The results of this analysis suggest there are three common groups among the studied countries, with different BZD/Z-drug consumption trends:
Countries where the sales of BZD and Z-drugs decreased since 2007: Greece, Finland and Denmark.
In Greece there was no anti-BZD campaign before the launch of PR-melatonin, and the consumption of the BZD and Z-drugs was stable. BZD and Z-drug consumption decreased by 14.5 % over 3 years after the introduction of PR-melatonin in the market. The decrease in BZD/Z drug consumption since 2008 can thus be attributed to the launch of PR-melatonin and its considerable market penetration. On average, an increase in 1 SU of PR-melatonin was associated with a decrease of about 4 SUs of BZD/Z-drugs.
The combined launch of PR-melatonin and anti-BZD campaigns in Finland and Denmark seems to be associated with a reduction of BZD/Z-drugs usage. This decrease is concomitant with the penetration of PR-melatonin on the market and the campaign implementation. Again, uptake of 1 SU PR-melatonin in Finland was associated with a decrease of 3 SUs of BZD/Z drugs consumption in this country.
Countries where the sales of BZD decrease while Z-drugs increase: Norway, the Netherlands and the UK. In these countries the anti-BZD campaigns seem effective for BZDs, but essentially resulted in a shift in prescription patterns towards Z-drugs.
In Norway, there was an overall increase in BZD/Z drugs consumption since 2005 but the BZD sales decreased in favor of Z-drugs. Since PR-melatonin was launched, the increase in Z-drug sales stopped and the consumption was stabilized, as if the switch from BZDs gradually shifted from Z-drugs to PR-melatonin.
The same evolution of BZD and Z-drug sales was observed in the Netherlands, but the decrease in BZD sales was mostly related to the change in the reimbursement status, suggesting that BZD/Z drug consumption in this country is price sensitive and reimbursement itself has some encouraging effect on hypnotic drug consumption. Nevertheless, Z-drug sales remained stable between 2009 and 2011. PR-melatonin sales did not rise considerably in the Netherlands perhaps because it is more expensive than the other drugs and is not actively promoted in this country.
In the UK, a decrease was seen only in BZD. There was a steady increase in Z-drug use of up to 7.3 % in 2011, although NICE has issued the following recommendation: "It is recommended that, because of the lack of compelling evidence to distinguish between zaleplon, zolpidem, zopiclone or the shorter-acting benzodiazepine hypnotics, the drug with the lowest purchase cost (taking into account daily required dose and product price per dose) should be prescribed” . Possibly, higher market acceptance of PR-melatonin might gradually change this situation as seen in Norway.
Countries where the sales of BZD were stable and Z-drug use increased, resulting in overall increases in BZD and Z-drug sales despite anti-BZD campaigns: France, Sweden and Spain.
In these countries the anti-BZD/Z-drug campaigns that were sometimes quite intense and long lasting (like in France) had no or very limited impact on prescription levels. As BZDs and Z-drugs are reimbursed while PR-melatonin is not, and these markets are reimbursement-sensitive, PR-melatonin was not commercially launched in France and was not put on the market in Spain.
Although real-life outcomes are difficult to interpret, as many factors could contribute to the occurrence of the outcome, some conclusions may be drawn with a reasonable level of certainty in the light of this research.
In countries where BZD/Z-drug campaigns were launched and PR-melatonin was not promoted nor prescribed, all campaigns failed to reach the desired outcome. This was the case for France, Spain, and Sweden.
In Greece, where no campaign was initiated, the sales reduction of BZD/Z-drugs was concomitant with PR-melatonin uptake. The case of Greece is a robust argument in favor of the role of PR-melatonin in the reduction of BZD/Z-drug sales.
In Finland and Denmark, the concomitant launch of BZD/Z-drug campaigns and PR-melatonin made it difficult to weight the impact of each factor on the reduction of BZD/Z-drug sales. However, in Finland the 3-year campaign from 2005 to 2008 ended with no appreciable effect at the launch of PR-melatonin. The drop of BZD/Z-drug sales clearly followed the uptake of PR-melatonin.
It should be noted that a standard unit is the smallest available drug dose. For PR-melatonin, an SU is the defined daily dose (DDD), as there is only one dosage available on the market. For BZD/Z-drugs there are often several dosages and therefore more than one SU may account for a DDD. Thus, the volume of BZD/Z-drugs in SUs replaced by the sales of PR-melatonin is higher than the raw number of SUs of PR-melatonin sold. In addition, the lower SU volumes of sold PR-melatonin as compared to unsold BZD/Z-drug SU volumes may in part reflect the fact that PR-melatonin can be discontinued without difficulty while BZD/Z-drugs cause withdrawal, tolerance and dependency, making discontinuation very difficult and causing abuse.
In Norway, the prescription shift of BZD toward Z-drugs stopped suddenly when PR-melatonin was launched. PR-melatonin appears to be a successful alternative option to Z-drugs.
In the UK and the Netherlands, in the absence of PR-melatonin uptake the reduction of BZD sales was associated with an increase of Z-drug use. The objective of total reduction was not achieved. The shift cannot be considered a success of the anti BZD/Z drug campaign, as the risk associated with Z-drugs is not considered significantly different from BZD in most studies . Some studies found Z-drugs to be even worse .
The marketing strategy toward positioning and promotion of pharmaceutical products is a critical element of the medical practice . In this case in Greece, Finland, Denmark and later Norway, unlike Sweden, PR-melatonin was perceived as an option to help chronic users withdraw from BZD/Z-drugs. Although this was not the only positioning, it was an important element of the marketing strategy also leading to volume market shares of 4–5.5 %. In those countries, the sales of PR-melatonin were associated with a decrease of BZD/Z-drug sales.
The lack of success of anti-BZD/Z-drug campaigns in the absence of an alternative pharmacological treatment option (France, Sweden) raises the question of the utility of such campaigns. Even if BZD drugs were actually reduced in countries like the UK and Norway, they were always associated with a shift in prescription toward another pharmacological agent, namely Z-drugs alone (UK) or Z-drugs followed by PR-melatonin when it became available (Norway). When both PR-melatonin and Z-drugs were available the prescriptions were consistently channeled toward PR-melatonin, resulting in a net decrease of the whole sedative hypnotics class including BZDs and Z-drugs (Finland and Denmark). The availability on the market of pharmacological alternative options to replace BZD/Z-drugs appears to be a critical factor for success of such campaigns. In the Netherlands, despite the fact that reimbursement was ended for both BZD and Z-drugs, there was a shift toward Z-drug prescription for some of the patients. It is unclear how the other patients were managed. Additionally, no information is available on alternative pharmacological or nonpharmacological prescriptions. Therefore, it is not possible to appreciate potential harm associated with this shift in practice.
The adoption of PR-melatonin as a treatment option is also important for BZD/Z drug use in countries where the product is reimbursed (e.g. the UK and Greece). In the UK the PR-melatonin launch was not associated with an HTA recommendation and sales didn’t take off, as the recommendation is a strong driver of general physician (GP) prescriptions. However in Greece, where the adoption of PR-melatonin was high, so was the decrease of sales of BZD/Z-drugs despite the lack of campaigns.
In Spain, where PR-melatonin was not available and the campaign was mild and geographically limited to regions, and in France were the campaign was intense and national, the sales of BZD/Z-drugs still tended to increase.
The findings of this study are consistent with a small size, double-blind randomized clinical trial that has shown the role of PR-melatonin in helping patients to withdraw from BZD/Z-drug use . It is also supported by an observational study showing a low rate of reinitiation of BZD/Z-drug after a course of PR-melatonin when patients were previously treated by BZD/Z-drugs .
The study has also some limitations.
No country without any campaigns and without a significant PR-melatonin existence was selected as control country. However, it is established that prescription habits of doctors are deeply anchored and without any intervention, no change occurs . Moreover, in order to compare trends with and without campaigns, some countries can be their own control by comparing the period before with the period after the launch of the campaign, for example France.
We used a database that is solely based on sales data and not prescriptions. We assumed that sales figures are a good proxy of what is consumed even if it is clearly higher. Indeed, some sold drugs are not then consumed by the patients. However, we assumed that the proportion of drugs sold and actually consumed by patients is the same, whatever the product. There are no reasons to believe that the proportion is different between products.
Unlike Z-drugs, BZD could be used for other indications such as epilepsy or anxiety [56, 57]. However, we only considered N5B1 IMS classification in this study, which is for non-barbiturate drugs and is mostly used for insomnia, while BZDs used for other indications are more likely to be reported under other IMS classes, such as N5C (Antidepressants and Anxiolytics).
We didn’t collect and analyze whole promotional materials, but we relied on interviews of the company’s marketing leader that provided a clear picture of the positioning and promotion of PR-melatonin. The dichotomy of positioning (or not) of PR-melatonin to help patients discontinue BZD/Z-drugs was quite clear. Moreover, the people interviewed were not aware of the ultimate research goal and therefore were unlikely to be biased.
There were no prescriber interviews to appreciate the drivers of their prescriptions, and the role of campaign and PR-melatonin promotion. This could limit the interpretation of the reasons for prescribing PR-melatonin as a means of discontinuing BZD/Z-drug use. In this research we were not assessing the causal relationship but just the existence or not of a relationship.
Finally, we didn’t perform a thorough review of campaigns to appreciate the reasons for failure, as this wasn’t the objective of our research.