1 Psychiatric Hospital Münsingen, 3110 Münsingen,
2 Department of Complementary Medicine (KIKOM), Inselspital, University of Berne, 3010 Berne,
3 Department of Social and Community Psychiatry, University of Berne, Laupenstrasse 49, 3010 Berne, Switzerland,
4 MRC Health Services Research Collaboration, Department of Social Medicine, University of Bristol, Bristol, UK and
5 Department of Social and Preventive Medicine, University of Berne, Finkenhubelweg 11, 3012 Berne, Switzerland
Received 1 February 2002; in revised form 11 March 2003; accepted 27 March 2003
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ABSTRACT |
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INTRODUCTION |
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SUBJECTS AND METHODS |
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Randomization and interventions
Within 24 h after admission, patients were randomized to one of three groups receiving daily sessions of: (1) low level laser stimulation, (2) needling or (3) sham laser stimulation at the ear. The randomization schedule was determined independently by one of us (P.S.) at a site remote from the hospital prior to the start of the study. The schedule was unblocked, generated by drawing lots, and concealed using sealed, opaque, sequentially numbered envelopes, which were opened only after a patient had definitely been registered in the trial. Patients were treated by one of two acupuncturists (F.T., S.O.), who chose between two and 10 (median eight) out of 24 pre-specified ear points, regarded as specific for chemical dependency (Nogier, 1969; Wen and Cheung, 1973
; Smith et al., 1982
). Points were chosen individually in each session according to principles of ear acupuncture, using pulse techniques (Nogier, 1982
) and an electronic detection device (Punctoscope DT, Sedaletec, Inc., Irigny, France). Most frequently used points were Diaphragm [point #0 according to Olesons nomenclature (Oleson, 1995
); 66% of sessions], Cheerfulness (#190; 62%), Insomnia (#195 F2, 58%), Sympathetic (#2; 53%), Spleen (#163; 51%), Laterality (#199; 50%), Lung (#70; 47%) and Shen Men (#1; 46%). Sessions lasted between 30 and 45 min and were performed daily until the end of withdrawal. Sessions were held in a quiet room detached from the unit, with hospital staff remaining uninvolved. Needle stimulation was performed after alcohol disinfection by inserting sterilized ear acupuncture needles (B type, stainless steel, 0.2 x 15 mm; Seirin, Inc., Neu-Isenburg, Germany) to a depth of 13 mm at ear points considered appropriate. Needles were twirled 180 degrees during insertion and left in place for up to 40 min. Because the local ethics committees were reluctant to accept invasive sham procedures, we were unable to include sham needling in this pilot trial. Therefore, patients could not be blinded as to the allocation to needle acupuncture. Low-level laser stimulation was performed using a 830 nm infrared semiconductor laser device (Modulas; schwa-medico, Inc., Ehringshausen, Germany), stimulating each point for the duration of 1 min. For sham stimulation we used a device of identical appearance and function, apart from an inactivated laser beam. Active and sham devices were coded with letters A and B, with acupuncturists unaware of the key, and codes changed twice during the trial. Acupuncturists, patients and hospital staff responsible for co-interventions and outcome assessment were therefore blinded for the laser versus sham laser comparison. Routine treatment of alcohol withdrawal in our hospital includes prescription of clomethiazole rather than benzodiazepines (Mayo-Smith, 1997
), and all patients were prescribed clomethiazole on an individual basis, with symptom-guided dosages (Banger et al., 1997
). In addition, patients could be prescribed benzodiazepines against withdrawal symptoms if it was considered appropriate by the treating psychiatrists. As was the case with clomethiazole, reduction of benzodiazepines was also symptom guided (Banger et al., 1997
). Other drugs taken before study entry had to be kept constant until the end of the trial. Acupuncturists were not involved in routine care, and their interaction with patients was limited to the time required for the stimulation procedures.
Assessments
Severity of withdrawal symptoms was assessed using the Mainz Alcohol Withdrawal Scale (MAWS), a validated 12-item composite scale developed for mild to moderate alcohol withdrawal states with scores ranging from 0 to 34, the higher scores reflecting more severe symptoms (Banger et al., 1992). Each patient was rated daily at 16.00 h by trained nurses using this scale. Nurses and other hospital staff were required not to communicate with the patients about the allocated treatment. Since they were involved in routine care, we cannot exclude the possibility, however, that they intentionally or unintentionally undermined blinding regarding needle stimulation. Therefore, only the laser versus sham laser comparison was considered to have adequate blinding of outcome assessors. The pre-specified primary outcome was the time from baseline to end of withdrawal, with end of withdrawal defined by scoring below two points on the MAWS (a priori). Time from baseline to end of pharmacological treatment of withdrawal symptoms (clomethiazole and benzodiazepines) was the secondary outcome. Because differential sedative intake across groups could potentially lead to performance bias (Jüni et al., 2001
), we also recorded daily clomethiazole doses, and accounted for additional benzodiazepine intake using equivalence doses (10 mg diazepam equivalent to 576 mg clomethiazole, a priori) (McGrath, 1975
; Lapierre et al., 1983
; Burroughs et al., 1985
; Mayo-Smith, 1997
). Assessments of side-effects of experimental treatments were performed daily until the end of inpatient care.
Statistical analysis
We chose a sample size of 48 (16 in each group) based on our experience that >90% of withdrawals in our unit are completed after 7 days. This sample size allowed us to detect a reduction of withdrawal duration of 1.5 days in active intervention groups as compared with the sham intervention group with 80% power at P = 0.05 (two-sided), assuming a standard deviation of 1.5 days and normally distributed data. However, outcome data were not normally distributed (P < 0.05 by Shapiro-Wilk test; Shapiro and Wilk, 1965). Therefore, we calculated medians and used KruskalWallis and Mann Whitney tests (Mann and Whitney, 1947
; Kruskal and Wallis, 1952
) for comparisons between groups. In exploratory analyses, we used the Cox proportional hazards model (Cox, 1972
) to determine associations of pre-specified potential confounding factors with success of withdrawal in univariable and multivariable models, including: (1) disease severity at baseline as defined by MAWS; (2) sedative intake at baseline (clomethiazole and benzodiazepine) using equivalence doses; (3) average daily reduction of sedatives from baseline to end of withdrawal using equivalence doses; and (4) the presence of psychiatric comorbidity at baseline (depression, anxiety or personality disorder). Assumptions of the Cox model were assessed graphically and found to be approximately satisfied for all variables. We then calculated hazard ratios for inter-group comparisons as estimates of the relative risk for successful withdrawal, adjusting for these potential confounders. Finally, to determine whether results could be explained by confounding by differences related to the two acupuncturists or to the choice of acupuncture points, we included identifiers for acupuncturists and for most frequently used points into the Cox proportional hazards model and found results to be unchanged. All analyses were based on the intention-to-treat principle, with all subjects analysed in the originally assigned groups. One patient allocated to sham laser was withdrawn and therefore lost to follow-up on the sixth day of withdrawal, after a clinical decision to stop the allocated intervention because of a lack of efficacy. For the calculation of hazard ratios, we censored the patient after 6 days. Since the patient was allocated to the sham intervention, we assigned a withdrawal duration of 7 days for non-parametric comparison purposes. Considering that the last observed MAWS score was 4 on the sixth day of withdrawal, 7 days represent the shortest withdrawal duration the patient could theoretically have achieved. All analyses were performed in Stata (Stata, Inc., College Station, TX, USA). No adjustments were made for multiple comparisons; P-values are two-sided.
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RESULTS |
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Figure 2 presents withdrawal durations of individual patients for each comparison group separately, whereas Fig. 3
shows KaplanMeier survival estimates for withdrawal. No differences were observed for the laser versus sham laser comparison, with identical median withdrawal durations and similar durations of clomethiazole use in the two groups (Table 2
). Patients allocated to needle acupuncture were found to have a significantly shorter duration of withdrawal symptoms than patients allocated to the sham intervention, and also tended to have a shorter withdrawal symptom duration than patients allocated to laser acupuncture. However, hazard ratios corresponding to these withdrawal durations, which were calculated for exploratory purposes, decreased considerably and ceased to be statistically significant after adjusting for four potential confounders pre-specified in the protocol (Tables 3 and 4
). Adjustment for sedative intake at baseline had a particular impact on effect estimates.
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DISCUSSION |
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The small sample size not only led to limited power, but also to potentially important baseline differences between groups regarding disease severity. In exploratory analyses, we adjusted for these differences, but found the hazard ratio for successful withdrawal and the corresponding confidence intervals comparing laser and sham stimulation to be unaffected, suggesting that confounding is an unlikely explanation for the lack of difference between laser and sham intervention. Conversely, adjusting for baseline differences considerably influenced the hazard ratio comparing needle with sham stimulation: after adjustment for sedative intake at baseline, the effect of needle acupuncture became less beneficial and non-significant. Hence, confounding by disease severity is one potential explanation for the observed differences between needle and sham interventions.
Another potential explanation for the observed differences relates to the lack of a comparison group receiving sham needling with patients only kept unaware of the allocations to laser and sham intervention. We attempted to blind the hospital staff who provided routine care and assessed the outcomes for all three comparison arms, but cannot exclude the possibility that blinding was undermined regarding the allocation of patients to the needle stimulation. Observed effects of needle acupuncture may therefore be entirely due to bias (Jüni et al., 2001). The unequal provision of care apart from randomized interventions could have led to performance bias. We partially addressed this by adjusting for daily decreases in sedative dosages during withdrawal, and found no evidence to support this notion. The control of co-interventions was not optimal, however: we found differences in the pharmacological management of withdrawal, with more patients allocated to sham intervention taking benzodiazepines. We used equivalence doses to account for benzodiazepine intake, but this may be problematic, because trials comparing benzodiazepines and clomethiazole (McGrath, 1975
; Lapierre et al., 1983
; Burroughs et al., 1985
) are scarce, small and methodologically inferior. Other potential biases related to the non-inclusion of sham needling are detection bias through unequal assessment of outcomes across groups, and differential placebo responses because of unequal patient expectations (Jüni et al., 2001
). These two potential sources of bias will only be properly addressed through the inclusion of a comparison group receiving an adequate sham intervention. A recently introduced telescopic sham needle, which does not penetrate the skin, could be used for this purpose (Park et al., 2001
).
High rates of losses to follow-up and drop-outs are a frequently encountered problem in clinical trials on alcohol addiction. Since patients excluded after randomization are unlikely to be representative of all patients included in a trial, this may introduce attrition bias (Jüni et al., 2001). All randomized patients should therefore be included in the analysis and kept in the originally assigned groups, regardless of their adherence to the study protocol (intention-to-treat analysis). All four previous acupuncture trials on alcohol addiction had outpatient settings with some measure of relapse as the primary outcome; consequently, rates of losses to follow-up and drop-outs were high, the analysis could not be performed according to the intention-to-treat principle, and the possibility of attrition bias made interpretation of results difficult. To avoid this, we chose a different approach and focused on inpatients in acute alcohol withdrawal states. In this setting, the primary outcome could be ascertained for all except one patient (98%), and potential attrition bias therefore appears to be minimal. No problems were encountered in patient recruitment: 58% of screened patients qualified for the trial, an extraordinary low proportion refused consent (8% of those who qualified), and the necessary number of patients needed for our pilot trial could be recruited in our 20-bed withdrawal unit within 5 months.
In conclusion, our preliminary results do not suggest a relevant benefit of auricular laser acupuncture in alcohol withdrawal. A large parallel group trial comparing auricular laser and needle acupuncture with adequate sham interventions is needed, however, to reliably determine their effectiveness in this condition. Unless results of such a trial indicate otherwise, the routine use of auricular acupuncture for alcohol withdrawal cannot be recommended.
Contributorship
François Trümpler conceived the trial, was responsible for protocol development and fundraising, performed acupuncture treatments, and was involved in data management. Suzan Oez participated in protocol development, performed acupuncture treatments, and was involved in data entry and management. Peter Stähli was involved in protocol development, was responsible for randomization procedures and advised on acupuncture treatment. Hans Dieter Brenner advised on the protocol and supervised the trial. Peter Jüni advised on the protocol, supervised the trial, had main responsibility for data checking and management, planned and performed data analyses, and wrote the first draft of the paper. All authors were involved in writing the final draft. François Trümpler and Peter Jüni are the guarantors of the trial.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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