- Email: [email protected]
Window of opportunity for pain control in the terminally ill
COMMENTARY
COMMENTARY
Window of opportunity for pain control in the terminally ill See page 1311 “When a man jumps out of the window rather than meet the police he is not choosing the more agreeable. . .It happens only sometimes that when we do not choose the lesser pain or the greater pleasure we choose what will produce these in the long run.”—Wittgenstein
Death and pain are two of the most persistent ingredients of the human condition. The former may be prevented, delayed, or cheated, but eventually overcomes every one. Does the latter also have to triumph? As probably the oldest symptom that faced primitive man, and hence primitive medicine-man or shaman, there has certainly been sufficient time since the dawn of health care for pain, if not death, to be conquered. In 1990 the WHO proclaimed a war on pain associated with cancer (itself a synonym for death in many people’s minds) with its influential report, Cancer and Pain Relief & Palliative Care.1 Yet in 2001, pain with cancer and other chronic disorders remains, more than ever, a major international public-health problem, even though its causes are clear, its pathophysiology is understood in detail, the way it thrives in poverty and among disadvantaged groups is known, and the public can be educated about it. Sometimes it seems as if patients prefer to bear pain rather than heed their physicians. Their Wittgensteinian dilemma is real—do they choose pain because the alternative is even worse, but what is the long-term gain of tolerating pain? In today’s Lancet, Stefan Weiss and colleagues put forward a fairly convincing case that for many people, at least in sections of US society, pain is the better short-term option. Interviews with 988 “terminally ill” patients in six diverse American cities revealed that, although half the patients had moderate or severe pain, only a third were seeking more drug therapy, and one in ten wanted to reduce or stop their medication. One in five had seen a pain specialist and half had seen their primary-care physician in the past month. Reasons for resisting more pain medication included fear of addiction (35%), physical side-effects such as constipation (31%), mental side-effects such as confusion (33%), and reluctance to take more pills or injections (30%). Patients from ethnic minorities were more likely to fear addiction, and depressed people were more likely to be wary of physical side-effects. This study was large, multicentre, and included patients with a variety of diagnoses (half had cancer, and heart disease and chronic obstructive pulmonary disease accounted for a further quarter). Amount of pain and desire for more treatment was similar across diagnoses. This finding is in keeping with a report that patients with 1304
chronic obstructive pulmonary disease have as much pain, as measured with a cancer-specific quality of life instrument, as do lung-cancer patients.2 Weiss and colleagues’ work also echoes studies that have identified patients concerns about analgesics, especially the opioids, as a major reason for refusal. Paice and colleagues3 found, however, that fear of tolerance from starting opioids too early was more powerful than fear of addiction as a barrier to taking medicines. It seems that the patients in Weiss and colleagues’ study were collectively ill-informed about pain, prejudiced possibly by bad experiences, and inadequately cared for by their physicians. This situation is not unique to the USA: only 17% of Israeli physicians reported they could control pain in more than 75% of their patients.4 Their reasons, too, were ineffective treatments (61%) central-nervoussystem (CNS) side-effects (43%), and gastrointestinal side-effects (26%). How reasonable are these fears? Genuinely terminally ill patients prescribed opioids for pain control rarely become addicted.5 Tolerance does develop, but hardly ever to the extent that modern potent opioids lose their effectiveness. A factor underlying tolerance is level of binding of opioid to receptors: drugs such as morphine, which need to occupy more receptors to cause an effect (because they have low intrinsic receptor affinity) are more likely to induce tolerance than those with high intrinsic receptor efficacy, such as fentanyl.6 The induction of tolerance depends crucially on the Nmethyl-D-aspartate (NMDA) receptor ion channel complex in the postsynaptic neurons of the dorsal horn. Activation of the NMDA complex with chronic pain increases sensitivity (“wind-up”) as well as tolerance to opioids. Other recently discovered mechanisms that influence tolerance and responsiveness to opioids involve spinal cholecystokinin, tumour-necrosis factor, neurokinin, and nitric oxide.6,7 Several chemicals can interfere with these mechanisms in animal models, and some are being used clinically. For example, ketamine and synthetic opioids such as ketobemidone and methadone, which block activation of the NMDA complex, have theoretical advantages in the relief of chronic cancer pain, especially when there is a neuropathic component. In a rat model8 the preoperative use of ketamine attentuated the development of post-operative abdominal pain: pre-emptive strikes in human pain syndromes need extensive clinical testing. The gastrointestinal side-effect of opioids and NSAIDs, especially dry mouth, nausea, and constipation may be sufficient to turn patients away from the potential benefits of these agents.3 The most persistent and devastating problem is constipation. In animal studies
THE LANCET • Vol 357 • April 28, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
Pyramid model for symptom control Surgical and physical procedures
Pharmacological palliation
Psychological and nursing interventions
Disease-modifying therapies Multidisciplinary and multimodal symptom control in cancer and chronic diseases, with any or all of the approaches represented on the pyramid faces, as appropriate for the patient's current needs, prognosis, and severity of the symptom. Reproduced with permission from Sam Ahmedzai, Andreas Lübbe, and Bart Van den Eynden
drugs that have a high penetration into the central nervous system because of lipophilicity, such as fentanyl, are less likely to cause constipation for the same degree of analgesia as drugs such as morphine, that do not penetrate centrally so well.9 This finding was also obtained in a multicentre randomised controlled trial, which showed constipation rates of 44·5% with morphine and 27·2% with transdermal fentanyl.10 This relative lack of constipation with fentanyl persisted many months into follow-up after entry into the trial.11 Patients need to be informed of these differences, so that they can choose the drug that suits their lifestyle and preferred side-effect profile. The other major dread of chronic pain patients is the sedation and cognitive impairment associated with the stronger opioids. Oxycodone acts on the opioid receptor, but it is not yet clear from randomised controlled trials whether it has an advantage over morphine ( receptor) in terms of mental obtundation. Interestingly, in an animal model the co-administration of subanalgesic doses of oxycodone not only enhanced the antinociceptive effect of morphine, but was also associated with a reduction in CNS side-effects.12 An alternative strategy to reduce sedation and also enhance analgesia is the concurrent use of psychostimulants such as methylphenidate with opioids,13 but physicians are inexplicably resistant to this approach, especially in Europe. Patients can justifiably think that residual pain is worth trading off against the toxic effects of commonly used drugs. But there are many other approaches for pain control in cancer and in chronic diseases. The WHO three-step pain ladder1 (put simply, non-opioid, weak opioid, strong opioid) has served well for the use of oral analgesics, but it overlooks the benefits of many other means of pain relief. A new model which is based on a pyramid to allow for multiple simultaneous attacks on symptoms, was presented and favourably received at a meeting in Geneva in September, 1999, of the European Association for Palliative Care (EAPC) held under the auspices of the Europena Organisation for Research and Treatment of Cancer, WHO, and the US National Cancer Institute. Pain due to cancer responds well to modern palliative chemotherapy, hormone manipulation, and radiation. Bisphosphonates and systemic radioisotopes can be very helpful in the long-term
THE LANCET • Vol 357 • April 28, 2001
management of metastatic bone pain. Nerve blocks with local anaesthetics or with neurolytics have increasingly become more useful with improvements in imaging and selection of cases. Psychological approaches such as cognitive behavioural therapy have little of the toxicities that patients dread.5 Intractable angina responds to spinal-cord stimulation, when drug therapy has lost its effect and merely produces toxic effects.14 Many of these approaches, such as spinal catheterisation and long-term intrathecal drug administration by external or implanted pumps are expensive, but in chronic pain they can pay for themselves in terms of reduced other health-care costs. Can society afford not to pay for good pain control? Furthermore, why is the management of pain in the terminally ill started so late? From what is known about spinal neurotransmission and the prevention of chronic pain and opioid tolerance by pre-emptive striking, patients would be better served by education and therapy early in their illnesses. Admittedly such an approach might make little difference in some cancers, but numerically the impact of pain prevention in nonmalignant disease could be very far-reaching. To come back to Wittgenstein’s fleeing man—to save a patient jumping out of the window, would it not help if a knock on the door came from a multidisciplinary team of clinicians backed by laboratory and clinical evidence, to offer pain relief? Sam Hjelmeland Ahmedzai Academic Palliative Medicine Unit, University of Sheffield, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK (e-mail: [email protected]) 1 2
3
4
5
6
7
8
9
10
11
12
13
14
WHO. Cancer pain relief and palliative care. WHO Tech Rep Ser 804. Geneva: WHO, 1990. Skilbeck J, Mott L, Page H, Smith D, Ahmedzai SH, Clark D. Palliative care in chronic obstructive airways disease: a needs assessment. Palliat Med 1999; 12: 245–54. Paice JA, Toy C, Shott S. Barriers to cancer pain relief: fear of tolerance and addiction. J Pain Symptom Manage 1998; 16: 1–9. Sapir R, Catane R, Strauss-Liviatan, Cherny NI. Cancer pain: knowledge and attitudes of physicians in Israel. J Pain Symptom Manage 1999: 17: 266–76. Beitbart W, Passik S, Payne D. Psychological and psychiatric interventions in pain control. In: Doyle D, Hanks GWC, McDonald N (eds). Oxford textbook of palliative medicine. Oxford: Oxford University Press, 1998: 437–54. Mercadante S, Portenoy RK. Opioid poorly-responsive cancer pain. Part 2: basic mechanisms that could shift dose response for analgesia. J Pain Symptom Manage 2001; 21: 255–64. Inturrisi CE. Opioid pharmacology: tolerance, receptor modulation and new analgesics. In: Payne R, Patt RB, Stratton Hill C (eds). Assessment and treatment of cancer pain. Seattle: IASP Press 1998; 275–88. Burton AW, Lee DH, Saab C, Chung JM. Pre-emptive intrathecal ketamine injection produces a long-lasting decrease in neuropathic pain behaviors in a rat model. Regional Anaesth Pain Med 1999; 24: 208–13. Megens A, Artois K, Vermeire J, et al. Comparison of the analgesic and intestinal effects of fentanyl and morphine in rats. J Pain Symptom Manage 1998; 15: 253–57. Ahmedzai S, Brooks DJ. Transdermal fentanyl versus sustainedrelease oral morphine in cancer pain: preference, efficacy and quality of life. J Pain Symptom Manage 1997: 13: 254–61. Nugent M, Davis S, Brooks D, Ahmedzai SH. Long-term observations of patients receiving transdermal fentanyl after a randomised trial. J Pain Symptom Manage (in press). Ross FB, Wallis SC, Smith MT. Co-administration of subantinociceptive doses of oxycodone and morphine produces marked antinociceptive synergy with reduced CNS side-effects in rats. Pain 2000; 84: 421–28. Dalal S, Melzack R. Potentiation of opioid analgesia by psychostimulant drugs: a review. J Pain Symptom Manage 1998; 16: 245–53. Nurmikko TJ, Nash TP, Wiles JR. Control of chronic pain. BMJ 1998; 317: 1438–41.
1305
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
Window of opportunity for pain control in the terminally ill See page 1311 “When a man jumps out of the window rather than meet the police he is not choosing the more agreeable. . .It happens only sometimes that when we do not choose the lesser pain or the greater pleasure we choose what will produce these in the long run.”—Wittgenstein
Death and pain are two of the most persistent ingredients of the human condition. The former may be prevented, delayed, or cheated, but eventually overcomes every one. Does the latter also have to triumph? As probably the oldest symptom that faced primitive man, and hence primitive medicine-man or shaman, there has certainly been sufficient time since the dawn of health care for pain, if not death, to be conquered. In 1990 the WHO proclaimed a war on pain associated with cancer (itself a synonym for death in many people’s minds) with its influential report, Cancer and Pain Relief & Palliative Care.1 Yet in 2001, pain with cancer and other chronic disorders remains, more than ever, a major international public-health problem, even though its causes are clear, its pathophysiology is understood in detail, the way it thrives in poverty and among disadvantaged groups is known, and the public can be educated about it. Sometimes it seems as if patients prefer to bear pain rather than heed their physicians. Their Wittgensteinian dilemma is real—do they choose pain because the alternative is even worse, but what is the long-term gain of tolerating pain? In today’s Lancet, Stefan Weiss and colleagues put forward a fairly convincing case that for many people, at least in sections of US society, pain is the better short-term option. Interviews with 988 “terminally ill” patients in six diverse American cities revealed that, although half the patients had moderate or severe pain, only a third were seeking more drug therapy, and one in ten wanted to reduce or stop their medication. One in five had seen a pain specialist and half had seen their primary-care physician in the past month. Reasons for resisting more pain medication included fear of addiction (35%), physical side-effects such as constipation (31%), mental side-effects such as confusion (33%), and reluctance to take more pills or injections (30%). Patients from ethnic minorities were more likely to fear addiction, and depressed people were more likely to be wary of physical side-effects. This study was large, multicentre, and included patients with a variety of diagnoses (half had cancer, and heart disease and chronic obstructive pulmonary disease accounted for a further quarter). Amount of pain and desire for more treatment was similar across diagnoses. This finding is in keeping with a report that patients with 1304
chronic obstructive pulmonary disease have as much pain, as measured with a cancer-specific quality of life instrument, as do lung-cancer patients.2 Weiss and colleagues’ work also echoes studies that have identified patients concerns about analgesics, especially the opioids, as a major reason for refusal. Paice and colleagues3 found, however, that fear of tolerance from starting opioids too early was more powerful than fear of addiction as a barrier to taking medicines. It seems that the patients in Weiss and colleagues’ study were collectively ill-informed about pain, prejudiced possibly by bad experiences, and inadequately cared for by their physicians. This situation is not unique to the USA: only 17% of Israeli physicians reported they could control pain in more than 75% of their patients.4 Their reasons, too, were ineffective treatments (61%) central-nervoussystem (CNS) side-effects (43%), and gastrointestinal side-effects (26%). How reasonable are these fears? Genuinely terminally ill patients prescribed opioids for pain control rarely become addicted.5 Tolerance does develop, but hardly ever to the extent that modern potent opioids lose their effectiveness. A factor underlying tolerance is level of binding of opioid to receptors: drugs such as morphine, which need to occupy more receptors to cause an effect (because they have low intrinsic receptor affinity) are more likely to induce tolerance than those with high intrinsic receptor efficacy, such as fentanyl.6 The induction of tolerance depends crucially on the Nmethyl-D-aspartate (NMDA) receptor ion channel complex in the postsynaptic neurons of the dorsal horn. Activation of the NMDA complex with chronic pain increases sensitivity (“wind-up”) as well as tolerance to opioids. Other recently discovered mechanisms that influence tolerance and responsiveness to opioids involve spinal cholecystokinin, tumour-necrosis factor, neurokinin, and nitric oxide.6,7 Several chemicals can interfere with these mechanisms in animal models, and some are being used clinically. For example, ketamine and synthetic opioids such as ketobemidone and methadone, which block activation of the NMDA complex, have theoretical advantages in the relief of chronic cancer pain, especially when there is a neuropathic component. In a rat model8 the preoperative use of ketamine attentuated the development of post-operative abdominal pain: pre-emptive strikes in human pain syndromes need extensive clinical testing. The gastrointestinal side-effect of opioids and NSAIDs, especially dry mouth, nausea, and constipation may be sufficient to turn patients away from the potential benefits of these agents.3 The most persistent and devastating problem is constipation. In animal studies
THE LANCET • Vol 357 • April 28, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
Pyramid model for symptom control Surgical and physical procedures
Pharmacological palliation
Psychological and nursing interventions
Disease-modifying therapies Multidisciplinary and multimodal symptom control in cancer and chronic diseases, with any or all of the approaches represented on the pyramid faces, as appropriate for the patient's current needs, prognosis, and severity of the symptom. Reproduced with permission from Sam Ahmedzai, Andreas Lübbe, and Bart Van den Eynden
drugs that have a high penetration into the central nervous system because of lipophilicity, such as fentanyl, are less likely to cause constipation for the same degree of analgesia as drugs such as morphine, that do not penetrate centrally so well.9 This finding was also obtained in a multicentre randomised controlled trial, which showed constipation rates of 44·5% with morphine and 27·2% with transdermal fentanyl.10 This relative lack of constipation with fentanyl persisted many months into follow-up after entry into the trial.11 Patients need to be informed of these differences, so that they can choose the drug that suits their lifestyle and preferred side-effect profile. The other major dread of chronic pain patients is the sedation and cognitive impairment associated with the stronger opioids. Oxycodone acts on the opioid receptor, but it is not yet clear from randomised controlled trials whether it has an advantage over morphine ( receptor) in terms of mental obtundation. Interestingly, in an animal model the co-administration of subanalgesic doses of oxycodone not only enhanced the antinociceptive effect of morphine, but was also associated with a reduction in CNS side-effects.12 An alternative strategy to reduce sedation and also enhance analgesia is the concurrent use of psychostimulants such as methylphenidate with opioids,13 but physicians are inexplicably resistant to this approach, especially in Europe. Patients can justifiably think that residual pain is worth trading off against the toxic effects of commonly used drugs. But there are many other approaches for pain control in cancer and in chronic diseases. The WHO three-step pain ladder1 (put simply, non-opioid, weak opioid, strong opioid) has served well for the use of oral analgesics, but it overlooks the benefits of many other means of pain relief. A new model which is based on a pyramid to allow for multiple simultaneous attacks on symptoms, was presented and favourably received at a meeting in Geneva in September, 1999, of the European Association for Palliative Care (EAPC) held under the auspices of the Europena Organisation for Research and Treatment of Cancer, WHO, and the US National Cancer Institute. Pain due to cancer responds well to modern palliative chemotherapy, hormone manipulation, and radiation. Bisphosphonates and systemic radioisotopes can be very helpful in the long-term
THE LANCET • Vol 357 • April 28, 2001
management of metastatic bone pain. Nerve blocks with local anaesthetics or with neurolytics have increasingly become more useful with improvements in imaging and selection of cases. Psychological approaches such as cognitive behavioural therapy have little of the toxicities that patients dread.5 Intractable angina responds to spinal-cord stimulation, when drug therapy has lost its effect and merely produces toxic effects.14 Many of these approaches, such as spinal catheterisation and long-term intrathecal drug administration by external or implanted pumps are expensive, but in chronic pain they can pay for themselves in terms of reduced other health-care costs. Can society afford not to pay for good pain control? Furthermore, why is the management of pain in the terminally ill started so late? From what is known about spinal neurotransmission and the prevention of chronic pain and opioid tolerance by pre-emptive striking, patients would be better served by education and therapy early in their illnesses. Admittedly such an approach might make little difference in some cancers, but numerically the impact of pain prevention in nonmalignant disease could be very far-reaching. To come back to Wittgenstein’s fleeing man—to save a patient jumping out of the window, would it not help if a knock on the door came from a multidisciplinary team of clinicians backed by laboratory and clinical evidence, to offer pain relief? Sam Hjelmeland Ahmedzai Academic Palliative Medicine Unit, University of Sheffield, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK (e-mail: [email protected]) 1 2
3
4
5
6
7
8
9
10
11
12
13
14
WHO. Cancer pain relief and palliative care. WHO Tech Rep Ser 804. Geneva: WHO, 1990. Skilbeck J, Mott L, Page H, Smith D, Ahmedzai SH, Clark D. Palliative care in chronic obstructive airways disease: a needs assessment. Palliat Med 1999; 12: 245–54. Paice JA, Toy C, Shott S. Barriers to cancer pain relief: fear of tolerance and addiction. J Pain Symptom Manage 1998; 16: 1–9. Sapir R, Catane R, Strauss-Liviatan, Cherny NI. Cancer pain: knowledge and attitudes of physicians in Israel. J Pain Symptom Manage 1999: 17: 266–76. Beitbart W, Passik S, Payne D. Psychological and psychiatric interventions in pain control. In: Doyle D, Hanks GWC, McDonald N (eds). Oxford textbook of palliative medicine. Oxford: Oxford University Press, 1998: 437–54. Mercadante S, Portenoy RK. Opioid poorly-responsive cancer pain. Part 2: basic mechanisms that could shift dose response for analgesia. J Pain Symptom Manage 2001; 21: 255–64. Inturrisi CE. Opioid pharmacology: tolerance, receptor modulation and new analgesics. In: Payne R, Patt RB, Stratton Hill C (eds). Assessment and treatment of cancer pain. Seattle: IASP Press 1998; 275–88. Burton AW, Lee DH, Saab C, Chung JM. Pre-emptive intrathecal ketamine injection produces a long-lasting decrease in neuropathic pain behaviors in a rat model. Regional Anaesth Pain Med 1999; 24: 208–13. Megens A, Artois K, Vermeire J, et al. Comparison of the analgesic and intestinal effects of fentanyl and morphine in rats. J Pain Symptom Manage 1998; 15: 253–57. Ahmedzai S, Brooks DJ. Transdermal fentanyl versus sustainedrelease oral morphine in cancer pain: preference, efficacy and quality of life. J Pain Symptom Manage 1997: 13: 254–61. Nugent M, Davis S, Brooks D, Ahmedzai SH. Long-term observations of patients receiving transdermal fentanyl after a randomised trial. J Pain Symptom Manage (in press). Ross FB, Wallis SC, Smith MT. Co-administration of subantinociceptive doses of oxycodone and morphine produces marked antinociceptive synergy with reduced CNS side-effects in rats. Pain 2000; 84: 421–28. Dalal S, Melzack R. Potentiation of opioid analgesia by psychostimulant drugs: a review. J Pain Symptom Manage 1998; 16: 245–53. Nurmikko TJ, Nash TP, Wiles JR. Control of chronic pain. BMJ 1998; 317: 1438–41.
1305
For personal use. Only reproduce with permission from The Lancet Publishing Group.