By Vadivelu, Nalini Schreck, Maggie; Lopez, Javier; Kodumudi, Gopal; Narayan, Deepak
Breast cancer is a potentially deadly disease affecting one in eight women. With the trend toward minimally invasive therapies for breast cancer, such as breast conserving therapies, sentinel node biopsies, and early treatments of radiation and chemotherapy, life expectancy after breast cancer has increased. However, pain after breast cancer surgery is a major problem and women undergoing mastectomy and breast reconstruction experience postoperative pain syndromes in approximately one-half of all cases. Patients post mastectomy and breast reconstruction can suffer from acute nociceptive pain and chronic neuropathic pain syndromes. Several preventative measures to control acute post operative pain and chronic pain states such as post mastectomy pain and phantom pain have been tried. This review focuses on the recent research done to control acute and chronic pain in patients receiving minimally invasive therapies for breast cancer, such as breast conserving therapies of mastectomies and breast reconstruction, sentinel node biopsies, and early treatments of radiation and chemotherapy. BREAST CANCER IS A POTENTIALLY deadly disease affecting one in eight women. It is the most commonly diagnosed form of cancer and the second leading cause of cancer-related death among women. It has been projected that by the year 2008, the number of new cases of breast cancer will increase to 270,000, which is expected to rise to 420,000 new cases in 2018.1
With the trend moving toward minimally invasive therapies for breast cancer, such as breast conserving therapies, sentinel node biopsies, and early treatments of radiation and chemotherapy, life expectancy after breast cancer has increased. Approximately 60 per cent of women afflicted with breast cancer will opt for a mastectomy. Although regarded as a life-saving procedure, a mastectomy takes away from a woman the one thing that often defines her femininity. The loss of one or both breasts can be devastating to a woman, both mentally and physically. Fortunately, advances in reconstructive surgery have given women the option of having breast reconstruction.
In 2004, more than 62,000 women elected to have some type of reconstructive breast surgery after a mastectomy. There are a variety of breast reconstructive techniques for women to choose from, using either prosthetic materials or autogenous tissue. Generally when a prosthetic material is chosen, a temporary, inflatable tissue expander is placed in the sub pectoral position and is gradually expanded over the course of several weeks by injecting saline through a port. Once a desired volume is achieved, the tissue expander is removed and replaced with a permanent implant. When an autogenous tissue is chosen for reconstruction, a procedure known as a flap is performed. A flap involves the transfer of tissue from the donor site to the recipient site with its vascular supply intact. There are a number of different sites from which tissue may be donated to create a flap. Typical flap procedures used for breast reconstruction include the transverse rectus abdominis myocutaneous flap, harvested from the anterior abdominal wall, and the latissimus dorsi myocutaneous flap, harvested from the back. Other flaps used for reconstruction include the inferior and superior gluteal flaps, and the lateral transverse thigh flap.2
Pain and functional compromise after breast cancer surgery is a major problem and women undergoing mastectomy and breast reconstruction experience postoperative pain syndromes in approximately one-half of all cases.3 Pain control in advanced breast cancer patients can be complicated with metastasis of tumor. This in turn can produce other conditions such as lymphedema, bowel obstruction, and headache. All these processes can cause additional pain along with antineoplastic therapies and interventions directed at other structural pathologies in patients with advanced stages of breast cancer. This review will focus on the recent research done to control pain in patients with minimally invasive therapies for breast cancer such as the breast conserving therapies of mastectomies and breast reconstruction, sentinel node biopsies, and early treatments of radiation and chemotherapy.
Studies have demonstrated that there are both positive and negative outcomes for women who elect to have reconstruction. A study conducted by Wallace et al.4 examined the pain in patients with breast cancer surgery and breast reconstruction. The study found that the incidence of pain was 49 per cent in women who underwent mastectomy with reconstruction compared with 31 per cent in women who underwent mastectomy alone. It also discovered that when breast implants were used during reconstruction, the incidence of pain was 53 per cent compared with an incidence of 30 per cent when reconstruction was done without implants.4
Pain and Quality of Life
Pain after breast surgery can impact the quality of life. The pain pathways and the neuromodulators of pain perception are closely related to the neuromodulators that produce mood disturbances. Therefore it is important to increase die quality of life and avoid mood disturbances in these patients post operatively to achieve optimum pain management. Studies concerning quality of life in women who have undergone mastectomy with reconstruction, compared with those who have had mastectomy alone, have shown that those having reconstruction generally have better body images and feelings of attractiveness. However, similar studies have shown that women who have undergone mastectomy with reconstruction also have a greater propensity to experience mood disturbances and have a poorer well- being than women who had mastectomy alone. One particular study, by Nissen et al.,5 identified potential contributing factors associated with a poorer quality of life in women who have had reconstruction, which include die length of surgery, length of hospitalization, time away from usual activities, and postoperative pain.5
Pathophysiology of Pain
The perception of pain involves both the peripheral and the central nervous systems. A noxious stimulus is initially detected by peripheral nociceptors located within the skin, which men send pain signals via Adelta and C nerve fibers. A-delta fibers are myelinated, large-diameter fibers, which are responsible for transmitting the initial response to a noxious stimulus. The initial stimulus is brief, sharp, and well-localized. C fibers are unmyelinated, small-diameter fibers, which conduct the second phase of the response to a noxious stimulus. This phase is more prolonged and is responsible for the dull, aching, diffuse pain experienced after the initial injury. The somas of these fibers are located in the dorsal root ganglion and their axons synapse in me dorsal horn of the spinal cord. From this point, signals are picked up by the spinothalamic tract of the spinal cord and relayed to the thalamus and the cortex.
When a patient endures a stressful surgical stimuli causing peripheral tissue damage or nerve injury, there is often a lasting effect on the nervous system. When individuals experience subsequent noxious stimuli after a surgical procedure, their body may react with a more heightened response, a phenomenon known as hyperalgesia. They may also experience allodynia, where an experience that was previously perceived as a painless sensation is now perceived as painful. It is also possible for a patient to develop a chronic condition that results in a continuous production of pain long after surgery has taken place.
If noxious stimuli occur on a continual basis, peripheral nociceptors become increasingly responsive. This responsiveness is furthermore increased by inflammatory mediators and a multitude of tissue factors released during tissue injury. These include prostaglandins, leukotrienes, hydroxyacids, bradykinin, serotonin, histamine, substance P, and reactive oxygen species, such as hydrogen peroxide, superoxide, and hydroxyl species.6 The process by which the neurons of the dorsal horn of the spinal cord become hyperexcitable is often referred to as central sensitization. Central sensitization refers to the increased spontaneous activity of spinal cord neurons, reduced threshold to afferent stimuli, and an increase in the receptive fields of dorsal root neurons. It is central sensitization that explains the concepts of hyperalgesia and allodynia.7 The mechanism of central sensitization enhances the body’s response to noxious stimuli, which potentially increases the level of pain experienced after surgery.7
The pain syndromes resulting from surgical injury are characterized as either neuropathic or nociceptive. Neuropathic pain is pain “initiated or caused by a primary lesion or dysfunction in me nervous system.” Nociceptive pain is the consequence of injury to peripheral tissues, which may result from surgical incisions, burns, or injury to a muscle or ligament6 or because of dysfunction in the nervous system.8 Women undergoing breast cancer surgery experience both neuropathic and nociceptive pain syndromes.
Literature concerning breast cancer surgery most frequently discusses pain syndromes associated with breast cancer surgery that focus on neuropathic pain syndromes resulting from a direct injury to the nervous system. These syndromes include intercostobrachial neuralgia and other nerve injury pain, phantom breast pain, and neuroma pain. The exact etiology of these syndromes is unclear but is likely multifactorial.4,8-12 The innervation of the breast and its surrounding tissues is closely associated with the brachial plexus. The chest wall is innervated by the intercostobrachial nerve, long thoracic nerve, thoracodorsal nerve, lateral pectoral nerve, and medial pectoral nerve. Each of the nerves innervating the breast and surrounding tissue has the potential for being injured; but studies have indicated that the intercostobrachial nerve is the most frequently-injured nerve during mastectomy. When surgeons remove axillary lymph nodes, the nerve is often cut, resulting in injury. This nerve provides sensation predominantly to the shoulder and upper arm. The intercostobrachial nerve is reportedly injured in 80 to 100 per cent of mastectomy patients undergoing axillary dissection.4 As a result of this injury, women are frequently left with pain hypersensitivity, numbness, and paresthesias in the upper arm and axillary area.
Acute Postoperative Pain
The vast majority of surgical procedures are associated with a certain degree of postoperative pain in addition to nausea and vomiting. Each of these factors has the potential to lengthen the time of hospitalization, and can also prolong an individual’s wait time before resuming normal activity. Although each surgical procedure and surgical candidate is unique, studies have demonstrated mat women who opt to have reconstructive breast surgery experience a variety of pain syndromes in approximately one-half of all procedures. These syndromes are both acute and chronic, ranging from moderate to severe in nature. These pain syndromes may include pain in the surgical scar, chest wall, and upper arm pain, shoulder discomfort, and phantom breast tactile sensations and phantom pain13 . Studies have also demonstrated that inadequately managed pain in the acute postoperative phase is one of the greatest predictors of chronic pain syndromes in breast surgery patients.10
Neurobiologic mechanisms and psychosocial processes could contribute to the development of acute pain after breast cancer surgery. This has been studied by Katz et al.14 who studied 86 women and showed that preoperative anxiety was an important variable that contributed to the prediction of acute pain after surgery. Pain was measured on a 0 to 10 numeric rating scale. Ratings were reported on the worst pain since surgery at the Day 2 assessment and of worst pain in the past week at the Day 10 and Day 30 assessments. Clinically relevant acute pain was considered to be present if patients rated their worst pain as greater to or equal to five, a value considered to be a validated and replicated cut point reflective of an increased impact of pain on health-related quality of life.15-17 If the patients reported their worst pain as greater than or equal to five at the Day 2, Day 10, and Day 30 assessments, the patients were considered to have persisting clinically-relevant acute pain. In Katz et al.’s study,14 the incidence of acute postoperative pain after breast cancer surgery was examined in 86 women. They determined that the incidence of clinically-relevant acute pain at the Day 2 assessment was 54 per cent. The incidence of persisting clinicallyrelevant acute pain was present in 16 per cent of the patients.14 Patients were studied up to 30 days after surgery and it was found on multiple logistic regression analyses that greater preoperative anxiety was the only variable that predicted acute pain at 2 days definitely after surgery, whereas younger age, being unmarried, and preoperative anxiety each made an independent contribution to predicting clinically meaningful acute pain that continued 2 to 30 days after surgery.
Much of the research on pain associated with breast cancer surgery focuses on neuropathic pain syndromes. Although it has received far less attention in research, nociceptive pain or acute pain is as prevalent in women as the more widely discussed neuropathic pain. Spasm of the pectoralis muscle, which leads to pectoral tightness and discomfort, has recently been suggested as a source of nociceptive pain after breast reconstruction with subpectoral tissue expanders.18-20 To decrease pectoral tightness during the course of breast reconstruction using tissue expanders, the musculature of the chest wall is subjected to significant surgical trauma. The creation of a submuscular cavity to accommodate the expander involves separating the muscular attachments of the serratus anterior muscles from the bony surfaces of the fifth, sixth, and seventh ribs. Posterior dissection of the serratus anterior muscles typically involves the attachments of these muscles to the rib cage at midaxillary level. The pectoralis major muscle is dissected medially along the sternal border and its attachments are left intact superiorly. This surgical trauma, in combination with the muscle spasms within the chest wall, is thought to be responsible for the acute discomfort experienced by the majority of patients immediately after their surgery.21 Another way to decrease post operative pain is the use of agents to provide preemptive analgesia.
Due to the high prevalence of postoperative pain syndromes after mastectomy and breast reconstruction, a great deal of research has recently been focused on developing perioperative techniques that surgeons can use to reduce the amount of acute postoperative pain experienced by patients. This is of particular concern when using subpectoral tissue expander reconstruction, as women who undergo this procedure have been found to have a greater incidence of postoperative pain than women undergoing reconstruction without implants. Pain resulting from subpectoral tissue expander reconstruction is secondary to tissue ischemia and nerve compression.4 Despite the incidence of pain, this method is preferred by 70 per cent of plastic surgeons in the United States due largely to the comparable ease of this procedure over use of a flap.18 Researchers have proposed a myriad of perioperative techniques to reduce the incidence, intensity, and duration of postoperative pain after breast surgery. One technique involves the use of preemptive analgesia, where patients are given some form of analgesia before the initial incision to prevent or reduce subsequent pain. Depending on the form of anesthesia administered, the treatment may be focused at the operative site, at inputs along sensory axons, or at central nervous system (CNS) sites.6
Use of Local Anesthetics
Local anesthetics over the surgical site have been studied over the years. Several studies have examined me effectiveness of preemptive analgesia in a variety of different surgical procedures.22-29 Some of the surgical procedures studied include abdominal surgery, orthopedic surgery, oral surgery, laparoscopic surgery, hysterectomy, thoracotomy, and breast surgery. The results of these studies have been inconclusive, but it seems that preemptive analgesia is more effective in particular areas of the body than others, the breast being one of them. Studies have suggested that infiltrating surgical sites with long-acting local anesthetics before the initial incision will prevent central sensitization from occurring.30 Local anesthetics block the sensation of pain by reversibly blocking impulse conduction along nerve axons and other excitable membranes that use sodium channels as the primary means of action potential generation.30 Therefore, if local anesthetics prevent nociceptive impulses from being transmitted from the surgical site to the central nervous system, central sensitization will not occur. This in turn inhibits the establishment of the hyperexcitable state within the central nervous system, thus allowing for better control and management of postoperative pain.
However, very few studies have looked specifically at the effect of infiltrating local anesthetic into the breast tissue. The studies mat have used this technique looked at its effects during lumpectomies, breast biopsies, and reduction mammoplasty procedures. A study done by Aida et al.,22 examined the effects of an epidural anesthetic as a form of preemptive analgesia but did not explore the potential effects of a local anesthetic.
It is thought that a significant percentage of women undergoing breast surgery for cancer may develop neuropathic pain in the chest, and/or ipsilateral axilla and/or upper medial arm, with impairment in performing daily occupational activities. In a study done by Fassoulaki et al.31 involving 46 females preoperatively and postoperatively, EMLA cream, an eutectic mixture of lidocaine (2.5%) and prilocaine (2.5%), or placebo was applied and pain scores and analgesic use was followed for a period of 3 months. They showed that the perioperative application of EMLA cream reduces analgesic requirements, as well as the acute and chronic pain after breast surgery.31
Use of Botulinum Toxin
Many women who have undergone expander reconstruction or who have subpectoral breast implants experience tightness and/or discomfort of the pectoralis muscle, as well as muscle spasms, according to recent studies. This often causes the implants to “ride high” because the pectoralis muscle has not been stretched sufficiently, which prevents the implants from descending.20, 18 A small number of anecdotal reports used botulinum toxin (BT) to paralyze the pectoralis muscle for pain relief after subpectoral breast implantation. 19,20,32 Each of these case reports demonstrated that infiltrating the pectoralis muscle with BT was effective in weakening the muscle, allowing for a more comfortable recovery. Botulinum toxin, produced by Clostridium botulinum, was discovered in 1894 by Emile Pierre van Ermengem, a Belgian, and found to be the causative agent of botulism. Layeeque et al.18 performed a study in which BT was infiltrated into the pectoralis major, serratus anterior, and upper rectus abdominis muscles at the time of mastectomy and immediate reconstruction with a subpectoral tissue expander. This study demonstrated that BT was effective at reducing postoperative pain and discomfort. Although the results of this study are quite promising, further research is necessary to confirm these results because patients in this study were not randomized. The study also had an extremely small sample size and was not powered to show statistical significance. The mechanism of action of BT occurs at the terminals of cholinergic neurons, which contain numerous small, clear membrane-bound vesicles containing Ach. These vesicles are concentrated at the synaptic portion of the cell membrane. In the absence of BT, during the course of a normal action potential, Ach is released from the vesicles into the neuromuscular junction. Ach molecules then bind to and activate Ach receptors on the postsynaptic membrane, which leads to membrane depolarization and contraction of muscle fibers. However, in the presence of BT, the release of presynaptic Ach is blocked due to the binding of the toxin to specific, high-affinity cell-surface receptors. The toxin receptor complex is then endocytosed into the nerve terminals. Once internalized, the complex is lysed, at which time it activates a particular set of proteins that inhibit the exocytosis of Ach by preventing the fusion of Ach vesicles with the cell membrane of the axon. This results in the depletion of Ach in the synaptic cleft, which ultimately results in flaccid muscle paralysis.18,33 The theory behind using BT within the musculature of the chest wall is that it will temporarily paralyze the muscles and therefore prevent muscle spasms from occurring, which will reduce the amount of postoperative pain. Confirming the ability of BT to reduce muscle spasm during mastectomy and expander reconstruction could possibly have significant therapeutic benefit.18 Venlafaxine
Rueben et al.34 studied the efficacy of the perioperative administration of venlafaxine in the prevention of post mastectomy pain syndrome. The preemptive administration of venlafaxine has been shown to be efficacious in reducing the incidence of neuropathic pain in the rat model. In the study by Vanlaxafine et al., 100 patients scheduled for either partial or radical mastectomy with axillary dissection were given either venlafaxine or placebo for two weeks starting the night before surgery. Patients were administered patient controlled analgesia (PCA) morphine for the first 24 hours after surgery and then acetaminophen/ oxycodone tablets. Pain scores were recorded at rest and movement on Day 1, at 1 month, and at 6 months after surgery. Perioperative administration of venlafaxine beginning the night before surgery significantly reduces the incidence of post mastectomy pain syndrome (PMPS) after breast cancer surgery.34
According to the International Association for the Study of Pain, chronic pain is defined as pain that has persisted beyond the normal time of healing, which is usually within 3 months. The chronic pain syndromes most frequently discussed throughout the literature include intercostobrachial neuralgia and other nerve injury pain, phantom breast pain, and neuroma pain.4,8,9,11,12
Studies estimate the incidence of chronic pain after breast cancer surgery to range from 20 per cent to 50 per cent and higher.8,35 Studies have also indicated that the frequency of pain syndromes associated with breast cancer surgery varies depending on the age of the patient. The incidence varies from 65 per cent in women ages 30 to 49 years to 40 per cent in women ages 50 to 59 years. The incidence significantly decreases in women over the age of 70.31 Risk factors believed to be associated with an increased incidence of chronic pain syndromes after breast cancer surgery include younger age, being unmarried, type of surgery, radiotherapy, chemotherapy, and preoperative anxiety. Severe postoperative pain is the lone risk factor that has been consistently associated with chronic pain after breast cancer surgery. Considering the degree of physical disability and emotional distress associated with chronic pain syndromes after breast cancer surgery, its occurrence is highly relevant. This occurrence is made more relevant because the pain syndromes experienced are refractory to the existing treatment regimens. In both retrospective and prospective studies, greater intensity of acute postoperative pain and greater consumption of postoperative analgesics have been associated with chronic breast and ipsilateral arm pain after breast cancer surgery.8,10 Sensory abnormalities are characteristic of chronic pain after breast surgery. Gottrup et al.36 examined pain and sensory abnormalities in women after breast cancer surgery. They studied 15 patients with spontaneous pain and 11 patients that were pain free, all of whom had undergone breast cancer surgery in the past. They found a decrease in pressure pain threshold in pain patients on the operated side compared with the contralateral side. No side to side difference was seen in pressure pain threshold in the pain-free group.
Post Mastectomy and Post Reconstruction Pain Syndromes
Undergoing a mastectomy with immediate reconstructive breast surgery is a major procedure that is unfortunately associated with a variety of adverse outcomes. Two of the most commonly encountered adverse outcomes are post mastectomy and post reconstruction pain syndromes, which can either be acute or chronic. Although both of these procedures have been shown to cause pain, the majority of research thus far has been on the incidence of chronic post mastectomy pain. In fact, there is only a single published study on the incidence of chronic pain after breast reconstruction. Wallace et al.4 examined the relationship between breast cancer surgery and breast reconstruction. The study found that the incidence of pain was 49 per cent in women who underwent mastectomy with reconstruction compared with 31 per cent in women who underwent mastectomy alone. It also discovered that when breast implants were used during reconstruction, the incidence of pain was 53 per cent compared with an incidence of 30 per cent when reconstruction was done without implants.4
Post mastectomy pain syndrome is a condition which can occur after breast surgery and has until recently been regarded as uncommon. Post mastectomy pain (PMP) is a distinct, chronic, pain syndrome. There seems to be a need for clinical trials to evaluate the effectiveness of nonpharmacological or cognitive behavioral therapies in alleviating this painful condition. Post mastectomy pain syndrome has been thought to be due to injury of the intercostobrachial nerve.37 Carpenter et al.41 have suggested that it may affect 20 per cent or more of women after mastectomy. The symptoms are distressing and may be difficult to treat; however treatment for neuropathic pain can be successful. In addition to pain due to hypersensitivity of nerves, other tissues can also be involved post surgery in the rehabilitation process. This includes muscle weakness, soft tissue fibrosis, and blockage of lymphatic flow and hypertonicity of muscles. These syndromes are both acute and chronic, ranging from moderate to severe in nature. These pain syndromes may include pain in the surgical scar, chest wall, and upper arm, shoulder discomfort, and phantom breast tactile sensations and phantom pain.13 Studies have also demonstrated that inadequately managed pain in the acute postoperative phase is one of the greatest predictors of chronic pain syndromes in breast surgery patients.10 It is known that axillary lymph node clearance is associated with post operative edema, numbness, pain, loss of strength, and impaired range of movement. Mastectomy can also be associated with the development of neuropathic pain. Studies have indicated that chronic pain, lymphoedema, post irradiation neuropamy, and other symptoms occur in as many as 75 per cent of women after breast cancer treatments.36
Several reasons have been put forth to explain the development of post mastectomy syndrome, including axillary hematoma post surgery, sentinel lymph node dissection, and severe acute pain postoperatively. Increased levels of nitric oxide has been suggested in chronic post surgical pain after breast surgery.38 Some cases of post mastectomy pain syndrome have been associated with the presence of axillary hematoma in the post operative period.39
In a study by Blunt et al.39 it was seen that three women undergoing wide local excision for cancer of the breast and block dissection of axillary lymph nodes subsequently developed severe PMPS. In these cases the symptoms were completely relieved by the aspiration or formal drainage of an encapsulated hematoma in the axilla. The removal of a minimal amount of blood brought instant improvement suggesting that pressure within the hematoma could be an etiological factor. An axillary hematoma, which may not be clinically obvious, should be considered as a possible cause of PMPS.39
Complete lymph node dissection has been associated with the development of post mastectomy pain syndrome. PMPS has been reported after procedures involving complete lymph node dissection. Because the triggering event is probably related to nerve injury, it is thought that sentinel lymph node dissection should decrease the incidence of PMPS. Miguel et al.40 concluded that PMPS is a complication of complete lymph node dissection. The increased use of sentinel lymph node dissection reduced the number of referrals to their pain clinic for treatment of PMPS.40
Findings also underscore the need to screen all women for PMP after breast cancer surgery. Carpenter et al.41 studied 36 women with PMP and found mat they were not significantly different from women without PMP (n = 98) on demographic, disease, treatment, or surgical variables. PMP intensity was not significantly associated with age at diagnosis, time post surgery, or time post treatment. Findings suggest that cases of PMP could not be identified uniformly based on the presence or absence of certain factors. PMP was found in women post lumpectomy without axillary dissection, women whose intercostobrachial nerve was spared, and women without documented postoperative complications. Chronic Regional Pain Syndrome after Breast Surgery
Invasive breast cancer is treated with axillary lymph node clearance. Several changes at the molecular level can occur leading to chronic pain. Khan et al.42 have reported the development of a Complex regional pain syndrome type 1 associated with axillary lymph node dissection. This patient had a left lumpectomy and axillary lymph node dissection. She reported constant pain in the left arm, shooting and knife like with associated swelling of the left hand, painful to touch with the left arm turning blue and cold several times a day. Examination of the left arm revealed a swollen, pale tender hand painful to light touch also called allodynia. Chronic regional pain syndrome (CRPS) has been reported to occur in the upper extremity in 44 to 61 per cent of the cases.43,44,45 This is a chronic painful debilitating condition that is difficult to treat, though early treatment could help in the recovery process. CRPS 1 corresponds to the reflex sympathetic dystrophy where a pain syndrome develops in the absence of a nerve injury and CRPS 2 occurs after a known nerve injury. CRPS 1 has been described in other surgeries such as arthroscopy,46 routine venupuncture,47 and carpal tunnel release.48 The etiology of CRPS 1 is still not clear, but it is known that it is a neuropathic persistent pain syndrome with increased nerve excitability and pain sensitivity. Because surgery is the mainstay of primary breast cancer therapy, it is possible that patients having breast reconstruction are at a risk for both CRPS type 1 and CRPS type 2. Molecular level changes include increased presence of neurotransmitters leading to sensitization of the N Methy D Aspartate receptor leading to pathological calcium influx, release of nitric oxide, and synthesis of prostaglandins.
Trigger points or areas of muscle tightness can occur after breast reconstruction and cause discomfort to patients. Trigger points can be diagnosed by the presence of palpable nodules accompanied sometimes with radiating pain.49 Myofascial dysfunction in the back and neck muscles are common in breast cancer patients. Shortening of the pectoral muscles in primary breast cancer surgery could result in the development of pectoral tightness with resultant overuse of the retractor muscles.
Phantom Breast Pain
Phantom breast pain is defined as a sensory experience of a removed breast that is still present and is painful.8 Women have expressed feelings of disturbing, painful sensations in particular areas, such as the nipple or scar, or over the entire breast. Phantom breast pain is related to deafferentation of neurons along with their spontaneous and evoked hyperexcitability. Studies have suggested that emotional factors and the sympathetic nervous system may also play a role in establishing phantom breast pain.12 A study conducted by Kroner et al.50 identified a significant relationship between preoperative breast pain and postoperative phantom breast pain. In a similar study conducted by Tasmuth et al.,10 the presence of preoperative pain was not found to be a predictive factor for postoperative phantom breast pain.
Neuromas are formed when peripheral nerves are severed or injured and are often located within scar tissue. They may be classified as either a macroneuroma or microneuroma. A macroneuroma is a palpable mass of tangled axons unable to regenerate to their target, fibroblasts, and other cells. A microneuroma consists of a small number of axons and is not palpable. Abnormal neuronal activity originating in neuromas or entrapped axons within the scar tissue is the most likely source of pain occurring in this area. Neuromas are known to be a source of ectopic discharges, which also contribute to pain.8
Much of the research on pain associated with breast cancer surgery focuses on neuropathic pain syndromes. Although it has received far less attention in research, nociceptive pain is as prevalent in women as the more talked-about neuropathic pain. Spasm of the pectoralis muscle, which leads to pectoral tightness and discomfort, has recently been suggested as a source of nociceptive pain after breast reconstruction with subpectoral tissue expanders.18,19,20,32 During the course of breast reconstruction using tissue expanders, the musculature of the chest wall is subjected to significant surgical trauma. The creation of a submuscular cavity to accommodate the expander involves separating the muscular attachments of the serratus anterior muscles from the bony surfaces of the fifth, sixth, and seventh ribs. Posterior dissection of the serratus anterior muscles typically involves the attachments of these muscles to the rib cage at midaxillary level. The pectoralis major muscle is dissected medially along the sternal border and its attachments are left intact superiorly. This surgical trauma, in combination with the muscle spasms within the chest wall, is thought to be responsible for the discomfort experienced by the majority of patients immediately after their surgery.21
There are a number of risk factors associated with an increased incidence of chronic pain syndromes after breast cancer surgery. Studies identifying these risk factors, however, have failed to produce a consistent set of findings. A study conducted by Kroner et al.50 identified a significant relationship between preoperative breast pain and postoperative phantom breast pain. In a similar study conducted by Tasmuth et al.,10 the presence of preoperative pain was not found to be a predictive factor for postoperative phantom breast pain.9 Additional risk factors believed to be associated with an increased incidence of chronic pain syndromes after breast cancer surgery include younger age, being unmarried, type of surgery, radiotherapy, chemotherapy, and preoperative anxiety. Severe postoperative pain is the lone risk factor that has been consistently associated with chronic pain after breast cancer surgery. In both retrospective and prospective studies, greater intensity of acute postoperative pain and greater consumption of postoperative analgesics have been associated with chronic breast and ipsilateral arm pain after breast cancer surgery8,10
Impact of Chronic Pain on Psychosocial Functioning
The pain that women experience after a mastectomy and breast reconstruction can have a negative impact on a patient’s physical and psychosocial functioning. In a study conducted by Tasmuth et al.,10 chronic pain was found to slightly affect the daily lives of approximately 50 per cent of the subjects, and moderately or more affect the daily lives of approximately 25 per cent of subjects. The impact of the pain occurs at both home and work. Some activities that are limited due to the presence of pain include work, exercise, chores, sleeping, sex, and socializing.35 For some, the pain is so severe that they must apply for disability benefits or reduce their work schedule to part-time.8,51
Studies measuring the levels of psychosocial distress in women undergoing mastectomy and breast reconstruction have produced inconsistent results. Tasmuth et al.10 found mat patients with chronic pain syndromes have significantly higher levels of psychosocial distress compared with the general population, but not all studies agree.52 Other research suggests that greater psychological or psychiatric morbidity, including depression and anxiety, is associated with the presence and intensity of chronic pain after breast cancer surgery.8
Prevention of Chronic Pain
All surgeons should take careful consideration and pay special attention to lessen the risk of developing chronic postoperative pain syndromes after breast cancer surgery. If the surgeon is able to preserve the intercostobrachial nerve throughout the surgery, there is a decreased chance of developing pain and sensory deficits in the axilla, medial upper arm, and/or the anterior chest wall.8 As previously noted, the intercostobrachial nerve is reportedly injured in 80 to 100 per cent of mastectomy patients undergoing axillary dissection,4 which helps account for the high incidence of chronic postoperative pain syndromes after breast cancer surgery.
Severe postoperative pain immediately after breast cancer surgery is one of the greatest risk factors for developing chronic postoperative pain syndromes. Researchers have recently suggested that reducing the amount of acute postoperative pain after breast cancer surgery may attenuate the risk of developing chronic pain.8 Therefore, it is important to determine whether the use of adjuvant analgesic therapy, such as local bupivacaine and botulinum toxin, or combinations thereof at the time of mastectomy and immediate reconstruction of the breast using tissue expander, can in fact reduce acute postoperative pain and in the long term reduce chronic pain.
Treatments for Acute and Chronic Pain after Breast Cancer Surgery
Pain after breast surgery can be acute or chronic and treatment of pain after breast surgery should focus on treating both acute and chronic pain. Studies indicate inadequately-managed pain immediately after surgery is one of the greatest predictors of chronic pain syndromes so it is vital to control acute pain adequately to prevent chronic pain syndromes. The majority of patients can achieve adequate relief of cancer pain with the use of NSAIDS, opioids, or adjuvant analgesics. In the immediate period after surgery, in the recovery room, pain is controlled by means of intravenous medications in the form of opioids and adjuvant medications. Adjuvants used to treat acute post operative pain include diclofenac, dextropropoxyphene hydrochloride, and acetaminophen and sometimes cox-2 inhibitors and botulinum toxin.38 Preoperative and post operative blocks for control of acute pain can also be used.
The presence of metastatic lesions can lead to an increase in acute and chronic pain post surgically. Treatment of chronic pain and associated comorbidities requires a multidisciplinary approach. Research is being done on topical, oral, intravenous, epidural, and peripheral nerve blocks to reduce acute post operative pain after breast surgery. If pain cannot be controlled with these measures, there can be a need for long term Epidural or Intrathecal pump infusions.53 A variety of medications have been tried to control acute and chronic pain after breast surgery.
The use of topical capsaicin has been found by Watson and Evans54 to provide significant pain relief and reduction in jabbing pain, but has not been found to be effective in decreasing steady pain or allodynia. This was studied in a double-blind, randomized controlled trial, but the double-blind in this trial was compromised due to me burning sensation caused by capsaicin. Pain scores were recorded in 13 patients with post mastectomy pain syndrome treated with capsaicin and 10 patients with post mastectomy pain syndromes treated with placebo. A significant difference was found, in the verbal analog pain score (VAS) for jabbing pain, both in category pain severity scales, and in overall pain relief scales, showing that capsaicin is useful for the treatment of acute post operative jabbing pain.
Local Anesthetic Treatment Postoperatively
Talbot et al.55 evaluated the use of a local anesthetic regimen after mastectomy. This prospective double-blind, randomized, placebo- controlled trial with local anesthetic irrigation of axillary wound drains was done post operatively during the first 24 hours after a modified Patey mastectomy (mastectomy with complete axillary node clearance). The treatment group received bupivacaine irrigation through the axillary wound drain every four hours. There were no statistical differences in morphine requirements or pain scores between the two groups, nor were there differences in antiemetic or supplemental analgesic consumption. Bupivacaine irrigation used in this manner did not seem to offer an effective contribution to postoperative analgesia.55 Morrison and Jacobs56 demonstrated a reduction or elimination of postoperative pain medication after mastectomy through use of a temporarily placed local anesthetic pump as compared with a control group for 72 hours after a mastectomy.
Muscle Spasm Treatments
The conventional treatment regimen for muscle spasm after tissue expander reconstruction typically includes heat, restriction of arm movement, and muscle relaxants. However, this treatment regimen has not been effective in relieving the discomfort experienced after surgery at all times. Huang21 pointed out that continuous pressure exerted on the serratus muscles by breast implants can cause pain in the lateral aspect of the breast mound and the subscapular area. For patients with this problem the best treatment seems to be the removal of the implants or repair of the cavity defects.21
Botulinum toxin (BT) treatment after breast surgery can also be used to treat acute pain caused by muscle spasms. The theory behind using BT within the musculature of the chest wall is that it will temporarily paralyze the muscles and therefore prevent muscle spasms from occurring, which will reduce the amount of postoperative pain. BT infiltration of the chest wall musculature after mastectomy would create a prolonged inhibition of muscle spasm and postoperative pain, facilitating tissue expander reconstruction.
Muscular infiltration of botulinum toxin for mastectomy and tissue expander placement significantly reduced postoperative pain and discomfort without complications in a study of 48 patients by Layeeque et al.18 The infiltration of the chest wall musculature was done after mastectomy and expander reconstruction. The sites of injection of 100 units of diluted BT were pectoralis major, serratus anterior, and rectus abdominis insertion.
The anticonvulsant gabapentin has been tried to treat pain after mastectomy. Experimental and clinical studies have demonstrated antihyperalgesic effects of gabapentin in models involving central neuronal sensitization producing chronic post operative pain. In a study by Dirks et al.,57 a single dose of 1200 mg oral gabapentin given 1 hour preoperatively resulted in a substantial reduction in postoperative morphine consumption and movement-related pain after radical mastectomy, without significant side effects. There were a total of 31 patients in the group who received gabapentin and 34 patients in the placebo group. Gabapentin could perhaps reduce central sensitization in the immediate post operative period.57
Epidural placement for control of acute post operative pain is a consideration. Sundarathiti et al.58 studied the role of thoracic epidural anesthesia, with 0.2 per cent ropivacaine, in combination with ipsilateral brachial plexus block for control of post operative pain after modified radical mastectomy. They found that there was better post operative pain relief, faster anesthetic recovery, and greater patient satisfaction in these patients without any untoward effects of sedation.
Kotake et al.59 studied the effectiveness of continuous cervical epidural block (C7-T1) using a low-dose fentanyl infusion in combination with mepivacaine, a local anesthetic, starting preoperatively and continuing on to the post operative period. They concluded mat continuous epidural infusion of the low-dose fentanyl mixture described above provided adequate intraoperative hemodynamic control and postoperative pain relief, with a low rate of side effects in mastectomy patients.
Kairaluoma et al.60 studied 60 patients scheduled for breast cancer surgery who were randomly given single-injection paravertebral block (PVB) at T3 with bupivacaine 5 mg/mL (1.5 mg/ kg) or saline before general anesthesia. They found that a single- injection paravertebral block before general anesthesia in 60 patients after breast surgery reduced post operative pain, opioid use, and post operative nausea and vomiting and resulted in improved recovery from anesthesia. Naja et al.61 found mat the use of a nerve stimulator guided paravertebral nerve blockade was associated with improved postoperative pain relief, a reduced incidence of nausea and vomiting after operation, and a shorter duration of hospital stay compared with general anesthesia in patients undergoing breast surgery. The primary end points in the 60 patients they studied were visual analogue scale and supplemental opioid requirements. Ninety seven per cent of the patients stated that the intraoperative conditions and the performance of the block were acceptable to them.
Buckenmaier et al.62 described the successful use of continuous paravertebral anesthesia in two patients undergoing major breast surgery. Disposable home infusion systems allowed extended analgesia after major breast surgery, while maintaining the ambulatory status in these two patients.62 The decrease in chronic pain after paravertebral blocks has yet to be studied.
Chronic pain after mastectomy can be treated with adjuvant medications such as antidepressants and anticonvulsants. Common drugs in these classes include amitriptyline, gabapentin, topiramate, oxcarbazepine, nortriptyline, venlafaxine, and clonazepam
Local Anesthetic Type Drugs for Relief of Chronic Pain
Mexiletene and other local anesthetic type drugs are used to treat chronic pain. A systematic review of randomized controlled trials of systemically administered local-anesthetic-type drugs in chronic pain was performed by Kalso et al.63 The main outcomes they looked at were pain relief or pain intensity difference and adverse effects. Kalso et al.63 concluded that local-anesthetic-type drugs are effective in pain due to nerve damage, but there is little or no evidence to support their use in cancer-related pain.
Alternate therapy such as acupuncture, acupressure, Transcutaneous nerve stimulation, relaxation training, biofeedback, and hypnosis and yoga could help decrease pain after surgery in patients after breast mastectomy and reconstruction.
Considering the degree of physical disability and emotional distress associated with chronic pain syndromes after breast cancer surgery, the studies of its occurrence are highly significant. This significance is heightened because the pain syndromes experienced are refractory to the existing treatment regimens.
When considering that severe postoperative pain immediately after surgery is one of the greatest risk factors for the development of chronic pain syndromes in women, reducing acute postoperative pain becomes a logical means of reducing the occurrence of chronic pain syndromes after breast cancer surgery. If the surgeon is able to preserve the intercostobrachial nerve throughout the surgery, there is a decreased chance of developing pain and sensory deficits in the axilla, medial upper arm, and/or the anterior chest wall.8 As previously noted, the intercostobrachial nerve is reportedly injured in 80 to 100 per cent of mastectomy patients undergoing axillary dissection,4 which helps account for the high incidence of chronic postoperative pain syndromes after breast cancer surgery. In addition service from different disciplines should be available to ensure that these patients have good quality of life without psychosocial problems and freedom from pain after surgery. The high prevalence of postoperative pain after mastectomy and reconstructive breast surgery using tissue expanders and its potential to cause chronic pain syndromes makes it critical to determine if using preemptive analgesia will enable surgeons to ameliorate immediate postoperative pain Therefore, it is important to determine whether the use of adjuvant analgesic therapy, such as local bupivacaine and botulinum toxin, or combinations thereof at the time of mastectomy and immediate reconstruction of the breast using tissue expander, can in fact reduce acute postoperative pain. There are presently no treatment regimens that have been shown to effectively treat all cases of acute and chronic postoperative pain syndromes after breast cancer surgery. There has to be focused effort to increase awareness of die problem of pain and to continue research to find optimum methods for control of post operative acute and chronic pain without functional compromise in this population.
We would like to thank Marie Warner and Vijay Kodumudi for their help in the preparation of this manuscript.
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NALINI VADIVELU, M.D., MAGGIE SCHRECK, P.A., JAVIER LOPEZ, M.D., GOPAL KODUMUDI, DEEPAK NARAYAN, M.D.
From the Department of Anesthesiology and Plastic Surgery, Yale University School of Medicine, New Haven, Connecticut
Address correspondence and reprint requests to Nalini Vadivelu, M.D., Yale University School of Medicine, Department of Anesthesiology, 333 Cedar Street, TMP-3, New Haven, CT 06510. E- mail: [email protected]
Copyright Southeastern Surgical Congress Apr 2008
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