- Email: [email protected]
γ-hydroxybutyrate as a treatment for alcoholism
Correspondence
decisions sanctioning widespread use, provision of more precise estimates of the ratio of costs to quality-adjusted life-years (QALYs) might be essential. A related dilemma arises if the effect on one important outcome—say, survival— is established, but the effect on quality of life is unknown. Would an RCT which sought to establish the effect on quality of life be deemed unnecessary if a small benefit in survival had been established? Finally, although identification of the point at which RCTs become unnecessary is easy retrospectively, identifying this point prospectively is much more difficult. Many factors beyond precision can contribute to sufficient uncertainty to be less conclusive than the 95% CI might superficially indicate in a review. Such factors include study quality, publication bias, missing data, population type, and insufficient coverage of other outcomes. Authoritative investigation of the influence of this multitude of factors is feasible when a large RCT dataset has accumulated (albeit partly unnecessarily), but may be impossible to disentangle with small numbers of RCTs. None of the above undermines the need for RCTs to better report preceding RCTs, and explain how they contribute
to the evidence base. However, any tendency to quick judgment needs to be tempered by the practical difficulties about gauging exactly when too much research has been done. We declare that we have no conflict of interest.
*Chris Hyde, Simon Stanworth, Susan Brunskill, Michael Murphy [email protected] National Blood Service, Systematic Reviews Initiative, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 3BQ, UK 1 2
3
Young C, Horton R. Putting clinical trials into context. Lancet 2005; 366: 107–08. Fergusson D, Glass K, Hutton B, Shapiro S. Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding? Clin Trials 2005; 2: 218–32. National Blood Service Systematic Reviews Initiative. http://www.transfusionguidelines. org/index.asp?Publication=SRI (accessed Aug 3, 2005).
-hydroxybutyrate as a treatment for alcoholism In their Review of the complications associated with the use of new emerging recreational drugs (June 18, p 2137),1 George Ricaurte and Una
Aprotinin RCTs included
Implications for practice
Implications for research
Fremes 1994
16
Laupacis 1997
45
Further primary research recommended No further research required
Laupacis 1998
45
Continued use of intervention, but with concern about cost Continued use of intervention, but with concern about cost ..
Munoz 1999
Unknown*
Levi 1999
45
Henry 1999
61
Update recommended to incorporate PRP, fibrin sealant, and newer trials in this area Whether targeted primary research is required that needs addressing .. Any trials involving aprotinin need to measure costs Continued use of intervention, Any further research needs to measure but with concern about cost mortality and compare active interventions Continued use of intervention, Further research recommended for but with concern about cost aprotinin in non-cardiac surgery. Further research needs to evaluate costs, mortality, and adverse events, and should consider comparing active interventions—eg, aprotinin vs TXA
TXA=tranexamic acid. PRP=platelet-rich plasmapheresis. *Review included 52 RCTs in total, but number on aprotinin was not specified.
Table: Appraisal of six systematic reviews addressing effectiveness of aprotinin
www.thelancet.com Vol 366 September 17, 2005
McCann highlight the complications related to overdose and consequent withdrawal syndrome induced by -hydroxybutyrate (GHB), an analogue of -aminobutyric acid (GABA). The GABA system is one of the most interesting areas of research in the field of pharmacological treatment of alcohol addiction.2 Among the GABA-ergic agents, GHB shares similarities with the pharmacological profile of ethanol, and acts through an alcohol-mimicking effect on the central nervous system in a similar manner to the substitution therapy with methadone used for the treatment of heroin addiction. In several European countries, GHB is successfully used in the treatment of alcohol withdrawal syndrome, maintenance of abstinence from alcohol, and reduction of craving for alcohol in alcoholdependent outpatients.3,4 During its administration in the clinical setting, craving for GHB may occur; however, GHB abuse seems limited, and other adverse effects related to this drug are modest.2 Awareness of the toxic effects associated with non-clinical, self-administration of GHB is essential for physicians. However, complications of recreational GHB use should not discourage physicians from using it to treat alcoholdependent patients. The safety of GHB as a treatment for alcoholism is shown by the fact that, when this drug is administered with the supervision of a designated family member and under continuous strict medical surveillance without exceeding the therapeutic dose of 50–100 mg/kg/day, cases of abuse are not documented and withdrawal syndrome does not occur when it is discontinued.5 We declare that we have no conflict of interest.
*Fabio Caputo, Giovanni Addolorato, Franco Trevisani, Mauro Bernardi [email protected] “G Fontana” Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, 40138 Bologna, Italy (FC, FT, MB); and Institute of Internal Medicine, Catholic University of Rome, Rome, Italy (GA)
981
Correspondence
1
2
3
4
5
Ricaurte GA, McCann UD. Recognition and management of complications of new recreational drug use. Lancet 2005; 365: 2137–45. Johnson BA, Swift RM, Addolorato G, Ciraulo DA, Myrick H. Safety and efficacy of GABAergic medications for treating alcoholism. Alcohol Clin Exp Res 2005; 29: 248–54. Gallimberti L, Canton G, Gentile N, et al. Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome. Lancet 1989; 30: 787–89. Gallimberti L, Ferri M, Ferrara SD, Fadda F, Gessa GL. gamma-Hydroxybutyric acid in the treatment of alcohol dependence: a doubleblind study. Alcohol Clin Exp Res 1992; 16: 673–76. Addolorato G, Caputo F, Leggio L, et al. Gamma hydroxybutyric acid (GHB) withdrawal does not occur at therapeutic dosage. Drug Alcohol Depend 2005; 77: 209.
Postnatal depression in fathers
Antionia Ringhom
In their large community study, Paul Ramchandani and colleagues (June 25, p 2201)1 found that paternal postnatal depression is associated with adverse emotional and behavioural outcomes in the child. The prominence given to this finding on the front cover of The Lancet has drawn appropriate attention to this key global public-health issue. Ramchandani and colleagues’ finding is important because of the size of the sample (12 884 fathers), although it is not entirely new. Almost all studies of postnatal depression in mothers have found that marital problems are associated with postpartum depression; the correlation found between mothers’ and fathers’ scores on the Edinburgh postnatal depression scale (EPDS) is not surprising. A study from Portugal by Areias and colleagues2 found that the onset of paternal depression often followed depression in the mother. The EPDS that I developed3 to screen for postnatal depression in mothers has indeed had wider uses; a cut off of 12, however, can only indicate the likelihood of clinical depression—not its severity or duration. A clinical interview is therefore necessary to determine the nature of the association of paternal depression with infant 982
behaviour and the quality of the parental relationship. Could this large ALSPAC research group obtain from the families information about the frequency of marital difficulties (including temporary separation), the uptake of relationship counselling services, and the actual number of parents who divorced within the study period? It is a plausible hypothesis, derived from clinical experience, that depressed fathers are living with depressed mothers, that both are struggling in their relationship at this vulnerable time, and that their infants are distressed. The WHO theme for Mental Health Day 2005 is “Healthy mothers and children”. It could also have been “Healthy parents and children” and so focused attention on fathers as well as mothers. The World Psychiatric Association is currently planning a perinatal mental health programme to help all members of the family affected by postnatal depression. I declare that I have no conflict of interest.
John Cox [email protected] Keele University Medical School, Academic Psychiatry Unit at Harplands Campus, Academic Suite, Hilton Road, Harpfields, Stoke-on-Trent ST4 6TH, UK 1
2
3
Ramchandani P, Stein A, Evans J, O’Connor TG, and the ALSPAC study team. Paternal depression in the postnatal period and child development: a prospective population study. Lancet 2005; 365: 2201–05. Areias ME, Kumar R, Barros H, et al. Correlates of postnatal depression in mothers and fathers. Br J Psychiatry 1996; 169: 36–41. Cox J, Holden J. Perinatal mental health: a guide to the Edinburgh Postnatal Depression Scale. London: Gaskell Press, 2003.
Upper gastrointestinal alarms in older people We agree with many of the sentiments and points brought up in the Comment by Sander Veldhuyzen van Zanten (June 25, p 2163).1 Furthermore, we agree that new models for investigation of patients with suspected upper gastrointestinal cancer, as proposed by
N Kapoor and colleagues,2 are required. These researchers found that dysphagia, weight loss, and age greater than 55 years were significant predictive factors for cancer, hence their value as “alarm features”. We want to highlight delays of referral in the latter subgroup of the population. One of the principal tenets of the UK’s National Service Framework for Older People is that health-care provision should not be delayed on the basis of age.3 We did a retrospective review of all upper gastrointestinal referrals made by general practitioners under the “2-week wait” cancer criteria to our Trust between January and May, 2004. For the purposes of study, the younger group comprised those aged 64 years or younger; the older group comprised those aged 65 years or older. 347 people were referred: 182 “older” people and 165 “younger” people; the mean age was 64 years (range 21–100). Demographics were similar between the groups in terms of sex, duration of symptoms, and medication use. 97 (53%) of the older group were referred for outpatient appointment rather than for direct-access endoscopy, compared with only 45 (27%) of the younger group (p0·0001). Those referred for directaccess endoscopy were significantly younger than those referred for outpatient appointment (mean 62 years [SD 12] vs 68 years [15], p0·0001). Of the older group seen in outpatients, 72 (74%) subsequently went on to have gastroscopy. Of these, 62 (86%) were done as day cases; 11 (15%) had cancer. Time to gastroscopy in this group ranged from 5 days to 2 months. We believe that these findings are not unique to our hospitals or region. General practitioners refer older people with a suspected diagnosis of upper gastrointestinal cancer more frequently for review in an outpatient clinic than for direct access endoscopy. After assessment by a secondary-care clinician, a large proportion required endoscopy, which yielded cancer in a www.thelancet.com Vol 366 September 17, 2005
decisions sanctioning widespread use, provision of more precise estimates of the ratio of costs to quality-adjusted life-years (QALYs) might be essential. A related dilemma arises if the effect on one important outcome—say, survival— is established, but the effect on quality of life is unknown. Would an RCT which sought to establish the effect on quality of life be deemed unnecessary if a small benefit in survival had been established? Finally, although identification of the point at which RCTs become unnecessary is easy retrospectively, identifying this point prospectively is much more difficult. Many factors beyond precision can contribute to sufficient uncertainty to be less conclusive than the 95% CI might superficially indicate in a review. Such factors include study quality, publication bias, missing data, population type, and insufficient coverage of other outcomes. Authoritative investigation of the influence of this multitude of factors is feasible when a large RCT dataset has accumulated (albeit partly unnecessarily), but may be impossible to disentangle with small numbers of RCTs. None of the above undermines the need for RCTs to better report preceding RCTs, and explain how they contribute
to the evidence base. However, any tendency to quick judgment needs to be tempered by the practical difficulties about gauging exactly when too much research has been done. We declare that we have no conflict of interest.
*Chris Hyde, Simon Stanworth, Susan Brunskill, Michael Murphy [email protected] National Blood Service, Systematic Reviews Initiative, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 3BQ, UK 1 2
3
Young C, Horton R. Putting clinical trials into context. Lancet 2005; 366: 107–08. Fergusson D, Glass K, Hutton B, Shapiro S. Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding? Clin Trials 2005; 2: 218–32. National Blood Service Systematic Reviews Initiative. http://www.transfusionguidelines. org/index.asp?Publication=SRI (accessed Aug 3, 2005).
-hydroxybutyrate as a treatment for alcoholism In their Review of the complications associated with the use of new emerging recreational drugs (June 18, p 2137),1 George Ricaurte and Una
Aprotinin RCTs included
Implications for practice
Implications for research
Fremes 1994
16
Laupacis 1997
45
Further primary research recommended No further research required
Laupacis 1998
45
Continued use of intervention, but with concern about cost Continued use of intervention, but with concern about cost ..
Munoz 1999
Unknown*
Levi 1999
45
Henry 1999
61
Update recommended to incorporate PRP, fibrin sealant, and newer trials in this area Whether targeted primary research is required that needs addressing .. Any trials involving aprotinin need to measure costs Continued use of intervention, Any further research needs to measure but with concern about cost mortality and compare active interventions Continued use of intervention, Further research recommended for but with concern about cost aprotinin in non-cardiac surgery. Further research needs to evaluate costs, mortality, and adverse events, and should consider comparing active interventions—eg, aprotinin vs TXA
TXA=tranexamic acid. PRP=platelet-rich plasmapheresis. *Review included 52 RCTs in total, but number on aprotinin was not specified.
Table: Appraisal of six systematic reviews addressing effectiveness of aprotinin
www.thelancet.com Vol 366 September 17, 2005
McCann highlight the complications related to overdose and consequent withdrawal syndrome induced by -hydroxybutyrate (GHB), an analogue of -aminobutyric acid (GABA). The GABA system is one of the most interesting areas of research in the field of pharmacological treatment of alcohol addiction.2 Among the GABA-ergic agents, GHB shares similarities with the pharmacological profile of ethanol, and acts through an alcohol-mimicking effect on the central nervous system in a similar manner to the substitution therapy with methadone used for the treatment of heroin addiction. In several European countries, GHB is successfully used in the treatment of alcohol withdrawal syndrome, maintenance of abstinence from alcohol, and reduction of craving for alcohol in alcoholdependent outpatients.3,4 During its administration in the clinical setting, craving for GHB may occur; however, GHB abuse seems limited, and other adverse effects related to this drug are modest.2 Awareness of the toxic effects associated with non-clinical, self-administration of GHB is essential for physicians. However, complications of recreational GHB use should not discourage physicians from using it to treat alcoholdependent patients. The safety of GHB as a treatment for alcoholism is shown by the fact that, when this drug is administered with the supervision of a designated family member and under continuous strict medical surveillance without exceeding the therapeutic dose of 50–100 mg/kg/day, cases of abuse are not documented and withdrawal syndrome does not occur when it is discontinued.5 We declare that we have no conflict of interest.
*Fabio Caputo, Giovanni Addolorato, Franco Trevisani, Mauro Bernardi [email protected] “G Fontana” Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, 40138 Bologna, Italy (FC, FT, MB); and Institute of Internal Medicine, Catholic University of Rome, Rome, Italy (GA)
981
Correspondence
1
2
3
4
5
Ricaurte GA, McCann UD. Recognition and management of complications of new recreational drug use. Lancet 2005; 365: 2137–45. Johnson BA, Swift RM, Addolorato G, Ciraulo DA, Myrick H. Safety and efficacy of GABAergic medications for treating alcoholism. Alcohol Clin Exp Res 2005; 29: 248–54. Gallimberti L, Canton G, Gentile N, et al. Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome. Lancet 1989; 30: 787–89. Gallimberti L, Ferri M, Ferrara SD, Fadda F, Gessa GL. gamma-Hydroxybutyric acid in the treatment of alcohol dependence: a doubleblind study. Alcohol Clin Exp Res 1992; 16: 673–76. Addolorato G, Caputo F, Leggio L, et al. Gamma hydroxybutyric acid (GHB) withdrawal does not occur at therapeutic dosage. Drug Alcohol Depend 2005; 77: 209.
Postnatal depression in fathers
Antionia Ringhom
In their large community study, Paul Ramchandani and colleagues (June 25, p 2201)1 found that paternal postnatal depression is associated with adverse emotional and behavioural outcomes in the child. The prominence given to this finding on the front cover of The Lancet has drawn appropriate attention to this key global public-health issue. Ramchandani and colleagues’ finding is important because of the size of the sample (12 884 fathers), although it is not entirely new. Almost all studies of postnatal depression in mothers have found that marital problems are associated with postpartum depression; the correlation found between mothers’ and fathers’ scores on the Edinburgh postnatal depression scale (EPDS) is not surprising. A study from Portugal by Areias and colleagues2 found that the onset of paternal depression often followed depression in the mother. The EPDS that I developed3 to screen for postnatal depression in mothers has indeed had wider uses; a cut off of 12, however, can only indicate the likelihood of clinical depression—not its severity or duration. A clinical interview is therefore necessary to determine the nature of the association of paternal depression with infant 982
behaviour and the quality of the parental relationship. Could this large ALSPAC research group obtain from the families information about the frequency of marital difficulties (including temporary separation), the uptake of relationship counselling services, and the actual number of parents who divorced within the study period? It is a plausible hypothesis, derived from clinical experience, that depressed fathers are living with depressed mothers, that both are struggling in their relationship at this vulnerable time, and that their infants are distressed. The WHO theme for Mental Health Day 2005 is “Healthy mothers and children”. It could also have been “Healthy parents and children” and so focused attention on fathers as well as mothers. The World Psychiatric Association is currently planning a perinatal mental health programme to help all members of the family affected by postnatal depression. I declare that I have no conflict of interest.
John Cox [email protected] Keele University Medical School, Academic Psychiatry Unit at Harplands Campus, Academic Suite, Hilton Road, Harpfields, Stoke-on-Trent ST4 6TH, UK 1
2
3
Ramchandani P, Stein A, Evans J, O’Connor TG, and the ALSPAC study team. Paternal depression in the postnatal period and child development: a prospective population study. Lancet 2005; 365: 2201–05. Areias ME, Kumar R, Barros H, et al. Correlates of postnatal depression in mothers and fathers. Br J Psychiatry 1996; 169: 36–41. Cox J, Holden J. Perinatal mental health: a guide to the Edinburgh Postnatal Depression Scale. London: Gaskell Press, 2003.
Upper gastrointestinal alarms in older people We agree with many of the sentiments and points brought up in the Comment by Sander Veldhuyzen van Zanten (June 25, p 2163).1 Furthermore, we agree that new models for investigation of patients with suspected upper gastrointestinal cancer, as proposed by
N Kapoor and colleagues,2 are required. These researchers found that dysphagia, weight loss, and age greater than 55 years were significant predictive factors for cancer, hence their value as “alarm features”. We want to highlight delays of referral in the latter subgroup of the population. One of the principal tenets of the UK’s National Service Framework for Older People is that health-care provision should not be delayed on the basis of age.3 We did a retrospective review of all upper gastrointestinal referrals made by general practitioners under the “2-week wait” cancer criteria to our Trust between January and May, 2004. For the purposes of study, the younger group comprised those aged 64 years or younger; the older group comprised those aged 65 years or older. 347 people were referred: 182 “older” people and 165 “younger” people; the mean age was 64 years (range 21–100). Demographics were similar between the groups in terms of sex, duration of symptoms, and medication use. 97 (53%) of the older group were referred for outpatient appointment rather than for direct-access endoscopy, compared with only 45 (27%) of the younger group (p0·0001). Those referred for directaccess endoscopy were significantly younger than those referred for outpatient appointment (mean 62 years [SD 12] vs 68 years [15], p0·0001). Of the older group seen in outpatients, 72 (74%) subsequently went on to have gastroscopy. Of these, 62 (86%) were done as day cases; 11 (15%) had cancer. Time to gastroscopy in this group ranged from 5 days to 2 months. We believe that these findings are not unique to our hospitals or region. General practitioners refer older people with a suspected diagnosis of upper gastrointestinal cancer more frequently for review in an outpatient clinic than for direct access endoscopy. After assessment by a secondary-care clinician, a large proportion required endoscopy, which yielded cancer in a www.thelancet.com Vol 366 September 17, 2005