Cochrane Database of Systematic Reviews

Treatment for inhalant dependence and abuse (Review)

Konghom S, Verachai V, Srisurapanont M, Suwanmajo S, Ranuwattananon A, Kimsongneun N,

Uttawichai K

Konghom S, Verachai V, Srisurapanont M, Suwanmajo S, Ranuwattananon A, Kimsongneun N, Uttawichai K.

Treatment for inhalant dependence and abuse.
Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD007537.
DOI: 10.1002/14651858.CD007537.pub2.

www.cochranelibrary.com

Treatment for inhalant dependence and abuse (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Treatment for inhalant dependence and abuse (Review) i

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Treatment for inhalant dependence and abuse

Suwapat Konghom2 , Viroj Verachai3 , Manit Srisurapanont1 , Somporn Suwanmajo4 , Apichart Ranuwattananon3 , Nipa Kimsongneun
2,Kanok Uttawichai5

1 Department of Psychiatry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. 2 Department of Research and Technol-

ogy Assessment, Thanyarak Institute, Pathumthani, Thailand. 3 Medicine, Thanyarak Institute, Prathumthani, Thailand. 4 Pharmacy
department, Thuanyarak Institute, Prathumthani, Thailand. 5 Medicine, Chiang Mai Drug Dependence Treatment Center, Chiangmai,
Thailand

Contact address: Manit Srisurapanont, Department of Psychiatry, Faculty of Medicine, Chiang Mai University, P.O. Box 102, Amphur
Muang, Chiang Mai, 50200, Thailand. msrisura@mail.med.cmu.ac.th.

Editorial group: Cochrane Drugs and Alcohol Group.

Publication status and date: New, published in Issue 12, 2010.
Review content assessed as up-to-date: 21 October 2010.

Citation: Konghom S, Verachai V, Srisurapanont M, Suwanmajo S, Ranuwattananon A, Kimsongneun N, Uttawichai K. Treat-

ment for inhalant dependence and abuse. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD007537. DOI:
10.1002/14651858.CD007537.pub2.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background

Inhalants are being abused by large numbers of people throughout the world, particularly socio-economically disadvantaged children and
adolescents. The neuropsychological effects of acute and chronic inhalant abuse include motor impairment, alterations in spontaneous
motor activity, anticonvulsant effects, anxiolytic effects, sensory effects, and effects and learning, memory and operant behaviour (e.g.,
response rates and discriminative stimulus effects).

Objectives

To search and determine risks, benefits and costs of a variety treatments for inhalant dependence or abuse.

Search methods

We searched MEDLINE (1966 - February 2010), EMBASE (Januray 2010) and Cochrane Central Register of Controlled Trials
(CENTRAL) (February 2010). We also searched for ongoing clinical trials and unpublished studies via Internet searches.

Selection criteria

Randomised-controlled trials and controlled clinical trails (CCTs) comparing any intervention in people with inhalant dependence or
abuse.

Data collection and analysis

Two reviewers independently selected studies for inclusion, assessed trial quality and extracted data.

Main results

No studies fulfilling the inclusion criteria have been retrieved.

Treatment for inhalant dependence and abuse (Review) 1
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Authors’ conclusions

Implications for practice: due to the lack of studies meeting the inclusion criteria, no conclusion can be drawn for clinical practice.

Implications for research: as a common substance abuse with serious health consequences, treatment of inhalant dependence and abuse
should be a priority area of substance abuse research.

PLAIN LANGUAGE SUMMARY

No evidence-based treatment option for inhalant dependence or abuse

Inhalants are being abused by large numbers of people throughout the world, particularly socio-economically disadvantaged children
and adolescents. This agent can cause many brain problems, for example, abnormal movement, sensory impairment, learning/memory
impairment. Authors aimed to search and determine risks, benefits and costs of a variety treatments for inhalant dependence or abuse.
Despite comprehensive searches of studies, the authors found no high quality study and, therefore, could not make any recommendation
for the treatment of inhalant dependence or abuse. Research in this area is needed.

III. Volatile alkyl nitrites: videocassette-recorder head cleaner, liq-

BACKGROUND
Description of the condition
The term “inhalant” encompasses a wide range of pharmacologi-
cally diverse substances that readily vaporize at room temperature
and rarely abused by routes other than inhalation. Inhalant abuse,
sometimes referred to as solvent or volatile substance abuse, can be
better understood when the expansive list of inhalant is classified
into 3 groups on the basis of what is currently known pharmaco-
logically (Williams 2007):
I. Volatile solvents:
1. Solvents: toluene, acetone, methylene chloride, ethyl
acetate, TCE (1,1,1-trichloroethane) in paint thinner, paint and
polish removers, correction fluid, and felt-tip marker fluid; TCE
and tetrachloroethylene in degreases, spot removers, and dry-
cleaning fluids; toluene, hexane, TCE, ethyl acetate, and methyl
chloride in glues and rubber cement; propellants and solvents
such as butane, propane, chlorofluorocarbons, hydrocarbons in
aerosol spray paint, computer/electronics-cleaning spray, spray
deodorant, hair spray, vegetable-oil cooking spray, air-freshener
spray, fabric-guard spray, and analgesic spray
2. Fuels: butane or propane lighters or pressurized fuel tanks,
gasoline (or petrol), racing car octane boosters, refrigerants (e.g.,
Freon)
3. Anaesthetics: ether, halothane, enflurane, ethyl chloride.
II. Nitrous oxide: diverted medical anaesthetic, whipped-cream
dispenser charger (whippets), whipping-cream aerosol.
Treatment for inhalant dependence and abuse (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
uid aroma/liquid incense air fresheners or room odorises (mostly
cyclohexyl nitrite), isobutyl nitrite or butyl nitrite, isopropyl ni-
trite.
Nitrous oxide and volatile alkyl nitrites have different modes of
actions, consequences, and are likely used by different types of
people than the volatile solvents. Only the volatile solvents are
considered inhalants in DSM-IV. For these reasons, this review
focused on the volatile solvents only. Because mixtures of inhalants
are commonly used, the mixtures have been taken into account in
this review.
Inhalants are being abused by large numbers of people throughout
the world, particularly socio-economically disadvantaged children
and adolescents. For some cultures, inhalant abuse is ubiquitous
and epidemic, most notably among street children living in Brazil,
Cambogia, India, Mexico, Peru, and Russia (NIDA 2005). Exper-
imentation with inhalants during adolescence has been shown to
be a risk factor for continued use of illicit drugs later in life and
premature death (Johnson 1995, Bowen 2006).
Current evidence suggests that the more commonly abused sol-
vents act in ways that are similar to several abused drugs, especially,
classing central nervous system depressants. However, the neuro-
psycho-pharmacological effects of abused solvents differ from one
inhalant to the next. In research with animal models of inhalant
abuse, NMDA, GABAA , glycine, nicotine, and 5HT3 receptors
appear to be important targets of action for several abused sol-
vents (Bowen 2006). The neuropsychological effects of acute and
chronic inhalant abuse include motor impairment, alterations in
spontaneous motor activity, anticonvulsant effects, anxiolytic ef-
2
fects, sensory effects, and effects and learning, memory and op-
erant behaviour (e.g., response rates and discriminative stimulus
effects).
Repeated exposure to these solvents may produce tolerance, de-
pendence and/or sensitization to these effects. Other than depen-
dence and abuse, according to DSM-IV, inhalant-related problems
also include intoxication, intoxication with delirium, psychotic
disorders, mood disorders, and anxiety disorder. Inhalants are one
of a few substances that can cause a long-term consequence of
persisting dementia.
Inhalant abuse also increases mortality. Common causes of death
from inhalant abuse are as follows (Williams 2007):
I. Acute:
1. Direct causes: immediate or “postponed” sudden sniffing
death syndrome; methaemoglobinaemia
2. Indirect causes: suffocation, aspiration, trauma, drowning
fire, other
II. Delayed:
1. Cardiomyopathy
2. Central nervous system toxicity: toluene dementia and
brainstem dysfunction
3. Haematological: aplastic anaemia, leukaemia
4. Hepatocellular carcinoma
5. Renal toxicity: nephritis, nephrosis, tubular necrosis
Description of the intervention
For the treatment of inhalant use disorders, most clinicians rely on
applying methods that are used to treat other addictive disorders,
such as cognitive-behavioural therapy, multi system and family
therapy, 12-step facilitation, and motivational enhancement ther-
apy (Reidel 1995). Some treatment facilities have used a peer-ad-
vocate system for patients (Beauvais 2002).
Why it is important to do this review
Treatment challenges are posed by the variety of abused inhalants
and abusers, physical and psychiatric co morbidity, psychosocial
problems, poly substance use. A serious issue of concern in treating
these patients is the little research on successful treatment modali-
ties specific to inhalant users. Due to the policy of Cochrane Col-
laboration in separating treatment and prevention trials, preven-
tion studies have not been considered in this review.
OBJECTIVES
To search and determine risks, benefits and costs of a variety treat-
ments for inhalant dependence or abuse.
Treatment for inhalant dependence and abuse (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
METHODS
Criteria for considering studies for this review
Types of studies
All relevant randomised controlled trials (RCTs) and clinical con-
trolled trials (CCTs) relevant to the treatment of inhalant use dis-
orders would be included. Interventions for the prevention of in-
halant use disorders, e.g., educational program, community inter-
ventions, were excluded.
Types of participants
Adults and adolescents (aged 13 years or more) with inhalant de-
pendence or abuse, diagnosed by any set of criteria. For the study
carried out in inhalant dependence/abuse people with co-morbid-
ity (e.g., conduct disorder), a sensitivity analysis would be con-
ducted to determine the appropriateness of including the study
data. The study carried out in both inhalant dependent/abuse
people and other substance dependent/abuse people would be in-
cluded only if:
1. The data of people with inhalant dependence or abuse were
reported separately
2. More than half of the participants were inhalant
dependent/abuse people. However, a sensitivity analysis will be
applied on these studies.
Types of interventions
Experimental interventions concerned were as follows
1. Any kind of pharmacological treatment,
2. Any kind of psychosocial treatment, and
3. Any kind of combined pharmacological and psychosocial
treatment
Controlled interventions were as follows:
1. Placebo,
2. No intervention (e.g., those are on wait-list),
3. Treatment as usual
Types of outcome measures
Because there are no highly sensitive/specific laboratory methods
for measuring the level of inhalant use, only self-report outcomes
would be considered.
The outcomes of interest were classified as primary and secondary
ones.
3
Primary outcomes
1. Number or percentage of people who return to inhalant use
2. Number or percentage of inhalant-use days
3. Overall discontinuation rate
4. Discontinuation rate due to adverse events
Secondary outcomes
1. Death
2. Time to the recommencement of inhalant abuse or use
3. Craving as measured by validated scales
4. Severity of dependence, abuse, or addiction as measured by
validated scales
5. Functioning, and Health status or health-related quality of
life
All outcomes were reported for the short term (12 weeks or 3
months), medium term (more than 12 weeks or 3 months to 1
year), and long term (more than 1 year). If any outcome was
assessed more than once in a particular term, only the results of
the longest duration in that term were considered.
Search methods for identification of studies
Electronic searches
The following databases were searched. There was no language
constraint.
1. MEDLINE (1966 - February 2010)
2. EMBASE (Januray 2010)
3. Cochrane Central Register of Controlled Trials
(CENTRAL) (February 2010)
Databases were searched using a strategy developed incorporating
the filter for the identification of RCTs (Higgins 2009) combined
with selected MeSH terms and free text terms relating to inhalant
abuse. The MEDLINE search strategy were translated into the
other databases using the appropriate controlled vocabulary as
applicable.
The search strategy for MEDLINE is shown in Appendix 1.
We searched for ongoing clinical trials and unpublished studies
via Internet searches on the following sites:
1. http://www.clinicaltrials.gov;
2. http://www.controlledtrials.com;
3. http://www.oss-sper-clin.agenziafarmaco.it/
Searching other resources
We also searched:
1. references of the articles obtained by any means were
searched
2. conference proceedings likely to contain trials relevant to
the review
Treatment for inhalant dependence and abuse (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3. contact investigators, relevant trial authors seeking
information about unpublished or incomplete trials.
All searches included non-English language literature and studies.
English abstracts were assessed for inclusion. When considered
likely to meet inclusion criteria, studies would be translated.
Data collection and analysis
Selection of studies
Reports identified by the electronic searches were assessed for rel-
evance. Two reviewers (SK & SS) independently inspected all re-
trieved abstracts identified by the electronic searches and full re-
ports of the studies of agreed relevance were obtained. Where dis-
putes arose the full report was acquired for more detailed scrutiny.
The reviewers (SK & SS) then independently inspected all these
full study reports.
Data extraction and management
Data were extracted independently by two reviewers (SK and SS)
onto data extraction forms. Again, if the disputes arose these would
be resolved either by discussion between the two reviewers or the
correspondence author of the paper.
Assessment of risk of bias in included studies
The ‘Risk of bias table’ in RevMan 5 would be used to assess the
methodological quality of included studies (Higgins 2009). For the
psychosocial treatment of addiction, blinding of participants and
personnel may not be possible. In addition, incomplete outcome
data (attrition) is often used as primary outcome of the study.
Only the risks of bias in the following domains would therefore be
assessed: i) sequence generation, ii) allocation concealment, III)
blinding of outcome assessor and iV) selective outcome reporting
(see Table 1). The risk of bias, both within a study across domain
and across studies for meta-analysis, would be summarized. Studies
with low and moderate risk of bias in the respect of allocation
concealment would be incorporated into the analysis. Plots of
intervention effect estimates (e.g., forest plots) stratified according
to risk of bias would be used to examine the potential of bias to
affect the results of a meta-analysis.
Measures of treatment effect
Dichotomous outcomes: The Relative Risk (RR), the ratio of risk
in the intervention group to the risk in the control group, with
the 95% confidence interval (95% CI) was an effect measure used
for dichotomous outcomes. An RR of one indicates no difference
between comparison groups. For undesirable outcomes, an RR
that is less than one indicates that the intervention was effective
4
in reducing the risk of that outcome. In addition, as a measure of
efficacy, the number needed to treat (NNT) was also calculated
for the outcomes with significantly different overall effects.
Continuous data: The Weighted Mean Difference (WMD) and
the Standardised Mean Difference (SMD), both with 95% con-
fidence intervals (CIs), would be used for the outcomes on the
same scale (e.g., body weight) and the different scales (e.g., differ-
ent rating scales for assessing craving), respectively. For the studies
that the treatment and/or controlled groups were divided into sub-
groups because of the differences of treatment, treatment intensity,
or treatment dosing, the continuous outcomes of the subgroups
receiving more rigorous treatment, e.g., higher doses of drug treat-
ment, more intensive psychotherapy, would be extracted.
Dealing with missing data
The reviewers would contact the authors for requesting the miss-
ing data. Intention-to-treat analysis would be conducted. For di-
chotomous outcomes, the reviewers would apply the following
guidelines to analyse data from included studies: (i) the analysis
included all those who entered the trial; and (ii) the analysis main-
tained the study groups according to the original randomisation
procedure. The authors would assign people lost to follow-up to
the worst outcome. For continuous outcomes, to be included in a
parametric test, means and standard deviations of the total num-
ber of participants had to be reported in the paper or would be
obtainable from the author.
Assessment of heterogeneity
Test of heterogeneity is important to ask whether the results of
studies are similar within each comparison. The reviewers will
check whether differences between the results of trials are high
by looking at the graphical display of the results and I-square test
(I2 ) (Higgins 2003). As recommended, an I2 of 75% or higher
suggested considerably high inconsistency of data. Only the data
with considerably high inconsistency will be mentioned in this
review.
Assessment of reporting biases
Funnel plots (plots of the effect estimate from each study against
the standard error) would be used to assess the potential for bias
related to the size of the trials, which could indicate possible pub-
lication bias. However, it would not be used if:
i) There were less than 10 studies included in the meta-
analysis.
ii) All studies were of similar sizes
iii) Only small-study effects could be found
Treatment for inhalant dependence and abuse (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Data synthesis
A random effect model, which can be use for the synthesis of high
or low inconsistent data, would be used. The reviewers would not
make any conclusion on high inconsistent data but would try to
explain its causes.
Subgroup analysis and investigation of heterogeneity
Because inhalant abuse by the youths is common, additional anal-
ysis of the data obtained from the studies specifically carried out
in children and adolescents would also be performed.
Sensitivity analysis
Sensitivity analysis is an analysis used to determine how sensitive
the results of a systematic review are to changes in how it was done.
It has been used to assess how robust the results are to uncertain
decisions or assumptions about the data and the methods that
were used. We applied this technique to examine the sensitivity of
the results by the inclusion and exclusion of following studies:
1. unpublished studies: as suggested by Cook et al (Cook
1993), a systematic review should present the results with and
without unpublished sources of data.
2. studies with some ambiguity as to whether their
participants meet the inclusion criteria, e.g., people with
inhalant use disorder plus physical or psychiatric co morbidity.
3. studies at high risk of bias for allocation concealment
For each outcome, if the inclusion and exclusion of the above
mentioned studies causes no significant difference in the respects
of heterogeneity and overall effect, the overall effect obtained by
the inclusion of all studies would be taken into consideration.
Otherwise, the overall effect obtained by the exclusion of the above
mentioned studies would be considered.
RESULTS
Description of studies
See: Characteristics of excluded studies.
Results of the search
The search identified a total of 182 published references. We re-
jected 179 references as not relevant on the basis of information
provided in the title and abstract. We were able to obtained full
text copies of the three selected papers (see Figure 1). We also con-
tacted an author (Brian Perron, Ph.D., University of Michigan,
School of Social Work, Ann Arbor, MI, USA) and were informed
that he also had no relevant randomised controlled trial.
5
 Figure 1. Flow Diagram

Included studies
None of the studies met the inclusion criteria. Studies awaiting assessment
Excluded studies None.
According to inclusion/exclusion criteria, we excluded all three Ongoing studies
selected papers for the following reasons: None.
1.1 Not a randomised controlled trial: We excluded two papers as
Risk of bias in included studies
they were case reports of risperidone treatment (Misra 1999) and
lamotrigine treatment (Shen 2007). No studies fulfilling the inclusion criteria have been retrieved.
1.2 Not a randomised controlled trial in inhalant dependence
or abuse: The other randomised controlled trial was a study of
carbamazepine and haloperidol in patients with inhalant-induced
psychotic disorders, which focused only on the improvement of Effects of interventions
psychotic symptoms (Hernandez-Avila 1998). No studies fulfilling the inclusion criteria have been retrieved.

Treatment for inhalant dependence and abuse (Review) 6

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DISCUSSION
Summary of main results
Despite a comprehensive searches we did not find studies to be
included in the review, in spite of the enlargement of inclusion
criteria to prospective controlled observational studies. We found
two case reports of risperidone and lamotrigine treatment for in-
halant dependence. The only randomised-controlled trial found
in our search was the study of carbamazepine and haloperidol for
the treatment of inhalant-induced psychotic disorder.
Overall completeness and applicability of evidence
The lack of available evidence may be caused by three reasons.
Firstly, inhalant users may not recognize inhalant-related prob-
lems. Most of them therefore do not want to seek treatment. Sec-
ond, inhalant users tend to be polysubstance users, and inhalant
dependece or abuse is not recognized by clinicians. Lastly, because
most people with inhalant dependence or abuse are the youths or
the youths in probation systems, conducting a trial in this pop-
ulation may need a special ethic consideration and are relatively
complicated.
Potential biases in the review process
By the comprehensive search on the electronic databases and con-
tacting some experts in this area, we could not find any relevant
study. It would be unlikely that we missed any relevant and im-
portant study in this area.
Agreements and disagreements with other studies or reviews
REFERENCES
References to studies excluded from this review
Hernandez-Avila 1998 {published data only}
Hernandez-Avila CA, Ortega-Soto HA, Jasso A, Hasfura-
Buenaga CA, Kranzler HR. Treatment of inhalant-induced
psychotic disorder with carbamazepine versus haloperidol.
Psychiatric Services 1998;49(6):812–5.
Misra 1999 {published data only}
Misra LK, Kofoed L, Fuller W. Treatment of inhalant abuse
with risperidone. Journal of Clinical Psychiatry 1999;60(9):
620.
Shen 2007 {published data only}
Shen YC. Treatment of inhalant dependence with
lamotrigine. Progress in Neuropsychopharmacology and
Biological Psychiatry 2007;31(3):769–71.
Additional references
Beauvais 2002
Beauvais F, Jumper-Thurman P, Plested B, Helm H. A
survey of attitudes among drug use treatment providers
Treatment for inhalant dependence and abuse (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
In a clinical review of inhalants (Brouette 2001), due to the lack of
randomised-controlled trial in this area, the authors recommend
only the general approach, e.g., psycho education, motivational
interviewing, for treating this condition. However, because the
present review find no randomised-controlled trial in this area, we
decline to recommend any treatment for this condition.
AUTHORS’ CONCLUSIONS
Implications for practice
Due to the lack of studies meeting the inclusion criteria, no con-
clusion can be drawn for clinical practice. A review of cohort stud-
ies or case series may be helpful in identifying lower levels of evi-
dence to guide the treatment of inhalant dependence and abuse.
Implications for research
As a common substance abuse with serious health consequences,
randomised-controlled trials of treatment for inhalant dependence
and abuse should be a priority area of substance abuse research.
ACKNOWLEDGEMENTS
We wish to thank Simona Vecchi for her assistance on database
searches.
toward the treatment of inhalant users. Substance Use &
Misuse 2002;37:1391–410.
Bowen 2006
Bowen SE, Batis JC, Paez-Martinez N, Cruz SL. The last
decade of solvent research in animal models of abuse:
mechanistic and behavioral studies. Neurotoxicology and
Teratology 2006;28:636–47.
Brouette 2001
Brouette T, Anton R. Clinical review of inhalants. American
Journal of Addiction 2001;10(1):79–94.
Cook 1993
Cook DJ, Guyatt GH, Ryan G, Clifton J, Buckingham L,
Willan A, McIlroy W, Oxman AO. Should unpublished
data be included in meta-analyses?. Journal of the American
Medical Association 1993;269:2749–53.
Higgins 2003
Higgins JPT, Thompson SG, Deeks JJ, Altman DG.
Measuring inconsistency in meta-analysis. British Medical
Journal 2003;327:557–60.
7
Higgins 2009
Higgins JPT, Green S. Cochrane Handbook of Systematic
Reviews of Interventions Version 5.0.2 [updated September
2009]. The Cochrane Collaboration, 2008.
Johnson 1995
Johnson EO, Shultz CG, Anthony JC, Ensminger ME.
Inhalants to heroin: a prospective analysis from adolescence
to adulthood. Drug and Alcohol Dependence 1995;50:
159–64.
NIDA 2005
National Institute on Drug Abuse. Inhaland Abuse among
Children and Adolescents: Consultation on Building an
Treatment for inhalant dependence and abuse (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
International Research Agenda (Meeting). Washington, DC:
National Institute of Health, 2005.
Reidel 1995
Reidal S, Hebert T, Byrd P. Treating Alcohol and Other
Drug Abusers in Rural and Frontier Areas. Treating
Alcohol and Other Drug Abusers in Rural and Frontier Areas.
Rockville, MD: Center for Substance Abuse Treatment,
1995.
Williams 2007
Williams JF, Strock M, and the Committee on Substance
Abuse and Committee on Native American Child Health.
Inhalant abuse. Pediatrics 2007;119(5):1009–17.
∗
Indicates the major publication for the study
8
CHARACTERISTICS OF STUDIES

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Hernandez-Avila 1998 Allocation: randomised controlled trial; Participants: patients with inhalant-induced psychotic disorder;
Intervention: carbamazepine vs haloperidol; Outcomes: psychotic symptoms and extrapyramidal side effects

Misra 1999 Allocation: non-randomised (a case report); Participants: a patient with inhalant abuse; Intervention: risperi-
done; Outcomes: descriptive

Shen 2007 Allocation: non-randomised (a case report); Participants: a patient with inhalant dependence; Intervention:
lamotrigine; Outcomes: descriptive

Treatment for inhalant dependence and abuse (Review) 9

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES
This review has no analyses.

ADDITIONAL TABLES
Table 1. Criteria for the assessment of risk of bias

Item Judgment Description

1 Was the method of randomisation ade- Yes The investigators describe a random component in the sequence gener-
quate? ation process such as: random number table; computer random num-
ber generator; coin tossing; shuffling cards or envelopes; throwing dice;
drawing of lots; minimization

No The investigators describe a non-random component in the sequence

generation process such as: odd or even date of birth; date (or day) of
admission; hospital or clinic record number; alternation; judgement of
the clinician; results of a laboratory test or a series of tests; availability
of the intervention

Unclear Insufficient information about the sequence generation process to per-

mit judgement of Yes or No

2 Was the treatment allocation concealed? Yes
Investigators enrolling participants could not foresee assignment be-
cause one of the following, or an equivalent method, was used to con-
ceal allocation: central allocation (including telephone, web-based, and
pharmacy-controlled, randomisation); sequentially numbered drug
containers of identical appearance; sequentially numbered, opaque,
sealed envelopes

No Investigators enrolling participants could possibly foresee assignments

because one of the following method was used: open random allocation
schedule (e.g. a list of random numbers); assignment envelopes without
appropriate safeguards (e.g. if envelopes were unsealed or non opaque
or not sequentially numbered); alternation or rotation; date of birth;
case record number; any other explicitly unconcealed procedure

Unclear Insufficient information to permit judgement of Yes or No. This is

usually the case if the method of concealment is not described or not
described in sufficient detail to allow a definite judgement

3 Was knowledge of the allocated inter- Yes
ventions adequately prevented during the
study? (blinding of patients, provider,
outcome assessor)
Objective outcomes
Blinding of participants, providers and outcome assessor and unlikely
that the blinding could have been broken;
Either participants or providers were not blinded, but outcome assess-
ment was blinded and the non-blinding of others unlikely to introduce
bias
No blinding, but the objective outcome measurement are not likely to
be influenced by lack of blinding

Treatment for inhalant dependence and abuse (Review) 10

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Criteria for the assessment of risk of bias (Continued)

4 Was knowledge of the allocated inter- Yes
ventions adequately prevented during the
study? (blinding of patients, provider,
outcome assessor)
Subjective outcomes
Blinding of participants, providers and outcome assessor and unlikely
that the blinding could have been broken;
Either participants or providers were not blinded, but outcome assess-
ment was blinded and the non-blinding of others unlikely to introduce
bias

No No blinding or incomplete blinding, and the outcome or outcome

measurement is likely to be influenced by lack of blinding;
Blinding of key study participants and personnel attempted, but likely
that the blinding could have been broken;
Either participants or outcome assessor were not blinded, and the non-
blinding of others likely to introduce bias

Unclear Insufficient information to permit judgement of Yes or No;

5 Were incomplete outcome data ade- Yes No missing outcome data;

quately addressed? Reasons for missing outcome data unlikely to be related to true out-
For all outcomes except retention in treat- come (for survival data, censoring unlikely to be introducing bias);
ment or drop out Missing outcome data balanced in numbers across intervention groups,
with similar reasons for missing data across groups;
For dichotomous outcome data, the proportion of missing outcomes
compared with observed event risk not enough to have a clinically
relevant impact on the intervention effect estimate;
For continuous outcome data, plausible effect size (difference in means
or standardized difference in means) among missing outcomes not
enough to have a clinically relevant impact on observed effect size;
Missing data have been imputed using appropriate methods
All randomised patients are reported/analysed in the group they were
allocated to by randomisation irrespective of non-compliance and co-
interventions (intention to treat)

No Reason for missing outcome data likely to be related to true outcome,

with either imbalance in numbers or reasons for missing data across
intervention groups;
For dichotomous outcome data, the proportion of missing outcomes
compared with observed event risk enough to induce clinically relevant
bias in intervention effect estimate;
For continuous outcome data, plausible effect size (difference in means
or standardized difference in means) among missing outcomes enough
to induce clinically relevant bias in observed effect size;
As-treated analysis done with substantial departure of the intervention
received from that assigned at randomisation;

Unclear Insufficient reporting of attrition/exclusions to permit judgement of

Yes or No (e.g. number randomised not stated, no reasons for missing
data provided; number of drop out not reported for each group);

Treatment for inhalant dependence and abuse (Review) 11

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
APPENDICES
Appendix 1. PubMed search strategy (1966-February 2010)
1. SUBSTANCE-RELATED DISORDERS [mesh]
2. ((drug or substance) AND (abuse* or use* or disorder* or misuse or addict* or dependen*)) [tiab]
3. (inhalant or solvent* or volatil*) AND (abuse* or use* or dependen* or misuse))
4. Administration, Inhalation [mesh]
5. 1 or 2 or 3 or 4
6. Inhalant* [tiab]
7. solvent* [tiab]
8. Solvents “[Pharmacological Action]
9. alkyl nitrite* [tiab]
10. Anaesthetic* [tiab]
11. Nitrous Oxide”[Mesh]
12. nitrous oxide [tiab]
13. nitrit* [tiab]
14. Fuel* [tiab]
15. 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14
16. randomized controlled trial[pt]
17. controlled clinical trial[pt]
18. random*[tiab]
19. placebo[tiab]
20. drug therapy[mesh]
21. trial[tiab]
22. groups[tiab]
23. 16 or 17 or 18 or 19 or 20 or 21 or 22
24. animals [mesh] not humans [mesh]
25. 23 NOT 24
26. 5 AND 15 AND 25

Appendix 2. EMBASE search strategies (January 2010)

1. drug abuse/exp
2. Addiction:MESH
3. ((drug or substance) (abuse* or use* or disorder* or misuse or addict* or dependen*))
4. (inhalant or solvent* or volatil*) AND (abuse* or use* or dependen* or misuse))
5. ’inhalational drug administration’/exp
6. 1 or 2 or 3 or 4
7. Inhalant* or solvent* or Anaesthetic*
8. “solvent“/exp
9. alkyl nitrite* [tiab]
10. “nitrous Oxide”/exp
11. “nitrous oxide” [tiab]
12. nitrit* [tiab]
13. Fuel* [tiab]
14. 7 or 8
15. random* or placebo
16. ’randomized controlled trial’/exp
17. ’phase 2 clinical trial’/exp
18. ’phase 3 clinical trial’/exp
19. ’double blind procedure’/exp
20. ’single blind procedure’/exp
Treatment for inhalant dependence and abuse (Review) 12
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
21. ’crossover procedure’/exp
22. ’latin square design’/exp
23. ’placebo’/exp
24. ’multicenter study’/exp
25. OR 9/18
26. 4 AND 5 AND 8 AND 19
27. limit 20 to humans

Appendix 3. CENTRAL search strategies (February 2010)

1. ((drug or substance) AND (abuse* or use* or disorder* or misuse or addict* or dependen*)) [tiab]
2. (inhalant or solvent* or volatil*) NEXT/2 (abuse* or use* or dependen* or misuse))
3. 1 or 2
4. Inhalant* or solvent* or Anaesthetic*
5. Solvents:mesh
6. Nitrous Oxide:mesh
7. “nitrous oxide”
8. nitrit* or Fuel*
9. 4 or 5 or 6 or 7 or 8
10. 3 AND 9

Appendix 4. Search strategy for ongoing registries (clinicaltrials.gov, controlledtrials.com, oss-sper-

clin.agenziafarmaco.it/ (January 2010)
Inhalant

Appendix 5. Criteria for assessing Risk of bias of RCTs and CCTs

Item Judgment Description

1 Was the method of randomization ade- Yes The investigators describe a random component in the sequence gener-
quate? ation process such as: random number table; computer random num-
ber generator; coin tossing; shuffling cards or envelopes; throwing dice;
drawing of lots; minimization

No The investigators describe a non-random component in the sequence

generation process such as: odd or even date of birth; date (or day) of
admission; hospital or clinic record number; alternation; judgement of
the clinician; results of a laboratory test or a series of tests; availability
of the intervention

Unclear Insufficient information about the sequence generation process to per-

mit judgement of Yes or No

2 Was the treatment allocation concealed? Yes Investigators enrolling participants could not foresee assignment be-
cause one of the following, or an equivalent method, was used to con-

Treatment for inhalant dependence and abuse (Review) 13

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

ceal allocation: central allocation (including telephone, web-based, and

pharmacy-controlled, randomization); sequentially numbered drug
containers of identical appearance; sequentially numbered, opaque,
sealed envelopes

No Investigators enrolling participants could possibly foresee assignments

because one of the following method was used: open random allocation
schedule (e.g. a list of random numbers); assignment envelopes without
appropriate safeguards (e.g. if envelopes were unsealed or non opaque
or not sequentially numbered); alternation or rotation; date of birth;
case record number; any other explicitly unconcealed procedure

Unclear Insufficient information to permit judgement of Yes or No. This is

usually the case if the method of concealment is not described or not
described in sufficient detail to allow a definite judgement

3 Was knowledge of the allocated inter- Yes
ventions adequately prevented during the
study? (blinding of patients, provider,
outcome assessor)
Objective outcomes
Blinding of participants, providers and outcome assessor and unlikely
that the blinding could have been broken;
Either participants or providers were not blinded, but outcome assess-
ment was blinded and the non-blinding of others unlikely to introduce
bias
No blinding, but the objective outcome measurement are not likely
to be influenced by lack of blinding

4 Was knowledge of the allocated inter- Yes
ventions adequately prevented during the
study? (blinding of patients, provider,
outcome assessor)
Subjective outcomes
Blinding of participants, providers and outcome assessor and unlikely
that the blinding could have been broken;
Either participants or providers were not blinded, but outcome assess-
ment was blinded and the non-blinding of others unlikely to introduce
bias

No No blinding or incomplete blinding, and the outcome or outcome

measurement is likely to be influenced by lack of blinding;
Blinding of key study participants and personnel attempted, but likely
that the blinding could have been broken;
Either participants or outcome assessor were not blinded, and the non-
blinding of others likely to introduce bias

Unclear Insufficient information to permit judgement of Yes or No;

5 Were incomplete outcome data ade- Yes No missing outcome data;

quately addressed? Reasons for missing outcome data unlikely to be related to true out-
For all outcomes except retention in treat- come (for survival data, censoring unlikely to be introducing bias);
ment or drop out Missing outcome data balanced in numbers across intervention groups,
with similar reasons for missing data across groups;
For dichotomous outcome data, the proportion of missing outcomes
compared with observed event risk not enough to have a clinically
relevant impact on the intervention effect estimate;
For continuous outcome data, plausible effect size (difference in means

Treatment for inhalant dependence and abuse (Review) 14

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

or standardized difference in means) among missing outcomes not

enough to have a clinically relevant impact on observed effect size;
Missing data have been imputed using appropriate methods
All randomized patients are reported/analyzed in the group they were
allocated to by randomisation irrespective of non-compliance and co-
interventions (intention to treat)

No Reason for missing outcome data likely to be related to true outcome,

with either imbalance in numbers or reasons for missing data across
intervention groups;
For dichotomous outcome data, the proportion of missing outcomes
compared with observed event risk enough to induce clinically relevant
bias in intervention effect estimate;
For continuous outcome data, plausible effect size (difference in means
or standardized difference in means) among missing outcomes enough
to induce clinically relevant bias in observed effect size;
As-treated analysis done with substantial departure of the intervention
received from that assigned at randomisation;

Unclear Insufficient reporting of attrition/exclusions to permit judgement of

Yes or No (e.g. number randomised not stated, no reasons for missing
data provided; number of drop out not reported for each group);

HISTORY
Protocol first published: Issue 1, 2009
Review first published: Issue 12, 2010

Date Event Description

22 October 2008 Amended ready to be published as protocol

21 April 2008 Amended Converted to new review format.

19 June 2007 New citation required and major changes Substantive amendment

Treatment for inhalant dependence and abuse (Review) 15

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CONTRIBUTIONS OF AUTHORS
Suwapat Konghom & Soporn Suwanmajo: protocol development, searching, study selection, data extraction, analysis, writing of final
report, and review maintenance
Manit Srisurapanont: protocol development, searching, analysis, writing of final report, and review maintenance
Viroj Veerachai, Apichart Ranuwattananon, Nipa Kimsongneun, and Kanok Uttawichai: protocol development, analysis, writing of
final report, and review maintenance

DECLARATIONS OF INTEREST
No conflict of interest

SOURCES OF SUPPORT

Internal sources
• New Source of support, Thailand.
Department of Medical Services, Ministry of Public Health

External sources
• No sources of support supplied

INDEX TERMS

Medical Subject Headings (MeSH)

Inhalant Abuse [∗ therapy]

MeSH check words

Adolescent; Adult; Humans

Treatment for inhalant dependence and abuse (Review) 16

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.