Study on Use of Non-Steroidal Anti-Inflammatory Drugs (Nsaids) in Chikugo City Hospital with a View to Promoting Rational Drug Use (1)

224 医療薬学 Vol.30, No.3 (2004)

Jpn. J. Pharm. Health Care Sci.

ノート30(3)224-230 (2004)

Study on Use of Non-steroidal Anti-inflammatory Drugs (NSAIDs) in Chikugo City Hospital with a View to Promoting Rational Drug Use (1)

Hideaki Kido1, Yen Sun1, Kumiko Takaba1, Mihoko Nakashima1, Mitsuhiro Wada1, Takashi Kawada2, Hiizu Hara2 and Kenichiro Nakashima*1 Course of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University1 Chikugo City Hospital2

Received June 9, 2003 〔Accepted December 20, 2003 〕

During the period March 2000-February 2001, we conducted a study on prescriptions to determine how non-steroidal anti-inflammatory drugs (NSAIDs) were being used in Chikugo City Hospital, a medium-sized hospital, in order to promote rational drug use. The use of NSAIDs was evaluated for 10 clinical departments, together and individually. We found that Diclofenac (DIC) and sodium loxoprofen were used to about the same extent in almost all departments and that Aceta- minophen (ACE) was also prescribed as frequently as DIC. Except for ACE, no NSAIDs were used for children, particularly in the case of those under 9 years in age. We also evaluated the co-prescription of NSAIDs with H2-receptor antagonists because NSAIDs are known to cause gastric adverse reactions. The number of patients who had been prescribed H2- receptor antagonists increased with patient age, especially for those over fifty years old. Zaltprofen was more frequently co- prescribed with H2-receptor antagonists than other NSAIDs. The prescription of etodolac was also found to increase with patient age, particularly so for those over fifty. Thus, we consider that information obtained by studying prescriptions can be used to evaluate the intentions of those prescribing drugs and clarify problems in the use of NSAIDs.

Key words- non-steroidal anti-inflammatory drugs (NSAIDs), prescription research, rational use of drugs, drug-drug interaction

PGs 8). Although COX-2 inhibitors that can inhibit only the formation of PGs being responsible for pain and inflamma- Introduction tion are required, there is no drug that can completely in- Non-steroidal anti-inflammatory drugs (NSAIDs), which hibit only COX-2. have several effects as analgesic, anti-inflammatory and anti- Recently, it has become very important to consider "ra- pyretic, are frequently and widely used clinically1). They are tional use of drug" due to the increase in interests of people actually prescribed for rheumatoid arthritis, osteoarthritis and in medical and health cares. The appropriate use of NSAIDs ankylosing spondylitis, moderate to heavy pains such as for controlling pain may be very difficult, since medical shoulder pain, menstrual pain and cramps. These pharma- providers have trouble in understanding pain rating scale for cological actions can be demonstrated by inhibiting cycloo- patients. The rating scales have been utilized to assess the xygenase (COX) activity and the following decrease of pros- pain levels of patients by many practitioners9). Other factors taglandins (PGs) biosynthesis at the site of inflammation2). for choice of NSAIDs are as follows : safety, gastrointestinal Recent studies have shown that COX has two isoenzyme pathology of the patients, whether the sickness is acute or forms, i.e. COX-1 and COX-23,4). The former protects the chronic process, and according to the type of inflammatory stomach lining and intestine, and the latter is related to the process of patients10). It is known that gastric disorder is the PGs formation in the inflammation process5-7). The main most frequent side effect of the NSAIDs. Thus, the appear- NSAID's side effect is recognized to be gastric disorders ance of a side effect is one of the most important factors to such as gastric ulcer and duodenal ulcer, which are caused evaluate the use of NSAIDs. Moreover, we have to consider by inhibiting COX-1 with a loss of local protective effects drug-drug interactions when NSAIDs are prescribed together of gastric mucosal cells and decreasing biosynthesis of with other drugs. As there are several types of pain, pre-

1 長崎市文教町1-14; 1-14, Bunkyo-machi, Nagasaki-shi, 852-8521 Japan 2 福岡県筑後市大字和泉917-1; 917-1, Izumi, Chikugo-shi, Fukuoka, 833-0041 Japan 医療薬学 Vol.30, No.3 (2004) 225

scriptions of analgesic drugs with NSAIDs are frequently Table 1. Standard Dosage of NSAIDs. performed. Therefore, to know these interactions, monitoring of NSAIDs concentrations in blood is required. For this purpose, a high-performance liquid chromatography (HPLC) method is recommended. In our previous study, the simultaneous determination ofarylpropionic acid derivatives, a group of NSAIDs, in human plasma was developed11).

On the other hands, it is considered that a prescription re-

search can give a significant information to a rational use of drugs. Recently, Butatsu et al. have been reported the analy-

sis using prescription database for urate-lowering drugs and antiarteriosclerotic agents, and successfully evaluated the rational use of drugs12'13). Thereupon, we attempted to survey how NSAIDs is actually used for considering the rational use of NSAIDs and drug-drug interaction of NSAIDs. Results and Discussions In this paper, a preliminary research to evaluate the use of

NSAIDs in Chikugo City Hospital for a year (March 2000•` 1. NSAIDs used in each clinical section

February 2001) is described by surveying the following ele- As shown in Fig. 1 A, DIC (30%) and LOX (29 %) were ments : 1) the practical use of NSAIDs at all or each of 10 used the most in the total amounts of NSAIDs that pre- clinical sections, 2) the practical use of NSAIDs on each scribed in all sections. The reason for this is that DIC has disorder in the special clinical section (orthopedics), 3) the many different product forms such as suppository, tablets prescription of NSAIDs with H2-receptor antagonists in or- and long-acting capsule. These product forms are adopted in thopedics. Chikugo City Hospital and the percentages for suppository, tablets and long-acting capsule were 42.7, 19.3 and 38.0%, respectively. LOX, a representative propionic acid derivative Method in NSAIDs is also prescribed very often, because it has mo-

The use of NSAIDs prescribed in Chikugo City Hospital derate anti-inflammation, analgesic, and antipyretic effects from March 2000 to February 2001 is studied by using the and shows only few side effects14'15). On the other hand, data from computer for demanding clinical fees (about 2000 ACE (30%) and DIC (27%) were most frequently pre- prescriptions) to patients. This hospital has 220 beds and scribed (Fig. 1 B). Though, ACE was used most frequently consists of 10 clinical sections such as orthopedics, medi- in pediatrics, the quantity of the standard dosage adminis- cine, surgery, pediatrics, rhinolarygology, urinology, ophtha- tered to child per dose was small. lmology, brain surgery, gynecotokology and actinogenics. The total amounts of NSAIDs prescribed to outpatients

Nine NSAIDs investigated in this study were sodium diclo- were largest in the orthopedics section (Fig. 2). In this sec- fenac (DIC), ampiroxicam (AMP), mefenamic acid (MEF) tion, the main symptom complained by outpatients was their etodolac (ETO), zaltprofen (ZAL), sodium loxoprofen (LOX), pain. LOX having few side effects and DIC in several pro-

oxaprozin (OXA), tiaramide hydrochloride (TIA) and aceta- duct forms were prescribed in most in this hospital. The ad- minophen (ACE). vantage of the use of DIC is its strong and rapid analgesic

Firstly, the use of NSAIDs prescribed for outpatients at all effect, and thus, this drug is suitable for acute pain16). Vari-

and each individual clinical section was investigated. Subse- ous prescriptions can be designed on a case-by-case and se-

quently, we focused on the use of NSAIDs prescribed in or- lected sustained-release form to avoid gastrointestinal disor- thopedics, especially rheumatoid arthritis, gout, herniated nu- der, and many other product forms have been released. cleus pulposis of the lumbar spine, osteoarthritis of the knee, ETO, a selective inhibitor of COX-2, has been prescribed to sciatic pain, lumbar spinal canal stenosis and osteoporosis. patients who need a long-term use due to a chronic pain. In Moreover, the use of NSAIDs prescribed with H2-receptor the medical section, ETO with few gastric side effects was antagonists in orthopedics was also examined. The particular prescribed to patients who have gastrointestinal disorder H2-receptor antagonists in this research were famotidine, risks caused by NSAIDs. The prescription frequencies of ranitidine and nizatidine. NSAIDs separated by age are shown in Fig. 3. In the under

The data were presented as frequency of prescription and 19 years old groups, ACE was mostly prescribed for outpa- total amounts of the NSAIDs. NSAIDs have several dosage tients. No NSAIDs, except for ACE, were used for children and product forms, such as tablets, capsules and supposito- especially in the under 9 years old group. Though ACE is ries. The amounts of NSAIDs were summarized up in every not included in NSAIDs, it has the same effects with them. prescription, and then, divided by the standard dosage ad- Owing to the safety consideration, ACE was frequently used ministered to adult per dose. Table 1 shows the standard for children in pediatrics to reduce sudden fever17). These dosages of NSAIDs, which were used for the conversion in demonstrate that the prescription was planned to reduce the this study. side effect of NSAIDs in case of these drugs use. In this re- 226 医療薬学 Vol.30, No.3 (2004)

(A) (B)

Fig. 1. Total Amounts (A) and Prescription Frequency (B) of NSAIDs for Chikugo City Hospital. NSAIDs, DIC : diclofenac sodium, LOX : loxoprofen sodium, MEF : mefenamic acid, ETO : etodolac, OXA : oxaprozin, AMP : ampiroxicam, ZAL : zaltprofen, ACE : acetaminophen, TIA : tiaramide hydrochloride.

Fig. 2. Kinds and Total Amounts of NSAIDs Used in Clinical Sections. NSAIDs, DIC : diclofenac sodium, LOX : loxoprofen sodium, MEF : mefenamic acid, ETO : etodolac, OXA : oxaprozin, AMP : ampiroxicam, ZAL : zaltprofen, ACE : acetaminophen, TIA : tiaramide hydrochloride.

search, thus, the appropriateness of NSAIDs using in pediat- ages of NSAIDs prescribed for each disease such as rheuma- rics was presumed in the Chikugo City Hospital. toid arthritis, gout, herniated nucleus pulposis of the lumbar

spine, osteoarthritis of the knee, sciatic pain, lumbar spinal

2. NSAIDs prescribed for disorders in orthopedics canal stenosis and osteoporosis are shown in Fig. 4. The

When one considers NSAIDs use, the basic understanding percentage of outpatients prescribed NSAIDs in this section of the situation and choice of drug is essential. With respect was about 28%. Among the diseases, sciatic pain, gout, her- to the amounts of NSAIDs prescribed in each clinical sec- niated nucleus pulposis and rheumatoid arthritis showed tion, the choice of NSAIDs was affected by the characteris- comparable and high percentages (•¬40%) of NSAIDs pre- tics of the drugs and patient's disorders. The details of scription. When prescribers in orthopedics use NSAIDs, con- NSAIDs used in orthopedics were examined. The percent- trol of pains and inflammations should be considered18). In 医療薬学 Vol.30, No.3 (2004) 227

Fig. 3. Prescription Frequency of NSAIDs in Each Age for Chikugo City Hospital. NSAIDs, DIC : diclofenac sodium, LOX : loxoprofen sodium, MEF : mefenamic acid, ETO : etodolac, OXA : oxaprozin, AMP : ampiroxicam, ZAL : zaltprofen, ACE : acetaminophen, TIA : tiaramide hydrochloride.

Fig. 4. Prescribing Percentage of NSAIDs for Disorders in Orthopedics. NSAIDs contain DIC, LOX, MEF, ETO, OXA, AMP, ZAL, ACE and TIA.

the case of lumbago, the treatment of NSAIDs and patient' s NSAIDs to weaker ones with decreasing patient' s pain and rest are important, and thus, the percentage of NSAIDs used start to increase bone density. here is high. Because the initial symptom of this disease is a Rheumatoid arthritis, an autoimmune disease of inflamed strong pain, NSAIDs with a strong analgesic effect are pre- joints, shows swelling, pain, and often with eventual de- ferable. Generally, NSAIDs having moderate analgesic ef- struction of the joint's interior. At first, small joints in the fects should be selected for patient with lesser pain. fingers, toes, hands, feet, wrists, elbows, and ankles become For osteoporosis, the percentage of NSAIDs used in this inflamed. Inflamed joints appear as pain and stiffness. In group is more than 20% ; this disorder progresses with de- this section, NSAIDs were prescribed in high frequency creasing the bone density, and finally results in bone fracture (about 40%) for rheumatoid arthritis. Corticosteroids, im- which causes pain. Treatment of osteoporosis requires some munosuppressives and/or NSAIDs were also administered factors which should be considered to control patient' s pain, for treatment of rheumatoid arthritis. The pain and swelling e.g., several hormones, active vitamin D and NSAIDs. Pre- in the affected joints are alleviated by NSAIDs. However, scribers have to gradually change the strong analgesic patients sometimes need to be administrated the drugs in a 228 医療薬学 Vol.30. No.3 (2004)

Fig. 5. Percentage of NSAIDs Prescribed with H2-receptor Antagonists in Orthopedics. NSAIDs, DIC : diclofenac sodium, LOX : loxoprofen sodium, ETO : etodolac, OXA oxaprozin, AMP : ampiroxicam, ZAL zaltprofen. H2-blocker contain famotidine, ranitidine and nizatidine.

Fig. 6. Prescription Frequency of NSAIDs with H2-receptor Antagonists in Each Age. H2-blockers contain famotidine, ranitidine and nizatidine.

long term. Therefore, the frequency appearance of side ef- pearance of gastric and duodenal ulcers, and ranitidine fects such as gastrointestinal complications by the use of seems to be effective in preventing duodenal ulcers20). NSAIDs is expected to be high. Serious gastrointestinal NSAIDs should not be prescribed to the patients with risk of complications may result from NSAIDs including perfora- gastrointestinal disease because of their side effects. The tion, obstruction and hemorrhage of gastric and duodenalul- percentages of NSAIDs with H2-receptor antagonists pre- cers19). Prescribers have to watch out the side effects of scribed in orthopedics were shown in Fig. 5. Four kinds of NSAIDs, when they prescribe NSAIDs to patients with NSAIDs, i.e ., LOX (1.7%), DIC (2.0%), ZAL (3.9%) and rheumatoid arthritis. ETO (2.2%), were prescribed with H2-receptor antagonists. Therefore, NSAIDs should be selected according to the The total percentage of the prescription for NSAIDs with symptom of disorders or characteristic of drugs such as low H2-blockers is about 1.2%. As the result few patients may side effects, length of activity and analgesic strength. have risk of gastrointestinal complication with the NSAIDs prescription. Therefore, patients having chronic pain with no 3. The NSAIDs prescribed with H2-receptor antagonists in gastric disorders may be prescribed this drug for long peri- orthopedics ods. The prescriptions of NSAIDs with H2-receptor antago- The use of NSAIDs prescribed with H2-receptor antagonists in each age were examined (Fig. 6). The patients who nists was examined. Famotidine is effective for reducing ap- have been prescribed NSAIDs with H2-receptor antagonists 医療薬学 Vol.30, No.3 (2004) 229

Fig. 7. Number of Patients for Disease of Digestive System in Each Age. Diseases of digestive system contain gastric ulcer, duodenal ulcer and reflux esophagitis.

increased with increase in outpatients' ages, especially in and in this case, the purpose of NSAIDs prescription is for over fifty years old. The percentage of LOX, DIC, ETO and anti-inflammatoric effect of the tissue. Therefore, neither ZAL with H2-receptor antagonists prescribed in over fifty NSAIDs nor morphine may not obtain sufficient efficacy. years old were 6.9, 6.9, 7.1 and 20.0%, respectively. Since The interaction between NSAIDs and morphine based on the the percentage of ZAL with H2-receptor antagonists ex- data obtained from a prescription research is under way. We tremely increased, this information should be fed back to consider that a prescription research can be of powerful as- prescriber when NSAIDs are prescribed to the patients over sistance to a rational use of drugs. fifty years old. Fig. 7 showed the number of patients for disease of digestive system such as gastric ulcer, duodenal ul- References cer and reflux esophagitis in each age in the Chikugo City hospital. The patients who have been prescribed NSAIDs 1) R. Polisson, Nonsteroidal anti-inflammatory drugs: with H2-receptor antagonists increased with a similar pattern practical and theoretical considerations in their selec- for patients diagnosed as diseases of the digestive system. tion, Am. J. Med., 100, 31-36(1996). A good relationship between the number of patients for dis- 2) J.R. Vane, Inhibition of prostaglandin synthesis as a ease of the digestive system and the percentage of NSAIDs mechanism of action for aspirin-like drugs, Nature. with H2-receptor antagonists prescribed in the orthopedics New. Biol., 231, 232-235(1971). was observed (r=0.969). This result suggested that the age- 3) W. Xie, J.G. Chipman, D.L. Robertson, R.L. Erikson, ing was one of the main factors for increasing percentages D.L. Simmons, Expression of a mitgen-resposive gene of NSAIDs prescribed with H2-receptor antagonists. Increas- encoding prostagrandin synthasis is regurated by ing of the prescription frequency of ETO to the aged pa- mRNA splicing, Proc. Natl. Acsd. Sci. USA., 88, 2692- tients might be taken into consideration (shown in Fig. 6), 2696(1991). because as described above, ETO is a selective COX-2 in- 4) D.A. Kujubu, B.S. Fletcher, B.C. Varnum, R.W. Lim, hibitor and has small effects for gastrointestinal homeostasis. H.R. Herschman, TIS 10, a phorbol ester tumor Some other drugs prescribed for gastric disorders are pro- promoter-inducible mRNA from Swiss 3 T 3 cells, en- ton pump inhibitor and misoprostrol, which might be used to codes a novel prostagrandin synthase 1-cyclooxygenase prevent gastric ulcers caused by NSAIDs. For the next step, homologue, J. Biol. Chem., 266, 12866-12872(1991). the prescription of these drugs with NSAIDs should be ex- 5) S. Kawai, Cyclooxygenase selectively and the risk of amined. gastro-intestial complications of various non-steroidal In conclusion, the practical use of NSAIDs in Chikugo anti-inflammatory drugs : A clinical considerations, In- City Hospital, a medium size hospital, has been clarified in flammation Res., 47, 102-106(1998). this study. The informations obtained here can be fed back 6) J.L. Masferrer, B.S. Zweifel, P.T. Mnning, S.D. Hauser, to prescribers. Considering this point, a prescription research K.M. Leahy, W.G. Smith, Selective inhibition of induc- is useful for the evaluation of practical use of drugs. More- ible cyclooxygenase-2 in vivo is anti-inflammatory and over, practical knowledges of drug use might be helpful to nonulcerogenic, Proc. Natl. Acad. Sci. USA., 91, 3228- study a drug-drug interaction. For instance, morphine, an 3232(1994). opioid receptor agonist, is used in cancer pain with NSAIDs, 230 医療薬学 Vol.30, No.3 (2004)

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