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Tamper-Resistant Oxycodone: A Review of the Clinical Evidence and Cost-effectiveness [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2015 Jun 25.

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Tamper-Resistant Oxycodone: A Review of the Clinical Evidence and Cost-effectiveness [Internet].

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APPENDIX 3Critical Appraisal of Included Publications

Table A3Strengths and Limitations of Randomized Controlled Trials using Downs and Black10

StrengthsLimitations
Colucci12
  • Objectives, interventions, patient characteristics clearly described.
  • Exact P-values reported
  • Subjects were blinded to what injection they were receiving. Study described as double blind – likely the outcome assessors (not those running statistical tests) were blinded. However, part of the inclusion protocol required patients to be able to identify the difference between OXY and placebo.
  • Important treatment emergent adverse events reported
  • Compliance reliable
  • Unclear if industry sponsorship had an effect on the results
  • Population likely not representative of those with substance abuse disorders.
  • Power calculation not reported; unclear if the study had sufficient statistical power to detect differences.
  • Disposition of patients not clearly described, nor were principle confounders.
  • Likely that men were overrepresented in the study (men are more often abusers of prescription opioids,1 but unclear if 87% of abusers are men)
  • Supervised use not representative of real-world use.
  • Intended OXY/naloxone ratio was 2:1, however this may not be representative of a real-world setting due to tablet crushing and dissolving.
Harris13
  • Study subjects were blinded, however, part of the inclusion protocol required patients to be able to identify the difference between OXY and placebo.
  • Important treatment emergent adverse events reported.
  • Objectives, interventions, patient characteristics clearly described.
  • Actual P-values reported
  • Compliance reliable
  • Population likely not representative of those with substance abuse disorders.
  • Supervised use not representative of real-world use.
  • Power calculation not reported, unclear if the study had sufficient statistical power to detect differences.
  • Likely that men were overrepresented in the study (men are more often abusers of prescription opioids,1 but unclear if 87% of abusers are men)
Webster9
  • Objectives, interventions, patient characteristics clearly described
  • Adequate washout period between treatments
  • P-values adjusted for multiple comparisons using the Benjamini-Hochberg method.
  • Reasons for discontinuation clearly described.
  • Important treatment emergent adverse events reported
  • Outcome measures were valid and appropriate
  • Power calculation not reported – authors state that the study is well-powered but do not present their calculation.
  • Likely that men were overrepresented in the study (men are more often abusers of prescription opioids,1 but unclear if 78% are men)
  • While the outcome measures are valid and appropriate for research, they are surrogates for predicting the behavior of those abusing the drugs.
  • Population likely not representative of those with substance abuse disorders.
  • Supervised use not representative of real-world use, protocol required fasting – it is unclear if ‘full’ participants would have the same aversion to niacin (as a high fat meal is known to reduce the negative effect of niacin)
Webster14
  • Objectives, interventions, participants clearly described
  • Participants were blinded – interventions were made to be identical. Primary investigator and research staff were also blinded – pharmacist was not.
  • Power calculation presented – 88% power to detect a one half SD difference between interventions.
  • Population likely not representative of those with substance abuse disorders.
  • Included males only.
  • Supervised use not representative of real-world use, protocol required fasting – unclear if that would be important in real-world use.
  • Actual P-values not reported (just P<0.05 or P≤0.001)
  • Unclear if study was powered for secondary outcomes or for safety.
Setnik15
  • Objectives, interventions, participants clearly described.
  • Washout periods likely adequate
  • Power calculation presented
  • Adjustment for multiple comparisons using Benjamini-Hochberg method.
  • Losses to follow-up and withdrawals mostly described.
  • Exact P-values reported.
  • Participants were blinded, assessors likely blinded (unclear which group was blinded other than the participants)
  • Drugs were administered under both ‘fasting’ and ‘full’ conditions.
  • Population likely not representative of those with substance abuse disorders.
  • Men likely overrepresented
  • Supervised use not representative of real-world use

Table A4Strengths and Limitations of Observational Studies using Downs and Black10

StrengthsLimitations
Cicero16
  • Objectives clearly described
  • The large SKIP sample was likely reasonably representative of a study of opioid abusers, drug use representative of real-life abuse rather than controlled clinical conditions. Data was from a large database sample.
  • Basic patient characteristics described
  • The smaller RAPID sample (more detailed questionnaire of 244 people) may not be representative of the full population as they self-selected into answering the survey.
  • Exact interventions (dosing etc.) not described.
  • Descriptive study – therefore, cannot determine causality.
  • Unclear if the results generalize to a non-treatment seeking population
Degenhardt8
  • Multiple data sources used.
  • Objectives, main findings clearly described.
  • Descriptive observational study – cannot determine causality – study was hypothesis generating.
  • Those who visit safe injection sites or needle exchange programs may not be representative of all drug users.
  • Time period examined may not be lengthy enough to determine long-term changes in use
Larochelle17
  • Patients were able to enter and exit the cohort over the 10 year period.
  • Objectives, main findings, patient population clearly described.
  • 95% confidence intervals presented
  • Insured patients represent only some of the patients taking non-medically necessary opioids.
  • Not randomized.
Cassidy18
  • Methods clearly described.
  • Outcomes were clearly described and defined
  • Model adjusted for potential covariates
  • Steps taken to minimize geographical, and other covariate confounding
  • Estimates using logistic regression
  • Those seeking treatment may not be representative of the entire drug using population
  • Power calculation not reported, however there was a large sample size so power was not likely an issue.
Havens19
  • Authors explored factors related to the time of the interview and whether that would result in confounding bias.
  • Single interviewer was used so if events were misclassified, they were likely consistently misclassified.
  • Self-reported drug use is considered a valid measure of drug use; 30 day time frame was likely short enough to reduce problems with recall.
  • Recall bias a potential issue due to being a self-reported survey – used anchoring to attempt to reduce recall bias.
  • Population being studied lived in an area where opioid abuse was considered epidemic – may not be generalizable to other populations.
Michna7
  • Objectives, methods, outcomes clearly described.
  • Classification of exposures well described.
  • Sensitivity analyses performed in order to control for potential confounders (time, primary opioid, coding of abuse)
  • Commercially-insured continuous users may not be representative of the broader oxycodone-using population.
  • Observational study – direct causation difficult to determine.
Rossiter20
  • Objectives, measures, interventions clearly described.
  • Same inclusion and exclusion criteria applied to all included patients
  • Pre- post- formulation change acted as a way to match patients; population-based study allowed for analyzing a large portion of users; pre-post- acted as a quasi-experimental design.
  • Authors allowed for a washout period.
  • Cases and controls well-matched
  • Outcomes unlikely to be misclassified.
  • No randomization.
  • Assumed that continuous and non-continuous users were the same.
  • Non-experimental design – cannot assume causation.
  • Number of people abusing or misusing opioids likely underrepresented.
Sessler21
  • Sensitivity analyses conducted ( included prescription numbers, reporter type or source, formulation specificity, missing date of death, and reporting time lag)
  • Authors examined non-fatal reports and comparator reports and determined that there was no temporal bias.
  • Outcomes were validated, definitions of outcomes well reported.
  • No randomization
  • Possibility that not all fatalities associated with oxycodone use were coded as such.
  • Voluntary reports of adverse events do not capture all events. (However, there was a large magnitude of change, and reporting of other adverse events did not decrease, therefore, it is more likely that the change seen was a real change and not a change in the way events were reported)
  • Longer-term follow-up may be needed to capture more permanent changes in death rates.
Butler22
  • Sensitivity analyses conducted using a national database.
  • Objectives, measures, main findings clearly described
  • Selection bias unlikely to account for changes in oxycodone but not other opioids.
  • Data was collected uniformly across time and collection sites.
  • Steps were taken to reduce reporting bias (pictures of the different formulations were shown to patients in order to accurately identify which drug was taken)
  • Confidence intervals, exact P-values reported.
  • Steps taken to minimize geographical, and other covariate confounding.
  • Patients being assessed for substance abuse may be different from other oxycodone users
  • Results may not be generalizable to the general population of prescription drug abusers.
  • Relied on self-reported data.
  • Not randomized
  • May not reflect patterns of abuse of the new formulation after more time has passed.
Coplan23
  • Objectives, methods, main findings clearly described.
  • Exposure classifications well described
  • Confidence intervals and exact P-values reported
  • Possible that changes in poison centre reporting, misclassification of original or ADF oxycodone occurred during the study period
  • Unclear if there was a representative sample, however, it was a large national sample.
Severston24
  • Large percentage of the US population was part of the surveillance. Therefore the results are likely generalizable to the US population.
  • 95% confidence intervals and exact P-values reported.
  • Demographic characteristics (such as gender, ethnicity, and age) of the source population did not change throughout the study.
  • Is a descriptive study, therefore it is difficult to determine causation.
  • Depended on voluntary reporting and therefore it is likely that not all cases were reported.
  • Misclassification of product exposure was possible.
  • Other interventions (such as prescription drug monitoring programs) may gave accounted for some of the reductions in abuse.
Butler25
  • Objectives, methods, main findings clearly described.
  • Exact P-values reported
  • Population likely fairly representative those seeking treatment.
  • Self-reported data – recall bias possible, however, patients entering treatment tend to report fairly accurately.
  • May not generalize beyond patients seeking treatment and who have access to a treatment facility.
  • Descriptive study, therefore cannot determine causality.
Rintoul26
  • Objectives, methods, main findings clearly described.
  • Confidence intervals and exact P-values reported.
  • Descriptive study – cannot determine causation.
  • Possible that not all deaths were identified or that drug-related deaths were misclassified.
Roxburgh2
  • Objectives, methods, main findings clearly described
  • Exposures well described
  • Descriptive study – cannot determine causation.
  • Likely that not all exposures were identified – some were likely classified as ‘opioid’ or misclassified as another opioid event.

Table A5Strengths and Limitations of the Included Qualitative Study

StrengthsLimitations
Buer27
  • Research objectives clearly stated and congruent with qualitative methods.
  • Sampling strategy clearly described – and was altered when it became clear that the youngest age group was underrepresented.
  • Participants described with sufficient detail.
  • Results consistent with the data.
  • Data collection clearly described and was congruent with the research objectives.
  • Ethics approval not reported, however it was likely sought as it was part of a larger quantitative study.
  • Small sample in a small geographic area – results may not generalize to other populations.
  • Self-reported data – therefore may be subject to recall bias.
  • Reporting socially undesirable behavior – therefore may be subject to responder bias.
  • Unclear how the data was checked for credibility (the interviews were audio-recorded and transcribed, but unclear if the transcriptions were checked or if there was another method of credibility checking)
  • Unclear if techniques were used to enhance the dependability

Table A6Strengths and Limitations of Economic Studies using Drummond11

StrengthsLimitations
White28
  • Multiple models used.
  • Models checked for robustness
  • Used real population data to inform estimates
  • Multiple data sources – exposures and drug formulations may be coded differently so data may not be consistent.
  • NSDUH past-year or past-month measures were not available and would likely be better predictors than the lifetime use that they used.
  • Small sample size, therefore results may not be generalizable.
  • Misclassification of data possible while coding entries into database.
  • Does not include general medical costs.
  • Likely not generalizable beyond the single payer perspective
Rossiter20
  • Their base case was set at 75% of the abuse rate found in the database and sensitivity analyses included 50% and 100% rates. ADF oxycodone was cost saving at all estimates.
  • Used real population data to inform estimates.
  • Not a full economic analysis
  • Indirect costs not considered
  • Based on data from an observational study (evaluation of claims data) – we cannot conclude the relationship was causal.
  • Cost estimates likely only relevant to the US population (however reductions likely in other jurisdictions, but monetary values not transferrable due to differences in price)

ADF = abuse deterrent formulation

Copyright © 2015 Canadian Agency for Drugs and Technologies in Health.

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