We found an overall incidence of 56% of patients with chronic pain after breast cancer surgery, which was significantly higher for sevoflurane anesthesia (67.4%) compared with propofol anesthesia (44.2%). The sevoflurane group was 1.514 times more likely to develop chronic pain than the propofol group (95% CI 1.146–1.809). Frequencies of hospital visits for pain treatment, ipsilateral arm and shoulder disability, and effects on daily life were significantly different. However, among patients with chronic pain, neither the severity (95% CI 0.516–7.419) nor duration (95% CI 0.106–1.007) differed between patients receiving sevoflurane or propofol. Therefore, patients with sevoflurane anesthesia developed chronic pain after breast cancer surgery with greater frequency, but the pain was not more severe nor the duration longer compared with propofol anesthesia.
The overall incidence of chronic pain in our study was higher than previously reported.1–10 This could have been due to chemotherapy received by all our patients, because chemotherapy is a risk factor for chronic pain after breast cancer surgery.2 Another reason for the higher incidence is that we asked patients whether they had persistent pain related to surgery for longer than 2 months. As a result of this question, there was a wide range of responses.
There have been several studies to identify risk factors for chronic pain after breast cancer surgery.1–10 However, this is the first attempt to include anesthetics into logistic regression models of chronic pain after breast cancer surgery. Moreover, the effects of inhaled and IV anesthetics on chronic pain were rarely compared. As was mentioned earlier, we began this study because propofol reduced acute pain under opioid-induced hyperalgesia,16 and severe acute pain could affect the development of chronic pain.1,7,10 However, anesthetics may make a difference in chronic pain not only by affecting severity of acute pain but also by independent (or direct) mechanisms. When multivariate analyses were conducted to control for association among the variables, including 24-hour postoperative morphine consumption and anesthetics, sevoflurane showed a stronger association with the development of chronic pain after breast cancer surgery compared with propofol. Thus, it seems that propofol has its own analgesic effects by preventing sensitization mechanisms.26,27 Although sevoflurane prevents sensitization by inhibiting the N-methyl-D-aspartate receptor, this effect cannot sufficiently prevent chronic pain.28
Anesthetics did not show significant effects on the severity of chronic pain. We are unsure of the interpretation of this finding. Propofol may inhibit development of chronic pain through modulation of sensitization, but once it develops, propofol might not contribute to reducing the severity. The lack of difference in severity of chronic pain between propofol and sevoflurane groups can also be explained by limited statistical power. The latter interpretation is a more reasonable explanation. Although not statistically significant, more patients with severe pain were in the sevoflurane group than the propofol group. Moreover, the sevoflurane group had significantly higher frequencies of hospital visits, more arm and shoulder disability, and daily life was affected to a greater extent.
In addition to sevoflurane, we found risk factors for the development of chronic pain after breast cancer surgery, such as age, axillary lymph node dissection, and 24-hour postoperative morphine consumption. Younger aged patients tend to have more aggressive breast cancer requiring more aggressive management, including surgical treatment, chemotherapy, and radiotherapy.29 During axillary lymph node dissection, significant nerve injury can occur, which leads to central sensitization and hyperalgesia associated with chronic pain.30 Severe acute postoperative pain has been reported to be associated with the development of chronic pain after breast cancer surgery1,7,10 and other types of procedures, such as thoracotomy,31 hernia,32 and limb amputation.33
There have been several studies to identify risk factors for chronic pain severity after breast cancer surgery4,5 using 2 categories, but no studies have been conducted to quantify the degree of association between those risk factors and 3 pain severity categories. Three pain severity categories are more widely used than 2 pain severity categories, because their clinical outcomes are different and therefore their treatment strategy should be different. First, we compared the duration of chronic pain, frequencies of hospital visits for pain treatment, ipsilateral arm and shoulder disability, and effects on daily life. There were significant differences among the 3 pain severity categories except for duration of chronic pain. Post hoc findings revealed there were significant differences between each category except for frequency of disability of the arm and shoulder. This suggests that the pain severity categories consider different qualities of life and that the categorization we used was clinically meaningful.
Using multivariate ordinal logistic regression analyses, 24-hour postoperative morphine consumption significantly affected the severity of chronic pain. It is interesting that the variables predicting development of chronic pain after breast cancer surgery, except 24-hour postoperative morphine consumption, did not affect pain severity. The mechanisms that govern the development and intensity of chronic pain seem different; however, this may be partially explained by a limitation of our study. We recruited 175 patients but only 98 patients (56.0%) developed chronic pain after breast cancer surgery. Only 23 patients developed moderate pain and 27 patients developed severe pain, both of which were relatively small compared with the mild pain category. This limited statistical power may explain why variables other than 24-hour postoperative morphine consumption failed to predict chronic pain severity. Because morphine consumption showed a significant relationship to pain severity, it is reasonable to assume that severe acute pain is a strong predictor of chronic pain severity, as in the development of chronic pain.
Our study has several limitations. As we mentioned above, limited statistical power may be a reason that factors influencing the incidence of chronic pain failed to predict pain severity. However, power of incidence of chronic pain between propofol and sevoflurane was calculated after data collection and the analysis revealed 87.76%. Second, our study includes a cross-sectional study that provided a questionnaire at a single point, 2.5 to 4 years after breast cancer surgery. Because of the nature of our study, interpretations of the results must be made with caution. The information obtained from the patients does not provide definite cause-and-effect relationships, and the long time interval between surgery and answering the questionnaire may have caused recall bias. Third, we conducted this study in a single hospital and patients were treated by a single surgeon. All their treatments were well controlled by consistent guidelines. Thus, we do not know whether our model can be generalized to other settings because the development of chronic pain from surgical and medical treatments may be affected differently.
This study suggests that anesthetics during breast cancer surgery may affect the development of chronic pain. Propofol reduced the incidence of chronic pain compared with sevoflurane. Young age, axillary lymph node dissection, and more 24-hour postoperative morphine consumption increased the incidence of chronic pain after breast cancer surgery. However, the above factors did not increase the severity of chronic pain, and only higher 24-hour postoperative morphine consumption did. In conclusion, according to this study, propofol may have a contributing role in perioperative preventive and multimodal analgesic management, and further prospective studies are needed to confirm the validity of these provocative findings.
APPENDIX 1: QUESTIONNAIRE FORM
Questionnaire for Chronic Pain After Breast Cancer Surgery
1. Did you suffer from pain for more than 2 months after your surgery?□ Yes □ No
2. If your answer to 1 is positive, how long has the pain lasted after surgery?( ) months
3. If your answer to 1 is positive, what was the worst pain intensity? Score it using a numeric rating scale (0 = no pain; 10 = worst pain imaginable).( )
Questionnaire for Quality of Life
2. Have you had any problem in using your ipsilateral arm and shoulder?
3. □ Yes □ No
4. Self-care and usual activities
5. Have you had any problem washing or dressing yourself, or performing your usual activities (e.g., work, study, housework, family or leisure activities)?
6. □ Yes □ No
8. Have you visited a hospital to manage your pain?
9. □ Yes □ No
Name: Ah-Reum Cho, MD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Ah-Reum Cho has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Jae-Young Kwon, MD, PhD.
Contribution: This author helped design the study.
Attestation: Jae-Young Kwon has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Kyung-Hoon Kim, MD, PhD.
Contribution: This author helped design the study.
Attestation: Kyung-Hoon Kim has seen the original study data and approved the final manuscript.
Name: Hyeon-Jeong Lee, MD, PhD.
Contribution: This author helped design the study.
Attestation: Hyeon-Jeong Lee approved the final manuscript.
Name: Hae-Kyu Kim, MD, PhD.
Contribution: This author helped analyze the data.
Attestation: Hae-Kyu Kim has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Eun-Soo Kim, MD.
Contribution: This author helped conduct the study.
Attestation: Eun-Soo Kim has seen the original study data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Jung-Min Hong, MD.
Contribution: This author helped write the manuscript.
Attestation: Jung-Min Hong approved the final manuscript.
Name: Choongrak Kim, PhD.
Contribution: This author helped analyze the data.
Attestation: Choongrak Kim has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Spencer S. Liu, MD.
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