Srinivasan 2021.

Study characteristics
Methods	Design: cross‐over Duration: cross‐over periods lasted 6 weeks Assessment: baseline and post‐cross‐over period Country: India
Participants	Pain condition: painful diabetic neuropathy Population: adults aged 18‐75 with type 2 diabetes and painful diabetic neuropathy Minimum pain intensity: ≥ 50 on 0‐100 scale Inclusion criteria Diabetic neuropathic pain present for at least 1 month Mean pain intensity of > 50% by patient assessment by VAS Exclusion criteria Physical and mental health comorbidities Total participants randomised: 67 Age in years (mean, SD): 49 (4) Gender: 32/67 were female Pain duration in years (mean, SD): 28 (6)
Interventions	Naltrexone 4‐8 mg Opioid receptor antagonist Identical appearance to amitriptyline Flexible dosing between 2 mg and 4 mg Mean dose: 3.84 mg/day Amitriptyline 10‐50 mg TCA Flexible dosing between 25 mg and 50 mg Mean dose: 24.02 mg/day
Outcomes	PGIC AEs Withdrawal
Missing data methods	ITT with multiple imputation
Funding source	Non‐pharmaceutical: postgraduate Institute of Medical Education and Research
Conflicts of interest	The authors have no COI pertaining to this study. The authors are thankful to M/s. Sun Pharmaceutical Industries Limited, Mumbai (India), and M/s. Wockhardt Pharmaceuticals, Mumbai (India), for providing the pure naltrexone active pharmaceutical ingredient and amitriptyline tablets, respectively, for this study.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomisation codes were generated by a random block randomisation method using the “random allocation software.”
Allocation concealment (selection bias)	Low risk	"The blinding and allocation concealment was maintained by labeling the container with the serial numbers provided for each randomisation code by a person not related to the trial. The drugs were dispensed by an investigator who was neither involved in screening nor involved in evaluating the end points of the study."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind, identical appearance and dosing
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Self‐reported outcomes from blinded participants
Incomplete outcome data (attrition bias) All outcomes	Low risk	Multiple imputation techniques (multivariate imputation by chained equations) was used to deal with the missing values for ITT. Low dropouts, balanced across arms Attrition Total: 7/67 (10.5%) Naltrexone 2‐4 mg: 2/67 (3.0%) Amitriptyline 25‐50 mg: 5/67 (7.5%)
Selective reporting (reporting bias)	Unclear risk	Trial registered retrospectively
Other bias	Low risk	No other sources of bias were identified.