Cancer breast is the most common cancer in women and second most common cancer overall. It is the fifth most common cause of death from cancer in women according to International Agency Of Research On Cancer and WHO. There are more than 1.7 million new cases diagnosed worldwide. This represents about 12% of all new cancer cases and 25% of all cancers in women 1.

The risk of breast cancer doubles each decade until menopause, after menopause the risk increase slows. Survival rates for breast cancer vary worldwide, but in general rates have improved. In most countries, the five-year survival rate of early stage breast cancers is 80–90 per cent, falling to 24 per cent for breast cancers diagnosed at a more advanced stage 2.

There are several factors which increase a woman's risk for the breast cancer; such as hyperprolactinemia due to neuroleptics and other dopamine antagonists. Breast cancer subtypes mostly are hormone-related. The natural history of the disease differs between those diagnosed before and after the menopause, which may be due to different kinds of tumors and possibly different effects of nutritional factors on hormones depending on menopausal status. Also, patients with Parkinson's disease have lower rates of malignancies specially breast cancer 3.

Variations observed in rates of incidence and mortality because to breast cancer, are due to a number of factors like age, race, socio-economic status, life style, reproductive history and finally family history 4.

As a consequence of advancements in both diagnosis and treatments, the survival rate patients have increased. So, population susceptible to develop pain as a complication is expected to increase 5. It has been estimated that about 70 percent of new breast cancer cases would be seen by 2020 in developing nations 6.

But although adequate treatment, many patients experience severe pain either from disease progression or from treatment related side effects (like surgery or radiotherapy). And this under managed pain affects negatively physical and psychosocial patients’ lives 6.

Pain arising in advanced stage of breast cancer can cause emotional suffering and affects quality of life of patients 6. As per the estimates of the International Association for the Study of Pain (IASP) the prevalence of pain in breast cancer ranges from 40-89 percent 7.

Breast cancer causes pain due to multiple causes. It may be due to cancer itself, release of inflammatory mediators, and distant spread to other tissues like bones or neuronal tissue or due to different modalities of treatment as chemotherapy which causes degeneration of sensory neurons and lead to neuropathic pain 8. And radiotherapy induce pain as a result of changes which occur at microvascular level and nerve compression The main causes for surgery induced pain are neuroma formation and intercostobrachial nerves damage 9. Finally Estrogen deficiency caused by aromatase inhibitors leads to arthralgias 10.

When we mention different modalities of treatment, we must know that surgery is the keystone in the treatment of solid neoplastic tumors in general including breast cancer. Paradoxically, there is high risk of metastatic spread the perioperative period represents in cancer patients 11. This is due to depression of antitumoral cellular immunity and depression occur in the postoperative period is linked to the metabolic and hormonal changes caused by the “stress reaction” to surgery 12.

‘By any reasonable code, freedom from pain should be a basic human right, limited only by our knowledge to achieve it’ Ronald Melzack13. It is the basic duty of all healthcare professionals to relieve pain, and the most important indication for treating pain after surgery is humanitarian 13. As pain is a nightmare for most patients and influences their overall experience 14.

Usually adequate analgesia is achieved by following the WHO’s step analgesic ladder. As the cancer progresses, the pain experienced by the patient increases. This necessitates the administration adjuvant analgesics with opioids to control this severe pain. Unfortunately, analgesics affect immunity and tumor development by direct interfering with cellular mechanisms (e.g., cell apoptosis) or indirect interacting with the sympatho-adrenal systems 15 .

Persistent pain after mastectomy is common and about 20-50 percent women are complaining of persistent neuropathic pain after mastectomy 16. More common among young patients, those undergoing radiotherapy and axillary lymph node dissection 17.

There is a strong evidence that; suppression of the immune system in the perioperative period increase postoperative complications which includes bad wound healing infections leading to sepsis, multiple organ failure and death 18. Also the development of residual malignant cells and the formation of new metastases are accelerated by immune suppression 19.

Other concerns of the anesthesiologists are prevention of post operative pain and suppression of the surgical stress response. Stress responses to surgical trauma and postoperative pain elicit diffuse changes in the hormonal secretion of cortisol and prolactin 20.

So this review aimed to summarize the different perioperative methods to prevent post mastectomy pain because Aggressive perioperative pain prevention can yield both short-term and long-term benefits as unrelieved pain affects patient recovery, prolongs hospital stays, increases hospital morbidity, and adds to the burden of growing health-care costs 21.

PMPS is a form of neuropathic pain caused by surgical trauma and is associated with an inflammatory reaction that has many consequences involving multiple organ systems, including local and systemic effects 33.

According to a previous review, the literature was inconsistent in defining chronic pain after mastectomy 38. To improve comparability between studies in the future, Jung et al suggested a time frame definition of chronic neuropathic syndrome classification based on the etiology.

The authors suggested that neuropathic pain syndromes due to breast surgery are considered chronic after 3 months and that shorter time frames should raise a consideration of pain associated with tumour recurrence. In Jung et al’s review, there were approximatly 21 studies with follow-up periods from 1-96 months which revealed the following:

Phantom breast pain prevalence is (3-44) per cent;

Intercostobrachial neuralgia (ICN) 16-39 percent for all breast cancer surgery;

Neuroma pain prevalence is (23-49) percent. 38

There were many trials (randomized, doubled-blinded, placebo-controlled) done to investigate the best neuropathic pain treatment algorithm. Many trials were included studying a lot of neuropathic conditions. The most studied oral medications were; anti-depressants, anticonvulsants, opioids, NMDA antagonists, mexilitine, topical lidocaine, cannabinoids, topical capsaicin, and glycine antagonist.

We here mention the most effective methods for controlling PMPS that were published in last few years:

One prospective randomized controlled clinical study was done in South Egypt Cancer Institute, titled (Analgesic efficacy of pregabalin in acute postmastectomy pain: placebo controlled dose ranging study) that published in Journal of Clinical Anesthesia, 2016. The conclusions was a single preoperative oral dose of pregabalin 150 mg is an optimal dose for reducing postoperative pain and morphine consumption in patients undergoing MRM 40.

Another important method is paravertebral block, as proved by study by Brian M. et.al. That published in 2015 and concluded that "Adding a multiple-day, continuous Ropivacaine infusion to a single-injection ropivacaine paravertebral nerve block may result in a decreased incidence of pain and pain-related physical and emotional dysfunction for 1 year after mastectomy 41.

Also, Pecs block (pectoral nerves block) which is an easy and reliable block inspired by the infra clavicular block approach and the intercostal abdominis plane blocks. Its technique as following, the pectoralis muscles are located under the clavicle then the space between the two muscles is dissected to reach the lateral pectoral and the medial pectoral nerves. The main indications are breast expanders and subpectoral prosthesis because the distension of these muscles is very painful 42.

A second version of the Pecs block was described, called ‘‘modified Pecs block’’ or Pecs block type II. This novel approach aims to block at least the pectoral nerves, the intercostobrachial, intercostals III-IV-V-VI and the long thoracic nerve. These nerves must be blocked to provide complete analgesia during breast surgery (Figure 3) 43.

In a study published 2012 in Elsevier Doyma ‘‘modified Pecs’s block’’ or Pecs block type II was described. Using Ultrasound images that was very conclusive as the contrast was taken up by the axilla and reaches the thoracodorsal nerve area, passing above the serratus muscle and hence, the long thoracic nerve, was anesthetized with the clinical usefulness. This approach aims to block the axilla that is vital for axillary evacuation and the intercostal nerves, necessary for wide local excisions of the tumor. Two needle approaches used to perform the Pecs II block or ‘‘modified Pecs’s block’’ instead of one 44.

We must know that, Thoracic epidural and paravertebralblocks became the gold standard techniques to achieve this goal, but not every anesthesiologist is comfortable performing these procedures (Figure 4) 45.

Other interventional method "interscalene brachial plexus block" which was proved by Kaya M et al, 2013 who evaluated the effects of interscalene brachial plexus block on postoperative pain relief and morphine consumption after modified radical mastectomy (MRM). Sixty ASA I–III patients scheduled for elective unilateral MRM under general anesthesia were included. Pain intensity was assessed with the visual analogue scale (VAS). Other parameters as morphine consumption, side effects of opioid, antiemetic requirement, and complications associated with interscalene block were recorded.VAS scores were significantly lower in interventional group, except in the first postoperative 24 h (p < 0.007). The patients without block consumed more morphine (group 1, 5 (0–40) mg; group 2, 22 (6–48) mg; p = 0.001) 46.

Until now paravertebral blocks and thoracic epidurals are the most effective and the gold standard pain treatment for breast cancer surgery. However, we questioned the effectiveness based on the fact that the brachial plexus nerves are the main component of this painful surgery and we described for the first time the use of pectoral nerve blocks with this indication 47.

We cannot ignore role of non-pharmacological methods of pain relief as preoperative explanation, education and Physical therapy techniques. As one of the best review that illustrated in detail effectiveness of postoperative physical therapy for upper-limb impairments after breast cancer treatment published in 2015 with the following recommendations 48:

1) First week post-op: low-intensity program involving elbow/wrist

2) 7-10 days post-op: gradually increase intensity passive mobilization (manual stretching, active exercises and increase muscle strength)

3) No recommendations can be made on length of time, content, intensity

4) Multifactorial therapy consisting of manual stretching and active exercises effectively treated impaired shoulder ROM 48.

2-Relaxation therapy

3-Hypnosis

4-Cold or heat

5-Splinting of wounds

6-Transcutaneous electrical nerve stimulation (TENS).

And sure the pharmacological methods of pain relief according to the ‘analgesic ladder’ introduced for treatment of cancer pain by the World Health Organization (WHO). It is formed of three steps according to intensity of pain. The first step involves the use of non-opioid +‏/- adjuncts (e.g. paracetamol, aspirin or non-steroidal anti-inflammatory drugs (NSAIDs). If pain is still uncontrolled, in addition to step 1 medication weak opioids (e.g. codeine, tramadol) can be added 49.

In moderate to severe pain or pain increasing in spite of step 2 treatment, stronger opioids are considered in addition. All these involve the concept known as multimodal analgesia. It is important to include the analgesic ladder in individual patient analgesic plan along with the adjunctive therapies. The analgesics act at different sites. Drugs that act at the site of injury and decrease pain associated with inflammatory reaction (e.g. NSAIDs), other drugs may alter nerve conduction (e.g. local anesthetics), some may modify transmission in the dorsal horn (e.g. opioids and antidepressants) while group of drugs may affect the central component and the emotional aspects of pain (e.g. opioids and antidepressants) 49.

Fourth step was added to WHO analgesic ladder which was interventional pain management such as stellate ganglion block (radiofrequency thermal neuro modulation) or local anesthetic injection of stellate ganglion block). Intervention pain management was advised to be done early before tumor spread or patient became deteriorated 51.

Opioid use could be associated with an increased incidence of opioid-related adverse drug events, including over sedation and respiratory depression 50. Further study are needed because opioid-related adverse drug events have been associated with an increase in overall cost, length of stay, and even decreased survival during in-hospital resuscitation 51.

It is frequently not possible to administer sufficient opioids alone, due to coexisting medical conditions, patient tolerance, allergies, or efforts to reduce total opioid use. In such cases, a multimodal approach to intravenous pain management must be employed. This may include the use of opioids, NSAIDS, and other adjuvant as needed to optimize patient pain control in the immediate postoperative period as a bridge until the patient can be transitioned to less potent oral medications 52.

And finally Minimizing damage to nerves during surgery Improved screening methods detect breast cancer at earlier stages. Earlier detection means smaller tumour sizes, which has made breast-conserving surgical treatments possible and widely used. These currently account for up to 40 per cent of breast cancer surgery 53.

Breast conserving techniques include lumpectomy, conservative breast surgery, wide local excision, partial mastectomy, segmentectomy, or tylectomy. Such approaches include reducing the number of axillary dissections required. Combining reduced surgical trauma with nerve preservation techniques may reduce the risk of sensory deficits and the occurrence of ICN 5455.

In this regard, the increased use of less invasive staging techniques such as sentinel lymph node biopsy has helped to reduce the number of patients undergoing axillary dissection and the resulting trauma to intercostobrachial nerves 56.

PMPS nowadays is frequency due to advances in diagnosis and treatment of breast cancer. Choosing proper treatments can improve the patients’ quality of life. Cancer breast is common and important disease to female in our family and all female must be aware of it, Improvement of the diagnosis and treatment of patients with breast cancer lead to increased incidence rate of PMPS. Treatment approaches include both pharmacological interventions and non-pharmacological strategies.

However, current treatments of the PMPS are near-optimal and prevention much better than treatment. Further investigations are required to achieve the appropriate developments in diagnosis and screening of breast cancer, and evaluation and treatment of PMPS that will provide less side effects, adequate analgesia, and finally, improved quality of life, and patient satisfaction in the future.

Not applicable.

None.

Praise to ALLAH who has guided us to this, never could it be done without the help of ALLAH.

I would like to express my deep thanks to all my colleagues, members of anesthesia, intensive care and pain management department in south Egypt cancer institute who kindly helped me in achieving this work.

I would like to immense gratitude and appreciation to my friend Rachel (Special Issue Manager) and all Editorial Office for great help in this work.