Psychotropic analgesic nitrous oxide for alcoholic withdrawal states (Review)

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1 Psychotropic analgesic nitrous oxide for alcoholic withdrawal states (Review) Gillman MA, Lichtigfeld F, Young T This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2008, Issue 4

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Analgesic nitrous oxide vs. standard benzodiazepine, Outcome 1 Anxiety 1 hour after intervention as measured by STA Analysis 1.2. Comparison 1 Analgesic nitrous oxide vs. standard benzodiazepine, Outcome 2 Depression 1 hour after intervention as measured by BDI Analysis 1.3. Comparison 1 Analgesic nitrous oxide vs. standard benzodiazepine, Outcome 3 Psychomotor functioning 1 hour after intervention as measured by QNST Analysis 1.4. Comparison 1 Analgesic nitrous oxide vs. standard benzodiazepine, Outcome 4 Positive therapeutic response APPENDICES WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT INDEX TERMS i

3 [Intervention Review] Psychotropic analgesic nitrous oxide for alcoholic withdrawal states Mark Alfred Gillman 1, Frederick Lichtigfeld 2, Taryn Young 3 1 Substance abuse, S.A.Brain Research Institute, Johannesburg, South Africa. 2 Substance Abuse, Brain Research Institute, Johannesburg, South Africa. 3 South African Cochrane Centre, Medical Research Council, Tygerberg, South Africa Contact address: Mark Alfred Gillman, Substance abuse, S.A.Brain Research Institute, 6 Campbell, Johannesburg, Gauteng, 2090, South Africa. Editorial group: Cochrane Drugs and Alcohol Group. Publication status and date: Edited (no change to conclusions), published in Issue 4, Review content assessed as up-to-date: 27 December Citation: Gillman MA, Lichtigfeld F, Young T. Psychotropic analgesic nitrous oxide for alcoholic withdrawal states. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T Alcoholism is a global problem with 5-10% of the world s population demonstrating alcohol-related diseases. One of the most severe consequences of alcohol dependence is the withdrawal syndrome, for which benzodiazepines are the most popular current treatment. An alternative method to benzodiazepine employs psychotropic analgesic nitrous oxide (PAN). Objectives To assess the effects of PAN for treating alcohol withdrawal states Search methods We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2005), MEDLINE, EMBASE, CINAHL (all to May 2005). We scanned Internet web sites, reference lists of relevant articles and abstracts of the international Conferences on Alcoholism. We contacted researchers in the field and industry to identify unpublished trials. No language and publication restrictions. Selection criteria Randomised controlled trials including voluntary participants dependent on alcohol. PAN was compared to oxygen and/or benzodiazepine regimens. Data collection and analysis Two authors independently assessed the methodological quality of the trials and extracted data. Main results Five studies, 212 participants, were included. PAN showed improvement of symptoms (RR 1.35; 95% CI 1.01 to 1.79), of the amount and duration of sedative medication and of psychomotor function (WMD -8.71; 95% CI to -3.71). At one hour post intervention, no significant differences were found for depression (WMD -2.40; 95% CI to 3.89) and anxiety (WMD -3.70; 95% CI to 3.12). None of the included studies reported any significant adverse effects of any treatment. 1

4 Authors conclusions Results indicate that PAN may be an effective treatment of the mild to moderate alcoholic withdrawal state. The rapidity of the therapeutic effect of PAN therapy coupled with the minimal sedative requirements, may enable patients to enter the psychological treatment phase more quickly than those on sedative regimens, accelerating the patients recovery. Our review does not provide strong evidence due to the small sample sizes of the included trials. Neither does the review indicate any causes for concern that PAN is more harmful than the benzodiazepines. Clinicians wishing to use PAN may initially wish to do so within trial settings. Further high quality trials should be done to confirm these findings and to investigate whether the PAN therapy has fewer adverse effects than other treatments for the alcohol withdrawal states. Studies to investigate the possible cost-effectiveness of PAN by reducing costly hospital admissions and decreasing post administration supervision also need to be performed. P L A I N L A N G U A G E S U M M A R Y Psychotropic analgesic nitrous oxide for alcoholic withdrawal states Alcoholism is a global problem with approximately 5-10% of the world s population demonstrating alcohol-related diseases. One of the most severe consequences of alcohol dependence is the withdrawal syndrome. This review assessed the effects of psychotropic analgesic nitrous oxide (PAN) in treating alcohol withdrawal. All trials were conducted in in-patient settings although PAN is also administered in outpatient settings. The review found that PAN is as effective as sedatives for managing mild to moderate alcohol withdrawal states. Nonetheless, it does not provide strong evidence in favour of the benefits or harms of using PAN over sedatives in managing acute alcohol withdrawal. Further high quality trials should be done before these findings can be confirmed. B A C K G R O U N D Alcoholism is a global problem with approximately 5-10% of the world s population demonstrating alcohol-related diseases. One of the most severe consequences of alcohol dependence is the withdrawal syndrome (Desjarlais 1995; O Brien 1996). The latter is a group of symptoms that occurs following absolute or relative withdrawal of alcohol, after repeated and prolonged use of alcohol (Desjarlais 1995). If the withdrawal state is associated with a serious medical complication it is a potentially lethal condition (O Brien 1996). In most cases the treatment of alcohol dependence is triggered by the presence of an alcohol withdrawal state, which forces the patient to seek treatment. There are no figures available for the prevalence of alcohol withdrawal states and this is aggravated by the fact that many cases of withdrawal are so mild that they do not receive formal treatment and therefore do not come to medical attention (O Brien 1996). The most popular current treatment for the alcohol withdrawal phase is by prescription with benzodiazepines, usually given in tapering doses over a period of days or titrated to the patients symptoms (O Brien 1996). Benzodiazepines are relatively safe (O Brien 1996) and, due to their widespread use, most health care professionals find them easy to administer. There are a number of disadvantages in using these agents. This includes excessive sedation, delays in entering the long-term treatment of alcohol dependence and most importantly the development of dependence on the benzodiazepines (O Brien 1996; Ross 1993). People dependent on alcohol are prone to secondary benzodiazepine abuse (Ross 1993), although the exact extent or prevalence of such secondary addiction is not known. An alternative method to benzodiazepine sedation has been conceptualised and pioneered in South Africa. This treatment employs psychotropic analgesic nitrous oxide (PAN). It is used in various South African National Council for Alcohol and Drug Dependence (SANCA) facilities as well as in Finland at a number of private clinics. It is possible that it is used elsewhere in the world, but we have no confirmation of this or publications to confirm its use elsewhere. PAN treatment involves administering low levels of nitrous oxide plus oxygen to the patient who remains conscious and coherent throughout gas administration. Nitrous oxide at low doses combined with a minimum of 30% oxygen differs from anaesthetic concentrations of nitrous oxide. Such analgesic concentrations of nitrous oxide are used largely for their psychotropic properties of anxiolysis, mood elevation and anti stress effects, hence the term PAN (Gillman 1994b; Gillman 1998). The dopaminergic system is directly implicated in the pathogenesis of substance abuse (Lichtigfeld 1996), mu opioids provoking the release of dopamine 2

5 and kappa opioids decreasing the release of dopamine in the nucleus accumbens (Di Chiara 1988; Dorris 1993; Lichtigfeld 1994; Lichtigfeld 1996; Spanagel 1992). PAN is thought to modulate both mu and kappa opioid systems thus restoring the homeostatic balance which has been disturbed during the withdrawal state (Gillman 1986b; Gillman 1998; Lichtigfeld 1996). There is no fixed concentration of nitrous oxide (N 2 O) or oxygen (O 2 ) because each patient receives a carefully titrated amount of N 2 O and O 2 sufficient only to ameliorate the patient s condition. These concentrations range between 15-70% N 2 O, although most patients respond at concentrations of N 2 O below 50% (Gillman 1990; Gillman 1991). The sequence of gases are O 2 followed by PAN and then O 2 washout. Each sequence lasts a total of 20 minutes (Gillman 1990). The exact dose is determined by the relaxation of the patient without euphoria and without significant obtunding of the patient s consciousness. Other signs associated with the endpoint are a deepening of the patient s voice, decrease in blinking, obvious relaxation of facial and body musculature and the subjective experience that the withdrawal symptoms are being lifted from him/her (Gillman 2002; Lichtigfeld 1982). PAN requires a short hands-on training period because without it practitioners are unlikely to be able to correctly assess the critical clinical endpoint. PAN has an excellent safety record (Clark 1999; Gillman 1987), but can cause minor side effects such as nausea, vomiting, headache and dizziness (Clark 1999). However, chronic exposure to PAN either as a pollutant in low concentrations (where scavenging is not employed) or in the rare cases of abuse can cause haematological (bone-marrow depression) and neurological sequelae similar to that found in subacute combined degeneration of the spinal cord. These changes are caused by interference of vitamin B12 metabolism which occurs following long-term exposure. The adverse effects of PAN as used for alcohol withdrawal are very limited and mild. Haematological and neurological toxicity has not occurred following the short-term exposure of less than 60 minutes used for treating alcohol withdrawal states (Gillman 1987; Gillman 1992; Gillman 1997). The main adverse effects are oversedation or euphoria, both of which can be readily avoided by the correct application of the PAN technique (Gillman 1990). The single absolute contraindication to the use of PAN is chronic obstructive airways disease (COPD) where the physical properties of nitrous oxide can cause expansion of bullae in the lungs and because the concurrent high oxygen concentrations can depress respiratory drive (Clark 1999). Administration requires specialised equipment to ensure safety and efficacy. This equipment is commercially available and is relatively inexpensive compared to most other routine medical equipment found in primary healthcare clinics and hospital outpatient departments. This equipment is usually serviceable, apart from routine maintenance, for 20 years or longer. The cost of gases per 30 minutes is less than ZAR10.00 (approximately US$1.50). It is important to note that, provided the correct technique and equipment are used, neurological and haematological changes should not occur in-patients treated with PAN, because of the brevity of exposure and low concentrations of nitrous oxide used (Gillman 1987). A Modified Gross Scale (Lichtigfeld 1982; Gillman 1990) and other scales described in PAN trials are used to assess the efficacy of PAN against a benzodiazepine. In randomised controlled studies (Lichtigfeld 1989; Lichtigfeld 1989a; Gillman 2002; Gillman 2004), patients responding positively to PAN improved by 50% or more on an alcoholic withdrawal rating scale. More than 90% of patients that recovered within the first 60 minutes required no further gas exposure (Gillman 1991; Gillman 2002; Ojutkangas 1994). For this reason the PAN therapy would seem to offer an extremely rapid screening test to distinguish those patients requiring more intensive therapy, including in-patient therapy, when the rapid therapeutic response does not occur (Gillman 1990). The treatment can be given by a registered nursing sister on the orders of a medical practitioner, who does not have to be present during gas administration (Christian 1991; Gillman 2002). Furthermore, there is a considerable reduction in concurrent medication requirements particularly the benzodiazepines, which are only used in low doses for the first and possibly second night of withdrawal to ensure adequate sleep (Gillman 1986a; Gillman 2002). Thus the very real danger of secondary addiction to benzodiazepines (Myers 2003) is potentially reduced (Gillman 1986a; Gillman 2002). Disadvantages of PAN therapy include a once-off capital outlay of relatively inexpensive commercially available equipment for the safe administration of the gases. Staff must also attend a short hands-on training course to ensure that they use the correct technique for administering PAN. To date no systematic review has been conducted to evaluate PAN to treat alcohol withdrawal. Given its potential to treat alcohol withdrawal and reduce the time required for detoxification, a systematic review of its efficacy was done. We hope that this review will provide useful information to clinicians, consumers and researchers working in the field. Although all the included studies in the current review were on in-patients, at present the PAN therapy is now only used on outpatients. As far as we are aware, nobody in South Africa where it is a recognised treatment for substance abuse withdrawal states (Gillman 2006) currently use it for inpatients. O B J E C T I V E S To assess the effects of PAN for treating alcohol withdrawal states in subjects suffering from alcohol withdrawal or alcohol withdrawal pre-delirium as defined in the DSM-IV (DSM-IV 1994). 3

6 M E T H O D S Criteria for considering studies for this review Types of studies Randomised controlled trials. Types of participants Voluntary consenting subjects dependent on alcohol who fulfil DSM-IV criteria for alcohol withdrawal (DSM-IV 1994). Trials which include participants with alcoholic delirium were excluded. Types of interventions In- or out-patients treated with PAN alone or in combination with other psychotropic agents for alcohol withdrawal states. Intervention: PAN individually titrated to the clinical needs of each patient as measured by their individual responses to the gas. This concentration might vary from 15-70% and differ from patient to patient. There is therefore no fixed target concentration of N 2 O. When PAN is used the concentration of N 2 O depends on the clinical response of the subject. Control: Oxygen (placebo) and/or benzodiazepine regimen. Types of outcome measures PRIMARY OUTCOMES (1) Improvement of at least 50% or more from baseline of alcohol withdrawal states as measured during the acute detoxification period using alcohol withdrawal rating instruments (Gross 1974; Lichtigfeld 1982; Sullivan 1989). Where possible these instruments were standardised. SECONDARY OUTCOMES (2) Completion of detoxification programme (treatment retention) as measured by the number (percentage) of subjects completing the detoxification programme (treatment retention). (3) Entry into rehabilitation programme as measured by the number (percentage) of subjects entering into a rehabilitation programme. If other outcomes were reported such as a decrease in craving for alcohol, these were recorded. Any adverse effects including abuse of PAN were also captured where recorded. Search methods for identification of studies To identify studies for this review electronic and manual searches were done. Electronic searches Detailed search strategies were compiled for each database searched. These were based on the search strategy developed for MEDLINE but revised appropriately for each database to take account of differences in controlled vocabulary and syntax rules. No language and publication restrictions were adopted. The MED- LINE search strategy was based on the Drugs and Alcohol group s phrase for substance-related disorders (Amato 2005) combined with phases 1 & 2 of the Cochrane Sensitive Search Strategy for Randomised Controlled Trials (RCTs) as published in Appendix 5b2 of the Cochrane Handbook for authors of systematic reviews (Alderson 2004) and specific subject search terms (MESH and free text terms). For the identification of studies included in this review we searched Cochrane Central Register of Controlled Trials (CENTRAL - The Cochrane Library Issue 2, 2005).This yielded nine records MEDLINE database (OVID January 1966 to May 2005). This yielded 29 records EMBASE database (OVID - January 1988 to May 2005). This yielded 12 records CINAHL (OVID - January 1982 to May 2005) PsycInfo 1985 to May 2005 for detailed search strategies see Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5. Database of Selective Dissemination of Information (SDI) of the National Institute on Health, Bethesda, USA was checked to identify additional studies. We scanned Internet web sites including the National Institute on Drug Abuse (U.S.A.), National Institute on Alcohol Abuse and Alcoholism (U.S.A.). Manual searches We scanned reference lists of relevant articles in textbooks and journals, and abstracts of the International Biological Psychiatry conferences, Collegium Internationale Neuropsychopharmacoligicum (CINP) conferences and other International Conferences on Alcoholism. We also contacted researchers in the field and industry (providers of nitrous oxide) to identify any unpublished trials. Data collection and analysis (1) Study Selection The titles and abstracts and descriptive terms of all downloaded material from electronic searches were independently read by two authors and irrelevant reports were discarded. Where there was disagreement these studies were then checked by the contact editor to establish their relevance using the criteria given above. If there was uncertainty the full article was obtained. (2) Data extraction 4

7 Data was extracted by two independent authors (Gillman and Young ). Any disagreements were resolved through discussion with the contact editor. The following characteristics were included in a standardised data extraction form: (a) Administrative details: Identification; author(s); published or unpublished; year of publication; year in which study was conducted; details of other relevant papers cited; (b) Details of study: location; date of enrolment; date of trial completion; (c) Characteristics of participants: age; sex; socio-economic status; education level; employment status; (d) Details of intervention: Type of treatment program; length of treatment program; detoxification regime; (e) Details of outcomes: Number of patients improving 50% or more on an alcohol withdrawal rating scale; mean improvement in alcohol withdrawal rating scale; number of patients who completed treatment versus number who did not complete treatment; number of patients entering long-term rehabilitation programme post detoxification. (3) Trial quality The quality of trial methods was qualitatively captured by recording the method of generating the randomisation sequence, the adequacy of allocation concealment, the presence of blinding of the participants, providers and assessors, and the differential lossto-follow-up in the comparison groups. We did not attempt to quantify trial quality, but described it in full. Allocation concealment was assessed as adequate (A in Table of included studies) if there were centralized randomisation by telephone; randomisation schemes controlled by a pharmacy; numbered or coded containers in which treatment from identical bottles are administered sequentially; on-site computer systems which can be assessed after entering the characteristics of an enrolled participant, where allocations are in a locked unreadable file, and sequentially numbered, sealed envelopes; unclear (B in Table of included studies) if sealed envelopes used but not sequentially numbered or opaque; a trial in which the description suggests concealment, but other features are suspicious (i.e. noticeably unequal controls and trial groups, randomisation stated but no details available); inadequate (C in Table of included studies)if any allocation procedure was transparent before assignment (open list of random numbers, alternation, date of birth, day of week, case record number. (4) Analysis Where trials were similar enough we conducted a meta-analysis. The weighted mean difference was calculated for continuous outcomes with 95% confidence intervals and for dichotomous outcomes, the relative risk was calculated. Use was made of the random effects model to calculate the overall measure of effect, as significant heterogeneity was anticipated. Testing for between study heterogeneity was carried out using the Chi 2 and I 2 provided by the RevMan software. The Chi 2 test for heterogeneity was computed with a P value of 0.10 to determine statistical significance. The I 2 statistic was computed to quantify inconsistency across studies. No significant heterogeneity was found and therefore no subgroup analyses were performed. When trials did not allow for meta-analysis, we re-calculated the effects for each outcome and if there was insufficient data we report the results reported by the trialists. R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies. The literature search and hand searching revealed 16 potentially relevant studies. Of these, five were included involving a total of 212 participants. Sample size ranged from 16 to 78 participants. All of these participants qualified as chronic alcoholic patients exhibiting symptoms of alcohol withdrawal (De Rooster 1983; Gillman 1986a; Janks 1992; Fey 1993; Gillman 2004). Excluded studies Ten studies were excluded. The main reason for exclusion was the lack of a comparison group. Reasons for excluding the ten journal articles (Lichtigfeld 1982;Lichtigfeld 1989a; Gillman 1991; Daynes 1989; Daynes 1994; Ojutkangas 1994; Alho 2002 ; Gillman 2002; Alho 2003) and one dissertation (Gillman 1985) are detailed in the Characteristics of excluded studies table. Included studies Two studies published in journals (Gillman 1986a; Gillman 2004) and three dissertations (De Rooster 1983; Janks 1992; Fey 1993) were included. All studies were conducted in South Africa and only included male, mainly white, participants. Detailed information on the participants, interventions, controls and outcomes are in the Characteristics of included studies table. Risk of bias in included studies Generation of allocation sequence A random number table was used by De Rooster 1983 and Gillman 2004, while Gillman 1986a and Janks 1992 used the flip of a coin to generate the allocation sequence. Fey 1993 did not report the method used. Allocation concealment Allocation concealment was unclear in Gillman 1986a and Janks 1992 and not reported in De Rooster 1983, Fey 1993 and Gillman Blinding 5

8 In De Rooster 1983 the interviewers were blind whereas the assessor was blind in Gillman 1986a. In Gillman 2004 the gas administrator, participants and the staff assessing the secondary outcomes were blinded. Blinding was unclear in De Rooster 1983, Janks 1992 and Fey Loss to follow-up In Gillman and Lichtigfeld s study (Gillman 1986a) 78 patients suffering from alcohol withdrawal entered the trial of which 11 in each arm were excluded from the analysis. The reason for these exclusions was that the sedative group did not receive placebo gas but instead received the first doses of benzodiazepine regimen. As a result, although requested not to discuss what they had received on admission, some patients inadvertently revealed this either to the staff or fellow patients. Patients were excluded from the analysis if there was any doubt that the code had been broken in this manner. As a result the loss to follow-up in this study was 28% in each arm. Loss to follow-up was 0% in the other four studies (De Rooster 1983; Janks 1992; Fey 1993; Gillman 2004). Effects of interventions Results are classified according to primary and secondary outcomes as reported in the included trials. In each case the outcomes were assessed before and after the PAN and at various time intervals after the gas administration and initial sedative dose had been given. Where no significant heterogeneity was found, the overall effect estimate was calculated using both the fixed and random effect models. Results of random effect models are reported as there were no significant differences between the results of the two models. Primary outcomes 1. Improvement of scores as measured on a modified Gross Scale In Gillman 2004 (N = 51) a positive response was considered to have occurred if the symptom scores on a modified Gross Scale were reduced by 50% or more (Gillman 2004). PAN significantly favoured a positive response (RR 1.35; 95% CI 1.01 to 1.79). There was no difference in the severity of withdrawal when comparing the subgroups who did and did not receive oxazepam the night before (Analysis 1.4). Secondary outcomes (1) Anxiety Three trials (N = 83) reported anxiety as an outcome (De Rooster 1983; Janks 1992; Fey 1993). All the studies used the State-Trait Anxiety Inventory (STAI) to measure the outcome. In Janks 1992 there was a general tendency for the anxiety scores of the control group to decrease at the three different testing occasions (pre intervention, at 1 hour and 24 hours post intervention) however the PAN group had no significant differences across the various testing occasions. At 1 hour after the intervention was administered (Janks 1992; Fey 1993), there was no significant difference between PAN and the control group (WMD -3.70; 95% CI to 3.12) with no significant heterogeneity (I 2 0%; Chi with P = 0.61) (Analysis 1.1). Due to the lack of data necessary to include in the meta-analysis, De Rooster was excluded from the meta-analysis. In De Rooster 1983 the experimental group had significantly less anxiety as compared to the control group although this difference disappeared at day seven. (2) Depression Three trials (N = 83) reported depression as an outcome (De Rooster 1983; Janks 1992; Fey 1993). Using the Beck Depression Inventory (BDI) Janks 1992 and Fey 1993 found no significant difference at 1 hour post intervention administration (WMD ; 95% CI to 3.89). There was no significant heterogeneity (I %; Chi with P = 0.28) (Analysis 1.2). Due to the lack of data necessary to include in the meta-analysis, De Rooster was excluded from the meta-analysis. Comparing the scores at the three different testing occasions in Janks 1992 (pre intervention, at 1 hour and 24 hours post intervention) there was a statistically significant positive effect of PAN on depression as measured by the BDI but not in the control group. The results of the ANOVA test on BDI were as follows: ANOVA Chi sq = 7.03 (df=2; p<0.05) for the experimental group and ANOVA Chi sq=4.07 (df=2; p>0.05) for the control group. The changes were greater one hour after gas administration than at 24 hours. These results were not conclusive because of the presence of an extremely high scorer in the PAN group, which could have been due to subject or measurement error as well as the fact that a quarter of the subjects in the experimental group received carbogen instead of PAN. De Rooster 1983 did not observe any differences in degree of depression at any time or on any of the scales he used to assess depression. (3) Guilt In De Rooster 1983 there was no significant difference between the two groups except in the middle phase (day 4 assessment), where the experimental group showed greater guilt than the control group. Those in the experimental group showed greater guilt at the middle phase as compared to basal condition as compared to the control group (p<0.05) using an ANOVA analysis of variance (De Rooster 1983). (4) Psychomotor functioning Fey 1993 (N = 31) compared the effect of PAN and sedatives on psychomotor functioning using the Quick Neurological Screening Test (QNST) and found that the PAN was significantly better than the sedative group (WMD -8.71; 95% CI to -3.71) (Analysis 1.3). De Rooster 1983 used the Brief Outpatient Psychopathology Scale. There was no difference between the 2 groups except that the experimental group showed less psychomotor activation than the control group at the beginning phase. (5) Craving Janks 1992 (N = 16) used the University of Connecticut Health 6

9 Centre Craving Scale which consists of a one item questionnaire and found that there was insufficient evidence to suggest that craving had changed across the testing points in either the PAN or the control group. (6) Amount of sedative medication required De Rooster 1983 recorded a range of the total night and sedation requirements for each group over the seven days of the trial which corresponds to the acute detoxification period at the facility where the trial was undertaken. The upper and lower dose for each group were provided. Averaging the lowest and highest doses in each group over 7 days and then summing these doses, the control group required an average of mgs night sedation (pentobarbital, oxazepam, diazepam) in addition to the daily sedative requirements (pentobarbital, oxazepam, diazepam; average= 230.5mgs) and the experimental group needed on average 120 mgs. The experimental group required no day sedation. Comparing the total sedative medication for the groups (using the average dose over the week), the control group required on average 1008 mgs (pentobarbital, oxazepam, diazepam), while the experimental group only required an average of 120mgs (oxazepam). In Gillman 1986a (N = 78), the mean dose for the control group was mg compared to mg for the PAN group. The total additional medication requirements (i.e. in addition to the daily requirements of the sedative group) were decreased by 76.44% (Gillman 1986a). Gillman and Lichtigfeld (Gillman 2004) also found that the night sedation requirements of the PAN group were markedly reduced in that sedation was only required on night one and two in the majority of cases, whereas in the control group, diazepam was given nightly during the patients stay in the detoxification centre (Gillman 2004). We only have the means. No ranges or standard deviations were available in any of these studies (De Rooster 1983; Gillman 1986a; Gillman 2004) and it was therefore not possible to undertake a meta-analysis. (7) Number of days that medication was required Gillman 1986a found that the period of sedation was 5 days in the PAN group compared to 7 days in the control group. De Rooster 1983 found that sedatives were only required for 3 days in the PAN group as compared to 7 days in the sedative group. Gillman and Lichtigfeld (Gillman 2004) also found that the night sedation requirements of the PAN group were markedly reduced, since most subjects in the experimental group required night sedation for the first 2 nights of treatment only, whereas patients in the control group required night medication for 7 nights. (8) Adverse Effects None of the included studies reported any significant adverse effects of any treatment. D I S C U S S I O N Five studies, of which three were unpublished, including a total of 212 participants met the criteria for inclusion in the review (De Rooster 1983; Gillman 1986a; Janks 1992; Fey 1993; Gillman 2004). Due to the difference between measured outcomes in each trial, it was not possible to conduct meta-analyses for most outcomes and results presented from the small individual trials must be treated with caution. Currently there is not strong evidence that PAN is beneficial or, importantly, harmful and our review clearly demonstrates a need for further trials to be conducted on this intervention. Nonetheless, there is some evidence that the PAN method leads to a more rapid amelioration of the withdrawal state than benzodiazepines (Gillman 2004) when the effects are measured with a withdrawal instrument measuring a composite range of different signs and symptoms. The rapidity of the response observed (Gillman 2004) support other work where the speed of the beneficial response of PAN after single exposure to the gas, within 60 minutes, with lasting effect was noted (Lichtigfeld 1982; Daynes 1989; Gillman 1990; Gillman 1991; Gillman 2002). Three included studies (De Rooster 1983; Gillman 1986a; Gillman 2004) showed that there was a significant reduction in the sedative medication requirements, both in terms of duration and quantity, of those treated with PAN as compared to those treated with sedatives. Since other sedatives were seldom required after the fifth day of therapy, following a single 20 minute PAN exposure (on admission day only, in most cases) (De Rooster 1983; Gillman 1986a; Gillman 2004), it is possible that patients treated on an in-patient basis with PAN can be discharged earlier than those receiving benzodiazepines and other sedatives. The reduction in sedative requirements, in particular benzodiazepines, is advantageous because of the problems associated with secondary abuse of the benzodiazepines by alcoholic subjects (Gillman 1986a; Ross 1993; O Brien 1996; Gillman 2002). Furthermore, the side effects of the benzodiazepines can be troublesome. These include syncope, confusion, motor incoordination resulting in accidents and oversedation (Gillman 1986a; Hobbs 1996). Other relatively common side effects of the benzodiazepines include weakness, headache, blurred vision, vertigo, nausea, vomiting and incontinence (Hobbs 1996). In this review none of the included studies reported on side effects. The rapidity of the response to PAN and the limited reliance on sedative medications renders the patient more amenable to psychological manipulation, which has been shown to be of importance in the treatment of the alcohol withdrawal states (Madden 1979; Whitfield 1980; Lichtigfeld 1982; Gillman 1986a; Ntais 2006). A number of isolated parameters were also measured with contrasting results. Janks 1992 and Fey 1993 were unable to demonstrate a statistical difference in anxiety scores between the PAN group and the benzodiazepine group at the one hour assessment. This is of interest because it is well known that both agents have marked anxiolytic effects (Hobbs 1996; Clark 1999) and indicates 7

10 that the PAN group produced the expected anxiolysis but that it was less so than with benzodiazepines (Janks 1992; Fey 1993). Contamination may account for this finding seeing that two of the eight subjects who were supposed to receive PAN actually received carbogen (Janks 1992), which is known to be anxiogenic (Woods 1986). In contrast, De Rooster 1983 demonstrated a statistically significant decrease in anxiety in the PAN group as compared to the benzodiazepine group over all testing times. De Rooster s work (De Rooster 1983) also gives further support to the therapeutic effects of PAN in relieving anxiety in alcohol withdrawal states, which has been shown repeatedly in other stress provoking situations e.g. dentistry (Clark 1999). Mild to moderate alcohol withdrawal states usually peak at between hours and tends to abate over the next day or so, even without therapy (O Brien 1996; Shaw 1982) and thus one can expect the disappearance of effects at day seven. No significant differences were found for depression at one hour post intervention. Janks 1992 showed that there was a significant improvement of depression in the PAN group, as opposed to the sedative group, at all testing times i.e. pre-intervention at one and 24 hours for depression. These findings should be treated with caution because she mentions that her results might have been influenced by a single high scorer, which might have skewed her results (Janks 1992). De Rooster 1983 observed that the sedative group showed more guilt at 96 hours than the PAN group. As mentioned above, this might indicate that the sedatives have a negative effect on recovery when given at the time that the withdrawal state would have been expected to normalise (Shaw 1982). Further work is necessary to confirm the effects of PAN on depression as well as to exclude the possible negative effects of sedatives in mild to moderate withdrawal states from the fourth day onwards, particularly as benzodiazepines do not have antidepressant properties (Schatzberg 1978). It is possible that the benzodiazepines may have a negative effect on the recovery of mild to moderate withdrawal states (Ntais 2006) and it has been showed that the incidence of side effects following their use is greater than when other agents are used (Ntais 2006). The possible negative effects of sedatives requires further study, since there seems to be evidence that they might interfere with the subjects normal recuperative processes and unnecessarily prolong recovery times. Fey (Fey 1993) was able to demonstrate that PAN was significantly better than the sedative group as regards psychomotor function, however this was not confirmed in the other study measuring psychomotor function (De Rooster 1983). It is possible that the latter work was unable to show a difference because the second assessment was only done after 98 hours and by this stage the sedative group were receiving less than half the sedatives that they would have received on days 1-3 (De Rooster 1983). That Fey s findings are probably closer to the actual effects of the two treatments appears to be supported by the evidence that the benzodiazepines have marked negative effects on motor function (Gillman 1986a; Hobbs 1996) and that the effects of PAN on motor function disappear within an hour after gas administration has ceased (Moyes 1979; Herwig 1984). Janks (Janks 1992) measured the effects of the two treatment conditions on craving but concluded that there was no difference. However, she mentions that her results were probably inaccurate because of a possibly unreliable single-question craving measuring instrument, which she used. These finding are further complicated by the fact that two subjects in the PAN group received carbogen instead of PAN with the overall sample size being very small at 16. The sample sizes of the included trials were small which limits our ability to draw robust conclusions. Only a single trial was methodologically sound (Gillman 2004) while the others had various methodological weaknesses. Further research into the effects of PAN for treating mild to moderate alcohol withdrawal states are needed. Careful clinical trials comparing PAN with benzodiazepine regimens would be useful to determine whether the rapid therapeutic effects of the PAN therapy can prevent the negative effects of the benzodiazepines, which have been highlighted by this review. However, any study in which the effects of PAN are tested should only be undertaken by those who have had handson training to use PAN correctly (Gillman 2006). A U T H O R S C O N C L U S I O N S Implications for practice These results indicate that PAN may be a rapidly effective treatment of the mild to moderate alcoholic withdrawal state, with minimal sedative requirements. The rapidity of the therapeutic effect of the PAN therapy coupled with the minimal sedative requirements and concomitant sedation, may enable patients to enter the psychological treatment phase more quickly than those on sedative regimens, thus accelerating the patients recovery Our review does not provide strong evidence in favour of the benefits of using PAN over sedatives in managing acute alcohol withdrawal due to the small sample sizes of the included trials. Neither does the review indicate any causes for concern that PAN is more harmful than the benzodiazepines. Clinicians wishing to use PAN may initially wish to do so within trial settings. Implications for research Further high quality trials should be done to confirm these findings and to investigate whether the PAN therapy has fewer adverse effects than the BZs or other treatments for the acute mild to moderate alcohol withdrawal states. Studies to investigate the possible cost-effectiveness of PAN by reducing costly hospital admissions and decreasing post administration supervision also need to be performed. 8

11 A C K N O W L E D G E M E N T S The staff of the South African Cochrane Centre, in particular Elizabeth Pienaar and Joy Oliver, have provided technical and methodological support to the protocol development and review completion. We also thank Dr Nandi Siegfried, contact editor for this review, for her valued support enthusiasm and positive criticism. We would also like to express our deep indebtness to the late Fred Lichtigfeld for his contribution to this work, both in its conception and development. Without his drive and guidance this review would not have appeared. R E F E R E N C E S References to studies included in this review De Rooster 1983 {published data only} De Rooster C. The effectiveness of nitrous oxide in the treatment of alcohol withdrawal states [Die effektiwiteit van distikstofoksied in die behandeling van die alkohol omtrekkingsindroom.]. Thesis accepted in partial fulfilment for the degree MA (Hons) Clinical Psychology, Rand Afrikaans University, Johannesburg, South Africa Fey 1993 {published data only} Fey W J. A comparative treatment study of the alcohol withdrawal syndrome: nitrous oxide and benzodiazepines. Thesis accepted in partial fulfilment BA (Hons) Clinical Psychology, University of the Witwatersrand, Johannesburg, South Africa Gillman 1986a {published data only} Gillman MA, Lichtigfeld FJ. Minimal sedation required with nitrous oxide - oxygen treatment of the alcohol withdrawal state. British Journal Psychiatry 1986;148: Gillman 2004 {published data only} Gillman MA Lichtigfeld FJ. Enlarged double-blind randomised trial of benzodiazepines against psychotropic analgesic nitrous oxide for alcohol withdrawal. Addictive Behaviors 2004;29(6): Janks 1992 {published data only} Janks A. The use of nitrous oxide in the treatment of the alcohol withdrawal syndrome. Thesis accepted in partial fulfilment for the degree BA (Hons) Clinical Psychology, University of the Witwatersrand, Johannesburg, South Africa References to studies excluded from this review Alho 2002 {published data only} Alho H, Methuen T, Paloheimo M, Strid N, Seppa K, Tiainen J, et al.long-term effects of and physiological responses to nitrous oxide gas treatment during alcohol withdrawal: a double-blind, placebo-controlled trial. Alcohol: Clinical Experimental Research 2002;26(12): Alho 2003 {published data only} Alho H, Metheun T, Paloheimo M, Seppä J. Nitrous oxide has no effect in the treatment of alcohol withdrawal syndrome: double-blind placebo-controlled randomized trial.. Journal of Clinical Psychopharmacology 2003;23(2): Daynes 1989 {published data only} Daynes G. The initial management of alcoholism using oxygen and nitrous oxide: a trans cultural study. International Journal of Neuroscience 1989;49(1-2):83 6. Daynes 1994 {published data only} Daynes G, Gillman MA. Psychotropic analgesic nitrous oxide prevents craving after withdrawal from alcohol, cannabis and tobacco. International Journal of Neuroscience 1994;76(1-2):13 6. Gillman 1985 {published data only} Gillman MA. Nitrous oxide as an opioid agonist: some experimental and clinical observations.. Thesis accepted in fulfilment of the degree DSc at Potchefstroom University, Transvaal South Africa, Gillman 1991 {published data only} Gillman MA, Lichtigfeld FJ. Placebo and analgesic nitrous oxide for treatment of the alcohol withdrawal state. British Journal of Psychiatry 1991;159: Gillman 2002 {published data only} Gillman MA, Lichtigfeld FJ. Randomised double-blind trial of psychotropic analgesic nitrous oxide compared with diazepam for alcohol withdrawal state. Journal of Substance Abuse Treatment 2002;22(3): Lichtigfeld 1982 {published data only} Lichtigfeld FJ, Gillman MA. The treatment of alcoholic withdrawal states with oxygen and nitrous oxide. South African Medical Journal 1982;61(10):

12 Lichtigfeld 1989a {published data only} Lichtigfeld FJ, Gillman MA. Analgesic nitrous oxide for alcohol withdrawal is better than placebo. International Journal of Neuroscience 1989;49(1-2):71 4. Ojutkangas 1994 {published data only} Ojutkangas R, Gillman MA. Psychotropic analgesic nitrous oxide for treating alcohol withdrawal in an outpatient setting. International Journal of Neuroscience 1994;76(1-2): Additional references Alderson 2004 Alderson P, Green S, Higgins JPT, editors. Cochrane Reviewer s Handbook The Cochrane Library Issue 1, Chichester, UK: John Wiley & Sons, LTD; Amato 2005 Amato L, Davoli M, Ali R, Auriacombe M, Faggiano F, Farrell M, et al.cochrane Drugs and Alcohol Group. The Cochrane database of Systematic Review John Wiley & Sons, LTD. Chichester, UK. Christian 1991 Christian MK. Analgesic nitrous oxide for management of addictive withdrawal: a successful implementation in a Third World alcohol rehabilitation programme. 36th International Institute on the Prevention and Treatment of Alcoholism (Paper). Stockholm, Clark 1999 Clark M, Brunick A. Handbook of nitrous oxide and oxygen sedation.. St Louis: Mosby, Desjarlais 1995 Desjarlais R, Eisenberg L, Good B, Kelinman A. World mental health. New York: Oxford, Di Chiara 1988 Di Chiara, G Imperato A. Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and the dorsal caudate of freely moving rats. J Pharmacol Exp Ther 1988;244(3): Dorris 1993 Dorris RL, Truong V. Locomotor effects of nitrous oxide in mice: requirement of newly synthesized and main intraneural storage pools of dopamine. J Pharm Pharmacol 1993;45(4): DSM-IV 1994 Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders. 4th Edition. Washington DC: American Psychiatric Association, 1994: Gillman 1994b Gillman MA. Psychotropic analgesic nitrous oxide as an investigative, diagnostic and therapeutic tool. International Journal of Neuroscience 1994;76(1-2):1 3. Gillman 1983 Gillman MA, Lichtigfeld FJ. Receptor hypothesis of the alcohol withdrawal state. In: P Mandel, FV DeFeudis editor(s). CNS receptor- from molecular pharmacology to behaviour. Advances in biochemical psychopharmacology. Vol. 37, New York: Raven Press, 1983: Gillman 1986b Gillman MA. Minireview: Analgesic (sub anaesthetic) nitrous oxide interacts with the endogenous opioid system : A review of the evidence. Life Sciences 1986;39(14):l209 2l. Gillman 1987 Gillman MA. Editorial. Haematological changes caused by nitrous oxide: Cause for concern?. British Journal Anaesthesiology 1987;59(2): Gillman 1990 Gillman MA, Lichtigfedl FJ. Analgesic nitrous oxide for alcohol withdrawal: a critical appraisal after 10 years use. Postgraduate Medical Journal 1990;159(2-4): Gillman 1992 Gillman MA. Nitrous oxide abuse in perspective. Clinical Neuropharmacology 1992;15(4): Gillman 1994 Gillman MA, Lichtigfeld FJ. Opioid properties of psychotropic analgesic nitrous oxide (Laughing Gas). Perspectives in Biology and Medicine 1994;38(1): Gillman 1995 Gillman MA. Nitrous oxide has a very low abuse potential. Addiction 1995;90(3):439. Gillman 1997 Gillman MA, Lichtigfeld FJ. The current status of analgesic nitrous oxide for treating alcoholic withdrawal states. Suomen Lääkärillehti (Finnish Medical Journal) 1997;52: Gillman 1998 Gillman MA, Lichtigfeld FJ. Clinical role and mechanisms of action of analgesic nitrous oxide. International Journal of Neuroscience 1998;93(1-2): Gillman 2006 Gillman MA, Lichtigfeld FJ. New Topics in Substance Abuse Treatment. New York: Nova Science, Gross 1974 Gross M, Lewis E, Hastey J. The biology of alcoholism. Vol. 3, New York: Plenum Press., Herwig 1984 Herwig D, Milam S B, Jones D L. Time course of recovery following nitrous oxide administration. Anaesthesia Progress 1984;31: Hobbs 1996 Hobbs WR, Rall TW, Verdoorn TA. Hyponotics and sedatives. Goodman and Gilman s The pharmacological basis of therapeutics. 9th Edition. McGraw-Hill, 1996: Lichtigfeld 1983 Lichtigfeld FJ, Gillman MA. The treatment of alcoholic withdrawal states with oxygen and nitrous oxide. South African Medical Journal 1983;63:

13 Lichtigfeld 1983a Lichtigfeld FJ, Gillman MA. The treatment of alcoholic withdrawal states with oxygen and nitrous oxide. S Afr Med J 1983;63:65 6. Lichtigfeld 1989 Lichtigfeld FJ, Gillman MA. The effect of placebo in the alcohol withdrawal state. Alcohol and Alcoholism 1989;24 (2): Lichtigfeld 1994 Lichtigfeld FJ, Gillman MA. Psychotropic analgesic nitrous oxide and neurotransmitter mechanisms involved in the alcohol withdrawal state. International Journal of Neuroscience 1994;76(1-2): Lichtigfeld 1996 Lichtigfeld FJ, Gillman MA. Role of dopamine mesolimbic system in opioid action of psychotropic analgesic nitrous oxide (PAN) in alcohol and drug withdrawal. Clinical Neuropharmacology 1996;19(3): Madden 1979 Madden JS. A Guide to Alcohol and Drug Dependence. Bristol: John Wright, Moyes 1979 Moyes D, Cleaton-Jones D, Leliot J. Evaluation of driving skills after brief exposure to nitrous oxide. South African Medical Journal 1979;56: Myers 2003 Myers B, Siegfried N, Parry CDH. Over-the-counter and prescription medicine misuse in Cape Town - findings from specialist treatment centers. S Afr Med J 2003;93: Ntais 2006 Ntais C, Pakos E, Kyzas P, Ioannidis JPA. Benzodiazepines for alcohol withdrawal. Cochrane Database of Systematic Reviews 2006, Issue 1. [DOI: / ] O Brien 1996 O Brein CP. Drug addiction and drug abuse. Goodman and Gillman s The pharmacological basis of therapeutics. 9th Edition. New York: McGraw-Hill, 1996: Ross 1993 Ross HE. Benzodiazepine use and anxiolytic abuse and dependence in treated alcoholics. Addiction 1993;88(2): Schatzberg 1978 Schatzberg AF, Cole JO. Benzodiazepines in depressive disorders. Archives of General Psychiarty 1978;35(11): Shaw 1982 Shaw GK. Alcohol dependence and withdrawal. Brit Med Bull 1982;38(1): Spanagel 1992 Spanagel R, Herz A, Shippenberg TS. Opposing tonically active endogenous opioid systems modulate mesolimbic dopmanergic pathway. Proc Nat Acad Sci USA 1992;89: Sullivan 1989 Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA- Ar). Brit J Addiction 1989;84(11): Whitfield 1980 Whitfield CH. Non-drug treatment of alcohol withdrawal. Current Psychiatric Research 1980;19: Woods 1986 Woods SW, Charney DS, Lake J, Goodman WK, Redmond DE, Heninger DR. Carbon dioxide sensitivity in panic anxiety. Ventilatory and anxiogenic response to carbon dioxide in healthy subjects and patients with panic anxiety disorder before and after alprazolam treatment. Archives of General Psychiatry 1986;43(9): Indicates the major publication for the study 11

14 C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of included studies [ordered by study ID] De Rooster 1983 Methods Participants Interventions Outcomes Notes Generation of allocation sequence: random number table Allocation concealment: not reported Blinding: interviewers were blind Loss to follow-up: 0% both arms 36 DSM III Alcoholic volunteers - 18 arm 1-18 arm 2 Recruitment: Primary care clinic All white males with mean age of the group being 42 years (range 28-57). Included: alcohol dependent who reported to Northlea hospital for withdrawal management, male, stay for 7 days, English Excluded: Lung, respiration or heart problems, delirium tremens or psychopathology All patients received routine anti-epileptic prophylaxis with phenytoin and vitamin therapy. The period of observation was 7 days for all patients. Arm 1: Nitrous oxide plus oxygen; gases administered by a Quantiflex dental relative analgesic machine. Initialy oxygen given at 8 litres/minute for 20 min followed by nitrous oxide (between 3 and 6 litres/ minute) and oxygen (not less than 3 litres / minute) for 20 min followed by 20 min oxygen. Received oxazepam nocte day 1,2 and 3. Arm 2: Barbiturates plus benzodiazepine. Received oxazepam nocte. Three patients in the experimental group required a single extra session with PAN within the first 24 hours because their withdrawal state was more severe than the others in this group Reduced psychopathology - anxiety, depression Baseline measurements were taken before any intervention and then on the fourth day and finally on day seven. Outcomes were measured using a questionnaire (Nowlis Mood adjective checklist and state anxiety inventory) and observation scales (brief outpatient psychopathology scale, psychotic inpatient profile and nurses observations) Country: South Africa Ethics: not reported Risk of bias Item Authors judgement Description Allocation concealment? Unclear B - Unclear 12

15 Fey 1993 Methods Participants Interventions Outcomes Notes Generation of allocation sequence: not reported Allocation concealment: not reported Blinding: unclear Loss to follow-up: 0% both arms 31 DSM III Alcoholic volunteers arm 1-15 arm 2 Recruitment: Primary care clinic. All white males with mean age years(sd 6.67) in arm 1 and 38.8 years (SD 7.3) in arm 2. Included: DSM III-R for alcohol dependent syndrome as diagnosed by medical personnel, no psychological problems, no severe withdrawal symptoms (delirium tremens) Arm 1: Nitrous oxide: Mixture of high concentration oxygen and low concentration nitrous oxide. Gases administered by a Quantiflex dental relative analgesic machine which incorporates a fail safe device. The latter halts the flow of nitrous oxide when the oxygen concentration delivered falls below 30%. A nasal mask is used in the administration of the gas making it a open circuit delivery system. Treatment individualized for each patient. Initially patient receive 100% oxygen for 20 min followed by a carefully titrated mixture of analgesic nitrous oxide for another 20 min followed by 5 min of 100% oxygen. Arm 2: Standard sedative therapy with benzodiazepine. Anxiety, depression, psychomotor functioning: one hour after commencement of treatment Measured the baseline status prior to the interventions and then an hour after the interventions. Used the State trait anxiety inventory, Beck depression inventory and the Quick neurological screening test for psychomotor functioning Country: South Africa. Ethics: written informed consent obtained Risk of bias Item Authors judgement Description Allocation concealment? Unclear B - Unclear Gillman 1986a Methods Participants Generation of allocation sequence: Flip of coin Allocation concealment: unclear Blinding: assessors were blind Loss to follow-up: 11 in each arm were excluded from the analysis. The reason for these exclusions was that the sedative group did not receive placebo gas and it was suspected that the blinding may have been inadequate for these excluded subjects 78 DSM III Alcoholic volunteers arm 1-39 arm 2 All males with overall mean age 34.2 years. Included: time to last drink not less than 8 hours and not more than 24 hours 13

16 Gillman 1986a (Continued) Excluded: chronic obstructive pulmonary disease, frank delirium tremens Interventions Outcomes Notes Arm 1: At admission only 20 min 100% oxygen followed by 20 min PAN where oxygen concentration was never less than 30% of the gas mixture delivered, followed by 20 min 100% oxygen washout. Arm 2: 5 mg diazepam 3x per day (days 1-3) and 2mg 3x per day (4-7). Additional benzodiazepines and barbiturates were provided as required (on clinical grounds), to both control and experimental group by a blinded assessor. The period of observation was 7 days for all patients Primary Arm 1: amount of sedative medication required after exposure to PAN regimen. Arm 2: amount of sedative medication in excess of routine sedative medication. Secondary Number of days that medication was required Involved observation of the patients over a seven-day period Setting: South Africa Ethics: not reported Risk of bias Item Authors judgement Description Allocation concealment? Unclear B - Unclear Gillman 2004 Methods Participants Interventions Generation of allocation sequence: random number table Allocation concealment: not reported Blinding: gas administrator, participants and staff used for assessment of secondary outcome Loss to follow-up: 0% per arm 51 DSM-IV Alcoholic volunteers - 23 arm 1-28 arm 2 Recruitment: Primary care clinic. All males with mean age 38.3 years (SD 5.59) arm 1 and 45.1 years (SD 8.34) arm 2. Included: mild to moderately severe alcohol withdrawal state using DSM-IV criteria Excluded: Acute alcoholic hepatitis, any other organic medical condition determined on clinical examination, history of other drug abuse, other psychiatric diseases (including epilepsy), alcoholic delirium or pre-delirium, placebo responders Arm 1: Placebo tablet (administered immediately prior to gas administration) plus 20 min PAN where oxygen concentration was never less than 30% of gas mixture delivered, followed by at least 5 min 100% oxygen washout received no oxazepam the previous night received oxazepam the previous night. Arm 2: Diazepam 5mg (administered immediately prior to gas administration) plus 20 min 100% oxygen, followed by at least 5 min 100% oxygen washout 14

17 Gillman 2004 (Continued) - 12 received no oxazepam the previous night received oxazepam the previous night. Outcomes Notes Primary Outcome: Improvement of scores by 50% or more as measured on a modified Gross Scale. The signs and symptoms of the alcohol withdrawal state measured by nurses before each treatment (basal readings at time=0) and after 120 minutes and compared across Arm 1 and Arm 2. Symptoms graded as mild (1 point), moderate (2 points) or severe (3 points). Maximum score of 39 possible. Secondary Outcome: Sedative medication requirements of the 2 groups over 7 days Country: South Africa. Ethics: SA Medical Research Council s Human Ethical Review Committee approved the study and written informed consent was obtained Risk of bias Item Authors judgement Description Allocation concealment? Unclear B - Unclear Janks 1992 Methods Participants Interventions Outcomes Generation of allocation sequence: flip of a coin Allocation concealment: unclear Blinding: unclear Loss to follow-up: 0% per arm 16 DSM-III Alcoholic volunteers. - 8 arm 1-8 arm 2 Recruitment: Primary care clinic. All white males with mean age 35 years (SD 4.38) arm 1 and 43.5 years (SD 7.27) arm 2. Included: met DSM III R (1980) criteria for alcohol dependant syndrome, time to last drink more than 4 and less than 36 hours, no previous psychiatric diagnosis, drinking for two or more days prior to day of selection, no delerium tremens or severe physical illness Arm 1: Nitrous oxide: 20 min oxygen then 20 min carefully titrated mix of analgesic nitrous oxide then 20 min oxygen to wash out residual nitrous oxide. Nitrous oxide dose as per individual needs. Dose administered ranged from 5% to 70% nitrous oxide. No sedatives received. Arm 2: Standard sedative therapy with benzodiazepine: Day 1 and 2 5mg three times per day; Day 3 2mg twice per day; Day 4 2mg once per day Primary Outcome: Anxiety, depression and craving. Baseline measurements were taken before any intervention and then one hour after the interventions and finally after 24 hours. Used the Beck depression inventory, Spielberger s state trait anxiety inventory and the University of Connecticut Health Centre craving scale 15

18 Janks 1992 (Continued) Notes Country: South Africa. Ethics: written informed consent obtained 2 of the 8 participants in the experimental group did not get nitrous oxide due to staff error. They received carbogen (a 95% oxygen / 5% carbon dioxide mixture) instead Risk of bias Item Authors judgement Description Allocation concealment? Unclear B - Unclear DSM= Diagnostic and Statistical Manual of Mental Diseases PAN= psychotropic analgesic nitrous oxide Characteristics of excluded studies [ordered by study ID] Study Alho 2002 Reason for exclusion Alho 2002 titrated to a fixed target end tidal volume of 30% (inhaled 60%) nitrous oxide and used the verbal response of the patient to decrease the dose to avoid unconsciousness and anaesthesia. In contrast the PAN method requires slow titration until a clinical endpoint at which the patient is relaxed but is nowhere near preanaesthetic excitation, with a different concentration of nitrous oxide needed for each individual patient. The PAN method (i.e. conscious sedation with nitrous oxide/oxygen) thus never presupposes a target concentration of nitrous oxide. Rather, it aims for a clinical response (within Stage 1 of Anaesthesia), which for each patient is usually found at a different concentration of nitrous oxide (and which is unique for them). Alho 2002 titrated to a predetermined concentration of nitrous oxide, close to or at pre-anaesthetic excitation (Stage II Anaesthesia). They reported evidence of at least Stage II Anaesthesia, in that the majority of their subjects manifested increased tension and not relaxation as would be found if PAN had been used. Data provided showed that most of their patients exhibited increased facial muscle tone as measured by facial muscle electromyographic activity (FEMG) levels. Alho 2003 Identical cohort and method used as in Alho 2002 Daynes 1989 Daynes 1994 Gillman 1985 Gillman 1991 Gillman 2002 No comparison group for the nitrous oxide intervention Not an experimental study as all patients were enrolled. No comparison group The study compared oxygen vs. carbogen and all participants with no response received analgesic nitrous oxide This study is part of Gillman of cohort who had not received a benzodiazepine were pooled with those who had received a benzodiazepine the previous night and used in Gillman The entire cohort of 51 were studied using the same protocol and over the same period 16

19 (Continued) Lichtigfeld 1982 Lichtigfeld 1989a Ojutkangas 1994 No comparison group No comparison group for the nitrous oxide intervention No comparison group 17

20 D A T A A N D A N A L Y S E S Comparison 1. Analgesic nitrous oxide vs. standard benzodiazepine Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Anxiety 1 hour after intervention 2 47 Mean Difference (IV, Random, 95% CI) [-10.53, 3.12] as measured by STA 2 Depression 1 hour after 2 47 Mean Difference (IV, Random, 95% CI) [-8.70, 3.89] intervention as measured by BDI 3 Psychomotor functioning 1 hour 1 31 Mean Difference (IV, Fixed, 95% CI) [-13.71, -3.71] after intervention as measured by QNST 4 Positive therapeutic response 1 51 Risk Ratio (M-H, Random, 95% CI) 1.35 [1.01, 1.79] 4.1 Oxazepam night before 1 28 Risk Ratio (M-H, Random, 95% CI) 1.33 [0.92, 1.93] the trial 4.2 No oxazepam night before the trial 1 23 Risk Ratio (M-H, Random, 95% CI) 1.36 [0.88, 2.12] Analysis 1.1. Comparison 1 Analgesic nitrous oxide vs. standard benzodiazepine, Outcome 1 Anxiety 1 hour after intervention as measured by STA. Review: Psychotropic analgesic nitrous oxide for alcoholic withdrawal states Comparison: 1 Analgesic nitrous oxide vs. standard benzodiazepine Outcome: 1 Anxiety 1 hour after intervention as measured by STA Study or subgroup PAN Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Fey (12.52) (9.01) 79.8 % [ , 3.03 ] Janks (12.83) (17.81) 20.2 % [ , ] Total (95% CI) % [ , 3.12 ] Heterogeneity: Tau?? = 0.0; Chi?? = 0.27, df = 1 (P = 0.61); I?? =0.0% Test for overall effect: Z = 1.06 (P = 0.29) Favours PAN Favours control 18

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