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Effect of Acupuncture on Aromatase Inhibitor–Associated Joint Pain in Women with Early-Stage Breast Cancer

Breast cancer is the most common type of cancer in the UK. Over 55,000 women are diagnosed with breast cancer each year in the UK, including around 4,700 in Scotland. Most women diagnosed with breast cancer are over 50, but younger women can also develop breast cancer. About one in eight women are diagnosed with breast cancer during their lifetime. There’s a good chance of recovery if it’s detected in its early stages. For this reason, it’s vital that women check their breasts regularly for any changes and always get any changes examined by their GP. In rare cases, men can also be diagnosed with breast cancer.

The exact causes of breast cancer aren’t fully understood. However, there are certain factors known to increase the risk of breast cancer. Such as age-related risk increases as you get older, a family history of breast cancer and excessive use of alcohol etc. The management of breast cancer depends on various factors, including the stage of the cancer and the person’s age. Treatments are more aggressive when the prognosis is worse or there is a higher risk of recurrence of the cancer following treatment. Drugs used after and in addition to surgery are called adjuvant therapy. Chemotherapy or other types of therapy prior to surgery are called neoadjuvant therapy. There are currently three main groups of medications used for adjuvant breast cancer treatment: hormone-blocking agents, chemotherapy, and monoclonal antibodies.

Some breast cancers are stimulated by the hormone oestrogen. This means that oestrogen in the body ‘helps’ the cancer to grow. This type of breast cancer is called oestrogen receptor positive (ER+), which can be treated with hormone blocking therapy drugs that either block the receptors, e.g. tamoxifen, or alternatively block the production of estrogen with an aromatase inhibitor, e.g. anastrozole or letrozole. Aromatase inhibitors are only suitable for women after menopause, however, in this group, they appear to be better than tamoxifen. This is because the active aromatase in postmenopausal women is different from the prevalent form in premenopausal women, and therefore these agents are ineffective in inhibiting the predominant aromatase of premenopausal women.

Despite the well-proven efficacy of aromatase inhibitors (AIs), namely anastrozole, letrozole and exemestane for the treatment of hormone-sensitive breast cancer, some patients suffer from side effects or even stop treatment early due to severe side-effects. The most common side effects of AIs are musculoskeletal pain, hot flashes, vaginal dryness and headache, and possibly alterations in serum lipid profiles. There was a significant change in musculoskeletal pain in women receiving AIs including physical changes in the affected joints seen on MRI, EMG, and ultrasound. For example, there had decreased grip strength and increased tenosynovial changes seen on MRI in women on AIs for six months.

The exact mechanism of AI-related arthralgia is unclear, but is thought to be related to estrogen deprivation. In elderly postmenopausal women, estrogen may be an important regulator of osteoarthritis. The long-term effects of profound estrogen suppression in breast cancer patients taking AIs are unknown. The acute and long-term side effects of AIs are becoming an increasingly important issue as more and more women are being treated with these agents. Musculoskeletal pain may be associated with a deterioration of quality of life due to physical disability, sleep disturbance, impaired cognitive function, depression and anxiety. This is a common complaint in early-stage breast cancer patients with joint pain related to the use of AIs, which can lead to the discontinuation of a life-saving therapy. Research has shown that even taking this medication less than 80% of the time can have a negative impact on survival. Therefore, targeted interventions that relieve AI-induced musculoskeletal pain are needed.

Acupuncture is a popular non-pharmacological modality used for treating various conditions, including musculoskeletal pain. Acupuncture has been shown to have short-term analgesic effect in musculoskeletal pain. Clinical trials have found a benefit to patients with knee osteoarthritis when acupuncture is used as an adjunct to conventional management strategies. In a randomized study of 97 patients with osteoarthritis of the knee, acupuncture as a complementary therapy to pharmacological treatments is more effective than pharmacological treatment alone, in terms of reducing pain, improving physical function and health-related quality of life (Vas et al., 2004). A trial conducted in Germany concluded that true acupuncture has a better effect than sham acupuncture in the treatment of knee and back pain (Brinkhaus et al., 2003). However, in two large multicenter trials of acupuncture for osteoarthritis of the knee, one found a benefit in joint pain and function compared to sham acupuncture and the other found no additional improvement in pain scores (Witt et al., 2005; Foster et al., 2007).

To improve understanding of the efficacy of acupuncture in breast cancer patients with AIs-related arthralgias, the aim of this review was to summarize and assess the evidence from available randomized clinical trials (RCTs) that examined acupuncture in the treatment of arthralgias of patients with breast cancer using AIs.

A small pilot study was conducted to evaluate the use of acupuncture to relieve symptoms of AI-associated arthralgias (Crew et al., 2007). In this study of 21 women treated with a 6-week course of total body and auricular acupuncture, improvements were reported in pain severity, pain-related functional outcomes, and physical well-being, and no significant adverse events were reported (Crew et al., 2007). This study was limited due to its small sample size and lack of an adequate control group. Investigators then went on to conduct a randomized, blinded, sham-controlled study in 38 breast cancer patients with AI-associated arthralgias (Crew et al., 2010). In this study, true acupuncture for 6 weeks was associated with about a 50% decrease in mean Brief Pain Inventory-Sort Form (BPI-SF) scores compared to sham acupuncture with superficial needling at non-acupuncture points (Crew et al., 2010). Similar findings were seen for the The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and modified Score for the Assessment and quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH) scores. Results found that acupuncture was an effective and well-tolerated strategy for managing this common AIs-related side effect in early-stage breast cancer patients (Crew et al., 2010). However, two randomized controlled clinical trials, with total patients numbers = 32 (Oh et al., 2013) and =47 (Bao et al., 2013) respectively, with similar settings showed no significant difference of arthralgia reduction following acupuncture treatment between TA and SA in breast cancer patients using AIs (Bao et al., 2013; Oh et al., 2013).

Mao et al., (2014) conducted a randomized controlled trial of acupuncture in postmenopausal women with breast cancer suffering from AIs-related arthralgia. Sixty-seven breast cancer patients were recruited and randomly assigned to true acupuncture (TA), sham acupuncture (SA) and waitlist control (WLC). The results showed that mean reduction in pain severity was statistically greater in the EA group than in the WLC group at week 8 and at week 12. Pain-related interference measured by BPI also improved in the EA group compared to the WLC group at both weeks 8 week 12. Meanwhile, SA produced a magnitude of change in pain severity and pain-related interference at week 8 and week 12, similar to that of EA (Mao et al., 2014). This randomized controlled trial met its primary endpoint, demonstrating that EA produced statistically significant and clinically important improvements in pain severity, pain-related interference and functional outcomes in both upper and lower extremities when compared to WLC usual care. The effects were observed at week 8 when intervention completed, and persisted at the week 12 follow-up visit.

Then, the first large multicenter randomized (2:1:1) controlled trial to investigate the effect of acupuncture in treating AI-induced joint symptoms in breast cancer patients was conducted to determine whether TA (n = 110) administered twice weekly for 6 weeks (8-12 sessions) compared to SA (n = 59) and WLC (n = 57) could produce a significant reduction in joint pain related to AIs in women with early stage breast cancer (Hershman et al., 2018).

Compared with baseline, the mean Brief Pain Inventory Worst Pain (BPI-WP) item score was 2.05 points lower (reduced pain) at 6 weeks in the TA group, 1.07 points lower in the SA group, and 0.99 points lower for the WLC group, with differences in adjusted 6-week mean BPI-WP scores between TA vs SA of 0.92 points and between TA vs WLC of 0.96 points (Hershman et al., 2018).

At 6 weeks, patients randomized to the TA group had statistically significant improved symptom scores compared with those randomized to the SA and WLC groups at 6 weeks according to BPI average pain, pain severity, and worst stiffness. Patients randomized to TA had improved symptoms at 6 weeks compared with those in the SA group, but not compared with the WLC group according to pain interference (Hershman et al., 2018).

Patients randomized to the TA group had improved symptoms compared with those in the SA group at 6 weeks according to the M-SACRAH, WOMAC, and Patient-Reported Outcomes Measurement Information System (PROMIS PI-SF) measures. Patients randomized to the TA group had improved symptoms compared with those in the WLC group at 6 weeks according to the M-SACRAH and WOMAC measures (Hershman et al., 2018). 

At 12 weeks, patients randomized to the TA group compared with the SA group had statistically significant improvements in average pain, but no significant improvement in worst pain, pain interference, pain severity, or worst stiffness. Compared with the WLC, patients randomized to the TA group had improved pain by all BPI measures (Hershman et al., 2018).

Bruising was the most common adverse event reported for those receiving TA or SA. More patients in the TA group experienced grade 1 bruising (47%) than in the SA group (25%; P = .01) (Hershman et al., 2018).

Overall, in this multicenter, sham- and waitlist-controlled clinical trial of patients with early-stage breast cancer and aromatase inhibitor–related joint pain, there were statistically significant but modest improvements in pain scores with true acupuncture administered twice a week for 6 weeks compared with both sham acupuncture and waitlist control.

Acupuncture may provide analgesia by increasing the levels of endogenous opioid peptides in the central nervous system (Sjolund et al., 1977) or by changing the levels of other signaling molecules such as serotonin, noradrenalin, dopamine, cholecystokinin, octapeptide, glutamate, and c-amino-butyric acid (Yoo et al., 2011). Moreover, in addition to potential immunomodulatory effects, acupuncture may influence the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, which is a biologically plausible explanation for the simultaneous pain relief induced by acupuncture in patients with cancer (Kim & Bae, 2010). Among the included studies, Bao et al., (2013) by analyzing blood samples from patients, observed no significant changes in estradiol, beta-endorphin, or other pro-inflammatory cytokine concentrations, except for a significant reduction in interleukin-17 in both acupuncture and sham groups, which was modestly associated with improvement in HAQ-DI and VAS scores, and a trend toward greater reduction in TNF-alpha level was also noted (Bao et al., 2013). Therefore, further rigorous studies are required to elucidate the mechanism of acupuncture on AI-induced arthralgia.

The results from included studies showed that acupuncture was well tolerated and has effectively and significantly alleviated AI-related joint pain compared with sham acupuncture, improving the quality of life of women with breast cancer. This information is important in order to develop evidence-based guidelines regarding the appropriate use of acupuncture and therefore potentially integrate acupuncture safely and effectively with conventional medicine within the healthcare system.

 

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