- Email: [email protected]
Protective efficacy of hepatitis B vaccination
’--...
recently dead should
is
a
cultural and moral tradition. The dead
other ends. The regarded issues are not the exclusive responsibility of doctors or health professionals; they are the responsibility of the society on whom these pace-setting activities are thrust. To maintain trust, acquiescence of the community is essential. Meanwhile transplant surgeons must control their activities or the presumed social benefit will be not
be
as mere means to
negated. Russell W Strong Princess Alexandra Hospital, Australia 4102
Woolloongabba, Brisbane, Qld,
1 Valero R, Manyalich M, Cabrer C, Salvador L, Garcia-Fages LC. Organ procurement from non-heart-beating donors by total body cooling. Transplant Proc 1993; 25: 3091-92. 2 Varty K, Veitch PS, Morgan JDT, Kehinde EO, Donnelly PK, Bell PRF. Response to organ shortage: kidney retrieval programme using non-heart beating donors. BMJ 1994; 308: 575. 3 Llioveras J, Ping JM, Cerdà M, et al. Optimisation of in situ renal perfusion of non-heart beating donors: four lumen catheter developed for continuous perfusion pressure determination. Transplant Proc 1993; 25: 3169-70. 4 Phillips AO, Snowden SA, Hillis AV, Bewick M. Renal grafts from non-heart beating donors. BMJ 1994; 308: 575-76. 5 Matsuno N, Sakurai E, Uchiyama M, Kozaki K, Tamaki I, Kozaki M. Use of in situ cooling and machine perfusion preservation for nonheart beating donors. Transplant Proc 1993; 25: 3095-96. 6 Howard RJ, Pfaff WW, Brunson ME, et al. Increased incidence of rejection in patients with delayed graft function. Clin Transpl 1994; 8: 527-31.
Protective efficacy of vaccination
hepatitis
B
See 1089 The latest results achieved by The Gambia Hepatitis Intervention Study (reported in this issue) confirm the long-term efficacy of immunisation in preventing carriage of the hepatitis B virus (HBV) and hence its sequelaechronic hepatitis, cirrhosis, and, most important, hepatocellular carcinoma. This is heartening news because there are some 300 million carriers of the virus in the world today and they account for as much as 80% of the more than 310000 new cases of hepatocellular carcinoma that occur each year.’ Most carriers live in the Far East or in Africa and they become infected with HBV early in childhood. Their lifetime relative risk of hepatocellular carcinoma exceeds 100, and 40-50% die from the tumour, cirrhosis, or both diseases.2 Apart from the very high incidence in the Far East and Africa, other reasons why prevention of hepatocellular carcinoma is a priority are the rarity with which the tumour is resectable when symptomatic and its unresponsiveness to conservative forms of treatment, the often fulminant course, and the grave prognosis. The protective efficacy of hepatitis B vaccination against both uncomplicated infection and carriage remains high in Gambian vaccinees even after eight years and despite rapidly decreasing serum concentrations of neutralising antibody. A small proportion of vaccinated children still become infected. Most of these episodes result from failure to finish the course of injections or to respond to the vaccine, or from infection before immunisation is completed.3 The first explanation is especially worrying in rural parts of Africa where immunisation programmes run without the financial and logistic support that is available to The Gambia Hepatitis Intervention Study have had unacceptably high failure
°
-.."
--<.-.,.- --....-’’;’.:,
rates, as judged by receipt of the second and especially the third injections.4 When an individual becomes infected despite successful vaccination (breakthrough infection), titres of protective antibody to HBV have usually declined to a low level. Fortunately, these infections seldom result in carriage because persistence is far less likely when infection is acquired after the first year of life.s A few breakthrough infections do occur in the presence of high circulating concentrations of neutralising antibody, and may result from the production of antibodies of low affinity6 or from infection with vaccine escape mutants of HBV.’ Escape mutants have been detected among vaccinees in Europe, the Far East, and North America, as well as The Gambia.7-9 In unvaccinated children in the Far East, early infection with HBV leading to a carrier state results mainly from perinatal transmission of the virus from replicative carrier mothers.’° To prevent this mode of infection the first dose of the vaccine must be given very soon after birth, and should ideally be supplemented by passive immunisation. Carriage in Asian children has already been substantially reduced by use of this approach: for example, at the age of 6 years, Taiwanese vaccinees have a carrier rate of only 1-7% compared with 10-6% in unvaccinated children (D-S Chen, personal communication). This pattern of transmission contrasts with that in Africa, where the predominant route of spread is horizontal, especially between siblings,"-’3 and where there is less urgency in initiating immunisation. With predominantly horizontal transmission and the high levels of infectivity of recently infected children," vaccination of all seronegative African children aged 1-5 years at the same time that immunisation of infants is begun would be expected to improve the overall protective efficacy of the vaccine. This was the case in The Gambia, where less than half the expected number of breakthrough infections occurred. Our main objectives must now be the universal inclusion of hepatitis B vaccination in the Expanded Programme of Immunisation and the global implementation of the latter, with a view to eventual eradication of this virus and its life-threatening consequences.
Michael C Kew MRC Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa 1 2
3
4
Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993; 54: 594-606. Beasley RP. Hepatitis B virus: the major etiology of hepatocellular carcinoma. Cancer 1988; 61: 1942-56. Fortuin M, Chotard J, Jack AD, et al. Efficacy of hepatitis B vaccine in the Gambian expanded programme on immunisation. Lancet 1993; 341: 1129-31. Schoub BI, Johnson S, McAnerney JM, et al. Integration of hepatitis B vaccination into rural African primary health care programmes. BMJ
1991; 302: 313-15. 5
6
7 8
Coursaget P, Yvonnet B, Chotard J, et al. Age- and sex-related study of hepatitis B virus chronic carrier state in infants from an endemic area (Senegal). J Med Virol 1987; 22: 1-5. Brown SE, Howard CR, Zuckerman AJ, Steward MW. Affinity of antibody responses in man to hepatitis B vaccine determined with synthetic peptides. Lancet 1984; ii: 184-87. Carman WF, Zanetti AR, Karayiannis P, et al. Vaccine-induced escape mutant of hepatitis B virus. Lancet 1990; 336: 325-29. Okamoto H, Yano K, Nozaki Y, et al. Mutations within the S gene of hepatitis B virus transmitted from mothers to babies immunised with hepatitis B immune globulin and vaccine. Pediatr Res 1992; 32: 264-68.
1065
1*4?;’ 9
10
11
12
13
Fortuin M, Karthigesu V, Allison L, et al. Breakthrough infections and identification of a viral variant in Gambian children immunised with hepatitis B vaccine. J Infect Dis 1994; 169: 1374-76. Beasley RP, Trepo C, Stevens CE, Szumness W. The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 1977; 105: 94-98. Barin F, Perrin J, Chotard J, et al. Cross-sectional and longitudinal epidemiology of hepatitis B in Senegal. Prog Med Virol 1981; 27: 148-62. Botha JF, Ritchie MJJ, Dusheiko GM, Mouton HWK, Kew MC. Hepatitis B virus carrier state in black children in Ovamboland: role of perinatal and horizontal infection. Lancet 1984; ii: 1209-212. Whittle H, Inskip H, Bradley AK, et al. The pattern of childhood hepatitis B infection in two Gambian villages. J Infect Dis 1990; 161: 1112-15.
Caffeine In the
dependence
politically
and
socially charged
arena
of human
behaviour the most obvious conclusions are often the most difficult to accept. This seems to be especially true for judgments about addictions to legal drugs. For years tobacco dependence was regarded as a "bad habit" while alcoholism was excused as a "drinking problem". The recent demonstration of caffeine dependence elicited a clamour of denial and insouciance in the popular press. Evidence for the existence of a caffeine dependence syndrome was lately bolstered by Strain et al’ at the Johns Hopkins University Behavioral Pharmacology Research Unit. In a structured psychiatric interview, subjects selfidentified as having problems with caffeine use were evaluated for features of a DSM-IV diagnosis of drug dependence. Those judged as caffeine dependent manifested at least three of four criteria-tolerance, withdrawal, persistent desire, or unsuccessful attempts to reduce consumption and persistent use despite adverse psychological or physical consequences. Of 99 people answering a newspaper advertisement soliciting volunteers who thought they were physically or psychologically dependent on caffeine, 27 were evaluated by means of a structured psychiatric interview3 modified for the diagnosis of caffeine dependence; 16 of those subjects (59%) met the criteria. In a second phase of the study, 11 of the 16 caffeine-dependent individuals participated in a 2-day double-blind cross-over study of caffeine deprivation. 9 showed evidence of caffeine withdrawal during the placebo phase, a finding that validated one of the criteria for the diagnosis of dependence. This report was the latest of a series of studies on the clinical behavioural pharmacology of caffeine from the same laboratory. Previous research had shown that orally administered caffeine at very low doses can be distinguished from placebo4,s and that caffeine withdrawal can occur with typical daily doses of caffeine.’ Since the presence of a withdrawal syndrome does not in itself constitute a clinical diagnosis of dependence, the latest investigation was carried out with the strict DSM-IV criteria. In an editorial accompanying Strain’s report Glass’ pointed out that the labelling of a medication as dependence-producing may cause it to be used inappropriately. For example, emphasis on the dependence-producing properties of opioids has resulted in their underprescription for severe pain. Likewise, fear of benzodiazepine dependence can lead to the undertreatment of anxiety disorders. These concerns do not seem to apply to caffeine, which is seldom used medically. However, caffeine use is not without medical
1066
,
,
"
’
, ’
-
It can cause gastritis, insomnia, and In a surveyS of 697 physicians, anxiety. palpitations, that caffeine recommended 75% consumption should be reduced or eliminated in patients with cardiac abnormalities (palpitations, arrhythmia, tachycardia), consequence.
insomnia, anxiety, fibrocystic disease, gastrointestinal disease (oesophagitis, hiatus hernia, ulcers). In addition, 68% of the physicians recommended caffeine cessation during pregnancy. Unlike ethanol and nicotine, which are implicated in the deaths of over 100000 and 400000 Americans each year, caffeine seems to cause dependence without lifethreatening medical consequences. In fact, caffeine’s relative safety commends it for further study9 of social attitudes about onset and patterns of use and the economic impact of dependence-producing drugs. Another interesting area of research is examination of the stimulant properties of caffeine. Although its analeptic effect is usually attributed to antagonism of central adenosine receptors, the relation between dependence and adenosine antagonism is unclear. The cardiac stimulant effect and diuretic action of caffeine also warrant further investigation. The familiar caffeine withdrawal headache may prove useful as a model for the study of migraine. I believe the importance of Strain’s research is that it promotes understanding of drug dependence. Public recognition that caffeine, a psychoactive drug used by 80% of the population of the USA, causes dependence may help to remove some of the social stigma surrounding the concept of addiction. Moreover, these latest results show that drug dependence is not medically defined by intoxication, contrary to the views of the tobacco industry and its agents." Voters, policy makers, and medical professionals would do well to recognise that their caffeine dependence is neither fundamentally nor psychologically different from dependence on harmful substances. They might then look more compassionately on those whose drug dependence has greater medical and social consequences. Wallace B Pickworth Pharmacology Branch, NIDA, Addiction Research Center,
Clinical
Baltimore, MD, USA 1
2
3
4
5
6
7
Strain EC, Mumford GH, Silverman K, Griffiths, RR. Caffeine dependence syndrome: evidence from case histories and experimental evaluations. JAMA 1994; 272: 1043-48. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric
Association, 1994. Spitzer RL, Williams JBW. Structured clinical interview for DSM-III R. New York: New York State Psychiatric Institute, Biometrics Research, 1985. Griffiths RR, Evans SM, Heishman SJ, et al. Low-dose caffeine discrimination in humans. J Pharmacol Exp Ther 1990; 252: 970-78. Silverman K, Griffiths RR. Low-dose caffeine discrimination and selfreported mood effects in normal volunteers. J Exp Anal Behav 1992; 57: 91-107. Silverman K, Evans SM, Strain EC, Griffiths RR. Withdrawal syndrome after double-blind cessation of caffeine consumption. N Engl J Med 1992; 327: 1109-14. Glass RM. Caffeine dependence: what are the implications? JAMA
1994; 272: 1065-66. 8 9
Hughes JR, Amori G, Hatsukami DK. A survey of physician advice about caffeine. J Sub Abuse 1998; 1: 67-70. Medical Research Council. The basis of drug dependence, 1994.
London: Medical Research Council, 1994. 10 Robinson JH, Pritchard WS. The role of nicotine in tobacco Psychopharmacology 1992; 108: 397-407.
use.
recently dead should
is
a
cultural and moral tradition. The dead
other ends. The regarded issues are not the exclusive responsibility of doctors or health professionals; they are the responsibility of the society on whom these pace-setting activities are thrust. To maintain trust, acquiescence of the community is essential. Meanwhile transplant surgeons must control their activities or the presumed social benefit will be not
be
as mere means to
negated. Russell W Strong Princess Alexandra Hospital, Australia 4102
Woolloongabba, Brisbane, Qld,
1 Valero R, Manyalich M, Cabrer C, Salvador L, Garcia-Fages LC. Organ procurement from non-heart-beating donors by total body cooling. Transplant Proc 1993; 25: 3091-92. 2 Varty K, Veitch PS, Morgan JDT, Kehinde EO, Donnelly PK, Bell PRF. Response to organ shortage: kidney retrieval programme using non-heart beating donors. BMJ 1994; 308: 575. 3 Llioveras J, Ping JM, Cerdà M, et al. Optimisation of in situ renal perfusion of non-heart beating donors: four lumen catheter developed for continuous perfusion pressure determination. Transplant Proc 1993; 25: 3169-70. 4 Phillips AO, Snowden SA, Hillis AV, Bewick M. Renal grafts from non-heart beating donors. BMJ 1994; 308: 575-76. 5 Matsuno N, Sakurai E, Uchiyama M, Kozaki K, Tamaki I, Kozaki M. Use of in situ cooling and machine perfusion preservation for nonheart beating donors. Transplant Proc 1993; 25: 3095-96. 6 Howard RJ, Pfaff WW, Brunson ME, et al. Increased incidence of rejection in patients with delayed graft function. Clin Transpl 1994; 8: 527-31.
Protective efficacy of vaccination
hepatitis
B
See 1089 The latest results achieved by The Gambia Hepatitis Intervention Study (reported in this issue) confirm the long-term efficacy of immunisation in preventing carriage of the hepatitis B virus (HBV) and hence its sequelaechronic hepatitis, cirrhosis, and, most important, hepatocellular carcinoma. This is heartening news because there are some 300 million carriers of the virus in the world today and they account for as much as 80% of the more than 310000 new cases of hepatocellular carcinoma that occur each year.’ Most carriers live in the Far East or in Africa and they become infected with HBV early in childhood. Their lifetime relative risk of hepatocellular carcinoma exceeds 100, and 40-50% die from the tumour, cirrhosis, or both diseases.2 Apart from the very high incidence in the Far East and Africa, other reasons why prevention of hepatocellular carcinoma is a priority are the rarity with which the tumour is resectable when symptomatic and its unresponsiveness to conservative forms of treatment, the often fulminant course, and the grave prognosis. The protective efficacy of hepatitis B vaccination against both uncomplicated infection and carriage remains high in Gambian vaccinees even after eight years and despite rapidly decreasing serum concentrations of neutralising antibody. A small proportion of vaccinated children still become infected. Most of these episodes result from failure to finish the course of injections or to respond to the vaccine, or from infection before immunisation is completed.3 The first explanation is especially worrying in rural parts of Africa where immunisation programmes run without the financial and logistic support that is available to The Gambia Hepatitis Intervention Study have had unacceptably high failure
°
-.."
--<.-.,.- --....-’’;’.:,
rates, as judged by receipt of the second and especially the third injections.4 When an individual becomes infected despite successful vaccination (breakthrough infection), titres of protective antibody to HBV have usually declined to a low level. Fortunately, these infections seldom result in carriage because persistence is far less likely when infection is acquired after the first year of life.s A few breakthrough infections do occur in the presence of high circulating concentrations of neutralising antibody, and may result from the production of antibodies of low affinity6 or from infection with vaccine escape mutants of HBV.’ Escape mutants have been detected among vaccinees in Europe, the Far East, and North America, as well as The Gambia.7-9 In unvaccinated children in the Far East, early infection with HBV leading to a carrier state results mainly from perinatal transmission of the virus from replicative carrier mothers.’° To prevent this mode of infection the first dose of the vaccine must be given very soon after birth, and should ideally be supplemented by passive immunisation. Carriage in Asian children has already been substantially reduced by use of this approach: for example, at the age of 6 years, Taiwanese vaccinees have a carrier rate of only 1-7% compared with 10-6% in unvaccinated children (D-S Chen, personal communication). This pattern of transmission contrasts with that in Africa, where the predominant route of spread is horizontal, especially between siblings,"-’3 and where there is less urgency in initiating immunisation. With predominantly horizontal transmission and the high levels of infectivity of recently infected children," vaccination of all seronegative African children aged 1-5 years at the same time that immunisation of infants is begun would be expected to improve the overall protective efficacy of the vaccine. This was the case in The Gambia, where less than half the expected number of breakthrough infections occurred. Our main objectives must now be the universal inclusion of hepatitis B vaccination in the Expanded Programme of Immunisation and the global implementation of the latter, with a view to eventual eradication of this virus and its life-threatening consequences.
Michael C Kew MRC Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa 1 2
3
4
Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993; 54: 594-606. Beasley RP. Hepatitis B virus: the major etiology of hepatocellular carcinoma. Cancer 1988; 61: 1942-56. Fortuin M, Chotard J, Jack AD, et al. Efficacy of hepatitis B vaccine in the Gambian expanded programme on immunisation. Lancet 1993; 341: 1129-31. Schoub BI, Johnson S, McAnerney JM, et al. Integration of hepatitis B vaccination into rural African primary health care programmes. BMJ
1991; 302: 313-15. 5
6
7 8
Coursaget P, Yvonnet B, Chotard J, et al. Age- and sex-related study of hepatitis B virus chronic carrier state in infants from an endemic area (Senegal). J Med Virol 1987; 22: 1-5. Brown SE, Howard CR, Zuckerman AJ, Steward MW. Affinity of antibody responses in man to hepatitis B vaccine determined with synthetic peptides. Lancet 1984; ii: 184-87. Carman WF, Zanetti AR, Karayiannis P, et al. Vaccine-induced escape mutant of hepatitis B virus. Lancet 1990; 336: 325-29. Okamoto H, Yano K, Nozaki Y, et al. Mutations within the S gene of hepatitis B virus transmitted from mothers to babies immunised with hepatitis B immune globulin and vaccine. Pediatr Res 1992; 32: 264-68.
1065
1*4?;’ 9
10
11
12
13
Fortuin M, Karthigesu V, Allison L, et al. Breakthrough infections and identification of a viral variant in Gambian children immunised with hepatitis B vaccine. J Infect Dis 1994; 169: 1374-76. Beasley RP, Trepo C, Stevens CE, Szumness W. The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 1977; 105: 94-98. Barin F, Perrin J, Chotard J, et al. Cross-sectional and longitudinal epidemiology of hepatitis B in Senegal. Prog Med Virol 1981; 27: 148-62. Botha JF, Ritchie MJJ, Dusheiko GM, Mouton HWK, Kew MC. Hepatitis B virus carrier state in black children in Ovamboland: role of perinatal and horizontal infection. Lancet 1984; ii: 1209-212. Whittle H, Inskip H, Bradley AK, et al. The pattern of childhood hepatitis B infection in two Gambian villages. J Infect Dis 1990; 161: 1112-15.
Caffeine In the
dependence
politically
and
socially charged
arena
of human
behaviour the most obvious conclusions are often the most difficult to accept. This seems to be especially true for judgments about addictions to legal drugs. For years tobacco dependence was regarded as a "bad habit" while alcoholism was excused as a "drinking problem". The recent demonstration of caffeine dependence elicited a clamour of denial and insouciance in the popular press. Evidence for the existence of a caffeine dependence syndrome was lately bolstered by Strain et al’ at the Johns Hopkins University Behavioral Pharmacology Research Unit. In a structured psychiatric interview, subjects selfidentified as having problems with caffeine use were evaluated for features of a DSM-IV diagnosis of drug dependence. Those judged as caffeine dependent manifested at least three of four criteria-tolerance, withdrawal, persistent desire, or unsuccessful attempts to reduce consumption and persistent use despite adverse psychological or physical consequences. Of 99 people answering a newspaper advertisement soliciting volunteers who thought they were physically or psychologically dependent on caffeine, 27 were evaluated by means of a structured psychiatric interview3 modified for the diagnosis of caffeine dependence; 16 of those subjects (59%) met the criteria. In a second phase of the study, 11 of the 16 caffeine-dependent individuals participated in a 2-day double-blind cross-over study of caffeine deprivation. 9 showed evidence of caffeine withdrawal during the placebo phase, a finding that validated one of the criteria for the diagnosis of dependence. This report was the latest of a series of studies on the clinical behavioural pharmacology of caffeine from the same laboratory. Previous research had shown that orally administered caffeine at very low doses can be distinguished from placebo4,s and that caffeine withdrawal can occur with typical daily doses of caffeine.’ Since the presence of a withdrawal syndrome does not in itself constitute a clinical diagnosis of dependence, the latest investigation was carried out with the strict DSM-IV criteria. In an editorial accompanying Strain’s report Glass’ pointed out that the labelling of a medication as dependence-producing may cause it to be used inappropriately. For example, emphasis on the dependence-producing properties of opioids has resulted in their underprescription for severe pain. Likewise, fear of benzodiazepine dependence can lead to the undertreatment of anxiety disorders. These concerns do not seem to apply to caffeine, which is seldom used medically. However, caffeine use is not without medical
1066
,
,
"
’
, ’
-
It can cause gastritis, insomnia, and In a surveyS of 697 physicians, anxiety. palpitations, that caffeine recommended 75% consumption should be reduced or eliminated in patients with cardiac abnormalities (palpitations, arrhythmia, tachycardia), consequence.
insomnia, anxiety, fibrocystic disease, gastrointestinal disease (oesophagitis, hiatus hernia, ulcers). In addition, 68% of the physicians recommended caffeine cessation during pregnancy. Unlike ethanol and nicotine, which are implicated in the deaths of over 100000 and 400000 Americans each year, caffeine seems to cause dependence without lifethreatening medical consequences. In fact, caffeine’s relative safety commends it for further study9 of social attitudes about onset and patterns of use and the economic impact of dependence-producing drugs. Another interesting area of research is examination of the stimulant properties of caffeine. Although its analeptic effect is usually attributed to antagonism of central adenosine receptors, the relation between dependence and adenosine antagonism is unclear. The cardiac stimulant effect and diuretic action of caffeine also warrant further investigation. The familiar caffeine withdrawal headache may prove useful as a model for the study of migraine. I believe the importance of Strain’s research is that it promotes understanding of drug dependence. Public recognition that caffeine, a psychoactive drug used by 80% of the population of the USA, causes dependence may help to remove some of the social stigma surrounding the concept of addiction. Moreover, these latest results show that drug dependence is not medically defined by intoxication, contrary to the views of the tobacco industry and its agents." Voters, policy makers, and medical professionals would do well to recognise that their caffeine dependence is neither fundamentally nor psychologically different from dependence on harmful substances. They might then look more compassionately on those whose drug dependence has greater medical and social consequences. Wallace B Pickworth Pharmacology Branch, NIDA, Addiction Research Center,
Clinical
Baltimore, MD, USA 1
2
3
4
5
6
7
Strain EC, Mumford GH, Silverman K, Griffiths, RR. Caffeine dependence syndrome: evidence from case histories and experimental evaluations. JAMA 1994; 272: 1043-48. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric
Association, 1994. Spitzer RL, Williams JBW. Structured clinical interview for DSM-III R. New York: New York State Psychiatric Institute, Biometrics Research, 1985. Griffiths RR, Evans SM, Heishman SJ, et al. Low-dose caffeine discrimination in humans. J Pharmacol Exp Ther 1990; 252: 970-78. Silverman K, Griffiths RR. Low-dose caffeine discrimination and selfreported mood effects in normal volunteers. J Exp Anal Behav 1992; 57: 91-107. Silverman K, Evans SM, Strain EC, Griffiths RR. Withdrawal syndrome after double-blind cessation of caffeine consumption. N Engl J Med 1992; 327: 1109-14. Glass RM. Caffeine dependence: what are the implications? JAMA
1994; 272: 1065-66. 8 9
Hughes JR, Amori G, Hatsukami DK. A survey of physician advice about caffeine. J Sub Abuse 1998; 1: 67-70. Medical Research Council. The basis of drug dependence, 1994.
London: Medical Research Council, 1994. 10 Robinson JH, Pritchard WS. The role of nicotine in tobacco Psychopharmacology 1992; 108: 397-407.
use.