Pain management in patients undergoing radiation therapy for head and neck cancer – a descriptive study

Introduction

Worldwide, head and neck cancer (HNC) affects more than 500,000 people, representing about 6% of all cancer diagnoses, and causes 350,000 deaths yearly [1], [, 2]. Head and neck cancer is a heterogenous group of diseases concerning incidence, treatment, and prognosis [3]. Treatment of HNC may include surgery, chemotherapy, and radiotherapy (RT) in various combinations [1], [, 4]. A common RT regimen is two gray (Gy) per day five days per week for a total cumulative dose of 50–70 Gy [4].

Patients treated for HNC suffer from several psychological and physical symptoms that negatively impact daily life, including depression and a sense of lack of meaning, pain, xerostomia and swallowing disorders [5]. According to the National Comprehensive Cancer Network Task Force, nausea, vomiting and mucositis are the most physical common adverse events in connection with cancer treatment [6]. Oral mucositis is an inflammation of the oral and oropharyngeal mucous membrane resulting from the toxic effects of RT and chemotherapy [7].

The onset of RT-induced mucositis is usually 10–14 days after start of treatment, and concomitant chemotherapy increases the frequency, duration, and severity of mucositis [4], [, 8]. The grade of mucositis is commonly assessed according to the World Health Organization (WHO) mucositis index scale (0=normal and 4=severe). Initial symptoms are usually mild pain with erythema of the mucous membrane (grade 1), followed by areas of mucosal ulceration (grade 2) that continue to spread and penetrate deeper with gradually increasing pain and an inability to swallow (grades 3 and 4) [8].

Prevalence of pain among patients with HNC is high, with up to 80% of patients reporting pain during their RT treatment [4], [7], [9], [10]. It has been reported that patients with HNC, in early treatment of RT (within 0–20 Gy), mainly describes low pain intensity and in this context the pain is in the first place considered as nociceptive [11]. However, neuropathic pain mechanisms are also thought to be involved [12]. Hence, oral mucositis RT-related pain probably includes both nociceptive and neuropathic pain components [13].

In accordance with the WHO pain ladder, strong opioids are the mainstay of analgesic therapy in treating moderate to severe cancer-related pain, including HNC pain [14], [15], [16]. Previous studies have described that adequate pain relief for patients with HNC who suffer from RT-related oral mucositis is difficult to achieve [13], [17], [18], [19], [20], [21]. For this group of patients, local guidelines at Pain and Rehabilitation Centre (PRC), University Hospital, Linköping, Sweden, are based on the WHO ladder, i.e., acetaminophen, non-steroid anti-inflammatory drugs (NSAID), and opioid analgesics [15]. As a complement all patients with HNC undergo weekly oral care checks by the hospital dentist and use daily mouthwash with lidocaine hydrochloride and mycostatin. When the pain mechanism is considered to be neuropathic, adjuvant analgesia can be provided with gabapentinoids such as pregabalin [21]. Attention is given to side effects of opioid therapy such as dry mouth, constipation, nausea, and decreased alertness [19], [, 22]. Fentanyl patches are usually prescribed when swallowing difficulties are present and/or to minimize side effects such as constipation and nausea [22] and, at PRC, the primary choice of opioid for this group of patients is fentanyl patches.

This longitudinal study evaluated the effects of the above-mentioned local guidelines in clinical practice in a cohort of patients with HNC undergoing RT, examining the relationships between opioid doses, oral mucositis, and pain.

Methods

Results

Oral mucositis, pain intensity, and opioid doses

The WHO mucositis index score in this study cohort changed over time (p<0.001) and were highest at MP 51–60 and thereafter decreased over time (Figure 1 and Table 2).

Figure 1:

Oral mucositis in relation to cumulative dose of Gy^0–70 and post RT^1–4=weeks after completed radiation therapy. Median values are represented by horizontal lines and the interquartile ranges by boxes. The ends of the whiskers represent minimum and maximum values. Points represent outliers.

Table 2:

Data of 63 patients with HNC. Distribution of cumulative dose of RT and changes within the groups: differences in pain intensity (NRS=numeric rating scale), grade of mucositis and weekly dose of morphine. Descriptive data are presented with median values (range) and statistical analysis is performed with the Friedman test (imputed data).

	Cumulative dose of radiotherapy
	0–10 Gy median (min–max)	11–20 Gy median (min–max)	21–30 Gy	31–40 Gy median (min–max)	41–50 Gy median (min–max)	51–60 Gy median (min–max)	61–70 Gy median (min–max)	Post RT1 median (min–max)	Post RT2 median (min–max)	Post RT3 median (min–max)	Post RT4 median (min–max)	p-Value (effect over time)
			Median (min–max)
Pain intensity a	0.67 (0–7)	2.00 (0–8)	2.67 (0–9)	3.00 (0–8)	3.33 (0–9)	3.67 (0–9)	2.33 (0–10)	3.00 (0–7)	2.00 (0–7)	1.33 (0–7)	2.00 (0–9)	0.000
Pain intensity b	0.67 (0–4)	1.33 (0–7)	2.00 (0–9)	2.33 (0–8)	2.33 (0–9)	2.33 (0–9)	2.00 (0–10)	2.00 (0–7)	1.17 (0–7)	1.00 (0–6)	2.00 (0–9)	0.000
Mucositis	0 (0–2)	1.00 (0–3)	2.00 (0–3)	2.00 (0–4)	2.00 (0–4)	2.00 (0–4)	2.00 (0–4)	1.00 (0–4)	1.00 (0–4)	1.00 (0–4)	0 (0–3)	0.000
Morphine mg/day	0 (0–120)	0 (0–180)	29 (0–340)	58 (0–420)	60 (0–605)	84 (0–430)	80 (0–430)	60 (0–300)	60 (0–420)	60 (0–440)	59 (0–240)	0.000

1. Gy, gray; post RT, post radiotherapy^{week 1–4}. ^a,b Pain intensity=The items on pain intensity included pain in connection with^a and without^b speaking, talking, and drinking (0–10); Morphine=mg/day; Mucositis=0 (normal) to 4 (severe).

Both function-related pain and spontaneous pain changed over time (p<0.001 and p<0.001) and were highest at MP 51–60, i.e., associated with cumulative dose of Gy and thereafter decreased over time (Figure 2 and Table 2).

Figure 2:

Pain intensity (NRS 0–10) in connection with (function-related pain) and not with (spontaneous pain) speaking, talking, and drinking, development of pain in relation to cumulative dose of Gy^0–70, post RT^1–4=weeks after completed radiation therapy. Median values are represented by horizontal lines and the interquartile ranges by boxes. The ends of the whiskers represent minimum and maximum values. Points represent outliers and asterisks represent extremes.

Opioids were used by 78% of patients (Table 1; Total column). In most cases, treatment with opioids included a fentanyl patch in combination with oral short-acting morphine as needed. The opioid doses changed over time (p<0.001) and were highest at MP 51–60 with a median of 84 (min-max 0–430) mg OME per day (Figure 3 and Table 2).

Figure 3:

Opioid dose in oral morphine equivalents (mg/d) in relation to cumulative dose of Gy^0–70 and post RT^1–4=weeks after completed radiation therapy. Median values are represented by horizontal lines and the interquartile ranges by boxes. The ends of the whiskers represent minimum and maximum values. Points represent outliers and asterisks represent extremes.

Other analgesic treatment

Majority of the participants used acetaminophen (84%) and nearly half also used NSAID (48%). Opioids in combination with NSAID were used by 41% of patients (Table 1), and 16% (n=8) of the patients undergoing opioid therapy had a supplement of pregabalin with a median of 75 (min-max 50–300) mg/day.

Treatment with NSAIDs and or pregabalin was not found to have a reducing effect on OME. Patients treated with pregabalin had a significantly (p=0.003) higher dose of OME than those who did not have pregabalin.

In-depth analysis at MP 51–60

Pain intensities and opioid doses were highest at MP 51–60 (Table 2). At that time point, significant and substantial positive correlations were found between the grade of mucositis and (1) pain intensity in connection with speaking, talking, and drinking (function-related pain) (r=0.48, p<0.001) and (2) resting pain (r=0.42, p=0.002), respectively. Patients with mucositis grade 0–1 (n=20) had significantly lower pain intensity than patients with mucositis grade 2–4 (n=31) at function-related pain (p=0.004) and at spontaneous pain (p=0.001) (Figure 4).

Figure 4:

Pain intensity (NRS 0–10) in connection with (function-related pain) and not with (spontaneous pain) speaking, talking, and drinking at MP 51–60 in relation to mucositis 0–1 and 2–4. Median values are represented by horizontal lines and the interquartile ranges by boxes. The ends of the whiskers represent minimum and maximum values.

Patients with mucositis grade 0–1 had significantly lower opioid doses than patients with mucositis grade 2–4 (p<0.001, Figure 5). For further comparisons between mucositis 0–1 and mucositis 2–4 groups, see Table 1.

Figure 5:

Opioid dose in oral morphine equivalents (mg/d) at MP 51–60 in relation to mucositis groups 0–1 and 2–4. Median values are represented by horizontal lines and the interquartile ranges by boxes. The ends of the whiskers represent minimum and maximum values. Points represent outliers.

Patients with mucositis grade 2–4 (n=39) were investigated further. Importantly, in patients with mucositis grade 2–4, there were no statistically significant differences in opioid doses between the mild pain group and the moderate to severe pain group (this concerns function-related pain, p=0.385; Figure 6). In addition, there was no correlation between opioid dose and function-related pain (r=0.21, p=0.26). Results were similar for spontaneous pain (data not shown).

Figure 6:

Opioid dose in oral morphine equivalents (mg/d) at MP 51–60 in patients with mucositis grade 2–4. Patients are divided according to pain intensity (function-related pain): mild pain (NRS 0–4) and moderate to severe pain (NRS 5–10) in function-related pain. The ends of the whiskers represent minimum and maximum values. Points represent outliers.

Multivariate association at MP 51–60

No patient was an outlier according to the PCA model (n=63, two principal components, R²=0.23 and Q²=0.07). The OPLS-DA model (one latent variable, R²=0.76 and Q²=0.71, p<0.001 by CV-ANOVA) showed that one of the two groups of patients (called Group 2, n=34, in Figure 7) identified by HCA was characterized by its association with chemotherapy, cancer site in pharynx, no surgery, and the presence of mucositis (see Figure 7). The corresponding p(corr) values for chemotherapy, cancer site in pharynx, no surgery, and the presence of mucositis were 0.87, 0.82, 0.58, and 0.54, respectively (i.e., all these were “significant”). The other group (Group 1, n=29) was the opposite. Hence, our MVDA analysis showed that, taking the whole correlation structure of the material into consideration, there was a group of patients characterized by cancer site in pharynx and being treated (in addition to RT) with chemotherapy and not with surgery, and that this group tended to have a higher degree of mucositis. This was confirmed by additional inferential statistics – i.e., the proportion of patients with mucositis grade 2–4 was significantly higher for patients with cancer site in pharynx compared to other sites (22/26 vs. 17/35, p=0.004). This was also true for patients receiving chemotherapy compared to not receiving chemotherapy (20/25 vs. 19/36, p=0.029). Descriptive data in Table 1 are consistent with this conclusion, as patients with pharynx cancer and patients undergoing chemotherapy had a high frequency of mucositis grade 2–4 (85 and 81%, respectively). As mentioned above, the MVDA analysis also showed that not undergoing surgery was associated with higher degree of mucositis, but this was only apparent in the MVDA model and not by additional inferential statistics (19/26 vs. 20/35, p=0.2).

Figure 7:

Predictive loadings column plot for clustering-based OPLS-DA model. See Methods. Briefly, variable columns near Group 1 are positively associated with Group 1 (and not with Group 2) and vice versa.

With_chemo, radiotherapy (RT) in combination with chemotherapy; Pharynx, cancer site in pharynx; RT_no_Surg, RT without surgery; Mucositis_Gy6, grade of mucositis at the cumulative dose of RT 51–60 gray=measurement point (MP) 51–60; Q1_Gy6, function-related pain at MP 51–60; Morfin_Gy6, morphine use at MP 51–60; Q2_Gy6, spontaneous pain at MP 51–60; ExSmokers, former smokers; Larynx, cancer site in larynx; RT_Surgery_before, surgery before RT; Other_loc, other types of tumours; nasopharynx, salivary glands, thyroid, lip and cancer of unknown primary location; Oralcav, cancer site in the oral cavity; RT_Surgery_after, surgery after RT; No_chemo, RT without chemotherapy.

Discussion

This real-life study evaluated the effectiveness of our local guidelines in clinical practice, investigating the relationships between opioid doses, oral mucositis and pain during HNC-related RT. We studied the temporal dynamics involved (longitudinal aspects), but we also focused on MP 51–60, which was the time point of highest opioid doses, highest grade of mucositis and highest pain intensities.

From a pathophysiological point of view, one of the strengths of the present study is that we structured the material from the point of view of accumulated radiation dose (Gy) and not according to the time (weeks) when patients were included. This strategy allowed us to relate the development of mucositis to actual radiation dose. As expected, this study found that patients diagnosed with HNC developed mucositis and pain during RT and that this was related to the dose of radiation.

Pain treatment according to local guidelines at PRC led to most of the patients (67% at MP51-60) experiencing only mild pain (NRS 0–4). This finding is consistent with one earlier study where mild pain intensities among patients with HNC undergoing RT were also reported [37]; however, that study did not report what pain treatment strategies were used and therefore its findings cannot be used to inform clinical practice from a pharmacological point of view. Thus, it is possible to achieve adequate pain control in a majority of HNC-patients receiving RT. This is not a self-evident finding as many studies have shown that pain in this group of patients is difficult to treat [13], [18], [38], [39].

All patients were referred to the PRC within two weeks before, and up to two weeks into, RT. This early surveillance strategy probably affected outcomes as it made early intervention possible. It has been reported that early pain management, i.e. pre-emptive medications during postoperative period for cancer patients, was associated with increased pain control [40]. In addition, early analgesic treatment might diminish the occurrence of chronic pain as well as reduce the physiological and psychological consequences of severe pain [22], [41], [42].

Based on early and continuous follow-up contacts, opioid doses should be adjusted according to the patient’s reported symptoms [22]. On the other hand, side effects can sometimes limit the dose of opioids, leading to unrelieved pain [43]. The interval between dose escalations should be long enough to allow for a steady state; concerning transdermal patches the interval should be between 3 and 6 days [22].

However, even in the present study, there is still a subgroup of patients who had moderate to severe pain despite pain treatment according to local guidelines (PRC). In our material, it seems clear that these treatment-refractive patients are to be found among patients with clinically significant oral mucositis; at MP51–60, only two patients with mucositis grade 0–1 had moderate pain and none had severe pain (Figure 4). Hence, in the absence of significant mucositis, good pain relief can be expected with comparatively low levels of opioids (Figures 4 and 5). These findings are consistent with two previous studies where pain in the oral cavity was found to increase with increased ulceration surface area and more extensive mucositis [44], [, 45].

We chose to specifically analyse patients with oral mucositis grade 2–4. We found that patients with mild pain did not receive more opioids than the moderate-to-severe pain group; if that had been the case, higher doses of opioids in the moderate-to-severe pain group would have been the obvious answer to the problem. Of course, it could be argued that the moderate-to-severe pain group should unequivocally have received much higher doses than was actually the case, and that one should therefore not be content with ensuring that they, on average, at least did not get less than those whose pain turned out to be well-controlled. However, in our opinion, this simple line of reasoning disregards some important facts. First, it is important not to automatically conflate the categories of “more” and “better”. Second, as can be seen in Figure 6, there is a wide range of dosages (0–400 mg OME/day); while indeed some patients might have been undertreated, it seems too simplistic to argue for higher doses in general and for all patients. Third, doses must be related to the speed of escalation. At MP51–60, the median dose in the moderate-to-severe pain group was 120 mg OME/day, a rather substantial dose for patients who have rather recently started their opioid treatment. Our clinical impression is that we have generally increased opioids in a rather proactive fashion, and that substantially increasing the “inclination” of the opioid escalation curve does not seem warranted. Treatment aggressiveness should be counterbalanced by thoughtful consideration of the risk of the troublesome and potentially dangerous side-effects of opioids. In this study, treatment was careful with standardized titration, i.e. at least three days between increases in opioids to avoid opioid related side effects.

So far, there is insufficient evidence from the literature to advise on a specific pharmacological management for pain in HNC patients. The current recommendation for these patients is simply to follow the WHO pain ladder, with some add-ons recommendations to use local drugs (e.g., lidocaine mouthwash) [14], [15], [16]. Local guidelines at the PRC are in line with this, and a strength of the present study is that it describes the outcome of such a strategy in clinical practice. Gender, age and smoking habits were generally representative of patients with HNC (which in itself suggests good validity).

There are, however, obvious limitations. The sample size of this uncontrolled study was relatively small (n=63) and therefore might be insufficiently representative for populations of patients with HNC, conditions that limit the generalisability of these findings. Detailed subgroup analysis in such a small sample is also fraught with difficulties. In addition, it is possible that the patients who agreed to participate were those who were least ill (i.e., risk of selection bias), which also might affect the external validity. Notably, the patients are also affected by other stressors that the study did not measure, for example nausea and vomiting, conditions which can affect how the patients report pain [5], [6], [46]. Furthermore only 16% of the patients were treated with pregabalin. Randomized controlled studies of adjuvant pregabalin for this group of patients would be of value.

In conclusion, this real-life study indicates that severe RT-related pain in HNC patients is not a fatality. However, further studies are needed to develop better pain treatment strategies for those patients who do develop severe oral mucositis-related pain despite adequate opioid treatment.