Pharmaceutical opioid use and cognitive and behavioural harms among people who experience chronic non-cancer pain

In Australia, pharmaceutical opioids are widely used for the treatment of chronic non-cancer pain (CNCP). However, opioids are typically not recommended for chronic use given the limited evidence of long-term analgesic efficacy and the potential for adverse side effects. In particular, people who are prescribed opioids for CNCP may experience impairments in key cognitive functions (e.g., concentration, memory) that are drawn upon for activities of daily living. This may subsequently impact driving-related abilities and increase the risk of physical injury (e.g., via falls, motor vehicle collisions). At the population level, increased opioid prescribing may also be associated with increasing rates of opioid-related motor vehicle collisions. Concern around the chronic effects of opioids on cognitive function stems from the known effects following acute administration of opioids in healthy people. However, these studies fail to capture the complexities of real-world opioid use among CNCP cohorts. In particular, little is known about the long term (>12 months) effects of opioids on cognition, and how both duration of use and opioid dose may be related to cognitive complaints and physical injuries in naturalistic settings. Related to this, there is a dearth of research examining consumer perceptions of risk of driving-related harms and opioid side effects. Finally, within Australia, relatively little is known about the relationship between increased opioid prescribing and population-level behavioural harms, particularly motor vehicle collisions. In light of the gaps identified above, the aim of the present thesis was to explore the association between chronic use of opioids for CNCP and cognitive and related behavioural harms. This included an examination of consumer perceptions of risk and opioid side effects. The research was guided by five aims: i) to examine objective cognitive performance in people who take opioids for CNCP; ii) to explore the relationship between duration of opioid use and cognition in people with CNCP; iii) to assess the association between opioid dose and related harms (e.g., cognitive dysfunction) in people who take opioids for CNCP; iv) to assess awareness of opioid-related driving impairment and associated factors in people with CNCP and; v) to assess whether opioid-related vehicle collisions have increased with increased prescribing. To assess these aims, five studies were undertaken: i) a systematic review and metaanalysis of studies (n=17) that examined objective cognitive task performance in people taking opioids for CNCP, compared with opioid-free groups (healthy or with CNCP) and over the course of opioid therapy; ii) a longitudinal study examining cognitive performance among people with chronic use of opioids for CNCP (n=14; use duration ≥3 months) and comparable opioid-free controls (n=12) at baseline and three months; iii) a cross-sectional, self-report online survey that examined how variations in opioid dose and use duration was associated with the frequency of cognitive complaints and physical injuries among people prescribed opioids for CNCP (n=226); iv) a cross-sectional, self-report online survey that examined the relationship between opioid use (including non-use) and perceptions of risk related to driving under the influence of opioids, knowledge of opioid side effects, and factors associated with risk perceptions among people with CNCP (n=218); and v) a population-level analysis of changes in the rate of opioid-related motor vehicle collisions per 100,000 opioid script dispensations from 2008–2016 in an Australian jurisdiction (Tasmania) with high rates of opioid prescribing. Study 1 indicated that people prescribed opioids for CNCP performed more poorly than did healthy controls on key functions (attention, memory). However, the magnitude of these effects was only moderate. Further, the study found small magnitude, non-significant differences in performance between people prescribed opioids for CNCP and opioid-free controls with CNCP. Finally, this study found relatively consistent improvements in key cognitive domains with continued opioid use (i.e., at follow-up compared with opioid-free baseline). Broadly, these findings indicate: i) factors that are common to both CNCP groups (e.g., pain, mental health conditions) may affect functioning to a greater degree than does opioid use, and ii) people who take opioids for CNCP did not experience cognitive worsening with continued use. Similarly, Study 2 found limited evidence of cognitive impairment in the opioid group compared to opioid-free CNCP controls, with only two attention outcomes robustly affected. Additionally, this study did not find continued cognitive decline in the opioid group across time. Following on from the first two studies, Study 3 found no clear relationship between opioid dose or use duration and cognitive complaints. However, the findings did highlight the role of key co-morbid factors that were commonly reported by participants. Cognitive complaints were common, and were positively associated with pain, psychological distress, and the experience of physical injuries. Study 4 aimed to explore perceptions of risk (e.g., driving-related harms) and knowledge of opioid side effects among people with CNCP with varying chronicity of opioid use (including non-use). The study found that most people with CNCP perceived alcohol to be more ‘risky’ than pharmaceutical opioids, and current opioid consumers had lower risk perceptions for opioid than did ex- or never-consumers. Factors associated with risk perceptions included previous opioid DUI and risk ratings for alcohol, as well as knowledge of side effects and cognitive function for risk of motor vehicle collision. Study 5, which examined the relationship between community-level opioid utilisation and opioid-related motor vehicle collisions (MVC), found that the rate of opioid-related MVC per 100,000 dispensations has remained stable across time. This adds to the conclusions of Study 1, Study 2, and Study 3, suggesting that opioids are not uniquely related to driving-related cognitive impairments, at least at the doses examined here. Broadly, the present thesis found that people who take opioids for CNCP frequently experience specific cognitive and behavioural harms, but these are not clearly associated with opioid use. Both subjective and objective cognitive function were impaired to some extent in people with CNCP compared to healthy populations. However, the experience of objective cognitive dysfunction was similar among people with CNCP regardless of whether they used opioids or not. Similarly, self-reported cognitive complaints did not vary according to opioid dose or use duration. At the population level, increased opioid prescribing was not associated with increasing rates of opioid-related MVC. However, characteristics that are common among this cohort (e.g., poorly controlled pain, psychological distress) were related to cognitive complaints and related harms (e.g., injuries). This may have implications in clinical settings, where practitioners can identify and educate people about risk factors for harms