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Opioids are prescribed early among workers’ compensation claimants with low back pain (LBP), despite little evidence supporting this practice. The comparative effect of early opioids relative to other medications on work disability is unknown. The objective was to examine the association between prescription opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and skeletal muscle relaxants (SMRs) dispensed in the first eight weeks following a compensated, work-related low back injury and work disability.Historical cohort study of workers’ compensation claimants in British Columbia, Canada filing a short-term claim for a LBP injury. Exposure variables were constructed using dispensing data from the first eight weeks after injury: drug class(es) dispensed, drug class(es) at first dispense, days supply, strength of opioids dispensed, and average daily morphine-equivalent dose (MED). Two outcomes (time on benefits, any benefit receipt) after eight weeks and up to one year were considered.Compared to claimants receiving NSAIDs and/or SMRs only, the incidence rate ratio (IRR) of days on benefits for claimants dispensed opioids only or opioids with NSAIDs and/or SMRs was 1.09 (95% CI: 1.04 to 1.14) and 1.26 (95% CI: 1.22 to 1.30), respectively. The IRR for claimants dispensed strong opioids only or strong and weak opioids combined was 1.21 (95% CI: 1.12 to 1.30) and 1.29 (95% CI: 1.20 to 1.39), respectively, compared to weak opioids only. Each 7 day increase in supply of opioids, NSAIDs, and SMRs resulted in a 10%, 4%, and 3% increase, respectively, in rate of days on benefits. Each 30 mg/day increase in daily MED resulted in a 4% increase in rate of days on benefits. Larger effect sizes were seen for benefit receipt outcome.Findings suggest early opioid provision has an adverse effect on work disability. However, residual confounding likely accounts for some of the findings. Research is needed that accounts for prescriber, system, and workplace factors and elucidates the mechanism underlying the relationship.