SUPPLEMENT Etable 1

Home , Cyclopentolate, Homatropine, Metharbital, Paramethadione, Phenacemide, Phensuximide

SUPPLEMENT eTable 1. List of medications used for exclusions and prescription drug history variables Anticonvulsants (past use Medications used for prescription drug history variables evaluated as an exclusion criterion) Antidepressants Anticholinergics Carbamazepine Bupropion Aclidinium Clobazam Atropine Clonazepam Other antidepressants: Cyclopentolate Clorazepate Amitriptyline Glycopyrrolate Diazepam Amoxapine Homatropine Divalproex Butriptyline Ipratropium Ethosuximide Citalopram Methscopolamine Ethotoin Clomipramine Scopolamine Ezogabine Desipramine Tiotropium Felbamate Desvenlafaxine Tropicamide Fosphenytoin Dibenzepin Gabapentin Dotheipin Lacosamide Doxepin Lamotrigine Duloxetine Levetiracetam Escitalopram Lorazepam Fluoxetine Mephenytoin Fluvoxamine Mephobarbital Imipramine Metharbital Iprindole Methsuximide Isocarboxazid Oxcarbazepine Levomilnacipran Paramethadione Lofepramine Phenacemide Maprotiline Phenobarbital Melitracen Phensuximide Mianserin Phenytoin Milnacipran Pregabalin Mirtazapine Primidone Nefazodone Rufinamide Nortriptyline Tiagabine Opipramol Topiramate Paroxetine Trimethadione Phenelzine Valproate Sodium Protriptyline Valproic Acid Sertraline Vigabatrin Tranylcypromine Zonisamide Trazodone Trimipramine Tryptophan Venlafaxine Vilazodone

eTable 2. Diagnostic codes used for medical history variables

Medical condition Diagnostic codes (ICD-9)a Stroke 431.xx, 433.xx, 434.xx, 436.xx Other cerebrovascular 430.xx, 432.xx, 435.xx, 437.xx, 438.xx disease Brain injury 850.xx-854.xx, 907.0x Hypoxemia 799.02 Infection 001.xx-039.xx Alzheimer's disease 331.0x, 290.1x Depression 296.2x, 296.3x, 300.4x, 311.xx Anxiety 300.0x, 300.2x, 300.3x Head injury 348.4x, 348.5x, 800.xx-804.xx, 830.xx, 850.xx-854.xx, 873.xx, 900.xx, 920.xx, 959.01, E927.3 Malnutrition 260.xx-263.xx Diabetes 250.xx Cancer 140.xx-239.xx aICD-9=International Classification of Diseases, version 9

eTable 3. Dose-response analysis of association between tramadol use and seizure (sensitivity analysis with revised dose categories)

Exposure within 90 days Cases Controls Crude OR Adjusted ORc (daily dose)a n (%) n (%) (95% CI) (95% CI)

(a) Primary analysis (sensitive seizure definition):

Tramadol, <=150 mg 956 (0.99) 3,609 (0.41) 1.10 (0.97, 1.25) 1.04 (0.91, 1.19) Tramadol, >150 to 250 mg 971 (1.00) 3,614 (0.41) 1.15 (1.01, 1.31) 1.12 (0.98, 1.28) Tramadol, >250 mg 870 (0.90) 3,292 (0.37) 1.18 (1.04, 1.35) 1.15 (1.01, 1.31)

Codeine, <=120 mg 426 (0.44) 1,783 (0.20) 1 (reference) 1 (reference) Codeine, >120 to 200 mg 461 (0.48) 1,975 (0.22) 1.02 (0.88, 1.18) 1.05 (0.90, 1.22) Codeine, >200 mg 339 (0.35) 1510 (0.17) 0.99 (0.85, 1.17) 1.01 (0.86, 1.19)

b Both therapies 106 (0.11) 240 (0.03) 1.93 (1.50, 2.49) 1.70 (1.31, 2.21) No exposure 92,624 (95.73) 872,517 (98.20) 0.49 (0.44, 0.55) 0.58 (0.52, 0.65)

(b) Secondary analysis (specific seizure definition):

Tramadol, <=150 mg 215 (1.05) 790 (0.39) 1.57 (1.17, 2.10) 1.51 (1.12, 2.04) Tramadol, >150 to 250 mg 207 (1.01) 765 (0.37) 1.55 (1.16, 2.09) 1.53 (1.13, 2.07) Tramadol, >250 mg 211 (1.03) 738 (0.36) 1.63 (1.22, 2.19) 1.68 (1.24, 2.27)

Codeine, <=120 mg 72 (0.35) 407 (0.20) 1 (reference) 1 (reference) Codeine, >120 to 200 mg 75 (0.37) 421 (0.21) 1.01 (0.71, 1.44) 1.06 (0.74, 1.52) Codeine, >200 mg 71 (0.35) 319 (0.16) 1.25 (0.87, 1.79) 1.28 (0.88, 1.84)

b Both therapies 30 (0.15) 50 (0.02) 3.44 (2.05, 5.77) 3.13 (1.82, 5.36) No exposure 19,626 (95.70) 201,041 (98.29) 0.55 (0.43, 0.71) 0.65 (0.50, 0.84)

OR=odds ratio aAverage daily dose dispensed during the 90-day exposure window. bPatients with exposure at any dosage to both tramadol and codeine were categorized under 'Both therapies.' cAdjusted for co-morbidities and health services use in the year prior to cohort entry: history of stroke, other cerebrovascular disease, brain injury, hypoxemia, infection, Alzheimer’s disease, depression, anxiety, head injury, malnutrition, diabetes or cancer (in hospital or outpatient diagnoses); the number of hospitalizations (0, 1, 2 or >=3); the number of drugs dispensed; and receipt of one or more prescriptions of bupropion, other antidepressants, or anticholinergics.