INTRODUCTION — Postmastectomy pain syndrome (PMPS) is a chronic neuropathic pain disorder that can occur following breast cancer-related operative procedures [1-5]. The optimal approaches to reducing the risk of and managing PMPS used in our center are presented here. The clinical manifestations and diagnosis of PMPS are reviewed separately. (See "Clinical manifestations and diagnosis of postmastectomy pain syndrome".)

RISK REDUCTION — Because the development of postmastectomy pain syndrome (PMPS) is complex and the treatment options are limited, the focus of current research is on perioperative measures that can mitigate the modifiable risk factors for PMPS and thereby prevent patients from developing PMPS in the first place. The specific risk factors targeted include acute postoperative pain, operative axillary nerve injury, and preexisting psychosocial impairments.

Preventive analgesia — Management of postoperative pain has evolved from the sole administration of opioid medication in response to pain to the administration of a variety of medications and use of techniques to prevent acute and chronic pain. Preventive analgesia for breast surgery includes the administration of local or regional (eg, wound infiltration, pectoral nerve or paravertebral block [6], anesthetic creams [7]) or systemic (eg, ibuprofen, ketorolac, gabapentin) analgesics before, during, and after breast surgery, both prior to and after the onset of noxious stimuli (eg, surgical incision). (See "Management of acute perioperative pain", section on 'Preventive analgesia'.)

Although management of acute postoperative pain as it arises may also reduce the risk of chronic neuropathic pain, there are no supporting data from randomized trials designed for patients undergoing breast cancer operations.

Our approach — Our approach to preventive analgesia is consistent with evidence-based enhanced recovery after surgery (ERAS) protocols [8], and the specifics vary between mastectomy and breast conserving surgery (lumpectomy):

●For patients undergoing mastectomy without reconstruction, we administer 1000 mg of acetaminophen and 600 mg of gabapentin orally in the preoperative period. Intraoperative interventions include a 5-level intercostal nerve block, a pectoral nerve block, and in some patients a serratus plane block, all administered by the surgeon after the breast has been removed.

●For patients undergoing mastectomy with planned immediate reconstruction, we administer the same 1000 mg of acetaminophen and 600 mg of gabapentin orally in the preoperative period, and a preoperative pectoral nerve block or paravertebral block (by an anesthesia provider).

●For patients undergoing lumpectomy, we infiltrate the skin with a mixture of lidocaine and bupivacaine prior to any surgical incision but omit the premedications and nerve blocks.

Supporting evidence — Most prospective studies identified a perioperative benefit (eg, fewer postoperative analgesic requirements) for administration of preventive analgesia for patients undergoing breast cancer procedures [9-13]. However, long-term pain control and reduced risk of PMPS with preventive analgesia have not been clearly established. This apparent dissociation between short- and long-term benefits is disconcerting given that acute pain is a known risk factor for chronic pain [14]. Variations in study design, including application and duration of administration of preventive analgesics and duration of observation, limit direct comparison between treatments.

Short-term benefit — The following medications or techniques have been associated with short-term pain relief in women undergoing breast cancer operations:

●Local anesthetic infiltration:

•Wound infiltration with a local anesthetic can provide immediate postoperative pain control lasting for several hours. A randomized trial of 46 patients undergoing a mastectomy or breast conservation surgery with an axillary dissection found that patients receiving ropivacaine wound infiltration (20 mL, 7.5 mg/mL) had less pain at rest at six hours compared with patients receiving saline (12 versus 32 approximate Visual Analogue Scale [VAS] score, respectively) [9]. In addition, patients with wound infiltration also had less pain on mobilization of the ipsilateral arm at six hours postoperatively (25 versus 38 approximate VAS score, respectively). However, there was no difference in pain and comfort scores two months after the procedure.

•In a randomized trial that included 106 women undergoing a mastectomy for breast cancer, women treated with a local infiltration of bupivacaine 100 mg in 40 mL immediately prior to incision required less morphine 4 to 12 hours postoperatively compared with women receiving a placebo infiltration of 40 mL of saline (1.24 versus 2.35 mg, p = 0.02) [15]. In addition, women treated with bupivacaine had a lower postoperative pain intensity score at the 4^th postoperative hour (mean VAS score 0.85 versus 1.69, p = 0.004) and 12^th postoperative hour (mean VAS score 0.48 versus 0.96, p = 0.02). Women receiving bupivacaine also required less intraoperative fentanyl administration (0.38 versus 0.43 mg, p = 0.011).

●Regional nerve blocks:

•Regional blocks that have been used include the paravertebral nerve block and the pectoral nerve block. First described in 2011, the pectoral block is an easy and reliable superficial block that aims to block the pectoral nerves; the intercostobrachial nerves; intercostal nerves III, IV, V, and VI; and the long thoracic nerves [16]. Together, blockade of these nerves can provide complete analgesia during breast surgery. The pectoral block has been shown to result in lower pain scores and lower perioperative opioid consumption in women with breast cancer undergoing modified radical mastectomy without reconstruction [17-19].

●Systemic medications:

•A randomized trial of 75 patients undergoing a breast cancer operation found that oral administration of mexiletine (600 mg) or gabapentin (1200 mg) for 10 days starting in the evening before surgery reduced the postoperative analgesic requirement by 50 percent compared with placebo, and gabapentin reduced pain after movement of the ipsilateral arm [12]. However, neither mexiletine nor gabapentin reduced the incidence of chronic pain at three months.

•Preoperative administration of oral gabapentin provided effective postoperative analgesia [20]. In a randomized trial of 50 patients undergoing a total mastectomy and axillary dissection, the mean postoperative morphine consumption was significantly lower for women receiving oral gabapentin 600 mg one hour before the procedure compared with women receiving an oral placebo (5.8±4.2 versus 11.0±3.4 mg, respectively) [13]. In addition, the median time to first administration of morphine was significantly longer for women receiving gabapentin (90 minutes [37.5 to 120, range] versus 0 minutes [0 to 90, range]), respectively. This trial did not assess longer-term pain control.

•Administration of ketamine before wound closure was associated with a decreased amount of morphine needed for pain control in the first two hours following the operation. A randomized trial of 130 women undergoing a total mastectomy and axillary dissection found that women receiving intravenous ketamine (0.15 mg/kg) at the time of skin closure required less morphine compared with women receiving ketamine administered before the surgical incision (p <0.04); however, there was no difference in morphine consumption 24 hours after the operation [11].

Long-term benefit — The following medications have been associated with long-term but not immediate postoperative pain relief in women undergoing breast cancer operations:

●In a prospective study of 100 patients undergoing a partial or total mastectomy with an axillary dissection, significantly fewer patients treated with venlafaxine 75 mg for two weeks beginning on the evening before the procedure had chest wall pain at six months compared with patients treated with a placebo (19 versus 55 percent) [21]. Fewer patients treated with venlafaxine also had arm pain (17 versus 45 percent) and axillary pain (19 versus 51 percent) at six months. However, there was no difference in the use of opioids for immediate postoperative pain control.

●A randomized trial that included 150 women undergoing a partial or radical mastectomy with axillary node dissection found that fewer women receiving venlafaxine 37.5 mg/day extended release had PMPS (symptoms of stabbing or pricking pain) at six months compared with women receiving gabapentin 300 mg/day or placebo for 10 days starting on the night prior to the procedure (7 versus 16 versus 20 women, respectively) [22].

●A randomized trial that included 46 patients found that application of a eutectic mixture of local anesthetics (EMLA) cream (20 mg) to the axilla, supraclavicular fossa, and sternum (postoperative days 0 to 4) was associated with less chronic pain in the chest wall (p = 0.004) and axilla (p = 0.025) evaluated at three months compared with patients treated with a placebo cream [7]. There was no difference in acute pain at rest or with movement and analgesics consumed during the first 24 hours following the procedure.

Preservation of axillary nerves — The axilla contains sensory (eg, intercostal brachial trunk, peripheral intercostal branches) and motor (eg, long thoracic, thoracodorsal, pectoral) nerves (figure 1). The anatomy of the axilla and the technique for performing an axillary lymph node dissection (ALND) and preserving the motor and sensory nerves are described separately. (See "Technique of axillary lymph node dissection".)

ALND is a well-recognized intraoperative risk factor for PMPS [23]. Many patients who undergo an ALND experience some degree of postoperative pain, hypersensitivity, and/or hyposensitivity in the axilla and medial aspect of the upper arm. This alteration in sensitivity is the result of transecting or traumatizing the sensory intercostal brachial nerves [24-28]. Findings from randomized trials, prospective studies, and retrospective reviews reveal inconsistent results for preservation of the intercostal brachial nerves. While some studies identified that preservation of the nerve is associated with decreased sensory deficits and/or less discomfort in the upper arm and axilla [28-30], other studies have found minimal effect on chronic sensory deficits and/or pain [30-32]. To minimize the risk of sensory deficits, we preserve the intercostal brachial nerve during the axillary dissection unless gross metastatic disease is present.

By comparison, sentinel lymph node biopsy (SLNB) is associated with a lower incidence of PMPS compared with ALND [33,34]. The adoption of SLNB as the current standard care for assessing axillary metastatic disease is a major contributor to reducing the incidence of PMPS.

Psychosocial intervention — Acute and chronic pain may be caused or exacerbated by psychosocial risk factors such as anxiety, depression, and interpersonal conflicts [35]. In addition, approximately one half of patients diagnosed with cancer exhibit some, if not all, of these emotional difficulties [36,37]. (See "Clinical features and diagnosis of psychiatric disorders in patients with cancer: Overview".)

The term "somatization" refers to a psychosocial impairment syndrome consisting of physical symptoms that cannot be explained by a known medical disease. Preoccupation with symptoms, such as chronic pain following breast cancer procedures, may indicate somatization. It is plausible that patients with somatization syndrome may experience PMPS in the absence of detectable clinical abnormalities. (See "Somatic symptom disorder: Epidemiology and clinical presentation" and "Somatic symptom disorder: Assessment and diagnosis".)

Psychosocial and pharmacologic interventions can reduce pain and psychosocial distress, and the best preventive intervention may be one that combines pharmacologic and psychosocial treatments [35]. Psychosocial interventions should start once the diagnosis of psychosocial impairment is made and be continued at least until the time of surgery, when pharmacologic interventions should be initiated to reduce acute postoperative pain to the greatest extent possible. (See "Management of psychiatric disorders in patients with cancer".)

Reducing preoperative psychosocial distress, relieving acute postoperative pain, and enhancing postoperative recovery provide the greatest potential to prevent chronic pain after breast cancer surgery.

MANAGEMENT — Since neuropathic pain, such as postmastectomy pain syndrome (PMPS), manifests months after the axillary operation, an assessment for chronic pain should be considered as a component of long-term follow-up of breast cancer patients. Management of PMPS should be initiated upon diagnosis, as with other chronic neuropathic pain disorders.

Our approach

●For patients amenable to taking medications, we prescribe gabapentin if the symptom is predominantly neuropathic pain, or venlafaxine or duloxetine if the pain is accompanied by other vasomotor symptoms such as hot flashes. We start gabapentin at 600 mg/day and titrate up to 900 mg/day in six weeks if necessary. (See 'Pharmacotherapy' below.)

●For patients who are reluctant to accept medical therapy at the time PMPS is diagnosed, we offer them acupuncture if they accept, or continued observation and assessment for worsening symptoms if they refuse acupuncture. (See 'Complementary and alternative medicine' below.)

●For patients with a suspected traumatic neuroma that responds to local anesthetic infiltration, we surgically excise the neuroma. (See 'Neuroma excision' below.)

●For patients with chronic pain associated with an axillary scar, we refer them for possible scar release with or without autologous fat grafting. (See 'Axillary scar release' below.)

Pharmacotherapy — Pharmacologic therapy remains the initial treatment for PMPS, although patients with neuropathic pain may respond poorly to commonly used analgesics, such as acetaminophen, nonsteroidal anti-inflammatory drugs, and opioid analgesics [38,39]. (See "Clinical features and diagnosis of psychiatric disorders in patients with cancer: Overview" and "Pharmacologic management of chronic non-cancer pain in adults".)

Antiepileptic medications, such as gabapentin, which inhibit neurotransmitter release, have proven efficacy in several neuropathic pain conditions and are our preferred initial approach [40]. Other antiepileptic medications, such as carbamazepine, have been used with moderate efficacy. (See "Pharmacologic management of chronic non-cancer pain in adults".)

Serotonin-noradrenaline reuptake inhibitors, such as venlafaxine and duloxetine, can enhance pain signal inhibition and provide effective pain relief for patients with neuropathic pain (table 1) [41]. In addition, tricyclic antidepressants such as amitriptyline [42], imipramine, nortriptyline, and doxepin are a pharmacologic mainstay for chronic pain conditions, with or without depression. However, adverse side effects often limit the tolerability of these medications (table 2) [43]. (See "Pharmacologic management of chronic non-cancer pain in adults".)

Surgical interventions — The following surgical interventions have been shown to be effective in treating PMPS in appropriately selected patients:

Neuroma excision — Patients with a painful neuroma that develops at the end of a transected nerve and causes painful nerve impulses along the distribution of the involved nerve may benefit from surgical excision of the neuroma [44]. (See "Peripheral nerve tumors", section on 'Neuroma'.)

Neuromas are typically diagnosed clinically. Palpation of the axilla may trigger painful radiating impulses (Tinel's sign [45]) and help identify the location of the neuroma. Once localized, a diagnostic test is performed by infiltrating the site with 1% lidocaine. If pain relief is achieved with local infiltration, excision of the neuroma may provide permanent relief.

During the operative procedure, the neuromas are most commonly identified at the site of transection of the intercostal brachial nerves along the lateral chest wall. Under tension, the nerves are dissected from the scar, the neuromas resected, and the cut proximal ends allowed to retract deep into the intercostal muscles where the risk of recurrence is lower.

In a retrospective review of five patients with an intercostal neuroma embedded in a scar following an axillary lymph node dissection (ALND), resection of the neuroma resulted in complete pain relief in four of the patients at 48 months of observation [44].

For patients who opt not to undergo a resection of a neuroma or who have a trigger point not associated with a resectable lesion, we will infiltrate the area as required for pain relief with a long-acting local anesthetic (eg, bupivacaine).

Axillary scar release — Anecdotally, if a scar in the axilla is the etiology of pain, an axillary scar release can be performed with or without fat grafting. (See "Z-plasty", section on 'Indications'.)

Autologous fat grafting — Autologous fat grafting has been found to be beneficial in select cases of PMPS. In several comparative studies [2,46,47] and small trials [48,49], fat grafting was associated with reduced postoperative pain and/or analgesic medication use after both mastectomy or lumpectomy. However, a placebo effect of fat grafting cannot be entirely excluded without larger randomized controlled trials.

The mechanism is not well elucidated, but several potential benefits of fat grafting are hypothesized, including (1) improved vascularization; (2) creation of a cushion around a transected nerve stump, reducing nerve compression and stimulation; (3) secretion of anti-inflammatory molecules that improve tissue differentiation and scar softness, and (4) nerve entrapment liberation. Additionally, autologous stromal vascular fraction (SVF)-enriched fat grafting may accelerate neuronal regeneration and prevent disorganized axonal outgrowth due to enhanced vascularization and reduced inflammatory processes, which leads to decreased fibrosis and hypertrophy of the adjacent tissues. 

The technique of fat grafting is discussed separately. (See "Overview of breast reconstruction".)

Regional nerve blocks — Regional nerve blocks can be used to treat PMPS as well, but usually as a last resort in patients who have failed medical therapy and are not candidates for surgical intervention. (See "Thoracic nerve block techniques".)

Injury to the intercostobrachial nerve, either through direct injury, traction, or postsurgical inflammation, is thought to be a possible contributing factor to postmastectomy pain. In a small case series, an intercostobrachial nerve block was shown to relieve PMPS pain [50]. Another emerging potential target for an interventional procedure for postmastectomy pain syndromes is the serratus plane. The serratus plane block is an ultrasound-guided nerve block that is able to anesthetize the hemithorax. Both a superficial serratus plane block [51] and the deep serratus anterior plane block [52] have been shown to alleviate chest wall pain related to PMPS with short-term follow-up, and more longitudinal studies are needed.

Physical therapy — Rehabilitation protocols for PMPS are highly variable and should be individualized [53]. Four core techniques are hypothesized to be beneficial in the functional rehabilitation of PMPS: restoring joint mobility and preventing tendon shortening with passive mobilization techniques, reducing pain with myofascial release and sustained trigger point compression, addressing tight muscles with manual stretching and transverse strain, and strengthening shoulder girdle muscles with active and/or active-assisted mobilization [54]. A systematic review of these core modalities demonstrated that a multimodal approach, involving stretching and active exercises, was useful for the treatment of breast cancer pain [55].

Complementary and alternative medicine — Complementary and alternative medicine (CAM), such as guided imagery, acupuncture, and biofeedback, has also been used in managing chronic neuropathic pain. (See "Acupuncture" and "Complementary and alternative therapies for cancer" and "Approach to the management of chronic non-cancer pain in adults", section on 'Complementary and integrative health therapies'.)

In addition, approximately 25 to 60 percent of breast cancer patients have used at least one form of CAM to treat cancer pain and the side effects of chemotherapy and radiation and to improve quality of life [56-58].

Acupuncture is an effective treatment strategy to manage some of the symptoms associated with breast cancer surgery, including pain, numbness, limited range of motion, and lymphedema [59]. These studies have demonstrated that acupuncture is a safe alternative with minimal complications or side effects [60]. The clinical evidence of the effectiveness of acupuncture to manage chronic pain conditions (low back pain, knee osteoarthritis) is reviewed separately. Both acupuncture and sham acupuncture appear to have much greater efficacy than when patients are untreated. (See "Acupuncture", section on 'Clinical evidence'.)

SUMMARY AND RECOMMENDATIONS — Postmastectomy pain syndrome (PMPS) is a chronic neuropathic pain disorder that can occur following breast cancer-related operative procedures. Once PMPS is established, treatment options are limited; hence, the focus of current research is on perioperative measures that can mitigate the modifiable risk factors for PMPS and thereby prevent patients from developing PMPS in the first place.

Risk reduction

●Preventive analgesia may minimize immediate postoperative pain but may not eliminate the development of PMPS. We premedicate mastectomy patients with oral acetaminophen (1000 mg) and gabapentin (600 mg) and perform a 5-level intercostal nerve block, a pectoral nerve block, and in some patients a serratus plane block after removal of the breast. We infiltrate the skin with a mixture of lidocaine and bupivacaine before surgical incision for lumpectomy patients. (See 'Preventive analgesia' above.)

●Transecting or traumatizing the intercostal brachial nerve during an axillary lymph node dissection can result in altered sensations in the medial upper arm. To minimize the risk of sensory deficits, we suggest preserving the intercostal brachial nerve during the axillary dissection (Grade 2C), unless gross metastatic disease is present. (See 'Preservation of axillary nerves' above.)

●Acute and chronic pain may be caused or exacerbated by psychosocial risk factors, such as anxiety, depression, and interpersonal conflicts. In such patients, psychosocial interventions (including pharmacologic and psychosocial treatments) should start once the diagnosis of psychosocial impairment is made and be continued at least until the time of surgery, when pharmacologic interventions should be initiated to reduce acute postoperative pain to the greatest extent possible. (See 'Psychosocial intervention' above and "Management of psychiatric disorders in patients with cancer".)

Management

●For patients with predominantly neuropathic pain who desire medical therapy, we suggest gabapentin as the first-line therapy (Grade 2C). We start at 600 mg/day and titrate up to 900 mg/day as necessary in six weeks. For patients with both neuropathic pain and vasomotor symptoms such as hot flashes, we suggest one of the serotonin-noradrenaline reuptake inhibitors (venlafaxine or duloxetine) as the first-line therapy (Grade 2C). We offer acupuncture or observation to those who refuse medical therapy. (See 'Pharmacotherapy' above and "Pharmacologic management of chronic non-cancer pain in adults", section on 'Pharmacologic therapy for neuropathic pain'.)

●For patients with pain from a traumatic neuroma, we initially infiltrate the site with a local anesthetic (eg, 1% lidocaine). For patients who experience pain relief following this procedure, we then perform an excision of the neuroma. Patients with a painful axillary scar may benefit from scar release and/or autologous fat grafting. (See 'Surgical interventions' above.)

●For patients who would prefer complementary therapies, we prescribe acupuncture therapy. In patients with chronic pain, both acupuncture and sham acupuncture appear to have much greater efficacy than when patients are untreated. (See 'Complementary and alternative medicine' above and "Acupuncture", section on 'Clinical evidence'.)