non-interventional study where patients are exposed to non-peripherally acting mu-opioid receptor antagonist (PAMORA) laxative

Presence of a diagnosis or symptom code

Presence of a diagnosis or symptom code

Presence of a diagnosis code

At least a doubling in opioid dose based on the morphine milligram equivalents (MME) from baseline

Total duration of medical history (as continuous), Calendar year of index date (2015, 2016, 2017, 2018, 2019, 2020, 2021), Time (months) since launch of naloxegol (October 2015 in the UK, December 2014 for the Netherlands) at index date (as continuous variable and categorical)

Prior constipation diagnosis, within the previous five years or from start of patients' history if this period is less than 5 years (yes/no)

Type of prior opioid use prior to and excluding the index date : natural opium alkaloids , phenylpiperidine derivatives, diphenylpropylamine derivatives, benzomorphan derivatives, oripavine derivatives, morphinan derivatives, methadone, other opioids including opioids used in combination, drugs used in opioid dependence excluding lofexidine

Amount (in mg converted to morphine milligram equivalent [MME] dose) of prior opioid use per day was determined using the last prescription within 180 days prior to and excluding index date.

The amount of opioid exposure within 180 days prior to and excluding index was categorised in four groups: at or below the median, above the median, dose = 0 and a separate category for missing.

Type of prior laxative use (prescribed prior to and excluding index): softeners and emollients, contact laxatives, bulk forming laxatives, osmotically acting laxatives, saline laxatives, and other drugs for constipation (e.g., lubiprostone, linaclotide, methylnaltrexone, prucalopride and enemas).

The last prescription of any laxative prior to Naloxegol/non-PAMORA prescription (index date) and within 180 days of index date (exclusive) was used to determine the strength. For every laxative treatment in the database the prescribed strength and the number of patients on this strength are reported.

Comorbidities were identified through diagnosis codes during patient's baseline period (yes/no) Prior conditions : Cardiovascular, Pulmonary, Prior conditions, Neurologic, Gastrointestinal, Endocrine, Rheumatologic, Psychiatric, Renal Disease, Hepatic disease, Cancer, Pain conditions, Miscellaneous, Charlson Comorbidity index.

Exposure to naloxegol (or the concurrent reference laxative) started on the index date. The exposure end date was calculated by an algorithm used to derive continuous exposure.

We utilised quantity and number of tablets per day to calculate the days of supply for each prescription; this was combined with the refill sequence of successive prescriptions to calculate duration of continuous exposure, average daily dose and cumulative dose over the study period.

Alanine aminotransferase: ≤35 U/L (females) or 40 U/L (males); >35 U/L (females) or 40 U/L (males); missing Serum creatinine: 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for women; below those values; above those values; missing.

Aspartate aminotransferase: ≤35 U/L; >35 U/L; missing Serum bilirubin: ≤1.9 mg/dL; >1.9 mg/dL; missing Tumour specific marker information (e.g., eGFR, JAK2, BRCA, Multiple Endocrine Neoplasia mutation)

Total number of hospitalisations (excluding A&E admission) Total number of specialist referrals (all specialities categorised as specialist/surgeon, GP, nurse, other health professionals, centre/team and other) Total number of lab tests Total number of outpatient physician visits (GP surgery visits) Total number of prescriptions (only prescriptions in primary care in THIN)

Other variables of interest: Covariates included in the study are those determined to be potential risk factors for a given outcome of interest or predictors of exposure

Exposure to naloxegol or the concurrent reference laxative started on the index date. The exposure end date was calculated by an algorithm used to derive continuous exposure. The algorithm utilised quantity (naloxegol or concurrent reference laxative strength and number of tablets) and number of tablets per day (when available) to calculate the days of supply for each prescription; this was combined with the refill sequence of successive prescriptions to calculate duration of continuous exposure, average daily dose and cumulative dose over the study period.

Prior and concomitant medications: prior was defined as any medications prescribed during patients' baseline period excluding the index date. Concomitant medications was defined as ongoing treatments at the initiation of naloxegol prescription. Prior medication and concomitant medication are not mutually exclusive groups. The drugs were classified in the following groups:

Cardiovascular disease/risk factor-indicated medications Psychiatric-indicated medications Neurologic-indicated medications Musculoskeletal-indicated medications Alimentary Tract and Metabolism medications Genito Urinary System medications and Sex Hormones Blood and Blood Forming Organ medications Respiratory System medications Anti-infectives for Systemic Use Opioids Non-opioid analgesics CYP3A inducer - including subgroups of mild, moderate and strong inducers CYP3A inhibitor - including subgroups of mild, moderate and strong inhibitors Pgp modulator Methadone