Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:

1. Define the characteristics of persistent pain after breast cancer surgery (PPBCS).

2. Formulate a differential diagnosis based on key features.

3. Identify commonly used preventive strategies for PPBCS.

4. List 2 nonpharmacologic approaches that may reduce the incidence or severity of PPBCS.

Breast cancer is the second most common newly diagnosed cancer and the second leading cause of cancer death among women in the United States.1 Although early detection and treatment have increased the rate of survival for women with breast cancer, a significant number of women (25%-60%) report persistent pain of the breast, arm, and/or chest wall that can last for months or years.2 Certain risk factors may increase the chance of persistent pain after breast cancer surgery, including younger age, preoperative chronic pain, maladaptive coping (anxiety, depression, and catastrophizing), the surgical approach, and medical treatments. This article reviews the defining features of persistent pain after breast cancer surgery, risk factors, therapeutic strategies, and potential preventive measures that can be used to reduce the incidence and severity of this challenging pain condition.

Definitions

More than 200,000 women are diagnosed with breast cancer each year, and of these, a substantial number will receive some type of surgical treatment1 Advances in breast cancer treatment have led to steady improvements in the rate of survival, and there are currently more than 3 million breast cancer survivors in the United States.2 Although the decreasing rate of death is noteworthy, many survivors report severe, disabling pain in the region of the affected breast that interferes with social and physical function and erodes quality of life.2 With the potential for preventing or alleviating persistent pain after breast cancer surgery (PPBCS), clinical studies to identify risk factors and potential treatment strategies have been undertaken.

Persistent pain after breast cancer surgery is typically defined by the following criteria:

1. Pain localized to the breast, arm, and/or chest wall;

2. Pain developing after surgical resection of the breast tumor; and

3. Pain lasting 3 months or longer according to the definition of chronic pain by the International Association for the Study of Pain.3

However, variability is considerable in the definition and measurement across studies.4 The term, postmastectomy pain syndrome (PMPS), is often used interchangeably with PPBCS. Symptoms are thought to be neuropathic in origin.5 However, persistent postsurgical pain can develop around the region of the breast after either lumpectomy or mastectomy; the syndrome may be mediated by radiation, hormonal therapy, or chemotherapy and the pain can evolve months after the surgical procedure. For this reason, the term PPBCS is more accurate than PMPS. Some authors advocate for the more broad term of persistent pain after breast cancer treatment.6,7 However, this term has been criticized as being too general and clinically irrelevant for informing treatment options. Therefore, the term PPBCS is more widely used.

Possible Etiologies of Persistent Pain After Breast Cancer Treatment

The characteristics of pain and sensory disturbances associated with PPBCS are most often consistent with a neuropathic origin.8 Nerve injury can occur during surgery because of mechanical forces (manipulation or section) and molecular events that cause sensitization of peripheral nerves and spinal and supraspinal processing centers. Jung and colleagues9 classified the types of neuropathic postsurgical pain (PPBCS; PMPS) as phantom breast pain; intercostobrachial neuralgia; neuroma pain; and other nerve injury pain (outside the distribution of the intercostobrachial nerve, such as the medial and/or lateral pectoral, long thoracic, thoracodorsal, or other intercostal nerves). The characteristics of different pain syndromes that may occur after breast surgery are briefly described and summarized in Table 1.

Table 1. Characteristics of Pain Syndromes After Breast Surgery

Phantom breast pain is a feeling of pain in the breast that has been removed and is reported in up to a third of women who undergo mastectomy regardless of whether reconstruction is performed.10 This type of pain is thought to occur from peripheral sensitization and central reorganization, similar to other phantom pain syndromes. Women are more likely to experience phantom breast pain if they had pain preoperatively.11 There is some evidence that depression and anxiety may influence phantom breast pain,10 and both exercise and massage have been suggested as therapeutic strategies, although these have not been formally evaluated in clinical studies.

Thoracic intercostal nerves innervate the breast. Damage to the intercostobrachial nerve (ICBN) has been identified as the most common cause of pain postsurgery.12 Pain associated with ICBN injury is localized to its distribution (T2) along the anterior and lateral region of the thorax, axilla, and/or medial upper arm. Intercostobrachial nerve pain may be described as burning, shooting, or pressure pain with or without numbness.13 Although it is most frequently reported during the immediate postoperative period, it can also appear months later. Nerves adjacent to the intercostobrachial branch are usually spared during surgery but may be injured by scarring or intraoperative traction. Careful surgical dissection of intercostal sensory nerves to avoid damage (stretch, transection, or cauterization) is ideally the approach to prevent PPBCS but is not always possible. Furthermore, intentional ICBN-sparing approaches have not reduced the incidence of PPBCS.14,15 Prophylactic measures may be reasonable for patients who have preoperative breast pain, in women who have a tumor located in the upper lateral quarter of the breast, or in those who will be undergoing axillary node dissection or more extensive surgical procedures. Prophylactic, perioperative, and postoperative strategies for reducing the incidence or severity of neuropathic PPBCS are presented in Table 2.

Table 2. Prophylactic, Intraoperative, and Postoperative Pain Management Options in Women With Breast Cancer

Neuroma pain is localized in the region of the surgical scar and is provoked or exacerbated by percussion (Tinel's sign).16 It may be more common in patients who undergo lumpectomy, axillary dissection, and radiotherapy than in those who undergo modified radical mastectomy.13 Intercostal neuromas can be treated with a local anesthetic block, excision and relocation, or nerve grafts.9 A small study among 19 women with postoperative neuroma along T4 or T5 reported that perineural infiltration of 2-mL equal ratio 0.5% bupivacaine and 4-mg/mL dexamethasone successfully resolved pain in 60% after 1 injection.17 The point of maximal pain was identified (along the intramammary fold directly inferior to the nipple or laterally along the midaxillary line) and the injection was administered at the level of the chest wall followed by 1 to 2 minutes of massage.

Central sensitization is another mechanism that may influence the development of PPBCS. Alterations in pain processing associated with central sensitization occur through amplification of nociceptive signal transmission with increased activity and expansion of receptive fields of wide-dynamic-range neurons in the spinal cord.18 Functionally, central sensitization diminishes descending inhibitory tone and enhances descending facilitation from supraspinal centers. Evidence of central sensitization comes from studies using quantitative sensory testing that have shown increased temporal summation and decreased descending inhibition (conditioned pain modulation).19,20 As with other surgical procedures, there is no apparent explanation for why some women develop PPBCS whereas others do not; however, there seems to be a heavy influence of maladaptive coping behaviors, such as catastrophizing, in women who develop PPBCS.4 Further studies are underway to determine whether central sensitization is a presurgical phenomenon that makes some women more vulnerable to PPBCS.

Preoperative Risk Factors

Variations in the definition used to study risk factors of PPBCS have led to inconsistent findings. Some studies have identified risk factors that include younger age, severity of immediate postoperative pain, heavier weight, and ethnicity.21-24 The most consistent risk factors include the extent of surgery (with higher incidence among women with total mastectomy or axillary node dissection) and preexisting breast pain.25,26

Means to Reduce the Incidence and Severity of Persistent Pain After Breast Cancer Surgery

In an effort to reduce the incidence of PPBCS, investigators have examined preoperative, intraoperative, and postoperative interventions. Paravertebral block (PVB) is an approach that has been studied as both a preoperative and intraoperative intervention, and has shown strong evidence for reducing acute postoperative pain, with moderate evidence for preoperative PVB in reducing the incidence of PPBCS. Because of the number of studies evaluating the effect of PVB on severity of postoperative pain, a potential risk factor of PPBCS, the findings are summarized in Table 2. For patients who develop PPBCS, strategies to reduce persistent postsurgical pain (pertaining to other locations or surgical procedures) have been evaluated.

Intraoperative Regional Analgesia for Pain Management

Working on the premise that the severity of immediate postsurgical pain may predict the occurrence of PPBCS, several studies have evaluated the efficacy of perioperative pain management strategies on acute postsurgical pain. Thoracic PVBs are routinely used to enhance postoperative pain management among patients undergoing breast surgery.44 Deposition of local anesthetic deep into the costotransverse ligament and superficial to the pleura results in blockade of the spinal nerve as it exits the intervertebral foramen. Local anesthetic injection into the paravertebral space results in both cranial and caudal local anesthetic spread, covering 4 to 6 thoracic dermatomes depending on the volume injected, which is typically 3 mL per level blocked.

A meta-analysis that assessed the efficacy and adverse events of PVB in 877 women undergoing breast surgery included 15 randomized controlled trials published between 1999 and 2009. The authors concluded that there is considerable evidence supporting PVB with sedation including propofol, midazolam, or both or as an adjunct to general endotracheal anesthesia in providing better postoperative pain control with little adverse effect.45 The trials evaluating PVB versus general anesthesia, or PVB combined with general anesthesia versus general anesthesia alone, demonstrated that patients who received PVB had significantly lower "worst" postoperative pain scores from 2 to 48 hours postsurgery. In addition, the number of women needing postoperative opioids was significantly lower and total morphine dose was significantly lower.45

A retrospective cohort analysis of patients undergoing mastectomy with or without PVB from 2008 to 2010 was conducted to determine whether PVB altered opioid use, antiemetic use, and length of stay.46 Of 526 patients who underwent uni- or bilateral mastectomy (294 without PVB; 232 with PVB), there was significantly less use of postoperative antiemetics and lower opioid use on the day of surgery. However, a similar retrospective study during the same period that included 337 patients found no difference in antiemetic or opioid use in women who underwent mastectomy with or without PVB.47

In a randomized, double-blinded, parallel-group, placebo-controlled trial, the effect of multilevel ultrasound-guided PVBs and total IV anesthesia on quality of recovery was examined in women after ambulatory breast tumor resection.48 Women were randomized to receive standardized general anesthesia (n = 33) or PVBs and propofol-based total IV anesthesia (n = 33; control group). The PVB group received T1-T5 PVBs with 5 mL of 0.5% ropivacaine per level, whereas the control group received sham subcutaneous injections.

The PVB group had higher quality of recovery scores than the control group upon discharge (146 vs 131; P < 0.0001) and on postoperative day 2 (145 vs 135; P = 0.013); improvements beyond postoperative day 2 lacked statistical significance. None of the patients in the PVB group required conversion to inhalation gas-based general anesthesia or experienced block-related complications. PVB group patients had improved pain scores on postanesthesia care unit admission and discharge, hospital discharge, and postoperative day 2; intraoperative morphine consumption, incidence of nausea and vomiting, and time to discharge were also reduced. The authors concluded that combining multilevel PVBs with total IV anesthesia provides reliable anesthesia, improves postoperative analgesia, enhances quality of recovery, and expedites discharge compared with inhalational gas- and opioid-based general anesthesia for ambulatory breast tumor resection. However, long-term pain outcomes were not evaluated.

Subsequently, 2 studies evaluated the effect of PVB on the prevalence of pain 12 months after surgery. The first included patients undergoing mastectomy with or without axillary lymph node dissection (ALND) or sentinel lymph node biopsy. The purpose was to evaluate PVB with 0.5% ropivacaine before surgery versus wound injection with 0.5% ropivacaine at the end of surgery.49 The prevalence of pain after the surgery was similarly low in both groups.

The second study included women undergoing mastectomy with or without ALND and evaluated PVB with 0.4% ropivacaine versus saline daily for 3 days after the surgery.50 The combined single-injection ropivacaine PVB along with the multiple-day, continuous ropivacaine infusion significantly reduced the prevalence and intensity of pain at 12 months after surgery.

Two studies have investigated the efficacy of anesthetic infiltration of the wound on postoperative pain in women undergoing surgery for breast cancer. Used alone (without PVB) the infiltration technique with ropivacaine did not reduce postoperative pain, opiate consumption, or chronic pain development.49,51 As a perioperative strategy, surgical wound infiltration does not seem to be effective.45

Pectoral nerve block, an interfascial plane block, is another strategy to reduce the severity of acute postsurgical pain, and possibly the prevalence of PPBCS. It is performed by injecting local anesthetic into the plane between the pectoralis major and pectoralis minor muscles (PECS-I block) and above the serratus anterior muscle at the third rib (PECS-II block) to block the pectoral, intercostobrachial, intercostals III-VI, and long thoracic nerves.

A retrospective study among women who underwent breast cancer surgery under general anesthesia (n = 36) or general anesthesia plus pectoral nerve block (n = 35) reported that the pectoral nerve block group required significantly less intraoperative remifentanil and had significantly lower pain scores through 48 hours postoperatively.52 Intraoperative remifentanil requirements, cumulative remifentanil dose, and postoperative pain scores up to 48 hours after surgery were significantly lower in the pectoral nerve block group as compared with the IV anesthesia-only group. Administration of fentanyl intraoperatively, percentage of patients requiring supplemental analgesics, and incidence of postoperative nausea and vomiting were not significantly different between groups. This study did not evaluate long-term pain outcomes.

In a prospective study to compare pectoral nerve block after modified radical mastectomy surgery, 120 female patients were randomly allocated to receive either general anesthesia plus pectoral nerve (PECS) block (n = 60) or general anesthesia only (n = 60). In patients receiving PECS block, opiate consumption was reduced both intraoperatively and for 12 hours postoperatively and pain scores were reduced for 24 hours postoperatively. Pectoral block patients were discharged earlier from the postanesthesia care unit and hospital.53 These 2 studies provide some evidence of improved pain management after surgery for breast cancer. However, long-term outcomes will need to be examined in future trials to determine whether this method may reduce the prevalence of PPBCS.

Pectoral block has been evaluated as a method to treat PPBCS. A small pilot study of the effectiveness of the PECS local anesthetic block on pain intensity and sensory function was carried out in 8 participants with PPBCS for more than 6 months after surgery and with a pain score of 4 or more on a daily basis.54 The block was performed using ultrasound with a total of 20-mL 0.25% bupivacaine injected under the pectoralis minor and between the 2 pectoral muscles via a 22-G needle using a single puncture site at the level of the third rib. Significant reduction in pain (P = 0.02) and reduced sleep interference, which is frequently reported, persisted for 7 days after the block.

More recently, a meta-analysis on the effectiveness of regional anesthetics for reducing PPBCS concluded that preoperative PVBs provide a safe and effective method for reducing chronic pain after breast cancer surgery.55 Another analysis of clinical studies evaluating the effect of perioperative analgesics used for acute pain treatment reported that although most analgesic strategies reduce acute postsurgical pain, the type of analgesic used during surgery has the greatest impact on long-term pain outcomes.56 The authors concluded that regional analgesics have the most significant beneficial effect on reducing persistent pain, although the best analgesic choice requires further study.

Nonpharmacologic Therapies for Persistent Pain After Breast Cancer Surgery

In addition to pharmacologic approaches for reducing or preventing PPBCS, nonpharmacologic approaches may be beneficial but are less studied. For instance, exercise interventions have been found to improve health-related quality of life in people during active cancer treatment.57 Exercise during cancer treatment improves multiple posttreatment adverse effects on bone health, muscle strength, and other physical performance and symptom measures. In particular, exercise is associated with a significant reduction in anxiety in women with breast cancer. Because of the importance of staying physically active, it is recommended that exercise be a component of the treatment plan.

For cancer survivors, exercise interventions have been found to improve multiple domains of health-related quality of life, including pain.58 Whether presurgical exercise interventions have an effect on the incidence of PPBCS requires well-designed research studies. However, the beneficial effects on mood and physical functioning are likely to improve clinical outcomes.

In another study, women with breast cancer who were scheduled to undergo adjuvant chemotherapy (N = 230) were randomly assigned to a low-intensity, home-based physical activity program (Onco-Move), a moderate- to high-intensity, combined supervised resistance and aerobic exercise program (OnTrack), versus usual care.59 Onco-Move and OnTrack resulted in less decline in cardiorespiratory fitness (P < 0.001), better physical functioning (P <= 0.001), less nausea and vomiting (P = 0.029 and 0.031, respectively), and less pain (P = 0.003 and 0.011, respectively) compared with usual care. Although this study did not evaluate PPBCS specifically, it does provide some evidence on the benefits of exercise over the continuum of care postsurgery.

Regarding patients with PPBCS, a study was conducted to analyze acute electrocortical changes after transcutaneous electrical neural stimulation (TENS).60 The study included 18 patients with intercostobrachial postmastectomy pain, who were divided into 2 different TENS modalities, acupuncture or burst. TENS acupuncture is preprogrammed with an automatic range of intensity and frequency, with a descending pulse time of 275 [mu]s and a rising pulse of 175 [mu]s and increasing pulse repetition frequency from 5 to 25 Hz over a period of 12.5 seconds. TENS burst is preprogrammed with 7 pulses of cycle-on of 28 min and cycle-off of 472 ms (2 Hz) with a pulse time of 150 [mu]s. Each group had pre- and posttreatment measurements for electroencephalogram analysis and percentage change score in pain, which decreased 88.4% and 66.3%, respectively. Although further investigation is necessary to determine the long-term effectiveness in women with PPBCS, such an intervention could reduce the costs and the adherence issues associated with having to take daily medication.

Studies have documented the benefit of physical exercise and strengthening for reducing pain, fatigue, and other symptoms associated with aromatase inhibitor-induced arthralgia.61,62 Current evidence-based exercise programs are recommended for women receiving aromatase inhibitors.63 Unfortunately, despite the sizeable problem of PPBCS, there have been no studies investigating integrative approaches for patients at risk for or who develop PPBCS. However, multiple studies have evaluated education-focused, relaxation-based, and supportive group therapy interventions for general pain severity and interference in survivors and patients receiving active treatment.64 With this in mind, mechanism-based investigations of PPBCS are needed to tease out the relevant contributors of persistent pain in this patient population. Current knowledge of risk factors with screening, education, options for preventive measures, and routine sensory monitoring postsurgery could potentially reduce the impact of PPBCS if systematically implemented in clinical practice.

Conclusion

Like other postsurgical pain syndromes, PPBCS remains a significant issue. Despite improvements in long-term survival of women with breast cancer, a significant number who receive surgical treatment will experience persistent postsurgical pain. Several preoperative and intraoperative strategies have shown efficacy in reducing the incidence of PPBCS. These strategies should be discussed during surgical planning, particularly with patients at high risk for PPBCS and including those with preexisting pain or those who will be undergoing extensive surgery.

Careful postoperative sensory monitoring and evaluation of pain symptoms can help to determine the most accurate differential diagnosis and inform appropriate referrals for surgical, interventional, or pharmacologic pain management. Nonpharmacologic therapies, such as exercise, should be recommended as part of the treatment plan to improve overall health and quality of life, and reduce the likelihood of persistent symptoms after breast cancer treatment.

References