title: Gender-related differences in response to placebo in benzodiazepine withdrawal: a single-blind pilot study.
abstract: BACKGROUND
  Benzodiazepines have dependency-producing properties, and the majority of patients who are prescribed benzodiazepines and are treated for benzodiazepine dependency are women. Inability to cope with withdrawal symptoms may lead to continued consumption of benzodiazepines, often with the development of tolerance and dose escalation as a consequence.
  
  
  OBJECTIVE
  In the present study we analyzed gender-related differences in reactions to placebo injections in a placebo-controlled study of the effects of the benzodiazepine antagonist flumazenil among patients previously treated for benzodiazepine dependency and healthy controls.
  
  
  METHODS
  Ten patients and ten controls (five males and five females in each group) received two placebo injections (separated by 15 min) on two separate occasions (1-13 weeks apart). The patients had been benzodiazepine free for 47 (4-266) weeks on the first occasion. Subjective ratings of symptoms, thought to be important during/after withdrawal of benzodiazepines, were made before and after each injection, as well as registrations of blood pressure and heart rate.
  
  
  RESULTS
  An overall difference existed between previously benzodiazepine-dependent subjects and healthy controls, with patients scoring higher on negative and somatic aggregates and lower on a positive aggregate. A four-way interaction (group x gender x occasion x time) was found for negative and somatic aggregates, which could mainly be explained by the reactions of female patients. Thus, females had the highest base-line ratings and were the only group that showed a significant reduction in symptom ratings after placebo injections on the first occasion. Gender differences were also found for systolic and diastolic blood pressure. There was no significant response to placebo among male patients or for controls (males or females) for ratings of any variable.
  
  
  CONCLUSIONS
  The results suggest that there might be gender-specific differences in reactions to placebo injections, with female patients being more affected. Arguments for and against explanatory factors such as expectation, provider factors, habituation, regression toward the mean, and reduction of anxiety are presented.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institute, Magnus Huss Clinic, Karolinska Hospital, Stockholm, Sweden. lars.saxon@cspo.sll.se
authors.forename: L
authors.initials: L
authors.lastname: Saxon
authors.forename: A J
authors.initials: AJ
authors.lastname: Hiltunen
authors.forename: P
authors.initials: P
authors.lastname: Hjemdahl
authors.forename: S
authors.initials: S
authors.lastname: Borg
mesh_terms: D000328:Adult; D014151:Anti-Anxiety Agents / Q000009:adverse effects*; D001794:Blood Pressure / Q000187:drug effects; D004361:Drug Tolerance; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D012727:Sex Characteristics; D016037:Single-Blind Method; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology / Q000523:psychology*
chemical_list: D014151:Anti-Anxiety Agents; D018757:GABA Modulators; D005442:Flumazenil