Table 2.
Breast cancer recurrence up to ten years after diagnosis, hazard ratios and associated 95% confidence intervals (95% CI) for stage I, II, or III breast cancer patients in Denmark from 1996 through 2008 by type of opioid use (weak and strong opioids).
| Opioid exposure definition | Number of recurrences (person-years) |
Crude hazard ratio (95% CI) |
Adjusted hazard ratio (95% CI)* |
|---|---|---|---|
| Non-users | 4469 (195,339) | 1.0 | 1.0 |
| Users of any opioid^ | 856 (37,791) | 0.98 (0.90 - 1.1) | 1.0 (0.92 - 1.1) |
| Strength of opioids exposure | |||
| Non-users | 4469 (195,339) | 1.0 | 1.0 |
| Only weak opioids | 636 (27,765) | 0.99 (0.90 - 1.1) | 1.0 (0.92 - 1.1) |
| Only strong opioids | 112 (5,396) | 0.94 (0.76 - 1.1) | 0.95 (0.77 - 1.2) |
| Both weak and strong opioids | 108 (4,632) | 0.93 (0.74 - 1.2) | 0.95 (0.75 - 1.2) |
|
Cumulative dose
(morphine equivalents) |
|||
| Non-users# | 3802#(162,107) | 1.0 | 1.0 |
| Low (1–≤500) | 753 (32,415) | 1.1 (0.98 - 1.2) | 1.1 (0.99 - 1.2) |
| Medium (501–≤5000) | 481 (23,914) | 0.94 (0.86 - 1.0) | 0.98 (0.89 - 1.1) |
| High (>5000) | 289 (14,694) | 0.93 (0.82 - 1.1) | 0.96 (0.84 - 1.1) |
|
Opioid exposure by
immunosuppressive effect§ |
|||
| Non-users | 4469 (195,354) | 1.0 | 1.0 |
| Strongly immunosuppressive | 358 (16,293) | 0.73 (0.55 - 0.95) | 0.75 (0.57 - 0.99) |
| Weakly immunosuppressive | 286 (12,514) | 0.99 (0.91 - 1.1) | 1.0 (0.94 - 1.1) |
| Other¤ | 212 (8,986) | 1.0 (0.90 - 1.2) | 1.0 (0.89 - 1.2) |
| Chronicity of use | |||
| Non-users | 4469 (195,341) | 1.0 | 1.0 |
| Chronic long-term use | 118 (4,741) | 1.1 (0.93 - 1.3) | 1.1 (0.93 - 1.4) |
| Short-term use | 738 (33,053) | 0.96 (0.89 - 1.0) | 0.99 (0.91 - 1.1) |
Breast cancer recurrence during opioid exposure.
Adjusted for age at diagnosis (as a continuous variable), menopausal status at diagnosis (pre- or post-menopausal), stage (I, II, or III), histologic grade (low, moderate, high), surgery type and radiotherapy receipt (mastectomy, breast-conserving surgery with radiotherapy), ER status and endocrine therapy receipt (ER+/ET−, ER+/ET−, ER−/ET−, ER−/ET+), receipt of chemotherapy (yes/no), post-diagnostic simvastatin use and post-diagnostic aspirin use (both as time-varying covariates lagged by one year and updated yearly), pre-diagnostic HRT (yes/no), myocardial infarction and congestive heart failure (yes/no), peripheral and cerebrovascular disease (yes/no), malignant disease (yes/no), diabetes mellitus (yes/no), rheumatoid arthritis (yes/no), and osteoarthritis (yes/no).
Opioids were classified as strongly immunosuppressive (codeine, morphine, fentanyl) and weakly immunosuppressive (buprenorphine, hydromorphone, oxycodone, tramadol) according to Sacerdote et al.22
Other opioids included mixed exposure to strongly and weakly immunosuppressive opioids, and/or exposure to ketobemidone, pethidine, pentazocine, tapentadol, nicomorphine, or dextropropoxyphene.
In the cumulative dose model, the number of “non-users” appears lower than in the other models. This is because once patients were exposed to opioids, they could not go back to being unexposed. Howeve,r in the other categories, “non-users” encompass a mixture of individuals who were exposed to opioids but were not exposed to opioids when they developed recurrent disease, and individuals who were never exposed to opioids.