Most subjects were white women; 90% had osteoarthritis, the rest had rheumatoid arthritis (). The mean age was 81 years for opioid users and 80 years for NSAIDs users. Our sample consisted of 4,874 patients who started NSAIDs and 12,436 who started opioids. Most opioid users in our study initiated use with propoxyphene (5,552), hydrocodone (3,805), or oxycodone (2,476). There were 371 users of codeine and 232 users of fentanyl. A greater proportion of opioid initiators, compared with NSAID initiators, were exposed to benzodiazepines, antidepressants, proton pump inhibitors, and oral corticosteroids before their index analgesic prescription date. A comparable proportion of opioid and NSAIDs patients used thiazide diuretics and osteoporosis medications. Compared with NSAID initiators, a greater proportion of opioid initiators suffered a fracture or had fallen in the year prior to the index analgesic prescription date. Opioid initiators also used a greater total number of medications, made more out-patient visits to physicians, were more frequently hospitalized, were more likely to have renal impairment, and had higher Charlson comorbidity scores, compared with NSAIDs initiators. Compared with initiators of long-acting opioids, initiators of short-acting opioids were more likely to have a history of diabetes, falls, and fractures, and less likely to have osteoporosis or to have used glucocorticoids in the year prior to starting opioids.
There were 587 fracture events among patients initiating opioids and 38 fracture events among patients initiating NSAIDs (). Fracture incidence among initiators of NSAIDs was 25 per 1,000 person-years (95% CI 17-- 34) and among opioid initiators it was 120 per 1,000 person-years (95% CI 111-- 130). Higher opioid dose was associated with higher fracture rates. Fracture incidence was significantly higher among users of short-acting opioids, 128 per 1,000 person-years (95% CI 118--138), than among users of long-acting opioids, 53 per 1,000 person-years (95% CI 34--79). This pattern was evident in stratified analyses of structurally identical opioids (e.g. 129 per 1,000 person-years (95% CI 110--151) among users of immediate release hydrocodone vs. 46 per 1,000 person-years (95% CI 24--79) among users of sustained release hydrocodone).
Distribution of Fracture Events, Incidence of Fractures per 1,000 Person-years (95% Confidence Interval) after Initiating Analgesic Medications, and Adjusted Hazards Ratio (95% confidence interval), among Medicare Beneficiaries with Arthritis
Fracture incidence was greatest during the first two weeks after initiating therapy (, ), especially for users of short-acting opioids, as seen by a steeper slope for short compared with long-acting opioids for the first two-weeks after initiating therapy, but similar slopes thereafter (). The incidence of fracture for the first two weeks after starting short-acting opioids, 902 per 1,000 person-years (95% CI 813--998), was significantly greater than the incidence of fracture thereafter, 46 per 1,000 person-years (95% CI 39--53) and approximately seven-fold higher than the risk of fracture among users of long-acting opioids during the first two weeks of therapy, 121 per 1,000 person-years (95% CI 33—310), but not thereafter, 47 per 1,000 person-years (95% CI 28—75) (). Two-thirds of all fracture events (65%) observed among patients who initiated opioids (and 45% among NSAID initiators) occurred between days 1–14 of continuous use (). Three percent of patients who used an opioid suffered a fracture within the first 14 days after initiating opioids (n=382), compared with 0.4% of those initiating NSAIDS (n=17). Over 90% of fracture events over the study period occurred within the first year after initiating analgesic therapy (98% of all fractures among NSAID users, 96% among users of short-acting opioids, and 93% among users of long-acting opioids).
Kaplan-Meier Survival Curves Showing Fracture-free Survival for the First 52 Weeks After Initiating NSAIDs vs. Short-acting Opioids vs. Long-acting Opioids, Among Medicare Beneficiaries with Arthritis
Distribution of Fracture Events, Incidence of Fractures per 1,000 Person-years (95% Confidence Interval) after Initiating Analgesic Medications, by Duration of Analgesic Use, Among Medicare Beneficiaries with Arthritis
After adjustment for demographic and clinical variables, health care utilization, co-medication and comorbidities, the risk of fracture among patients initiating opioids remained significantly higher than the risk among patients initiating NSAIDs (HR 4.9, 95% CI 3.5 – 6.9). Higher doses of opioids were associated with higher fracture risk. For users of less than 75 milligram equivalents of codeine/day, the hazard ratio was 2.2, 95% CI 0.9 -- 5.2; for users of 76–225 milligram equivalents of codeine/day, the HR was 4.6, 95% CI 3.2 -- 6.6; and for users of greater than 225 milligram equivalents of codeine/day, the HR was 5.1, 95% CI 3.7 -- 7.2.
For the study period as a whole, compared with initiators of NSAIDs, the relative risk of fracture for users of short-acting opioids (HR 5.1, 95% CI 3.7 -- 7.1) was higher than for users of long-acting opioids (HR 2.6, 95% CI 1.5 -- 4.4) (). Because long-acting opioids were prescribed predominantly at high doses, we ran additional analyses restricted to patients prescribed high doses of opioids. Among high-dose opioid users, the risk of fracture (relative to risk among NSAID users) was greater among initiators of short-acting opioids (HR 6.4, 95% CI 4.6 -- 8.9), than among initiators of long-acting opioids (HR 2.8, 95% CI 1.6 -- 4.7). A direct comparison of initiators of high-dose-short-acting opioids to initiators of high-dose-long-acting opioids found that users of short-acting opioids were twice as likely as were users of long-acting opioids to experience a fracture, even after controlling for exact dose as a continuous variable (HR 2.1, 95% CI 1.3 -- 3.5).
Figure 3 shows results from additional sensitivity analyses. The estimated hazards ratio for fractures among opioid users (relative to users of NSAID) derived from analyses that controlled for confounding using propensity score matching, HR 4.9, 95% CI 3.5 -- 7.0, and the hazards ratio derived from conventional multivariable outcome regression techniques, HR 4.9, 95% CI 3.5-- 6.9, were virtually identical. Excluding patients with prior fractures or osteoporosis at baseline did not change our findings. Compared with initiators of NSAIDs, the risk of fracture among patients who started short-acting opioids was significantly greater than the risk among patients starting long-acting opioids for the first two weeks after initiation, HR 8.0, 95% CI 4.9 -- 13.0 vs. HR 1.3, 95% CI 0.4 -- 3.8, but not thereafter, HR 2.6, 95% CI 1.6 -- 4.1 vs. HR 2.8, 95% CI 1.5 -- 5.4.