Opioids for oral mucositis-related pain: a narrative review

Introduction

Oral mucositis (OM) is a common side effect of cancer treatment and affects more than 75% of patients undergoing cancer therapy (1,2). Compared with patients who do not develop OM, patients who develop OM have twice the risk of developing infections, including life-threatening systemic sepsis, during periods of immunosuppression, and 4 times the risk of death (3-5). Furthermore, patients with OM often require increased supportive care measures such as fluid replacement, pain management, and prophylactic antibiotics, which increases their hospitalization time and cost of care (2,3). To better understand and manage OM-related pain, researchers have investigated the temporal characterization and toxicity kinetics of the condition. Because OM causes both nociceptive and neuropathic pain, a combination of drugs that target both the nociceptive and neuropathic elements would appear to have a role in the treatment of OM-related pain (6). Based on this theoretical framework, single-agent opioid analgesics are not expected to fully access the nociceptive pathways of OM-related pain.

A lack of high-quality studies has resulted in limited evidence for the treatment of OM-related pain. The clinical practice guidelines of the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society of Oral Oncology (ISOO) offer mostly preventive measures, and treatment recommendations were prematurely limited to the use of topical 0.2% morphine mouthwash (7), later controverted with more recent studies. Studies of targeted therapies, including growth factor inhibitors and anti-inflammatory cytokine inhibitors, have been inconclusive (1). Even before they undergo definitive cancer treatment, many patients are already receiving opioid analgesics for cancer-associated pain. Therefore, these patients, rather than being opioid-naïve, receive escalating doses of opioids for OM-related pain. Because OM often results in moderate to severe pain, most patients, even those already receiving the agents for cancer-related pain, are treated with opioid analgesics at high doses (8). Given the lack of OM-specific treatment guidelines, clinicians often rely on their clinical expertise and the World Health Organization (WHO) analgesic ladder. The WHO analgesic ladder provides guidelines for stepwise medication intensification, but it is neither patient- nor pain syndrome-specific, which can limit its effectiveness in guiding analgesic treatment. Thus, approximately one-third of cancer patients receiving treatment for OM still present to the emergency department with uncontrolled pain (9). Given the lack of standard guidelines, we reviewed the current literature for studies investigating the use of opioid analgesics for OM-related pain in cancer patients. We present this article in accordance with the Narrative Review reporting checklist (available at https://joma.amegroups.com/article/view/10.21037/joma-24-4/rc).

Methods

A systematic search of the literature was constructed and performed by a qualified medical librarian (Rachel S. Hicklen).

Search strategy: on November 3, 2023, our qualified medical librarian conducted a literature search utilizing terms included the following: (oral or mouth or tongue or gums), oral mucositis/ or *Stomatitis. (opioid* or opiate*), Analgesics, Opioid/. MEDLINE (Ovid), Embase (Ovid), and Scopus were queried including the timeframe during which eligible articles were published, using both natural language and controlled vocabulary terms for “oral mucositis”, “pain”, and “opioids”. Results were limited to English language articles, exclusively addressing the use of opioids in OM queried from November 2, 2018, through November 2, 2023. Publications on conferences abstracts were eliminated. After duplicate articles were removed, the authors consensus yield to 117 unique records (MEDLINE, n=45; Embase, n=69; Scopus, n=3) were identified and included in this review. Only a subset of these 117 articles were considered relevant for the review (Figure 1, Table 1).

Figure 1 PRISMA 2020 flow diagram.

Discussion

OM pathogenesis

Although the mechanisms of chemotherapy-induced OM and radiation-induced OM are thought to be similar, chemotherapy-induced OM usually occurs within 1 week of treatment initiation and resolves within 3 weeks, whereas radiation-induced OM usually takes longer to develop and usually resolves within 3–4 weeks after treatment (10). The pathogenesis of OM is complex and multifactorial and occurs over five phases: (I) initiation; (II) primary damage response; (III) signal amplification; (IV) ulceration; and (V) healing (11,12). In the initiation phase, chemotherapy or radiation induces DNA damage that results in the death of the basal epithelial cells and the generation of reactive oxygen species (1,3). In addition to causing direct cell death, reactive oxygen species cause indirect cell death by upregulating proinflammatory cytokines. In the ulceration phase, metabolic byproducts of the colonizing oral bacterial flora and inflammatory cells can further infiltrate the submucosa, activating tissue macrophages and resulting in clinically apparent mucosal damage (11). The intensity of OM-related pain and the risk of infection are greatest during the ulceration phase (12). Lastly, the healing phase occurs as the integrity of the epithelium is restored. In several models of radiation-induced OM, the ulceration phase also includes the activation of transcription factors, such as nuclear factor kappa B, and the release of several pro-inflammatory cytokines (e.g., interleukin-1) (13,14). In both patients with chemotherapy-induced OM and those with radiation-induced OM, a superimposed infection during the ulceration phase can lead to a detrimental infection, including bacteremia and sepsis. In this population, the proposed immunosuppressive effects of opioids must be considered when choosing analgesics (15,16).

Studies of OM-related pain patterns suggest that the descriptors “sore” and “aching” indicate a component of inflammatory and nociceptive pain, whereas the descriptor “burning” is often reported with the pathobiology of neuropathic pain and/or the escalation of pain intensity, which is likely underdiagnosed and mismanaged (17,18). During cancer treatment, the onset of symptomatic OM and associated pain intensifies; as a result, low- or weak-dose, then high- or strong-dose of opioid analgesics are frequently needed. However, the high complexity of the patient population mandates a multimodal management.

OM grading

Scales for grading the severity of OM include the WHO scale, which is scored from grade 0 to grade 4, based on the presence or absence of erythema, ulceration, and alimentary compromise (Table 2) (19). The severity of OM can depend on different risk factors, including age, sex, smoking status, and nutritional status, as well as genetic predisposition and microbial effects (20). Another commonly used scale is the National Cancer Institute (NCI) described in Table 3 (21), which includes one scale measuring Mucositis Functional/Symptomatic Score and the other measuring Mucositis Clinical Score, both also graded from 0 to 4.

Mechanisms and administration of opioids

Opioid receptors

Opioid receptors, which are located throughout the peripheral and central nervous system, predominantly in the dorsal horn of the spinal cord (22), play an important role in pain modulation. The mu (µ) opioid receptors are found primarily in the brain stem and medial thalamus, where they modulate input at the supraspinal level (23). Different µ receptor subtypes are responsible for supraspinal analgesia and side effects that include respiratory depression, euphoria, sedation, decreased gastrointestinal motility, and physical dependence (23). The kappa (κ) receptors, found in the limbic and other diencephalic areas, as well as the brain stem and spinal cord, are responsible for spinal analgesia and side effects like those associated with the µ receptors. The delta (δ) receptors are not as well studied as the µ and κ receptors, but they are believed to influence mechanical and inflammatory pain as well as psychomimetic and dysphoric effects (24).

Opioids produce their analgesic effects by binding primarily to the µ receptors. Activated opioid receptors initiate molecular pathways to indirectly inhibit nociceptive fibers’ release of pain neurotransmitters, such as glutamate, substance P, and calcitonin gene-related peptide, resulting in analgesia (25). Opioids are classified as agonists, partial agonists, or antagonists, depending on their actions on the opioid receptors. An agonist has both affinity and efficacy, whereas an antagonist has affinity but not efficacy (26); a partial agonist has only partial affinity.

Opioids that are commonly used clinically, including codeine, morphine, hydrocodone, oxycodone, hydromorphone, and fentanyl, are opioid agonists and provide analgesia by activating the opioid receptors. Methadone, a synthetic µ receptor agonist, also acts as an antagonist of the N-methyl-D-aspartate (NMDA) receptor, which makes it a useful agent for treating neuropathic pain. Tramadol, in addition to its action on the µ receptors, has noradrenergic and serotonergic effects. Buprenorphine is a partial agonist of the µ receptors and an antagonist of the κ receptors, making it useful in opioid abuse, detoxification, and maintenance therapies (27).

Opioid metabolism

Most opioid metabolism occurs in the liver, through either glucuronidation or the cytochrome P450 system. Each agent’s metabolic pathway is unique. Multiple factors, including variations in individual patients’ opioid receptors, affect the metabolism, absorption, and clearance of an opioid (28). The polymorphic nature of the genes that encode opioid receptor enzymes leads to substantial variation in drug pharmacokinetics among patients (29). Whereas patients with the ultrarapid metabolizer phenotype may have supratherapeutic levels of morphine, patients who lack the phenotype may not experience the analgesic effects of opioids (30). Furthermore, because cytochrome P450 enzymes are involved in the metabolism of many different drugs, drug interactions can also play a key role in the effectiveness of analgesia achieved, particularly in cancer patients with a complex medical history and/or medication list.

Opioid administration

Routes of opioid administration include oral, sublingual, buccal, intranasal, transdermal, intravenous, and intrathecal administration. Given its convenience and flexibility, oral administration is often preferred. However, oral administration may not be possible for many cancer patients, including those with OM. Transdermal administration may be preferred for patients who cannot tolerate oral administration, especially those who have OM and cannot tolerate sublingual or buccal administration.

Opioid-based treatment of OM

In patients with OM, pre-treatment pain is an independent predictor of poor survival (31). Challenges in selecting agents for pain control in patients with OM include organ failure, intolerance of oral administration, polypharmacy, anxiety, psychiatric disorders, addiction, allergies, poor tolerance of medications, and lack of insurance coverage. These findings are in alignment with the rates of acute toxicities among head and neck cancer patients in recent randomized controlled clinical trials, in which 42–46% of patients had grade 3 or 4 OM and 15% had severe acute pain (32). However, these toxicity rates may not be accurate, as the trials lacked temporal information about how acute pain was managed.

The most recent MASCC and the ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy are largely focused on prevention measures (33). In fact, the updated guidelines no longer include information about the use of transdermal fentanyl. The only treatment the guidelines mention is the use of 0.2% morphine mouthwash for head and neck cancer patients receiving chemoradiotherapy, a suggestion that was based on grade III evidence.

Our literature review identified 9 clinical studies of opioid use for OM-related pain in cancer patients (Table 4). A study by Nielsen et al. demonstrated that topical morphine did not result in significant pain relief compared to placebo (34). These findings are contradictory to the suggestions made by MASCC and ISOO.

Schaller et al. (35) reviewed 63 head and neck cancer patients with radiation-induced OM. Most patients (78%) used opioids; among these patients, most received a combination of a long-acting fentanyl patch and short-acting oral morphine as needed. Other analgesic treatment included acetaminophen (84%) and non-steroidal anti-inflammatory drugs (48%). Although the WHO analgesic ladder was followed, 21 patients (33%) reported moderate to severe pain. In the moderate-to-severe pain group, the median opioid dose was 120 mg oral morphine equivalent per day at the time of highest mucositis grade and highest opioid dose. Given the high opioid doses reported in this study, it is not surprising that Joshi et al. (36) found that tramadol, a weak opioid, did not have an effect like that of diclofenac. Given the severity of OM-related pain, most patients with OM will likely often require strong opioids, per the WHO guidelines.

Hu et al. in 2018 (37) followed 60 nasopharyngeal carcinoma patients who had OM and were receiving extended-release (ER) oxycodone. They divided the patients into an experimental group [i.e., those with moderate pain scores on a numerical rating scale (NRS)] and a control group (i.e., those with severe pain scores on the NRS). Each patient’s ER oxycodone dose was increased up to 30 mg twice daily until the patient’s pain score on the NRS was 3 or less. The authors reported an average pain relief rate [(NRS score before administration − NRS score after 24 hours of administration)/NRS score before administration × 100%] of 78.3%. Similar study was replicated by Sun et al. in 2020 (38) on a larger population utilizing a randomized, double-blind, placebo-controlled approach. Both studies concluded that the combination of OxyContin and standardized nursing care improved the analgesic efficacy and life quality in patients treated for nasopharyngeal carcinoma.

However, the validity of both studies is questionable given the poor design of the study, as well as unrelated variables (dose of radiotherapy and the use of OxyContin were directly correlated), and non-defined and unmeasurable variables (standardized nursing care), were proposed as the intervention that improved the analgesic efficacy.

In a similar study, Hua et al. (39) followed 56 nasopharyngeal carcinoma patients who had OM and no previous exposure to opioid analgesics. The patients were divided into two groups: a moderate pain group (NRS score of 4–6) and a severe pain group (NRS score of 7–10). For each patient, ER oxycodone was started at 10 mg twice daily and was increased by 20 mg per day until the patient’s NRS score was 3 or lower. Most patients (85.7%) had a pain reduction of at least 25% over 24 hours. Although the length of duration of the moderate pain and severe pain groups did not differ significantly, the titration time to achieve pain relief (i.e., an NRS score ≤3) in the moderate pain group (2.45±0.60 days) was significantly shorter than that in the severe pain group (3.60±1.98 days; P=0.012). The authors recommended that the earlier introduction of ER oxycodone at a lower pain severity may provide better pain relief and help reduce the total dose of the medication required.

In 2016, Haumann et al. (26) conducted a randomized controlled trial in 52 head and neck cancer patients who had OM with a neuropathic pain component (score >4 on the Douleur Neuropathique 4 questionnaire). Compared with fentanyl, methadone resulted in significantly greater reductions in NRS scores at 1, 3, and 5 weeks. In 2017, Haumann et al. (40) conducted another randomized controlled trial in 82 head and neck cancer patients who had radiation-induced OM and an NRS score of 4 or higher. Forty-two patients were treated with methadone, and 40 were treated with fentanyl. Methadone was not inferior to fentanyl at 1 and 3 weeks, and it decreased average pain more than fentanyl did, as evidenced by a difference of 0.75 points on the NRS scale.

In 2020, Hermann et al. (41) performed a small prospective pilot study of 60 head and neck squamous cell carcinoma patients who developed OM after receiving chemoradiotherapy. The patients were randomized to receive either (I) high-dose gabapentin (2,700 mg daily) with standard opioid therapy (hydrocodone-acetaminophen progressing to fentanyl as needed) or (II) low-dose gabapentin (900 mg daily) with methadone (5 mg twice daily titrated up to 15 mg twice daily) with oxycodone (5–10 mg up to every 4 hours as needed). Compared with those receiving high-dose gabapentin with standard opioid therapy, patients receiving low-dose gabapentin with methadone had better patient-reported quality-of-life outcomes and a significantly shorter time to the global health scale returning to baseline following treatment (4 weeks vs. 4–6 months; P=0.049) without increased risks of adverse events or pain. However, pain significantly worsened throughout treatment in both study arms, highlighting the need to identify an optimal analgesic regimen.

In 2022, Meyer et al. (42) reported that a buprenorphine-based analgesia protocol incorporating transdermal and patient-controlled parenteral drug delivery significantly reduced opioid requirements and pain on swallowing for bone marrow transplant patients with severe OM.

Limitations

Studies in which the effects of opioid analgesics were isolated from those of combinations of other adjuvant analgesic drugs were not available. Publication bias may be present. A standard methodology for conducting prospective clinical trials of pain management techniques in patients with OM has not been established.

Conclusions

Although opioids play a key role in the management of OM-related pain, research guiding clinical practice is lacking. Therefore, the use of analgesic opioids in this population is led by providers’ experience and available resources, experts’ recommendations, and by general guidelines from medical societies.

The characterization of pain in OM presents unique features such a neuropathic component which analgesic pathways are not properly compatible with opiate analgesics. Thus, patients receiving gabapentin and/or methadone, both of which fit well the neuropathic pain mechanism, reported more favorable outcomes and a significantly shorter time to recovery.

Currently, most cases of OM-related pain are treated with an approach consisting of both pharmacological and non-pharmacological treatments, including oral rinses, over-the-counter agents, and opioid analgesics. Shortcomings in patient care and thus guidelines providing a more structured approach are necessary. Clear guidelines for using opioids to treat OM-related pain would help provide a more structured approach to its management. Additional studies evaluating the efficacy and safety of opioids in patients with OM are needed.

Acknowledgments

The authors want to acknowledge Rachel S. Hicklen for her diligent librarian work.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://joma.amegroups.com/article/view/10.21037/joma-24-4/rc

Peer Review File: Available at https://joma.amegroups.com/article/view/10.21037/joma-24-4/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://joma.amegroups.com/article/view/10.21037/joma-24-4/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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