Khoromi 2007.

Methods	Allocation: randomised. Control: placebo and active comparator. Blinding: double‐blind. Arm: 4‐arm, 4‐period cross‐over. Centre: single. Study dates: February 2001 to March 2004. Setting and location: NIH Clinical Center, Bethesda, Maryland, USA.
Participants	Inclusion criteria: lumbar radiculopathy (diagnostic criteria described in paper), average leg pain score ≥ 4/10, willingness to stop other medications, aged 18‐65 years. Exclusion criteria: serious medical illness; prostatic disease; pregnancy or lactation; history of narcotic or alcohol abuse; narrow angle glaucoma; seizures; fibromyalgia; severe pain other than back or legs; polyneuropathy and peripheral vascular disease associated with symptoms of numbness or burning; allergy to morphine, nortriptyline, or benztropine; multisomatoform disorder; unwilling to taper off current opioids. Baseline characteristics n: 55. Gender: F 25, M 30. Age: median 53 years (range 19‐65). Number randomised: 55 Number completed: 28. Baseline pain intensity: 5.0/10 (SD 2.3) (average overall).
Interventions	Morphine: target dose 90 mg daily. Nortriptyline: target dose 100 mg daily. Morphine + nortriptyline: target dose 90 mg + 100 mg. Placebo (benztropine) 0.25 mg to 1 mg daily. Duration: 4 × 9 weeks; 5 weeks of dose escalation, 2 weeks at maximum tolerated dose, 2 weeks of dose tapering. Additional analgesics: no opioids, SSRIs and tricyclic medications outside of protocol during study; no changes to other stable analgesic medication regimen; anti‐inflammatory medications and paracetamol (acetaminophen) were allowed as rescue medications.
Outcomes	Primary outcome Pain intensity: 0‐10, daily over previous 24 hours; group mean during 2 weeks of maintenance used. Secondary outcomes Global Pain Relief (6‐point NRS, worse to complete relief). Oswestry Low Back Pain Disability questionnaire. Beck Depression Scale. 36‐item Short Form.
Notes	Efficacy analyses included only participants who had completed ≥ 2 treatment periods (34 participants; 28 participants completed whole study) No information on how missing data were handled (withdrawals or missing points). Oxford Quality Score: R2, DB2, W1.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed by the NIH Pharmaceutical Development Service. Patients were assigned by random numbers within blocks of four to one of four treatment sequences specified by a Latin square."
Allocation concealment (selection bias)	Unclear risk	Comment: method used to conceal allocation not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Patients and staff were blinded to the randomisation order." Comment: double‐dummy method used, with 'active' placebo to mimic adverse events. Tablets were colour coded by pharmacists for the active treatments and active placebos. Note: switches from calling them 'pills' to 'capsules' mid‐way through.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: participant‐reported outcomes, participant blinded to intervention.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: analysis for study completers (n = 28) and those completing ≥ 2 treatment periods (n = 34). Comment: no information for how missing data points handled.
Selective reporting (reporting bias)	Low risk	Comment: all planned outcomes in the methods were reported in the results.
Size	High risk	Comment: 55 participants began, but number completing < 50.