Summary
The main finding in this study was that patients starting with oxazepam, compared with diazepam, increased their risk for reaching consumption level 2 during a 5-year period. This was true even when accounting for differences in sociodemographic status and previous drug use (HR 1.33, 95% CI = 1.17 to 1.51).
New users of oxazepam had more often used antidepressants, lithium, antipsychotics, opioids, anti-alcohol and smoking cessation drugs, and drugs for COPD previously, than had new users of diazepam. They had a somewhat lower education and income, and had to a greater extent no registered work. Thus, former drug consumption and sociodemographic profiles characterising new users of oxazepam were associated with reaching level 2.
The difference in dose escalation risk for the two user groups was interesting as diazepam is described as having higher liability for dependence compared with oxazepam.13,14 Diazepam is absorbed more rapidly, followed by a fast distribution phase (distribution half-life of about 1 hour) and a terminal elimination phase with a half-life of 20–200 hours,15 whereas oxazepam is absorbed more slowly, covering also the distribution phase, followed by a terminal elimination phase with a half-life of 4–15 hours.15 These pharmacokinetic differences are mainly a result of diazepam being more lipophilic than oxazepam. The fast invasion of the central nervous system (CNS, fast ‘on-rate’) during the absorption phase and the fast fall in the CNS concentration (fast ‘off-rate’) during the distribution phase by diazepam compared with oxazepam are expected to be the typical pattern for causing dependency. Thus, these differences constitute the basis for the recommendation to start with oxazepam rather than diazepam if prescribers suspect substance use disorder.1,2,13,14
Previous use of psychopharmacological drugs, opioids, and anti-alcohol and smoking cessation drugs could indicate a psychiatric disorder and problems with pain, and perhaps also a more general proneness to dependency. The present study findings indicate that prescribers took such patient histories into account and chose drugs regarded as less addictive. For individuals with previous COPD medication, oxazepam was perhaps considered to be a safer drug regarding respiratory problems.
Overall 8.48% (oxazepam) and 5.36% (diazepam) reached level 2 and hence consumed above the recommended dosage. There could be several explanations for this. A greater fraction of new users of oxazepam may have wanted a faster-acting drug and experienced an insufficient initial drug effect, and therefore compensated for the slow absorption by increasing the dose.
DDD for diazepam and oxazepam are 10 and 50 mg, respectively.15 Another possible explanation for the different patterns of use between the two drugs could simply be that DDD for oxazepam has been set too low. Some individuals perhaps did not experience a sufficient effect with the average dose.13,14,16
Even when accounting for differences in sociodemographic status and previous drug use, there was a difference in BZD consumption between new users of diazepam and oxazepam. Perhaps a greater fraction of users of oxazepam had more serious psychiatric conditions, not accounted for by the available background variables, and therefore experienced an insufficient effect with recommended dosages.
A higher fraction of patients redeeming different BZDs reached level 2 compared with those who only used one BZD. This could indicate that those switching BZDs were dissatisfied and perhaps also more prone to dose escalation. As expected, individuals redeeming different BZDs needed a longer time to reach level 2. This is reasonable as it takes time to try new drugs and thereafter increase the dose. Furthermore, to have prescriptions issued by a psychiatrist also characterised the path to reach level 2. Those visiting a psychiatrist may encompass a group of more seriously ill patients with psychiatric conditions in need of more extensive treatment regimes.
Strengths and limitations
As a population-based analysis there was no observational bias. However, drug dependency was only discussed in terms of reaching consumption level 2. A study focusing on low-dosage long-term use could also indicate drug dependency. Also, observational cohort studies may have unmeasured/unmeasurable confounders. For example, the lack of knowledge of indications for prescribing BZDs and of clinical data on psychiatric history is important missing information from the analysis.
There were no redemptions registered prior to 2004. New users had had 2 years without redemptions. Still, only individuals with a first redemption between 10 and 30 DDDs, and individuals who redeemed <1 DDD daily on average in the first 3 months, were considered. This made the new-user assumption reasonable. Register-based studies can only consider the amount of drugs redeemed, not the amount consumed. Unfortunately, possible discrepancies could not be controlled for.
Comparison with existing literature
This study confirmed that most prescribers and consumers follow recommendations regarding dosage and treatment duration.17 This is in line with previous findings.7 This gives credit to the robustness of the analysis regarding the new findings on new users of oxazepam.
The present finding of higher BZD consumption for individuals with lower socioeconomic status is in line with findings for more deprived members of the population in previous studies.18,19 Clearly, many doctors unsure of the risk for dependency chose oxazepam rather than diazepam for these patients.
Implications for research and practice
Many doctors acted according to recommendations by prescribing oxazepam to individuals for whom they feared dependency problems. This study describes the real ‘post prescription situation’ and showed that these individuals to a larger degree reached a consumption level beyond what was recommended compared with those starting on diazepam. These findings could be considered by guideline providers and by doctors initiating BZD treatment, and could help prescribers identify patients who might need a closer follow-up throughout treatment.
The present findings indicate that, although in theory pharmacokinetic profiles with longer absorption time and slower availability in the CNS, such as for oxazepam, should account for differences in liability for dose escalation, this might not apply in practical use. This is because slower absorption and availability can be compensated for by higher consumption.
