Surgery

(i) Post surgical pain syndromes are now recognized as a distinct clinical entity with an overall incidence of 1-2%.32 In addition to the syndromes mentioned in this chapter, these include syndromes of post-Coronary Artery Bypass Graft pain, post-sternotomy pain,33 and post-herniorrhaphy pain.34 During surgery, nociceptive stimulation leads to a barrage of C fiber impulses that activate spinal cord receptors and result in the development of central sensitization and a clinical hyperalgesic state.35

There have been few randomized clinical trials in this area. In the largest such trial to date, 99 patients with neuropathic pain resulting from mastectomy, thoraco-tomy or nephrectomy, were randomized to capsaicin (0.075%) for 8 weeks followed by placebo, or placebo followed by capsaicin. The study cream was placed over the painful area. The patients who started with capsaicin had more skin burning but subsequently reported pain reduction of 53% compared to 17% in patients who did

not get capsaicin.

(ii) Phantom pain is defined as pain referred to a surgically removed limb or a portion thereof.37 Traditionally associated with limbs, phantom pain has been reported for resected internal organs such as the stomach, rectum, uterus, and bladder.38 Phantom pain should be differentiated from stump pain and phantom sensations. Phantom pain sensations may vary considerably over time.39 Worsening phantom limb pain after a period of stable pain should raise suspicion for a new malignancy.40-42

Data are limited on the appropriate management of patients with phantom pain. A large variety of treatments have been studied in small number of patients with few findings.43 The goal of treatment is to control both the peripheral painful stimulus and the cortical reorganization which accompany phantom pain. There has been much interest in nonmedical approaches such as transcutaneous electrical nerve stimulation (TENS), hypnosis and acupuncture with limited data. Regarding medical treatments, small randomized clinical trials have found analgesic effects for morphine 70 mg to 200 mg orally,44 and gabapentin for up to 2400 mg daily at 6 weeks.45 A small crossover trial found that dextromethorphan 60 or 90 mg orally twice a day decreased pain intensity by greater than 50%.46 Ketamine boluses increased pressure pain thresholds and reduced wind up pain.47 Mirrors can induce analgesia.48 A randomized trial of amitriptyline up to 125 mg daily did not show any effect.49 Currently, patients with phantom pain should be approached in the same way as other patients with neuropathic pain syndromes until a better evidence base is developed.50,51

6.2. Radiation Therapy

(i) Brachial plexopathy: This condition has been seen more frequently in patients with breast cancer, and some patients with lung cancer and Hodgkin's lymphoma.

Risk factors for plexopathy in breast cancer patients include larger doses of radiation, radiation technique, and administration of chemotherapy. A key feature is delayed onset. Most patients present at a median of 1.5 years after treatment. In one larger study of 150 patients, long-term effects and onset of symptoms could present at 30 years after radiation.52 In another study of women who had received radiation to the supraclavicular lymph nodes, median time to onset of brachial plexopathy was 88 months and the incidence did not decrease over time.53 As radiation delivery becomes more precise, the incidence of this complication should decrease in the future.

Patients' complain of causalgia and weakness in the arm and shoulder, followed by chronic pain and progressive weakness. Milder forms may resolve spontaneously, but for many patients, pain is chronic and severe, and may be accompanied by motor deficits. The finding of myokymia on EMG studies may help in making a diagnosis of radiation induced brachial plexopathy. The syndrome may be difficult to distinguish from recurrent tumor or radiation induced malignancy even with MRI imaging. Published experience with PET scans is limited.54

Data on treatment are sparse. In one series of 33 patients, morphine was effective and given long term for 17 patients, and 3 patients improved with chemical sympathectomy.55 Surgical interventions have generally not been successful,56 although there have been successful case reports of neurolysis and Dorsal Root Entry Zone lesions in patients.57,58 A randomized trial of hyperbaric oxygen versus placebo did not show any difference.59 Nonpharmacological methods, such as occupational therapy, can be helpful for patients.60

(ii) Radiation lumbosacral plexopathy: Lumbosacral plexopathy has been reported in patients who received radiation for prostate or gynecological cancer, and is thought to occur rarely. In a retrospective study, the median time to onset of symptoms was 5 years, with a range of 1 to 30 years. The differential diagnosis is recurrence of cancer. Patients with radiation lumbosacral plexopathy may present with bilateral weakness followed by mild to moderate pain whereas patients with tumor recurrence may present first with unilateral, often severe pain followed by weakness.6162 No specific treatments have been reported for this syndrome.

(iii) Pain with movement in patients with fibrosis: In a review of 152 patients with limb sarcoma who had received limb sparing surgery followed by radiation therapy at the National Cancer Institute from 1975 to 1986, with a mean follow-up of 7 years, pain requiring opioids was reported by 10 patients (7%), and was associated with a high Nominal Standard Dose, as was edema, decreased range of motion, decreased manual muscle strength, and skin telangiectasia.63

(iv) Pelvic pain: Pelvic insufficiency fracture of the sacrum or pubis can occur in women who have received radiation therapy for pelvic malignancies with an actuarial incidence over 5 years estimated at 2.1%.64 This syndrome presents as new pain in the sacroiliac joints and pubis in a previously radiated field, and may be mistaken for metastases. CT scan shows fractures65 and further workup is not indicated. The pain usually responds to NSAIDs. While it is most well described in patients with gynecological malignancies, this syndrome has also been reported in patients with other indications for pelvic radiation, such as prostate cancer and rectal cancer.

6.3. Chemotherapy

Long-term studies have suggested that survivors who received chemotherapy as adjuvant therapy have decreased physical functioning compared to survivors who received other forms of local therapy. Interaction between treatment and diagnosis was found for aches and pains in one study of breast and lymphoma survivors, and lymphoma patients who received chemotherapy had the lowest quality of life. The authors speculated that enduring side effects of chemotherapy could affect physical aspects of quality of life.66 In another study of breast cancer survivors, past chemotherapy was associated with poorer quality of life.67 Chemotherapy-related pain could be an explanatory variable.

Chemotherapy-related peripheral neuropathy has been reported for a number of chemotherapy agents, including vinca alkaloids68 (lymphoma and Acute lymphocytic leukemia patients), paclitaxel,69 docetaxel70 (ovarian cancer, lung cancer, breast cancer), cis-platin (germ cell tumor, lung cancer, ovarian cancer, head and neck cancer, colon cancer, lymphoma), oxaliplatin71 (gastrointestinal malignancy), thalidomide72 (hematological malignancy, GVHD), and bortezomib (multiple myeloma, myelodysplastic syndromes).

Multiple studies have been performed to study preventive measures. There are no specific recommendations for management of chemotherapy-related neuropathy.73,74

6.4. Hormonal Therapy

Patients with prostate and breast cancer are at increased risk for osteoporosis-associated fracture because of hormonal and other forms of cancer therapy.75 In recent reports, prostate cancer patients have a 19% incidence of fracture after androgen deprivation, compared to 12% in patients who did not receive androgen deprivation.76 In another large study, the relative risk of hip fracture for men who underwent orchiectomy was 2.11 (95% CI: 1.97-2.36), with the increase seen after orchiectomy and persisting for at least 15 years.77 These findings are higher than earlier findings of a 9% fracture incidence in patients treated with LHRH agonists.78

Data from the Women's Health Initiative Observational Study show that the marrow density in breast cancer survivors is decreased compared to age-matched controls because of decreased use of hormonal therapy, but the rate of bone loss and of underdiagnosis is similar for both survivors and controls.79 Patients with a diagnosis before the age of 55 are at increased risk for fracture (Hazard ratio 1.78, 95% CI: 1.28-2.46), and the overall risk of fracture for all survivors is 1.15(95% CI: 1.05-1.25).80

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