Scott S. Reuben, MD
Professor of Anesthesiology and Pain Medicine,
Department of Anesthesiology
Baystate Medical Center and the
Tufts University School of Medicine
Preventing postmastectomy pain syndrome
Postmastectomy pain syndrome (PMPS) is a neuropathic pain syndrome that is poorly documented, poorly understood, and understudied. This syndrome consists of persistent pain in the anterior chest, axilla, medial and posterior parts of the arm following breast surgery. The exact mechanism producing PMPS is unclear, but is believed to be due to surgical injury to the intercostobrachial nerve . The reported incidence of PMPS following surgery for breast cancer varies considerably with reports from as low as 4-6%  to as high as 100% . This pain can be sufficiently severe enough to interfere with sleep and performance of daily activities [77,78]. In addition, if poorly treated, patients may develop an immobilized arm, which can lead to severe lymphedema, frozen shoulder syndrome, and complex regional pain syndrome .
A variety of perioperative analgesics have been administered for mastectomy surgery in an attempt to “preempt” the process of central sensitization and thus the incidence of pain. Previous studies have evaluated the analgesic efficacy of administering either ibuprofen, mexiletine, gabapentin, venlafaxine, eutectic mixture of local anesthetics (EMLA), local anesthetic infiltration, and brachial plexus block on the incidence of acute and/or chronic pain following breast cancer surgery [80-84]. Lakdja et al.  were the first investigators to examine the efficacy of utilizing preemptive analgesia in an attempt to prevent the occurrence of PMPS. This study prospectively evaluated thirty patients scheduled for partial or total mastectomy with axillary dissection who received either ibuprofen (n=15) or placebo (n=15). Ibuprofen 400 mg was administered, 90 minutes before surgery, 2 hours after surgery and then every 8 hours in the first 32 postoperative hours. This study revealed no significant reduction in either the incidence of acute pain for the first 42 postoperative hours or the incidence of PMPS at six months postoperatively. This study can be criticized for utilizing both a sub-therapeutic dose of ibuprofen  and administering this NSAID for a rather brief period of time following the surgical procedure.
It has been noted that the process of central sensitization following surgery may take days to develop and that analgesics should be administered until the process of wound healing has been completed . Therefore, failure to adequately treat clinical pain well into the postoperative period may lead to the persistence of nociceptive pathways and the development of chronic pain . Further, centrally-acting NSAIDS may be more effective analgesics in preventing central sensitization following peripheral trauma . Since ibuprofen has little effect on the upregulation of COX-2 in the CNS and resultant central PGE2 synthesis,  it may not effectively prevent the development of central neuroplasticity and the subsequent development of chronic pain.
In an attempt to attenuate the ectopic neural activity that is believed to be associated with the pathogenesis of PMPS, Fassoulaki et al.  investigated the effect of regional brachial plexus block, oral mexiletine, and the combination of both on acute and chronic pain following breast cancer surgery. Patients were administered mexiletine 200 mg twice a day for the first 6 postoperative days starting the night before surgery. This study demonstrated that analgesic requirements were reduced in the immediate postoperative 24 hours by regional block, while the addition of mexiletine reduced the total oral analgesic requirements during the first 5 postoperative days. However, there was no significant reduction in the incidence of PMPS with the only long-term change noted being a reduction in hypoesthesia observed in patients who received both treatments. In an attempt to further improve on its analgesic efficacy, Fassoulaki  evaluated an increased mexiletine dose (600 mg/day) administered for a prolonged duration (10 days) following breast cancer surgery. This study also compared the efficacy of this dosing regimen of mexiletine to that of gabapentin 1,200 mg/day. Gabapentin would seem to be the ideal analgesic for managing acute and chronic pain following breast cancer surgery since it possesses antihyperalgesic and antiallodynic effects in the setting of peripheral tissue injury . In addition, gabapentin has been shown to enhance the analgesic effects of morphine in healthy volunteers  and a single 1,200 mg dose of gabapentin prior to mastectomy surgery reduced both acute pain and morphine use . Unfortunately, Fassoulaki et al.  were unable to demonstrate a reduction in the incidence of chronic pain following mastectomy surgery with the perioperative administration of gabapentin 1,200 mg/day for 10 postoperative days.
Recently the perioperative administration of EMLA has demonstrated both acute and longterm analgesic efficacy following mastectomy surgery . This study evaluated the application of 5 g of EMLA or placebo on the sternal area 5 minutes before surgery, and 15 g on the supraclavicular area and axilla at the end of the operation. In addition, treatment with EMLA cream 20 g or placebo was applied daily for the first 4 days after surgery. This study revealed a significant reduction in postoperative analgesic requirements and the incidence and intensity of chronic pain with the application of EMLA. Although proven effective, the authors did not evaluate systemic levels of local anesthetic with this technique that may vary considerably following surgery and peripheral inflammation .
In an attempt to improve on the analgesic efficacy observed in this study , Fassoulaki evaluated the effect of utilizing multiple analgesics including gabapentin, local anesthetic infiltration, and EMLA cream on acute and chronic pain following breast cancer surgery . In this study, fifty patients were randomized to receive gabapentin 400 mg every 6 hours starting the evening before surgery and continued for the first eight postoperative days; EMLA cream 20 gm applied on the day of surgery and continued until the third postoperative day; and irrigation of the axillary brachial plexus and third, fourth, and fifth intercostal nerves with 19 mL ropivacaine 0.75%. In the control group, matching placebo capsules, placebo cream, and normal saline irrigation were utilized in a double-blind fashion. This study demonstrated a significant reduction in acute and chronic pain following surgery with this multimodal analgesic therapy. Patients in the treatment group reported lower pain scores and consumed fewer analgesics in the postoperative period. Three months after surgery, significantly more patients (18/22; 82%) in the treatment group versus (12/21; 57%) of patients in the control group developed chronic pain (p=0.028). Although at six months after surgery 10 of 22 (45%) and 6 of 30 (30%) developed chronic pain in the treatment versus control groups, this did not reach statistical significance
Venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI) that is devoid of either antihistaminergic, anticholinergic, or alpha-adrenergic effects  was shown to be effective in the management of PMPS . Further, the preemptive administration of venlafaxine was shown to be efficacious in mitigating hyperalgesia in the rat model of neuropathic pain . Reuben et al.  examined the efficacy of administering perioperative venlafaxine for acute and chronic pain following breast cancer surgery. In this study, venlafaxine 75 mg or placebo was administered for two weeks starting the night before surgery to 100 patients scheduled for either partial or radical mastectomy with axillary dissection. Patients were administered PCA morphine for the first 24 hours following surgery and then acetaminophen/oxycodone tablets. There were no differences between the two groups in postoperative pain scores or opioid use during the first week following surgery. At six months postoperatively, there was a significant decrease in the incidence of chronic pain including: chest wall pain (55% vs. 19%;P=0.0002), arm pain (45% vs. 17%;P=0.003) and axilla pain (51% vs. 19%;P=0.0009) between the control group and the venlafaxine group respectively. Unlike the previous studies that demonstrated a reduction in chronic pain following breast surgery, [81,84] this was the first study to demonstrate a reduction in chronic pain without a concomitant reduction in acute pain. This is surprising, since one of the predictive risk factors for the development of PMPS is unrelieved acute pain .
PREVENTING OTHER CHRONIC PAIN DISORDERS
Phantom limb pain (English)
Chronic donor site pain (English)
Postthoracotomy pain syndrome (English)
Part II: Algorithm for Perioperative Management of CRPS Patients
Part III: Highlights for Patients