151
EDITORIALS
Sumatriptan, serotonin, migraine, and money The total cost of migraine is enormous. In economic terms alone the figures are staggering-in the UK, for example, the estimated burden of migraine to the national economy is 150-300 million annually.’ The annual cost to the National Health Service may be only 23 million.1 Neither of these sums includes the element of lost quality of life to migraineurs. If 10% of the UK population (5-6 million) have an average of one attack per month (67 million attacks per year), a new acute therapy achieving 100% market penetration at C20 per treated attack would cost 1-344 billion. Enter sumatriptan. After a lengthy period of media-generated "hype", which had the highly unusual result of patients asking by name for a drug not licensed anywhere in the world (and bent the minds of city analysts charged simultaneously with forecasting pharmaceutical fortunes3), Glaxo launched their new antimigraine drug, first in the Netherlands and New Zealand, and then in the UK. The company’s development costs-certain to be at least into nine figures for a programme started in 1972-will be well repaid once the drug enters the USA, where it has already been recommended for
approval. Sumatriptan is the product of an entirely new development in acute migraine therapy, which hitherto has largely depended on simple analgesics, antiemetics, and restricted use of ergotamine with all its nasty side-effects and addictive potential. Many hardened migraineurs bear witness to the low or unpredictable efficacy of these therapies; most migraine sufferers, however, do not seek medical help and presumably find over-the-counter preparations adequate. Sumatriptan is chemically closely related to serotonin (5-hydroxytriptamine, 5-HT), whose essential but still poorly understood role in migraine pathophysiology is now widely accepted. The drug is a highly selective agonist at 5-HT receptors of the 5-HT or 5-HTj-like subtype.6,9 It is virtually devoid of activity at 5-HTZ and 5-HTreceptors, and does not cross the blood-brain barrier. Sumatriptan causes contraction of various blood vessels in vitro, and in vivo selectively increases carotid vascular resistance.
This last effect, in some species at least, is confined to the arteriovenous anastomotic compartment. 10.11 Dilatation of these vessels may be important in Inhibition migraine pathophysiology. 12 by sumatriptan of plasma extravasation from dural vessels,13 another proposed pathophysiological mechanism in migraine,14 may or may not be secondary to vasoconstriction. Unlike ergotamine, does not cause sumatriptan peripheral vasoconstriction in man. Initial fears of clinically vasoconstriction are important coronary unsubstantiated in clinical trials,15 although all the patients entering these trials have had normal electrocardiograms and the drug is contraindicated for the time being in ischaemic heart disease. Glaxo’s carefully planned programme of clinical trials is unique in the development of antimigraine drugs,l6 and the patient-base now exceeds 8000. Although the frequency of side-effects is high, these complaints are generally trivial. Efficacy far beyond that of placebo or other acute treatments is well established: symptom-relief from severe or moderate headache to mild or no headache in less than 1 hour is reported in 75% of attacks treated by subcutaneous injection of 6 mg sumatriptan.17 A second dose of 6 mg after 1 hour seems to offer little further benefit, but early treatment within the attack may be less important for efficacy than with other acute treatments for migraine. Associated symptoms of nausea, vomiting, photophobia, and phonophobia also respond to sumatriptan-surprisingly, since these features were not formerly thought to be secondary to the headache. Oral treatment (already licensed in the Netherlands) may be similarly or slightly less effective at doses of 100-300 mg.18,19 Data held by Glaxo suggest no tendency towards either tachyphylaxis or overuse in patients allowed unrestricted access to the oral preparation. At least 30% of patients who respond to sumatriptan experience a recurrence of their headache within 24 hours. 11,19 This effect is difficult to evaluate because there is no previous experience with effective therapies. Sumatriptan shows little protein-binding, is metabolised mainly in the liver, and has a short half-life (1-5-2 hours);20does the effect simply wear off, so that symptoms return, or is a new attack initiated? Many patients feel they must endure a full-blown attack to reach the serene state of refractoriness to further attacks. Perhaps the susceptibility that triggered the first attack persists, rather than the attack itself, and triggers another episode. Rather than switching off a specific migraine generator, the drug probably operates against a process "down line". Subcutaneous sumatriptan is dispensed for selfadministration in packs of two prefilled syringes, with or without an autoinjector, at a cost close to C20 per syringe. In the UK, patients have already noted that some
at
general practitioners are unwilling to prescribe cost. Nevertheless, this agent is going to be
such
152
important in migraine management and it is difficult to see how any doctor treating migraineurs can turn his back on it. This being so, general practitioners should start familiarising themselves with its use. The worry to those who will pick up the bill is that the vast horde of self-medicating patients will now come out of the woodwork, showing that their past reticence in seeking medical help stemmed not from the adequacy of over-the-counter preparations but from low expectation of what doctors had to offer.
triglycerides for storage in adipose tissue. During fasting, blood glucose concentrations need to be
JN, Drummond MF. Migraine. London: Office of Health Economics, 1991. 2. Bosanquet N, Zammit-Lucia J. Migraine: a strategy for treatment.
alterations-gastrointestinal absorption (1-6 hours), glycogenolysis (1-2 days), gluconeogenesis (from 12 hours up to 1 week), and ketosis (3 days onwards). Until lately, methods for measuring metabolic turnover depended largely on isotopic labelling of
1. Blau
University of London Health Policy Unit review paper no 1. Cambridge: Daniels Publishing, 1991. 3. Editorial. Mystifying headaches. Economist March 2, 1991: 96-97. 4. Lance JW. 5-hydroxytryptamine and its role in migraine. Eur Neurol 1991; 31: 279-81. 5. Raskin NHH. Serotonin receptors and headache. N Engl J Med 1991; 325: 353-54. 6. Buzzi MG, Moskowitz MA. Evidence for 5-HT1B/1D receptors mediating the antimigraine effect of sumatriptan and
dihydroergotamine. Cephalalgia 1991; 11: 165-68. J. What is migraine? Controversy and stalemate in migraine pathophysiology. J Neurol 1991; 238: S2-5. 8. Humphrey PPA. 5-hydroxytryptamine and the pathophysiology of migraine. J Neurol 1991; 238: S38-44. 9. Humphrey PPA, Feniuk W, Marriott AS, Tanner RJN, Jackson MR, Tucker ML. Preclinical studies on the anti-migraine drug, sumatriptan. Eur Neurol 1991; 31: 282-90. 10. Perren MJ, Feniuk W, Humphrey PPA. The selective closure of feline arteriovenous anastomoses (AVAs) by GR43175. Cephalalgia 1989; 9 (suppl 9): 41-46. 11. Saxena PR, Den Boer MO. Pharmacology of antimigraine drugs. J Neurol 1991; 238: S28-35. 12. Heyck H. Pathogenesis of migraine. Res Clin Study Headache 1969; 2: 7. Edmeads
1-28. 13. Buzzi MG, Moskowitz MA. The antimigraine drug sumatriptan (GR43175) selectively blocks neurogenic plasma extravasation from blood vessels in dura mater. Br J Pharmacol 1990; 99: 202-06. 14. Moskowitz MA, Buzzi MG. Neuroeffector functions of sensory nerves: implications for headache mechanisms and drug actions. J Neurol 1991; 238: S18-22. 15. Brown EG, Endersby CA, Smith RN, Talbot JCC. The safety and tolerability of sumatriptan: an overview. Eur Neurol 1991; 31: 339-44. 16. Steiner TJ, Clifford Rose F. Problems encountered in the assessment of treatment of headache and migraine. In: Hopkins A, ed. Headache: problems in diagnosis and management. London: Saunders, 1988: 305-48. 17. Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. N Engl J Med 1991; 325: 316-21. 18. Patten JP, for the Oral Sumatriptan Dose-defining Study Group. Clinical experience with oral sumatriptan: a placebo-controlled, dose-ranging study. J Neurol 1991; 238: S62-65. 19. Goadsby PJ, Zagami AS, Donnan GA, et al. Oral sumatriptan in acute migraine. Lancet 1991; 338: 782-83. 20. Fowler PA, Lacey LF, Thomas M, Keene ON, Tanner RJN, Baber NS. The clinical pharmacology, pharmacokinetics and metabolism of sumatriptan. Eur Neurol 1991; 31: 291-94.
Insights into fasting Modem
a hunterthe metabolic gatherer sedentary worker but processes evoked by feeding and starvation remain undisturbed. Conventional wisdom suggests that three priorities are essential for survival: (a) provision of fuel from food for immediate metabolic requirements; (b) expansion of the modest glycogen reserves in liver and muscle and replacement of protein broken down in tissues since the previous meal; and (c) conversion of any excess calories into man
to a
may have evolved from
normal cerebral function. The series of hormonal and metabolic body undergoes changes to draw selectively on its extensive supply of calories in adipose tissue and to spare the breakdown of vitally needed proteins-for example, those involved in muscle contractility or in the enzymes of critical organs such as heart or liver. According to this conventional view, transition from the fed to the fasted state is characterised by a sequence of metabolic
maintained
to ensure a
constituents or measurement of arterial-venous differences. Magnetic resonance spectroscopy (MRS) has important advantages over these techniques. Spectroscopic measurement of changes in the frequency of resonance of atomic nuclei (chemical shift) permits non-invasive assessment of metabolic processes at multiple time points.zRothman and colleagues have used 13C MRS to measure hepatic glycogen concentrations in fasting volunteers; their data challenge conventional teaching. Before we consider these new findings, it is appropriate to review the traditional concepts. The first phase of fasting largely depends on the carbohydrate concentration of the preceding meal. After a big, predominantly carbohydrate-containing meal the liver will actively remove glucose in response to increased insulin secretion and suppression of glucagon. This glucose is incorporated into glycogen and undergoes glycolysis to pyruvate and lactate. If the meal is low in carbohydrate the liver is poised to produce glucose, although circulating insulin will exceed basal concentrations in response to the food, because the glucagon concentration is increased. Sensitive mechanisms within hepatocytes respond to small changes in glucose and lead to increased or decreased rates of hepatic glucose production.l Insulin and glucagon regulate the concentration of cyclic AMp4 which, in turn, initiates complex enzyme changes to inhibit glycogen synthesis and simultaneously activate glycogen breakdown and gluconeogenesis. The liver contains about 10% by weight of glycogen or about 150 g. Since the rate of carbohydrate utilisation in an average subject leading a normal life is between 100 and 200 g daily, liver glycogen cannot serve as a long-term fuel store but merely buffers variations for up to 24 hours. According to the classic model, glycogenolysis maintains a normal blood glucose for 12-16 h into a fast, when it is largely superseded by gluconeogenesis.The switch to gluconeogenesis is brought about by two processes: a raised glucagon to insulin ratio, which further increases hepatic cyclic AMP, and a higher concentration of free fatty acids, which increases fat oxidation to stimulate fat-derived
EDITORIALS
Sumatriptan, serotonin, migraine, and money The total cost of migraine is enormous. In economic terms alone the figures are staggering-in the UK, for example, the estimated burden of migraine to the national economy is 150-300 million annually.’ The annual cost to the National Health Service may be only 23 million.1 Neither of these sums includes the element of lost quality of life to migraineurs. If 10% of the UK population (5-6 million) have an average of one attack per month (67 million attacks per year), a new acute therapy achieving 100% market penetration at C20 per treated attack would cost 1-344 billion. Enter sumatriptan. After a lengthy period of media-generated "hype", which had the highly unusual result of patients asking by name for a drug not licensed anywhere in the world (and bent the minds of city analysts charged simultaneously with forecasting pharmaceutical fortunes3), Glaxo launched their new antimigraine drug, first in the Netherlands and New Zealand, and then in the UK. The company’s development costs-certain to be at least into nine figures for a programme started in 1972-will be well repaid once the drug enters the USA, where it has already been recommended for
approval. Sumatriptan is the product of an entirely new development in acute migraine therapy, which hitherto has largely depended on simple analgesics, antiemetics, and restricted use of ergotamine with all its nasty side-effects and addictive potential. Many hardened migraineurs bear witness to the low or unpredictable efficacy of these therapies; most migraine sufferers, however, do not seek medical help and presumably find over-the-counter preparations adequate. Sumatriptan is chemically closely related to serotonin (5-hydroxytriptamine, 5-HT), whose essential but still poorly understood role in migraine pathophysiology is now widely accepted. The drug is a highly selective agonist at 5-HT receptors of the 5-HT or 5-HTj-like subtype.6,9 It is virtually devoid of activity at 5-HTZ and 5-HTreceptors, and does not cross the blood-brain barrier. Sumatriptan causes contraction of various blood vessels in vitro, and in vivo selectively increases carotid vascular resistance.
This last effect, in some species at least, is confined to the arteriovenous anastomotic compartment. 10.11 Dilatation of these vessels may be important in Inhibition migraine pathophysiology. 12 by sumatriptan of plasma extravasation from dural vessels,13 another proposed pathophysiological mechanism in migraine,14 may or may not be secondary to vasoconstriction. Unlike ergotamine, does not cause sumatriptan peripheral vasoconstriction in man. Initial fears of clinically vasoconstriction are important coronary unsubstantiated in clinical trials,15 although all the patients entering these trials have had normal electrocardiograms and the drug is contraindicated for the time being in ischaemic heart disease. Glaxo’s carefully planned programme of clinical trials is unique in the development of antimigraine drugs,l6 and the patient-base now exceeds 8000. Although the frequency of side-effects is high, these complaints are generally trivial. Efficacy far beyond that of placebo or other acute treatments is well established: symptom-relief from severe or moderate headache to mild or no headache in less than 1 hour is reported in 75% of attacks treated by subcutaneous injection of 6 mg sumatriptan.17 A second dose of 6 mg after 1 hour seems to offer little further benefit, but early treatment within the attack may be less important for efficacy than with other acute treatments for migraine. Associated symptoms of nausea, vomiting, photophobia, and phonophobia also respond to sumatriptan-surprisingly, since these features were not formerly thought to be secondary to the headache. Oral treatment (already licensed in the Netherlands) may be similarly or slightly less effective at doses of 100-300 mg.18,19 Data held by Glaxo suggest no tendency towards either tachyphylaxis or overuse in patients allowed unrestricted access to the oral preparation. At least 30% of patients who respond to sumatriptan experience a recurrence of their headache within 24 hours. 11,19 This effect is difficult to evaluate because there is no previous experience with effective therapies. Sumatriptan shows little protein-binding, is metabolised mainly in the liver, and has a short half-life (1-5-2 hours);20does the effect simply wear off, so that symptoms return, or is a new attack initiated? Many patients feel they must endure a full-blown attack to reach the serene state of refractoriness to further attacks. Perhaps the susceptibility that triggered the first attack persists, rather than the attack itself, and triggers another episode. Rather than switching off a specific migraine generator, the drug probably operates against a process "down line". Subcutaneous sumatriptan is dispensed for selfadministration in packs of two prefilled syringes, with or without an autoinjector, at a cost close to C20 per syringe. In the UK, patients have already noted that some
at
general practitioners are unwilling to prescribe cost. Nevertheless, this agent is going to be
such
152
important in migraine management and it is difficult to see how any doctor treating migraineurs can turn his back on it. This being so, general practitioners should start familiarising themselves with its use. The worry to those who will pick up the bill is that the vast horde of self-medicating patients will now come out of the woodwork, showing that their past reticence in seeking medical help stemmed not from the adequacy of over-the-counter preparations but from low expectation of what doctors had to offer.
triglycerides for storage in adipose tissue. During fasting, blood glucose concentrations need to be
JN, Drummond MF. Migraine. London: Office of Health Economics, 1991. 2. Bosanquet N, Zammit-Lucia J. Migraine: a strategy for treatment.
alterations-gastrointestinal absorption (1-6 hours), glycogenolysis (1-2 days), gluconeogenesis (from 12 hours up to 1 week), and ketosis (3 days onwards). Until lately, methods for measuring metabolic turnover depended largely on isotopic labelling of
1. Blau
University of London Health Policy Unit review paper no 1. Cambridge: Daniels Publishing, 1991. 3. Editorial. Mystifying headaches. Economist March 2, 1991: 96-97. 4. Lance JW. 5-hydroxytryptamine and its role in migraine. Eur Neurol 1991; 31: 279-81. 5. Raskin NHH. Serotonin receptors and headache. N Engl J Med 1991; 325: 353-54. 6. Buzzi MG, Moskowitz MA. Evidence for 5-HT1B/1D receptors mediating the antimigraine effect of sumatriptan and
dihydroergotamine. Cephalalgia 1991; 11: 165-68. J. What is migraine? Controversy and stalemate in migraine pathophysiology. J Neurol 1991; 238: S2-5. 8. Humphrey PPA. 5-hydroxytryptamine and the pathophysiology of migraine. J Neurol 1991; 238: S38-44. 9. Humphrey PPA, Feniuk W, Marriott AS, Tanner RJN, Jackson MR, Tucker ML. Preclinical studies on the anti-migraine drug, sumatriptan. Eur Neurol 1991; 31: 282-90. 10. Perren MJ, Feniuk W, Humphrey PPA. The selective closure of feline arteriovenous anastomoses (AVAs) by GR43175. Cephalalgia 1989; 9 (suppl 9): 41-46. 11. Saxena PR, Den Boer MO. Pharmacology of antimigraine drugs. J Neurol 1991; 238: S28-35. 12. Heyck H. Pathogenesis of migraine. Res Clin Study Headache 1969; 2: 7. Edmeads
1-28. 13. Buzzi MG, Moskowitz MA. The antimigraine drug sumatriptan (GR43175) selectively blocks neurogenic plasma extravasation from blood vessels in dura mater. Br J Pharmacol 1990; 99: 202-06. 14. Moskowitz MA, Buzzi MG. Neuroeffector functions of sensory nerves: implications for headache mechanisms and drug actions. J Neurol 1991; 238: S18-22. 15. Brown EG, Endersby CA, Smith RN, Talbot JCC. The safety and tolerability of sumatriptan: an overview. Eur Neurol 1991; 31: 339-44. 16. Steiner TJ, Clifford Rose F. Problems encountered in the assessment of treatment of headache and migraine. In: Hopkins A, ed. Headache: problems in diagnosis and management. London: Saunders, 1988: 305-48. 17. Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. N Engl J Med 1991; 325: 316-21. 18. Patten JP, for the Oral Sumatriptan Dose-defining Study Group. Clinical experience with oral sumatriptan: a placebo-controlled, dose-ranging study. J Neurol 1991; 238: S62-65. 19. Goadsby PJ, Zagami AS, Donnan GA, et al. Oral sumatriptan in acute migraine. Lancet 1991; 338: 782-83. 20. Fowler PA, Lacey LF, Thomas M, Keene ON, Tanner RJN, Baber NS. The clinical pharmacology, pharmacokinetics and metabolism of sumatriptan. Eur Neurol 1991; 31: 291-94.
Insights into fasting Modem
a hunterthe metabolic gatherer sedentary worker but processes evoked by feeding and starvation remain undisturbed. Conventional wisdom suggests that three priorities are essential for survival: (a) provision of fuel from food for immediate metabolic requirements; (b) expansion of the modest glycogen reserves in liver and muscle and replacement of protein broken down in tissues since the previous meal; and (c) conversion of any excess calories into man
to a
may have evolved from
normal cerebral function. The series of hormonal and metabolic body undergoes changes to draw selectively on its extensive supply of calories in adipose tissue and to spare the breakdown of vitally needed proteins-for example, those involved in muscle contractility or in the enzymes of critical organs such as heart or liver. According to this conventional view, transition from the fed to the fasted state is characterised by a sequence of metabolic
maintained
to ensure a
constituents or measurement of arterial-venous differences. Magnetic resonance spectroscopy (MRS) has important advantages over these techniques. Spectroscopic measurement of changes in the frequency of resonance of atomic nuclei (chemical shift) permits non-invasive assessment of metabolic processes at multiple time points.zRothman and colleagues have used 13C MRS to measure hepatic glycogen concentrations in fasting volunteers; their data challenge conventional teaching. Before we consider these new findings, it is appropriate to review the traditional concepts. The first phase of fasting largely depends on the carbohydrate concentration of the preceding meal. After a big, predominantly carbohydrate-containing meal the liver will actively remove glucose in response to increased insulin secretion and suppression of glucagon. This glucose is incorporated into glycogen and undergoes glycolysis to pyruvate and lactate. If the meal is low in carbohydrate the liver is poised to produce glucose, although circulating insulin will exceed basal concentrations in response to the food, because the glucagon concentration is increased. Sensitive mechanisms within hepatocytes respond to small changes in glucose and lead to increased or decreased rates of hepatic glucose production.l Insulin and glucagon regulate the concentration of cyclic AMp4 which, in turn, initiates complex enzyme changes to inhibit glycogen synthesis and simultaneously activate glycogen breakdown and gluconeogenesis. The liver contains about 10% by weight of glycogen or about 150 g. Since the rate of carbohydrate utilisation in an average subject leading a normal life is between 100 and 200 g daily, liver glycogen cannot serve as a long-term fuel store but merely buffers variations for up to 24 hours. According to the classic model, glycogenolysis maintains a normal blood glucose for 12-16 h into a fast, when it is largely superseded by gluconeogenesis.The switch to gluconeogenesis is brought about by two processes: a raised glucagon to insulin ratio, which further increases hepatic cyclic AMP, and a higher concentration of free fatty acids, which increases fat oxidation to stimulate fat-derived
