Opioid availability statistics from the International Narcotics Control Board do not reflect the medical use of opioids: comparison with sales data from Scandinavia

INCB methodology

The 12 opioids studied in the INCB-based paper of Berterame et al. [10] (codeine, dextropropoxyphene, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, ketobemidone, morphine, oxycodone, pethidine, tilidine, and trimeperidine), either as isolated substances or as fixed combinations, were coded according to the ATC-code system (except for trimepiridine that lacks a defined ATC-code and does not have marketing approval in the countries in this study) and are referred to in this article as INCB-opioids. Berterame et al. studied the above-mentioned opioids, but only reported the total of opioid DDD, i.e. they did not report the particular DDD values of each opioid.

Importantly, opioids tabulated in yearly so-called technical reports from INCB are not exactly the same as the ones reported by Berterame et al. [10, 14, 15]. For instance, the technical reports include methadone [14, 15], and some also buprenorphine (15). In contrast, Berterame et al. exclude methadone and buprenorphine “because their use for pain relief cannot be distinguished from their predominant use in the treatment of dependence” [10]. The special reports intermittently published by INCB also differ somewhat in their choice of reported opioids [16]. In addition to INCB data published by Berterame et al., we also retrieved data from two INCB technical reports and two special reports [14], [15], [16], [17].

INCB uses a non-standardised measurement unit of “Defined Daily Doses for statistical purposes”, S-DDD. According to Berterame et al., “levels of use, expressed in S-DDD per million inhabitants per day, are calculated with the following formula: annual use divided by 365 days, divided by the population in millions of the country or territory during the year, divided by the DDD” [10]. What the authors call “annual use” will be extensively discussed and problematised later in the present paper.

ATC and DDD

In the ATC-classification, a specific substance can have several ATC-codes for different formulations with different therapeutic use. Morphine, for instance, is classified in group A07D Antipropulsives as fixed combinations as A07DA52; in group N02AA Natural opium alkaloids as only morphine N02AA01 in oral, parenteral and rectal formulations and as fixed substances N02AA51; and in N02AG Opioids in combination with antispasmodics as N02AG01 in fixed combinations of morphine and antispasmodics [6].

DDD is an administrative measure and denotes the assumed average maintenance dose per day for a drug used for its main indication in adults. The advantage of DDD is that, with only one DDD assigned per ATC code and route of administration (e.g. oral formulation), it provides a fixed unit of measurement independent of price, currencies, package size and strength, thus enabling researchers to assess trends in drug consumption and perform comparisons between population groups [6].

Different DDDs can be defined when the bioavailability is substantially different for various administration routes (e.g. oral and parenteral administration of morphine) or if the dosage forms are used for different indications. When parenteral formulations represent only a minor fraction of the total use for a specific indication, these products have normally not received a separate DDD. The DDD for combination products can be established based on different principles, for instance, based on the substance deemed the main active ingredient. Another way is to base the DDD on the average number of dosing intervals per day, i.e. two tablets is the DDD for combinations given twice daily, and three tablets is the DDD for combinations given three times daily and so forth. In this case, the assigned DDDs may differ from the DDD assigned for the main active ingredient. Also, it is possible to have local adaptions of DDD [6].

Importantly, DDD does not necessarily reflect neither recommended nor equipotent doses. If a change in use over time encompasses switches between substances where assigned DDD do not reflect equipotent doses, then a methodological confound might be introduced. This issue is a significant problem in opioid statistics.

National drug sales statistics

Aggregated data on total statistics over the legal sale of medical opioids, including sale to hospitals, were collected from the Swedish e-Health Authority which maintains a database with aggregated sales data (i.e. dispensed at pharmacies + used in hospitals + over-the-counter (OTC)). The data are publicly available as aggregated statistics without the need for approval by an ethical review board. In the present study, opioid national data were retrieved for the total population in Sweden. Total sales data for Denmark and drugs dispensed at pharmacies in Norway are publicly available through the relevant authorities’ web-sites [18, 19]. Total sales data for Norway are available and can be applied for, however in this study we chose to use only the publicly available data from the Norwegian Prescription Database (prescription opioids constituting the vast majority of sales statistics).

For fixed combinations of drugs, the DDD assigned to the fixed combination can be either one DDD/unit or a DDD that represents one of the substances. In the Scandinavian countries, the DDD for fixed combinations with opioids reflects the amount of the opioid. A common fixed combination in Scandinavia is 30 mg of codeine combined with paracetamol or acetylsalicylic acid. In the national drug consumption statistics in Sweden, Denmark and Norway, such a fixed combination is registered with a DDD of 0.3, reflecting that 100 mg of codeine is defined as one DDD.

Of the 28 member states of EU, 13 permitted the sale of codeine OTC in 2014 [20]. No opioids were available OTC in Sweden and Norway during the study period. In Denmark, where codeine combinations with 10 mg codeine per tablet are sold OTC, a nationally specified DDD for codeine in these tablets is 60 mg based on a usual daily dose of 6 tablets. Depending on whether a codeine combination tablet is sold as a prescribed drug or OTC, different DDD definitions will thus be used in the national statistics. The fraction of the total sale of fixed combinations of codeine as OTC was, however, less than 10% during the studied period. Because of this, no correction was applied to the data.

Time periods and chronology

Berterame et al. studied the total availability of opioids in the period 2001–2003 compared with 2011–2013 [10], and we have therefore compiled Scandinavian sales data accordingly. To enable a more in-depth study per substance of INCB data, an INCB special report covering 2007–2009 (i.e. in the middle of the above-mentioned period) was compared to sales data; see Annex 1, pp 63–63, in the INCB special report for details [16]. Also, in order to enable a better appreciation of long-term trends, we retrieved Scandinavian sales data for a broader time frame (2001–2016).

Consumption or availability

First, Berterame et al. claim they are studying opioid “use”, while INCB reports alternate between the terms “availability” (in the text) and “consumption” (in the figures) [15, 16]. The methodology used by INCB is challenging to follow. Our interpretation is that the annual use reported by INCB is equivalent to the administrative difference between the reported sum of national production + import and the national export of the 12 opioids as mentioned above. According to Berterame et al., the INCB methodology seems to consist of two stages. In stage 1, countries provided data on “the amounts that each country’s competent national authority estimates are needed and used annually, including reporting of medicines destroyed, losses during manufacture, and so on” [10].

According to INCB, Swedish data were provided by representatives from the Swedish Medical Products Agency (personal communication, Berterame). As stated in a technical report, “the analysis … is based on statistical data furnished by Government”, and “the quality of the analysis depends on the data provided” [15]. Then, in stage 2, “this information was verified by the INCB using data from export and import notifications” [10]. Hence, the verification principle used by INCB seems to focus on the difference between export and import. However, if this is the case, Berterame et al.’s claim that their study provides “an assessment of changes to opioid analgesic use worldwide” (emphasis added) [10] is debatable at best. Availability expressed as the difference between the sum of gross production and the import vs. the export, is not the same as actual legal use in healthcare.

INCB data are, at least for Sweden (personal communication with Swedish Medical Products Agency) based on manually compiled data from pharmaceutical companies on the national level. This way of collecting data is necessary for many countries without validated national drug consumption statistics globally. However, it introduces many possible errors and inaccuracies. A better term would be “reported availability”. It should neither be confused with the legal drug consumption in healthcare nor with the illegal use in the society (also comprising illegal production and smuggling and Internet sale of opioids). As a contrast, the publicly available Scandinavian national drug consumption statistics that we present reflect the volume of opioids prescribed/dispensed within the healthcare.

Tramadol

Secondly, neither Berterame et al. nor the two INCB special reports reported data on tramadol. Tramadol is an opioid used to treat moderate to severe pain, and there is a genuine and increasing problem with addiction and illegal abuse. During the studied period, it increased to almost a third of the total use of legally prescribed opioids in Denmark and Sweden, and one-fifth of the opioids dispensed at pharmacies in Norway. Tramadol was classified as a restricted narcotic drug in Sweden in March 2007 after reports of drug dependence [21]. In Denmark, this restriction was imposed in 2017 [22]. By not including tramadol, a methodological flaw is introduced that makes it impossible to compare countries with different use of tramadol and distort the national trends in opioid use.

Codeine

Thirdly, according to INCB, codeine is almost not available for consumption in the Scandinavian countries. Nevertheless, according to public drug statistics, it is the dominant opioid in these countries (whether studied as a fraction of INCB-opioids or all opioids). The majority of codeine prescribed in healthcare in Scandinavia is in fixed combinations with paracetamol (N02AJ06) or with acetylsalicylic acid (N02AJ07). During the studied period, codeine constituted more than half of the DDD for INCB-opioids in all Scandinavian countries, and more than one-third of all opioids, but in the INCB-reports the amount of codeine is almost zero.

In Denmark, codeine (R05DA04) as a single substance constitutes more than one-fourth of the total amount of codeine prescribed, while it is a negligible part of the codeine prescribed in Norway and Sweden. In 2014, codeine was also available over the counter in 14 of the 28 countries in the European Union [20]. In Denmark, but not in the rest of Scandinavia, codeine is available over the counter (OTC) in a fixed combination of 10 mg codeine together with either acetylsalicylic acid or propyphenazone [23].

For the rest of Europe, the availability of codeine 2007–2009 according to the INCB special report [16] varies from 0 to 4,818, expressed in S-DDD. Most countries however are below 100, while Iceland is an extreme outlier in the world reporting 4,818, which is more than 6 times as much as Canada with 783 (USA reports less than 1).

Fentanyl

Fourthly, the highly lipophilic and potent opioid fentanyl is the dominant opioid in the Scandinavian countries according to INCB, constituting approximately two-thirds of the amount in DDD/1,000 inhabitants of the opioids studied by INCB in 2007–2009. In national drug consumption statistics for the same period, fentanyl measured in DDD made up only 4–9% of the 12 opioids studied by INCB and 4–6% of all opioids. Fentanyl as a parenteral opioid anaesthetic (N01AH01 + N01AH51) lacks an assigned DDD in national consumption statistic, but the use measured in delivered orders and units have decreased over time, not increased.

Prescribed fentanyl is mainly used in patches. A transdermal patch can be assigned one DDD per unit or a DDD that reflects the substance’s bioavailability. In national drug consumption statistics, the amount of DDD per patch is based on the bioavailability or amount absorbed into the body over the number of days the patch is used. Since only 34–63% of the fentanyl in the patches will diffuse into the body (see Web Extra Material 2), the DDD in national drug consumption statistics will be lower than the total amount fentanyl in the patch. However, this discrepancy between available and absorbed fentanyl cannot explain the 4-8-fold higher volume of fentanyl in the INCB-data.

Recent data published by INCB point to a dramatic increase of fentanyl availability worldwide from 1997 to 2016, the availability of fentanyl (expressed as S-DDD) in 2016 being more than five times higher than for any other opioid [24]. All in all, this strikes us as prima facie incorrect, and we suggest that INCB carefully review the quality of their data in general and of fentanyl in particular.

Drugs used in opioid dependence

Fifth, methadone and buprenorphine are two opioids commonly used in treatment of opioid dependence. Preparations intended for this purpose are classified in the ATC-system in N07BC Drugs used in opioid dependence, more specifically N07BC01 and N07BC51 for buprenorphine and N07BC02 for methadone. For buprenorphine, preparations intended for treatment of pain are classified as N02AE01. In national drug consumption statistics, it is thus possible to separate buprenorphine prescribed for different indications. This is of course not possible when using the INCB-method gathering data over production, import and export of substances.

While the article by Berterame et al. does not include methadone or buprenorphine (neither for pain relief nor for treatment of opioid dependence), the INCB special report covering 2007–2009 does include methadone, but not buprenorphine.

DDD vs. oral morphine equivalents

Sixth, although reporting OMEQ is more appropriate than DDD for opioids, calculating DDD irrespective of equianalgesic effects is acceptable for the purposes of the present paper. For Sweden, we have elsewhere shown that the decrease in total DDD over time shown in Table 2 corresponds to an initial rise in OMEQ with 22% from 2000 to 2006, followed by a slight rise of 3% from 2007 to 2015 [11]. Hence, given the high equianalgesic ratio of fentanyl, and the relatively low equianalgesic ratio of tramadol and codeine, fentanyl would be expected to figure more prominently if Figure 1 was in OMEQ, whereas tramadol and codeine would be expected to be less prominent.

Accessibility to opioids in healthcare

The above-mentioned discrepancies pertain to the situation in Scandinavia. From a global point of view, a few things are worth underlining. It is important to remember that access to medical opioids is scarce in many countries because of strict regulations [5], even for palliative care patients. This is highly problematic, and we do of course agree with Berterame et al. when they write that impediments to use “urgently need to be addressed by governments and international agencies” [10] concerning certain regions such as for instance Africa and Asia. This kind of advocacy is an important endeavour. However, it is essential that such advocacy is based on solid facts. Sadly, the discrepancies we have described call the overall reliability of INCB data into question, also globally. Once again, we do not doubt that there is a dramatic underuse of medical opioids in many parts of the world, e.g. concerning end-of-life pain [25]. But this fact does not in itself automatically validate the methodology used by INCB.