title: Indicators of drug-seeking aberrant behaviours: the feasibility of use in observational post-marketing cohort studies for risk management.
abstract: BACKGROUND
  Problematic prescription drug use is reflected by or associated with drug-seeking aberrant behaviours. Research gaps include lack of post-marketing evidence and instruments. As part of the pharmacovigilance requirements, a risk management plan was developed for fentanyl buccal tablets (FEBT) by the manufacturer, with an additional pharmacovigilance activity requested by the regulatory authority, to investigate the risks of misuse, abuse, criminal use, off-label use and accidental exposure to FEBT after the product became commercially available. A Modified Prescription-Event Monitoring (M-PEM), observational, post-authorisation safety surveillance (PASS) study was conducted, with an overall aim to examine the use of FEBT in relation to their safety as prescribed in primary care in England. One of the exploratory objectives included estimating the prevalence of aberrant behaviours during FEBT treatment.
  
  
  OBJECTIVE
  To determine the feasibility of estimating the prevalence of risk factors associated with dependence on starting treatment and aberrant behaviours in patients during treatment with a prototypical abuse liable substance (fentanyl), as based on the application of an existing index (the Chabal criteria).
  
  
  METHODS
  Data were collected as part of the M-PEM PASS study; exposure and outcome data (including risk factors for dependence and aberrant behaviours based on behavioural not clinical manifestations) were derived from questionnaires sent to primary care physicians in England during April 2008 to June 2011. For the exploratory objective of interest, descriptive statistics and simple (non-weighted) risk scores were constructed on aggregate counts (score ≥3 considered 'high-risk'). Supplementary analyses explored the relationship between the two indices and the characteristics of patients with aberrant behaviours and those without (crude odds ratios plus 95% confidence interval (CI) were calculated).
  
  
  RESULTS
  In a cohort of 551 patients, the prevalence of at least one pre-existing risk factor for dependence was 26% (n = 145), whilst the frequency of aberrant behaviours observed during treatment was 8% (n = 46). Patients with aberrant behaviours had several different characteristics to patients without. The two indices were associated (χ (2) df (20) = 58.72, p < 0.001), but a high-dependence risk-factor score provided a poor indication of high aberrant behaviour risk; the area under the receiver operating characteristic curve was 0.58 (95% CI 0.41, 0.74).
  
  
  CONCLUSIONS
  Study limitations included subjectivity in relation to physicians identifying aberrant behaviours, and under-reporting thereof in PASS observational study designs. The presence of these criteria does not confirm misuse, but should be considered as a signal of problematic opioid misuse, which requires investigation. Further research is needed to develop a more robust analytical construct.
  
  
  CONCLUSIONS
  In this PASS study, the prevalence of at least one pre-existing risk factor for dependence was 26%, whilst the frequency of aberrant behaviours observed during treatment was 8%. Patients with aberrant behaviours had several different characteristics to patients without. This study demonstrates the feasibility of the systematic collection of physician reports of risk factors for dependence and aberrant behaviours to facilitate the development of risk scores, using these reports to support the post-marketing risk management of products with misuse potential.
authors: Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, SO31 1AA, UK, deborah.layton@dsru.org.
authors: Deborah
authors: D
authors: Layton
authors: Vicki
authors: V
authors: Osborne
authors: Mohammad
authors: M
authors: Al-Shukri
authors: Saad A W
authors: SA
authors: Shakir
mesh_terms: D000328:Adult; D000368:Aged; D016739:Behavior, Addictive / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control* / Q000523:psychology*; D015331:Cohort Studies; D004739:England / Q000453:epidemiology; D005240:Feasibility Studies; D005260:Female; D005283:Fentanyl / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019370:Observation; D009293:Opioid-Related Disorders / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control* / Q000523:psychology*; D060735:Pharmacovigilance; D063487:Prescription Drug Misuse / Q000706:statistics & numerical data*; D015995:Prevalence; D012308:Risk Management / Q000379:methods*
chemical_list: D005283:Fentanyl