First-Trimester Maternal Alcohol Consumption and the Risk of Infant Oral Clefts in Norway: A Population-based Case-Control Study

             Lisa A. DeRoo 1, Allen J. Wilcox 1, Christian A. Drevon 2, and Rolv Terje Lie 3,4

Although alcohol is a recognized teratogen, evidence is limited on alcohol intake and oral cleft risk. The authors examined the association between maternal alcohol consumption and oral clefts in a national, population-based case-control study of infants born in 1996–2001 in Norway. Participants were 377 infants with cleft lip with or without cleft palate, 196 with cleft palate only, and 763 controls. Mothers reported first-trimester alcohol consumption in self-administered questionnaires completed within a few months after delivery. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusting for confounders. Compared with nondrinkers, women who reported binge-level drinking (>5 drinks per sitting) were more likely to have an infant with cleft lip with or without cleft palate (odds ratio ¼ 2.2, 95% confidence interval: 1.1, 4.2) and cleft palate only (odds ratio ¼ 2.6, 95% confidence interval: 1.2, 5.6). Odds ratios were higher among women who binged on three or more occasions: odds ratio ¼ 3.2 for cleft lip with or without cleft palate (95% confidence interval: 1.0, 10.2) and odds ratio ¼ 3.0 for cleft palate only (95% confidence interval: 0.7, 13.0). Maternal binge-level drinking may increase the risk of infant clefts.

alcohol drinking; cleft lip; cleft palate

        Alcohol is a human teratogen that produces a range of effects depending on the timing of exposure and the amount of alcohol consumed (1). One of the best-described and most severe outcomes of heavy maternal drinking is fetal alcohol syndrome, characterized by a specific pattern of craniofacial malformations, prenatal and postnatal growth retardation, and central nervous system disorders (2). It is less clear that women’s alcohol consumption during pregnancy is related to individual congenital malformations such as oral clefts (3). Cleft lip with or without cleft palate occurs in about 9–18 percent of infants with fetal alcohol syndrome but is not diagnostic of the syndrome (4).

         Some evidence exists that women who drink alcohol during pregnancy are more likely than nondrinkers to have infants with facial clefts (5–8), but summarizing previous findings is hampered by different categories of drinks and time points of reference across studies. Few studies have examined binge-level drinking (7–10), usually defined as the consumption of five or more drinks per sitting (11). Maternal drinking is uncommon in some populations, and the small numbers of exposed women in many studies have made it difficult to assess this association.

        In Norway and other Nordic countries,weekend binge drinking is a common pattern of alcohol consumption (12, 13).In a population-based survey, 25 percent of Norwegian women reported at least one binge drinking episode during early pregnancy (14). We examined the relation between maternal alcohol consumption, including binge-level drinking,and infant oral clefts in Norway by using a populationbased

case-control study.

MATERIALS AND METHODS

       Eligible cases were all newborn infants with orofacial cleft defects born in Norway in May 1996 to October 2001 and referred for surgical treatment. In Norway, all surgery for clefts is paid for by the government and takes place at one of two surgical centers (Oslo and Bergen). An infant with a cleft is routinely referred for surgery shortly after birth. Our study office was notified of all referrals, at which time a letter of invitation was sent to the family. We randomly selected controls (with a probability of about 4 per 1,000) from all livebirths recorded in the Medical Birth Registry of Norway from September 1996 to April 2001. Families of selected controls were mailed an invitation to participate. These infants served as controls for both cleft case groups, with control-case ratios of about 2:1 for cleft lip with or without cleft palate and 4:1 for cleft palate. Study materials were in Norwegian; mothers who did not speak Norwegian were excluded. The study was approved by the Norwegian Data Inspectorate, the Regional Medical Ethics Committee ofWestern Norway, and the Institutional Review Board of the US National Institute of Environmental Health Sciences. Parents provided informed consent.

     Mothers completed a self-administered, mailed questionnaire on demographic characteristics, medical history, family history of clefts, cigarette smoking, alcohol consumption, and other exposures during pregnancy. Questions pertaining to maternal exposures and diet were asked specifically for the first 3 months of  regnancy, the relevant exposure period for early facial development. During this time period, the structures that form the embryonic lip and palate fuse: closure of the lip occurs during weeks 5 and 6 postconception,

followed by closure of the palatal shelves during weeks 7–10 (15). Median time from the infant’s delivery to the mother’s completion of the main questionnaire was 14 weeks for cases and 15 weeks for controls. After returning the main questionnaire, mothers completed a quantitative food frequency questionnaire (16–18) on dietary habits during the first 3 months of pregnancy, including the types of alcoholic beverages (beer, wine, and liquor) consumed. The study questionnaires (with English translations) are available online at http://www.niehs.nih.gov/research/atniehs/labs/epi/studies/ncl/question.cfm.

       Information on noncleft birth defects was collected from three sources: the mother’s questionnaire, the infant’s medical records at the time of cleft repair surgery, and the Medical Birth Registry, which contains information from the infant’s delivery records and hospital records during the first week of life. Cases with any accompanying birth defect or syndrome were categorized as nonisolated.

       Information on maternal alcohol consumption was collected for the first 3 months of pregnancy and the time period before the pregnancy. Mothers were asked to recall the average number of days per week or month they drank alcohol, and the average number of drinks consumed on each occasion. Total number of drinking days in the first trimester was estimated by extrapolating weekly or monthly drinking frequency over the 3-month period. Total number of alcoholic beverages consumed in the first trimester was estimated by multiplying the total number of drinking days by the average number of drinks per occasion. Categorical variables were used to summarize total drinks (1–3, 4–6, 7), number of drinking days (1–2, 3–6, 7), and average number of drinks per occasion (1, 2–4, 5) in the first trimester. The categories were defined to ensure adequate case numbers within categories and to capture binge-level drinking (defined as an average of 5 drinks per sitting.) An additional categorical variable was used to examine number of drinks and frequency of consumption simultaneously: one to four drinks on one to two occasions, one to four drinks on three or more occasions, five or more drinks on one to two occasions, and five or more drinks on three or more occasions. Nondrinkers served as the referent group for all measures of first-trimester alcohol exposure. We calculated odds ratios and 95 percent confidence intervals for the associations between infant clefts and maternal alcohol consumption. Because cleft outcomes are rare, the odds ratios are close approximations of risk ratios and can be interpreted as such.

       We conducted separate analyses of cleft lip with or without cleft palate, and cleft palate only. We calculated separate estimates for infants with isolated and with nonisolated cleft defects. Multivariable logistic regression models were used to estimate odds ratios adjusted for child’s year of birth, mother’s age group (<25, 25–29, 30–34, 35 years), education (less than high school, high school,technical college, 2–4-year college, university), first-trimester smoking (none; passive only; active, 1–5 cigarettes per day; active, 6–10 cigarettes per day; active, 11 cigarettes per day), household per capita income ( 50,000, 50,001–75,000,

75,001–100,000, 100,001–150,000, 150,001 kroner), and family history of clefts among parents or grandparents (yes/no). Dummy variables were used for variables with more than two levels. Further adjustment for mother’s marital status, parity,employment during the first trimester, folic acid supplement

use, dietary folate, multivitamin use, and prepregnancy body mass index did not substantially change the estimates.

       We explored the possible effect of heavy drinking before the pregnancy by restricting analysis to mothers who drank an average of five or more alcoholic beverages per sitting before pregnancy but reported no drinking during pregnancy. We calculated the risk of infant clefts among these women compared with women who abstained from drinking alcohol both before and during their pregnancies. Pearson chi-square tests were used to compare the percentages of beer, wine, and liquor drinkers among the women who reported an average of five or more drinks per sitting and those who reported four or fewer. To assess possible differences in infant cleft risk by the type(s) of alcohol the mothers consumed, separate multivariable logistic regression models were conducted to examine beer/wine consumption (alone or in combination) and liquor consumption (alone or in combination with beer or wine).

RESULTS

Participants

There were 676 infants referred for orofacial cleft surgery during the study recruitment period (May 1996–October 2001). Excluding 24 mothers who did not speak Norwegian

or whose infants died after birth left 652 eligible mothers of cases. Of these, 573 (88 percent) agreed to participate (377 infants with cleft lip with or without cleft palate, 196 with cleft palate only). A total of 1,022 controls were randomly selected within 6 weeks of their deliveries in September 1996–April 2001. After excluding 16 mothers who did not speak Norwegian or whose infants had died, 1,006 mothers of controls

were eligible, of whom763 (76 percent) agreed to participate.

      Ninety-five percent of mothers were married or living as married (table 1). The mean age of mothers was 29 years,and about 40 percent were primiparous. Thirty percent of mothers of controls reported drinking alcohol during the first trimester, with a median of three drinks total (range,1.5–780 drinks); 3 percent reported binge-level drinking of an average of five or more drinks per occasion. Among the cases, noncleft birth defects were present in 17 percent of infants with cleft lip with or without cleft palate and 40 percent of infants with cleft palate only. The associations between cleft defects and maternal alcohol consumption did not differ substantially by the presence of noncleft defects (appendix table 1), and we therefore present

the results for isolated and nonisolated clefts combined.

Maternal alcohol consumption in the first trimester

       Total drinks and number of drinking days. There were no clear patterns of increased infant cleft risk for categories of total drinks or number of drinking sessions (table 2). Mothers who drank between four and six drinks total were twice as likely as nondrinkers to have an infant with cleft palate (odds ratio ¼ 2.0, 95 percent confidence interval: 1.1, 3.7), but risk declined with seven or more drinks. For both cleft types, odds ratios rose among women who reported 1–2 or 3–6 drinking days, but they decreased among those who

drank on 7 or more days.

       Average drinks per sitting. Women who reported drinking five or more drinks per occasion were more than twice as likely to have an infant with either of the cleft types: for cleft lip with or without cleft palate, odds ratio ¼ 2.2 (95 percent confidence interval: 1.1, 4.2); for cleft palate only, odds ratio¼ 2.6 (95 percent confidence interval: 1.2, 5.6) (table 2). The odds ratios ranged from 1.1 to 1.6 for lower levels of alcohol

consumption.

        Average drinks per sitting by drinking days. Odds ratios for mothers who consumed an average of five or more drinks per sitting during one or two drinking days were 1.8 (95 percent confidence interval: 0.8, 4.0) for infant cleft lip with or without cleft palate and 2.5 (95 percent confidence interval: 1.0, 6.0) for cleft palate only (table 2). The odds ratios were further increased among women who drank this amount on three or more occasions: for cleft lip with or without cleft palate, odds ratio ¼ 3.2 (95% confidence interval: 1.0, 10.2) and cleft palate only, odds ratio ¼ 3.0 (95 percent confidence interval: 0.7, 13.0).

       Binge-level drinking before pregnancy. Among the women who drank an average of five or more drinks per occasion before pregnancy, two thirds reported no alcohol consumption during the first trimester of pregnancy. These women showed no evidence of increased risk of infant clefts compared with women who reported no alcohol consumption before or during their pregnancies (table 3). Those who continued to drink during the first trimester but reduced the amount to one to four drinks per sitting also showed little evidence of increased risk of clefts in their offspring. Odds ratios were increased, however, among the women who maintained binge-level drinking of an average of five or more drinks per occasion in the first trimester.

       Types of alcoholic beverages consumed. The types of alcohol consumed were available for 69 percent of the mothers who drank an average of five or more drinks per session and 80 percent of the other drinkers. A higher percentage of the binge-level drinkers reported consuming liquor compared with the lighter drinkers (36 percent vs. 14 percent; chi-square p < 0.001), whereas a lower percentage reported drinking wine (52 percent vs. 70 percent; chisquare p ¼ 0.005). The percentage of beer drinkers was the same for the two groups (54 percent). Infant cleft risk did not appear to differ for beer/wine and liquor drinkers, but small numbers of women in some drinking categories precluded a definite conclusion (appendix table 2).

DISCUSSION

       We found increased risks of orofacial clefts among infants whose mothers reported binge-level drinking of an average of five or more drinks per occasion during the first trimester compared with nondrinkers. Risk was further increased for women who drank at this level most frequently.The evidence was weaker for increased risk of infant clefts at lower levels of maternal alcohol consumption. The risk for women who reported habitual binge-level drinking before their pregnancies but who reduced or stopped drinking during their pregnancies was similar to that for women who abstained before and during pregnancy. The higher percentage of liquor drinkers and lower percentage of wine drinkers among women who drank at binge levels compared with the other drinkers may reflect greater alcohol dependence or different social patterns of drinking among heavy drinkers.

       Associations were weaker when measuring alcohol consumption as total drinks or number of drinking days. Both animal and human studies suggest that the dose of alcohol consumed per episode, rather than the frequency or total amount over time, is the most relevant alcohol measurement for assessing potential adverse fetal outcomes (11). Maternal binge drinking may be particularly harmful because it results in greater peak blood alcohol concentrations and prolonged fetal alcohol exposure compared with drinking fewer drinks over more occasions (19). The body’s rate of alcohol metabolism remains relatively constant regardless of the amount of alcohol consumed. The greater the blood alcohol concentration, the longer it takes to clear the alcohol,resulting in longer fetal exposure (19). The crucial stages of embryonic development for lip and palate are relatively brief. Even a single binge episode at the crucial time would presumably be enough to result in harm. Strengths of this study include the virtually complete ascertainment of cleft cases drawn from a large, well-defined population; the high participation rate among mothers of cases (88 percent); and the clinical confirmation of cleft malformations. The participation rate for controls was lower (76 percent), although with the advantage of being drawn from a random sample of the entire population of births. The study collected extensive data on relevant maternal characteristics assessed as potential confounders. This study has some possible limitations that should be considered. We relied on retrospective self-report of alcohol consumption, which is generally considered less valid than concurrent reports. Some studies, however, have shown that mothers’ recall of prenatal alcohol consumption after pregnancy revealed greater intake than concurrent reports (20, 21), perhaps because it was easier for women to disclose socially sensitive behavior when it occurred in the past. This situation was found in Norway, where Alvik et al. (22) reported that women tended to report less drinking when asked during pregnancy than when asked about the same period later in the pregnancy or 6 months postnatally. Self-administered questionnaires tend to reveal

greater consumption of alcohol than interview-administered questionnaires (23), suggesting that our data collection methods were appropriate for prenatal alcohol consumption.

       Mothers of controls may be more likely than mothers who have an affected child to admit drinking alcohol during pregnancy after giving birth to a healthy infant. This possibility would tend to underestimate the association between maternal prenatal alcohol consumption and infant clefts. Conversely, the effect may have been overestimated if mothers of cases were more likely to remember past drinking, perhaps in an effort to explain the occurrence of the malformation. In a prospective study, Verkerk et al. (24) compared concurrent and retrospective reports of alcohol consumption during pregnancy among women whose infants had congenital malformations and those who did not. The differences in reporting for the two groups did not substantially change risk estimates. Their findings suggest that recall bias may not have a large impact on effect estimates in studies using retrospective alcohol information; however, we cannot rule it out in our study.

        Confounding is always a potential concern in observational studies, but we were able to adjust for confounders including mother’s smoking, education, household income, and other important variables. Such adjustments tended to weaken the associations with cleft lip with or without cleft palate, whereas they strengthened the associations with cleft palate only (table 2). Further adjustment for other variables had little impact on the estimates.

       Selection bias may have resulted if heavy drinkers selected as mothers of controls were less likely to participate in the study than heavy drinkers whose infants had clefts. Restriction of the analysis to mothers of cases and controls who were heavy drinkers before pregnancy led to the same general finding of increased infant cleft risk for the mothers who continued to drink at high levels in the first trimester, giving some reassurance that differential participation was not responsible for the results in the full analysis.

       The structure of our questionnaire did not enable us to measure the number of binge drinking episodes or to capture sporadic binge drinking (defined as periods of no or little drinking punctuated by episodes of drinking large quantities of alcohol) (11). When answering our alcohol consumption questions, a woman who drank one alcoholic beverage a day during 6 drinking days and had one binge episode of eight drinks would have reported an average consumption of two drinks per sitting (14 drinks total/seven sittings). The women who make up our category of an average of five or more drinks per occasion are therefore probably a mixture of chronic heavy drinkers and episodic binge drinkers. This group experienced a high level of alcohol consumption on average, but we were unable to assess in more detail the effect of periodic binge drinking. Missing data in the food frequency questionnaire on the types of alcoholic beverages the mothers consumed hindered our ability to assess infant cleft risk by alcohol type. We were also unable to determine the type(s) of alcohol consumed specifically during binge drinking episodes, if that differed from usual drinking. Respondents

may have miscalculated average drinks per sitting (and underreported consumption) if they interpreted the question as usual (modal rather than mean) number of drinks and did not incorporate drinks consumed during atypical drinking sessions (25). We would not expect this factor to differ for mothers of cases and controls.

       Previous studies on maternal alcohol consumption and infant clefts have reported conflicting results (5–10, 26–28) probably in part because of differences in ascertaining and classifying subjects, measuring the amount and timing of exposure, and evaluating confounders. All of the previous studies used case-control designs, although Bille et al. (27) conducted a case-control study nested within a cohort, thus avoiding recall bias by collecting exposure information prospectively. Their results based on 192 cases suggested an

increased risk of infant cleft lip (odds ratio = 1.48, 95 percent confidence interval: 0.68, 3.19) and cleft palate (odds ratio = 1.36, 95 percent confidence interval: 0.45, 4.15)among women who drank three or more drinks per week,but the confidence limits were wide.

       Our findings are consistent with four studies reporting risks ranging from 2.8 to 4.0 for cleft lip with or without cleft palate among mothers in the highest drinking categories (ranging from >4 drinks per month to >5 drinks per drinking day) (5–8). Some studies reported increased risks of infant cleft palate among women in the highest drinking categories, although a lack of power limits their interpretation (5, 6, 28). Four previous papers examined binge-level drinking. Two studies used the same definition of binge drinking as ours (average of >5 drinks per sitting), and both reported threefold increases in cleft lip with or without cleft palate among the binge-level drinkers compared with nondrinkers but did not find increased risks for cleft palate (7, 8).

The other two studies based their definition on the maximum number of drinks consumed at one sitting and categorized women who reported drinking a maximum of five or more drinks as binge drinkers. These studies did not find an increased risk of infant clefts among binge drinkers, but the women who drank a ‘‘maximum’’ of five or more drinks on any occasion may have consumed less alcohol than the women in our study who drank an average of five or more drinks per sitting (9, 10).

       Many previous studies have examined isolated and nonisolated clefts separately, or only one or the other. We found little difference in our results for infants with isolated and nonisolated clefts. By studying the combined groups, we increased statistical power to detect associations. There has been debate in oral cleft research on whether cases with associated anomalies should be included in etiologic studies (29). Combining groups for analysis makes sense when the exposure of interest may be an etiologic factor in both nonsyndromic and syndromic cases. This seems likely for alcohol, which may act through different mechanisms to cause a variety of teratogenic effects. Besides oral clefts, children diagnosed with fetal alcohol syndrome often have other anomalies suspected to be related to alcohol exposure, including  those of the limb and joints, heart, kidney, and reproductive organs (30).

        In summary, our findings suggest that maternal bingelevel drinking (an average of >5drinks per occasion) in the first trimester increases the risk of infant oral clefts. These data on possible further teratogenic effects of alcohol reinforce the public health message that women should not drink alcohol during pregnancy.

ACKNOWLEDGMENTS

This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences.

Conflict of interest: none declared.

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Manfaat AINS Terhadap Nyeri Gangguan Muskuloskeletal Pada Usia Lanjut

Sesuai dengan pertambahan usia harapan hidup penduduk dunia, proporsi penderita lanjut usia (lansia) makin bertambah yang secara farmakologi merupakan kelompok khusus dan mempunyai problema tersendiri dalam pemberian obat-obatan. Lansia sendiri untuk kebanyakan obat merupakan faktor risiko mudahnya timbul efek samping (Lelo, 1998). Sebagai akibat semakin bertambahnya keluhan dan ragam penyakit maka terapi polifarmasi makin bertambah pada penderita lansia. Penggunaan beberapa macam obat akan meningkatkan risiko interaksi obat yang merugikan dan reaksi ikutan obat yang berbahaya. Cooper (1999) juga mendata faktor yang paling nyata menjadi penyebab penderita lansia dirawat inap akibat obat, ternyata jumlah obat yang digunakan merupakan faktor yang menentukan. Mereka yang dirawat inap akibat reaksi sampingan obat (7.9 +/- 2.6 item) menggunakan ragam obat yang lebih banyak daripada mereka yang dirawat inap bukan karena reaksi sampingan obat (3.3 +/- 1.3 item). Penderita lansia menggunakan obat-obatan yang diresepkan tiga kali lebih banyak dari penderita dewasa muda sebagai akibat makin meningkatnya kejadian penyakit kronis (Chrischilles dkk, 1992).
Setiap jenis obat yang digunakan pada penderita lansia harus mempertimbangan secara khusus perubahan farmakokinetik dan farmakodinamik obat karena pertambahan usia, dimana masa kerja obat menjadi lebih lama sebagai akibat eliminasi obat makin lambat (Greenblatt dkk, 1982). Perubahan farmakokinetik lain yang cukup menonjol adalah dalam hal ikatan protein dan metabolisme obat sebagai akibat makin berkurangnya masa hati, aliran darah hati dan aktivitas enzim. Penurunan protein plasma akan berakibat meningkatnya kadar obat bentuk bebas, terutama analgetik AINS. Cooper (1999) mendata kejadian merugikan akibat obat sehingga penderita lansia harus dirawat inap. Obat yang paling banyak sebagai penyebab adalah obat anti-inflamasi non-steroid (AINS), psikotropika, kardiotonika digoxin dan antidiabetika insulin.
Nyeri muskuloskeletal pada lansia
Kejadian nyeri makin meningkat sesuai dengan pertambahan usia manusia. Nyeri pada lansia sangat berbeda dengan yang dijumpai pada dewasa muda. Banyak penderita lansia memiliki lebih dari satu macam penyebab nyeri. Penyebab nyeri yang paling sering pada lansia adalah arthritis (termasuk nyeri punggung bawah), polimialgia, Paget’s disease, neuropati, penyakit pembuluh darah perifer dan jantung serta proses keganasan. Oleh karena itu tujuan utama dalam penanggulangan nyeri pada lansia adalah (Davis dan Srivastava, 2003).:
• Meredakan nyeri
• Mengoptimalkan aktifitas harian
• Mendapatkan dosis terendah dari obat yang digunakan
Oleh karena itu prinsip dasar pendekatan farmakologi dalam penggunaan analgetika pada lansia adalah mulai dengan dosis rendah dan bila diperlukan secara perlahan-lahan dosis ditingkatkan. Petunjuk Badan Kesehatan Dunia WHO membolehkan kombinasi analgetik opiate dan non-opiat terhadap penderita dengan tingkat nyeri menengah sampai berat. Selain itu, pemilihan analgetika yang tepat juga dipengaruhi oleh kepatuhan penderita, polifarmasi, keparahan dan jenis nyeri, ketersediaan obat, keluhan dan gejala yang menyertai dan harga (Davis dan Srivastava, 2003). Opiate merupakan analgetik sentral menghambat transduksi syaraf didalam medulla spinalis. Sedangkan analgetik non-opiat merupakan analgetik perifer menghambat aktivitas cyclooxygnase dalam pembentukan prostaglandin sehingga sistem nosiseptor perifer tidak teraktivasi. Masing-masing analgetik memberikan efek samping tertentu, dengan menggabungkan beberapa jenis analgetik dengan mekanisme kerja berbeda akan meningkatkan khasiat dan keamanannya dalam pengobatan nyeri sedang sampai berat, seperti pada nyeri kanker (Ladner dkk, 2000).
Fakta yang ada menunjukkan bahwa AINS berkhasiat sebagai analgetik, antipiretik dan antiinflamasi. Sediaan ini bekerja dengan cara menghambat aktivitas enzim siklooksigenase (cyclooxygenase, COX), apakah isoenzim COX-1 atau COX-2 atau keduanya, dalam pembentukan prostanoid prostaglandin (PG), prostacyclin dan tromboxan. Tiap sediaan OAINS akan memberikan efek analgetik anti-inflamasi yang sepadan apabila digunakan dosis yang sepadan pula (Simon & Strand, 1997). Namun ada kalanya dibutuhkan kombinasi parasetamol dengan AINS untuk meningkatkan khasiat analgetiknya. Pada kenyataannya tidak semua penambahan AINS dapat meningkatkan khasiat analgetik parasetamol. Breivik dkk (1999) mendemonstrasikan bahwa khasiat analgetika parasetamol akan makin meningkat bila ditambahkan OAINS diclofenac dan/atau kodein. Pickering dkk (2002) membandingkan efek sinergis ini pada anak-anak yang mengalami tonsilektomi dan mendapatkan bahwa penambahan COX-2 inhibitor spesifik rofecoxib tidak meningkatkan khasiat analgetik parasetamol, berbeda dengan penambahan AINS klasik ibuprofen.
Nyeri muskuloskeletal dapat juga terjadi bukan sebagai akibat reaksi inflamasi. Satu sampai dua bulan setelah penggunaan antihiperlipidemia statin dapat terjadi gangguan muskuloskeletal berupa nyeri otot, nyeri sendi, kelemahan otot dan sebagainya. Statin menghambat enzim HMG CoA reductase sehingga cholesterol tidak terbentuk yang pada gilirannya akan diikuti dengan gangguan hormon dan fungsi sel-sel tubuh. Dalam penanggulangannya yang terbaik adalah dengan penghentian sediaan statin (Chazerain dkk, 2001).
Problema penggunaan AINS pada lansia
Meskipun AINS kelihatannya menjadi analgetika yang selalu digunakan pada lansia, bukan berarti sediaan ini aman bagi pemakai. Nyeri pada lansia selalu berlangsung kronis, menuntut untuk memberikan AINS jangka lama. Timbulnya efek samping AINS yang tak berterima selalu menjadi penyebab untuk tidak meneruskan penggunaan AINS. Lansia sendiri sudah menjadi faktor risiko untuk terjadinya efek samping AINS. Tambahan lagi, Tamblyn dkk (1997) menemukan sekitar 35% penderita mendapat resep AINS yang tidak diperlukan.
Problema penggunaan AINS pada lansia antara lain adalah:
• Efek samping AINS
• AINS sebagai sediaan penyebab kaskade peresepan
• AINS memberikan interaksi yang tak menguntungkan dengan obat lain
Efek samping AINS
Mekanisme kerja utama sediaan ini diperkirakan berkaitan dengan hambatan sintesis prostaglandin dari asam arakidonat. Prostaglandin disintesis oleh dua enzim siklooksigenase (Cyclooxygenase, COX), yaitu COX-1 dan COX-2. Prostaglandin yang disintesis melalui jalur COX-1 dipercayai berperan dalam proses sistem keseimbangan tubuh, sedangkan yang disintesis melalui jalur COX-2 dipercayai terlibat dalam proses inflamasi. Prostaglandin merupakan sediaan pro-inflmasi, tetapi juga merupakan sediaan gastroprotector. Oleh karena analgetika penghambat COX-2 diyakini tidak menghambat aktifitas isoenzim COX-1, maka sediaan ini diduga bebas dari berbagai efek samping yang menakutkan. Kejadian perdarahan saluran makanan bagian atas meningkat 2 – 6 kali lipat akibat penggunaan AINS oleh lansia, teristimewa perempuan (Johnson dan Day, 1991).
Russell (1999) mengkaji factor risiko terjadinya efek samping gastrointestinal (dyspepsia, erosi, ulserasi, perdarahan atau perforasi) akibat AINS dan menemukan bahwa kejadian efek samping AINS pada saluran cerna makin meningkat apabila AINS:
• Diberikan pada lansia (usia > 60 tahun; RR 5.52) daripada dewasa muda (usia < 60 tahun; RR 1.65),
• Diberikan pada mereka dengan riwayat tukak peptic (RR 2,39), dan makin meningkat kejadian berikutnya (RR 4,76)
• Digabungkan dengan kortikosteroid (RR 14,6)
• Diberikan pada mereka yang sedang menggunakan dosis kecil asetosal
Risiko efek samping saluran cerna berbeda menurut jenis sediaan, AINS yang memberikan risiko paling tinggi adalah azapropazone, ketoprofen dan piroxicam, dan yang memberikan risiko paling rendah adalah ibuprofen, diclofenac and etodolac (Russell, 1999). Tingkat keparahan efek toksik AINS pada saluran cerna berbeda diantara sediaan. AINS dengan waktu paruh panjang lebih toksik pada lansia. Berdasarkan hilangnya darah yang terpantau melalui tinja, Scharf dkk (1998) berkesimpulan bahwa AINS dengan waktu paruh pendek (diclofenac) dapat dikaitkan dengan toksisitas saluran cerna yang rendah dibandingkan dengan AINS dengan waktu paruh menengah (naproxen) dan panjang (piroxicam) (Scharf dkk, 1998).
Sementara farmakokinetik diclofenac kelihatannya tidak dipengaruhi oleh usia, gangguan faal ginjal dan kronisitas pemberian obat (Kendall dkk, 1979). AINS meloxicam (Turck dkk, 1996) dan nimesulide (Olive & Rey,1993) menunjukkan hal yang sama, dimana tidak banyak perbedaan farmakokinetik ke dua sediaan ini dengan pertambahan usia sehingga tidak diperlukan penyesuaian dosis pada lansia. Davies dkk (2000) menyatakan farmakokinetik celecoxib berbeda antara dewasa muda dan lansia, dimana dijumpai penurunan bersihan pada lansia.
Perubahan farmakokinetik AINS akibat pertambahan usia, mengharuskan pengurangan dosis AINS pada lansia yang sehat. Sementara bila penderita lansia mengalami penurunan faal ginjal dosis AINS diflunisal, indomethacin, sulindac dan asam mefenamat harus dikurangi. Karena eliminasi obat lebih lambat pada lansia, maka hindari penggunaan AINS dengan waktu paruh panjang, sebagai gantinya berikan sediaan dengan waktu paruh singkat yang pada dewasa muda digunakan 3 kali sehari, sedangkan pada lansia cukup digunakan sekali atau dua kali sehari (Lelo, 1998).
AINS yang lebih selektiv menghambat COX-2 diperkirakan akan memberikan kejadian efek samping pada saluran cerna yang lebih rendah, paling tidak untuk waktu penggunaan yang singkat. Berdasarkan farmakodinamik AINS maka dapat diperkirakan bahwa sediaan AINS mampu mengganggu sistem kardiovaskular dalam bentuk perburukan klinis hipertensi dan payah jantung serta meningkatkan kejadian perdarahan akibat pencegahan agregasi trombosit melalui hambatan aktivitas COX-1. Penghambat COX-2 celecoxib, nimesulid dan lainnya secara eksperimental tidak mengganggu pembekuan darah. Namun sampai saat ini baru Crofford dkk (2000) yang melaporkan temuan mereka adanya trombosis pada penderita yang diobati dengan celecoxib. Bersamaan dengan meningkatnya proses vasokonstriksi, peningkatan pembekuan darah akibat makin bebasnya jalur COX-1 dalam mensintesis tromboxan akan mempermudah terjadinya serangan jantung pada pemakai AINS dengan penghambatan COX-2 yang sangat selektif.
Pada penderita lansia, perubahan tekanan darah diluar batas yang terkontrol akan menjadi problema bila AINS dikonsumsi secara intermitten (Morgan dkk, 2000). Pengkajian meta-analisis sebelumnya oleh Pope dkk (1993) menunjukkan bahwa peninggian mean arterial pressure pada penderita hipertensi yang mendapat indometasin adalah 3.59 mm Hg dan yang mendapat naproxen adalah 3.74 mm Hg. Sementara perubahan mean arterial pressure pada mereka yang mendapat ibuprofen (0.83 mm Hg), piroxicam (0.49 mm Hg), dan sulindac (0.16 mm Hg) relatif sangat minimal. Data yang ada berkaitan dengan penggunaan AINS dengan hambatan selektif COX-2 pada tekanan darah penderita hipertensi sangat terbatas. Graves dan Hunder (2000) menemukan perburukan tekanan darah penderita hipertensi yang mendapat AINS dengan hambatan selektif COX-2 celecoxib dan rofecoxib dengan peninggian tekanan darah sistol (18 - 51 mmHg) dan diastole (10 - 22 mmHg) yang cukup besar. Page dan Henry (2000) melaporkan bahwa penggunaan AINS meningkatkan kejadian rawat inap pertama akibat payah jantung pada penderita lansia. Kejadian ini berhubungan dengan dosis dan waktu paruh sediaan AINS yang dikonsumsi.
Pengembangan sediaan AINS dengan hambatan sangat selektif COX-2 celecoxib dan rofecoxib membuat para dokter untuk lebih peduli dengan peran masing-masing COX-1 dan COX-2 pada faal ginjal. Bukti menunjukkan bahwa hambatan aktivitas COX-2 akan menyebabkan retensi natrium. Hal ini sudah tentu dapat meninggikan tekanan darah penderita. Lebih lanjut, kejadian edema pada penderita osteoartritis yang mendapat sediaan AINS dengan hambatan sangat selektif COX-2 menunjukkan bahwa makin selektif (rofecoxib, 25 mg) makin nyata kejadian edemanya dibandingkan yang kurang selektif (celecoxib, 200 mg) (Whelton,2001).

Interaksi AINS dengan obat lain
Terapi polifarmasi selalu dijumpai pada lansia. Risiko interaksi AINS dengan obat-obatan lain atau AINS dengan penyakit penyerta pada penderita lansia disebabkan banyak sediaan obat diberikan untuk mengatasi klinis penyakit kronis yang ada (misalnya hipertensi, diabetes mellitus, tuberculosis, kanker dan sebagainya).
Hipertensi dan rematik adalah dua penyakit yang selalu ditemui bersamaan pada penderita lansia dan kedua keadaan ini sangat membutuhkan obat-obatan. Seperti telah disebutkan sebelumnya, AINS selalu memberikan interaksi obat yang tidak menguntungkan dengan obat-obat antihipertensi (diuretik, beta blocker, ACE-inhibitor) yang sering diresepkan pada lansia, sehingga pengaturan tekanan darah tidak optimal. Tekanan darah kembali normal setelah AINS tersebut dihentikan pemakaiannya. Oleh karena itu, jika tekanan darah penderita lansia sudah terkontrol dengan sediaan antihipertensi, penambahan AINS dalam terapi yang ada mengharuskan penderita untuk selalu memantau tekanan darahnya.
Bentuk interaksi lain antara gabungan AINS dan antihipertensi dilaporkan oleh peneliti lain. Kurata dkk (1999) melaporkan kejadian sinkope sebagai efek samping pemberian gabungan laxoprofen dan ACE inhibitor imidapril pada nenek tua (85tahun). Akibat gabungan kedua sediaan ini, nenek tersebut mengalami hiperkalemia, diikuti dengan bradikardia dan sinkop. Sedangkan Hay dkk (2002) mendapatkan interaksi COX-2 specific inhibitor dan ACE-inhibitor enalapril berakibat hiperkalemia yang fatal. Davie dkk (2000) mendapatkan bahwa dosis kecil asetosal tetap mampu melawan efek vasodilatasi asam arachidonat.
Meskipun dinyatakan bahwa AINS yang selektif menghambat COX-2 celecoxib dan rofecoxib sangat minimal mencederai mukosa saluran cerna, hasil kajian Fiorucci dkk (2002) pada tikus menunjukkan bahwa celecoxib dan rofecoxib secara signifikan meningkatkan keparahan efek samping asetosal pada lambung. Kemudian Fiorucci dkk (2003) mengkajinya pada manusia sehat dan membuktikan bahwa bila celecoxib digabung dengan asetosal maka pencederaan mukosa saluran cerna lebih banyak bila diberikan sendiri-sendiri. Celecoxib dan rofecoxib secara nyata meningkatkan keparahan kerusakan mukosa saluran cerna.


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