much a part of the daily experience of large numbers of British citizens for us to scoff at the inability of our American cousins to tackle their problems. Much remains to be done on both sides of the Atlantic. KEN JUDGE
Director, King's Fund Institute, London NW1 7NF
I Enthoven AC, Kronick R. Universal health insuLrance through incentives rcform. 7A..1LA
1991;265:2532-6.
2 I-riedmani E. The uninstired: from dilemma to crisis. 7AMA 1991;265:2491-5. 3 Spriniger M1D, Lundberg GD. Foresword. In: Caring Jor the uninsured and underinsured. Chicago: American Medical Association, 1991. 4 Lundberg GD. National health care reform: an aura of inevitability is tipon tLis. _7J.m 1991 ;265:2566-7. 5 Blenidon RJ, Edwards JN. C arittg for the uninsured: choices for reform.jA.M1A 1991;265:2563-5. 6 Gittzberg E, Ostow M. Bevond universal health insturanice to effective health care. 7AMA
1991;265:2559-62.
Haemopoietic growth factors Stimulation of white cells and platelets may transform cancer chemotherapy The development of effective chemotherapy for cancer has been limited by drug resistance and the toxic effects of treatment on normal tissues, predominantly the bone marrow. The emergence of drug resistance may be prevented by the early use of drug combinations in full "conventional" doses delivered on schedule, and in some tumours resistance may be overcome by escalating the dose.' The problem of the bone marrow toxicity of current chemotherapeutic regimens may now also be solvable by the use of haemopoietic growth factors, and these may also allow the safer administration of more intensive treatments. These growth factors regulate the production of the mature cellular constituents of the blood. They include specific granulocyte, macrophage, and granulocyte-macrophage colony stimulating factors; interleukin 3; and erythropoietin.2 Although the precise part these factors play in maintaining steady state numbers of blood cells is uncertain (except in the case of erythropoietin), the clinical administration of recombinant haemopoietic growth factors does lead to large increases in circulating cell counts. Very high doses of cytotoxic treatment that would normally cause permanent bone marrow aplasia may be used with the technique of haematological "rescue" with previously stored cryopreserved marrow or haemopoietic progenitors harvested from the peripheral blood.3 Such procedures, however, cause substantial morbidity, though the mortality is relatively low. The adverse effects are largely due to the period of profound cytopenia while the reinfused progenitors divide and differentiate into mature cells. Both granulocyte-macrophage and granulocyte colony stimulating factors have been shown in several uncontrolled studies to accelerate this process and shorten the period of neutropenia, but these factors have no consistent effects on the recovery of platelets or red cells.46 Prospective randomised placebo controlled trials are in progress to determine whether this enhancement of the recovery of neutrophils has objective benefits such as lower infection rates and a reduced time in hospital. Treatment with haemopoietic growth factors is unlikely to reduce mortality since death from infection often occurs in the period of most severe neutropenia and this is unaffected by such treatment. Death is also commonly caused by toxicity to other organs, predominantly the lungs.7 Treatment with haemopoietic growth factors has been well tolerated: the granulocyte macrophage factor may cause low grade fever, bone pain, and a capillary leak syndrome (the last only at very high doses),5 and the granulocyte factor may cause bone pain.8 These symptoms are usually controllable by simple measures. Both factors may be given by subcutaneous injection, which provides effective plasma concentrations for 24 hours.9 Antibodies to granulocyte-macrophage colony stimulating factor have been reported to develop in a few patients, but their clinical importance is as yet unclear.'0 1164
Receptors for growth factors, mainly granulocyte-macrophage colony stimulating factor, are present on several malignant cell lines, including small cell lung cancer cells," but any stimulation of growth of primary cells from biopsy specimens of solid tumours is rare.'2 There has been no suggestion so far of any acceleration of growth or increase in relapse rate of tumours in patients receiving haemopoietic growth factors, but prospective studies are needed to confirm this. Almost all patients with chemosensitive malignant disease given cytotoxic drugs receive them in standard doses, and several trials have shown that treatment with growth factors reduces the neutropenic morbidity associated with such conventional chemotherapy.'3 14 This, however, seems an expensive way of making already well tolerated treatment regimens more tolerable. What treatment with haemopoietic growth factors also offers is the chance to address the question: does early exposure of a tumour to higher cytotoxic doses or to standard regimens without dose reductions or delays enforced by bone marrow toxicity improve response rates and, ultimately, survival? Eventually, with the drugs currently available other side effects-for example, the cardiotoxicity of anthracyclines-may become limiting. If higher doses of cytotoxic drugs are given thrombocytopenia becomes more likely and may need supportive treatment. Interleukin 3 and interleukin 6 produce megakaryocyte colonies in vitro, and both are now being evaluated for their ability to increase platelet numbers in vivo.'6 In the future, combination treatment with haemopoietic growth factors - for example, granulocyte-macrophage colony stimulating factor and interleukin 3-is likely to prove more successful than treatment with single factors. Trials are also in progress to assess whether treatment with erythropoietin can improve the anaemia of malignancy and reduce requirements for transfusion of red cells. Early results suggest that it may do SO. '7
In addition to their actions on progenitor cells, growth factors enhance many of the functions of mature granulocytes and monocyte-macrophages, including microbial phagocytosis and killing and antitumour cytotoxicity.2 These effects have been shown both in vitro and in cells taken from patients receiving growth factors.' '1 This raises the possibility of using growth factors as adjuncts to standard antimicrobial treatment-for example, in the treatment of systemic fungal infection in immunocompromised patients - and as antitumour agents, perhaps in combination with tumour specific monoclonal antibodies. Not all the effects of haemopoietic growth factors on phagocyte function, however, are necessarily beneficial -granulocyte-macrophage colony stimulating factor has been shown to impair the ability of neutrophils to migrate into an inflammatory site,20 and the widespread activation of neutrophils has the potential to cause damage to vascular endothelium. BMJ VOLUME 302
18 MAY 1991
Growth factor technology has moved very quickly from the laboratory to the bedside, and it is too early to reach any firm conclusions. Probably the most effective way of using growth factors will be in combination as many have been shown to be synergistic in vitro and in preclinical studies.'5 New factors are being identified and include molecules that act as negative regulators of the activity of haemopoietic stem cells,2' thus opening up the possibility of protecting normal cells from the effects of cytotoxic treatment. The ultimate place of growth factors in cancer medicine will be determined only from properly controlled trials with clinical end points-not by inferring benefit from changes in blood counts alone. ASIM KHWAJA Wellcome Research Fellow ANTHONY H GOLDSTONE Consultant
Department of Haematology, University College and Middlesex School of Medicine, University College Hospital, London WC1E 6AU I DeVita VT. IPrinciples of chemotherapy. In: DeV'ita vr, ed. Cancer principles and practice of Onzcology%. Philadelphia: Lippincott, 1989:276-96. 2 Clark SC, Kamen R. I'he huiman hematopoietic colony-stimulating factors. Science 1987;236: 1229-37. 3 Goldstone AH, Gribben J(i. 'I'he rolc of autologotis bone marrow transplantation in the treatment of malignant disease. Blood Rez, 1987;1:193-200. 4 Deesreux S, Linch DC, (iribben JG, McMillan A, Patterson K, Goldstone AH. (iM-CSF
accelerates neutrophil recovery aftcr autologotus bone marrow transplantation for Hodgkin's disease. BonelMarrov Transplant 1989;4:49-54. 5 Brandt SJ, Peters WP, Atwater SK, et al. Effects of recombinant human granulocitc-macrophage colony-stimulating factor on hematopoietic reconstituition after high-dosc chcmothcrapy and autologous bone marrow transplantation. N EnglJ Med 1988;318:869-76. 6 Sheridan WP, Morstyn (, Wolf M, et al. Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lancet 1989;ii:891-5. 7 (ioldstone AH, Khwaja A. The role of haemopoietic growth factors in bone marrow transplantation. - Leuk Res 1990;14:721-3(0. 8 Morstvn G, Campbell L, Souza LM, et al. Effect of granulocyte colonv-stimulating factor on neutropenia indtuced by cytotoxic chemotherapy. Lancet 1988;i:667-72. 9 Cebon J, Dempsey P, Fox R, et al. Pharmacokinetics of human granulocyte-macrophage colonystimulating factor using a sensitive immunoassay. Blood 1988;72:1340-7. 10 Gribben JG, Devereux S, 'Thomas NSB, et al. Devclopment of antibodies to unprotected glycosylation sites on recombinant human GM-CSF. Lancet 1990;335:434-7. 11 Baldwin GC, Gasson JC, Kaufman SE, et al. Nonhematopoietic tumour cells express functional GM-CSF receptors. Blood 1989;73:1033-7. 12 Salmon SE, Liu R. Effects of granulocyte-macrophagc colony-stimulating factor on in vitro growth of human solid tumors. J Clin Oncol 1989;7:1346-50. 13 Bronchud MH, Scarffe JH, [hatcher N, et al. Phase I/II study of recombinant human granulocyte colony stimulating factor in patients receiving intensive chemotherapy for small cell lunig cancer. BrJ Cancer 1987;56:809-13. 14 Herrmann F, Schulz G, Wieser Ai, et al. Effect of granulocyte-macrophage colony stimulating factor on neutropenia and related morbidity induced by myclotoxic chemotherapy. Am j AMed 1990;88:619-24. 15 Devereux S, Linch DC. Present status of haemopoietic growth factors. QJ Med 1990;75:537-50. 16 Ganser A, Lindemann A, Ottman O(G, et al. Effect of recombinant human interleukin-3 in vivo-a phase I trial. Exp Hematol 1989;17:40. 17 Medenica R, Huschart T. Ervthropoietin prevents anemia in chemotherapy cancer patients. Blood 1990;76(suppl 1):154a. 18 Jaswon 1\S, Khwaja A, Jones HM, Roberts PJ, Linch D)C. 'I'he effect of rh(.M-CSF on the neuttrophil respiratory burst in whole blood. BrJ7Haemaiol 1990;75:181-7. 19 Khwaja A, Johnson B, Addison IE, ct al. In vivo effects of macrophage colony stimtllating factor on human monocyte function. Br_7 Haematol 1991;77:25-31. 20 Addison IE, Johnson B, Devereux S, Goldstone AH, Linch DC. Granulocyte-macrophage colony stimulating factor may inhibit ncutrophil migration in sivo. Clin Exp Immunol 1989;76:149-53. 21 Graham GJ, Wright EG, Hewick R, et al. Identification and characterization of an inhibitor of haemopoietic stem cell proliferation. Nature 1990;334:442-4.
Taking pains to take away pain Time for hospitals to set up an acute pain service The inadequacy of postoperative pain relief is shameful. But, for at least a decade, drawing attention to the inadequacies of current practice has provoked a familiar response: if only enough people were available to minister to our patients' suffering any one of several approaches could provide very satisfactory comfort. This is no longer good enough. Pain After Surgery, commissioned jointly by the Royal College of Surgeons and the College of Anaesthetists, suggests how things may be improved, here and now. ' Basic physiological and pharmacological research continues to emphasise the plasticity and diversity of nociception,2 and prospects for a "magic bullet"are no closer. Applying present knowledge more conscientiously promises more immediate therapeutic returns. Testing the many permutations and combinations of promising options requires many patients and much patience because the central assessments -pain and pain relief-are inherently imprecise. It is no work for university departments pressed for short term returns, but it does lend itself to perseverance in a well audited clinical setting.
The conventional approach to relieving severe postoperative pain is to give intermittent intramuscular injections of opioids at doses determined by medical guesswork and intervals determined by nursing expediency. Newer approaches address themselves to the limitations of this approach-for example, patient controlled analgesia with doses of systemic opioids tailored to the patient's individual perceptions of pain.34 But modestly supraoptimal doses are liable to impair ventilatory responsiveness, particularly to obstructive challenges. Depending on the severity of the pain, prostaglandin synthetase inhibitors may partially or completely replace opioids, but alternative or additional drugs have their own risks, and the therapeutic index of the replacement or combination may not necessarily be improved. BMJ
VOLUME 302
18 MAY 1991
Various forms of regional analgesia attempt to circumvent the limited therapeutic index of opioids given systemically. Intrathecal or epidural administration of opioids is intended to bathe target segments of the spinal cord with opioid-laden cerebrospinal fluid while the systemic concentrations remain low.5 The unpredictable mobility of the cerebrospinal fluid may, however, cause the brain stem to be bathed as well and stop breathing. The unpredictability of a rare catastrophe is perceived as more dangerous than the familiar ventilatory depression with systemic opioids. The conventional wisdom is not to use intrathecal or epidural opioids in patients who cannot be closely nursed: consequently very effective pain relief is withheld from most patients undergoing major surgery. But all concerted attacks on severe postoperative pain carry risks that are too big to neglect but too small to quantify easily. Sufficiently confident estimates of relative risk have not been made to justify strong statements about either the relative merits of different analgesic approaches or the effectiveness of optimal analgesia in reducing mortality, morbidity, or the costs of treatment. Conventional approaches tend to be favoured by default. It is probably also true, however, that the inherent risks of each approach are much smaller than the avoidable risks arising from the failure of equipment, human error, poor communication, and poor education. Some anaesthetists feel under pressure to provide more effective pain relief by using more aggressive measures. Pain After Surgery endorses guidelines that are emerging to reduce the recognised risks of using such measures. Because pain that has been recorded is less easily ignored assessments of pain should be included in the regular recording of vital signs. Once an analgesic approach is chosen it should be put into effect meticulously. Clear prescriptions for continuing management should be backed up by clear 1165
Director, King's Fund Institute, London NW1 7NF
I Enthoven AC, Kronick R. Universal health insuLrance through incentives rcform. 7A..1LA
1991;265:2532-6.
2 I-riedmani E. The uninstired: from dilemma to crisis. 7AMA 1991;265:2491-5. 3 Spriniger M1D, Lundberg GD. Foresword. In: Caring Jor the uninsured and underinsured. Chicago: American Medical Association, 1991. 4 Lundberg GD. National health care reform: an aura of inevitability is tipon tLis. _7J.m 1991 ;265:2566-7. 5 Blenidon RJ, Edwards JN. C arittg for the uninsured: choices for reform.jA.M1A 1991;265:2563-5. 6 Gittzberg E, Ostow M. Bevond universal health insturanice to effective health care. 7AMA
1991;265:2559-62.
Haemopoietic growth factors Stimulation of white cells and platelets may transform cancer chemotherapy The development of effective chemotherapy for cancer has been limited by drug resistance and the toxic effects of treatment on normal tissues, predominantly the bone marrow. The emergence of drug resistance may be prevented by the early use of drug combinations in full "conventional" doses delivered on schedule, and in some tumours resistance may be overcome by escalating the dose.' The problem of the bone marrow toxicity of current chemotherapeutic regimens may now also be solvable by the use of haemopoietic growth factors, and these may also allow the safer administration of more intensive treatments. These growth factors regulate the production of the mature cellular constituents of the blood. They include specific granulocyte, macrophage, and granulocyte-macrophage colony stimulating factors; interleukin 3; and erythropoietin.2 Although the precise part these factors play in maintaining steady state numbers of blood cells is uncertain (except in the case of erythropoietin), the clinical administration of recombinant haemopoietic growth factors does lead to large increases in circulating cell counts. Very high doses of cytotoxic treatment that would normally cause permanent bone marrow aplasia may be used with the technique of haematological "rescue" with previously stored cryopreserved marrow or haemopoietic progenitors harvested from the peripheral blood.3 Such procedures, however, cause substantial morbidity, though the mortality is relatively low. The adverse effects are largely due to the period of profound cytopenia while the reinfused progenitors divide and differentiate into mature cells. Both granulocyte-macrophage and granulocyte colony stimulating factors have been shown in several uncontrolled studies to accelerate this process and shorten the period of neutropenia, but these factors have no consistent effects on the recovery of platelets or red cells.46 Prospective randomised placebo controlled trials are in progress to determine whether this enhancement of the recovery of neutrophils has objective benefits such as lower infection rates and a reduced time in hospital. Treatment with haemopoietic growth factors is unlikely to reduce mortality since death from infection often occurs in the period of most severe neutropenia and this is unaffected by such treatment. Death is also commonly caused by toxicity to other organs, predominantly the lungs.7 Treatment with haemopoietic growth factors has been well tolerated: the granulocyte macrophage factor may cause low grade fever, bone pain, and a capillary leak syndrome (the last only at very high doses),5 and the granulocyte factor may cause bone pain.8 These symptoms are usually controllable by simple measures. Both factors may be given by subcutaneous injection, which provides effective plasma concentrations for 24 hours.9 Antibodies to granulocyte-macrophage colony stimulating factor have been reported to develop in a few patients, but their clinical importance is as yet unclear.'0 1164
Receptors for growth factors, mainly granulocyte-macrophage colony stimulating factor, are present on several malignant cell lines, including small cell lung cancer cells," but any stimulation of growth of primary cells from biopsy specimens of solid tumours is rare.'2 There has been no suggestion so far of any acceleration of growth or increase in relapse rate of tumours in patients receiving haemopoietic growth factors, but prospective studies are needed to confirm this. Almost all patients with chemosensitive malignant disease given cytotoxic drugs receive them in standard doses, and several trials have shown that treatment with growth factors reduces the neutropenic morbidity associated with such conventional chemotherapy.'3 14 This, however, seems an expensive way of making already well tolerated treatment regimens more tolerable. What treatment with haemopoietic growth factors also offers is the chance to address the question: does early exposure of a tumour to higher cytotoxic doses or to standard regimens without dose reductions or delays enforced by bone marrow toxicity improve response rates and, ultimately, survival? Eventually, with the drugs currently available other side effects-for example, the cardiotoxicity of anthracyclines-may become limiting. If higher doses of cytotoxic drugs are given thrombocytopenia becomes more likely and may need supportive treatment. Interleukin 3 and interleukin 6 produce megakaryocyte colonies in vitro, and both are now being evaluated for their ability to increase platelet numbers in vivo.'6 In the future, combination treatment with haemopoietic growth factors - for example, granulocyte-macrophage colony stimulating factor and interleukin 3-is likely to prove more successful than treatment with single factors. Trials are also in progress to assess whether treatment with erythropoietin can improve the anaemia of malignancy and reduce requirements for transfusion of red cells. Early results suggest that it may do SO. '7
In addition to their actions on progenitor cells, growth factors enhance many of the functions of mature granulocytes and monocyte-macrophages, including microbial phagocytosis and killing and antitumour cytotoxicity.2 These effects have been shown both in vitro and in cells taken from patients receiving growth factors.' '1 This raises the possibility of using growth factors as adjuncts to standard antimicrobial treatment-for example, in the treatment of systemic fungal infection in immunocompromised patients - and as antitumour agents, perhaps in combination with tumour specific monoclonal antibodies. Not all the effects of haemopoietic growth factors on phagocyte function, however, are necessarily beneficial -granulocyte-macrophage colony stimulating factor has been shown to impair the ability of neutrophils to migrate into an inflammatory site,20 and the widespread activation of neutrophils has the potential to cause damage to vascular endothelium. BMJ VOLUME 302
18 MAY 1991
Growth factor technology has moved very quickly from the laboratory to the bedside, and it is too early to reach any firm conclusions. Probably the most effective way of using growth factors will be in combination as many have been shown to be synergistic in vitro and in preclinical studies.'5 New factors are being identified and include molecules that act as negative regulators of the activity of haemopoietic stem cells,2' thus opening up the possibility of protecting normal cells from the effects of cytotoxic treatment. The ultimate place of growth factors in cancer medicine will be determined only from properly controlled trials with clinical end points-not by inferring benefit from changes in blood counts alone. ASIM KHWAJA Wellcome Research Fellow ANTHONY H GOLDSTONE Consultant
Department of Haematology, University College and Middlesex School of Medicine, University College Hospital, London WC1E 6AU I DeVita VT. IPrinciples of chemotherapy. In: DeV'ita vr, ed. Cancer principles and practice of Onzcology%. Philadelphia: Lippincott, 1989:276-96. 2 Clark SC, Kamen R. I'he huiman hematopoietic colony-stimulating factors. Science 1987;236: 1229-37. 3 Goldstone AH, Gribben J(i. 'I'he rolc of autologotis bone marrow transplantation in the treatment of malignant disease. Blood Rez, 1987;1:193-200. 4 Deesreux S, Linch DC, (iribben JG, McMillan A, Patterson K, Goldstone AH. (iM-CSF
accelerates neutrophil recovery aftcr autologotus bone marrow transplantation for Hodgkin's disease. BonelMarrov Transplant 1989;4:49-54. 5 Brandt SJ, Peters WP, Atwater SK, et al. Effects of recombinant human granulocitc-macrophage colony-stimulating factor on hematopoietic reconstituition after high-dosc chcmothcrapy and autologous bone marrow transplantation. N EnglJ Med 1988;318:869-76. 6 Sheridan WP, Morstyn (, Wolf M, et al. Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lancet 1989;ii:891-5. 7 (ioldstone AH, Khwaja A. The role of haemopoietic growth factors in bone marrow transplantation. - Leuk Res 1990;14:721-3(0. 8 Morstvn G, Campbell L, Souza LM, et al. Effect of granulocyte colonv-stimulating factor on neutropenia indtuced by cytotoxic chemotherapy. Lancet 1988;i:667-72. 9 Cebon J, Dempsey P, Fox R, et al. Pharmacokinetics of human granulocyte-macrophage colonystimulating factor using a sensitive immunoassay. Blood 1988;72:1340-7. 10 Gribben JG, Devereux S, 'Thomas NSB, et al. Devclopment of antibodies to unprotected glycosylation sites on recombinant human GM-CSF. Lancet 1990;335:434-7. 11 Baldwin GC, Gasson JC, Kaufman SE, et al. Nonhematopoietic tumour cells express functional GM-CSF receptors. Blood 1989;73:1033-7. 12 Salmon SE, Liu R. Effects of granulocyte-macrophagc colony-stimulating factor on in vitro growth of human solid tumors. J Clin Oncol 1989;7:1346-50. 13 Bronchud MH, Scarffe JH, [hatcher N, et al. Phase I/II study of recombinant human granulocyte colony stimulating factor in patients receiving intensive chemotherapy for small cell lunig cancer. BrJ Cancer 1987;56:809-13. 14 Herrmann F, Schulz G, Wieser Ai, et al. Effect of granulocyte-macrophage colony stimulating factor on neutropenia and related morbidity induced by myclotoxic chemotherapy. Am j AMed 1990;88:619-24. 15 Devereux S, Linch DC. Present status of haemopoietic growth factors. QJ Med 1990;75:537-50. 16 Ganser A, Lindemann A, Ottman O(G, et al. Effect of recombinant human interleukin-3 in vivo-a phase I trial. Exp Hematol 1989;17:40. 17 Medenica R, Huschart T. Ervthropoietin prevents anemia in chemotherapy cancer patients. Blood 1990;76(suppl 1):154a. 18 Jaswon 1\S, Khwaja A, Jones HM, Roberts PJ, Linch D)C. 'I'he effect of rh(.M-CSF on the neuttrophil respiratory burst in whole blood. BrJ7Haemaiol 1990;75:181-7. 19 Khwaja A, Johnson B, Addison IE, ct al. In vivo effects of macrophage colony stimtllating factor on human monocyte function. Br_7 Haematol 1991;77:25-31. 20 Addison IE, Johnson B, Devereux S, Goldstone AH, Linch DC. Granulocyte-macrophage colony stimulating factor may inhibit ncutrophil migration in sivo. Clin Exp Immunol 1989;76:149-53. 21 Graham GJ, Wright EG, Hewick R, et al. Identification and characterization of an inhibitor of haemopoietic stem cell proliferation. Nature 1990;334:442-4.
Taking pains to take away pain Time for hospitals to set up an acute pain service The inadequacy of postoperative pain relief is shameful. But, for at least a decade, drawing attention to the inadequacies of current practice has provoked a familiar response: if only enough people were available to minister to our patients' suffering any one of several approaches could provide very satisfactory comfort. This is no longer good enough. Pain After Surgery, commissioned jointly by the Royal College of Surgeons and the College of Anaesthetists, suggests how things may be improved, here and now. ' Basic physiological and pharmacological research continues to emphasise the plasticity and diversity of nociception,2 and prospects for a "magic bullet"are no closer. Applying present knowledge more conscientiously promises more immediate therapeutic returns. Testing the many permutations and combinations of promising options requires many patients and much patience because the central assessments -pain and pain relief-are inherently imprecise. It is no work for university departments pressed for short term returns, but it does lend itself to perseverance in a well audited clinical setting.
The conventional approach to relieving severe postoperative pain is to give intermittent intramuscular injections of opioids at doses determined by medical guesswork and intervals determined by nursing expediency. Newer approaches address themselves to the limitations of this approach-for example, patient controlled analgesia with doses of systemic opioids tailored to the patient's individual perceptions of pain.34 But modestly supraoptimal doses are liable to impair ventilatory responsiveness, particularly to obstructive challenges. Depending on the severity of the pain, prostaglandin synthetase inhibitors may partially or completely replace opioids, but alternative or additional drugs have their own risks, and the therapeutic index of the replacement or combination may not necessarily be improved. BMJ
VOLUME 302
18 MAY 1991
Various forms of regional analgesia attempt to circumvent the limited therapeutic index of opioids given systemically. Intrathecal or epidural administration of opioids is intended to bathe target segments of the spinal cord with opioid-laden cerebrospinal fluid while the systemic concentrations remain low.5 The unpredictable mobility of the cerebrospinal fluid may, however, cause the brain stem to be bathed as well and stop breathing. The unpredictability of a rare catastrophe is perceived as more dangerous than the familiar ventilatory depression with systemic opioids. The conventional wisdom is not to use intrathecal or epidural opioids in patients who cannot be closely nursed: consequently very effective pain relief is withheld from most patients undergoing major surgery. But all concerted attacks on severe postoperative pain carry risks that are too big to neglect but too small to quantify easily. Sufficiently confident estimates of relative risk have not been made to justify strong statements about either the relative merits of different analgesic approaches or the effectiveness of optimal analgesia in reducing mortality, morbidity, or the costs of treatment. Conventional approaches tend to be favoured by default. It is probably also true, however, that the inherent risks of each approach are much smaller than the avoidable risks arising from the failure of equipment, human error, poor communication, and poor education. Some anaesthetists feel under pressure to provide more effective pain relief by using more aggressive measures. Pain After Surgery endorses guidelines that are emerging to reduce the recognised risks of using such measures. Because pain that has been recorded is less easily ignored assessments of pain should be included in the regular recording of vital signs. Once an analgesic approach is chosen it should be put into effect meticulously. Clear prescriptions for continuing management should be backed up by clear 1165
