Central pain in cancer patients

Central Pain in Cancer Patients Gilbert R. Gonzales,* Sara L. Tuttle,‡ Howard T. Thaler,† and Paolo L. Manfredi* Abstract: The prevalence of pain caused by injury to the central nervous system (CNS), or central pain (CP), in cancer patients is unknown. In order to define prevalence and characteristics of central pain in hospitalized patients with cancer, we performed a retrospective review of medical records of patients evaluated by 2 different services: the Pain Service and the Neurology Service, at Memorial Sloan-Kettering Cancer Center. The prevalence of CP in these patients was 4% and 2%, respectively. Primary and metastatic tumors and their therapy, including surgery, radiation and chemotherapy, were all potential causes of CP. The occurrence of CP in patients with primary CNS tumors was higher in patients with spinal cord tumors compared to patients with brain tumors (P < .0001). © 2003 by the American Pain Society Key words: Central pain, cancer, central nervous system, neuropathic.

C

entral pain (CP) is defined as pain due to disease of the central nervous system (CNS). This definition includes pathology in the spinal cord, brainstem, or cerebral hemispheres. Lesions in the peripheral nervous system (PNS) are known to produce CNS changes, but these are secondary CNS changes and are not categorized as CP syndromes.2,7 The most common causes of CNS injuries that result in CP include poststroke central pain, spinal cord trauma and multiple sclerosis.2 One of the earliest described CP syndromes, Dejerine-Roussy syndrome, is one of the least encountered clinically and it most often results from ischemic injury to the lateral thalamus.2 CP is idiosyncratic: patients with apparently identical lesions may or may not go on to develop CP.2,7,10 CP caused by cancer is known to exist through case reports alone. Cases of primary intra-axial CNS tumors causing CP include a study of thalamic tumors by Cheek and Taveras.4 Pagni and Canavero, and Gan and Choksey have reported CP from extra-axial tumors such as meningiomas.9,6 Delattre et al have reported CP caused by leptomeningeal disease.5 More than 15% of patients with systemic cancer have metastases to the brain or spinal cord.3 Although other authors have explored the prevalence of neuropathic pain in cancer patients, CP was not differentiated from other kinds of neuropathic pain.1 The purpose of this study was to obtain preliminary data on the prevalence and clinical characteristics of CP in cancer patients. Received November 14, 2002; Revised March 26, 2003; Accepted April 22, 2003. From the *Department of Neurology, Section of Pain and Palliative Care, and the †Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, and ‡Weil Medical College at Cornell, New York, NY. Address reprint requests to Paolo L. Manfredi, MD, Section of Pain and Palliative Care, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue Box 52, New York, NY 10021. E-mail: [email protected] © 2003 by the American Pain Society 1526-5900/2003 $30.00 ⫹ 0 doi:10.1016/S1526-5900(03)00639-4

Methods We retrospectively reviewed the hospital records of all inpatients seen for a pain consultation by 1 neurologist pain specialist (GRG) at Memorial Sloan-Kettering Cancer Center (MSKCC) and all admissions to the neurology inpatient floor seen by the neurology attendings at MSKCC between July 1, 1998 and June 30, 1999. All patients were stratified into noncancer patients or cancer patients according to histological diagnosis. Cancer and noncancer patients were further stratified into “central pain” and “no central pain.” Patients were categorized as “central pain” only if a definite diagnosis could be made based on history, physical examination and radiological studies. In order to be diagnosed with CP, patients had to have radiological documentation of a lesion within the CNS, pain in a distribution compatible with the CNS lesion, and no other lesions that could potentially cause pain in the same area. In the pain consultation group, when possible or definite CP was diagnosed, a detailed temperature examination of the affected area was also performed. Temperature examination included cold testing with ethyl chloride spray. Heat perception testing was not performed except in patients with possible CP without cold testing abnormalities. Heat perception testing was then performed with a thermal iron at 42° centigrade.8 The site of CNS injury responsible for the pain was categorized in the pain-consultation patients and in the neurology-admission patients as follows: spinal cord (intramedullary, extradural), leptomeningeal, brain (not thalamus or brainstem), brainstem and thalamus. In order to compare the prevalence of central pain between patients with brain or spinal cord lesions, we focused on the patients with primary CNS tumors from both groups, the Pain Service consultations and the Neurology Service admissions. We performed the Fisher exact test for each group, and a combined test after verifying whether the 2 groups had comparable odds ratios.

The Journal of Pain, Vol 4, No 6 (August), 2003: pp 351-354

351

352

Figure 1. Prevalence of central pain diagnosed in pain consultations and neurology admissions over 1 year.

Results Pain Service Consultations A total of 462 consultations in 396 individual patients were seen by 1 pain consultant (GRG) over 12 consecutive months (66 patients were seen more than once). Four patients did not have cancer and 4 patients did not have pain. Among 388 cancer patients with pain, we found 16 patients with CP (4%) (Fig 1). Thirteen of the 16 patients had CP caused by spinal cord lesions, only 3 had CP caused by a brain lesion, and none had brainstem or thalamic lesions. Table 1 shows a summary of demographic and clinical data for these 16 CP patients. Abnormalities in cold or heat perception, including cold allodynia and reduced perception of temperature, were found in all 16 patients diagnosed with CP. The following are examples of patients with cancer seen by the Pain Service who developed CP. Patient 16 (Table 1) was treated with radiation for epidural thoracic spinal cord compression 1 week after the onset of midthoracic back pain without neurological deficits. Five months later the patient developed right leg supersensitivity to touch and cold allodynia despite total resolution of the epidural thoracic spinal cord compression. Myelomalacia, thought to be secondary to radiation, was noted on MRI. Patient 6 (Table 1) had advanced right sided head and neck squamous cell carcinoma and developed a right parietal lobe infarct followed by left face, neck, shoulder and arm burning and loss of cold sensation. This patient’s infarct was due to right-sided internal carotid artery occlusion from tumor invasion and mass effect.

Neurology Service Admissions In the Neurology Service admissions group, there was a total of 800 admissions, with 600 individual patients admitted (Fig 1). Many patients were admitted several times during the 1-year study period. Eleven patients or 2% of patients with cancer admitted to the neurology ward had CP. Table 2 shows a summary of demographic and clinical data for these 11 CP patients. Abnormalities

Central Pain in Cancer Patients in temperature perception were not tested in these patients. The following are examples of patients with cancer admitted to the Neurology Service who developed CP. Patient 10 (Table 2) developed bilateral burning sensations in both legs 3 years after successful resection of a thoracic ependymoma. Patient 7 (Table 2) was admitted 5 times over the 12-month period of study and received radiation to the brain followed by 5 courses of methotrexate. This patient had a left thalamic mass consistent with primary CNS lymphoma with exacerbation of right hemibody pain, described as deep burning, immediately following each of his intravenous methotrexate treatments.

Pain Service Consultations and Neurology Service Admissions With Primary CNS Tumors Among Pain Service consultations, none of the 5 patients with primary brain tumors had central pain, whereas all 4 patients with primary spinal cord tumors had central pain (Fisher exact test: P ⫽ .008). Among Neurology admissions, 3 of the 308 (1%) patients with brain tumor had central pain while 6 of 23 (26%) patients with spinal cord tumor had central pain (Fisher exact test: P ⬍ .0001). These results were compatible with a common odds ratio for the 2 sources of patients, and the positive association between central pain and spinal cord tumors for the combined sample was significant at P ⬍ .0001.

Discussion A relatively high number of general oncology patients seen in consultation by the Pain Service at MSKCC were found to have CP (4%). Among the cancer patients admitted to the neurology ward, 2% had CP. When the Pain Service consultations and Neurology Service admission with CP and cancer were combined, 27 patients had cancer or cancer-treatment–related CP. It is important to underscore that the prevalence of central pain seen in our patients may not be representative of the true prevalence of central pain in hospitalized patients with cancer because our patients were selected by their referral to the pain service or admission to the neurology ward. Except for the brainstem, nearly all levels of the CNS were involved in causing CP. Seventeen patients had thoracic spinal cord injury, 2 had cervical spinal cord injury, 2 had leptomeningeal injury, 3 had thalamic injury and 3 had parietal (2 left and 1 right) injury. In this study, spinal cord lesions were by far more likely to cause CP compared to brain and brainstem lesions. If the 2 leptomeningeal CP patients were included in the spinal cord CP patients, a total of 21 of 27 patients, or 77.77% of CP patients with cancer had a spinal cord site of injury (70.37% if leptomeningeal disease was not included). In addition, we were able to show that primary spinal cord tumors are more likely to cause pain than primary brain tumors (P ⬍ .0001), as is the case in patients with noncancer causes of CP.7

PATIENT

Pain Service Patients With Central Pain AGE

M/F

1 2

69 43

F F

3

66

M

4

56

F

5

43

F

6

71

M

7

32

M

8 9

52 68

M M

10

50

M

11 12 13

73 66 47

F F F

14

40

F

15

27

F

16

56

M

TREATMENT FOR PAIN Steroids, opioids, gabapentin, XRT Phenytoin, opioids, gabapentin, topical anesthetic Opioids, acetaminophen, gabapentin, lizanadine Gabapentin, carbamazepine, opioids, acetaminophen Opioids, acetaminophen, gabapentin TENS, sumatriptan, steroids, gabapentin, opioids, lidocaine, trazodone XRT, steroids, surgery, imipramine, opioids, tamoxifen, methotrimeprazine XRT, surgery, steroids, gabapentin, opioids Baclofen, gabapentin, opioids, acetaminophen, spinal cord shunt, XRT Gabapentin, opioids, acetaminophen, steroids, XRT, surgery Steroids, XRT Steroids, pamidronate, opioids Opioids, acetaminophen, haloperidol, lorazepam XRT, intrathecal chemotherapy, opioids, gabapentin XRT, intrathecal chemotherapy, steroids, gabapentin, phenytoin, morphine XRT, steroids, opioids

DURATION OF PAIN

PAINFUL SIDE

TIME OF CP ONSET

TUMOR TYPE

LESION

Merkel’s carcinoms Breast

Epidural T3-4 Parietal, left

5 months 10 days

Chest Right hemibody

Same day 10 days

Male breast

Epidural T10

1 month

Left leg

Same day

Breast

Parietal left

15 months

Right vulva vagina, rectum

2 years

Spinal cord ependimoma Laryngeal carcinoma

Intramedullary

10 years

Left leg

6 years

Parietal, right

3 months

Left face, neck, arm

2 months

Spinal cord glioblastoma

Intramedullary T10

7 months

Right leg

Same day

Neuro-ectodermal Melanocytoma, syrinx

Intramedullary T6 Intramedullary T10

1 month 2 years

Below T8 Both legs

1 month 1 year

Lung

Epidural T12

1 week

Right thigh

2 weeks

Cervix Carcinoid Pancreas ca

Epidural C4 Epidural T3-T4 Epidural T5,6

1 week 10 months 4 months

Thoracie bilateral Right leg Right leg

2 weeks 2 months 2 months

Breast ca

Epidural T11

same day

Left leg

5 days later

Melanoma

Leptom, conus

1 month

Back, butlocks, legs

1 month

Prostate ca

Epidural T8,9

1 week

Right leg

5 months

ORIGINAL REPORT/Gonzales et al

Table 1.

Abbreviation: TENS, transcutaneous electrical nerve stimulation; XRT, radiation treatment.

353

354 Table 2.

Central Pain in Cancer Patients

Neurology Admissions with Central Pain

PATIENT AGE M/F

TUMOR TYPE

LESION

1 2 3

50 38 32

F F M

Breast Ca Leptomeningeal Spinal cord ependymoma Cervical cord C3-4 Oligodendroglioma thalamus Right thalamus

4

68

M

Spinal cord melanocytoma

5

45

F

Ependymoma spinal cord

6 7 8 9 10 11

72 52 26 33 36 32

F M M M F M

Astrocytoma, spinal cord Lymphoma left thalamus Anaplastic astrocytoma Germ cell ca Ependymoma cord Ependymoma spinal cord

TREATMENT FOR PAIN

XRT, steroids, opioids, chemotherapy surgery, steroids, opioids, acetaminophen surgery, XRT, steroids, opioids, gabapentin, amitriptyline, acetazolamide Thoracic cord T10 gabapentin, opioids, acetaminophen, nortriptyline, clonazepam, XRT Thoracic cord T10 TENS, paraspinal nerve block, desipramine, opioids, surgery XRT, naproxen Astracytoma, entire cord acetaminophen Left thalamus chemotherapy Bilateral thalamic XRT, surgery, steroids Spinal cord infarct T7-T12 diazepam, morphine, amitriptyline, trazodone Thoracic cord T6 opioids, intrathecal opioids, gabapentin, amitriptyline Thoracic cord T5 XRT, steroids, opioids, intrathecal opioids, imipramine

Abbreviation: XRT, radiation therapy; TENS, transcutaneous electrical nerve stimulation.

Central pain may be delayed by days to years after CNS injury.8 In one of our cancer patients, CP was found to be delayed up to 6 years after the diagnosis and treatment of the spinal cord tumor. This is much longer than the delay usually seen in nonmalignant causes of spinal cord CP. The treatment strategies in our patients included antitumor therapies such as radiation, chemotherapy, surgical resection and steroids to decrease edema (Tables 1 and 2). Aside from addressing the treatment of the tumor, the treatment of CP was approached as with nonmalignant CP7 and included antidepressants, anticonvulsants, opioids, clonidine, baclofen, acetaminophen, and NSAIDs (Tables 1 and 2). In this retrospective chart review, central pain was diagnosed more frequently in pain-consultation patients compared to neurology-admission patients. Pain-consultation

patients may be more likely to have CP compared to neurology-admission patients; however, the diagnosis in some of the neurology patients may have been missed because of a lack of a careful temperature perception examination. The finding of altered temperature sensation was seen in all the CP patients examined by the pain specialist, as expected from the experience with nonmalignant causes of CP.7 Temperature testing, sometimes critical in making the diagnosis of CP, was not documented in patients on the Neurology Service. Special attention to thermal testing may be required to recognize that CNS injury by cancer or its treatment has lead to a CP syndrome. In summary, cancer and its treatment may result in CP. Cancer patients with spinal cord lesions are at higher risk for developing CP compared to patients with lesions at other levels of the CNS.

References

6. Gan YC, Choksey MS: Parafalcine meningioma presenting with facial pain: evidence for cortical theory or pain? Br J Neurosurg 15:350-352, 2001

1. Caraceni A, Portenoy RK: An international survey of cancer pain characteristics and syndromes. Pain 82:263-274, 1999 2. Casey KL: Pain and central nervous system disease: a summary and overview. in: Casey KL (ed): Pain and Central Nervous System Disease: The Central Pain Syndromes. New York, NY Raven Press, 1991, pp 1-11 3. Clouston PD, DeAngelis LM, Posner J: The spectrum of neurological disease in patients with systemic cancer. Ann Neurol 31:268-273, 1992 4. Cheek WR, Taveras JM: Thalamic tumors. J Neurosurg 24: 505-513, 1966 5. Delattre JY, Walker RW, Rosenblum MK: Leptomeningeal gliomatosis with spinal cord or cauda equina compression: a completion of supratentorial gliomas in adults. Aeta Neurol Scand 79:133-139, 1989

7. Gonzales GR, Casey KL: Central pain syndromes. in: Rice ADS, Washeld CA, Justins D, Eccleston C (eds): Clinical Pain Management Chronic Pain. London, Arnold Press, 2003, pp 403-416 8. Gonzales GR: Central pain: diagnosis and treatment strategies. Neurology 45(suppl 9):S11-S16, 1995 9. Pagni CA, Canavero S: Paroxysmal perineal pain resembling tic doubureux, only symptom of a dorsal meningioma. Ital J Neurol Sci 14:323-324, 1993 10. Tasker RR, DeCorvalho G, Dostrovosky JO: The history of central pain syndromes, withobservations concerning pathophysiology and treatment. in: Casey KL (ed): Pain and central nervous system disease: The central pain syndromes. New York, NY, Raven Press, 1991, pp 31-58