Dependence and withdrawal reactions to benzodiazepines and selective serotonin reuptake inhibitors. How did the health authorities react?

AIM: Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time. METHODS: Documentary study. We searched the web-sites of the European Medicines Agency and the drug agencies in USA, UK, and Denmark for documents mentioning benzodiazepines or SSRIs. We supplemented with other relevant literature that could contribute to our study. The searches were performed in 2009 in PubMed, Google, BMJ and JAMA. RESULTS: It took many years before the drug regulators acknowledged benzodiazepine dependence and SSRI withdrawal reactions and before the prescribers and the public were informed. Drug regulators relied mainly on the definitions of dependence and withdrawal reactions from the diagnostic psychiatric manuals, which contributed to the idea that SSRIs do not cause dependence, although it is difficult for many patients to stop treatment. In the perspective of a precautionary principle, drug agencies have failed to acknowledge that SSRIs can cause dependence and have minimised the problem with regard to its frequency and severity. In the perspective of a risk management principle, the drug agencies have reacted in concordance with the slowly growing knowledge of adverse drug reactions and have sharpened the information to the prescribers and the public over time. However, solely relying on spontaneous reporting of adverse effects leads to underestimation and delayed information about the problems. CONCLUSION: Given the experience with the benzodiazepines, we believe the regulatory bodies should have required studies from the manufacturers that could have elucidated the dependence potential of the SSRIs before marketing authorization was granted.

Treatment-induced stress syndromes.

Placebo controlled trials in disease states as currently constituted are designed to show a drug "works" when in fact it may not. Efficacy of this type may be constructed in trials that demonstrate some marginal superiority of a drug over placebo in disease states that do not take into account any potentialities of the drugs being tested to cause dependence and consequent deleterious effects on withdrawal. This paper reviews the history of the concept of physical dependence. While outlined in terms of the psychotropic drugs, it will be clear that such has been the neglect of this feature of drug actions that it must, until proven otherwise, be assumed to apply to all drugs. Filling the gap in our knowledge would require studies of new compounds in healthy volunteers. In the absence of such studies, any clinical information on therapeutic agents should point to the lack of information on this matter.

Morphine withdrawal, treatments 1900-30.

The treatments used between 1900 and 1930 for morphine withdrawal are discussed. The accounts are mainly taken from contemporary textbooks which contain fascinating descriptions of their authors' preferred methods and criticisms of regimes given by other therapists. Delirium, produced by atropine or similar substances, is advocated to cover withdrawal symptoms. The present paper draws parallels with current issues, e.g. withdrawal of opiate under cover of general anaesthesia, follow-up studies and cost-benefit analyses. The particular problems of addicted doctors in 1900-1930 are addressed as are the comparisons then made with non-medically qualified addicts. It is important we keep in mind past mistakes and over-valued ideas so as to reduce any similarly misplaced optimism in our current treatment options.

Pharmacological treatments for alcohol dependence and withdrawal--an historical perspective.

In an article published in 1984 Teeling-Smith referred to pharmacological treatments for alcohol problems as a challenge to pharmaceutical innovation. This challenge still exists and seems most likely to be met by the application of drugs developed for some other purpose to the treatment of alcohol abuse, rather than the empirical development of drugs for treating alcohol abuse per se. The papers which follow in this symposium enlarge upon some of the areas covered in this brief survey.

The treatment of narcotic withdrawal: a historical review.

The history of narcotic withdrawal treatment is filled with "cures" enthusiastically received and then quietly dropped when they turned out to be either ineffective, dangerous, or both. Methods reviewed include the Towns-Lambert belladonna treatment, sodium thiocyanate, bromide sleep treatment, Narcosan, insulin, autogenous serum, ECT, hibernation, methadone, phenothiazines, propranolol, propoxyphene, acupuncture, vitamin C, and the naloxone flush. There is need to be aware of the psychologic as well as physical aspects of withdrawal. Better detoxification techniques would help patients who are ready to discontinue the use of methadone as well as those who want to start naltrexone treatment.