EEE Frequency of Analgesic Use and Risk of Hypertension Among Men John P. Forman, MSc, MD; Eric B. Rimm, SeD; Gary C. Curhan, MD, SeD Background: Nonnarcotic analgestes are the most com- monly used drugs in the United States. To our know! edge, the association between the use of these analge- sics, particularly acetaminophen, and the risk of hypertension among men has not been extensively'stud- ied. Methods: The association between analgesic use and risk, of incident hypertension was analyzed in a prospective cohort analysis of 16031 male health professionals with- ‘outa history of hypertension at baseline. Detailed infor- mation about the frequency of use of acetaminophen, non- steroidal anti-inflammatory drugs, and aspirin was gathered at baseline and updated 2 years later. The rela- live risk of incident hypertension during 4 years of fol- low-up was analyzed using mulivariable proportional haz- ards regression. Results: We identified 1968 incident cases of hyperten- sion, Afler adjusting for multiple potential confound- cers, men who used acetaminophen 6 to 7 days per week. ‘compared with nonusers had a relative risk for ineident hypertension of 1.34 (05% confidence interval, 1.00-1.79; for trend). This same comparison resulted in rela- tiverisksof 38 (05% confidenceinterval,1.09-1.75;P=002 for trend) for nonsteroidal anti-inflammatory drugs and 1.26 (05% confidence interval, 1.14-1 40;P<.001 for trend) for aspirin, We observed similar results when the num- ber of pills per week was analyzed rather than frequency of use in days per week. Conelustons: The frequency of nonnarcotic analgesic use is independently associated with a moderate increase in the risk of incident hypertension. Given the widespread use of these medications and the high prevalence of hy- pertension, these results may have important public health implications. Arch Intern Med. 2007;167:394-399 Author Affiliations: Channing Laboratory, Department of ‘Medicine, Brigham and ‘Women's Hospital and Harv ‘Medical School (Drs Forman, Rimm, and Curhan): Renal Division, Deparment of Medicine, Brigham and ‘Women's Hospital (Drs Forman and Curhan);and Departments of Epidemiology (Des Forman, Rimm, and Cuthan) and ‘Nutrition (Dr Rimm), Harvard School of Public Health Boston, Mass CETAMINOPHEN, IBUPRO- fen, and aspirin are the 3 most frequently used drugs inthe United States These drugs may increase blood pressure through various mechanisms in- cluding inhibition of vasodilatory prosta- glandins.*? In addition, nonsteroidal ant inflammatory drugs (NSAIDs) increase renal sodium reabsorption,” acetaminophen may increase cellular oxidative stress." and both acetaminophen and NSAIDs may impair en- ddothelial function. In 2 large, prospective, female co- horts,"* an association between the fre- quency of analgesic use (measured in days per month) and the risk of developing hy- pertension was reported. Recently, re- ported results from a large cohort of male physicians noted a significant association be- ween frequency of acetaminophen use (during the past year) and risk of hyper- tension.”” Although the results for [re- {quency of NSAID and aspirin use were not significant in that study, the highest cat- cegory of analgesic use was only 61 or more limes per year (perhaps as litle as once or twice per week). To further examine these associations, we studied the association between fre- {quency of acetaminophen, NSAID, and as- pirin use and the risk of incident hyperten- sion during a 4-year period among 16031 male health professionals, LESS STUDY POPULATION ‘The Health Professionals Follow-up Study fs an ongoing prospective cohort study of 51520 male health professionals that began {in 1986, Biennial questionnaites gather infor ‘mation about health-related behavior and ‘medical events. In 2000, detailed information hou analgesic use was first queried. The in- stitutional review board at Brigham and ‘Women's Hospital reviewed and approved this study Men were excluded from the analysis if they died before 2000 (n=696+), had preva- lent hypertension at baseline (n=19973), were using hlood pressure-lowering medica tions at baseline but did not have a history of hypertension (n=1317),or did not retura rel evant questionnaires (n=7244). Participants ‘who did not provide information on analgesic tse in 2000 but provided this information in 2002 contributed person-time from 2002 10 2004, The final stu sample included 16031 (©2007 American Medical Association, All rights reserved.ASCERTAINMENT OF ANALGESIC USE “The 2000 biennial questionnaire queried parcipants bout their tic of acetaminophen, NSAIDs an aspirit Thee questions sed shout usa frequency of sein days per week (0,1, 23,45, and 67) and numberof pills consumed per week (0, 1-2,3-5,6-14, snd 215). Information about past use was not gathered, and dose information was only asked fr aspirin, Idenisl questions ap- aed onthe 2002 lennal questionnaire, and expose info Ihation was updated to reflect level of analgesic se. ASCERTAINMENT OF INCIDENT HYPERTENSION inna mailed questionnaires ask prticipantsto report whether Seliicien tad ean digests of hyperictaton dring te preceding years self epored hypertension wasshown be Highly reliable inthe Health Professionals Follow-up Sadly” Among asset of men who reported hypertension, 100% had the diagnosis confirmed by medial rezord review. In adi- ton, sel-reported byperission ws highly predictive of sb sequent cordiovesctlar events” A pert ipent was considered tohave prevalent hypertension and, this xcluded i he pt- ttpant reported thicingnosis on any questionnaire tod incading the 2000 questionnaire. Therefore cases wer indi ‘nels Who fst eporied hypercrton on steer es Somires 2002 an 2008). ASCERTAINMENT OF COVARIATES Age, body mass index (BMI) (calculated as weight in kilograms dlvided by the square of height in meters) smoking status, and physical aetivity were ascertained from the 2000 questionnaire and updated in 2002, Because dietary information fom the food lrequency questionnaire (including intakes of alcohol, folate, s0- dium, potassium, calcium, magnesium and fiber) isavailable ev- ery 4 years (and not assessed in 2000), we imputed 1998 dietary {information for 2000, and updated dietary data with the 2002 food frequency questionnaire. Information about these covariates has ‘bcen validated compared with “gold standard” measures, with cor- relations of 0.97 for weight and 0.79 for physical activity; and among dietary variables, correlations ranged from 0.61 for po- lassi to 0.90 for alcohol" Family history of hypertension was available om the 1990 questionnaire. Participants reported their systolic and diastolic blood pressure (measured in milime- ters of mercury) on the 2000 questionnaire. Participants re- ported their race on the 1986 questionnaire. STATISTICAL ANALYSES ‘The frequency of us ofa particular analgesic categorizedin days perweek (0,1,23,45,ando-7) wasanalyzedin the primary analy ‘Ses defining nonusers ofthat drugs the reference group. Insc ondary analyses, we examined number ofpillsconsumed per week (0,1-2,3-5,6-14, and =15), using as the reference group. For each participant, person-months of follow-up were counted from the date of return of the first questionnaire to the mailing date ofthe last questionnaire, and allocated ac- cording to exposire statis, Person-time was truncated when ‘an event occurred, Participants were censored atthe date of death or ifthey did not return asubsequent questionnaire, at thedate the subsequent questionnaire was mated, -Age- and multvariable-adjusted relative risks (RRs) werecal- culated using Coxproportional hazards regression models. AIIRRS foracetaminophen, NSAIDs, andaspirinsimlaneouslycontrlled {or ise ofthe otheranalgesiypes, Multivariable models were fur- ther adjusted for variables that have been proposed to be associ- ated with hypertension (age [continuous race [5 categories] BML [continuous], physical activity [quintiles], smoking status [past ‘current, or never] family history of hypertension [yesor no} al- ‘cohol intake [6 categories], and intakes of folate, potassium, cal- ‘um, magnesium, and sodium [quinils)). Secondary analyses ‘excluding men who reported coronary heart disease at baseline ‘werealso performed. Inadditional analyses, we controlled or base- line systolic and diastolic blood pressure, and limited the anal sestothe subset of men who reported having clinician examnina- tions during the period of follow-up. Because age and BMI are stich powerful risk factors for hy- pertension, we investigated whether the association between analgesic use and hypertension varied according to age (<00, {00-70, and >70 years) or BMI (=25 or =25), stratified tivariable analyses were performed, and appropriate interac- lion terms were generated to lst whether interactions were sta. Uistieally significant For all RRs, we calculated 95% confidence intervals (Cis) ALP values are 2tsiled. Statistical tests were performed using ‘SAS statistical software, version (SAS Institute Inc, Cary, NC), ss BASELINE CHARACTERISTICS At baseline in 2000, the mean age of men in the analysis, ‘was 64.6 years (median, 63 years; interquartile range, 57-71 years) and the mean BMI was 24.8 (median, 25.1; interquartile range, 23.2-27.2). The baseline charactei istics of these men, stratified by category of analgesic fr ‘quency, are shown in Table ¥. 4 history of smoking was ‘consistently more common with increasing analgesic in- take; for other characteristies, the correspondence to an- algesic use was not as consistent. For example, age, BMI, and folate intake were higher with increasing frequency ‘ofacetaminophen use, whereas level of physical activity ‘was lower. In contrast, no variables seemed to consis tently correspond to NSAID frequency; and with increas- ing aspirin frequency, physical activity level increased long with folate intake. Baseline blood pressure report ing did not seem to differ across medications. FREQUENCY OF ANALGESIC USE During 4 years and 52.673 person-years of follow-up, 1968 participants reported a new diagnosis of hypertension. We observed a significant independent association b tween frequency of analgesic use and risk of incident hy- pertension among all 3 analgesic classes (Rabble 2). Com- pared with nonusers, men who took acetaminophen 6 to 7 days per week had a multivariable RR for incident hypertension of 1.34. This same comparison yielded a RR of 1.38 for NSAIDs and a RR of 1.26 for aspirin. Further adjustment for baseline systolic and dia- stolic blood pressure may be overcontrol, but we did so in secondary analyses. After adding baseline blood pres sure to the multivariable models, the RR comparing men who used acetaminophen 6 to 7 days per week com- pared with nonusers was 1.31 (05% Cl, 0.96-1.80; P=.05 for trend). The RR for NSAID use was 1.33 (95% Cl, 1.02- 1.74; P=.02 for trend), and the RR for aspirin use was 131 (059% C1, 117-147; P<.001 for trend). These estimates are not substantially different (<5% change) from mod- tls that did not include baseline blood pressure. (©2007 American Medical Association, All rights reserved. jamanetwrork.com/ on 01/30/2023.‘Table 1. Characteristics of the Health Professionals Follow-up Study for Participants Without Baseline Hypertension in 200% ‘Fraquancy ot Acetaminophen, NSAID, or Aaprn nak, wk charter 4 28 a 7 ‘eslaminophon Data Noo partipans 403s 28r sm 16 260 Ige.y 53,5771) 52 6660) 63 67-71) 57505) 69,6078) Bd ass indoxt wilestzt) 22086277) ast A323) —asB(zASATA) 256 (231-278) Physical actay, MET zs(ie2sta) 216941) akg TOA) BGI THG6) T0876 404) Dieta intake ‘Aloha id ba (09148 0/0132) 560-136) 55(15.148), 52/0146) Calcium. mld 00 (6a2-1208) 80267-1230) 87 (6821100) 4 (74326) 105 (765-1428) Magnsiom, malt 91 (335462) 501 420-48) SOT ROBT) 86 (HOt) 300 (248-53) Potassium, ald 3586 (42-4022) 3400 @tt0.anes) 3514 1224012) 4a (st0e4012) 7 (at 123086) Felt dl 965 (542-1408) 1085 (6151362) 1005 6554816) 1138 (6551406) 1213 (566-428). ‘Smoking status Pat m2 ar 451 wr 469 Curent 43 49 43 48 42 Family history ot yparensiont 318 5 37 30 ma ‘WEA Bate Noo partipans 2580 ats 187 6 wt Ageny 64 57.72) 50(65-65) 60,8857) 61 (5.58) 55 (5873) Bay assindoxt Wi @stz.0 255087274) aS ATITS) © —aBTBABITS) 255 (237-289 Physical actay, MET ws2(iisdns) — 278(120803) —S10(150578) | S8B(t7OSN3) 284143545) Dieta intake ‘Aeohal id se(0o143) —713(18-146) 93 (27-165), 93(18.179) 72(09150) Calcium. mld 00605-1235) 885 (6721150) 883 (6801Ton) 806051170) 00 (702-247) Magnsiom, malt 00 (635468) S84 GOLA) SOD RAHI) 86 (suz-4td) 38 34.) Potassium, ald 3866 (342-4035) 3479 117-2808) 3534 3130-2061) 05 st00-u22) 3512 (3155-028) Felt ld 877 (42-1408) 96 (652.1380) 1035 (640-4305) 108 (646387) 1040 (S438) ‘Smoking status Pat m0 wa 26 49 a8 Curent 44 40 38 39 57 Family history ottypatensong 31.1 32 aud EY m0 ‘spa Daa Noo partipans 508 221 138 18 021 Ageny 635671) 52 6670) 6257-50) 62(57-59) (5872) Bay assindoxt siesta 251984273) ast gAs273) —asBAASATS) 25.1 33.27) Physical actay, MET vs3(iiodgs) — 252(121471) 278127801) 27S (HBS) 280(131528) Dieta intake ‘Aloha id 55(09139 © $.4(09141) 75 18-158) a2(18157, 76(15-156) Calcium, mid 00 (680-1212) 840 674-1164) a0 (684-205) a GOL HBT) ada (T1278) Nagnesivm, malt 85620456) 370(S31-450) 385445454) 50D (S857) 408 (348-475). Potassium, ald 3531 (918-2001) 3487 GoeLaD50) Ass sto2-aBDI) a7 (st22-027) SS (2218-14) Felt ld 865 (610-1879) 831 (634-1366) 983 (546-840) 100 (6551879) 1206 601-1488) ‘Smoking status Pat aa sao 08 410 aa Curent 45 56 46 63 35 Family history ot parensiont 305, m0 35 87 zr ‘Abrevitons: de, itary flat equivalent: MET, meal equivalent ask; NSAID, nonstaoial an-inftaratory drug. “Daa are gen a¢ median (trqurle range) ules ohare nde {Caled weight in hlograre ded byte square of haght mete. ata are gen as porenag ofeach group. Because men who frequently use analgesics may visit their clinicians more often, thereby having « higher [re- {quency of blood pressure measurements and correspond ingly an increased chance of being diagnosed as having hypertension, we also examined only the subset of men who reported visiting their clinicians during follow-up (n=14868). In this subset, the multivariable RR for 6 to 7 days per week of use compared with nonusers was 1.26 (95% Cl, 0.94-1.70; P=.05 for trend) for acetamino- phen, 1.35 (05% Cl, 1.06-1.72; P2008 for trend) for NSAIDs, and 1.23 (95% Cl, 1.10-1.37; P<.001 for rend) for aspirin, NUMBER OF ANALGESIC PILLS We also examined the number of analgeste pills taken per week and the risk of incident hypertension; the sults were similar to those when frequency of use was analyzed. For total number of analgeste pills, men who took 15 or more pills per week compared with men who took 0 had a multivariable RR of 1-48 (05% Cl, 1.22- 1.80; P<.001 for trend). Comparing men who took 15 ‘or more pills per week ofa particular analgeste with those who took 0, the multivariable RRs were 1.04 (95% Cl, 0.61-1.76; P=01 for trend) for acetaminophen, 1.33 (95% (©2007 American Medical Association, All rights reserved.Table 2. Frequency of Analgesic Use and Risk of incident Hypertension “estaminophen Data Person years ane 13a ‘| ei 0 na No, eases 1743, a 0 % 50 Na BR (08% Che ‘ge adused ‘1Retrenee 101/075-1386) 101 (079430) 1641117230) 1.36 (101-182) v7 iar acute ‘Retrenca —100(078135) 100 (07812 150(113228) _134 (100-179) ot TWeADoat Personas ‘2507 as 3068 161 1s na No, leases 1888 5 158 8 78 Na BR (08% chit ‘ge adused ‘Reterence —097(078-420) 112,005-15 121 (000182) 14s (tAS1aH <0. iar acute ‘Retrence —095(07-118) 100 (002120) —1.18(085-158) 138 (100-175) 2 "spate Personas ranae 187 3858 360, 14a na lo, feaee 20 Py 164 116 C7 Na BR (08% chit ‘ge adused 1Retrenee —099(070-123) 138 (116-184) 135(1AT6) 1.28 (116-149) tiara acute ‘Reference 092(060-122) 136 (114-161) 1.20(105487) 1.26 (118-140) ‘Abrevtons: Gl, contdence tral NA. data ot pplzabl; USAID, rostered antlamatory dug RR, elae isk ‘Tate were ising datas flows: acetaminophen, 93 person-years wh 25 cases MSAD, 74D person-years wih 43 cases; and asp, 1008 parsons with ass “ge and mutvariabieajusted models simulanoously conto for all 3 anaes pes, Mutiaable-ajsted adele contl fo ape, boy mass inde, phil acto smoing tts, fly Mistry hypertension, race and ae of aleholcleum. magnesium, polarsum fl and sod, 12 for trend) for NSAIDs, and 1.17 (05% 001 for trend) foraspirin. The signifi- ‘cant P valles for linear trend in the acetaminophen and aspirin analyses seemed to be driven by men in the 6 10 14 pills per week categories, with significant RRs of 152 for acetaminophen and 1.32 for aspirin, EFFECT MODIFICATION The association between acetaminophen tse and risk of incident hypertension was greater among men with a BMI of less than 25; among men with a BML of 25 or more, the association was reduced and not significant (P=.01 for the interaction). In contrast, the association be- tween NSAID frequency and risk of hypertension was {greater among overweight and obese men, and dimin- ished and not significant among men with BMI of less than 25 (P=.01 for the interaction). No modification of | the aspirinhypertension association by BML was ob- served (P=.04 for the interaction). The association between NSAID or aspirin use and hy pertension was not significantly modified by age (P=16 for NSAIDs and P=.2¢ for aspirin for the interaction). The as- sociation between acetaminophen frequency and incident hypertension tended tobe greater among men younger than 660 years compared with older men, but this was not sta- Usticaly significant (P=09 for the interaction). Se} ——_ Among 16031 men not diagnosed as having hyperten- sion, we observed that the frequency of acetaminophen, NSAID, and aspirin use was independently associated with the risk of incident hypertension The association between acetaminophen use and hy- pertension may be mediated through inhibition of vaso- latory prostaglandins, increases in cellular oxidative stress, and reduction of proper endothelial function. Acctamino- phon produces its analgesic elect by inhibiting prostaglan- din H, synthase, the same enzyme that is the target of NSAIDs and aspirin.” However, because acetaminophen blocks this enzyme at its peroxidase rather than cyclooxy- genase catalytic site, the issue specfety difers from that ‘of NSAIDs and aspirin.” This explains why acelamino- phen is an effective blocker of prostaglandin synthesis in endothelial cells and in the kidney, but isa less elective antiplatelet and antiinflammatory gent”? By produe- ingits therapeutic action, acetaminophen fre radicals are generated and are quenched by the consumption of ghi- lathione.* Endothelial prostaglandin inbibition and o dave sess may lead ig endothelial dysfunction,» and acetaminophen might also inhibit nitric oxide formation Usrough other mechanisms. The associations between NSAIDsand aspirin and hy- pertension may also be dic to inhibition of vasodilatory prostaglandins." In addition, NSAIDs lead to increased renal sodium and water eabsorption,** and may exert a deleterious elfect on endothelial function by increasing ‘endothelin-1 production." ‘Our findings of moderately increased risks are consis- tentwith those ofthe Nurses’ Health Study; the mulivart- able RRs (95% Cls) comparing the highest with lowest frequency ofuseamong the nurses were 1-20 (1.08-1.33) foracetaminophen, 1.35 (1-25-1-46) for NSAIDs, and 1.21 (©2007 American Medical Association, All rights reserved.(2.15.1 30) for aspirin The men in our study and the ‘women i the Nurses’ Health Study" are more similar in age (mean ages, 03 and 55 years) compared with the much younger Nurses Health Study participants (mean age, 39 years)" In the Nurses’ Health Study I, the as- sociation between frequency of acetaminophen (RR, 2.00; 95% CI, 1.52-2.62) and NSAID (RR, 1.86; 95% CI, 1.51- 2.28) use and incident hypertension was considerably ‘Our findings are also consistent with the analysis of frequency of use in the Physicians’ Health Study.” Al though the investigators found a significant association only with frequency of acetaminophen intake, the high- est intake eategory was 61 oF more pills per year, which averages to approximately 1 to 2 pills per week.” In the Physicians’ Health Study, men who estimated taking 61 ‘or more NSAID pills per year compared with those who took O had a RR for hypertension of 1.01. In our study the RR for men taking 1 to 2 NSAID pills per week com pared with 0 was 0.99 (95% CI, 0.68-1.37), consistent ‘with results from the Physicians’ Health tidy. For as- pirin,a similar argument can be made. The RR for 1 of tore pills per year of aspirin was 1.08 in the Physicians Health Study and 1-11 (05% CI, 0.92-1.34) for 1 toils per week in our study. ther epidemiologic and small interventional stud- ies have also examined the relation between analgesics and hypertension: most have focused on NSAIDs. Two ‘community-based cross-sectional studies" in elderly poptlations found significant associations between NSAID Use (Ves oF no, rather than dose used) and hyperten- son, with odds ratios of 14 10.2.2, aller adjusting for vari ‘ous potential confounders, stich as age and BMI. large case-control study” of elderly Medicaid ben ported a 1.6-fold increased odds of filling an inital pre- scription for antihypertensive medication if an NSAID prescription was filled during the prior 60 days alter con- trolling for age, sex, ace, nursing home status, and health care use, Two meta-analyses” of randomized trials re- ported that NSAIDs inereased mean blood pressure. One found that, among 771 primarily white participants of ‘various ral, NSAIDs increased mean blood pressure by 5 mum Hg overall (95% Cl, 12-8.7 mm Hg)."* However, the effect was largely limited to those participants re- ceiving therapy for existing hypertension (5.4-mm Hg imerease; 95% Cl, 1.2-9.6-mm Hg); among the studies of normotensive individuals, blood pressure increases with NSAIDs were sinall and not statistically significant, Fur- thermore, inthe trials in which anuypertensive medi- cines were administered, NSAIDs antagonized the effect of these drugs."* The second meta-analysis" found a S-mm Hg merease in mean blood pressure with NSAIDs that was also limited to participants with preexisting by pertension. In addition, only certain NSAIDs, such as in- domethacin and naproxen, were associated with in- creased blood pressure, while others, such as ibuprofen and sulindae, Were not.” Taken together, these meta- analyses suggest that NSAIDs may antagonize the elli- cacy of antbypertensive medication Less information has been published concerning acet- aminophen’s potential ellect on blood pressure and risk of hypertension. A short-term randomized crossover study" of 20 patients with treated hypertension re- ported that 1000 mg of acetaminophen given 4 mes per day vs placebo for + weeks led to a statistically signifi- ‘cant 4mm Hg increase in systolic blood pressure. As- pirin has also received less attention, A prospective co- hort study” of 1040 women found a moderate but not statistically significant association between baseline as- pirin use (determined by urinary salicylates) and inci- dent hypertension during a 20-year period (odds rat 1.3; P=.11). In the 2 meta-analyses" of NSAIDs previ- ously mentioned, aspirin use was also examined: al- though slight increases in blood pressure were noted, the ls were wide and not statistically significant. We observed a stronger association between acetami ‘ophen use and hypertension among leaner compared with, heavier men; in contrast, the association between NSAIDs and hypertension as more pronounced in heavier com- pared with leaner men, The mechanisms that may wn- derlie this finding are unclear. Higher BML is associated, ‘with oxidative stress, endothelial dysfunction, and salt sensitivity." Thus, ifthe mechanisms through which BMI and analgesics are associated with hypertension over- lap, then interactions between BML and analgesics are likely to be complex. Although we did not find effect modification by age, the youngest person in our anal sis was 55 years old. If, indeed, younger individuals are more susceptible to analgesics, as suggested by the r ssultsin younger women.” then itis possible ourage range ‘was insulliciently broad to detect an interaction, ‘Our study has weaknesses and strengths that deserve mention, We did not directly examine participants during follow-up to confirm self-reported hypertension; how- ‘ever all participants were health professionals, and hyper- tension reporting has previously been shown to be rel able2* Also, t was possible that men taking analgesics were more likely to visit their clinicians and, thus, more likely tobe diagnosed as having hypertension. Nevertheless, most ‘men in this study (02.7%) reported at least | clinician visit during follow-up, and after limiting ouranalysis to thissub- set, the results were similar. Random misclassfieation of analgesic use may have occurred because of variable anal- zgesic use in time and, hence, imprecise categorization, but ‘such misclassfication inthis prospective study would have, ifanything, led to an underestimation of the true associ tion. Residual confounding is always a potential concern in observational studies, but we used reliable information ‘on many known hypertension risk factors to carefully ad- just our multivariate models; furthermore, we are un- aware of common medical conditions that are simula neously indications for analgesic use and independently associated with hypertension, These data add further support to the hypothesis that nonnarcotic analgesics independently elevate the risk of hypertension. Given their common consumption and the high prevalence of hypertension, our results may have substantial public health implications, and suggest that these agents be used with greater caution. The contri- bution of nonnarcotic analgesics to the hypertension di ‘ease burden merits further study Accepted for Publication: November 10, 2006. Correspondence: John P. Forman, MSe, MD, Channing (©2007 American Medical Association, All rights reserved. jamanetwrork.com/ on 01/30/2023.Laboratory, 181 Longwood Ave, Third Floor, Boston, MA 02115 (jforman@partners.org). Author Contributions: Dr Forman had full access to all, the data in the study and takes responsibility for the in- tegrity ofthe data and the accuracy of the data analysis. Study concept and design: Forman and Curhan, Acquisi- tion of data: Rimm and Curhan. Analysis and interpreta tion of data: Forman. Drafting of the manuscript: For- man, Critical revision of the manuscript Jor important intellectual content: Forman, Rimm, and Curhan. Statis- tical analysis: Forman, Rimm, and Curhan. Obtained fund- ing: Forman, Rimm, and Curhan. Administrative, echni- cal, and material support: Forman and Curhan. Stu supervision: Rimm and Curhan, Financial Disclosure: None reported, Funding/Support: This study was supported by scien- Uist development grant 0535401 from the American Heart Association and by grants HL 35464 and CA 550750 from, the National Institutes of Health. Role of the Sponsor: The funding bodies had no role in data extraction and analyses, in the writing of the manu- script, or in the decision to submit the manuscript for publication, es 1. Kavfoan OW Kety J, Rosenberg. Andrson TE, Mice AA. cet pt ‘sas of eat sen the anual ppsn ethene Sates: ‘he lone sue. JAMA 20022875734, 2 Zea TV, Matarnal ME, Harman, Jet, Dvie BE, Etat fs pen on prostagudin 2 an prestaina Fa yc inte ea net ‘meal of Bloch Boys Act 178286405, {8 PavonC, Dunn The cial siianoe af htitn of real prstaga imps. Kay in. 08732112 4 Maal, Zar TV, roan WN, Herman CA Dai BB chasm ot ‘hbo fran prsaglnpedcton by ctminaphen, J Pharmacol xp Ther era0406-400 5 Blovean The tt of aspinand east anntarmatry ogo posta. 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Obs! inn resstans asset wend uncon: mpstonstorthe ‘drone of insists J Cin nest 109697 2601-2510 ‘She SFr ND, Stan ota NK Body ma idx nd ‘itnsin-dpenden control of the election in haahy humane ypenesion 2005 46: 1316-100, (©2007 American Medical Association, All rights reserved. ‘Downloaded From: https:/jamanetwork.com/ on 01/30/2023