Trends in major opioid analgesic consumption in Taiwan, 2002–2014

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Journal of the Formosan Medical Association (2016) xx, 1e7

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.jfma-online.com

ORIGINAL ARTICLE

Trends in major opioid analgesic consumption in Taiwan, 2002e2014 Kai-Hsiang Kang a,b, Li-Fen Kuo a, I-Chen Cheng a, Chih-Shiuh Chang a, Wen-Ing Tsay a,* a Division of Controlled Drugs, Food and Drug Administration, Ministry of Health and Welfare, Taipei, Taiwan b Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan

Received 3 May 2016; received in revised form 8 September 2016; accepted 8 September 2016

KEYWORDS consumption; defined daily dose; opioid analgesics; Taiwan FDA

Abstract Background/Purpose: According to WHO guideline, the consumption of opioids is an important sign of national progress in cancer pain relief. However, precise data on the consumption of opioid analgesics consumption in Taiwan has not been published. We investigate opioid analgesic consumption in Taiwan between 2002 and 2014 compare the results with those in other countries to see what we could learn about other methods of pain management. To find out the different patterns between Taiwan and other country, improves the quality of pain management. Methods: We extracted from the Controlled Drugs Management Information System (CDMIS) database, the consumption data of morphine, fentanyl, and pethidine, three strong opioids, and of codeine and buprenorphine, two weak ones. Data were presented as defined daily doses for statistical purposes per million inhabitants per day (S-DDD/m/d). The number of inhabitants was extracted from the Taiwan Ministry of Interior Statistics population database. Results: During the thirteen studied years, the total consumption of opioids markedly increased in Taiwan. By category, the consumption of morphine, fentanyl and buprenorphine increased, but the use of pethidine and codeine decreased. Compared with the selected regions and countries, the use of opioid in Taiwan progressed in Asia, but it was still lower than in Western countries. Conclusion: Opioid analgesics are probable addictive; however, they can improve a patients’ quality of life if properly used. The Taiwan FDA continuously introduces new opioid analgesics and educates physicians on how to use them correctly. These measures will improve the quality of pain management in Taiwan. Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Conflicts of interest: The authors have no conflicts of interest relevant to this article. * Corresponding author. 161e2, Kunyang Street, Nangang District, Taipei City, 11561, Taiwan. E-mail address: [email protected] (W.-I. Tsay). http://dx.doi.org/10.1016/j.jfma.2016.09.004 0929-6646/Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Kang K-H, et al., Trends in major opioid analgesic consumption in Taiwan, 2002e2014, Journal of the Formosan Medical Association (2016), http://dx.doi.org/10.1016/j.jfma.2016.09.004

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Introduction Pain is the most common reason people seek medical help; it is also a major public health concern.1 According to the World Health Organization (WHO), the number of cancer patients worldwide has risen dramatically and patients urgently need pain relief in all stage of cancer.2 Opioid analgesics are the mainstay treatment for cancer pain.3 Opioid consumption is an important sign of national progress in cancer pain relief.2 Gilson et al4 reported that after the WHO announced its three-step analgesic ladder for cancer pain relief in 1986, which encouraged using oral morphine, opioid consumption markedly increased in the western world. However, total opioid consumption in Asian counties, such as Japan, Hong Kong, Korea, and China, is still much lower than in North America and Europe.5 Every year, each WHO member country or area submits its opioid consumption data to the International Narcotics Control Board (INCB), which provides international comparisons in its annual report.5 Unfortunately, because Taiwan is not a member of the WHO, there are no opioid consumption data for Taiwan in the INCB annual report. However, most opioid drugs are controlled substances in Taiwan. To manage the diversion of controlled drugs and confirm the propriety of controlled drug usage, the Taiwan Food and Drug Administration (TFDA) has developed a Controlled Drugs Management Information System (CDMIS).6 According to the Controlled Drugs Act,7 all institutions and companies have to use online reporting when they import, export, manufacture, sell, or purchase controlled drugs using the CDMIS. Thus CDMIS can provide data on overall patterns of opioid wholesale levels in Taiwan. Pan et al8 reported that the average daily opioid consumption in Taiwan lagged far behind those in other developed countries between 2002 and 2007. Nevertheless, opioid consumption in Taiwan has recently rapidly increased.8 In this descriptive study, we examined the consumption of five major opioid analgesics (fentanyl, morphine, pethidine, buprenorphine, and codeine) on a wholesale level in Taiwan and made multicountry comparisons using the official data from the INCB.

Materials and methods Our data source was the CDMIS database. Official data from other Asian countriesdJapan, Hong Kong, and Chinadwere also used for the comparison. To analyze the five major opioid analgesics, we divided them into two categories: strong (morphine, fentanyl, and pethidine); and weak (buprenorphine and codeine). Data were converted into defined daily doses for statistical purposes per million inhabitants per day (S-DDD/m/d). The number of Taiwan’s inhabitants at midyear was extracted from the Taiwan Ministry of Interior Statistics population database. International mean DDD values from the INCB are shown in Table 1. The formula was calculated as follows: annual opioid consumption ðmgÞ DDD ðmgÞ  inhabitants ðmillionÞ  365 ðdaysÞ

ðEq:1Þ

Although some studies have reported that oral morphine equivalents are more useful than S-DDD/m/d for analyzing opioid consumption,9e11 Lu et al12 stated that the S-DDD

Table 1 Defined daily doses (DDD) values in mg from the International Narcotics Control Board. Drug

DDD (route)

Morphine

30 mg (parenteral) 100 mg (oral) 0.6 mg (parenteral, oral) 400 mg (parenteral, oral) 1.2 mg (sublingual) 8 mg (sublingual, for heroin substitution) 240 mg (parenteral, oral) 100 mg (oral, cough suppressant)

Fentanyl Pethidine Buprenorphine Codeine

formula (Eq. 1) could compare not only single drugs and multidrugs, but also the wholesale level of opioid consumption. Moreover, S-DDD is commonly used in INCB publications.5 Thus, we chose this method for our study.

Results Trends in the total consumption of opioid drugs in Taiwan, 2002e2014 Consumption of these opioid drugs between 2002 and 2014 rose by 41%: from 631.2 S-DDD/m/d to 889.5 S-DDD/m/ d (Table 2). Morphine, fentanyl, and buprenorphine consumption rose, but codeine and pethidine fell. Furthermore, buprenorphine consumption accounted for the largest increase: from 6.5 S-DDD/m/d in 2002 to 81.5 S-DDD/m/d in 2014 (12.54 times more). In 2002, codeine consumption was 272.7 S-DDD/m/d; it was the most consumed opioid and accounted for 43.2% of total consumption. In 2014, however, fentanyl consumption was 509.2 S-DDD/m/d; it had replaced codeine as the most consumed opioid and accounted for 57.2% of total opioid consumption. Between 2002 and 2014, the consumption of strong opioids markedly increased from 352.0 S-DDD/m/d to 734.4 S-DDD/m/d (Fig. 1), and that of weak opioids decreased from 279.2 S-DDD/m/d to 155.1 S-DDD/m/d.

The consumption of each opioid drug during the 13year period The consumption of strong opioids increased during the 13year period between 2002 and 2014. The consumption of morphine (þ121.7%) and fentanyl (þ119.8%) steadily increased, and of pethidine decreased (41.2%; Fig. 2A). The changes in the consumption of weak opioids during 2002e2014 by category were: total consumption decreased (44.4%) based on the decreasing usage of codeine (73.0%; Fig. 2B). Buprenorphine consumption markedly increased (þ1153.8%) and surpassed codeine consumption in 2014. However, codeine consumption for pain relief was stable (þ2.0%).

Comparisons the total opioid consumption between Taiwan and other regions The North America region (10,814 S-DDD/m/d) consistently had the highest total opioid consumption of all

Please cite this article in press as: Kang K-H, et al., Trends in major opioid analgesic consumption in Taiwan, 2002e2014, Journal of the Formosan Medical Association (2016), http://dx.doi.org/10.1016/j.jfma.2016.09.004

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Opioid consumption in Taiwan 2002e2014

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regions, and Africa (33 S-DDD/m/d) most frequently had the lowest consumption (Fig. 3). Total opioid consumption in Taiwan exceeded that of South America (154 S-DDD/m/ d), Asia (154 S-DDD/m/d), and Central America (60 S-DDD/ m/d) and was second to that of North America, Oceania (9022 S-DDD/m/d), and Europe (6379 S-DDD/m/d) during this period. The average consumption in Taiwan’s three Asian neighbors was higher only in Japan (1070 S-DDD/m/ d in Japan vs. 846 S-DDD/m/d in Taiwan). Average consumption in Hong Kong (183 S-DDD/m/d) and China (83 SDDD/m/d) was much lower than in Taiwan (Fig. 4A). Interestingly, weak opioid consumption in Taiwan (149 SDDD/m/d) was much higher than that in Japan (48 S-DDD/ m/d). Furthermore, there were clear differences in the amounts of strong opioids consumed in these four Asian countries (Fig. 4B). Fentanyl consumption in Japan (951 SDDD/m/d) was much higher than that in Taiwan (474 SDDD/m/d), Hong Kong (63 S-DDD/m/d), and China (48 SDDD/m/d). However, morphine consumption was highest in Taiwan (205 S-DDD/m/d), more moderate in Japan (68 S-DDD/m/d) and Hong Kong (92 S-DDD/m/d), and much lower in China (25 S-DDD/m/d). Pethidine consumption was small significantly lower than that of morphine and fentanyl (Fig. 4B). Buprenorphine consumption was significantly higher in Taiwan than in its three Asian neighbors, as was codeine consumption (Fig. 4C).

Discussion We found that the total consumption of five major opioid analgesicsdmorphine, fentanyl, and pethidine: all strong, and codeine and buprenorphine: both weakdin Taiwan

Figure 1 Number of defined daily doses for statistical purposes per million inhabitants per day (S-DDD/m/d) for total opioid consumption in Taiwan 2002e2014. Note that the total consumption of opioid analgesics was markedly increased based on an increase in the consumption of strong morphine during examined period.

markedly increased between 2002 and 2014. Although the consumption of strong opioids steadily rose during this 13year period, the consumption of weak opioids fell. Morphine, fentanyl, and buprenorphine markedly rose, but the consumption of codeine and pethidine markedly fell. Morphine is used for anesthesia and moderate pain, especially cancer pain. After the WHO published the first edition of Cancer Pain Relief,2 morphine consumption dramatically increased worldwide.12 From 2002 to 2012, morphine consumption increased by about 3% to 14% per annum;

Table 2 Opioid consumption in defined daily doses for statistical purposes per million inhabitants per day from the Taiwan Food and Drug Administration Controlled Drugs Management Information System database.

Morphine Oral Parenteral Fentanyl Transdermal Parenteral Pethidine Oral Parenteral Buprenorphine Sublingual (low dose) Parenteral Substitution treatment a Codeine Oral Parenteral For pain relief Total

b

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

94.8 42.7 52.1 231.7 212.3 19.4 25.5 2.7 22.8 6.5 6.4

103.6 47.4 56.2 295.2 273.0 22.2 25.6 3.0 22.6 7.9 7.6

115.5 51.5 64.0 313.1 286.9 26.2 25.6 2.4 23.2 9.4 8.9

132.5 58.4 74.1 311.0 283.0 28.0 23.6 1.6 22.0 8.2 7.4

150.8 69.0 81.8 325.8 294.6 31.2 22.8 1.2 21.6 9.8 8.9

164.6 75.9 88.7 337.9 301.6 36.3 23.0 1.2 21.8 11.8 11.1

169.6 80.8 88.8 364.9 323.5 41.4 22.4 1.1 21.3 11.7 10.8

183.5 86.8 96.7 560.6 513.3 47.3 22.4 0.9 21.5 13.3 11.7

191.4 91.5 99.9 600.1 547.7 52.4 21.7 1.1 20.6 19.9 11.2

197.0 97.5 99.5 454.1 393.4 60.7 19.4 1.0 18.4 39.3 12.3

208.4 101.4 107.0 474.8 410.1 64.7 17.7 1.0 16.7 56.8 11.1

209.7 103.4 106.3 491.4 423.6 67.8 16.5 0.9 15.6 71.9 9.0

210.2 102.4 107.8 509.2 433.1 76.1 15 0.7 14.3 81.5 7.8

0.1 d

0.3 d

0.5 d

0.8 d

0.9 d

0.7 d

0.9 d

1.3 0.3

1.1 7.6

0.8 26.2

1.0 44.7

1.4 61.5

1.3 72.4

272.7 272.0 0.7 35.4 631.2

229.8 229.1 0.7 36.2 662.1

203.7 202.9 0.8 38.1 667.3

188.6 187.8 0.8 40.5 663.9

150.6 149.7 0.9 41.2 659.8

140.8 139.9 0.9 39.2 678.1

122.0 121.1 0.9 39.2 690.6

112.3 111.3 1.0 38.0 892.1

102.3 101.3 1.0 37.4 935.4

104.9 103.8 1.1 38.3 814.7

94.0 93.0 1.0 38.4 851.7

81.5 80.5 1.0 36.1 871.0

73.6 72.5 1.1 36.1 889.5

a Only 2-mg and 8-mg buprenorphine sublingual tablets (with naloxone), all of which are used as a substitute for heroin in maintenance programs. b Only 15-mg and 30-mg codeine tablets and 15-mg codeine injections, all of which are used primarily to relieve pain.

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Figure 3 The total consumption of the opioid analgesics in all world regions and Taiwan 2011e2013. Note that the average opioids consumption in Taiwan was much higher than that in Asian region but lower than that western countries.

Figure 2 The consumption of selected strong and weak opioids in Taiwan 2002e2014. (A) Strong opioid analgesics are morphine, fentanyl, and pethidine. (B) Weak opioid analgesics are buprenorphine and codeine.

however, it was stable from 2012 to 2014 (annual increases: 0.6% and 0.2%, respectively). This might be attributable to a greater choice of new opioid analgesics, formulations of fentanyl in Taiwan.13 Fentanyl is more potent than morphine and has fewer side effects.14 Fentanyl consumption doubled between 2002 and 2014; however, transdermal fentanyl (fentanyl patches) consumption was much higher than was parenteral consumption. This might be because many elderly patients in pain are not given adequate analgesia at the end of life.15e17 Some doctors avoid prescribing morphine and use transdermal fentanyl, particularly for those who are frail and unable to take oral morphine.18 Fentanyl consumption markedly increased in 2009 because the TFDA introduced two new fentanyl formulations (25 mg/g/h and 50 mg/g/h) that year. In contrast, the consumption of pethidine in Taiwan has decreased. Pethidine is a synthetic opioid analgesic metabolized in the liver by N-demethylation to normeperidine. It has been widely used to relieve pain and to control postanesthetic shivering.19 However, normeperidine has a long half-life and it easily accumulates in the body and causes adverse effects, such as tremors, mydriasis, and, eventually, even seizures.20 Thus, pethidine is not recommended as a first choice analgesic by The American Pain

Society and The Institute for Safe Medication Practice.21,22 The clinical use of pethidine should be limited to patients allergic to or unable to otherwise tolerate all other opioid drugs.23 In addition, in September 2011, the TFDA’s Guidelines on Clinical Use of pethidine came into force to educate physicians on how to use pethidine safely. Thus, the consumption of pethidine in Taiwan had continuously fallen from 21.7 S-DDD/m/d in 2010 to 15 S-DDD/m/d in 2014 down 30.88%. The only strong opioid analgesic with a decline in total consumption between 2002 and 2014 was pethidine. This might indicate that physicians now consider pethidine a second-line agent for treating severe pain. Buprenorphine is not a typical weak opioid analgesic.24 It is a partial m-opioid receptor agonist with low intrinsic activity and high receptor affinity.25 Strain et al26 reported that patients can safely tolerate doses of buprenorphine substantially higher than their usual maintenance dose. Although the mechanism is still unclear, buprenorphine has a ceiling effect for respiratory depression, and the respiratory rate of patients treated with high-dose buprenorphine rarely drops below 50% of the baseline.27 Moreover, buprenorphine is an effective cancer pain reliever that has fewer side-effects than do other analgesics, such as tramadol.28 In their systematic review, Zedler et al29 indicated that using buprenorphine to treat pregnant women with opioid-use disorder was much safer than was using methadone. Consequently, the safety of buprenorphine is even greater in opioid-tolerant patients. In Taiwan, buprenorphine is used to treat pain and opioid addiction. The marked increase in its consumption is because buprenorphine began to be used as a substitute treatment for heroin beginning in 2009. Methadone can also be used for substitute treatment. However, opioiddependent patients are required to take methadone in

Please cite this article in press as: Kang K-H, et al., Trends in major opioid analgesic consumption in Taiwan, 2002e2014, Journal of the Formosan Medical Association (2016), http://dx.doi.org/10.1016/j.jfma.2016.09.004

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Opioid consumption in Taiwan 2002e2014

Figure 4 Comparing the consumption of opioids of Taiwan and Pan-Asian neighboring countries 2011e2013. (A) Total opioids consumption; (B) selected strong opioids; (C) selected weak opioids.

medical institutions with the approval of the central competent health authority. Because of buprenorphine’s pharmacological and safety profile, it can be prescribed for home use.30 Taking sublingual buprenorphine is an attractive treatment for opioid-dependent patients and substantially more convenient than methadone treatment. This is one possible reason that buprenorphine treatment in Taiwan surpassed codeine consumption in 2014. Codeine is a weak opioid analgesic, low doses of which are used to treat cough. The total consumption of codeine fell between 2002 and 2014. Furthermore, codeine syrups and low-dose codeine tablets and capsules are not for pain

5 relief. After excluding these formulations, codeine consumption was stable in Taiwan. Other study indicates that the physicians in Taiwan have prescribed codeine conservatively and used nonopioid analgesics directly or other strong opioid analgesics instead.31,32 The latest published study reported that the WHO guidelines for cancer pain relief recommended three-step ladder-use analgesics33; however, the current pain guidelines of the National Comprehensive Cancer Network, European Society of Medical Oncology, and European Association of Palliative Care suggested using twostep opioids. These guidelines recommended that physicians prescribe short-acting low-dose strong opioids instead of weak opioids for cancer pain management.33 This study also reported that tramadol, not codeine, was the weak opioid, with which most cancer pain patients in Taiwan are treated.33 Taken together, these factors caused the growth of codeine consumption to stagnate. The total consumption of morphine, fentanyl, pethidine, codeine, and buprenorphine in Asia between 2011 and 2013 was lower than that in North America, Oceania, Europe, and South America but higher than that in central America and Africa.5 Lower opioid consumption might be the result of economic problems,5 fear of addiction or diversion of opioids,5,34 different cultural values about using opioids,12,35 or physician reluctance to prescribe opioids and insufficient training.5,34e37 Opioids may cause dependence, but they are essential for pain relief. Scholten34 recently claimed that Asia is conservative about using opioids because of the Opium Wars in the 1840s. Opioid consumption in Taiwan today is much higher than that in the rest of Asia, but it is still far from adequate and some weak points of opioid use require change.33,34 This means that there is still room to improve treatment for pain in Taiwan. Healthcare professionals should educate the public and help them establish the correct model of opioids use. A joint effort by government, healthcare professionals, and all of Taiwan’s citizens and legal residents is required to solve the problem of proper treatments to relieve pain, especially in patients with cancer. In Japan and Taiwan, the two most developed Asian countries, opioid consumption levels are inadequate.34,38 The average total consumption of opioids in Taiwan between 2011 and 2013 was lower than that in Japan but higher than that in Hong Kong and China. However, morphine consumption in Taiwan was higher than that in Japan. Studies have reported that the use of transdermal fentanyl has increased in developed countries and that it has changed opioid prescription patterns for pain management.18,24,39 In addition, the national health insurance system in Japan supports caregivers at home for the elderly.40 Thus, everyone in Japan should have access to effective and convenient pain management because physicians prescribe transdermal fentanyl instead of morphine.41 Conversely, the consumption of weak opioids in Taiwan between 2011 and 2013 was much higher than that in Japan. Japanese traditional culture emphasizes stoicism, which might induce some Japanese to accept chronic pain.42,43 If the pain is not severe, people often like to conceal both their physical pain and their emotions, which appears to lead to the low level of consumption of weak opioid analgesics in Japan. In conclusion, total opioid consumption steadily increased in Taiwan between 2002 and 2014; nevertheless, it was much

Please cite this article in press as: Kang K-H, et al., Trends in major opioid analgesic consumption in Taiwan, 2002e2014, Journal of the Formosan Medical Association (2016), http://dx.doi.org/10.1016/j.jfma.2016.09.004

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6 lower than that in developed western countries. Because Taiwan, like most of the rest of the world, is rapidly becoming an aging society, the number of people with chronic pain and cancer pain are bound to increase. This means that there will be a greater demand for opioid analgesics in our country. The use of opioid analgesics is conservative in Taiwan. The country’s controlled drugs policy is well established and the availability of opioid analgesics has much improved. More effort is needed to strengthen education programs on the adequate use of opioids for pain management. To promote the most efficient use of opioid analgesics for treating pain, nonprofit organizations, medical associations, and hospital controlled drugs management committees can provide continuing education and improve health professional knowledge for the most efficient use of opioid drugs on pain management. All Taiwanese nationals should be educated about opioid analgesics through the media or forums provided by related health professionals. They need to understand that even though opioid analgesics are probably addictive, using them probably to palliate chronic pain will greatly improve the quality of life for many patients. To provide more options for the treatment of pain relief, the TFDA has continuously introduced new types and new formulations of opioid analgesics, such as prolonged-release hydromorphone hydrochloride, buccal soluble fentanyl, and oxycodone. We believe that if physicians are well-educated in the proper use of opioid analgesics, the quality of pain management in Taiwan will continue to improve.

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Please cite this article in press as: Kang K-H, et al., Trends in major opioid analgesic consumption in Taiwan, 2002e2014, Journal of the Formosan Medical Association (2016), http://dx.doi.org/10.1016/j.jfma.2016.09.004