Long-term opioid use in curative-intent radiotherapy: One-Year outcomes in head/neck cancer patients

Abstract

Background:

No study has determined the incidence of long-term opioid use, or risk factors for long-term use, ≥1 year after radiotherapy.

Methods:

Medical records of 276 head/neck cancer patients were retrospectively assessed for persistent opioid use 1-year after curative-intent radiotherapy. Numerous potential risk factors were assessed and the physicians’ documented reasons for continued use were qualitatively categorized as suspected opioid use disorder (OUD) or as medically indicated for control of ongoing pain.

Results:

Of note, 20 of 276 patients continued using opioids long-term. High maximum opioid dose and the use of opioids and/or psychotropics/non-opioid analgesics at the radiation oncology intake visit were associated with this outcome. Three patients continued due to suspected OUD and 17 due to medical indications.

Conclusion:

Of note, 7.2% of patients developed long-term opioid use, which was associated with high maximum opioid dose and early initiation of opioids and/or psychotropics/non-opioid analgesics. Physicians cited medical indications as the primary reason for continued use.

1 |. INTRODUCTION

The opioid epidemic in the United States is a public health emergency.¹ The incidence of opioid overdose is rising at an ever-increasing rate and some states have tightened regulations on opioid prescribing.² In the past, prescribing for cancer patients was largely exempted from these new regulations. For example, in 2018, the Florida legislature limited prescribing of opioids to no more than 3 days.³ Cancer patients were exempted from this regulation. However, additional regulations on opioid prescribing (a requirement to provide information on opioid alternatives) were added in 2019 without any exemption for cancer patients.⁴ If tightening regulations on opioid prescribing continue to include cancer patients, the efforts of regulators to prevent opioid addiction may compromise patients’ control over cancer pain. Discussions about improving opioid regulation are necessary, but are limited by a paucity of data on long-term opioid use and addiction after cancer treatment to inform decision-making.

Head/neck cancer is of interest for this topic because disease, surgery, and especially radiation- or chemoradiation-induced oral mucositis cause patients to have the highest prevalence of pain of all cancer sites.⁵ Further, the demographics of patients with head/neck cancer are changing due to the increasing incidence of HPV-associated oropharyngeal cancer in younger and otherwise healthier patients.⁶ These patients have a high cure rate, making the issue of long-term opioid addiction even more relevant. Head/neck cancer patients may also be at high risk because they frequently require large doses of opioids to complete treatment without interruption.

Four studies have reported short-term rates of continued opioid use 6 months following curative-intent radiotherapy (7%−38%).^7–10 Unfortunately, there are no studies in the literature with longer follow-up and the previous studies did not examine the reasons for continued opioid use. The cases of continued opioid use deserve detailed review to inform our understanding of which factors may lead to this outcome. In addition, further qualitative analysis may provide insight to the question: Does prescribing opioids to control pain in head/neck cancer patients undergoing curative radiotherapy carry a significant risk of causing long-term opioid dependence after the sources of pain have resolved?

2 |. PATIENTS (OR SUBJECTS) AND METHODS

2.1 |. Study design

This is a retrospective study conducted at a single institution. A full waiver of Health Insurance Portability and Accountability Act (HIPAA) was approved by our Institutional Review Board to identify head/neck cancer patients treated with external beam radiotherapy between 2013 and mid-2017. A list of patients was obtained from the Tumor Registry. Patients were excluded if they had any of the following: (a) no radiotherapy at our institution, (b) no follow-up 1 year (±2 months) after completing radiotherapy, (c) continued active malignancy-related pain defined by: persistent disease, pain from a second primary or distant lesion within 18 months (rather than 12 months to account for any painful smoldering tumors with impending recurrence), or locoregional recurrence within 18 months, (d) chronic opioid use for non-cancer pain leading up to cancer symptoms or diagnosis, per the radiation oncology intake questionnaire, (e) no documentation of more than 1 day of opioid use.

2.2 |. Data collection

We reviewed available medical records for each eligible patient. We sought information specifically from documents related to the first radiation oncology consultation (intake), third week of radiotherapy, sixth week of radiotherapy, 6 weeks of follow-up after completing radiotherapy (±1 week), 12 weeks of follow-up (±2 weeks), and 1 year of follow-up (±2 months). If two visits occurred in the same range, the later visit was used. Baseline characteristics and numerous treatment-related factors were collected for each patient (Table 1).

TABLE 1.

Patient factors and reference national averages

		All
Category	Variable	No. of pts/value	Percent of pts	National average (%)
	All	276	100	-
Baseline characteristics
Age (years)	Mean	60	-	-
Sex	Female	58	21	-
	Male	218	79	-
Race/ethnicity	Non-Hispanic White	147	53.3	60.711
	Hispanic White	92	33.3	15.911
	Black	17	6.2	13.411
	Other/Unknown	20	7.2	1011
Social factors
Income class by median household income	Lower (<$45 600)	96	34.8	4012
	Middle ($45 600-<$74869)	142	51.4	2012
	Upper (≥$74 869)	31	11.2	4012
	No address/out of country	7	2.5	-
Primary language	English	206	74.6	79.213
	Spanish	63	22.8	12.913
	Other	7	2.5	7.913.
Marital status	Married	186	67.4	48.414
	Not married	88	31.9	51.614
	Not documented	2	0.7	-
Religion	No affiliation	53	19.2	15.015
	Any religion	184	66.7	85.015
	Not documented	39	14.1	-
Dependent children	No	124	44.9	70.214
	Yes	59	21.4	29.814
	Not documented	93	33.7	-
Living situation	Alone	23	8.3	26.714
	With family/others	172	62.3	73.314
	Not documented	81	29.3	-
Employment	Employed	163	59.1	6311
	Unemployed	68	24.6	3711
	Not documented	45	16.3	-
Insurance	None	4	1.4	8.816
	Private	131	47.5	67.216
	Medicare	122	44.2	17.216
	Medicaid	19	6.9	19.316
Medical factors
Smoking/tobacco	Never	116	42	54.617
	Former	141	51.1	22.217
	Current	18	6.5	23.317
	Not documented	1	0.4	-
Substance history stopped before intake	Negative hx	236	85.5	-
	Positive hx	40	14.5	-
Substance history continued at intake	No use	252	91.3	-
	Pos use	24	8.7	-
Psychiatric disorder	None	255	92.4	-
	Any	21	7.6	-
Chronic pain condition	None	175	63.4	-
	Any pain	101	36.6	-
Oncologic factors
Cancer histology	Squamous cell carcinoma	224	81.2	-
	Other cell carcinoma	52	18.8	-
Cancer location	Nasal cavity and paranasal sinuses	14	5.1	-
	Oral cavity/salivary glands	98	35.5	-
	Pharynx (naso, oro, hypo)	118	42.8	-
	Larynx	46	16.7	-
Cancer stage	I-II	66	23.9	-
	III-IV	204	73.9	-
	Unknown	6	2.2	-
Treatment factors	No	160	58	-
Surgery	Yes	116	42	-
Chemotherapy	No	150	54.3	-
	Yes	126	45.7	-
Total radiation exposure (Gy)	Mean	66.2	-	-
Number of fractions	Mean	32	-	-
Maximum opioid dose (MME/d)	Mean	94.8	-	-
Opioid use at intake	No	211	76.4	-
	Yes	65	23.6	-
Psychotropic/non-opioid analgesic use at intake	No	139	50.4	-
	Yes	137	49.6	-

Abbreviations: HW, Hispanic White; MME/d, morphine milligram equivalents per day; N.A., national average; NHW, non-Hispanic White; No., number; Pts, patients.

Opioid use data were obtained exclusively from the electronic medical record (EMR) as E-FORCSE, Florida’s prescription drug monitoring database, cannot be used for research purposes (personal communication, Florida Prescription Drug Monitoring Program, E. Marshall, B.S., 11/2017). The primary outcome was opioid use status at the 1-year follow-up visit. Continued, or long-term, opioid use was defined by the algorithm in Figure 1.

FIGURE 1.

Algorithm for opioid use status at 1 year of follow-up. This algorithm was used from left to right to categorize patients’ opioid use status at the 1-year follow-up visit (gray boxes). Med, medication; Rx, prescription

Opioid dose was recorded at each visit and converted to morphine milligram equivalents per day (MME/d) using standard conversion ratios.¹⁸ It was calculated in this way to determine daily opioid consumption rates that allows for comparison between all patients. Daily consumption was determined by the following in order of priority: (a) description in the physician’s note, (b) total prescribed opioid dose divided by the number of days until the next refill, (c) total prescribed opioid dose divided by the number of days the medication was instructed to be used, or (d) total prescribed opioid dose divided by the number of days between the prescription date and the next follow-up visit.

History of substance use disorder was collected from the radiation oncology intake visit and defined by previous diagnosis of substance use disorder or documented recurrent use of any illegal substance, including marijuana. This was further categorized as either past use (ie, quit) or continued use at the intake visit. The presence of any chronic pain conditions were also collected from the intake visit and included any painful long-term or recurrent musculoskeletal, neurological, gastrointestinal, or genitourinary conditions.

2.3 |. Analysis

Continuous variables were summarized using descriptive statistics. Categorical variables were reported using counts and proportions. Due to small numbers of patients with long-term opioid use, we considered only univariable analysis. Univariable analysis was conducted to examine for associations between opioid use status at 1 year and various factors using a logistic regression model to estimate odds ratios, corresponding 95% confidence intervals, and P-values. All tests were two-sided and P < .05 was considered statistically significant. Statistical analyses were performed using SAS (version 9.4).

A qualitative analysis was conducted on the patients with long-term opioid use. Case summaries were reported and categorized as either suspected opioid use disorder (OUD) or medically indicated based on the treating physicians’ reported reasons for continuing opioid therapy. The term suspected OUD was used to stratify patients with the highest likelihood of having an OUD. It was defined by physician documented suspicion for opioid misuse, addiction, or OUD. The term medically indicated was used to stratify patients with the lowest likelihood of having an OUD. It was defined by the absence of documented physician suspicion for OUD with clear documentation of a pain syndrome that led the treating physician to continue opioid treatment. Any patient who continued using opioids without clear documentation of a pain syndrome was assigned to the suspected OUD group.

3 |. RESULTS

A list of 678 head/neck cancer patients treated with external beam radiotherapy between 2013 and mid-2017 was obtained from the institution’s Tumor Registry. Of these, 276 were included. Figure 2 highlights the exclusion process with patient counts for each exclusion.

FIGURE 2.

Exclusion process and counts. Patients were sequentially excluded for the above reasons (gray boxes). White boxes represent patients who were not excluded. Dx, diagnosis; H/N, head and neck; LR, locoregional; RT, radiotherapy; SPM, second primary malignancy; Sx, symptom

Patients’ baseline characteristics and reported reference national averages are presented in Table 1. Patients were predominantly male (79%) and non-Hispanic White (53%) or Hispanic White (33%) with a mean and median age of 60.

A total of 20/276 (7.2%) patients continued using opioids at 1 year of follow-up. Analysis of factors for association with long-term opioid use are presented in Table 2. The factors associated significantly with long-term opioid use were maximum opioid dose (P = .005) and use of psychotropics/non-opioid analgesics at the intake visit (P = .010). In addition, patients who started opioid use for cancer-related or cancer treatment-related pain before radiotherapy (ie, pre-radiation opioid use) had a rate of long-term opioid use of 20% (13/64) compared to a rate of 3% (7/212) for patients who started opioid use during or after radiotherapy (P = .001).

TABLE 2.

Association between patient factors and outcomes

		Continued opioids		Discontinued opioids
Category	Variable	No. of pts/value	Percent of pts (%)	No. of pts/Value	Percent of pts (%)	OR (95% CI)	P value
	All	20	7.2	256	92.8	-	-
Baseline characteristics
Age (years)	Mean	57.3	-	60.2		0.97 (0.93, 1.02)	.242
Sex	Female	3	5.2	55	94.8	Reference
	Male	17	7.8	201	92.2	1.38 (0.42, 4.55)	.599
Race/ethnicity	Non-Hispanic White	11	7.5	136	92.5	Reference
	Hispanic White	7	7.6	85	92.4	1.04 (0.40, 2.73)	.935
	Black	2	11.8	15	88.2	1.91 (0.43, 8.59)	.397
	Other/Unknown	0	0	20	100	0.29 (0.02, 5.46)	.408
Social factors
Income class by median household income	Lower (<$45 600)	4	4.2	92	95.8	Reference
	Middle ($45 600-<$74869)	12	8.5	130	91.5	1.97 (0.65, 6.01)	.234
	Upper (≥$74 869)	4	12.9	27	87.1	3.36 (0.84, 13.49)	.087
	No address/out of country	0	0	7	100	NE	NE
Primary language	English	17	8.3	189	91.7	Reference
	Spanish	3	4.8	60	95.2	0.63 (0.19, 2.06)	.442
	Other	0	0	7	100	0.72 (0.03, 16.02)	.837
Marital status	Married	13	7	173	93	Reference
	Not married	7	8	81	92	1.18 (0.46, 3.01)	.725
	Not documented	0	0	2	100	2.57 (0.06, 110.41)	.623
Religion	No affiliation	6	11.3	47	88.7	Reference
	Any religion	14	7.6	170	92.4	1.18 (0.46, 3.01)	.725
	Not documented	0	0	39	100	2.57 (0.06, 110.41)	.623
Dependent children	No	11	8.9	113	91.1	Reference
	Yes	5	8.5	54	91.5	1.00 (0.34, 2.91)	.994
	Not documented	4	4.3	89	95.7	0.50 (0.16, 1.54)	.224
Living situation	Alone	2	8.7	21	91.3	Reference
	With family/others	15	8.7	157	91.3	0.85 (0.20, 3.56)	.82
	Not documented	3	3.7	78	96.3	0.38 (0.07, 2.14)	.274
Employment	Employed	12	7.4	151	92.6	Reference
	Unemployed	4	5.9	64	94.1	0.85 (0.28, 2.60)	.77
	Not documented	4	8.9	41	91.1	1.31 (0.42,4.11)	.639
Insurance	None	0	0	4	100	Reference
	Private	8	6.1	123	93.9	0.62 (0.02, 17.47)	.779
	Medicare	10	8.2	112	91.8	0.84 (0.03, 23.40)	.918
	Medicaid	2	10.5	17	89.5	1.29 (0.04, 44.20)	.889
Medical factors
Smoking/tobacco	Never	9	7.8	107	92.2	Reference
	Former	10	7.1	131	92.9	0.90 (0.36, 2.26)	.828
	Current	1	5.6	17	94.4	0.97 (0.15, 6.10)	.974
	Not documented	0	0	1	100	3.71 (0.04, 366.82)	0.576
Substance history stopped before intake	Negative hx	16	6.8	220	93.2	Reference
	Positive hx	4	10	36	90	1.65 (0.54, 5.00)	.378
Substance history continued at intake	No use	17	6.7	235	93.3	Reference
	Pos use	3	12.5	21	87.5	2.19 (0.63, 7.66)	.219
Psychiatric disorder	None	17	6.7	238	93.3	Reference
	Any	3	14.3	18	85.7	2.58 (0.73, 9.15)	.143
Chronic pain condition	None	12	6.9	163	93.1	Reference
	Any pain	8	7.9	93	92.1	1.19 (0.48, 2.96)	0.71
Oncologic factors
Cancer histology	Squamous cell carcinoma	17	7.6	207	92.4	Reference
	Other cell carcinoma	3	5.8	49	94.2	0.84 (0.25, 2.78)	.773
Cancer location	Nasal cavity and paranasal sinuses	2	14.3	12	85.7	Reference
	Oral cavity/salivary glands	8	8.2	90	91.8	0.47 (0.10, 2.26)	.346
	Pharynx (naso, oro, hypo)	8	6.8	110	93.2	0.39 (0.08, 1.85)	.233
	Larynx	2	4.3	44	95.7	0.28 (0.04, 1.89)	.192
Cancer stage	I-II	5	7.6	61	92.4	Reference
	III-IV	15	7.4	189	92.6	0.91 (0.33, 2.54)	.864
	Unknown	0	0	6	100	0.86 (0.03, 21.72)	.927
Treatment factors
Surgery	No	9	5.6	151	94.4	Reference
	Yes	11	9.5	105	90.5	1.74 (0.71, 4.27)	.227
Chemotherapy	No	11	7.3	139	92.7	Reference
	Yes	9	7.1	117	92.9	0.98 (0.40, 2.40)	.966
Total radiation exposure (Gy)	Mean	64.8	-	66.3	-	0.96 (0.90, 1.02)	.178
Number of fractions	Mean	32.1	-	32	-	0.98 (0.83, 1.15)	.806
Maximum opioid dose (MME/d)	Mean	155.1	-	89.8	-	1.12a (1.03, 1.21)	.005
Opioid use at intake	No	7	3.3	204	96.7	Reference
	Yes	13	20.0	52	80.0	7.01 (2.72, 18.07)	.001
Psychotropic/non-opioid analgesic use at intake	No	4	2.9	135	97.1	Reference
	Yes	16	11.7	121	88.3	4.09 (1.40, 11.97)	.010

Abbreviations: CI, confidence interval; HW, Hispanic White; MME/d, morphine milligram equivalents per day; N.A., national average; NE, not examined; NNHW, non-Hispanic White; No., number; OR, odds ratio; Pts, patients.

^aOdds ratio for every 20 units increased in maximum opioid dose.

The progression of opioid use statuses over the course of 1 year is shown for both groups in Figure 3. Peak prevalence of opioid use was at 6 weeks of radiotherapy. The specific opioid agents used at each visit are displayed in Figure 4 (excluding cases in which opioid agents were not specified).

FIGURE 3.

Opioid use patterns over 1 year. The left-most column shows the percentages of patients using opioids (purple) and not using opioids (green) at the intake visit. The next column to the right subdivides the two groups from the first column into a total of four groups based on any changes in opioid use status between the first and second visit. The new subgroups and the groups they divided from maintain the same position on the chart as the previous visit. Each subsequent visit further subdivides each group while maintaining the positions of the previous visit. The cumulative effect displays all patterns of opioid use, and their frequencies, over 1 year. FU, follow up; RT, radiotherapy

FIGURE 4.

Opioid agents at each visit. This figure demonstrates the frequency at which opioid agents were used at key time points in the patients’ treatment course. FU, follow up; RT, radiotherapy

Case summaries of patients with long-term opioid use are presented in Table 3. Based on the treating physicians’ documentation, 17 of 20 (85% or 6.1% of the total cohort) were categorized as medically indicated and 3 of 20 as suspected OUD (15% or 1.1% of the total cohort). In two of the patients with suspected OUD, the treating radiation oncologist documented a suspicion for OUD. One of these patients was referred to a pain specialist for management and the other was lost to follow-up 14 months after radiotherapy. In the third case, a pain syndrome was not clearly delineated and the indications for prescribing opioids were not documented. The patient received a prescription of tramadol from his oncologist 13 months after completing radiotherapy, but no additional opioids were prescribed or pain syndrome delineated in the subsequent 3 years of follow-up.

TABLE 3.

Case summaries of long-term opioid use

	Ref. No.	Basic demographics	Cancer factors	Cancer treatment	Pain medication at intake	Pain medication at 1y FU	Records of pain meds beyond 1y FU	Description of continued opioid use
Suspected opioid use disorder	1	52yo Hispanic White Male Never smoker English	SCC Tongue base Stage 3	Chemoradiation with 70GY (2GY x 35fx)	Fentanyl Oxycodone 184.29 MME Acetaminophen	Oxycodone 7.5 MME Acetaminophen	Last follow-up was 14 months after radiotherapy and the last opioid prescription expired 16mo after completing radiotherapy	Xerostomia. 12mo after radiotherapy, physician noted: “I am concerned that he has become addicted [to oxycodone]”
	2	51yo Hispanic White Male Former smoker English	SCC Tongue Stage 4A	Surgery (partial glossectomy and modified radical unilateral neck dissection) followed by radiotherapy with 60GY (2 GY x 30fx)	Oxycodone MME CNBC Acetaminophen	Codeine Nine MME Acetaminophen	Referred to pain management. Discontinued all opioids <18mo after completing radiotherapy.	Physician noted that patient had recovered from all side effects 12mo after completing radiotherapy, but required help tapering off opioids.
	3	61yo Non-Hispanic black Male Former smoker English	Lymphoepithelial carcinoma Nasopharynx Stage 2	Chemoradiation with 69.96GY (2.12GY x 33fx)	Oxycodone MME CNBC Acetaminophen Benzodiazepine Zolpidem	Tramadol MME CNBC (could not be calculated)	“Rare use” of left over oxycodone at a visit 12mo after completing radiotherapy. Patient received one prescription for tramadol at 13mo with end date at 19mo. No subsequent opioids were prescribed.	Documented opioid use, but no clear documented indication.
Medical indication	4	46yo Non-Hispanic White Male Former smoker English	SCC Maxillary sinus Stage 4A	Surgery (enucleation) followed by chemoradiation with 60GY (2GY x 30fx)	Oxycodone 7.5 MME Acetaminophen	Oxycodone 7.5 MME Acetaminophen Biotene SNRI	The most recent record was by pain management 14mo after completing radiotherapy and the patient was continuing gabapentin and tramadol (15 MME).	Neuropathic facial pain in region of enucleation with flap.
	5	30yo Female Hispanic White Former smoker English	SCC Tongue base Stage 3	Surgery (glossectomy and neck dissection) followed by radiotherapy with 60GY (2GY x 20fx)	Acetaminophen NSAIDs	Tramadol 2.5 MME Gabapentin NSAIDs	Patient was managed by pain management for 4mo after radiotherapy, but did not follow up after that. She underwent physical therapy and numerous cervical nerve blocks. She discontinued opioids 20mo after completing radiotherapy.	Chronic neck and upper back myofascial and neuropathic pain
	6	63yo Male Hispanic White Former smoker Spanish	SCC Tongue base Stage 4A	Surgery (segmental mandibulectomy, tonsil resection, partial glossectomy, and anterolateral thigh flap) followed by radiotherapy with 60GY (2 GY x 60fx)	Oxycodone 21.44 MME Acetaminophen Gabapentin	Oxycodone 15 MME Acetaminophen Gabapentin	Followed up with pain management 20mo after radiotherapy. The most recent record was 33mo after radiotherapy and patient was continuing tramadol (7.4 MME) due to necrosis of the mandible and suspected bone exposure.	Neuropathic neck pain on the side of surgery and moderate–severe odynophagia causing PEG dependence
	7	68yo Non-Hispanic White Male Never smoker English	SCC Tongue base Stage 4A	Chemoradiation with 69.96GY (2.12GY × 33fx)	Oxycodone 22.5 MME Acetaminophen	Oxycodone 15 MME Oxycodone 15 MME Acetaminophen Biotene NSAIDs	Discontinued all opioids 15mo after completing radiotherapy. No pain management follow up.	Persistent odynophagia and xerostomia that was not controlled with NSAIDs, but was with oxycodone.
	8	71yo Hispanic White Male Former smoker Spanish	SCC Supraglottis Stage 2	Chemoradiation with 70GY (2 GY X 35fx)	NSAIDs	Guaifenesin-codeine MME CNBC	Discontinued all opioids 22mo after completing radiotherapy.	Patient did not use opioids during radiotherapy, but started guaifenesin-codeine shortly before 1 year of follow up due to laryngeal edema.
	9	64yo Male Non-Hispanic White Former smoker English	SCC Nasal cavity Stage 4A	Chemoradiation with 69.96GY (2.12GY × 33fx)	None	Codeine Fentanyl 66.43 MME Acetaminophen	Discontinued all opioids 15mo after completing radiotherapy. He did not follow up with pain management.	Stopped opioids when radiotherapy was complete. Underwent resection/debridement at 9mo of follow up for suspected recurrence, but pathology was negative. Patient had chronic sinusitis with drainage and pain after procedure that was not controlled with NSAIDs.
	10	58yo Non-Hispanic White Male Former smoker English	SCC Larynx, overlapping lesion Stage 4A	Surgery (total laryngectomy, lymph node dissection, and anterolateral thigh flap) followed by chemoradiation with 60GY (2GY × 30fx)	Oxycodone 12.5 MME Acetaminophen NSAIDs	Oxycodone 30 MME Acetaminophen NSAIDs	Underwent physical therapy, cervical nerve blocks x7, and a shoulder injection. The most recent record was by pain management 38mo after radiotherapy and patient was continuing oxycodone and buprenorphine.	Patient had cervical spondylosis that began 1 year before cancer. He started opioids for cancer pain and continued for mutli-factorial cervical pain (post-surgical pain, multiple sites of severe cervical degeneration, osteophytes, and disc protrusion) and shoulder pain.
	11	48yo Hispanic White Male Never smoker Spanish	SCC Tonsil Stage 4B	Surgery (unilateral excision of tonsillar fossa mass and debulking) followed by chemoradiation with, 69.96GY (2.12GY × 33fx)	Oxycodone 33.75 MME Acetaminophen	Tramadol 12.5 MME	Managed by pain management 5-17mo after radiotherapy. Underwent multiple pharyngeal dilations. All opioids (tramadol) were discontinued 31mo after radiotherapy.	PEG dependence at 1 year of follow up due to neuropathic pain (CNIX), severe trismus with very limited mouth opening, and esophageal stricture with dilations x2.
	12	51yo Non-Hispanic White Male Current smoker English	SCC Tonsil Stage 4A	Surgery (radical resection of tonsil, tongue base, and hypopharynx and modified radical neck dissection) followed by chemoradiation with 66GY (2 GY x 33fx)	None	Fentanyl Oxycodone 55.05 MME	Kenalog injection in oropharynx. Followed by pain management from 4 weeks before radiotherapy to 23mo after completing radiotherapy. Discontinued all opioids 25mo after radiotherapy.	Oropharyngeal pain at resection scar with scarring of vallecula and supraglottis causing distortion of epiglottis with suspected lingual nerve involvement.
	13	55yo Non-Hispanic White Male Former smoker English	Papillary SCC Pharynx Stage 4A	Chemoradiation with 69.96GY (2.12GY X 33fx)	Oxycodone 8.04 MME Acetaminophen	Methadone Oxycodone 276 MME Acetaminophen	Followed by pain management 5-16mo after completing radiotherapy. Patient’s last recorded prescriptions included oxycodone and methadone (MME 276) from pain management. There are no records beyond 16mo.	Stopped all opioids by 6 weeks of follow up. Restarted due to chondroradionecrosis of the larynx.
	14	63yo Non-Hispanic White Male Never smoker English	SCC Tonsil Stage 4A	Surgery (radical tonsillectomy, partial pharyngectomy, partial glossectomy, and unilateral neck dissection) followed by chemoradiation with 66GY (2 GY × 33fx)	None	Tramadol 19.15 MME Acetaminophen	Managed by pain management 7-15mo after radiotherapy. The most recent record was 43mo after radiotherapy and patient was continuing tramadol (MME CNBC)	Oral pain, suspected to be neuropathic. Pain management describes pain in detail and recommended use of tramadol.
	15	64yo Non-Hispanic White Male Never smoker English	SCC Tonsil Stage 1	Surgery (tonsillectomy, pharyngectomy, and glossectomy) followed by chemoradiation, 64GY (2 GY × 34fx)	Oxycodone 90 MME Acetaminophen	Fentanyl Oxycodone 210 MME Acetaminophen	Managed by pain management 30mo after radiotherapy to the present. The most recent record was 49mo after RT and patient was continuing oxycodone and fentanyl 210 MME. Physician noted no aberrancies on E-FORCSE.	Osteoradionecrosis of mandible.
	16	67yo Non-Hispanic White Female Former smoker English	SCC Tongue border Stage 2	Surgery (left glossectomy, left neck dissection, tracheostomy, right radical free forearm flap) followed by radiotherapy with 60GY (2GY x 30fx)	Oxycodone 11.25 MME Acetaminophen Benzodiazepine SSRI	Oxycodone 11.03 MME Acetaminophen Magic mix	Discontinued all opioids 18mo after completing radiotherapy when oral ulcers resolved.	Stopped opioids 2mo after completing radiotherapy. Restarted at 12mo FU for approximately 6mo for recurring oral ulcers. Biopsies x4 were negative for recurrence.
	17	57yo Hispanic White Male Never smoker English	Basaloid SCC Tonsil Stage 4A	Chemoradiation with 70GY (2 GY X 35fx)	Benzodiazepine SSRI Zolpidem	Oxycodone 257.15 second generation anti-psychotic Benzodiazepine SSRI	Managed by pain management long-term. Began exhibiting aberrant/addictive behavior between 24–36mo after completing radiotherapy. Marijuana, cocaine, and non-prescribed buprenorphine were detected in urine. Patient filled benzodiazepine and zolpidem prescriptions monthly, but these were not detected in urine. Opioids were	Osteoradionecrosis and severe trismus (mouth opening 1–1.5 cm) causing G-tube dependence.
	18	54yo Non-Hispanic White Male Never smoker English	Lymphoma, NK/T-cell, nasal & nasal-type Hard palate Stage 2A	Chemoradiation with 50.4GY (1.8Gy x 28fx)	Fentanyl 120 MME	Hydromorphone 56 MME	The most recent record was 26mo after radiotherapy and patient was continuing fentanyl and oxycodone (MME CNBC). He had follow-up with pain management while undergoing radiotherapy, but none after treatment.	Chronic sinus infection with discharge and headaches. This required hard palate debridement 13mo after completing radiotherapy followed by multiple intermittent debridements.
	19	35yo Non-Hispanic White Male Never smoker English	SCC Pyriformis sinus Stage 3	Chemoradiation with 70GY (2 GY × 35fx)	NSAIDs	Oxycodone 27.78 MME Anti-histamine Magic mix NSAIDs Sodium selenite Zolpidem	Followed by pain specialists 17-66mo after radiotherapy. Discontinued all opioids 39mo after completing radiotherapy.	Re-irradiation after childhood lymphoma. Very severe dysphagia with complete hypopharynx stricture requiring multiple dilations and PEG dependence.
	20	87yo Non-Hispanic black Female Never smoker English	SCC Mouth floor Stage 4A	Surgery (segmental mandibulectomy, resection of the mouth floor and ventral tongue, bilateral lymph node dissections, and fibula free flap reconstruction) followed by radiotherapy with 60GY (2GY × 30fx)	Hydrocodone Oxycodone MME CNBC Acetaminophen NSAIDs	Oxycodone 30 MME Acetaminophen	Discontinued all opioids 21mo after completing radiotherapy. She had no pain management follow up.	Osteoradionecrosis and bone/plate exposure requiring debridement and local flap at 8mo after radiotherapy. Plate exposed again which required removal 20mo after radiotherapy.

Abbreviations: CNBC, could not be calculated; FU, follow up; fx, fraction(s); MME, morphine milligram equivalents/day; Mo, month(s); No., number; NSAID, non-steroidal anti-inflammatory drug; Pt, patient; Ref., reference; SCC, squamous cell carcinoma; SSR1, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; y, year; yo, year old.

4 |. DISCUSSION

This is the first report describing long-term outcomes (≥1 year) of treating patients undergoing curative-intent radiotherapy with opioids to manage pain from tumor or treatment. We identified 20 of 276 (7.2%) head/neck cancer patients who continued using opioids 1 year after radiotherapy. All or none of these 20 patients may have continued due to medical indications and all or none may have continued due to OUD (0%−7.2% of the total cohort). However, qualitative analysis of the physician records suggests that 17 of 20 (85% or 6.1% of the total cohort) continued due to clearly documented pain syndromes, mainly related to overt complications such as osteoradionecrosis. The other 3 of 20 (15% or 1.1% of the total cohort) were suspected by the treating physician to have an OUD or the reasons for continuation were not documented. These findings suggest that, among head/neck cancer patients without persistent or recurrent disease after radiotherapy, long-term opioid use is due primarily to medical indications rather than suspected OUD. Further, at least two of the three patients with suspected OUD discontinued opioids within 2 years of completing radiotherapy (18 and 19 months, one patient was lost to follow-up after 14 months) suggesting that OUD causing indefinite opioid use is very uncommon.

Our findings differ from a previous review synthesizing 34 studies on OUD in cancer patients that reported approximately 1 out of 5 (20%) are at risk of developing an OUD based on screening questionnaires and urine drug screens.¹⁹ However, the studies used in the review were conducted primarily in palliative and end-of-life care patients rather than curative-cancer treatment patients. A distinction between these populations is important. Patients in this study undergoing curative-intent therapy appeared to have a comparatively low rate of suspected OUD (1.1%) based on their treating physicians’ documented interviews and assessments. This may be due to the methodology of assessment for OUD. If the screening methods in the review were used on our cohort, the suspected OUD rate at 1 year could in theory include all 20 of the patients with long-term opioid use (7.2% of the cohort). This conservative estimate would be considerably higher than the rate we obtained by categorizing the treating physicians’ documented interviews and assessments (1.1% of the cohort), but would remain markedly lower than the previously reported 20% for palliative and end-of-life care patients. To our knowledge, this is the first study to report such an outcome so there are no available comparisons in the literature. However, there is an abundance of research on the pervasive problem of undertreatment of cancer pain. Two meta-analyses found approximately 33%−50% of cancer patients are undertreated for pain.^20,21 This is associated with poorer quality of life, greater depression, and more emergency room visits and hospital admissions.²² Undertreatment of pain is often due to patient and provider fear of triggering an OUD.²³ Based on the findings in this study, the risk of this outcome appears to be low in the curative cancer treatment setting.

The risks of opioid use are not negligible and risk stratification is an important aspect of opioid management. High maximum opioid dose and opioid initiation for cancer-related pain before radiotherapy were found to be associated with long-term opioid use. These associations may have been due to more severe complications of treatment, such as osteoradionecrosis, or due to the addictive properties of opioids. The more severe complications explanation suggests pre-radiation opioid use and maximum opioid dose may be markers of excessive pain requiring aggressive opioid management, rather than underlying causes of long-term use. For example, surgical patients tended to use opioids before radiotherapy more than nonsurgical patients. This may be because opioids are routinely prescribed in combination with non-opioid analgesics to manage postoperative pain. The addition of postoperative radiotherapy likely increases the risk of chronic pain syndromes (eg, trismus, neck fibrosis) that require more aggressive and long-term opioid management. The use of opioids at the intake visit could, therefore, be considered an early marker of patients who are at increased risk of long-term complications of cancer treatment.

Another possible reason high maximum dose and pre-radiation opioid use were associated with long-term opioid use is because of the addictive properties of opioids. Previous reports have linked both high doses of opioids and long duration of use to OUD.²⁴ In our cohort, longer durations of opioid use occurred in patients who started opioids before radiotherapy and continued through at least 6 weeks of treatment, including the three patients with suspected OUD. The longer duration of use in the first year of radiotherapy may have contributed to these three being assigned to the suspected OUD group. Duration and high maximum opioid dose may also explain the outcome of patient #17 in Table 3 who had a maximum opioid dose of 600 MME/d and who continued using opioids for at least 2 years after radiotherapy. He continued opioid use for medical indications (osteoradionecrosis and severe trismus limiting mouth opening to 1–1.5 cm), but began displaying aberrant/addictive behavior at 24 months of follow-up. This suggests severe treatment complications and the addictive properties of opioids may both be important contributors to long-term opioid use with varying influences in different patients at different time points. An awareness of maximum opioid dose and pre-radiation opioid use as overall risk factors for long-term use may enable clinicians to identify groups of patients who could benefit from additional attention, possibly from pain management specialists, to wean off opioids as their sources of pain resolve.

This study was conducted in head/neck cancer, but the findings may be applicable to the use of opioids in other curative cancer treatment settings. Head/neck patients are known to have the highest prevalence of pain of all cancer sites.⁵ They also have the highest association with alcohol use and one of the highest associations with tobacco use.²⁵ In our cohort, 58% had past or current tobacco use and 23% had past or current nontobacco substance use disorders. Despite these risk factors for misuse, patients had relatively low rates of longterm opioid use (7.2%) and long-term use due to suspected OUD (1.1%).²⁶ If other cancer populations have comparable or fewer risk factors for OUD, the risks of opioid treatment for those patients may be similar or even better than that seen in this study. Clinicians from many areas of oncology treating with curative intent might consider using the risk profiles and outcomes demonstrated in this study to contribute to clinical decision-making and discussions with patients regarding the risks and benefits of opioid use for managing pain related to cancer and/or cancer treatment. Further, the data from this study may have implications for state and federal regulation as policy makers consider the degree to which cancer patients should be included in ever-tightening limitations on opioid prescribing implemented in response to the opioid epidemic in the United States.

The primary limitation of this study is its retrospective nature. Florida’s controlled substance monitoring database, E-FORCSE, was not available because Florida law does not permit its use for research purposes (personal communication, Florida Prescription Drug Monitoring Program, E. Marshall, B.S., 11/2017). As a result, data collection was limited to the institutional EMR. This likely affected data related to opioid use statuses, opioid doses, and qualitative assessments. Most radiation oncologists’ notes provided detailed descriptions of opioid use, but few notes from other specialists did, causing opioid data to be derived from less reliable medication lists. In addition, opioids prescribed by providers outside our institution might not have been accounted for. A prospective study could be designed to improve the integrity of opioid use data with (a) access to a drug monitoring database, (b) tracking of opioid doses between visits (maximum opioid dose was likely underreported in many patients without this), (c) detailed questionnaires regarding pain assessments, (d) more aggressive effort to ensure patients followed up at 1 year (±2 months), and (e) evaluation of substance use with periodic urine tests.

Another limitation of this study was patient selection from a single academic hospital. This may introduce a bias relating to the patient population the hospital serves. However, the baseline characteristics presented in Table 1 were fairly representative of national averages with the exception that our cohort included a relatively high minority representation with Hispanic ethnicity at 37% and non-English primary language at 25%. Comparing the demographics and outcomes of our cohort with non-academic hospitals and hospitals in different states would help confirm the applicability of our results to the rest of the country.

5 |. CONCLUSION

In an academic hospital population of head/neck cancer patients without evidence of persistent or recurrent disease who were treated with radiotherapy and given opioids for pain control, the incidence of continued opioid use at 1 year was 7.2%. Secondary qualitative analysis of each case of continued opioid use suggests well-documented continuing pain syndromes in 6.1% and suspected OUD in 1.1% of the cohort. High maximum opioid dose and opioid use for cancer-related pain before radiotherapy were associated with long-term opioid use. These may be due to the addictive properties of opioids or to more long-term pain issues relating to surgery or to the combination of surgery and postoperative radiotherapy. Given head/neck cancer’s high prevalence of pain and high correlation with substances of abuse, clinicians and regulators should consider that the results from this study may be applicable to the use of opioids in other curative-intent cancer populations with similar or better risk profiles for opioid misuse. In the setting of an opioid epidemic, these results may inform decision-making for clinicians relating to their individual patients and for regulators at the state and national levels.