Hanna 2008

Methods	Allocation: randomised Blindness: double‐blind Duration: up to 24 days Funding: Johnson & Johnson (previously ALZA Corporation) Setting: multicentre (37 centres in Belgium, Canada, France, Germany, the Netherlands, Spain, Sweden and the UK); inpatients, outpatients and day patients Design: parallel
Participants	Diagnosis: people with moderate to severe chronic cancer pain requiring 60 mg to 540 mg of oral morphine (or equivalent) every 24 hours n = 200 Age (mean): 59.8 years Sex: 98 men (49%); 102 women (51%) History: cancer type: breast (56), lung (39), genitourinary (30), gastrointestinal (32), oral cavity (6), lymphoma (3), leukaemia (3), bone (2) and other (29) Included: inpatients, outpatients and day patients ≥ 18 years of age; moderate to severe chronic cancer pain; currently receiving strong oral or transdermal opioid analgesics (60 mg to 540 mg of oral morphine or equivalent every 24 hours); appropriate candidate for strong oral or transdermal analgesics (anticipated requirement, 60 mg to 540 mg of oral morphine or equivalent every 24 hours); pain suitable for treatment with a once‐daily formulation. Exclusion: pain not considered potentially responsive to opioids; pain present only upon movement; need for other opioid analgesics (except study medication and breakthrough pain medication) after randomisation; current or recent (within 6 months) history of drug or alcohol abuse (or both); pregnant or lactating, seeking pregnancy or failing to take adequate contraceptive precautions; intolerance of, or hypersensitivity to, hydromorphone or other opioids; presence of gastrointestinal disease of sufficient severity to likely interfere with oral analgesia (e.g. dysphagia, vomiting, no bowel movement or bowel obstruction due to impaction within 5 days of study entry, severe gut narrowing that may affect analgesic absorption or transit); use of monoamine oxidase inhibitors within 2 weeks prior to study entry; investigational drug use within 4 weeks of study entry; presence of conditions for which risks of opioid use outweigh potential benefits (e.g. raised intracranial pressure, hypotension, hypothyroidism, asthma, reduced respiratory reserve, prostatic hypertrophy, hepatic impairment, renal impairment, older and debilitated people, convulsive disorders, Addison's disease). Consent: "All patients who entered the trial were informed of the nature of the study, and provided written informed consent for participation. The study was conducted in accordance with the principles of the Declaration of Helsinki."
Interventions	Hydromorphone IR 12 mg/day to 108 mg/day; dose titrated to next higher dose level if participant had > 3 breakthrough pain episodes requiring pain medication within the previous 24 hours, maximum once a day, dose titration continued until dose‐stable pain* control achieved; n = 99 Morphine IR 62 mg/day to 540 mg/day, dose titrated to next higher dose level if participant had > 3 breakthrough pain episodes requiring pain medication within the previous 24 hours, maximum once a day, dose titration continued until dose‐stable pain* control achieved; n = 101 Initial IR phase and subsequent SR phase IR phase: formulations of either hydromorphone (Dilaudid, Abbott Laboratories) or morphine (morphine sulphate IR (Sevredol, Napp Laboratories)) every 4 hours (6 times daily) for 2 to 9 days. Individual dose levels based on participant characteristics and selected according to available tablet strength and a working conversion ratio of 1:5 (1 hydromorphone: 5 morphine equivalence). Concomitant chemotherapy or radiotherapy was permitted. SR phase: duration 10 to 15 days: same drugs received but in SR formulation (OROS hydromorphone, once daily, or CR morphine (morphine sulphate SR (MST Continus, Napp Laboratories)), twice daily. Same starting dose level as dose‐stable pain achieved in IR phase, adjusted as required every 2 days at most. * dose‐stable pain control: defined as participants who experience 2 consecutive days with ≤ 3 breakthrough pain episodes requiring rescue medication ‐ they could then begin SR phase of the study. Participants not achieving dose‐stable pain control by day 9 were withdrawn from the study.
Outcomes	Pain ('worst pain in the past 24 hours' item of the BPI) Adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised 1:1, with a central computer‐generated randomisation list
Allocation concealment (selection bias)	Low risk	There was no explicit description on allocation concealment, but we considered concealment is likely to have been used since the randomisation was done via a central list
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind ‐ no further details
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias) All outcomes	High risk	Withdrawals from study were addressed Quote: "All efficacy variables were analyzed using the intent‐to‐treat (ITT) population, which included all patients who took at least one dose of study medication and had at least one assessment from each study phase" The proportion of dropout appeared to be higher in hydromorphone group; however, the reasons for dropout were comparable between groups, thus review authors consider the proportional difference between groups is unlikely to have had an effect on effect estimate. However, because the dropout rate was > 10%, we rated this domain as high risk
Selective reporting (reporting bias)	Low risk	Detailed data of the following 2 scales were not given: Mini‐Mental State Examination and Eastern Cooperative Oncology Group performance status was administered, but authors did comment that the assessment scores were similar between groups
Other bias	High risk	Drug company‐funded One of writers was employed by Johnson & Johnson (study sponsor) Study size small, < 200 participants per treatment arm