Medical expenses are increasing year by year in Japan. However, the quantity of disposed medical opioids is not well known. In this study, we assessed disposed medical opioids in community pharmacies of Fukuoka city and in all of medical organizations of Kumamoto cities for 3 and 2 years, respectively. We collected official opioid disposal reports in Kumamoto city and Fukuoka City Pharmaceutical Association (FCPA) disposal information sheet in Fukuoka city. The total amount of disposed opioids was worth 7.1 million Yen from 2017 to 2019 in Fukuoka city, and 8.9 million Yen in for 2 years (2018 and 2019) in Kumamoto city. In Fukuoka city, the most disposed opioid was 20 mg Oxycontin®, worth approximately 940000 Yen. In Kumamoto city we assessed data in different organizations. The most disposed opioid was 5 mg Oxinorm® at a cost of 600000 Yen at the medical institutions over the 2-year study period. The most disposed opioid was 40 mg Oxycontin®, at a cost of 640000 Yen in community pharmacies. Two hundred micrograms E-fen® buccal tablet was the most disposed of opioid, was amounting to 960000 Yen in wholesalers. On the whole in Kumamoto city, non-dispensing was the most common reason of disposal. These results indicate that the amount of disposed opioids is huge. Small package simulation studies suggest that smaller package units of MS-Contin®, Anpec® suppository, and Abstral® sublingual tablet may be able to reduce the amount of disposed opioids.
The amount of medical expenses is about 45 trillion Yen in Japan.1) Due to the Covid-19 pandemic the expenses have been increasing. The role of pharmacists includes decreasing cost along with proper dispensing and use of drugs. Among various drugs, medical opioids are crucial in relieving pain. The use and disposal of opioid drugs are also increasing with the expansion of palliative care to control pain in Japan.2)
On the other hand, the opioid crisis is a serious problem in the world. In the United States, various research reported opioid overuse and related accidents.3–5) The rules on opioid disposal are different in across countries. The frequency of opioid related accidents may depend on the degree of strictness of the rules. In Japan, strict rules on the medical use and disposal of opioids are in place.6) In Europe and the United States the pharmacist provide drugs by the box. On the other hand, the pharmacist provides prescribed number or quantity of drugs to the patients according to the prescription in Japan. Accurate dispensing is required. Then, the disposed quantity at end of use must be recorded in official disposed sheet. Moreover, opioids should be disposed in the presence of an official and an accompanying formal disposal report must be filed.7) Owing to these rules, drug abuse in Japan may be less than other countries.
Only few studies reported the quantity of disposed opioids in Japan.8) Identifying drug names, doses and amounts of disposed opioids will help decrease the cost of drug expenses. In this study, we collected data to assess disposed opioids and identifies ways to decrease the cost associated in Fukuoka and Kumamoto cities. In Fukuoka city, opioid disposal information sheets, compiled by the Fukuoka City Pharmaceutical Association (FCPA), were assessed. Furthermore, official disposal sheets were analysed in community pharmacies, medical organizations, wholesalers, and research institutes of Kumamoto city. Finally, we estimated the extent by which the waste would be decreased in case smaller packages of three drugs were available.
We made out disposal information sheets, and sent to 717 pharmacies. The pharmacists describe drug names, the doses and the quantity of disposed opioids and disposed reason in the period between October 2017 and September 2020. Data was collected from November 12th to 24th 2020 in FCPA, then, the amount and disposed reason were assessed. We calculated the medical fee by standard price in each year.9)
Assessment of Disposed Opioids in Kumamoto CityOfficial opioid disposal reports, sent by pharmacists to the Department of Health and Welfare in Kumamoto Prefecture from April 1st 2018 to Mar 31st 2020 were collected. The reports contained disposed drug names, dose, quantity, date, disposed reason, responsible pharmacist’s name and organization. We assessed the total amount of the sheets. And then, the data were divided into 5 types of organization (community pharmacies, medical organizations, and wholesalers and others). We also analyzed the amount in each organization.
Package SimulationWe focused on undispensed and expired opioids in community pharmacies of Kumamoto city. We simulated packages containing 5 drug doses [MS-Contin®; 3 doses, Abstral sublingual tablet (Abstral®), and Anpec® suppository (Anpec®)] due to expiration using undispensed ones in community pharmacies of Kumamoto city. Available products include 100-tablet package of 10 and 30 mg MS-Contin®, 40-tablet package of Abstral® and 50-suppository package of Anpec®. We assumed 50- and 20-tablet package of MS-Contin®, 20-tablet package of Abstral® and 30-suppository package of Anpec®, and calculated the amount of disposed opioids in case that the proposed packages exists in Kumamoto city.
The simulation methods are as follows. We calculated in each official opioid disposal report. At first, the used quantity was calculated by subtracting the disposed quantity from the quantity in the package. Then, temporary disposed number was estimated in case that small package exists. From actual and temporary number, each drug fee was extracted. The difference between actual disposed fee and temporary one is assessed. An example of simulated package was shown in Fig. 1. When 35 tablets are used, 65 tablets are left in 100-ablet package. If 50-tablet package exists, 15 tablets are left. Then, if 20-tablet package exists, only 5 tablets are left.
◯: Used tablet, ●: left tablet
In the simulation study, statistical difference was assessed by Mann–Whitney U test or Steel test using JMP statistical software package, version 16 (SAS Institute Inc., Cary). A p value <0.05 was considered statistically significant.
Ethical ConsiderationsThis study was approved by the Ethics Committees of Kyushu University (22103-01).
Two hundred and sixty four of 717 pharmacies (37%) replied (Fig. 2). Among these, 264 pharmacies were opioid retail dealers (Fig. 2). However, 54 pharmacies did not keep a stock of opioids. Furthermore, 113 pharmacies disposed opioids at least once every 3 years. We assessed the data of these 113 pharmacies and found that the number of disposed kinds of opioids was 58. The reported number of disposed opioid items was 514. The total amount of disposed opioids amounted to 7125479 Yen over the 3 years period. Twenty milligrams Oxycontin® was the most disposed opioid, at a cost of about 942783 Yen for the same 3 years (Table 1). Followed by 40 mg Oxycontin® and 10 mg MS-Contin®. However, the items in each year were slightly different. The most common reason of disposal was hospital change or death of the patient in all of reports (60%). The second and third largest reason is drug change (19%) and cure (1%), respectively.
| Medical institutions | Amount (Yen) |
|---|---|
| Brand name (dose; mg) | |
| (Generic name) | |
| Oxycontin tablet (20) | 942783 |
| (Oxycodone Hydrochloride Hydrate) | |
| Oxycontin tablet (40) | 811557 |
| (Oxycodone Hydrochloride Hydrate) | |
| MS-Contin tablet (10) | 450788 |
| (Morphine sulfate Hydrate) | |
| Oxycontin tablet (5) | 390920 |
| (Oxycodone Hydrochloride Hydrate) | |
| Anpec suppository (10) | 352208 |
| (Morphine Hydrochloride Hydrate) | |
| Fentos tape (4) | 348440 |
| (Fentanyl Citrate) | |
| Oxycontin tablet (10) | 319984 |
| (Oxycodone Hydrochloride Hydrate) | |
| Abstral Sublingual tablet (200) | 283641 |
| (Fentanyl Citrate) | |
| Abstral Sublingual tablet (100) | 270515 |
| (Fentanyl Citrate) | |
| MS-Contin tablet (30) | 257574 |
| (Morphine sulfate Hydrate) |
Four thousand, four hundred and seventy-one from 4572 cases were assessed (Fig. 3). The number of medical institutions, community pharmacies, wholesalers and others were 3515, 897, 54 and 5, respectively (Fig. 3). We assessed the data in each organization between 2018 and 2019 (Table 2). The total amount of disposed opioids amounted to 26780840 Yen over the 2 years period. The amount amounted to 13553165 Yen over the same period in medical institutions. The amount amounted to 8859465 Yen over the same period in community pharmacies. The total amount amounted to 4005078 Yen over the same period in wholesalers. The top disposed opioid was 5 mg Oxinorm®, at a cost of 591129 Yen at medical institutions. The next two most disposed opioids were 10 mg Oxinorm® and 10 mg Anpec®. On the other hand, the top disposed opioid was 40 mg Oxycontin®, at a cost of 642315 Yen in community pharmacies. The next two most disposed opioids were 20 mg Oxycontin® and 6 mg Fentos® tape. The most disposed opioid in wholesalers was 200 µg E-fen® buccal tablet, amounting to 958600 Yen. Followed by 8 mg Fentos® tape and 16.8 mg Fentanyl tape for 3 d.
| Medical institutions | Community pharmacies | Wholesalers | |||
|---|---|---|---|---|---|
| Brand name (dose) | Amount (Yen) | Brand name (dose) | Amount (Yen) | Brand name (dose) | Amount (Yen) |
| (Generic name) | (Generic name) | Generic name | |||
| Oxinorm powder (5 mg) | 591129 | Oxycontin tablet (40 mg) | 642315 | E-fen buccal tablet (200 µg) | 958600 |
| (Oxycodone) | (Oxycodone) | (Fentanyl) | |||
| Oxinorm powder (10 mg) | 521890 | Oxycontin tablet (20 mg) | 574587 | Fentos tape (8 mg) | 282097 |
| (Oxycodone) | (Oxycodone) | (Fentanyl) | |||
| Anpec suppository (10 mg) | 435976 | Fentos tape (6 mg) | 350139 | Fentanyl tape for 3 d (16.8 mg) | 275933 |
| (Morphine) | (Fentanyl) | (Fentanyl) | |||
| Fentanyl tape for 3 d (8 mg) | 432796 | Fentos tape (4 mg) | 348275 | Durotep MT patch (12.6 mg) | 258438 |
| (Fentanyl) | (Fentanyl) | (Fentanyl) | |||
| Narusus tablet (24 mg) | 426713 | Oxinorm powder (10 mg) | 329446 | Durotep MT patch (4.2 mg) | 253168 |
| (Hydromorphone) | (Oxycodone) | (Fentanyl) | |||
| Fentos tape (2 mg) | 420048 | Oxycontin tablet (5 mg) | 293996 | Ultiva intravenous (5 mg) | 196920 |
| (Fentanyl) | (Oxycodone) | (Remifentanil) | |||
| Oxycontin TR tablet (5 mg) | 416606 | MS-Contin tablet (30 mg) | 285400 | Fentanyl tape for 3 d (8.4 mg) | 189086 |
| (Oxycodone) | (Morphine) | (Fentanyl) | |||
| Durotep MT patch (12.6 mg) | 404886 | Durotep MT patch (8.4 mg) | 269060 | E-fen buccal tablet (600 µg) | 157760 |
| (Fentanyl) | (Fentanyl) | (Fentanyl) | |||
| Fentos tape (1 mg) | 373766 | Morphine Hydrochloride tablet (10 mg) | 264270 | E-fen buccal tablet (400 µg) | 136150 |
| (Fentanyl) | (Morphine) | (Fentanyl) | |||
| Abstral sublingual tablet (100 µg) | 370730 | Durotep MT patch (4.2 mg) | 256333 | OneDuro patch (3.4 mg) | 131222 |
| (Fentanyl) | (Fentanyl) | (Fentanyl) | |||
The most common reason of disposal was non-dispensing (59%). The second and third largest reason is death or hospital change (21%) and drug change (19%), respectively. Top 3 reason is non-dispensing (39%), drug change (37%) and death or hospital change (22%) in medical institutions. The reason is non-dispensing (69%), death or hospital change (29%) and drug change (2%) in community pharmacies. The reason is non-dispensing (58%), death or hospital change (22%) and drug change (20%) in wholesalers.
Package SimulationSimulated results are expressed as box-and-whisker plot. (Figs. 4–6). The vertical lines extend to 10 and 90%, respectively. We focused on the expired opioids in community pharmacies of Kumamoto city. We targeted MS-Contin® due to the relatively large amount of disposal and there is only one packing available (10 tablets×10 pieces per box). We estimated the amount of disposal if a smaller MS-Contin® package (10 tablets×2 or 5 pieces per box) exist. We compared the real and estimated amount using statistical analysis. If 20- and 50-tablet packages existed of MS-Contin®, the median amount disposed was significantly decreased from 25000 to less than 10000 Yen per 1 official opioid disposal report on undispensed opioids (Fig. 4). Furthermore, we found that the disposed amount of the 10 mg and 30 mg was significantly lower in case of both 50- and 20-tablet package existence (supplementary Figs. 1 and 2). If a 30-tablet package exists of Abstral®, the disposal amount would significantly decrease from 22000 to 5000 Yen (Fig. 5). Moreover, if a 30-tablet package exists of Anpec®, disposal amount would significantly decrease from 14000 to 8000 Yen in 30 mg MS-Contin® (Fig. 6).
The boxes represent the upper and lower quartiles. The lines in the boxes represent median values. The vertical lines extend to 10 and 90%, respectively. *** p<0.001, ** p<0.01, Steel test.
The boxes represent the upper and lower quartiles. The lines in the boxes represent median values. The vertical lines extend to 10 and 90%, respectively. *** p<0.001, Mann–Whitney U-test.
The boxes represent the upper and lower quartiles. The lines in the boxes represent median values. The vertical lines extend to 10 and 90%, respectively. *** p<0.001, Mann–Whitney U-test.
Cancer treatment has been progressing. With the progress in palliative care, pain control is becoming increasingly important. Therefore, the use of opioids is increasing to enhance the quality of life. Onishi et al.10) reported the comparison of opioid use in pain. One hundred and twenty different kinds of opioids in 2009 were identified and increased to 234 in 2019. In Kumamoto city, the number of disposed opioid reports increased from 213 in 2009 to 473 in 2019. This data indicates that the use and disposal of opioids has been showing an upward trend. However, the medical expenses are also increasing. Therefore, efforts should be made to decrease the expenses of drugs. Nonetheless, very few studies were conducted to assess the disposal of opioids. In this study we assessed opioid disposal it in the cities of Fukuoka and Kumamoto. This is the first Japanese study on the disposal of opioids at such a large scale. In Fukuoka city, the total disposed amount for 3 years was 2.4 million Yen. The mean amount per one pharmacy was about 9700 Yen in one year. In 2019, the number of pharmacies was 60000. Eighty-five percent of them had opioid retail dealer license in Japan. Therefore, 462 million Yen per year is estimated if the same amount is disposed in all of Japan. We also conducted similar calculation in Kumamoto city, at an amount of 640 million Yen per year in all of Japan. Top 10 drugs are not so different in community pharmacies between These estimation shows that quite a large amount seems to be disposed. In Setsuyaku-Bag Campaign, we reported that the amount of leftover drugs is estimated about 330 billion Yen in community pharmacies of Japan.11) However, disposed amount is not assessed in the study. Total amount of disposed opioids is not so large compared with that of leftover drugs in Setsuyaku-Bag Campaign. Then, we calculated the disposed rate. The amount of 1 million and 718 thousand Yen was distributed on e-fen buccal tablet in Kumamoto prefecture of 2019, and the amount of 730 thousand Yen was disposed (42.5%) only in Kumamoto city. In the case of Anpec® 1 million and 586 thousand Yen was distributed in Kumamoto prefecture, and 32.4% of the amount was disposed in Kumamoto city. Thus, we found that the rate of medical opioid disposal is not low. Therefore, efforts should be made to reduce the amount by various ways.
Top 10 drugs are not so different in community pharmacies between Fukuoka and Kumamoto city. However, the drugs are different within medical institutions, community pharmacies and wholesalers. Oxycodone preparations were the top disposed amount in community pharmacies and medical institutions. Since oxycodone is widely prescribed due to its low side effects and its possible use in patients with renal dysfunction, it would necessarily be disposed frequently. Moreover, there were many high-dose formulations of Oxycontin®, such as 40 mg and 20 mg, were discarded in pharmacies. It is likely that fewer patients receive opioids in pharmacies than in hospitals, especially those using high doses of opioids as a result of the titration. When the prescriptions for these patients are discontinued due to opioid rotation, death, or other reasons, pharmacies may have a surplus of high-dose formulations. Furthermore, Most of the drug disposal amount at wholesalers was of fentanyl preparations. One reason for this may be that the approval of new drugs such as tapentadol and hydromorphone in recent years has reduced the use of fentanyl and caused it to expire. Other various factors including the high price for fentanyl preparations might be included in these results.
In the United States opioid crisis is a bigger problem compared to that of Japan. Many studies have been published on drug abuse of disposed opioids.12,13) Drugs are dispensed by unit-of-use packaging.14) Then, since doctors and pharmacists do not have guidance on drug disposal.15) Therefore, a large quantity of drugs is disposed. The opioid crisis is also easy to happen in the United States. Furthermore, half the amount of disposed opioids is prescribed for palliative care.16) Thus, the United States has various difficulties to solve the opioid crisis. On the other hand, opioid crisis is rarely known by now in Japan. Therefore, strict rule might be effective to prevent drug abuse on medical opioid disposal.
Opioid disposal is involved in various factors such as prescription period, package unit and so on. Here, we focused package unit. One of the means to reduce the amount of disposed opioids is smaller packing units, which seems to be useful in reducing disposal. Therefore, we simulated smaller packing unit of MS-Contin®, Abstral® and Anpec®. The results of this simulation showed that the disposed amount was significantly reduced in all drugs. It is an estimation, but 13% of the total amount may be decreased by smaller package existence of only 3 drugs. In 30 mg MS-Contin®, the amount was not significantly reduced by small packing unit. Therefore, small packing unit alone is not fully able to reduce opioid disposal. We should grasp the present situation and research countermeasures. As described above, we had better propose that pharmaceutical companies manufacture smaller packing unit as a way to reduce opioid disposal. Then, transfer and assignment are permitted within nearby pharmacies in case that pharmacies keep opioids more than 90 d. However, this rule is not fully utilized because of the limitation. Higher convenient change of the law is also desirable.
In conclusion, we clarified that so many opioids are disposed. This is the first study on opioid disposal in Japan. We would like to contribute to the reduction of medical expenses.
This work was supported by JSPS KAKENHI Grant Number JP20K10378.
Ichiro Inaba is an employer of Heartfelt Inc., and Tomoko Amagata is an employee of the company.
This online version of this article contains supplementary materials.
