List of abbreviations
American Academy of Otolaryngology-Head and Neck Surgery Foundation
advanced pneumatic compression devices
central nervous system
enhanced recovery after surgery
Food and Drug Administration
glomerular filtration rate
head and neck cancers
morphine milligram equivalents
National Comprehensive Cancer Network
nonsteroidal antiinflammatory drugs
opioid use disorder
patient controlled analgesia
peripheral nervous system
per os (by mouth)
quality of life
randomized clinical trial
squamous cell carcinoma
surveillance, epidemiology, and end results
serotonin-norepinephrine reuptake inhibitors
World Health Organization
Introduction: head and neck cancer-associated morbidity and pain
Head and neck cancers (HNCs) account for ∼5% of cancers globally (excluding nonmelanoma skin cancers) and are associated with significant morbidity including pain. HNCs primarily include malignancies of the oral cavity, oropharynx, nasopharynx, sinonasal cavities, hypopharynx, larynx, skin, and salivary glands. Prognoses for this group of cancers have only modestly improved with advances in surgical techniques, therapeutic radiation methodology, and novel targeted and immune-modulating systemic agents. There is a rise in HNC incidence rates from 2000 to 2018 according to the surveillance, epidemiology, and end results database with increased survivorship in large part related to the rising incidence of HPV-associated oropharyngeal cancers. The improved survivorship necessitates concomitant progress in managing the negative sequelae of these malignancies and their treatments, such as pain syndromes commonly associated with HNC. Acute pain syndromes are experienced by up to 80% of patients with HNC, with chronic pain in up to 60% of cases. ,
HNC and its treatments negatively impact patient quality of life (QOL) by causing pain, difficulties with swallowing, eating, phonation, and speech, and worsening psychosocial health that can manifest as depression, anxiety, and suicidal ideation. Importantly, these HNC-related morbidities do not exist in isolation, but intimately influence one another. Thus, understanding and alleviating pain has the capacity to improve not only the physical discomfort, but multiple aspects of QOL. For instance, greater pain is associated with an increased risk of suicide in advanced cancers. , Survivors of HNC compared to all other cancers combined were twice as likely to die from suicide, and the incidence of suicide in patients with HNC is worsening with an increase of 27% during the period from 2010 to 2014 compared to 2000–04. Benefits of pain control extend beyond improving other elements of patient QOL and are also associated with improved surgical outcomes and reduced overall healthcare system burden.
Pain control methods in HNC include multimodal therapeutic approaches involving opioid and nonopioid analgesics for a variety of malignancy and treatment-associated pain syndromes. Guidelines for optimal pain control in HNC are shifting with increasing knowledge of the efficacy and risks of analgesic interventions. The World Health Organization’s (WHO) three-tiered cancer pain treatment ladder, beginning with nonopioid analgesics for less severe pain and increasing to stronger opioids for more severe and refractory pain, has been a widely used general guideline for treatment escalation ( Fig. 7.1 ). Recent guideline updates from both national and international groups support the use of multimodal pain control regimens that expand treatment options and emphasize opioid stewardship. Collectively, these guidelines highlight that high-quality pain management should be an integral part of cancer care, with pain management screening at each patient contact, and a personalized plan for each individual with strong consideration of the risks associated with specific interventions in each case. Overall guiding principles of cancer pain management recommend that when possible treatment be given by mouth, on a scheduled basis, with upfront patient education regarding a plan. Herein, we review opioid and nonopioid analgesic therapies for HNC-associated pain.
HNC-associated pain syndromes and neurobiological mechanisms
HNC-associated pain is often heterogenous in its neurobiological mechanisms, with a mixed etiologies due to the disease itself as well as treatment side-effects. Within this complex pain picture, common pain syndromes have been described that are associated with specific disease statuses and/or anticancer treatment sequelae ( Table 7.1 ). These syndromes include acute and chronic pain from head and neck surgery, neuropathic pain, postradiation pain, myofascial pain, mucositis, dermatitis, symptomatic lymphedema, and skeletal pain, among others. The neurobiological etiology of the pain experienced in these syndromes should be addressed by analgesic treatment paradigms when possible. Ideally, optimal pain control strategies are individualized to target the characteristics of each patient’s pain patterns.
|Pain syndrome||Relation to disease and/or treatment||Treatment options overview|
|Surgery-associated acute and chronic pain a||Acute disruption of local soft tissue and/or nerves and chronic fibrosis, structural tissue changes, irreversible nerve injury|
|Postradiation pain a||Acute dermatologic and/or mucosal disruption and nerve injury, chronic scarring, fibrosis, or adhesions|
|Neuropathic pain a||Damage from invasive diagnostic (biopsy) or treatment procedures/radiation, local tumor invasion. Distinguished from nociceptive pain from end-organ pain stimuli|
|Myofascial pain||Severely sensitive muscle injury due to tumor or treatments|
|Mucositis a||Acute effect of radiation and/or chemotherapy|
|Dermatitis a||Acute effect of radiation and/or chemotherapy|
|Symptomatic lymphedema a||Damage to lymphatics due to tumor or invasive treatments|
|Skeletal pain||Acute pain of local tumor destruction or treatment-induced osteonecrosis|
a Treatment is further discussed in Section “Management updates for common HNC-associated pain situations and syndromes”.
Further distinction of the acute or chronic nature of the pain can help establish the pain syndrome and influence treatment choice. Two time points wherein acute pain is common include malignancy-induced pain seen at initial patient presentation and in the course of treatment including surgery, chemotherapy, and/or radiotherapy. Treatments can cause disruption of tissue in and around the tumor bed, with localized inflammation and edema causing nerve compression, mucositis, and dermatitis. Chronic HNC-associated pain can be defined as pain lasting longer than 3–6 months or that extends beyond the period of “normal” healing time. In HNC this is often ongoing pain directly related to persistent malignancy or longer-term sequelae of the anticancer therapies but frequently has unclear and mixed etiologies. Multiple studies in the late 1990s and early 2000s assessed the prevalence of chronic pain in cancer patients and within the subpopulation of patients with HNCs. A meta-analysis of 52 studies spanning clinical data over 40 years found that 33% of cancer patients continued to experience pain after curative treatment and that patients with HNC had the highest prevalence of pain in a subgroup analysis of pooled data including all disease severities and treatment outcomes (70% in HNC with vs. 50% in all cancer types). Similarly, a prospective study evaluating the longitudinal prevalence of pain in patients with HNC found that 26% of patients in their cohort ( n = 93) continued to experience pain 24 months after completing curative treatment. However, this study found that the prevalence of “severe” pain decreased posttreatment, with 8% of patient reporting severe pain at their first encounter and 4% at 24 months posttreatment. Recently, an analysis of 296 5-year HNC survivors in France revealed that nearly two-thirds of patients continued to experience pain up to 5 years after treatment. Multivariate analysis of this dataset identified decreased levels of physical activity, oropharyngeal original primary tumor site, and a lower level of education as significant risk factors for chronic pain. Importantly, in patients with HNC who have received curative treatment, it is essential to evaluate for possible cancer progression or recurrence if new pain arises or chronic pain worsens. It is also important to acknowledge many HNC patients have comorbid conditions that can contribute to chronic pain.
Mechanistically, HNC-associated pain is classified into nociceptive and neuropathic pain ( Table 7.2 ).
|Type||Neural mechanism||HNC example|
|Nociceptive||Visceral||Stimulation of pain receptors on normal sensory nerve endings||Lung metastases|
|Somatic||Mucosal tumors; bone invasion|
|Neuropathic||Nerve compression||Stimulation of nervi nervorum||Mass effect on cranial nerves of spinal rootlets|
|Nerve injury||1. Lowered firing threshold in PNS sensory nerves |
2. Injury to the CNS
3. Mixed PNS + CNS injury
|Tumor invasion of cranial nerves or the skull base|
|Sympathetically maintained||Sympathetic nervous system dysfunction||First-bite syndrome and parapharyngeal surgery|
Nociceptive pain is caused by the activation of normal nerve endings of C and Aδ fibers, often from noxious stimuli and damage to nonneuronal tissue. In HNC, nociceptive pain can be caused by the destruction of local tissue by the tumor itself, invasive diagnostic and therapeutic interventions including surgery, or by effects of radiation and chemotherapy such as mucositis, dermatitis, and local injury in the tumor treatment field. , , Nociceptive pain is subcategorized as somatic and visceral based on location and quality. Somatic pain is perceived as well-localized often sharp and/or stabbing pain, while visceral pain, mediated by the sympathetic nervous system, is more diffuse, can be referred from another area, and has a dull or achy quality. Treatments helpful in nociceptive pain include agents that inhibit inflammatory signaling and central and peripheral neurotransmission pathways.
Neuropathic pain is caused by damage to the nerve itself resulting in increased, abnormal activation patterns. Frequently, this is perceived as a burning and/or tingling sensation. In HNC, neuropathic pain can be caused by tumor invasion or compression of nerves in either or both the peripheral nervous system or central nervous system (CNS). , Analgesics that can be utilized in neuropathic pain include more centrally acting neuromodulating therapeutics that are historically utilized in the treatment of general neurologic and psychiatric disorders.
Despite these distinctive neurologic causes of pain, the experience of pain in HNC is complex. Potter and colleagues found that in HNC patients who had pain present at the time of diagnosis, 93% had mixed nociceptive and neuropathic pain. Additionally, the intricate anatomy of the head and neck and the invasive patterns of primary cancers in this region contribute to the variability of pain across different types of HNCs. For instance, it has been proposed that the higher density of nerve endings in the oral cavity coupled with the higher propensity of oral cavity cancer to invade bone contribute to higher reported pain in oral cavity cancers compared to those within the larynx and pharynx, in some studies. , , Moreover, in their most recent update, the International Association for the Study of Pain now defines pain as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage,” incorporating the psychological aspects of pain.
Treatment overview for HNC-associated pain
Overview of analgesics and pain management in HNC
Given the heterogeneity of HNC-associated pain, multiple pain modifying pharmacologic and nonpharmacologic strategies exist. Analgesics refer to any intervention that modifies pain. Analgesics can be categorized into opioid, nonopioid, and other treatments ( Table 7.3 ).
|Analgesic category||Example agents/techniques|
|Common opioid pharmacologic agents|
|Nonopioid pharmacologic agents|
|Nonpharmacologic pain-modifying interventions|
Opioids include a range of naturally occurring, semisynthetic, and synthetic compounds that modulate opioid receptors in the CNS and peripheral tissues through a variety of mechanisms. Opioids are available with different strengths, routes of administration, and length of their analgesic effects that can be tailored to the pain level and lifestyle of each patient. The potencies of different opioids and routes of administration can be approximated relative to morphine utilizing established and widely available conversion tables.
Nonopioid analgesics include pharmacologic and nonpharmacologic techniques with varying mechanisms of actions, many of which are being actively studied for their role in cancer pain modulation ( Table 7.4 ). Annex six in the WHO Cancer Pain Guidelines provides detailed resources for drug profiles and important prescribing information of many of these medications including acetylsalicylic acid, codeine, fentanyl, hydromorphone, ibuprofen, methadone, morphine, naloxone, oxycodone, paracetamol. Nonpharmacologic analgesic treatments include physical therapy, compression devices, nerve stimulation, acupuncture, and mind–body techniques.
|NSAIDS||Ibuprofen, ketorolac, celecoxib, acetylsalicylic acid|
|Steroids||Dexamethasone, methylprednisolone, prednisolone|
|Anticonvulsants||Carbamazepine, gabapentin, Pregabalin|
Treatment of HNC-associated pain is a multistep process. First, a thorough assessment of the pain’s location and severity, its impact on QOL, and patient’s goals of care is done. Multiple tools exist for the initial evaluation including the Brief Pain Inventory form, Pain Observation Tool, Comprehensive Pain Assessment, Pain Assessment with Advanced Dementia, and Integrated Palliative Care Outcome Scales. , Pain-related health consequences should also be assessed including depression, anxiety, and suicidal ideation. If these are identified they should be treated expeditiously as part of the overall cancer care plan.
In the pain management plan, treatment should then be selected based on the results of pain evaluation in the context of the individual’s goals of care, medical comorbidities, lifestyle, and personal beliefs. HNC-associated safety risks should be considered. Direct tumor and treatment effects on the upper airway make some analgesic side effects such as nausea, vomiting, and respiratory depression uniquely dangerous. Additional considerations include an increased risk of opioid dependence in this population and growing evidence of the superior therapeutic efficacy of multimodal opioid-free analgesic treatments, as described in the following subsections. Collectively, recent society guidelines support the use of opioid-sparing regimens, often with acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs), for mild-to-moderate pain, addition of longer-acting opioids when pain is severe and/or insufficiently controlled with other multimodal techniques, and rapid-acting analgesics available for breakthrough pain. , Some nonopioid analgesics such as NSAIDs continue to be used cautiously in perioperative settings because of their perceived bleeding risk, although data on actual bleeding risk are conflicted. Again whenever possible, medications should be given enterally on a scheduled basis.
Ideally pain management includes both psychosocial care and pharmacologic treatments. It is important to recognize that the experience of pain is multifactorial and includes both neurological physiology described above and psychological, social, cultural, and spiritual contexts.
Special considerations for opioid use in HNC
Opioids are often used to treat general pain and pain syndromes associated with HNC in the acute and chronic settings. However, due to their risks and emerging evidence for opioid-sparing analgesia, there is strong support to increase usage of nonopioid therapies. Nonetheless, opioids remain a staple for alleviating acute and chronic, moderate-to-severe pain (4–10 of 10 on the pain scale) in HNC. Guidelines from the WHO and National Comprehensive Cancer Network (NCCN) provide detailed recommendations for their use in adult cancer pain. , ,
Selection of the specific opioid, dose, and route of administration are done on an individualized basis. Commonly, pure agonists such as morphine, oxycodone, and fentanyl are used for cancer pain. Morphine is often one of the preferred first-line agents for opioid-naïve patients, with a starting dose of 5–15 mg PO for moderate pain or 2–5 mg IV for severe pain. , , Of note, active morphine metabolites can accumulate in patients with renal disease; extra caution should be taken in these cases. When possible, the WHO recommends an oral route of administration; however, this can be complicated in HNC where tumor and treatments can affect swallowing, medication safety, and where certain topical formulations may help with localized symptom management while limiting systemic side effects. When prescribing opioids, clinicians should utilize the lowest effective dose for the shortest duration to limit the risk of developing opioid dependence. Effective dosing often varies patient-to-patient due to individual opioid tolerance and metabolism. For instance, genetically derived variations in CYP3A4 enzymatic activity results in inconsistent codeine metabolism to its active metabolite, leading to variable pain control and increased toxicity risks. Prescribing pain medications individually rather than in combined formulations enable dose titration of each analgesic independently. Short half-life agents such as oxycodone and morphine also assist with dose titration.
Since the late 1980s, multiple clinical studies have compared the efficacy of opioids at alleviating acute and chronic pain in cancer patients. Collectively, no consistent advantage has been attributed to a specific choice of opioid for time to pain relief, durability of the analgesic effect, overall QOL benefit, and tolerance of adverse effects. Bandieri and colleagues recently completed a multicenter, randomized clinical trial (RCT) comparing the efficacy of low-dose morphine and weak opioids in moderate cancer pain in patients with a variety of solid and hematologic cancers. In this study of 240 patients, low-dose morphine (up to 30 mg daily) was associated with a higher percentage of patients achieving at least a 20% reduction in their pain compared to weak opioids; both groups had comparable tolerance of adverse effects. Similarly, two recent RCTs comparing morphine and oxycodone for the treatment of cancer pain found no difference in adverse effects or pain relief efficacy between the agents. , Another recent four-arm multicenter, RCT (NCT01809106) compared PO morphine, PO oxycodone, TD fentanyl, or buprenorphine for 28 days. As in the other studies, no significant difference was found in the tolerability or efficacy of the different opioid treatment arms. Thus, the specific opioid selection is a collective decision between patient and provider, accounting for an individual analgesic response, medical comorbidities, side effect tolerability, analgesia and QOL goals, and ability to adhere to the dosage schedule.
Breakthrough pain, an acute flare in pain in the setting of chronic pain management, remains a common issue in HNC patients. A rapid-acting opioid medication, such as immediate-release morphine, can be effective to treat acute pain crises. The initial dosing will vary for opioid-naïve patients compared to patients with a history of opioid use. For opioid-naïve patients, an oral dose of 5–15 mg or an IV dose of 2–5 mg morphine sulfate is reasonable, again with the choice of other rapid-acting opioids. For patients chronically utilizing opioid medications, a dose of 10%–20% of their total opioid dose taken in the prior 24 h is recommended. Dosing should then be individually titrated based on patient assessments every 60 min for enteral formulations, and every 15 min for IV formulations ( Table 7.5 ).