Efficacies of Regulatory Policies to Control Massive Use of Diphenoxylate
Iran has been one of the highest users of diphenoxylate in the world in 2008. Iranian food and drug organisation (FDO) established some rules to control the usage of this drug included rationalizing the supply and doubling the price. Data were gathered from the distributors and wholesalers of this medicine in the country during 2006-2010. These data were cross-checked with importation data in the Ministry of Health and a trend analysis was tabulated. In 2009, the average consumption reached to less than 650 million tablets which show 42% decrease in comparison to the previous year. After the second intervention, there has been no significant change in the trend. The first intervention has controlled the use of diphenoxylate by reduction of market need and lessening diphenoxylate unauthorized use. Data do not support the efficiency of second intervention meaning that doubling the price does not work.
Received: March 27, 2012;
Accepted: April 03, 2012;
Published: June 13, 2012
To have a secure pharmaceutical market an effective strategy is needed to recognize
all health indicators such as exact rates of diseases and adverse drug reactions,
demands, resources and opportunities (Abdollahiasl et
al., 2011a) but unfortunately, the system, structures and mechanisms
for control of drugs in Iran, although is in place but they do not function
properly in some topics (Nikfar et al., 2005).
Diphenoxylate is a synthetic derivate of pethidine that is mainly used in supportive
management of acute and chronic diarrhea. Because of opioid-like effects, diphenoxylate
is a choice of abuse and it is listed in Schedule III of the 1961 Convention
(Katzung, 2011). Based on United Nation reports, China
and India are the main producers and also users of diphenoxylate in the world.
Iran is the top importer and the third user of diphenoxylate in the world. Iran
imported 2 of 16 tons (17%) of total diphenoxylate produced in 2007 (United
Nations, 2009). The question is why a country with 1% of the world population
could consume about 17% of the whole production of diphenoxylate in the world.
The Iranian Food and Drug Organisation (FDO) as the main responsible body for
rationalizing drug use established some rules to limit the usage rate (Soleymani
et al., 2009). Despite diphenoxylate is a prescription drug but some
estimations indicates that only less than 5% is used by prescriptions and the
main use seems misusage by addicts or any unknown reason. One of the reasons
behind this extreme use of diphenoxylate is its low price that makes it affordable
for most of abusers and meanwhile lead to a competitive mass production by various
pharmaceutical companies to compensate demand of pharmacies. The same trend
of misuse was already confirmed for antibiotics in Iran (Abdollahiasl
et al., 2011b). Compatible with data from use of diphenoxylate, our
recent study indicated that naloxone as an antidote of diphenoxylate and other
opioids is produced in high amounts in Iran to provide requirements of poisoning
centers (Nikfar et al., 2011). To solve this
problem immediately, FDO tried to control import of the active ingredient followed
by more control on distributors and pharmacies (Dinarvand,
2009). The other policy was doubling the user price that became effective
in the middle of 2009. This study aimed to show the effectiveness of these two
interventions by evaluating monthly use of diphenoxylate.
MATERIALS AND METHODS
The monthly production and sale of this medicine were requested from the six
manufacturers and 15 distributors around the country. Although, the request
letters were sent by the Narcotic Control Office of FDO to guarantee receiving
a true answer, data were cross-checked with raw material importation data within
FDO. A time-trend analysis was done on summarized tabulated data. DDD (defined
daily dose) and DID (DDD per 1000 inhabitant patient per day) were calculated
by the following formula:
||DDD = Defined daily doses used by a thousand of population
in a day
||DID = Annual sale multiplied by DDD and 1000 divided by (strength of drug
multiplied by population and 365):
Therefore, the monthly data were calculated as follows:
||DID = (monthly sale multiplied by DDD and 1000) divided by
(strength of drug multiplied by population and 30)
RESULTS AND DISCUSSION
There are some variations in monthly use of diphenoxylate but annual data show
that 0.786, 1.215, 1.044 and 0.610 billion tablets of diphenoxylate 2.5 mg were
sold in 2006, 2007, 2008 and 2009, respectively (Fig. 1).
For adjusting the monthly sales data, the average sale of three months including
a month before and a month after of each considered as that month sale. This
kind of moving average could decline some sharp differences in monthly sale
and smooth the chart (Fig. 2). For removing the effect of
population growth, data changed to DDD/1000 inhabitants/day (DID). Usually,
calculation of DID is based on annual data. Both annual and monthly data were
considered (Fig. 3). Figure 4 illustrates
the exact monthly changes that is adjusted by moving average trend and compared
to unit price of diphenoxylate 2.5 mg tablet.
The monthly sale is a surrogate for use of drug while a gap between the amounts of diphenoxylate bought by pharmacies and the amounts used is clear. This can be explained by pharmacies stocks level and the leftovers drugs in houses. In this study, trend of sale was obtained and we could not find any reason for considerable changing of these factors during the study. The annual sale shows an increasing trend until 2007 where a small decline occurred in 2008 and a major reduction happened in 2009 (Fig. 1). Two kinds of up and down in the trend is obvious. The small changes seem usual and can be explained by usual errors in distribution system, work calendar, transportation lag time and the cash flow between producers and distributors. By applying a three-month moving average (putting the average sales of each tree months instead of the middle month and moving this pattern for all months), the trend was smoothed (Fig. 2). Interpretation of major up and down needs full information about the interventions, events and policies happened during the examined period. The highest sale happened in the third season of 2007 (more than 120 million tablets per month) and a major decline after that continued to the first season of 2008 that was because of saturation of pharmacies stocks but it went up again in middle of 2008. In the third season of 2008, after the first intervention, a gradual decline was started and continued up to end of 2009 and reached to a plateau in the last 6 months. The first intervention was started by controlling the imported active ingredient through official power of FDO. This intervention was supported by a warning letter sent to all distributors describing the undergoing inspection for any unauthorized use of diphenoxylate.
||Annual and monthly sales of diphenoxylate 2.5 mg tablets in
Iran during 2006-2010
||Three months moving average sales of diphenoxylate 2.5 mg
tablets in Iran during 2006-2010
||Defined daily dose/1000 inhabitants/day of diphenoxylate 2.5
mg tablets in Iran during 2006-2010
||Adjusted monthly sales against unit price of diphenoxylate
2.5 mg tablets in Iran during 2006-2010
FDO believed that this policy could control behavior of manufacturers of diphenoxylate
but meanwhile they believed that the policy could not be effective for market
demand. Since, a big difference between anti-diarrhea dose and opiate-like dose
exists, the abusers of this drug have learned to use many tablets. Then the
FDO decided to make it unaffordable for abusers by serious warning of pharmacies.
The price of each tablet of diphenoxylate was 43 Iranian Rials (IRR) equal to
0.0043 US Dollar (USD) till the first season of 2008 when it had a small increase
because of usual inflation rate and reached 60 IRR equal to 0.006 USD. Then
FDO decided to a marked increasing the price of some drugs that might be abused.
The offered price for diphenoxylate changed to 1000 IRR equal to 0.1 USD per
tablet and the producers were asked to return the margin to the FDO. According
to rules, this kind of cash flow must get parliament approval. The parliament
agreed to just double the price. Although, FDO believed that doubling the price
could not affect the affordability of this drug (120 IRR = 0.012 USD) but FDO
was obliged to apply it in the last months of 2009. But the results did not
show any significant change in the existing trend (Fig. 4)
confirming unhelpfulness of the rule for the purpose of drug usage control.
If the study period is divided into three parts including before the first policy,
between two policies and after the second policy to check the correlations,
a positive slop is evident that means an increase in the sale. After the first
intervention, the trend significantly went down and the slope became negative.
After the second intervention, the slope was still negative but its absolute
value was reduced. This means that after the second policy became effective,
not only the trend did not decrease but also it reached a plateau phase (Fig.
2). For eliminating the effect of population growth on the trend, data changed
to the index named DID that has been defined by WHO collaborating center for
drug statistics methodology. As shown in Fig. 3, the sale
on the basis of DID has the same trend indicating that population growth has
no significant effect on the sale of diphenoxylate.
Taken collectively, limiting the supply of diphenoxylate and warning to the
distributors controlled the abuse of diphenoxylate. But this plan to decrease
affordability has no effect on the trend and it has only increased workload
of narcotic office in the MOH (Niens et al., 2010).
At the end of period it sounds that the trend reaches a plateau and thus some
other interventions are needed to rationalize the use. A significant tax mark-up
on the price, promoting loperamide as a therapeutic substitute, penalizing pharmacies
which do not observe the (Over-the counter markets) OTC rules and promoting
the other legal methods for treating addicts are some policies that should be
1: Abdollahiasl, A., A. Kebriaeezadeh, S. Nikfar, A. Farshchi, G. Ghiasi and M. Abdollahi, 2011. Patterns of antibiotic consumption in Iran during 2000-2009. Int. J. Antimicrob. Agents, 37: 489-490.
CrossRef | PubMed |
2: Abdollahiasl, A., S. Nikfar, A. Kebriaeezadeh, R. Dinarvand and M. Abdollahi, 2011. A model for developing a decision support system to simulate national drug policy indicators. Arch. Med. Sci., 7: 744-746.
CrossRef | PubMed | Direct Link |
3: Dinarvand, R., 2009. New national drug policy in Iran leading to expanded pharmaceutical market and extended access of public to medicines. Iran. J. Public Health, 38: 158-161.
Direct Link |
4: Katzung, B.G., 2011. Opioid Analgesics and Antagonists. In: Basic and Clinical Pharmacology, Katzung, B.G., B. Katzung, S. Masters and A. Trevor (Eds.). 12th Edn., McGraw-Hill, New York, USA., ISBN-13: 9780071764018, pp: 713.
5: United Nations, 2009. Narcotic Drugs: Estimated World Requirements for 2009 (Statistics for 2007). United Nations Publications, USA., ISBN-13: 9789210481243, Pages: 424.
6: Niens, L.M., A. Cameron, E. van de Poel, M. Ewen, W.B.F. Brouwer and R. Laing, 2010. Quantifying the impoverishing effects of purchasing medicines: A cross-country comparison of the affordability of medicines in the developing world. PLoS Med., Vol. 7. 10.1371/journal.pmed.1000333
7: Nikfar, S., A. Kebriaeezadeh, R. Majdzadeh and M. Abdollahi, 2005. Monitoring of National Drug Policy (NDP) and its standardized indicators; conformity to decisions of the national drug selecting committee in Iran. BMC Int. Health Hum. Rights, Vol. 5. 10.1186/1472-698X-5-5
8: Nikfar, S., M. Khatibi, A. Abdollahi-Asl and M. Abdollahi, 2011. Cost and utilization study of antidotes: An Iranian experience. Int. J. Pharmacol., 7: 46-49.
CrossRef | Direct Link |
9: Soleymani, F., M. Valadkhani and R. Dinarvand, 2009. Challenges and achievements of promoting rational use of drugs in Iran. Iranian J. Public Health, 38: 166-168.
Direct Link |