Task‐Dependent Development of Cross‐Tolerance to Psychomotor Effects of Lorazepam in Man

Development of cross-tolerance between lorazepam and four other benzodiazepines (BZ) was studied in two trials by measuring objective psychomotor performance and by subjective assessments. In trial I, nitrazepam 10 mg (NZ), temazepam 20 mg (TZ) or placebo were administered to 14 healthy students for 10 consecutive nights. After each pretreatment, psychomotor impairment by the challenge dose of lorazepam 3 mg (LZ) was measured. In trial II, responses to LZ after pretreatment with diazepam 5 mg (DZ) (8 subjects) or alprazolam 0.25 mg (AZ) (10 subjects), both t.i.d., were compared to LZ responses measured after one-month wash-out period. In trial I no cross-tolerance between BZs was found in objective tests, and LZ induced exophoria was even increased. However, the subjects rated LZ to cause less drowsiness after pretreatment with NZ in a situation where the manifestation of cross-tolerance was facilitated by ingestion of caffeine. In trial II a clear but task-dependent development of tolerance to the challenge dose of LZ was documented. One-week pretreatment with DZ reduced subjects responses to LZ. The total serum BZ activity bioassayed by radioreceptor method after intake of LZ was significantly (P<0.05) higher after pretreatment with DZ than in the end of wash-out period. Thus a functional cross-tolerance was documented on complex tasks after the subjects have been continuously working under DZ burden.