In France, the withdrawal of DXP/PC took place in two phases, with a first decrease in 2009 following an EMA opinion, and a second, final decrease in 2011 due to national regulatory decisions. The global dispensation data of prescribed analgesics suggest that the DXP/PC withdrawal had a small impact on the overall use of analgesics in France, as the total dispensations of these drugs decreased by 14% over the four years considered. However, over the same period, there was an increased use of PC, a step 1 analgesic, and to a lesser extent, of step 2 analgesics, codeine, opium, and tramadol, mostly combined with PC.
The data suggest that physicians replaced DXP/PC quickly after withdrawal from the French market. This was not straightforward, as this medication had been widely prescribed since 1964 – e.g., figures from 2009 show a use of 29 DDDs/1000 inhabitants/day – in a large set of indications. Part of the explanation for this quick replacement could be the fact that the benefit-risk ratio of DXP/PC was considered – by EMA, health care professionals (HCPs) and scientific societies – to be disputable. For instance, in 2008, a consensus conference on postoperative pain care concluded that DXP/PC should not be prescribed for this indication [18]. Surveys conducted among HCPs also revealed concerns regarding the safety profile or the limited efficacy of DXP/PC [19].
However, the use of analgesics after DXP withdrawal had not been predicted. Before withdrawal, step 2 analgesics, particularly tramadol/PC and codeine/PC, were expected to be used much more frequently, but our data show that after DXP withdrawal, the use of PC increased more than the use of step 2 analgesics. The reasons for this limited increase of step 2 analgesics could be related to safety concerns as tramadol is known for its poor tolerability, while codeine is under surveillance for its respiratory effects [20,21,22]. Also, opium-containing drug are seldom prescribed, except for elderly patients. In that context, for the prior indications of DXP/PC, prescribers probably chose PC, i.e. a less effective, but safe alternative to step 2 analgesics.
Of interest, the results of this study differ from the results of a survey performed among Pain specialists asked to describe alternatives to DXP in France [23]. HCPs declared tramadol combined with PC to be the substitutive analgesic of choice, while only 24% of considered PC alone as a substitute.
By contrast, another study conducted in a teaching hospital in 1997, i.e. long before withdrawal, suggested that DXP/PC should be predominantly replaced by PC alone, in agreement with our findings [7]. Also in line with our data, a study conducted after withdrawal among community-dwelling elderly suffering from chronic pain and previously treated with DXP/PC, showed that a majority of patients remained treated with step 2 analgesics, mainly tramadol, but that 40% were switched to step 1 drugs [24]. Altogether, the available data suggest that the choice of replacement analgesics depended on physician specialty, setting – e.g. primary vs. secondary care – indication, patients’ comorbidities and age.
The effects of DXP withdrawal have also been investigated in other countries, notably in the UK, where withdrawal was effective in 2008. In the UK, a 23%-increase in codeine/PC, a 19%-increase in tramadol and a 16%-increase in PC prescriptions were reported [25], confirming international differences in pain management.
Our findings had some limitations. This study relied on the use of aggregated data, i.e. monthly dispensations delivered to a population of five million people after analgesic prescribing by regional physicians. As such, it was not possible to distinguish successive episodes of use of analgesics in individuals, to identify analgesic therapy prescribed after DXP/PC withdrawal in chronic or repeated users. It was also not possible to assess the impact of therapeutic changes on the effectiveness of pain therapy, in the absence of patient-reported data. Access to individual drug histories would have allowed exploring differences in patients’ characteristics, such as gender, age or comorbidities, and differences in prescribers’ specialties, in addition to providing some markers of treatment effectiveness.
Also, our data did not allow to verify the occurrence of a storage phenomenon that was shown to delay DXP replacement in the UK, where 30% of patients were still using DXP/PC one year following its withdrawal [25].
A last limitation refers to the absence of over-the-counter data, since claims data include only information on drugs that were both prescribed and dispensed. However, prior research on this issue support the validity of the results obtained with claims data, as in France, PC is mostly used as prescribed therapy, while step 2 and step 3 analgesics are Prescription-Only-Medicines [26].
