of the peak value during a 4-hour dosing cycle (the modulating effect of absorption from the gastrointestinal tract is disregarded in these statements). In general the patient's inactivation rate is beyond the therapist's control. Slow inactivation rates carry the risk of sluggish equilibration with the medication (that is, doses that are well tolerated for 36 to 48 hours may produce dose-related side effects at that time), while rapid inactivation rates result in irreducible swings in drug concentrations within each dosing cycle. The references in their article to the use of antidotes and to unsuccessful relief of pain indicate that Melzack and colleagues have encountered these problems. The observation that pain in some patients is not relieved by massive doses of morphine does not warrant the conclusion that even larger doses will resolve the problem. Increased drug intake does not differentiate between patients who require high blood concentrations for a certain pharmacologic response but in whom the drug is absorbed and metabolized at a normal rate (pharmacologic habituation), and those in whom a high drug intake is needed to ensure a reasonable plasma concentration (metabolic habituation, first-pass effect, enzyme induction, poor drug absorption, etc.). Most therapeutic failures of analgesia, in my experience, occur in the latter group. It is important to realize that by further increasing the individual doses one is not going to solve the problems in such patients. This will merely exchange periods of underdosage for periods of overdosage, a potentially more serious complication, without adding to the useful period within each dosing cycle during which the patient is both alert and free of discomfort, able to relate to his or her surroundings and able to pursue the "work" of resolving whatever problems demand his or her attention. Melzack and colleagues correctly observe that the failure to relieve pain promptly (within a few minutes) is a powerful tool of aversive conditioning resulting in a complex phenomenon known as anticipatory pain. They do not seem to realize, however, that, by the same token, each successful transaction of
prompt relief of pain reinforces psychologic power and self-confidence in most patients. This is lost when drugs are given to them on a fixed schedule. Orally administered drugs, even when available at the bedside, do not act fast enough for such reinforcement. We have had extensive experience with the intravenous administration by the patient of small increments (demand analgesia). We have yet to see patients abuse this technique; indeed, our experience is that when patients are offered a trade-off between some residual pain and a slight clouding of their sensorium, they will opt for full alertness. Satisfactory analgesia has frequently been achieved with one third of the medication dose that previously proved ineffective when different dosing strategies were used. The technique allows a much finer gradation of morphine dosage through constant feedback than can be achieved by the daily adjustment of individual doses. Demand analgesia is less of a technical problem than might be assumed. I urge that it be considered at least in the patients who do not obtain full benefit from the Brompton mixture. M. KEERI-SZANTO, MD, FRCP[C], EcP
Clinical professor of anesthesia University of Western Ontario London, Ont.
To the editor: The issues raised in Dr. Keeri-Szanto's letter are significant. Demand analgesia, as recommended by Dr. Keeri-Szanto, involves repeated intravenous selfadministration of morphine by the patient to control recurrent pain. That the principle of continuously preventing pain can be discarded as "an article of faith" on the assumption that patients with recurring pain acquire "psychologic power and selfconfidence" when their pain is repeatedly successfully treated is curious. The question of whether one would advocate continuous relief of pain or intermittent cyclic return of pain is never an issue if one has the pain oneself. Our aims in treating intractable pain of advanced malignant disease include identification of the cause, prevention of pain, erasure of the memory of pain, an unclouded sen-
18 CMA JOURNAL/JULY 7, 1979/VOL 121
sorium, normal affect and ease of
administration.1 Demand analgesia with intravenously administered drugs fails to meet the second, third and sixth goals, and thus, in our opinion, is unacceptable as the basis for treating intractable pain. Further objection to the intravenous route for treating chronic pain lies in a consideration of pharmacokinetics. Berkowitz and colleagues' have studied the disposition of morphine by radioimmunoassay techniques. The half-life was found to be from 2 to 4 hours, which closely parallels that in the plasma. Because its therapeutic ratio is not large, some important conclusions can be made about both the peak plasma concentration and the frequency of dosing. The aim is to keep the plasma concentration within the zone of efficacy but below the zone of toxicity. Oral administration, which yields a more rounded peak, is safer than intravenous injections. The curve of the latter, though of similar subtending area to that of the former in a plot of dose against time, will have a sharper initial peak that may reach toxic levels at a dose that is safe when given orally. Vere' has presented a helpful review of these issues. Twycross4" has shown, and our experience1 has verified, that narcotic analgesics used as described need not lead to tolerance as a practical problem. Furthermore, psychologic dependence does not occur. While physical dependence may develop, it does not appear to prevent the downward adjustment in dose or even the discontinuation of the narcotic when it is clinically feasible. Increased dose requirements, even after many months of narcotic use, has, in general, suggested, not pharmacologic habituation, but a change in the clinical status of the tumour. The frequency of therapeutic failure is low, as is the median dose of morphine required to treat such patients.6 When pain control is inadequate the significant factor is usually one of the nonphysical components of the patient's "total pain", such as anxiety, depression, insomnia, social stress or unresolved spiritual concerns. These are factors not assisted by further narcotic administration, whether intravenous or oral.
Since pharmacologic habituation is not a problem with this approach, the possibility of malabsorption from the gastrointestinal tract or other metabolic aberrations may be considered as the cause of high-dose requirements. It has been observed, however, that even in the presence of total malignant bowel obstruction absorption does occur and pain can frequently be managed with orally administered narcotics, particularly if the obstruction is low in the gastrointestinal tract.7 In any event, since analgesia is encountered at a lower dose than toxicity, one may rely on the clinical response as a pragmatic and faithful indicator of the appropriate dose for that patient. Individual variation in the disposition of morphine is seen in patients of any age, but it is particularly marked in the very young and very old. However, respiratory depression is caused by opiates given in doses above the analgesic dose except in patients with poor respiratory reserve. Even so, the margin of safety is not wide, particularly when they are given intravenously.3 It follows that one should begin with small doses and work up quickly until the pain is controlled, while watching ventilation at each dose increase. This requires some experience and attention to detail of both doctor and nurse until the effective dose is found. In treating several hundred patients over the past 5½ years we have administered a narcotic antagonist on only two occasions when morphine was used as described: in one case following an error in the dose of narcotic given by a nurse, and in the second case, probably unnecessarily, to a somnolent, terminally ill cancer patient who had long-standing chronic respiratory insufficiency. In short, overdosage is not a problem. As to unsuccessful relief of pain, in our experience considerably less than 10% of patients with intractable pain have unsuccessful pain control when the morphine dose, given orally or, if that fails, given intramuscularly, is titrated carefully to the patient's need and given regularly as described. In Saunders'8 experience 1% (34 of 3362 patients) have had inadequate pain control.
The merit of our approach is not simply the economy and convenience Dr. Keeri-Szanto suggests, but also the documented excellent and reliable control of pain that it affords in an alert patient. We would be concerned if we had to offer a "trade-off" between some residual pain and a slight clouding of the sensorium, as Dr. KeenSzanto describes. In our experience it is possible, with few exceptions, to attain both continuous pain relief and a clear sensorium. Where demand analgesia with intravenously administered agents may have a useful role is in the rapid control of unpredictable episodic pain spasms, where the question is one of acute pain. The rapid effectiveness of the intravenous route in this situation commends it. This problem is, however, irrelevant to the efficacy of orally administered morphine given regularly in the treatment of chronic pain associated with advanced malignant disease.
"The Harvard Guide to Modem Psychiatry" To the editor: Dr. John D. Adamson has commented on my review of the book entitled "The Harvard Guide to Modern Psychiatry" (Can Med Assoc 1 120: 918, 1979). Dr. Adamson's concern about the book's value as the sole source of information for candidates for the Canadian specialty examinations in psychiatry is correct; indeed, in my review I suggested that the book be used by first-year residents only. No one knows for certain whether one should distinguish between endogenous and reactive depressions. Kierman is hardly the first person to suggest that one should not. The data demonstrating the utility of this distinction are open to criticism. Dr. Adamson's comment on the difference of the response between depressed persons taking imipramine and those taking amitriptyline, and much of his concern about Klerman's failure to discuss lithium BALFOUR M. MOUNT, MD, FRCS[C] carbonate, were covered in the Director, palliative care service chapter on chemotherapy by BalAssociate professor of surgery dessarini. This point illustrates that McGill University Montreal, PQ the text allows very little overlap, which I think is a virtue. References It is true that some patients with manic depression remain continu1. MOUNT BM, AJEMIAN I, Scorr JF: ously ill, but it is a matter of Use of the Brompton mixture in treating the chronic pain of malignant opinion whether this small group disease. Can Med Assoc 1 115: 122, should be mentioned in such a 1976 2. BERKOWITZ BA, NGAI SH, YANG JC, short chapter. Klerman did err in et al: The disposition of morphine in failing to mention diurnal mood surgical patients. Clin Pharmacol Ther variation as a useful diagnostic 17: 629, 1975 sign in depression. 3. VERE DW (ed): Pharmacology of It is difficult to understand how morphine drugs used in terminal care, one could produce a shorter textin Topics in Therapeutics, vol 4, Pitbook, as suggested by Dr. Adamman, London, 1978, p 75 4. Twx'caoss RG: Clinical experience son, and also introduce more facts. with diamorphine in advanced malignant disease. mt I Clin Pharmacol 9: 184, 1974
5. Twx'cRoss RG, WALD SJ: Long-term use of diamorphine in advanced can-
cer, in Advances in Pain Research and
MORTON S. RAPP, MD
Associate professor Department of psychiatry University of Toronto Toronto, Ont.
Therapy, vol 1, BoNICA JJ, ALBE-
FESSARD D (eds), Raven Pr, New York, 1976, p 653
Intussusception in infants and children by hydrostatic reduction 6. MELZACK R, OFIEsH JG, MOUNT BM: The Brompton mixture: effects on To the editor: We take issue with pain in cancer patients. Can Med several of the points made by Dr. Assoc 1 115: 125, 1976 7. MOUNT BM: Palliative care of the Joseph N.H. Du in his article on this terminally ill. Ann R Coil Physicians subject (Can Med Assoc 1 119: Surg Can 11: 201, 1978 1075, 1978). Although Dr. Du has 8. SAUNDERS C: Caring for the Dying. discussed most of the modern Presented at the Second International present-day concepts and treatment Seminar on Terminal Care, Montreal, of intussusception, there are several Nov 2, 1978 CMA JOURNAL/JULY 7, 1979/VOL. 121 21
prompt relief of pain reinforces psychologic power and self-confidence in most patients. This is lost when drugs are given to them on a fixed schedule. Orally administered drugs, even when available at the bedside, do not act fast enough for such reinforcement. We have had extensive experience with the intravenous administration by the patient of small increments (demand analgesia). We have yet to see patients abuse this technique; indeed, our experience is that when patients are offered a trade-off between some residual pain and a slight clouding of their sensorium, they will opt for full alertness. Satisfactory analgesia has frequently been achieved with one third of the medication dose that previously proved ineffective when different dosing strategies were used. The technique allows a much finer gradation of morphine dosage through constant feedback than can be achieved by the daily adjustment of individual doses. Demand analgesia is less of a technical problem than might be assumed. I urge that it be considered at least in the patients who do not obtain full benefit from the Brompton mixture. M. KEERI-SZANTO, MD, FRCP[C], EcP
Clinical professor of anesthesia University of Western Ontario London, Ont.
To the editor: The issues raised in Dr. Keeri-Szanto's letter are significant. Demand analgesia, as recommended by Dr. Keeri-Szanto, involves repeated intravenous selfadministration of morphine by the patient to control recurrent pain. That the principle of continuously preventing pain can be discarded as "an article of faith" on the assumption that patients with recurring pain acquire "psychologic power and selfconfidence" when their pain is repeatedly successfully treated is curious. The question of whether one would advocate continuous relief of pain or intermittent cyclic return of pain is never an issue if one has the pain oneself. Our aims in treating intractable pain of advanced malignant disease include identification of the cause, prevention of pain, erasure of the memory of pain, an unclouded sen-
18 CMA JOURNAL/JULY 7, 1979/VOL 121
sorium, normal affect and ease of
administration.1 Demand analgesia with intravenously administered drugs fails to meet the second, third and sixth goals, and thus, in our opinion, is unacceptable as the basis for treating intractable pain. Further objection to the intravenous route for treating chronic pain lies in a consideration of pharmacokinetics. Berkowitz and colleagues' have studied the disposition of morphine by radioimmunoassay techniques. The half-life was found to be from 2 to 4 hours, which closely parallels that in the plasma. Because its therapeutic ratio is not large, some important conclusions can be made about both the peak plasma concentration and the frequency of dosing. The aim is to keep the plasma concentration within the zone of efficacy but below the zone of toxicity. Oral administration, which yields a more rounded peak, is safer than intravenous injections. The curve of the latter, though of similar subtending area to that of the former in a plot of dose against time, will have a sharper initial peak that may reach toxic levels at a dose that is safe when given orally. Vere' has presented a helpful review of these issues. Twycross4" has shown, and our experience1 has verified, that narcotic analgesics used as described need not lead to tolerance as a practical problem. Furthermore, psychologic dependence does not occur. While physical dependence may develop, it does not appear to prevent the downward adjustment in dose or even the discontinuation of the narcotic when it is clinically feasible. Increased dose requirements, even after many months of narcotic use, has, in general, suggested, not pharmacologic habituation, but a change in the clinical status of the tumour. The frequency of therapeutic failure is low, as is the median dose of morphine required to treat such patients.6 When pain control is inadequate the significant factor is usually one of the nonphysical components of the patient's "total pain", such as anxiety, depression, insomnia, social stress or unresolved spiritual concerns. These are factors not assisted by further narcotic administration, whether intravenous or oral.
Since pharmacologic habituation is not a problem with this approach, the possibility of malabsorption from the gastrointestinal tract or other metabolic aberrations may be considered as the cause of high-dose requirements. It has been observed, however, that even in the presence of total malignant bowel obstruction absorption does occur and pain can frequently be managed with orally administered narcotics, particularly if the obstruction is low in the gastrointestinal tract.7 In any event, since analgesia is encountered at a lower dose than toxicity, one may rely on the clinical response as a pragmatic and faithful indicator of the appropriate dose for that patient. Individual variation in the disposition of morphine is seen in patients of any age, but it is particularly marked in the very young and very old. However, respiratory depression is caused by opiates given in doses above the analgesic dose except in patients with poor respiratory reserve. Even so, the margin of safety is not wide, particularly when they are given intravenously.3 It follows that one should begin with small doses and work up quickly until the pain is controlled, while watching ventilation at each dose increase. This requires some experience and attention to detail of both doctor and nurse until the effective dose is found. In treating several hundred patients over the past 5½ years we have administered a narcotic antagonist on only two occasions when morphine was used as described: in one case following an error in the dose of narcotic given by a nurse, and in the second case, probably unnecessarily, to a somnolent, terminally ill cancer patient who had long-standing chronic respiratory insufficiency. In short, overdosage is not a problem. As to unsuccessful relief of pain, in our experience considerably less than 10% of patients with intractable pain have unsuccessful pain control when the morphine dose, given orally or, if that fails, given intramuscularly, is titrated carefully to the patient's need and given regularly as described. In Saunders'8 experience 1% (34 of 3362 patients) have had inadequate pain control.
The merit of our approach is not simply the economy and convenience Dr. Keeri-Szanto suggests, but also the documented excellent and reliable control of pain that it affords in an alert patient. We would be concerned if we had to offer a "trade-off" between some residual pain and a slight clouding of the sensorium, as Dr. KeenSzanto describes. In our experience it is possible, with few exceptions, to attain both continuous pain relief and a clear sensorium. Where demand analgesia with intravenously administered agents may have a useful role is in the rapid control of unpredictable episodic pain spasms, where the question is one of acute pain. The rapid effectiveness of the intravenous route in this situation commends it. This problem is, however, irrelevant to the efficacy of orally administered morphine given regularly in the treatment of chronic pain associated with advanced malignant disease.
"The Harvard Guide to Modem Psychiatry" To the editor: Dr. John D. Adamson has commented on my review of the book entitled "The Harvard Guide to Modern Psychiatry" (Can Med Assoc 1 120: 918, 1979). Dr. Adamson's concern about the book's value as the sole source of information for candidates for the Canadian specialty examinations in psychiatry is correct; indeed, in my review I suggested that the book be used by first-year residents only. No one knows for certain whether one should distinguish between endogenous and reactive depressions. Kierman is hardly the first person to suggest that one should not. The data demonstrating the utility of this distinction are open to criticism. Dr. Adamson's comment on the difference of the response between depressed persons taking imipramine and those taking amitriptyline, and much of his concern about Klerman's failure to discuss lithium BALFOUR M. MOUNT, MD, FRCS[C] carbonate, were covered in the Director, palliative care service chapter on chemotherapy by BalAssociate professor of surgery dessarini. This point illustrates that McGill University Montreal, PQ the text allows very little overlap, which I think is a virtue. References It is true that some patients with manic depression remain continu1. MOUNT BM, AJEMIAN I, Scorr JF: ously ill, but it is a matter of Use of the Brompton mixture in treating the chronic pain of malignant opinion whether this small group disease. Can Med Assoc 1 115: 122, should be mentioned in such a 1976 2. BERKOWITZ BA, NGAI SH, YANG JC, short chapter. Klerman did err in et al: The disposition of morphine in failing to mention diurnal mood surgical patients. Clin Pharmacol Ther variation as a useful diagnostic 17: 629, 1975 sign in depression. 3. VERE DW (ed): Pharmacology of It is difficult to understand how morphine drugs used in terminal care, one could produce a shorter textin Topics in Therapeutics, vol 4, Pitbook, as suggested by Dr. Adamman, London, 1978, p 75 4. Twx'caoss RG: Clinical experience son, and also introduce more facts. with diamorphine in advanced malignant disease. mt I Clin Pharmacol 9: 184, 1974
5. Twx'cRoss RG, WALD SJ: Long-term use of diamorphine in advanced can-
cer, in Advances in Pain Research and
MORTON S. RAPP, MD
Associate professor Department of psychiatry University of Toronto Toronto, Ont.
Therapy, vol 1, BoNICA JJ, ALBE-
FESSARD D (eds), Raven Pr, New York, 1976, p 653
Intussusception in infants and children by hydrostatic reduction 6. MELZACK R, OFIEsH JG, MOUNT BM: The Brompton mixture: effects on To the editor: We take issue with pain in cancer patients. Can Med several of the points made by Dr. Assoc 1 115: 125, 1976 7. MOUNT BM: Palliative care of the Joseph N.H. Du in his article on this terminally ill. Ann R Coil Physicians subject (Can Med Assoc 1 119: Surg Can 11: 201, 1978 1075, 1978). Although Dr. Du has 8. SAUNDERS C: Caring for the Dying. discussed most of the modern Presented at the Second International present-day concepts and treatment Seminar on Terminal Care, Montreal, of intussusception, there are several Nov 2, 1978 CMA JOURNAL/JULY 7, 1979/VOL. 121 21
