Volume 87, Issue 12 , Pages 1618-1622, December 2006
The Effect of Zaltoprofen on Physiotherapy for Limited Shoulder Movement in Breast Cancer Patients: A Single-Blinded Before-After Trial
Article Outline
Abstract
Hase K, Kamisako M, Fujiwara T, Tsuji T, Liu M. The effect of zaltoprofen on physiotherapy for limited should movement in breast cancer patients: a single-blinded before-after trial.
Objective
To determine the efficacy of oral administration of zaltoprofen on shoulder range of motion (ROM) exercises for breast cancer patients after surgery.
Design
Single-blind, before-after trial.
Setting
Rehabilitation facility in a Japanese university hospital.
Participants
Forty breast cancer patients (age range, 37−72y) with limited shoulder movement after surgery.
Intervention
Single session of physiotherapy (PT) with or without oral administration of zaltoprofen.
Main Outcome Measures
Active shoulder ROM in flexion, abduction, and external rotation, as well as subjective pain score during shoulder movements.
Results
Active shoulder movements after ingesting a zaltoprofen tablet significantly improved in flexion, abduction (P<.001), and external rotation (P<.005). PT treatment improved flexion and abduction ROM in both the zaltoprofen and control groups and led to significantly larger flexion and abduction movements in the zaltoprofen group than in the control group (P<.01). There were no differences in pain scores between groups, but 2 patients who did not receive zaltoprofen complained of increased pain just after ROM exercises.
Conclusion
Zaltoprofen taken orally before ROM exercises for painful shoulder after breast cancer surgery may enhance the effects of PT.
Key Words: Anti-inflammatory agents, non-steroidal, Breast cancer, Pain, Physiotherapy techniques, Range of motion, articular, Rehabilitation
RESTRICTION OF SHOULDER JOINT motion is a major problem for breast cancer surgery survivors in the postoperative period.1, 2, 3 The morbidities associated with the type of surgery or treatment, such as axillary lymph node dissection4, 5, 6, 7, 8 or radiotherapy,9, 10, 11, 12 have been well documented and postoperative physiotherapy (PT) treatment has been used to prevent shoulder dysfunction.13, 14, 15 The rehabilitation program should be based on the evaluation of the various problems that occur after breast cancer treatments, including pain, swelling, axillary tightness, anxiety about shoulder movement, and limitation of activities. In particular, pain experienced when performing usual activities of daily living (ADLs) with the arm ipsilateral to the breast operated on is a critical factor leading to limited shoulder movements. Furthermore, anxiety about pain induced by shoulder movement leads to nonuse of the arm and an arm sling posture.
Limited shoulder abduction in the early postoperative period after axillary surgery, called axillary web syndrome,6 is a self-limiting disorder caused by the dysmobility associated with pain. This occasionally makes it difficult for a patient to put her arm in the treatment posture for radiotherapy. Furthermore, a recent prospective survey3 found that about one third of patients still had shoulder pain 1 year after surgery; this late morbidity of the upper limb is significantly related to perceived disabilities in ADLs and a reduction in quality of life.
The painful disorders that contribute to limited shoulder movement in breast cancer survivors have various etiologies, including rotator cuff tendonitis, adhesive capsulitis, axillary tightness, lymphatic cording, and phlebitis. Unless the pain is resolved, PT will not be effective in extending the joint range of motion (ROM). A systematic review of shoulder pain treatment16 revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) and subacromial glucocorticosteroid injections may be superior to placebo in improving range of abduction in rotator cuff tendinitis. These agents are usually used to accelerate the effects of PT, although, surprisingly, few studies have quantified the benefits of analgesic treatments in PT interventions using ROM measurements. The most expected effect of PT is immediate success in enabling limb movement through muscle relaxation or eliminating the patient’s anxiety. In some cases, subacromial injections are given to ease spontaneous severe pain, but after breast cancer surgery injections to the arm ipsilateral to the breast must be avoided to prevent infection or edema. We planned this clinical study to verify the immediate effect of an NSAID on shoulder ROM exercises.
Hyperalgesia in arthritic or postoperative states results from sensitization of the nociceptive system by mediators associated with tissue damage, such as prostaglandin and bradykinin. The analgesic effects of NSAIDs are based on the inhibition of prostaglandin synthesis. Zaltoprofen has also been shown to have a strong inhibitory effect on bradykinin-induced pain.17 Bradykinin is a primary mediator of pain and inflammation, acting both as a potent and direct activator of nociceptors, and as an inducer of prolonged inflammatory hyperalgesia.18, 19 Bradykinin is generated in the exercising muscle20 and causes excitation of nociceptors in skeletal muscles.21, 22 The blood bradykinin concentration is immediately increased after eccentric weight-training exercises in humans,23 which is similar to the contraction pattern induced in passive ROM exercises under painful conditions.
Recently, a postoperative pain model18 suggested the possible preemptive analgesic efficiency of zaltoprofen underlying the inhibitory function of B2-type bradykinin receptor in nerve endings. Therefore, we designed this study to determine the immediate analgesic effect of zaltoprofen on shoulder ROM exercises in breast cancer patients.
Methods
Protocol
This was a single-blinded, before-after trial. The study design is shown in figure 1. Breast cancer patients with limited shoulder movement after surgery who were referred to our rehabilitation department between December 2001 and April 2005, were asked to participate in the trial. Inclusion criterion was a restricted shoulder ROM on the side ipsilateral to the breast operated on. Restriction was defined as movement 50° or less than that on the nonsurgical side in any direction of flexion, abduction, and external rotation. Exclusion criteria consisted of preoperative shoulder dysfunction on the surgical side, use of other NSAIDs, and a history of intestinal ulcers. Patients were provided with written information about the study and gave their informed consent before their participation.
Fig 1.
Overview of the study design.
We examined the ROM of the shoulder on the surgery side of patients who enrolled in the study. In addition, we assessed them for the presence of spontaneous pain, lymphatic cording, or swelling. Subjects were then randomized to receive either a single 80-mg tablet of zaltoprofen or no treatment. The examiner and physiotherapists were blinded as to the treatment groups.
Examination of Shoulder ROM, Pain, Lymphatic Cording, and Swelling
To certify any effects in patients who received zaltoprofen, as well as to maintain blinding of the examiner as to the allocation groups, ROM measurements of all patients were taken upon their inclusion in the study (baseline) and just before the PT treatment (pre-exercise measurement). Because zaltoprofen reaches a peak plasma concentration approximately 30 minutes after dosing,24 this pre-exercise measurement (that did not include pain assessment to avoid a measurement bias due to analgesic effect), was performed 45 to 60 minutes after patients received envelopes either with or without a zaltoprofen tablet. After eating a light meal, patients whose envelopes contained a tablet were instructed to ingest it and to not tell anyone that they had taken the medication until all measurements were completed. The final evaluation of active shoulder ROM was made immediately after the PT session (postexercise measurement). At this time, pain was also assessed.
Active shoulder motion was examined with a large hand-held goniometer with patients seated during all tested movements. They were asked to move their arm while keeping their trunk upright. Flexion and abduction were measured as the angles formed in raising the stretched arm as far as possible in the sagittal and frontal plane, respectively. External rotation was assessed as the range of forearm movement in the transverse plane as far outward as possible with the upper arm at 0° elevation, the elbow flexed at 90°, and the thumb up. The active shoulder ROM was estimated by the same physiatrist and recorded in increments of 5°.
To identify sensitively whether the subjective pain during shoulder elevation was changed after PT, pain at baseline was designated as having a score of 10. If pain was perceived to have increased after PT, patients were asked to score the pain in points above 10. For instance, a score of 20 would indicate that pain was twice as painful as the baseline score of 10. Also, at study inclusion, the presence of spontaneous pain, lymphatic cording, and swelling were evaluated as pain of the shoulder girdle while resting in a chair, the feeling of a tight string on the skin down the arm to the elbow and occasionally to the wrist, and a right and left difference of 2cm or more in the center part of the upper- and forearm, respectively.
Physiotherapy
PT consisted of passive stretching exercises for full ROM in flexion, abduction, and external rotation directions, with the physiotherapist supporting the arm while obtaining muscular relaxation. In addition, active and passive ROM exercises were performed using a wooden stick or wall while in the supine, seated, or standing positions. The total exercise time was approximately 20 minutes, including instructions for doing exercises at home.
Statistical Analysis
We used the Mann-Whitney U test to compare patient characteristics and shoulder ROM between the control and zaltoprofen groups. We used the Friedman test and the Wilcoxon signed-rank test to test significant differences within groups of the active shoulder joint movements in each direction before and after PT. The level of significance was set at P less than .05. To adjust for multiple comparisons of data for the shoulder ROM in each group, however, when the Friedman test showed a significant difference within groups (P<.05), we applied the Bonferroni adjustment, that is, the level of significance for each set of data from 3 measurements was accepted as P less than .016. We also performed a Mann-Whitney U test to compare changes in active shoulder ROM at pre- and postexercise measurements, with significance set at P less than .025.
Results
Patient Characteristics
Forty female patients with limited shoulder movement after breast cancer surgery (age range, 37−72y) participated in this study. Their baseline characteristics are shown in table 1. The time from breast cancer surgery to study inclusion was 87.9±73.4 days in the control group (range, 8−256d) and 84.0±75.5 in the zaltoprofen group (range, 10−223d). There were no significant baseline differences in age, time from surgery to study inclusion, active shoulder ROM, and other symptoms between the groups. All patients complained of pain at the end of maximum ROM and 9 patients (5 in the control group, 4 in the zaltoprofen group) had spontaneous dull pain. Four patients (1 in the control group, 3 in the zaltoprofen group) had lymphatic cording at the medial upper arm and radiating pain into the elbow caused by shoulder movement. No patient had swelling in the arm of interest of more than 2cm when compared with the contralateral arm.
Table 1. Patient Characteristics (N=40)
| Characteristics | Control (n=20) | Zaltoprofen (n=20) |
|---|---|---|
Age (y) | 51.4±8.2 | 50.8±7.1 |
| Duration of time from surgery to study inclusion(d) | 87.9±73.4 | 84.0±75.5 |
| Breast-conserving surgery | 9(45) | 8(40) |
| Shoulder ROM(deg) | ||
| Flexion | 100.8±17.3 | 97.8±17.8 |
| Abduction | 93.5±21.2 | 90.8±16.9 |
| External rotation | 44.5±18.0 | 46.3±19.8 |
| Spontaneous pain | 5(25) | 4(20) |
| Lymphatic cording | 1(5) | 3(15) |
Active flexion and abduction ROMs in all patients decreased but external rotation was maintained in some patients. To further characterize our patients, we categorized them into 2 groups based on the time lapse from surgery to study inclusion (≤3mo, >3mo). We found a significant restriction of external rotation (P<.001) in patients who had surgery more than 3 months previously, compared with patients who had surgery within 3 months of study enrollment (table 2).
Table 2. Patient Characteristics Based on Duration of Time From Breast Cancer Surgery to Study Inclusion
| Characteristics | Early (≤3mo) (n=22) | Delayed (>3mo) (n=18) |
|---|---|---|
| Duration(d)⁎ | 24.1±10.1 | 161.4±36.2 |
| Shoulder ROM(deg) | ||
| Flexion | 100.0±20.1 | 98.3±13.9 |
| Abduction | 93.9±17.6 | 90.0±20.8 |
| External rotation⁎ | 58.0±13.2 | 30.0±11.4 |
| Spontaneous pain | 3(13) | 6(33) |
⁎P<.001. |
Shoulder ROM
Figure 2 shows the mean ± standard deviation (SD) of active shoulder ROM before and after a single session of PT treatment. Friedman analysis revealed significant differences in the shoulder ROM in every direction (P<.05). The Wilcoxon signed-rank test with Bonferroni adjustment showed that active movement ranges of flexion, abduction (P<.001), and external rotation (P<.005) after taking a zaltoprofen tablet (pre-exercise) were significantly larger than the baseline measurement ranges. The PT treatment improved the active shoulder ROMs of flexion and abduction in the control group (P<.016 for both directions) and zaltoprofen group (P<.005 for flexion, P<.001 for abduction), but not the ROM of external rotation. Significantly larger flexion and abduction movements after pre- (P<.05) and postexercises (P<.01) were found in the zaltoprofen group compared with the control group (P<.01). There was no significant difference in shoulder ROM between the postexercise measurement in the control group and the pre-exercise measurement in the zaltoprofen group.
Fig 2.
Changes in active shoulder movements before and after PT. Active shoulder ROM in (A) flexion, (B) abduction, and (C) external rotation before and after a single session of PT treatment. NOTE. Values mean ± SD. Significant differences before and after PT in each group are indicated by: *P<.016, †P<.005, and ‡P<.001. Significant differences between the corresponding measurements in the control and zaltoprofen groups are indicated by: §P<.05 and ‖P<.01.
Table 3 shows the means and 95% confidence intervals (CI) of changes of active shoulder ROMs from baseline to pre-exercise measurements and from pre-exercise to postexercise measurements. In all directions, the extent of improvement in shoulder ROM from the baseline to the pre-exercise measurement after taking zaltoprofen was significantly greater compared with that of the control group (P<.001 for flexion and abduction; P<.005 for external rotation). In terms of changes of shoulder ROM between pre- and postexercise measurements, however, the abduction movement tended to be improved in the zaltoprofen group (P=.030), but there was no significant difference in the active movement range in any direction between the 2 groups (see fig 2).
Table 3. Changes of Shoulder ROM Between Baseline and Pre-Exercise Measurements and Between Pre-Exercise and Postexercise Measurements
| Measurements | Control (n=20) | Zaltoprofen (n=20) |
|---|---|---|
| Flexion | ||
| Baseline to pre-ex | 0.75(−0.11to1.60) | 16.50(11.13to21.87)† |
| Pre-ex to post-ex | 4.75(1.15to8.35) | 6.50(3.10to9.90) |
| Abduction | ||
| Baseline to pre-ex | 0.50(−0.55to1.55) | 17.75(11.15to24.35)† |
| Pre-ex to post-ex | 3.50(0.65to6.35) | 7.75(4.49to11.01) |
| External rotation | ||
| Baseline to pre-ex | −0.50(−1.22to0.22) | 7.25(3.57to10.93)⁎ |
| Pre-ex to post-ex | 3.75(0.73to6.78) | 1.25(0.21to2.29) |
⁎P<.005; |
†P<.001. |
Pain Score During Shoulder Movement
The pain score during active shoulder movements decreased after ROM exercises in the control (8.85±1.39) and zaltoprofen (7.95±1.67) groups (fig 3). Two patients in the control group complained of increased pain just after ROM exercises but the Mann-Whitney U test did not reveal any significant difference in the pain scores between groups (P=.146). Also, in each group, the extent of changes in the pain score did not correlate with improvement in shoulder ROM.
Fig 3.
Pain score during active shoulder movements after PT. Means and 95% CIs of the pain score during active shoulder elevation movements after a single PT session in both groups. Note that the degree of pain at the baseline measurement was defined as 10.
Discussion
Results of this study demonstrate the efficacy of taking oral zaltoprofen for a painful shoulder before ROM exercises after breast cancer surgery. After taking zaltoprofen, the active shoulder movements in each direction were improved without ROM exercises. Because the additional effects from PT intervention in the zaltoprofen group were similar or somewhat superior to the ones in the control group, a single session of PT combined with taking zaltoprofen enabled breast cancer patients to elevate their involved arm higher. We did not find any differences in the subjective pain score while elevating the arm to the maximum position among patients in the zaltoprofen group compared with those in the control group, but the improved active shoulder movements are most likely due to the analgesic action of zaltoprofen. The immediate effects on limited shoulder ROM gave some patients an expectation of succeeding in achieving the elevated-arm position required for radiotherapy.
The cause of shoulder pain in breast cancer survivors is multifactorial, but this pain often restricts patients to nonuse of the shoulder or to a fixed position, such as a sling posture. Rietman et al8 reported that upper-limb morbidity 1 year after axillary intervention included limited external rotation, as well as flexion and abduction movements. This corresponds with reports of shoulder dysfunction in patients having a longer postoperative period after breast cancer surgery. In contrast, we found that restriction of external rotation was spared in the patients who had undergone surgery within 3 months of our study. These results suggest that shoulder dysfunction in the early postoperative period arises from mechanisms different from the so-called frozen shoulder characterized by the limited movement of external rotation. Because the longer period of morbidity may contribute to additional shoulder dysfunction6 in patients who are at risk of this condition worsening, intensive PT interventions should be scheduled in the earlier periods after surgery.
On the other hand, a meta-analysis25 of 6 randomized controlled trials of early versus delayed shoulder mobilization after breast cancer surgery revealed that delayed mobilization reduced the risk of seroma formation. The incentive to delay arm exercises may potentially lead to prolonged shoulder dysfunction. Even though PT is performed in the early period after surgery, complaints of decreased shoulder function are frequent.2 A recent study15 reported that additional postoperative PT 2 months after surgery had positive effects on shoulder movement. Therefore, we must establish a postoperative education system for breast cancer patients in which a gate manager determines the indication for intensive PT, in addition to the routine rehabilitation program.3
We did not examine long-term effects of PT with oral intake of zaltoprofen because most patients who were enrolled within 3 months after surgery were to undergo radiotherapy, which is a known risk factor for shoulder dysfunction.9, 10, 11, 12 The significance of analgesic treatment applied before PT may, however, affect the immediate success of therapeutic intervention, which is important for patients who are concerned about whether they will be able to undergo radiotherapy. On the contrary, if no immediate effect had been found with zaltoprofen, it would be wise to use another method to achieve analgesia. Because zaltoprofen inhibits both bradykinin and cyclooxygenase activities, it may have a desirable property for movement-induced and subsequent inflammatory pain in rehabilitation treatments. In particular, the antinociceptive mechanism through blockage of B2-type bradykinin receptors that mediate acute pain is suggested to be advantageous in achieving preemptive analgesic effects.18 Our study showed the efficacy of using zaltoprofen before a single session of PT to treat painful shoulder in breast cancer patients. Future studies need to examine the long-term effect of zaltoprofen and to compare effects of other NSAIDs used for pain control.
Conclusions
This study showed that an 80-mg zaltoprofen tablet taken before postsurgical PT interventions improved limited shoulder movements in breast cancer patients.
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No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated.
PII: S0003-9993(06)01322-0
doi:10.1016/j.apmr.2006.08.339
© 2006 American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.
Volume 87, Issue 12 , Pages 1618-1622, December 2006
