Pain is common among patients with head and neck cancer (HNC). However, there are very limited data on chronic pain among HNC patients treated with radiation therapy (XRT). In this retrospective study, we focused on the characteristics of chronic post-XRT pain in such patients. Post-XRT pain is common among HNC patients; however, we found discrepancy between frequency of treatment and frequency of chronic pain, suggesting poor documentation of pain in the medical records. Among patients who reported to have chronic post-XRT pain, most of them described having severe pain and used descriptors of neuropathic pain. Pharynx was the commonest site of cancer as well as the commonest site of cancer-related chronic pain; squamous cell carcinoma was the most frequent histological pattern, and opioids were used most often to treat such chronic pain. There was a significant association between chronic pain and number of sites of pain, and chronic pain was also associated with use of opioids.
Pain is common among patients with head and neck cancer (HNC) prior to treatment and may be attributed to the cancer and/or cancer treatment. Pain in HNC patients could be due to tissue damage from several mechanisms such as mucosal injury, nerve compression, and invasion of the tumor into adjacent tissue structures with inflammation or ischemia [
HNC can take up to 3 months to disappear histologically after completion of treatment, thus indicating remission of disease [
Oral mucositis is a common cause of acute pain in HNC patients, and it typically lasts for 2–4 weeks after the end of radiation therapy (XRT) [
This retrospective study was conducted at Southern Illinois University (SIU) School of Medicine and Memorial Medical Center, Springfield, IL. All head and neck cancer patients aged 18 years and above, treated with radiotherapy from February 2011 to February 2016, were included in the study. Head and neck cancer patients treated only with chemotherapy were excluded. The chart review identified a total of 53 patients, who met the inclusion criteria. Demographic features such as age at diagnosis, gender and race, clinicopathologic features (location, histology, and staging of the cancer), cancer therapy (surgery and chemotherapy) and details pertinent to XRT (such as dose, duration, and area involved) were collected. In terms of location, data pertaining to upper aerodigestive tract sites (oral cavity, pharynx, larynx, nasal cavity, and paranasal sinuses) as well as salivary glands were collected. We focused on cancers of the oral cavity, pharynx, and larynx in this study because of their similarities in epidemiology, treatment, and prognosis; cancers of the lip, salivary gland, nose, paranasal sinuses, middle ear, nerves and bones, thyroid, nonmelanoma skin cancers, lymphoma, and sarcomas were excluded.
Data were also collected regarding the characteristics of pain: location, onset, frequency, severity, nature of pain, and information regarding use of medications including opioids, gabapentin, TCAs, and NSAIDs. Data regarding characteristics of pain up to 3 months after completion of XRT were categorized as “data related to acute pain,” and subsequent data (after 3 months of completion of XRT) were considered as “data related to chronic pain.” Pain was documented as mild, moderate, or severe based on the documentation in the charts. If pain severity was documented numerically, it was converted into mild (documented as 1–3 in the charts), moderate [
Data were analyzed with the use of SAS software, version 9.4, and Zotero bibliography software was used for citing references. Descriptive statistics were computed for all study variables. Continuous variables are described with measures of central tendency (mean and median) and dispersion (range and standard deviation). Categorical variables are summarized as frequencies and percentages. Given smaller cell sizes, the following adaptations were made during statistical analyses: cancer stages were grouped into “stage 1 or 2” and “stage 3 or 4”; data for mild, moderate, and severe pain were combined into one group, and number of sites of pain were grouped into three categories such as “pain at 0 site,” “pain at 1 site,” and “pain at 2 + sites.” Statistical analysis was not performed for use of TCA’s given smaller sample size. Fisher’s exact tests were used to compare categorical variables. Independent
Demographic and clinicopathologic factors are described in Tables
Demographic and clinicopathologic factors (categorical variables) (frequency and percentage of demographic factors including age, gender, and race and clinicopathologic factors such as histology, cancer staging, severity of pain, and cancer treatment).
Variable |
|
% | |
---|---|---|---|
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Gender | Female | 14 | 26.4 |
Male | 39 | 73.6 | |
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Race | White | 46 | 86.8 |
AA | 5 | 9.4 | |
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Histology | Squamous | 47 | 88.7 |
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Staging | 1 | 4 | 7.6 |
2 | 4 | 7.6 | |
3 | 5 | 9.4 | |
4 | 21 | 39.6 | |
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Surgery | No | 32 | 60.4 |
Yes | 21 | 39.6 | |
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Chemo | No | 21 | 39.6 |
Yes | 32 | 60.4 | |
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Severity of chronic pain | No pain | 35 | 66.0 |
Mild | 1 | 1.9 | |
Moderate | 4 | 7.5 | |
Severe | 13 | 24.5 | |
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Use of opioids | No | 20 | 37.7 |
Yes | 33 | 62.3 | |
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Use of gabapentin | No | 45 | 84.9 |
Yes | 8 | 15.1 | |
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Use of TCAs for chronic pain | No | 47 | 88.7 |
Yes | 6 | 11.3 | |
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Use of NSAIDs | No | 39 | 73.6 |
Yes | 14 | 26.4 |
Demographic and clinicopathologic factors (continuous variables).
Variable |
|
Mean | Std. error | Median | Std. dev. | Min. | Max. |
---|---|---|---|---|---|---|---|
Age at diagnosis | 53 | 61.23 | 1.73 | 59.00 | 12.62 | 40.00 | 91.00 |
XRT dose | 53 | 6063.34 | 201.30 | 6600.00 | 1465.47 | 600.00 | 7000.00 |
XRT duration | 53 | 43.04 | 1.77 | 45.00 | 12.85 | 4.00 | 75.00 |
Number of sites of pain | 53.00 | 1.21 | 0.19 | 1.00 | 1.38 | 0.00 | 6.00 |
A total of 41 patients (77.4%) reported any kind of treatment for chronic pain, whereas only 32 patients (60.38%) reported any kind of chronic pain, suggesting poor documentation of pain characteristics in the charts. There was insufficient description of nature of pain; among the patients who reported any kind of chronic pain (
Pharynx (Table
Site of cancer: frequency and percentage of prevalence of cancer by site and subsites and association between site of cancer and use of medications
Site of cancer | Total | Use of opioids | Use of NSAIDs | Use of gabapentin | |||||
---|---|---|---|---|---|---|---|---|---|
|
% | % yes |
|
% yes |
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% yes |
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|
No | 47 | 88.7 | 61.7 | 1 | 25.5 | 0.649 | 12.8 | 0.219 |
Yes | 6 | 11.3 | 66.7 | 33.3 | 33.3 | ||||
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1A. Lip | No | 53 | 100 | 62.3 | — | 26.4 | — | 15.1 | — |
Yes | 0 | 0 | |||||||
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1B. Buccal mucosa | No | 53 | 100 | 62.3 | — | 26.4 | — | 15.1 | — |
Yes | 0 | 0 | |||||||
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1C. Alveolar ridge, retromolar trigone | No | 50 | 94.3 | 62.0 | 1 | 24.0 | 0.167 | 16.0 | 1 |
Yes | 3 | 5.7 | 66.7 | 66.7 | 0.0 | ||||
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1D. Floor of mouth | No | 50 | 94.3 | 60.0 | 0.282 | 26.0 | 1 | 12.0 | 0.056 |
Yes | 3 | 5.7 | 100.0 | 33.3 | 66.7 | ||||
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1E. Hard palate | No | 52 | 98.1 | 63.5 | 0.377 | 26.9 | 1 | 15.4 | 1 |
Yes | 1 | 1.9 | 0.0 | 0.0 | 0.0 | ||||
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1F. Oral tongue | No | 51 | 96.2 | 60.8 | 0.521 | 25.5 | 0.462 | 15.7 | 1 |
Yes | 2 | 3.8 | 100.0 | 50.0 | 0.0 | ||||
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No | 32 | 60.4 | 62.5 | 1 | 31.3 | 0.362 | 25.0 |
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Yes | 21 | 39.6 | 61.9 | 19.0 | 0.0 | ||||
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2A. Nasopharynx | No | 52 | 98.1 | 63.5 | 0.377 | 26.9 | 1 | 15.4 | 1 |
Yes | 1 | 1.9 | 0.0 | 0.0 | 0.0 | ||||
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No | 35 | 66 | 60.0 | 0.768 | 25.7 | 1 | 22.9 |
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Yes | 18 | 34 | 66.7 | 27.8 | 0.0 | ||||
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No | 44 | 83 | 63.6 | 0.715 | 27.3 | 1 | 18.2 | 0.324 |
Yes | 9 | 17 | 55.6 | 22.2 | 0.0 | ||||
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2D. Soft palate | No | 49 | 92.5 | 63.3 | 0.627 | 28.6 | 0.563 | 16.3 | 1 |
Yes | 4 | 7.5 | 50.0 | 0.0 | 0.0 | ||||
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No | 43 | 81.1 | 58.1 | 0.286 | 25.6 | 1 | 18.6 | 0.327 |
Yes | 10 | 18.9 | 80.0 | 30.0 | 0.0 | ||||
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No | 46 | 86.8 | 65.2 | 0.405 | 30.4 | 0.17 | 17.4 | 0.577 |
Yes | 7 | 13.2 | 42.9 | 0.0 | 0.0 | ||||
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No | 36 | 67.9 | 55.6 | 0.225 | 19.4 | 0.109 | 5.6 |
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Yes | 17 | 32.1 | 76.5 | 41.2 | 35.3 | ||||
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No | 44 | 83 | 56.8 | 0.129 | 27.3 | 1 | 9.1 |
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Yes | 9 | 17 | 88.9 | 22.2 | 44.4 | ||||
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No | 46 | 86.8 | 60.9 | 0.697 | 21.7 | 0.07 | 13.0 | 0.283 |
Yes | 7 | 13.2 | 71.4 | 57.1 | 28.6 | ||||
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3C. Subglottis | No | 50 | 94.3 | 60.0 | 0.282 | 26.0 | 1 | 14.0 | 0.394 |
Yes | 3 | 5.7 | 100.0 | 33.3 | 33.3 | ||||
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4. Nasal cavity | No | 50 | 94.3 | 62.0 | 1 | 28.0 | 0.557 | 16.0 | 1 |
Yes | 3 | 5.7 | 66.7 | 0.0 | 0.0 | ||||
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5. Paranasal sinuses | No | 53 | 100 | 62.3 | — | 26.4 | — | 15.1 | — |
Yes | 0 | 0 | |||||||
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6. Others | No | 50 | 94.3 | 64.0 | 0.549 | 28.0 | 0.557 | 16.0 | 1 |
Yes | 3 | 5.7 | 33.3 | 0.0 | 0.0 | ||||
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7. Salivary gland | No | 50 | 94.3 | 66.0 | 0.049 | 26.0 | 1 | 16.0 | 1 |
Yes | 3 | 5.7 | 0.0 | 33.3 | 0.0 |
Pharynx (26.4%) was the commonest site of cancer-related chronic pain, followed by oral cavity (24.5%) (Table
Various sites of pain among HNC patients and association between site of pain and use of medications
Site of pain | Total | Use of opioids | Use of NSAIDs | Use of gabapentin | |||||
---|---|---|---|---|---|---|---|---|---|
|
% | % yes |
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% yes |
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% yes |
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No | 40 | 75.5 | 55.0 | 0.098 | 27.5 | 1 | 15.0 | 1 |
Yes | 13 | 24.5 | 84.6 | 23.1 | 15.4 | ||||
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No | 39 | 73.6 | 56.4 | 0.203 | 28.2 | 0.735 | 17.9 | 0.665 |
Yes | 14 | 26.4 | 78.6 | 21.4 | 7.1 | ||||
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3. Eyes | No | 52 | 98.1 | 61.5 | 1 | 26.9 | 1 | 15.4 | 1 |
Yes | 1 | 1.9 | 100.0 | 0.0 | 0.0 | ||||
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4. Nasal cavity, paranasal sinuses | No | 52 | 98.1 | 61.5 | 1 | 26.9 | 1 | 15.4 | 1 |
Yes | 1 | 1.9 | 100.0 | 0.0 | 0.0 | ||||
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No | 44 | 83 | 59.1 | 0.456 | 25.0 | 0.684 | 13.6 | 0.611 |
Yes | 9 | 17 | 77.8 | 33.3 | 22.2 | ||||
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6. Headache | No | 50 | 94.3 | 60.0 | 0.282 | 24.0 | 0.167 | 14.0 | 0.394 |
Yes | 3 | 5.7 | 100.0 | 66.7 | 33.3 | ||||
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No | 48 | 90.6 | 58.3 | 0.144 | 27.1 | 1 | 14.6 | 0.574 |
Yes | 5 | 9.4 | 100.0 | 20.0 | 20.0 | ||||
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No | 45 | 84.9 | 57.8 | 0.234 | 24.4 | 0.422 | 13.3 | 0.59 |
Yes | 8 | 15.1 | 87.5 | 37.5 | 25.0 | ||||
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No | 45 | 84.9 | 60.0 | 0.695 | 22.2 | 0.186 | 8.9 |
|
Yes | 8 | 15.1 | 75.0 | 50.0 | 50.0 |
There was a significant association between chronic pain and number of pain sites (
Characteristics of chronic pain.
Chronic pain | Fisher’s | ||||||
---|---|---|---|---|---|---|---|
Variable | No | Yes | Total | % no | % yes |
| |
Gender | Female | 10 | 4 | 14 | 71.4 | 28.6 | 0.748 |
Male | 25 | 14 | 39 | 64.1 | 35.9 | ||
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Staging | Stage 1 or 2 | 4 | 4 | 8 | 50.0 | 50.0 | 0.679 |
Stage 3 or 4 | 17 | 9 | 26 | 65.4 | 34.6 | ||
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Surgery | No | 22 | 10 | 32 | 68.8 | 31.3 | 0.768 |
Yes | 13 | 8 | 24 | 54.2 | 33.3 | ||
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Chemo | No | 16 | 5 | 21 | 76.2 | 23.8 | 0.247 |
Yes | 19 | 13 | 32 | 59.4 | 40.6 | ||
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Opioids | No | 18 | 2 | 20 | 90.0 | 10.0 |
|
Yes | 17 | 16 | 33 | 51.5 | 48.5 | ||
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Gabapentin | No | 33 | 12 | 45 | 73.3 | 26.7 | 0.014 |
Yes | 2 | 6 | 8 | 25.0 | 75.0 | ||
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TCA | No | 32 | 15 | 47 | 68.1 | 31.9 | 0.397 |
Yes | 3 | 3 | 6 | 50.0 | 50.0 | ||
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NSAID | No | 28 | 11 | 39 | 71.8 | 28.2 | 0.191 |
Yes | 7 | 7 | 14 | 50.0 | 50.0 | ||
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Number of sites of pain | 0 | 20 | 1 | 21 | 95.2 | 4.8 |
|
1 | 11 | 4 | 15 | 73.3 | 26.7 | ||
2+ | 4 | 13 | 17 | 23.5 | 76.5 | ||
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Variable | Chronic pain | N | Mean | Std. dev. | Std. error |
|
|
Age | Pain = no | 35 | 62.23 | 13.831 | 2.338 | 0.425 | |
Pain = yes | 18 | 59.28 | 9.916 | 2.337 | |||
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Dose | Pain = no | 35 | 5854 | 1562.68 | 264.14 | 0.149 | |
Pain = yes | 18 | 6470 | 1191.5 | 280.84 | |||
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Duration | Pain = no | 35 | 42.37 | 14.534 | 2.457 | 0.604 | |
Pain = yes | 18 | 44.33 | 8.957 | 2.111 |
Surgery and medications.
Surgery | No | Yes | Total | Fisher’s |
---|---|---|---|---|
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No | 14 | 18 | 32 | 0.3859 |
Yes | 6 | 15 | 21 | |
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No | 29 | 3 | 32 | 0.2403 |
Yes | 16 | 5 | 21 | |
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No | 28 | 4 | 32 | 1 |
Yes | 19 | 2 | 21 | |
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No | 23 | 9 | 32 | 1 |
Yes | 16 | 5 | 21 |
Chemotherapy and medications.
Chemo | No | Yes | Total | Fisher’s |
---|---|---|---|---|
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No | 9 | 12 | 21 | 0.5733 |
Yes | 11 | 21 | 32 | |
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No | 16 | 5 | 21 | 0.2403 |
Yes | 29 | 3 | 32 | |
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No | 18 | 3 | 21 | 0.6711 |
Yes | 29 | 3 | 32 | |
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No | 13 | 8 | 21 | 0.2017 |
Yes | 26 | 6 | 32 |
XRT dose and medications.
|
Mean | Std. dev. | Std. error |
|
Test | ||
---|---|---|---|---|---|---|---|
Opioids | No | 20 | 5398.00 | 1910.38 | 427.17 | 0.05 | Mann–Whitney |
Yes | 33 | 6466.58 | 937.33 | 163.17 | |||
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Gabapentin | No | 45 | 5981.80 | 1561.94 | 232.84 | 0.342 |
|
Yes | 8 | 6522.00 | 579.23 | 204.79 | |||
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TCA | No | 47 | 6101.21 | 1422.24 | 207.45 | 0.603 |
|
Yes | 6 | 5766.67 | 1899.12 | 775.31 | |||
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NSAID | No | 39 | 5922.69 | 1618.93 | 259.24 | 0.247 |
|
Yes | 14 | 6455.14 | 839.43 | 224.35 |
XRT duration and medications.
|
Mean | Std. dev. | Std. error |
|
Test | ||
---|---|---|---|---|---|---|---|
Opioids | No | 20 | 38.20 | 16.13 | 3.61 | 0.277 | Mann–Whitney |
Yes | 33 | 45.97 | 9.51 | 1.66 | |||
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Gabapentin | No | 45 | 41.89 | 13.36 | 1.99 | 0.124 |
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Yes | 8 | 49.50 | 6.97 | 2.46 | |||
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TCA | No | 47 | 42.81 | 11.92 | 1.74 | 0.72 |
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Yes | 6 | 44.83 | 20.19 | 8.24 | |||
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NSAID | No | 39 | 42.56 | 13.42 | 2.15 | 0.659 |
|
Yes | 14 | 44.36 | 11.47 | 3.07 |
Pain is common among HNC patients and can be nociceptive, inflammatory, or neuropathic in nature. Nociceptive pain refers to the response to noxious stimuli and continues in the maintained presence of noxious stimuli [
Pain is common among patients with HNC; acute post-XRT pain typically lasts for less than 3 months whereas chronic pain lasts for more than 3 months. Based on our clinical experience in managing post-XRT patients with HNC, we observed that chronic pain is commonly encountered; however, there are very limited data in the literature on the characteristics of chronic pain among HNC patients treated with XRT. Kuo and Williams listed 14 studies investigating pain in HNC patients, in which 3 studies reported persistence of pain up to 6–24 months, and prevalence of pain varied from 15% to 46% [
We found discrepancy between frequency of treatment and frequency of chronic pain suggesting poor documentation of pain in the medical records, and less than 4 individuals reported onset (
Mean age at diagnosis in our group was 61.23 years [
Among 53 patients in our study, pharynx was the most common site (39.6%), followed by larynx (32.1%), and among subsites of larynx, supraglottic carcinoma (17%) was the most common site that is consistent with the previous literature [
Site of chronic pain was also associated with use of medications; chronic neck pain was associated with higher use of gabapentin. HNC patients treated with XRT are found to have neuropathic pain [
There was a significant association between chronic pain and number of pain sites, and individuals with chronic pain were more likely to be treated with opioids. Murphy et al. found increased pain in HNC population to be associated with increased use of opioids [
Higher doses of XRT are known to have a positive correlation with chronic pain among HNC patients, possibly related to radiation-induced fibroatrophic processes [
In our study group, surgery was not associated with chronic pain or use of pain medications (Table
Limitations of our study include the fact that it is a retrospective single center study. Comorbid chronic medical conditions were also not adjusted during the statistical analysis. The overall sample size in our study is small, and particularly, very small cell sizes (
In summary, post-XRT pain among HNC patients is common not only during the acute period but also in the chronic period lasting well beyond three months after completion of XRT. We found discrepancy between frequency of treatment and frequency of chronic pain, suggesting poor documentation of pain in the medical records. Among patients who reported having chronic post-XRT pain, most of them described having severe pain and used descriptors of neuropathic pain. Pharynx was the commonest site of cancer as well as the commonest site of cancer-related chronic pain; squamous cell carcinoma was the most frequent histological pattern, and opioids were used most often to treat such chronic pain. There was a significant association between chronic pain and number of pain sites, and chronic pain was associated with use of opioids. Surgery was not associated with chronic pain or use of pain medications. Similarly, chemotherapy had no effect on chronic pain or use of analgesics. XRT dose had no effect on chronic pain or use of pain medications. Likewise, XRT duration was not associated with chronic pain or use of pain medications. There was no difference in rates of survival among patients with chronic pain as compared to those without pain. Site of cancer and site of cancer-related chronic pain were associated with use of pain medications. However, these results have to be carefully interpreted, given small sample size. Further research using prospective studies with larger samples is needed to explore the characteristics of chronic pain among HNC patients treated with XRT and parse the roles of chemotherapy and radiation.
The clinical data used to support the findings of the study are restricted by the Springfield Committee for Research in Human Subjects (SCRIHS) in order to protect patient privacy. Data are available from Krishna Rao for researchers who meet the criteria for access to confidential data.
This is an unfunded investigator-initiated project. All authors, except Dr. Kallurkar, worked for SIU School of Medicine at the time of data collection.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
The authors gratefully acknowledge the role of Kissindra Moore, who greatly assisted us in manuscript preparation.