Temporal characterization of acute pain and toxicity kinetics during radiation therapy for head and neck cancer. A retrospective study

Objectives: Pain during Radiation Therapy (RT) for oral cavity/oropharyngeal cancer (OC/OPC) is a clinical challenge due to its multifactorial etiology and variable management. The objective of this study was to define complex pain profiles through temporal characterization of pain descriptors, physiologic state, and RT-induced toxicities for pain trajectories understanding. Materials and methods: Using an electronic health record registry, 351 OC/OPC patients treated with RT from 2013 to 2021 were included. Weekly numeric scale pain scores, pain descriptors, vital signs, physician-reported toxicities, and analgesics were analyzed using linear mixed effect models and Spearman’s correlation. Area under the pain curve (AUCpain) was calculated to measure pain burden over time. Results: Median pain scores increased from 0 during the weekly visit (WSV)-1 to 5 during WSV-7. By WSV-7, 60% and 74% of patients reported mouth and throat pain, respectively, with a median pain score of 5. Soreness and burning pain peaked during WSV-6/7 (51%). Median AUCpain was 16% (IQR (9.3–23)), and AUCpain significantly varied based on gender, tumor site, surgery, drug use history, and pre-RT pain. A temporal increase in mucositis and dermatitis, declining mean bodyweight (−7.1%; P < 0.001) and mean arterial pressure (MAP) 6.8 mmHg; P < 0.001 were detected. Pulse rate was positively associated while weight and MAP were negatively associated with pain over time (P < 0.001). Conclusion: This study provides insight on in-depth characterization and associations between dynamic pain, physiologic, and toxicity kinetics. Our findings support further needs of optimized pain control through temporal data-driven clinical decision support systems for acute pain management.


Introduction
Acute pain is a commonly debilitating symptom experienced by patients with oral cavity or oropharyngeal cancer (OC/OPC) even before undergoing definitive or post-operative radiation therapy or concurrent chemoradiation (RT/CRT).Effective management of pain during RT/CRT is challenging due to a heterogeneous patient population, its multifactorial etiology, and lower than anticipated responsiveness to opioids [1,2].In general, over 90% of head and neck cancer (HNC) patients report acute pain with 50-80% requiring opioid therapy [3][4][5].While the World Health Organization (WHO) offers "analgesic ladder" guidelines for stepwise medication intensification [6][7][8][9], it is neither patient nor pain syndrome-specific, resulting in a relative paucity of analgesia effectiveness with approximately one-third of cancer patients still presenting to the emergency department with uncontrolled pain as a chief complaint [10][11][12][13].Whereas the presence of pre-treatment pain, an independent predictor of survival, organ failure, the inability to use the oral route, polypharmacy, anxiety and psychiatric disorders, addiction, allergies, poor tolerance to medications, in addition to the lack of insurance coverage are additional challenges to overcome to provide adequate pain control during RT/CRT [14].Published studies suggest pathophysiologic mechanisms of pain with varying clinical manifestations [15,16].Pain characterization as inflammatory, nociceptive-somatic, nociceptive-visceral, and neuropathic have been reported using different symptom attributes such as "burning sensation", to describe inflammatory pain, or "burning, numbness, shooting, or stabbing" for neuropathic pain [17][18][19][20].However, in cancer patients including those undergoing RT/CRT, pain is considered mixed, with overlapping nature.
The ability to adequately characterize and differentiate mechanistic properties of acute pain experienced by OC/OPC patients during RT/CRT may facilitate symptoms management, thus alleviating morbidity and reducing the cost of care.While HNC pain-related studies exist in the literature [1,15,21,22], they are often limited by their broad scope (i.e., generalized multi-symptom burden analysis) or focused on chronic pain and/or opioid dependency at a specified time after oncologic therapy.These studies also lack the inclusion of pain descriptors and physiologic kinetics (i.e., vital signs) which may elucidate underlying mechanisms of acute pain.
To address this unmet need, the objective of this study was to provide an in-depth analysis on dynamic, acute pain profiles experienced by a modern, prospective OC/OPC cohort treated with curative RT/CRT.Temporal characterization of vital signs, provider-based treatment-related toxicity assessments [23], and analgesic prescription patterns during RT/CRT are also reported.

Study procedures and population
This study was approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center (UT-MDACC).
A radiation oncology electronic data capture system (Brocade) developed at UT-MDACC, which is EHR-interoperable and allows for prospective clinical data collection during RT and populates to the EHR (i.e., Epic), was used for cohort identification [24].This secure database was queried for patients diagnosed with squamous cell carcinoma (SCC) of the OC/OPC, or metastatic to the neck with unknown primary, who were treated with curativeintent RT/CRT from 2013 to 2021.RT prescriptions including 60-70 Gy in about 30-33 fractions were included, and modalities included intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and proton therapy.OC cancer patients had surgery with postoperative RT or CRT while OPC patients were treated primarily with definitive RT/CRT.All patients included must had documented toxicity data and reportable pain score data from at least 3 weekly see visits (WSVs).

Cohort characteristics and study measures
Patient demographics, exposure history (i.e., smoking, alcohol, illicit drugs), clinical stage per AJCC (American Joint Committee on Cancer) 7th edition or 8th edition for recent patients [25,26], RT details, and WSV subjective (i.e., reported by patient) and objective (i.e., reported by provider) data were extracted from Brocade in addition to our EHR for any additional collection of baseline pain scores (i.e., prior to RT/CRT) and WSV-based data on analgesic prescriptions and nursing assessments of pain.
Temporal pain measures extracted included patient-reported pain scores using a numeric rating scale (NRS, scores of 0-10) and qualitative parameters such as pain location (i.e., mouth, throat, skin), description (i.e., aching, sore, burning, sharp), onset and progression.Pain trajectories were reported as occurring at baseline or during WSV# (i.e., WSV6 signifies the 6th WSV).Of note, some results focus on WSV6 as "end of treatment" as it captures all OC/OPC cases treated to fraction 30 (i.e., mainly patients receiving >31 fractions underwent a WSV7 assessment).
WSV-based objective toxicity measures collected include physician-graded mucositis and dermatitis reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0; CTCAE) [23].Provider-based overall treatment toxicity assessments (i.e., absent, mild, moderate, or severe) were also extracted.
Prescribed analgesics data and the cumulative analgesics used by patients was categorized into the following groups: topical analgesics (lidocaine/Xyloxylin); systemic analgesics including non-opioids (i.e., non-steroidal anti-inflammatory drugs); weak, commonly referred as codeine-based opioids such as codeine, hydrocodone, and dihydrocodeine, and tramadol [9,28]; strong opioids including morphine and semisynthetic/synthetic agents such hydromorphone, fentanyl and methadone [28]; and gabapentin.A categorization of weak versus strong opioids has been used in other studies [8,29,30].

Statistical analysis
Temporal characterization of pain scores, weight, and vitals were assessed using one-way ANOVA tests.Trends in temporal pain scores and vital signs were assessed using a linear mixed-effect model (LMM) with random intercepts, accounting for associations between repeated measurements in the same subject.The study time period (i.e., during RT/CRT) was treated as a fixed effect and the subject as a random effect.Spearman's rank correlation was used to calculate the correlation between changes in pain and physiologic measures.Differences in treatment toxicities and opioid prescribing patterns were analyzed using the Chi-square test.AUCpain scores were calculated using previously described methods [31].Briefly, the area under the curve of temporal pain scores was calculated and divided by the total area (maximum pain score × number of followed weeks).AUC pain metrics were then compared using the Wilcoxon rank-sum test for binary variables and Kruskal-Walli's test for multilevel variables based on gender, age (≥ 60 years old or <60 years old), primary tumor site, exposure history, receipt of chemotherapy or surgery, and pre-RT pain score.The Wilcoxon rank-sum test was used for binary variables of pain scores between the analgesics' groups.
All statistical tests were 2-sided with statistical significance indicated at P < 0.05.Analyses were performed using graph pad prism (version 8), JMP PRO 15,and R statistical software (version 4.0.3).

Analgesics/opioid prescribing patterns
A temporal increase in the cumulative frequency of analgesics prescribed was detected throughout the weeks of RT (Fig. 4a).Topical analgesics and low dose or weak opioids were the most used agents, with peak use during WSV5 (70%) for topical analgesics and WSV6 (68%) for opioids.Higher dose or strong opioid use started during WSV1 at 3% and reached a peak of 34% during WSV6.Gabapentin use during WSV1 and WSV5 were 13% and 27%, respectively.A fivefold increase in strong opioid prescribing was noted over time from WSV1 (10%) to the end of RT (55%), concurrent with a temporal decrease in weak opioid (90% in WSV1 to 53% in WSV7; P < 0.001).See Fig. 4b for details.Median patient reported pain levels among low dose or weak opioids users was 2 in WSV1, increased up to 4 by WSV4/5 reaching to 5 by WSV6/7 compared to non-users with median pain scores 0, 3, and 4 by WSV1, WSV4 and WSV6, respectively.Median pain levels among high dose or strong opioids users were 3 in WSV1 with sharp increase to 6 and 7 by WSV6 and WSV7, respectively, compared to non-users who reported median pain scores 0, 3, and 4 during WSV1, WSV5 and WSV6/7, respectively.There was no significant difference in median pain levels in gabapentin or non-opioid analgesics users compared to non-users (Table 3.).Analysis of pain trajectory among patients receiving opioids during treatment demonstrated significant higher AUCpain scores compared with patients who did not (Yes 17%, (10.5-23.5),No 7%, (IQR 4.0-13.0),P < 0.001) (Fig. 2o.).Significant difference in AUCpain scores in subsets population based on weak or low dose opioids use during RT (Yes 16.75%,No 9.5%,, P = 0.0006), and high dose or strong opioids (Yes 20.5%,No 11.5%,.00),P < 0.001).

Discussion
Acute pain is defined as a response of the nervous system to the presence of a harmful stimuli not extended beyond the healing process, typically with a duration of 3 months or less [32].In this comprehensive analysis we aimed to review the patients' characterization of acute pain, associated physiologic changes, and provider-based assessment and analgesic approaches during radiation therapy of head and neck cancer.At our institution, most radiation oncology providers implement a tiered approach for pain management that often includes gabapentin, non-opioids systemic and topical analgesics as the foundation (i.e., started during WSV1).As pain intensifies, low dose or weak, then high dose or strong opioid analgesics are frequently used.However, the high complexity of our patient population mandates an interdisciplinary management including both, non-interventional disciplines (Medical Oncology and Supportive care), as well as interventional (Surgical Oncology and Interventional Pain Management) especially in high-risk patients.Despite these strategic interventions and the escalation in opioids usage, this OC/OPC cohort showed a direct correlation between the increase in cumulative pain scores and the progression of RT-induced oral mucositis and dermatitis.Similarly, a correlation between pain severity and declining physiologic status was observed.Our findings are in alignment with rates of acute toxicities seen in recent randomized HNC clinical trials whereby grade 3-4 oral mucositis affected 42-46% of the cohort and 15% reported grade 3-4 acute pain [33].Limitations to toxicity reporting in such trials included lack of temporal information or insight on how acute pain was managed.
Our group has previously reported on progressive symptom burden in a prospective longitudinal HNC cohort study using a validated patient-reported outcome (PRO) tool called the MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN) [1].The current study builds upon those results by providing an in-depth analysis of acute pain, including novel reporting of AUCpain scores which have the advantage of consolidating time-series data into a single quantitative metric.Using calculations reported by van Dijk et al.
[31], we found a significantly higher AUCpain burden in male patients and those who had a prior history of drug use, pre-therapy reported pain, no surgery (i.e., definitive RT/CRT), or a primary tumor site in the tongue base.Sex-based studies suggest a higher sensitivity to pain in females than males with differences in analgesic response being mixed or minimal between both sexes [34,35].However, there are concerns that published studies are male-biased and not confirmed in female populations [36].Interestingly with only 26% of our cohort being female (n = 90) (as 75% HNC patients are men), we found a statistically significant difference in pain trajectories, favoring increased pain sensitivity and scoring among men, not women.This may be related to sample size and distribution, but it may also reflect different acute pain mechanisms triggered in females [37] that are more readily identifiable when analyzing temporal pain data over central tendencies of pain scores.Similarly, worse AUCpain metrics in patients with pre-RT pain and/or substance abuse corroborate existing studies and reflect a higher-risk patient population [15,21,38].Observed differences in AUCpain based on receipt of surgery may be dose-dependent (i.e., definitive non-surgical cases receive higher doses of radiation [15], versus nerve injuries acquired during surgery.Overall, the single AUCpain metric is a unique measure of longitudinal symptom burden that can potentially optimize future prediction models of treatment-related toxicities. In our study, descriptions of pain as a "sore" or "burning" sensation escalated over time which may elucidate the known subjective intensity and characterization of some mechanisms behind the grading of mucositis and dermatitis.Several models of oral mucositis exist with radiation-induced activation of transcription factors such as nuclear factor kappa B and the release of several pro-inflammatory cytokines (i.e., interleukin (IL)-1β) playing critical roles in the ulceration phase [39,40].While "sore" and "aching" descriptors may indicate a component of inflammatory nociceptive pain, a "burning" characteristic is often reported with the pathobiology of neuropathic pain (a landmark of pain centralization, as a result of prolonged high intensity, or poorly controlled nociceptive stimuli) and/or underdiagnosed and mismanaged pain in HNC patients receiving RT/CRT [41][42][43].Overall, enhanced knowledge of active and evolving pain mechanisms during RT/CRT is needed for the strategic use of analgesic pharmacology.For example, NSAIDs and mu-opiates may effectively control inflammation and hyperalgesia respectively, more efficiently than gabapentanoids which have a more specific efficiency profile for managing allodynia, a classic manifestation of neuropathic pain [44].
After the use of retrospectively collected clinical data from a large, modern cohort of OC/OPC patients treated with RT, certain limitations apply to our study.These include attrition rates in documented pain descriptors which were not mandatory for reporting.Additionally, analgesic data analysis was restricted to generic groupings of medication prescriptions instead of temporal changes in drug usage.Our next study on algorithmic pain management will incorporate morphine-equivalent drug dosing data to best reflect weekly adjustments in pain medication prescriptions.Analysis of other confounding factors affecting pain experiences such as medical history is warranted.Further prospective data collection to improve the recording of patient medication use data is also needed to improve the accuracy of analgesic use for pain control.
In conclusion, our results demonstrate a significant temporal increase in the severity of pain and other radiation treatment-related acute toxicities throughout the course of RT/CRT in OC/OPC patients and an ongoing need for better and safer pain control in this population.AUCpain metrics and the significant impact of different clinical and demographic features on acute pain burden will be used in the future to develop a predictive algorithm for pain management optimization.Overall pain description reported in the weekly see visits.(d) Physician reported grades showed significant increase over the weeks of RT (P < 0.001).(e) Physician reported dermatitis grades showed significant increase over the weeks of RT (P < 0.001).
(f) Physician reported overall treatment toxicity plan showed significant increase over the weeks of RT (P < 0.001).).e. AUCpain scores based on chemotherapy type showed no significant difference (P =0.468).f.AUCpain scores based on pre-RT surgery, patients had RT post-surgery (Post) had significant lower pain curve than patients did not have surgery (None) (P < 0.001).g.AUCpain scores based on drug abuse, patients had history of drug abuse had significant higher pain curve than patients did not (No) (P = 0.003).h.AUCpain scores based on smoking status showed no significant difference (p = 0.234).i.
AUCpain scores based on alcohol status showed no significant difference (P = 0.315).j.
AUCpain scores based on primary cancer type, oropharynx group had significant higher curve than oral cavity (P = 0.002).k.AUCpain scores based on primary cancer site, Base of tongue group had significant higher curve than tonsils and others (P = 0.003).l.AUCpain scores based on pre-RT pain scores, group had non-mild pain score (0-4) had lower curve than group with moderate-severe (5-10) pain (P = 0.012).m.AUCpain scores based on HPV status showed no significant difference between HPV positive and HPV negative (p = 0.073).n.AUCpain scores based on survival status showed no significant difference between Alive and Deceased patients (P = 0.685).o.AUCpain scores based on opioids use, patients used opioids (Yes) had significant higher pain curve than patients did not use opioids (No) (P < 0.001).Abbreviations: n = number, % = percentage.Note: the number and the percentages are based on the total number of patients reported pain each week.
Oral Oncol Rep. Author manuscript; available in PMC 2024 April 18.

Fig. 1 .
Fig. 1.Acute pain profile and acute toxicities: (a) Overall change of patient reported pain score (delta pain) showed significant increase in the mean of pain score during the weeks of RT (WCVs) (P < 0.001).(b) Overall pain location reported in the weekly see visits.(c)

Fig
Fig. 2. AUCpain scoresa.Overall pain AUC curve (16%).b.AUCpain scores based on gender, male group had significant higher AUC pain curve than female (P =0.048).c.AUCpain scores based on age of 60 years, no significant difference between < 60 (No) and >=60 (Yes) years old (P = 0.385).d.AUCpain scores of systemic medication (chemotherapy) use showed no significant difference (p=0.575).e. AUCpain scores based on chemotherapy type showed no significant difference (P =0.468).f.AUCpain scores based on pre-RT surgery, patients had RT post-surgery (Post) had significant lower pain curve than patients did not have surgery (None) (P < 0.001).g.AUCpain scores based on drug abuse, patients had history of drug abuse had significant higher pain curve than patients did not (No) (P = 0.003).h.AUCpain scores based on smoking status showed no significant difference (p = 0.234).i.

Fig. 3 .
Fig. 3. Physiologic changes: (a) temporal overall change in the mean of body weight change during the weeks of RT.(b) Frequency of feeding tube used through the weekly see visits of RT.(c) Temporal change in the mean of mean arterial pressure (MAP) change during the weekly see weekly see visits.(d) Temporal change in heart rate (HR) change during the weekly see visits.(e) Spearman r correlation matrix showing correlation between the change in pain and the change in vital signs.

Fig. 4 .
Fig. 4. (a) Temporal cumulative frequency of analgesics used by patients during the weekly see visits (WSVs) of radiotherapy.(b) The frequency of weak opioids versus strong opioids prescribed during the WSVs shows significant difference in opioids prescription (P < 0.001).(c) AUCpain scores in subgroups based on weak opioids use (P = 0.0006).(d) AUCpain scores in subgroups based on strong opioids use (P < 0.001).(e) AUCpain scores in subgroups based on gabapentin use (P =0.062).(f) AUCpain scores in subgroups based on non-opioids use (P = 0.07).