Cancer is among the diseases that kill the most in the world and, in most cases, its treatment is aggressive, leading most people to fear the disease. Among women, the most common type is breast [1] [2] . It is generally necessary to combine several therapeutic approaches, including radiotherapy, chemotherapy, surgery and/or medication [3] [4] .

Fortunately, a great advance has already been observed in these therapies, significantly increasing the survival rate of patients [3] [5] [6] . However, depending on the type of therapeutic resource adopted, there may be impacts on the woman’s life for months or years after the end of treatment.

Mastectomy is still indicated in many cases and is associated with persistent pain, which greatly impacts patients’ quality of life [7] . Chronic pain, usually accompanied by lymphedema, reduced mobility of the upper limb, asthenia and fatigue reduce productivity at work, in addition to generating high costs with medical consultations, difficulty in taking care of the house and children, and become a constant reminder of the disease [5] [8] [9] .

In this context, it is notable that this patient starts to have substantial psychophysical changes, leading to anxiety, depression, and sleep disturbance in the survivors [9] [10] [11] .

That said, it is clear the importance of understanding post-mastectomy pain syndrome, its main risk factors, pathophysiology, diagnosis and, mainly, possible conducts to not only treat, but also prevent the onset of the condition. This mission must be carried out by a multidisciplinary team [12] understanding that the focus should not only be on fighting cancer, but also enabling the patient, after treatment, to return to her activities and recover her functionality and quality of life.

In this context, this study is justified, as it seeks information on pain management in post-mastectomy women, aiming to provide better care for this population, since a large proportion of these women are susceptible to experiencing chronic pain.

The objective of the study is to understand alternatives for pain management in patients undergoing mastectomy, especially in those in whom pain persists for more than 3 months.

After eliminating duplicates and selecting publications, the articles were read in full, from which the parameters proposed in the analytical matrix of the present study were analyzed.

T his systematic literature review analyzed 28 scientific studies that rigorously met the previously established characteristics in the sample selection. Of this total of articles, 6 were quantitative/qualitative studies, 9 were a quantitative study and 13 were qualitative.

The synthesis of these selected scientific articles is presented below, covering the following aspects: author/year of publication, article title, objective, type of study and database (Table 1).

Breast cancer is the most common malignancy among women [1] [2] [13] and

its treatment usually involves the association of radiotherapy and/or chemotherapy with surgical approaches. Thanks to the great advances in science, with genetic mapping and sequencing [5] , more diagnoses have been made and, over the years, there are more and more survivors of the disease [3] [6] .

However, the treatment can leave marks on patients, reducing their quality of life, with high levels of anxiety and depression [7] [13] . Among these sequelae, one of the most reported and that greatly impacts women’s functionality is persistent pain, especially in those undergoing mastectomy [4] [5] [8] . In this sense, the term Post-Mastectomy Pain Syndrome (PMPS) was established, defined by the International Association for the Study of Pain (IASP) as “chronic pain in the anterior wall of the chest, axilla and/or upper half of the arm, beginning after mastectomy or quadrantectomy and persisting for more than three months after surgery” [3] [4] [6] [14] [15] . Studies indicate that this pain after breast surgery occurs in more than 50% of women, being classified as moderate to severe [2] [8] [13] [16] [17] .

The details of pathophysiology of this pain condition has not yet been elucidated, but it is known that it is multifactorial, with different etiologies [7] [8] [12] . Chief among these is neuropathic injury, where there is damage to the nerves during surgery and/or radiation, with the intercostobrachial nerve being the most frequently affected [3] [5] [6] [18] .

Injury to the nerve can occur intraoperatively, with retraction and malpositioning of the arm, leading to nerve compression, or postoperatively, with stretching and pressure from bruising and scarring [6] . However, neuromas formed by traction and/or laceration also justify neuropathy, as they function as a pacemaker, resulting in continuous firing.

Other causes of pain are musculoskeletal (such as scapulothoracic bursitis, shoulder impingement syndrome, and glenohumeral adhesive capsulitis), myofascial [3] , lymphedema (usually due to associated radiotherapy or lymphadenectomy), and nociplastic [5] .

Post-Mastectomy Pain Syndrome can occur in any patient undergoing breast surgery. However, some responsible factors are already known by increasing the risk of developing the condition, such as young people, pre-existing depression and anxiety [13] , sleep disorders, high body mass index (BMI), bilateral mastectomy and surgical technique (manipulation of nerves and axillary lymph node resection have greater chances of compromise) [1] [2] [7] [8] [11] [17] [19] . In addition, several studies point out that inadequate control of acute pain after surgery is strongly related to the persistence and chronicity of pain [1] [10] [11] [13] , since prolonged stimulation of nociceptive neurons contributes to the core awareness [11] .

The diagnosis is clinical, with a physical examination being mandatory [20] . Thus, by excluding non-neuropathic causes of pain such as infection, musculoskeletal or oncological recurrence, neuropathy is defined [12] . Complementary tests can be used, such as magnetic resonance imaging or positron emission tomography to check for brachial plexus infiltration or fibrosis, and electromyography to assess sensory and motor delay in the brachial plexus [20] .

Patients often describe the pain as continuous or intermittent, burning and/or pinpoint, associated with palpable allodynia and hyperalgesia [8] [16] [18] . Furthermore, it is influenced by temperature variations, with periods of worsening and improvement [15] . It may also be associated with lymphedema, numbness, stiffness, and limited range of motion of the shoulder [9] .

Therefore, it is clear that post-mastectomy pain has a negative impact on quality of life, with significant impairment of functionality and psychosocial distress [1] [9] . Research indicates that this impairment has a greater influence on the routine of young women, with greater loss of work days and difficulties in caring for children. Furthermore, the occurrence of pain in cancer survivors represents an ongoing memory of the disease and treatment and is seen by some as a sign of residual disease, leading to fears of worsening or recurrence [9] .

That said, it is extremely important to treat the various approaches to Post-Mastectomy Pain Syndrome, ranging from clinical and minimally invasive measures to surgeries and complementary methods [3] [4] .

Initially, it is interesting to address measures aimed at preventing the condition, which mainly involves the reduction of immediate postoperative pain. With less acute pain, the chances of chronic pain are also reduced. Among these measures, the association of intraoperative fentanyl with ultrasound-guided peripheral block stands out, since high doses of opioids activate N-methyl-D-aspartate (NMDA), which has a pro-nociceptive effect and consequently causes hypersensitivity [8] [13] [21] . The most commonly performed blocks are PEC 2, with blockade of the lateral and medial pectoral, intercostal, and intercostobrachial nerves [4] [14] [19] . With this association, patients feel less post-surgical pain, have fewer adverse effects (especially nausea and vomiting), and have shorter hospital stays [11] [21] [22] [23] .

This practice is included in the enhanced post-surgical recovery protocol (ERAS—Enhanced Recovery After Surgery), which also indicates the use of intraoperative antiemetics, warns about the use of volatile anesthetics and the importance of a good doctor-patient relationship, with pre-operative counseling, in which the patient feels safe with the procedure and the team [10] [11] [22] [23] [24] .

Studies also indicate that the administration of 8 mg of dexamethasone concomitantly with analgesics contributes to reducing the inflammatory process, resulting in less intense pain [25] . The main objective of these behaviors is to promote a better quality of recovery [22] .

Continued use of opioids for more than two weeks after surgery is associated with sleep disturbances, which negatively affects recovery, increasing the risk of pain persisting [13] .

However, even with all these precautions, the pain can become chronic, determining the post-mastectomy pain syndrome. In these cases, treatment is complex, involving a pain specialist, plastic surgeon (if reconstruction is necessary) [6] , physiotherapist, among others [12] . Treatment refractoriness is mainly associated with multiple facets of pain. Neuroinflammation leads to the release of inflammatory markers. The values of interleukin (IL)-1β, IL-6 and IL-10 and C-reactive protein (CRP) can be used as prognostic predictors of long-term pain, being higher in more chronic pain [8] [13] [26] [27] . In addition, there is an increase in cortisol and a decrease in prolactin and CD4, CD8 and CD56 lymphocytes [8] .

In these cases, first-line treatment is anti-neuropathic drugs such as tricyclic antidepressants, amitriptyline, serotonin-norepinephrine reuptake inhibitors, duloxetine, and gabapentinoids [3] [15] . If adequate analgesia is not available, tramadol and peripheral nerve blocks are considered second-line. Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) do not usually work well [8] .

In addition, corticosteroids may be useful when neuroma is present, in which the medication contributes to stimulus inhibition, generating rapid or delayed pain relief [16] and topical capsaicin at 0.075% improves burning sensation [3] .

Associated with conventional treatments, complementary techniques have been proposed, with good analgesic results. Cognitive behavioral therapy (CBT), physical exercise, acupuncture, aromatherapy and music therapy are some examples.

The great influence of depression, anxiety and sleep disorders makes clear the need for a psychosocial approach, with CBT having a primordial role. [3] [10] [11] . Physical activity is essential for providing better recovery of functional capacities, strength and flexibility, as well as improvement of pain, asthenia and reduction of hematological alterations such as neutropenia, anemia and thrombocytopenia, and stretching and exercises should aerobic and resistance exercises should be integrated into treatment as soon as possible after surgery [9] [26] .

Studies indicate that patients who underwent acupuncture sessions for four weeks improved physical health problems and perceived general health [10] . In addition, transcutaneous electrical stimulation at acupuncture points before anesthetic induction in patients undergoing mastectomy is related to a decrease in opioid consumption and the incidence of chronic pain six months after surgery, and should be a considerable conduct [17] .

Aromatherapy and music therapy, which have already been used for other clinical conditions, are associated with reduced anxiety, pain and IL-6 levels, with enhanced results when both techniques are combined [27] .

However, in some cases, the pain remains refractory to such procedures, requiring more invasive approaches, such as autologous fat grafting in an area of cicatricial retraction with pain and nerve entrapment [12] , blockade of the erector spinae plane (ESP) [28] , excision of neuroma, transplantation of lymph nodes from the inguinal region to the axillary region (in cases of lymphedema) and pulsed radiofrequency [3] . Studies show that thoracic nerve blocks lead to immediate improvement in pain, but for a short period of time, less than one month [3] [4] .

One study aimed to validate a scale to determine a woman’s risk of having moderate or severe post-mastectomy pain so that, in these cases, more intense analgesia could be performed. In this scale, eight points would be assessed: age at the time of surgery, BMI, depression, stress, previous use of pain medication, neoadjuvant chemotherapy, extent of surgery (single or bilateral) and reconstruction (yes or no) [11] . This measure has not yet been adopted as a protocol, but it is a possibility for physicians to adopt a more active posture, avoiding the onset of post-mastectomy pain syndrome and its consequences for women.

With the advancement of treatments for breast cancer, more and more women are surviving the disease. Therefore, it is essential that efforts are made to understand the marks that therapies leave on patients, so that they can be minimized and women can return to their activities and functionality, with quality.

Currently, there are several measures that aim to reduce the chances of the patient developing post-mastectomy pain syndrome, most of which are described in ERAS, including the use of antiemetics and the association of peripheral blockade with intraoperative anesthesia, aiming to reduce the consumption of opioids and, as a consequence, less nausea and vomiting, shorter hospital stay and lower risk of postoperative hyperalgesia. This is because the better the acute pain control, the lower the chances of pain chronification.

When it comes to treating post-mastectomy pain, several drugs are available; tricyclic antidepressants (amitriptyline, duloxetine) and gabapentinoids are included in the first line of treatment. In the absence of satisfactory analgesia, tramadol and peripheral blocks are options. For some patients, it may also be necessary to use more invasive measures, such as autologous fat grafting, excision of neuromas or lymph node transplantation.

Concomitant to these measures, complementary behaviors that are extremely valuable include cognitive behavioral therapy, which will help with the patient’s psychological aspect, reducing anxiety and assisting in the way they view the painful condition, and the practice of physical activities, which will provide improved mobility and asthenia.

It is notable that there are several viable approaches, and the healthcare team must be attentive to the patient’s needs and provide assistance not only during the presence of the disease, but also after the end of treatment.

Thus, the need for a better understanding of post-mastectomy pain syndrome and its approach is evident, as well as the adoption of new measures and/or multidisciplinary approaches, which will certainly bring greater comfort and a better prognosis for the population addressed.

Furthermore, it is also important to highlight the need for more research, especially with regard to the combination of drugs with alternative therapies, aiming to expand the evidence of the benefits related to these associations.

The authors declare no conflicts of interest regarding the publication of this paper.

Costa, V.F.D.D.D., Mazzucca, G.S., Zerbini, C.A.P., Pires, O.C. and Leite, C.D.S. (2023) Therapeutic Approaches to Post-Mastectomy Pain Syndrome. Journal of Biosciences and Medicines, 11, 304-317. https://doi.org/10.4236/jbm.2023.1112023