.

Further evidence 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.

The pain-signaling 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 or burning.

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.

FURTHER READING

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 171-186; 1986.

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.