Tramadol for Noncancer Pain and the Risk of Hyponatremia Jean-Pascal Fournier, MD, PhD, a,b Hui Yin, MSc, a Sharon J. Nessim, MD, MSc, c Jean-Louis Montastruc, MD, PhD, d,e Laurent Azoulay, PhD a,f a Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; b Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada; c Department of Medicine, Division of Nephrology, Jewish General Hospital, Montreal, Quebec, Canada; d Laboratoire de Pharmacologie Médicale et Clinique, Equipe de PharmacoEpidémiologie, Faculté de Médecine, Université Paul Sabatier, Toulouse, France; e Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de PharmacoEpidémiologie et d’Information sur le Médicament, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; f Department of Oncology, McGill University, Montreal, Quebec, Canada. ABSTRACT BACKGROUND: Case reports have signaled a possible association between tramadol, a weak opioid anal- gesic, and hyponatremia. The objective of this study was to determine whether the use of tramadol is associated with an increased risk of hyponatremia, when compared with codeine. METHODS: Using the UK Clinical Practice Research Datalink and Hospital Episodes Statistics database, a population-based cohort of 332,880 patients initiating tramadol or codeine was assembled from 1998 through 2012. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of hospitalization for hyponatremia associated with the use of tramadol, compared with codeine, in the first 30 days after initiation. A similar analysis was conducted within a highly restricted sub-cohort, which additionally excluded patients with any serum sodium level abnormality in the year before cohort entry. All models were adjusted for propensity score quintiles. RESULTS: The incidence rates of hospitalization for hyponatremia were 4.6 (95% CI, 2.4-8.0) and 1.9 (95% CI, 1.4-2.5) per 10,000 person-months for tramadol and codeine users, respectively. In the adjusted model, the use of tramadol was associated with a 2-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 2.05; 95% CI, 1.08-3.86). In the highly restricted sub-cohort, the use of tramadol was associated with an over 3-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 3.54; 95% CI, 1.32-9.54). CONCLUSIONS: In this first population-based study, the use of tramadol was associated with an increased risk of hyponatremia requiring hospitalization. Ó 2015 Elsevier Inc. All rights reserved. The American Journal of Medicine (2015) 128, 418-425 KEYWORDS: Adverse drug reaction; Codeine; Cohort study; Hyponatremia; Tramadol Tramadol is a weak opioid analgesic used for the treatment of moderate to severe pain. Its use has increased steadily worldwide, including in the US, where there was a 1.5-fold increase in the dispensing of tramadol between 2007 and 2011. 1 In recent years, however, there have been several case reports and a signal from a pharmacovigilance database that have associated the use of this opioid with hypona- tremia, all of which occurred rapidly (within the first 30 days) after initiation. 2-6 Hyponatremia (a serum sodium concentration <135 mmol/L), is an overlooked but important clinical event. 7,8 Profound (<125 mmol/L) hyponatremia may be associated Funding: This study was funded in part by research grants from the Canadian Institutes of Health Research and Canada Foundation for Inno- vation. Conflict of Interest: None. Authorship: All authors participated in the study design. LA acquired the data. JPF, LA, and HY did the statistical analyses. JPF wrote the initial draft, and all authors critically revised the manuscript. LA is the guarantor. Requests for reprints should be addressed to Laurent Azoulay, PhD, Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine, H-425.1, Montreal, Quebec H3T 1E2, Canada. E-mail address: [email protected]0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.10.046 CLINICAL RESEARCH STUDY
Transcript
CLINICAL RESEARCH STUDY
Tramadol for Noncancer Pain and the Riskof Hyponatremia
Laurent Azoulay, PhDa,faCentre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; bDepartment ofEpidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada; cDepartment of Medicine, Division ofNephrology, Jewish General Hospital, Montreal, Quebec, Canada; dLaboratoire de Pharmacologie Médicale et Clinique, Equipe dePharmacoEpidémiologie, Faculté de Médecine, Université Paul Sabatier, Toulouse, France; eService de Pharmacologie Clinique, CentreMidi-Pyrénées de Pharmacovigilance, de PharmacoEpidémiologie et d’Information sur le Médicament, Centre Hospitalier Universitaire deToulouse, Toulouse, France; fDepartment of Oncology, McGill University, Montreal, Quebec, Canada.
Funding: ThiCanadian Institutevation.
Conflict of InAuthorship: A
the data. JPF, LA,draft, and all autho
Requests for rCentre for ClinicaHospital, 3755 C1E2, Canada.
E-mail address
0002-9343/$ -seehttp://dx.doi.org/1
ABSTRACT
BACKGROUND: Case reports have signaled a possible association between tramadol, a weak opioid anal-gesic, and hyponatremia. The objective of this study was to determine whether the use of tramadol isassociated with an increased risk of hyponatremia, when compared with codeine.METHODS: Using the UK Clinical Practice Research Datalink and Hospital Episodes Statistics database, apopulation-based cohort of 332,880 patients initiating tramadol or codeine was assembled from 1998through 2012. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95%confidence intervals (CIs) of hospitalization for hyponatremia associated with the use of tramadol,compared with codeine, in the first 30 days after initiation. A similar analysis was conducted within a highlyrestricted sub-cohort, which additionally excluded patients with any serum sodium level abnormality in theyear before cohort entry. All models were adjusted for propensity score quintiles.RESULTS: The incidence rates of hospitalization for hyponatremia were 4.6 (95% CI, 2.4-8.0) and 1.9 (95%CI, 1.4-2.5) per 10,000 person-months for tramadol and codeine users, respectively. In the adjusted model,the use of tramadol was associated with a 2-fold increased risk of hospitalization for hyponatremia,compared with codeine (adjusted HR 2.05; 95% CI, 1.08-3.86). In the highly restricted sub-cohort, the useof tramadol was associated with an over 3-fold increased risk of hospitalization for hyponatremia, comparedwith codeine (adjusted HR 3.54; 95% CI, 1.32-9.54).CONCLUSIONS: In this first population-based study, the use of tramadol was associated with an increasedrisk of hyponatremia requiring hospitalization.� 2015 Elsevier Inc. All rights reserved. � The American Journal of Medicine (2015) 128, 418-425
KEYWORDS: Adverse drug reaction; Codeine; Cohort study; Hyponatremia; Tramadol
s study was funded in part by research grants from thes of Health Research and Canada Foundation for Inno-
terest: None.ll authors participated in the study design. LA acquiredand HY did the statistical analyses. JPF wrote the initialrs critically revised the manuscript. LA is the guarantor.eprints should be addressed to Laurent Azoulay, PhD,l Epidemiology, Lady Davis Institute, Jewish Generalôte Sainte-Catherine, H-425.1, Montreal, Quebec H3T
front matter � 2015 Elsevier Inc. All rights reserved.0.1016/j.amjmed.2014.10.046
Tramadol is a weak opioid analgesic used for the treatmentof moderate to severe pain. Its use has increased steadilyworldwide, including in the US, where there was a 1.5-foldincrease in the dispensing of tramadol between 2007 and2011.1 In recent years, however, there have been severalcase reports and a signal from a pharmacovigilance databasethat have associated the use of this opioid with hypona-tremia, all of which occurred rapidly (within the first30 days) after initiation.2-6
Hyponatremia (a serum sodium concentration <135mmol/L), is an overlooked but important clinical event.7,8
Profound (<125 mmol/L) hyponatremia may be associated
Fournier et al Tramadol and the Risk of Hyponatremia 419
with important negative clinical outcomes, ranging fromconfusion, seizures, and coma, to even death.9 Drug-inducedhyponatremia is a well-documented etiology of this condi-tion. Indeed, it has been shown that some prescription drugs,such as selective serotonin reuptake inhibitors (SSRIs) andopioids, may induce syndrome of inappropriate antidiuretic
CLINICAL SIGNIFICANCE
� In a large population-based cohort, theinitiation of tramadol was associatedwith an at-least 2-fold increased risk ofhospitalization for hyponatremia, whencompared with codeine.
� This increased risk was limited to the first30 days of use.
� Physicians should be aware of this rarebut clinically significant adverse drugevent.
hormone secretion (SIADH), re-sulting in hyponatremic events.10
With respect to tramadol, it hasbeen hypothesized that it may in-crease the risk of hyponatremia byactivating m-receptors or inhibitingserotonin-norepinephrine reup-take.11 To date, no population-based study has investigated theassociation between tramadol andthis clinically significant event.
Thus, given the increasing useof tramadol and the negative con-sequences of hyponatremia, weconducted a large population-based study to assess whether theuse of tramadol, when compared
with codeine, another weak opioid, is associated with anincreased risk of hyponatremia.
METHODS
Data SourcesThis cohort study was conducted using 2 databases fromthe UK: Clinical Practice Research Datalink (CPRD) andHospital Episode Statistics (HES) databases. The CPRDdatabase includes the longitudinal patient records of over 13million patients from over 680 general practices in the UK.Patients registered in the CPRD have been shown to be arepresentative sample of the UK population in terms of ageand sex distributions.12 The CPRD records information ondiagnoses, prescriptions, referrals to specialists, lifestylehabits (such as smoking and excessive alcohol use), andanthropometric measurements such as body mass index. TheRead code classification is used to enter medical diagnosesand procedures, and a coded drug dictionary based on the UKPrescription Pricing Authority Dictionary is used for re-cording drug prescriptions. All information in the CPRD isregularly audited and has been shown to be highly valid.13,14
For the purposes of this study, the CPRD was linked tothe HES database. This database records information ondates of hospital admissions, discharge diagnoses codedusing International Classification of Diseases, 10th Revision(ICD-10), and related procedures (coded using ICD-10 andOffice of Population Censuses and Surveys Classification ofInterventions and Procedures, 4th version [OPCS-4]).
The study protocol was approved by the IndependentScientific Advisory Committee of the CPRD (protocol14_099RAR) and by the Research Ethics Board of theJewish General Hospital, Montreal, Canada.
Study PopulationPrimary Cohort. Using the CPRD population, we assem-bled a primary cohort composed of patients newly treatedwith oral formulations of tramadol or codeine (excludingformulations for cough or diarrhea) between April 1, 1998and March 1, 2012. The cohort entry date was defined as the
date of the first prescription forthese drugs during the studyperiod. Patients were required tobe at least 18 years of age, andhave at least 1 year of medicalhistory in the CPRD and HESbefore cohort entry. Patients con-currently prescribed other opioidsat cohort entry were excluded, aswere those previously diagnosedwith any cancer (other than non-melanoma skin cancer) at any timebefore cohort entry. Finally, weexcluded patients with previousclinically significant episodes ofhyponatremia in the year beforecohort entry. These were defined
as outpatient laboratory serum sodium test results at mod-erate (125-129 mmol/L) or profound (<125 mmol/L) levels,hospitalizations for hyponatremia or SIADH (ICD-10 codesE87.1 and E22.2, in primary or secondary position), or useof vasopressin receptor antagonists.
Highly Restricted Sub-cohort. To further minimize anypotential residual confounding, we assembled a highlyrestricted sub-cohort,15 which was constructed by applyingadditional exclusion criteria to the primary cohort. There-fore, patients in the highly restricted sub-cohort wereadditionally required to have at least one serum sodiumlaboratory test in the year before cohort entry, and with notest result outside the reference range (135-145 mmol/L) atany time during that time period (ie, excluding patients withmild hyponatremia [130-134 mmol/L] or hypernatremia[>145 mmol/L]). Furthermore, we excluded patients withnonhospitalized hyponatremia or hypernatremia, as well aspatients with hospitalized hypernatremia (ICD-10 code:E87.0, in primary or secondary position) in the year beforecohort entry. Thus, the highly restricted sub-cohort con-sisted of patients with no evidence of any serum sodiumlevel abnormality in the year before cohort entry (ie, nor-monatremic patients).
Follow-up. Patients in the cohorts described above wereconsidered continuously exposed (analogous to an inten-tion-to-treat approach) from cohort entry until the outcome(hospitalization for hyponatremia, recorded within the first 2days of admission; ICD-10 codes E87.1 [hyponatremia] andE22.2 [SIADH], in primary or secondary position), a hos-pitalization unrelated to hyponatremia, death from anycause, end of registration in the practice, end of the 30-day
420 The American Journal of Medicine, Vol 128, No 4, April 2015
follow-up period, or end of the study period (March 31,2012), whichever occurred first.
Potential ConfoundersAll models were adjusted for propensity score quintiles,which were calculated using multivariate logistic regressionanalysis as the probability of being exposed to tramadol vscodeine, conditional on 57 predefined baseline covariates.These covariates consisted of age, sex, calendar year of cohortentry, bodymass index, smoking status, excessive alcohol use(defined as alcohol-related disorders such as alcoholism,alcoholic cirrhosis of the liver, alcoholic hepatitis, and hepaticfailure), comorbidities (mild hyponatremia [defined as aserum sodium between 130 and 134 mmol/L or a nonhospi-talized hyponatremia], renal diseases [acute kidney injury,chronic renal diseases, and nephrotic syndromes], liver dis-ease, pancreatic disease, chest infections, asthma and chronicobstructive pulmonary disease, congestive heart failure, hy-pothyroidism [defined by diagnostic codes or thyroid hor-mone therapies], adrenal insufficiency, diabetes insipidus,cerebrovascular diseases, meningitis, and encephalitis; allmeasured in the year before cohort entry), co-medications10
(diuretics [thiazides, loop diuretics, others], angiotensin-converting enzyme inhibitors, angiotensin receptorblockers, beta-blockers, calcium channel blockers, other an-tihypertensives, fibrates, amiodarone, SSRIs, serotoninnorepinephrine reuptake inhibitors [SNRIs], other antide-pressants, carbamazepine, valproic acid, other antiepileptics,antiparkinson drugs, proton pump inhibitors, vasopressinanalogues, mineralocorticoids, fluoroquinolones, cotrimox-azole, macrolides, other antibiotics, dextropropoxyphene,other opioids, aspirin, nonsteroidal anti-inflammatory drugs,all measured in the 90 days before cohort entry), as well asproxies of health status (number of general practice visits andnumber of hospitalizations in the year before cohort entry, andnumber of prescription drugs in the 90 days before cohortentry), and finally, known indications for tramadol and co-deine (type of pain [headache, abdominal and pelvic pain,musculoskeletal pain, neuralgia, other pain], and pain-relatedevents [injury-trauma, surgery]; all measured in the 90 daysbefore cohort entry). Variables with missing data were codedwith an “unknown” category.
Overall, there was excellent overlap in the propensityscore distributions between the exposure groups(Supplementary Figures 1 and 2, available online), in boththe primary cohort and highly restricted sub-cohort. Bothpropensity score models had a c-statistic of 0.64.
Statistical AnalysisDescriptive statistics were used to summarize the charac-teristics of tramadol and codeine users. Crude incidencerates of hospitalization for hyponatremia, with 95% confi-dence intervals (CIs) based on the Poisson distribution, werecalculated for each exposure group.
Kaplan-Meier curves were plotted to compare the cumu-lative incidence of hospitalization for hyponatremia of
tramadol and codeine users up to 30 days after initiation. Coxproportional hazards models were used to estimate crude andpropensity score quintile-adjusted hazard ratios (HRs) with95% CIs of hospitalization for hyponatremia, associated withthe use of tramadol, compared with codeine. The propor-tionality assumption was met based on Schoenfeld residuals.
Secondary Analyses. We conducted 2 secondary analyses.First, as alternate outcome definition, we used outpatientlaboratory sodium serum test results in the 30 days aftertreatment initiation. For this analysis, we assessed the as-sociation between the use of tramadol and moderate hypo-natremia (125-129 mmol/L), as well as the association withprofound hyponatremia (<125 mmol/L). Finally, the pri-mary analysis was stratified by age (using 65 years as thecutoff), given the association between increasing age andthe risk of hyponatremia.
Sensitivity Analyses. We conducted a series of sensitivityanalyses to ascertain the robustness of the results. First, theaccuracy of the outcome was assessed by restricting theevents to those coded in primary position, while censoringthose in secondary position. Second, as burns and thepostoperative period have been associated with anincreased risk of hyponatremia,7,8,16 we repeated the pri-mary analysis after excluding patients with these events inthe 90 days before cohort entry. Third, while all effortswere directed at identifying new users of tramadol andcodeine, it was possible that some patients may have beenprevalent users if they received prescriptions for thesedrugs in the hospital setting (the CPRD does not recordinpatient prescriptions). To assess this possible misclassi-fication, we repeated the primary analysis after excludingpatients hospitalized for any cause in the 30 daysimmediately before cohort entry. Fourth, we conducted anas-treated analysis, where patients were consideredcontinuously exposed to tramadol or codeine if theyreceived successive overlapping prescriptions, allowing agrace period of 20% based on the duration of last pre-scription. Thus, patients not receiving a subsequent pre-scription were censored at the end of the grace period, aswere patients who added or switched to any other weakopioid. Finally, we assessed the potential of residual con-founding by fitting the outcome model with high-dimensional propensity score (HD-PS) quintiles.17 TheHD-PS algorithm is an automated technique that examinesthousands of candidate covariates that might be proxies forunmeasured confounders among different data dimensionsin the study population (such as prescription drugs, di-agnoses, and procedures; additional information is providedin the Appendix material). All analyses were performedusing SAS version 9.3 (SAS Institute Inc., Cary, NC).
RESULTSA cohort of 332,880 patients met the study inclusioncriteria, which included 27,951 tramadol users and 304,929
Fournier et al Tramadol and the Risk of Hyponatremia 421
codeine users (Figure 1). Table 1 presents the baselinecharacteristics of tramadol and codeine users included inthe primary cohort. Overall, tramadol and codeine userswere similar with respect to age, sex, comorbidities, andprescription drug use. In contrast, tramadol users weremore likely to have undergone surgery in the 90 daysbefore cohort entry, compared with codeine users.
During the 320,613 person-months of follow-up, therewere 68 hospitalizations for hyponatremia, generating anincidence rate of 2.1 (95% CI, 1.6-2.7) per 10,000 person-months. Of these, 8 (11.7%) were fatal.
Compared with codeine, the use of tramadol was asso-ciated with a higher cumulative incidence of hospitalizedhyponatremia, with the risk highest in the first 30 days afterinitiation (log-rank P-value ¼ .01, Figure 2). In thepropensity score-adjusted model, the use of tramadol wasassociated with a 2-fold increased risk of hospitalization forhyponatremia, compared with codeine (adjusted HR 2.05;95% CI, 1.08-3.86; Table 2).
In the age-stratified analysis, the use of tramadol wasassociated with a nearly 5-fold increased risk of hospitali-zation for hyponatremia in patients younger than 65 years ofage (adjusted HR 4.98; 95% CI, 1.29-19.18). The HR waselevated in patients over 65 years of age, but did not achieve
Patients newly-treated with tramadol for non-cancer pain
(n=27,951)
Patients prescribed tramadol or codApril 1, 1998 and March 1,
(n=734,690)
Patients newly-treated with tramadonly between April 1, 1998 and M
(n=446,869)
Excluded (n=5654)Patients with any cancer (n=5474)Patients with history of hospitalization for hyponatremia or SIADH in the previous year (n=45)Laboratory-confirmed serum sodium concentrations <130 mmol/L (n=131)No follow-up (n=3)Non overlapping propensity score distribution (n=1)
P
Patients newly-treated with oral formulation of tramadol
Highly Restricted Sub-cohortA total of 91,796 (27.6%) patients were included in thehighly restricted sub-cohort, with 9151 tramadol and 82,645codeine users. Overall, tramadol and codeine users hadsimilar baseline demographic and clinical characteristics(Supplementary Table 2, available online). In this highlyrestricted sub-cohort, the use of tramadol was associatedwith an over 3-fold increased risk of hospitalization forhyponatremia (adjusted HR 3.54; 95% CI, 1.32-9.54;Table 3).
Laboratory Serum Sodium-based OutcomesDuring the 30-day follow-up, 2190 (7.8%) tramadol and21,379 (7.0%) codeine users had at least one serum sodiumlaboratory test. Overall, there was a total of 39 profoundhyponatremia events (<125 mmol/L) and 200 moderatehyponatremia events (125-129 mmol/L). Compared withcodeine, the use of tramadol was not associated with anincreased risk of moderate hyponatremia (adjusted HR 1.00;
eine between 2012
ol or codeine arch 1, 2012
Excluded (n=287,821)<18 years of age (n=18,239)<1 year of baseline medical history or date inconsistencies (n=242,392)>1 opioid at treatment initiation (n=8714)Use of tramadol or codeine before April 1, 1998 (n=18,476)
Excluded (n=67,000)Patients treated with injectable or transdermal tramadol or codeine (n=41)Patients treated with codeine formulations marketed for cough or diarrhoea (n=66,959)
atients newly-treated with codeinefor non-cancer pain
(n=304,929)
atients newly-treated with oral formulation of codeine
(n=346,264)
Excluded (n=41,335)Patients with any cancer (n=40,196)Patients with history of hospitalization for hyponatremia or SIADH in the previous year (n=205)Laboratory-confirmed serum sodium concentrations <130 mmol/L (n=874)No follow-up (n=33)Non overlapping propensity score distribution (n=27)
f inappropriate antidiuretic hormone secretion.
Table 1 Baseline Characteristics of Patients Initiating OralFormulations of Tramadol and Codeine for Noncancer Pain
Baseline CharacteristicsTramadol(n ¼ 27,951)
Codeine(n ¼ 304,929)
Male, n (%) 12,111 (43.3) 121,076 (39.7)Age (years), mean (SD) 52.2 (17.8) 50.7 (19.0)Body mass index, n (%)
*In the year before cohort entry.†In the 90 days before cohort entry.‡Nonmutually exclusive categories.§Cells with <5 patients are not displayed, as per Clinical Practice
Research Datalink confidentiality policies.
422 The American Journal of Medicine, Vol 128, No 4, April 2015
95% CI, 0.62-1.61, Supplementary Table 2, available on-line). In contrast, the incidence rate of profound hypona-tremia was higher in tramadol compared with codeine users(2.3 vs 1.1 per 10,000 person-months, respectively), but didnot achieve statistical significance (adjusted HR 1.88; 95%CI, 0.78-4.56, Supplementary Table 3, available online).
Sensitivity AnalysesOverall, the sensitivity analyses yielded results that wereconsistent with those of the primary analysis (SupplementaryTables 4-8, available online).
DISCUSSIONTo our knowledge, this is the first population-based study toinvestigate the association between the use of tramadol andthe risk of hyponatremia. Overall, the use of this opioid wasassociated with a 2-fold increased risk of hospitalization for
Figure 2 Time to first hospitalization for hyponatremia for patients newly treated with tra-madol and codeine, in the first 30 days after treatment initiation.
Fournier et al Tramadol and the Risk of Hyponatremia 423
hyponatremia, when compared with codeine. Furthermore, a>3-fold increased risk was observed in a highly restrictedsub-cohort of patients with no evidence of any serum so-dium abnormality. Overall, the results remained consistentin a number of secondary and sensitivity analyses.
Four case reports have previously described hypona-tremia in patients at least 70 years of age using tramadol atrecommended dosages.2-4 In each of these cases, hypona-tremia occurred rapidly (between 2 and 9 days after initia-tion), was profound (<125 mmol/L), and was associatedwith clinical complications (confusion, falls, or seizures). Inall cases, SIADH was determined to be the basis for thehyponatremia. Profound hyponatremia due to SIADH hasalso been reported in a patient with an intentional tramadoloverdose.5 Additionally, a recent analysis of a Frenchpharmacovigilance database identified that, among the 296serious adverse drug reactions reported with tramadol be-tween 2010 and 2011, 5 (2.1%) were hyponatremia, 3 ofwhich were confirmed SIADH.6
The analgesic properties of tramadol rely on 2 pharma-codynamic pathways: activation of m-opioid receptors andthe inhibition of central reuptake of serotonin and norepi-nephrine (the latter pathway differentiates tramadol fromcodeine, the active comparator).11 These 2 pharmacologicalmechanisms may be implicated in the increased risk ofhyponatremia observed with tramadol. Firstly, opioids areknown to have multiple effects on renal regulation of water
Table 2 Crude and Adjusted Hazard Ratios of Hospitalization for HypPatients with Noncancer Pain in the Primary Cohort
Exposure No. of Patients No. of Events Person-monthsInc(Pe
CI ¼ 95% confidence interval; HR ¼ hazard ratio.*Adjusted for propensity score quintiles.
excretion, including stimulation of antidiuretic hormone,resulting in impaired free water excretion.18 Secondly, tra-madol may additionally mediate its effect through the in-hibition of central reuptake of serotonin and norepinephrine.Serotonin has complex effects on aquaresis, includingincreased release of antidiuretic hormone (via 5-HT2 and5-HT1c receptors) that may lead to SIADH.19 The use ofdrugs acting on serotonin pathways (SSRIs and SNRIs an-tidepressants) has long been known to be associated with anincreased risk of hyponatremia.20-22
The strengths of this study include the use of the CPRDlinked to HES database, which allowed the assembly of alarge population-based cohort of patients newly treated withtramadol and codeine in the natural setting of clinicalpractice. These databases also allowed us to take into ac-count a large number of potential confounders in the pro-pensity score model. Also, both databases were used toassess the risk of hyponatremia using 2 complementaryoutcome definitions (ie, hospitalization and laboratory-basedvalues), which brought consistency to the study results.Furthermore, the new-user design avoided biases related tothe inclusion of prevalent users.23 Finally, the use of codeineas an active comparator (which has an equipotent analgesiceffect as tramadol24), likely minimized any confounding byindication, as evidenced by the remarkably similar baselinecharacteristics of tramadol and codeine users. Indeed, thelow c-statistic for the propensity score model (0.64) is
onatremia Associated with Tramadol, Compared with Codeine, in
Table 3 Crude and Adjusted Hazard Ratios Hospitalization of Hyponatremia Associated with Tramadol, Compared with Codeine, inPatients with Noncancer Pain in the Highly Restricted Sub-cohort
Exposure No. of Patients No. of Events Person-monthsIncidence Rate(Per 10,000 Person-months) Crude HR Adjusted HR (95% CI)*
Note: The highly restricted sub-cohort consisted of restricting the primary cohort to patients with no history of hyponatremia or hypernatremia in theyear before cohort entry, and with baseline serum sodium levels in the reference range (135 to 145 mmoL/L).
CI ¼ confidence interval; HR ¼ hazard ratio.*Adjusted for propensity score quintiles.
424 The American Journal of Medicine, Vol 128, No 4, April 2015
indicative of good balance in the covariate distributionsbetween the exposure groups.25
This study does have some limitations. First, CPRD pre-scriptions represent those written by general practitioners andit is unknown whether patients complied with the treatment.However, it is unlikely that this possible misclassification ofexposure was different between the exposure groups. Second,while ICD-10 codes for hyponatremia have not been vali-dated in the HES database, validation studies conducted insimilar databases have reported high specificities, but lowsensitivities.26,27 Thus, while hospitalization for hypona-tremia may be underestimated in the HES database, we do notexpect it to be different between tramadol and codeine users.As with any observational study, residual confounding needsto be considered. However, we observed consistent resultswith different design (highly restricted sub-cohort) and ana-lytic (HD-PS) approaches, suggesting that residual con-founding was likely minimal.
The results of this large population-based study suggestthat, compared with codeine, the use of tramadol is asso-ciated with an at least 2-fold increased risk of hyponatremiarequiring hospitalization. Given the potential life-threatening consequences of hyponatremia, physiciansshould be aware of this possible association, and shouldexercise caution when initiating this drug.
APPENDIXSupplementary data associated with this article can be foundin the online version at http://dx.doi.org/10.1016/j.amjmed.2014.10.046.
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Appendix
Supplementary Figure 1 Propensity score density distributions for new users of oralformulations of tramadol and codeine in the primary cohort.
Supplementary Figure 2 Propensity score dformulations of tramadol and codeine in the higrestricted sub-cohort consisted of restricting the phyponatremia or hypernatremia in the year befosodium levels in the reference range (135 to 145
ensity distributions for new users of oralhly-restricted sub-cohort. Note: The highlyrimary cohort to patients with no history ofre cohort entry, and with baseline serummmoL/L).
Supplementary Table 1 Crude and Adjusted Hazard Ratios for Severe Hospitalization for Hyponatremia Associated with Tramadol,Compared with Codeine, in Patients with Noncancer Pain, Stratified by Age
Exposure No. of Patients No. of Events Person-monthsIncidence Rate(Per 10,000 Person-months) Crude HR Adjusted HR (95% CI)*
Less than 65 yearsCodeine 228,196 8 221,122 0.4 (0.2-0.7) 1.00 1.00 (reference)Tramadol 21,028 <5† e† e† 4.12 4.98 (1.29-19.18)
More than 65 yearsCodeine 76,733 48 73,173 6.6 (4.8-8.7) 1.00 1.00 (reference)Tramadol 6923 9 6383 14.1 (6.4-26.8) 2.14 1.83 (0.89-3.78)
CI ¼ confidence interval; HR ¼ hazard ratio.*Adjusted for propensity score quintiles.†Cells with <5 patients are not displayed, as per Clinical Practice Research Datalink confidentiality policies.
Fournier et al Tramadol and the Risk of Hyponatremia 425.e2
Supplementary Table 2 Baseline Characteristics of PatientsInitiating Oral Formulations of Tramadol and Codeine for Non-cancer Pain (Highly Restricted Sub-cohort)
Baseline CharacteristicsTramadol(n ¼ 9151)
Codeine(n ¼ 82,645)
Male, n (%) 3931 (43.0) 34,421 (41.7)Age (years), mean (SD) 57.9 (17.1) 57.9 (18.1)Body mass index, n (%)
The highly restricted sub-cohort consisted of restricting the primarycohort to patients with no history of medical diagnosis of hyponatremia,no medical diagnosis of hospitalization for hypernatremia in the yearbefore cohort entry, and with baseline serum sodium in the referencerange (135-145 mmoL/L).
*In the year before cohort entry.†In the 90 days before cohort entry.‡Non-mutually exclusive categories.§Cells with <5 patients are not displayed, as per Clinical Practice
Research Datalink confidentiality policies.
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Supplementary Table 3 Crude and Adjusted Hazard Ratios of Moderate (Serum Sodium between 125 and 129 mmol/L) and ProfoundHyponatremia (Serum Sodium Concentration <125 mmol/L) Associated with Tramadol, Compared with Codeine, in Patients with NoncancerPain
Exposure No. of Patients No. of Events Person-monthsIncidence Rate(Per 10,000 Person-months) Crude HR Adjusted HR (95% CI)*
CI ¼ confidence interval; HR ¼ hazard ratio.*Adjusted for propensity score quintiles.
Supplementary Table 4 Crude and Adjusted Hazard Ratios of Hospitalization for Hyponatremia Associated with Tramadol, Comparedwith Codeine, in Patients with Noncancer Pain, Restricting the Events to Those Coded in Primary Position
Exposure No. of Patients No. of Events Person-monthsIncidence Rate(Per 10,000 Person-months) Crude HR Adjusted HR (95% CI)*
CI ¼ confidence interval; HR ¼ hazard ratio.*Adjusted for propensity score quintiles.†Cells with <5 patients are not displayed, as per Clinical Practice Research Datalink confidentiality policies.
Supplementary Table 5 Crude and Adjusted Hazard Ratios of Hospitalization for Hyponatremia Associated with Tramadol, Comparedwith Codeine, in Patients with Noncancer Pain, Restricting the Cohort to Patients without Burn or Surgery in the 90 Days before CohortEntry
Exposure No. of Patients No. of Events Person-monthsIncidence Rate(Per 10,000 Person-months) Crude HR Adjusted HR (95% CI)*
CI ¼ confidence interval; HR ¼ hazard ratio.*Adjusted for propensity score quintiles.
Supplementary Table 6 Crude and Adjusted Hazard Ratios of Hospitalization for Hyponatremia Associated with Tramadol, Comparedwith Codeine, in Patients with Noncancer Pain, Restricting the Cohort to Patients without Hospitalization in the 30 Days Before CohortEntry
Exposure No. of Patients No. of Events Person-monthsIncidence Rate(Per 10,000 Person-months) Crude HR Adjusted HR (95% CI)*
CI ¼ confidence interval; HR ¼ hazard ratio.*Adjusted for propensity score quintiles.
Fournier et al Tramadol and the Risk of Hyponatremia 425.e4
Supplementary Table 7 Crude and Adjusted Hazard Ratios of Severe Hospitalization for Hyponatremia Associated with Tramadol,Compared with Codeine, in Patients with Noncancer Pain (As-treated Analysis)
Exposure No. of Patients No. of Events Person-monthsIncidence Rate(Per 10,000 Person-months) Crude HR Adjusted HR (95% CI)*
CI ¼ confidence interval; HR ¼ hazard ratio.*Adjusted for propensity score quintiles.
Supplementary Table 8 Crude and Adjusted Hazard Ratios of Severe Hospitalization for Hyponatremia Associated with Tramadol,Compared with Codeine, in Patients with Noncancer Pain (High-dimensional Propensity Score Adjustment)
Exposure No. of Patients No. of Events Person-monthsIncidence Rate(Per 10,000 Person-months) Crude HR Adjusted HR (95% CI)*
In the fourth sensitivity analysis, all models were adjusted for high-dimensional propensity score (HD-PS) quintiles, which is a method that empiricallyselects covariates based on their prevalence and potential for confounding. Thus, for each patient, we used multivariate logistic regression to calculate apropensity score, which was the probability of being exposed to tramadol oral monotherapy compared with codeine, conditional on 500 empiricallyidentified and 57 predefined covariates measured at cohort entry. The empirical covariates were estimated from 7 data dimensions (i. drug prescriptions, ii.procedures, iii. diagnoses, iv. disease history, v. administrative information, and hospitalizations [vi. diagnoses and vii. procedures]), while the 57 pre-defined covariates consisted of the following variables: age, sex, calendar year of cohort entry, body mass index, smoking status, excessive alcohol use(defined as alcohol-related disorders such as alcoholism, alcoholic cirrhosis of the liver, alcoholic hepatitis, and hepatic failure), comorbidities previouslyassociated with an increased risk of hyponatremia (mild hyponatremia [defined as a serum sodium between 130 and 134 mmol/L or a nonhospitalizedhyponatremia], renal diseases [acute kidney injury, chronic renal diseases, and nephrotic syndromes], liver disease, pancreatic disease, chest infections,asthma and chronic obstructive pulmonary disease, congestive heart failure, hypothyroidism [defined by diagnostic codes or thyroid hormone therapies],adrenal insufficiency, diabetes insipidus, cerebrovascular diseases, meningitis, and encephalitis; all measured in the year before cohort entry), co-medications associated with an increased risk of hyponatremia10 (diuretics [thiazides, loop diuretics, others], angiotensin-converting enzyme inhibitors,angiotensin receptor blockers, beta-blockers, calcium channel blockers, other antihypertensives, fibrates, amiodarone, selective serotonin reuptake in-hibitors, serotonin norepinephrine reuptake inhibitors, other antidepressants, carbamazepine, valproic acid, other antiepileptics, antiparkinson drugs,proton pump inhibitors, vasopressin analogues, mineralocorticoids, fluoroquinolones, co-trimoxazole, macrolides, other antibiotics, dextropropoxyphene,other opioids, aspirin, nonsteroidal anti-inflammatory drugs, all measured in the 90 days before cohort entry), as well as proxies of health status (number ofgeneral practice visits and number of hospitalizations in the year before cohort entry, and number of prescription drugs in the 90 days before cohort entry),and finally, known indications for tramadol and codeine (type of pain [headache, abdominal and pelvic pain, musculoskeletal pain, neuralgia, other pain],and pain-related events [injury-trauma, surgery]; all measured in the 90 days before cohort entry).
Overall, there was excellent overlap in the propensity score distributions between the exposure groups, with only 109 patients trimmed due tononoverlapping propensity scores. The HD-PS model had a c-statistic of 0.69.
CI ¼ confidence interval; HR ¼ hazard ratio.*Adjusted for high-dimensional propensity score quintiles.
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