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Research overview

Benzodiazepine treatment for drug-dependent subjects


  • Issued/Revised: 2007
  • By: Norwegian Knowledge Centre for the Health Services
  • Nilsen E , Bachs L , Bjørner T , Høiseth G , Johnsen J , Ørbeck A L, Waal H , Ormstad S , Kornør H , Paulsen E , Hofmann B.. Benzodiazepine treatment for drug-dependent subjects, Norwegian Knowledge Centre for the Health Services. Research overview 2007. ISBN (digital): 978-82-8121-147-6, ISSN (digital): 1890-1298. Available at www.fhi.no/en

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Key message

Background
The Norwegian Knowledge Centre for the Health Service (NOKC) was requested by the Norwegian Institute of Public Health to do a health technology assessment (HTA) on the effectiveness of prophylactic vaccines against human papillomavirus (HPV) infection. This part of the report, has evaluated the effectiveness and safety of such vaccines. Part two evaluates the cost-effectiveness and will be published at a later stage.

More than 120 subgroups of HPV have been identified, and at least 14 of these are oncogenic types. Persistent HPV infections are necessary, but not sufficient for development of cervical cancers. HPV types 16 and 18 cause about 70% of cervical cancers and HPV 6 and 11 cause 90% of anogenital warts.

HPV infection is common in sexually active women. Infections with HPV and cellular abnormalities in the cervix are dynamic processes. Most infections are incidental but sometimes the infections become persistent and the risk to generate cellular abnormalities is higher.

Two vaccines against human papillomavirus are developed, Gardasil® and Cervarix®. Gardasil is developed by Merck and is marketed in Europe by Sanofi Pasteur MSD, while Cervarix is developed by GlaxoSmith Kline. Both vaccines are type specific and are directed against the two most common causes of cervical cancer in the world, type 16 and 18. Gardasil, in addition, includes HPV 6 and 11 that are related to anogenital warts.

Objective
This report is a systematic review of the literature on effect and safety of prophylactic vaccines against human papillomavirus infection. The report will be part of the basis for a working group at the Norwegian Institute of Public Health. The working group shall advice the Ministry of Health and Care Services on the issue if vaccines against HPV will be implemented in the Norwegian vaccination program.

Methods
The work was carried out together with a review team of external professionals. Systematic searches were performed after published systematic reviews and randomized controlled trials in international databases. The literature was evaluated in a stepwise manner according to general principles of HTA. Studies that fulfilled our predetermined inclusion criteria were assessed and summarized.

Results
Ten randomized controlled trials are included in the report, of which two are follow-up studies. More than 5000 participants are included. Four of the publications evaluated immunogenicity and safety, while six publications in addition evaluate the efficacy of the vaccines against incident/persistent infection, cytological abnormalities (ASC-US, LSIL, HSIL) and/or cervical intraepithelial neoplasia (CIN 1, 2 and 3). In addition to analysis performed in the per protocol population (PPP); the studies on Cervarix includes results based on Intention-To-Treat (ITT) population, while the studies on Gardasil includes results based on modified ITT (MITT) population. These two populations (ITT and MITT) are almost identical and include participants who received at least one vaccination. In summary the results for Cervarix and Gardasil are as follows:

Efficacy of the vaccine against HPV 16/18 (Cervarix)
In the ITT analyses, vaccine efficacy was 83% (62.0-92.4%) and 94.4% (77.9-99.3) against incident infection after 27 and 48 months, respectively. In the PPP analyses, vaccine efficacy was 91.6% (64.5-98%) and 96.9% (81.3-99.3%) against incident infection after 18 and 48 months, respectively.
In the ITT analyses, vaccine efficacy was 95.1% (63.5-99.3%) and 100% (57.0-100%) against persistent infection (at least two positive HPV-DNA PCR assays for the same viral genotype separated by at least five or ten months) after 27 and 48 months, respectively. In the PPP analyses, vaccine efficacy was 100% (47.0-100%) and 100% (33.6-100%) against persistent infection after 18 and 48 months, respectively.

In the PPP analyses, no cases of CIN 2/3 were found in the vaccine group compared to five in the control group. There were not possible to calculate any meaningful estimates for this endpoint.

Efficacy of the vaccine against HPV 6/11/16/18 (Gardasil)
After 36 months follow-up, vaccine efficacy was 88% (72-96%) against persistent infection (at least two positive HPV-DNA PCR assays for the same viral genotype separated by at least four months or positive test during the last visit before lost to follow-up ) in the MITT cohort and 89% (70-97%) in the per protocol cohort. In the PPP analyses, no cases of CIN 2/3 were found in the vaccine group compared to three in the control group. There were not possible to calculate any meaningful estimates for this endpoint.

Safety
No serious adverse events related to vaccination, occurred in either vaccine or control groups. Most included participants, both in the vaccine and control group, had injection site adverse events as pain, swelling and redness. Most adverse events were of mild or moderate intensity.

Comments
The included studies show high HPV type specific vaccine efficacy against incident/ persistent infections, in addition to cytological and histological endpoints within the tested time interval. The follow-up time is too short (< 4 years) to conclude about the duration of the vaccine effect. The requirements of booster doses are still unknown. The longterm data regarding effects and sideeffects of the two vaccines will be important.

Summary

Background
Benzodiazepines are drugs used in treatment of anxiety and insomnia, in addition to muscle pain and seizures. The benzodiazepines bind to gamma-aminobutyric acid (GABA) receptors located in the central nervous system.

Benzodiazepines are widely used in the general population and the sales figures correspond to a daily consumption of therapeutic doses of 4-5% of the population. Benzodiazepines are effective drugs with low toxicity. Benzodiazepines are also popular as drugs of abuse and its consumption may contribute to exacerbate an existing drug abuse problem. The cost benefit considerations are therefore especially interesting when these drugs are prescribed to subjects with pre-existing problems of drug abuse. Seven different benzodiazepines are on the market in Norway.

The Norwegian Knowledge Centre for the Health Service (NOKC) was requested by the Medical Faculty at the University of Oslo to do a health technology assessment (HTA) on benzodiazepine treatment for drug-dependent subjects.

Objective
The report is a systematic review of the literature on benzodiazepine treatment for drugdependent people.

Methods
The work was carried out together with a review team of professionals from the drug abuse field. Systematic searches were performed after published systematic reviews and randomized controlled trials in international databases. Observational studies were included for the endpoints death and car-accidents. The literature is evaluated in a stepwise manner according to general principles of HTA. Studies that fulfilled our predetermined inclusion criteria are assessed and summarized.

Results
The report includes 38 studies; one systematic review, 33 randomised controlled trials and four observational studies. There were only two randomised controlled trials involv- ing drug-dependent subjects. The other studies involve long-term users of therapeutic doses of benzodiazepines (14 studies), non-dependent subjects with a history of drug abuse (12 studies) and subjects with alcohol-dependence (6 studies). The report is therefore focused on subjects with general drug abuse problems or long-term users of therapeutic doses of benzodiazepines.

No studies were found on the therapeutic effects of benzodiazepines for the usual indications (anxiety, insomnia, epilepsy) in subjects with drug abuse problems. Use of benzodiazepines in treatment of drug dependent subjects therefore often takes place without documented effect and on uncertain indications.

Our report documents negative effects of benzodiazepines in drug-dependent subjects. The studies showed that benzodiazepines have potential of abuse liability in this population and may lead to dependence problems. In addition, benzodiazepines impaired psychomotor skills and cognitive functions in drug abusers as well as in long-term users of benzodiazepines. These problems are present with all known benzodiazepines and are dependent on dosesize, treatment period, high absorption speed and high bioavailability. Diazepam, flunitrazepam and alprazolam are benzodiazepines with these two last characteristics and the studies reported problems with those drugs. On the other side, oxazepam had slow absorption and gave fewer problems. Clonazepame is less well characterized but it has characteristics similar to diazepam and alprazolam.

Our report shows that even though benzodiazepines reduce symptoms related to alcohol withdrawal, this could as well be achieved with other drugs without abuse potential.

  • No studies were found on effect of benzodiazepines on the indications anxiety, insomnia or epilepsy in drug-dependent subjects
  • Randomised controlled trials (12 studies) showed that benzodiazepines had potential of abuse liability and could cause dependence in people with a history of drug abuse
  • Randomised controlled trials (12 studies) showed that benzodiazepines gave reduced psychomotoric and cognitive functions in drug-dependent people, as in persons with a history of drug abuse
  • Diazepam showed greater abuse liability than oxazepam
  • Diazepam, lorazepam, flunitrazepam and triazolam showed similar effects on psychomotoric and cognitive functions. Oxazepam had some more favourable profile on these two endpoints
  • Withdrawal from benzodiazepines gave significant better psychomotoric function compared to the control group remaining on benzodiazepines
  • There were no studies on withdrawal from benzodiazepines in drug dependent people. The studies included long-term users of benzodiazepines • Slow withdrawal was better than fast withdrawal
  • The studies showed improved effect of diazepam compared to placebo as symptom relieving agent and as seizure prophylactic in withdrawal from alcohol
  • The studies showed no improved effect of benzodiazepines compared to other agents as symptom relieving agent or as seizure prophylactic in withdrawal from alcohol
  • The effect of benzodiazepines in opioid maintenance treatment are not systematic investigated

Conclusion
The systematic review did not found any studies that could document the effect of benzodiazepines in drug dependent subjects. The report documents evidence of negative effects in subjects with drug abuse problems. Benzodiazepines have abuse liability and may lead to dependence problems. The studies showed that benzodiazepines impaired psychomotor skills and cognitive functions in drug abusers as well as in long-term users of benzodiazepines. The magnitude of the effects on psychomotor and cognitive functions is less apparent for oxazepam and roughly equivalent for other benzodiazepines.

This is a publication from the Norwegian Knowledge Centre for the Health Services. The Knowledge Centre became part of the Norwegian Institute of Public Health 01/01/2016.