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Legends to Supplemental Figures

Supplemental Figure 1. Model by surgery type. The significance of the predictive model was assessed for each surgery type. The model coefficients correlated significantly with pain on POD1 for each surgery type (p<0.001). Bars, boxes, and whiskers represent the median, interquartile range, and 95% confidence interval, respectively.

Supplemental Figure 2. Model by study center. The significance of the predictive model was assessed for the three centers contributing the largest numbers of patients. The model coefficients correlated significantly with pain on POD1 for each center (p<0.03). Bars, boxes, and whiskers represent the median, interquartile range, and 95% confidence interval, respectively.

Supplemental Figure 3. Additional clinical and pharmacological parameters. Other model parameters correlated with pain on POD1 including: surgery duration (A), preoperative pain (B), intraoperative dose (C), volatile anesthetic use (D), and sex (E) (all parameters p<0.001). Black bars, boxes, and whiskers represent the median, interquartile range, and 95% confidence interval, respectively.

Supplemental Table 1: Case Load by Country

Number of Number Country Percent Institutions of cases Czech Republic 1 197 19.5 France 1 93 9.2 3 191 18.9 Israel 1 11 1.1 Italy 2 6 0.6 Malaysia 1 2 0.2 Serbia 1 4 0.4 Spain 5 61 6.1 Sweden 1 86 8.5 Switzerland 3 253 25.1 United Kingdom 1 10 1.0 United States of America 4 94 9.3

Supplemental Table 2: Medication Dosing Information

Dose Dose Medication (median and interquartile Medication (median and interquartile range) range)

Chronic use Intraoperative medication continued TC (mcg/h) 28 (25‐50) Non‐opioid PO (mg) 8 (6‐15) Acetaminophen IV (mg) 1000 (1000‐1000) PO (mg) 20 (11‐38) IV (mg) 75 (75‐75) Tilidine PO (mg) 160 (100‐200) IV (mg) 50 (50‐50) PO (mg) 200 (100‐225) IV (mg) 30 (30‐30) Metamizol IV (mg) 1000 (1000‐1500) Preoperative medication (IV (mg) 20 (20‐20) Fentanyl IV (mcg) 100 (100‐150) Recovery room medication Oxycodone PO (mg) 10 (5‐20) Opioids Tilidine PO (mg) 200 (100‐200) IV (mg) 8 (5‐15) Tramadol PO (mg) 140 (100‐200) Tramadol IV (mg) 100 (100‐100) Non‐opioid analgesics Non‐opioid analgesics Acetaminophen PO (mg) 1000 (1000‐1000) Acetaminophen IV/PO (mg) 1000 (1000‐1000) Diclofenac PO (mg) 75 (75‐150) Celebrex PO (mg) 200(100‐200) PO (mg) 90 (90‐90) PO (mg) 50 (50‐50) PO (mg) 600 (600‐750) Diclofenac IM (mg) 75 (75‐75) PO (mg) 1200 (800‐1600) Diclofenac IV (mg) 75 (50‐75) Metamizol PO (mg) 1000 (1000‐1500) Ibuprofen PR (mg) 500 (500‐500) PO (mg) 75 (75‐150) Ketoprofen IV (mg) 50 (50‐50) Sedatives Ketorolac IV (mg) 30 (30‐60) Midazolam PO (mg) 8 (8‐8) Metamizol IV and PO (mg) 1000 (1000‐1000) Midazolam IV (mg) 2 (2‐2) Nefopam IV and PO (mg) 20 (20‐20) IV and PO (mg) 40 (40‐40) Intraoperative medication Pregabalin PO (mg) 50 (50‐50) Opioids Sedatives Fentanyl IV (mcg) 250 (100‐450) IV (mcg) 45 (45‐55) Morphine IV (mg) 10 (7‐10) Ketamine IV (mg) 10 (10‐10) Piritramid IV (mg) 5 (5‐8) Midazolam IV (mg) 2 (1‐3) (mcg) 1581 (939‐2950) Tramadol IV (mg) 100 (100‐100)

Supplemental Table 3: Use of Multiple Drugs within the Same Drug Class

Relative Time of administration Name frequency (%)

Intraoperative medication Combination of 2 Opioids Fentanyl and Remifentanil 23.7 and Morphine 21.2 Fentanyl and Piritramid 19.8 Fentanyl and Morphine 17.7 Sufentanil and Tramadol 5.8 Combination of 3 Opioids Fentanyl, Remifentanil and Morphine 38.2 Sufentanil, Remifentanil and Morphine 24.1 Fentanyl, Remifentanil and Piritramid 16.8 Fentanyl, Remifentanil, and Tramadol 10.5 Combination of 2 non‐opioid analgesics Acetaminophen and Metamizol 50.5 Acetaminophen and NSAID 29.1 NSAID and Metamizol 13.1 Combination of 3 non‐opioid analgesics Acetaminophen, Metamizol and NSAID 96.7

Recovery room medication Combination of 2 Opioids Morphine and Tramadol 70.0 Morphine and Second Opioid 26.7 Combination of 2 non‐opioid analgesics Acetaminophen and Metamizol 50.3 Acetaminophen and NSAID 25.8 Acetaminophen and Nefopam 8.3

Supplemental Table 4. Elastic Net Parameters

Elastic net Spearman p‐value coefficient correlation (Bonferroni coefficient corrected)

Patient characteristics Age ‐ ‐8.4E‐02 2.2E‐01 Sex ‐2.2E‐01 ‐1.5E‐01 5.1E‐05 Chronic pain 1.5E‐02 1.1E‐01 2.4E‐02

Preoperative medication Opioids ‐ 1.2E‐01 3.9E‐03

Intraoperative and adjuvant medication Remifentanil 1.8E‐02 1.5E‐01 4.8E‐05 Non‐opioid analgesics ‐1.6E‐01 ‐2.0E‐01 3.4E‐09 Ketamine 3.0E‐03 1.6E‐01 2.0E‐05

Intraoperative anesthetic Volatile anesthetics only ‐2.8E‐02 ‐1.7E‐01 8.1E‐07 Volatile and intravenous anesthetics ‐ 1.4E‐01 2.0E‐04

Recovery room medication Opioids 2.3E‐02 2.7E‐01 1.0E‐17

Other factors Surgery duration (hours) 1.4E‐01 2.5E‐01 8.0E‐14

Supplemental Table 5: p‐values of Potential Confounders of Individual Model Parameters

‐

use

non

use

surgery use room

anesthetic pain

analgesic analgesics

Sex

duration Intraoperative remifentanil Male Chronic Increased Intraoperative ketamine Intraoperative opioid Volatile only Recovery opioid Patient characteristics Increased Age ‐ ‐ 6.7E‐07 9.3E‐03 ‐ ‐ ‐ ‐ BMI ‐ ‐ 1.3E‐02 ‐ ‐ ‐ ‐ ‐ Chronic pain 2.2E‐07 x ‐ ‐ ‐ ‐ ‐ ‐ Medical history Cancer ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ Smoking ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ Hypertension ‐ ‐ 2.2E‐02 ‐ ‐ ‐ ‐ ‐ Coronary artery disease ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ Asthma 2.8E‐02 ‐ ‐ ‐ ‐ ‐ ‐ ‐ COPD ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ Pharmacologic parameters Preoperative medication Opioids ‐ ‐ ‐ 3.4E‐05 ‐ ‐ ‐ 2.2E‐02 Non‐opioid analgesics ‐ ‐ ‐ 2.8E‐06 3.4E‐03 ‐ ‐ 2.8E‐02 Sedatives ‐ ‐ 3.0E‐04 ‐ 4.0E‐02 1.4E‐02 ‐ ‐ Intraoperative analgesic and adjuvant medication Opioids ‐ ‐ 1.8E‐03 7.7E‐07 1.7E‐03 ‐ ‐ ‐ Clonidine ‐ ‐ ‐ 1.1E‐04 ‐ ‐ ‐ ‐ Intraoperative anesthetics IV anesthetic only 1 ‐ ‐ 5.0E‐02 1.8E‐175 1.1E‐06 ‐ x 2.2E‐03 IV and VA 2 ‐ ‐ 1.1E‐05 1.2E‐11 6.1E‐61 9.3E‐04 x 1.9E‐06 Wound infiltration 3 ‐ ‐ ‐ ‐ ‐ ‐ ‐ 7.7E‐03 Recovery room medications Non‐opioid analgesics 4 ‐ ‐ ‐ 1.6E‐06 4.7E‐08 ‐ ‐ ‐ Clonidine ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ Other factors Information 5 ‐ ‐ ‐ 5.5E‐05 ‐ ‐ 9.8E‐04 ‐ Participation 6 ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐

1) Intravenous anesthetics, 2) Volatile anesthetic, 3) With local anesthetics, 4) Number of drug classes, 5) Patients received information about pain treatment option, 6) Patients were allowed to participate in decision making about pain treatment

Intraoperative ketamine dose (mg) Surgery duration (h)

Pain on POD1 (0-10 scale) 100 200 300 400 10 10 DE C AB 4 6 8 2 0 0 0 5 012345678910 012345678910 anesthetic only Intravenous Pain onPOD1(0-10scale) Pain onPOD1(0-10scale) anesthetic only Volatile

Preoperative Pain (0-10 scale) Pain on POD1 (0-10 scale) 10 10 4 6 8 0 5 2 0 012345678910 Female Pain onPOD1(0-10scale) Male 10 Center A n = 178 p <0.001 r = 0.371 8 Center B n = 165 6 p <0.001 r = 0.238

4 Center C n = 197 p <0.03 r = 0.153 Model coefficient 2

0 012345678910 Pain on POD1 (0-10 scale) 10 Decompression n = 472 p <0.001 r = 0.314 8 Fusion n = 280 6 p <0.001 r = 0.381

4 Disk surgery n = 209 p <0.001 r = 0.493 Model coefficient 2

0 012345678910 Pain on POD1 (0-10 scale)