n CJON Writing Mentorship Article

Role of Gabapentin in Managing

Mucositis Pain in Patients Undergoing Radiation
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Therapy to the Head and Neck

Carol Ann Milazzo-Kiedaisch, MSN, APRN, NP-C, Joanne Itano, RN, PhD, APRN, and Pinaki R. Dutta, MD, PhD

Background: Oral mucositis (OM) is a painful and debilitating side effect that affects 80%–100%
of patients undergoing radiation therapy for head and neck cancer. This dose-limiting side effect
may potentially lead to pain, dehydration, malnutrition, infection, and treatment breaks. Treatment
breaks can lead to decreased disease control and suboptimal patient outcomes. No primary preven-
tion exists for OM, and management is focused on pain control. Compelling evidence exists that
© Mark Kostich/iStock/Thinkstock OM pain has somatic and neuropathic components.
Objectives: This article reviews the existing literature on the use of gabapentin (Neurontin®) as a co-analgesic in treating
the neuropathic pain in OM.
Methods: A literature search was performed using CINAHL® and PubMed with the search terms gabapentin and oral mu-
cositis. The selected articles were briefly screened for relevance, and three were included in this review.
Findings: No systematic reviews exist on the role of gabapentin for neuropathic pain in radiation-induced OM. Two ret-
rospective studies concluded that gabapentin reduced escalation of opioid doses and unplanned treatment breaks. One
retrospective study demonstrated favorable swallowing outcomes. Pain and OM are nursing-sensitive outcomes that can be
significantly affected by evidence-based nursing interventions.
Carol Ann Milazzo-Kiedaisch, MSN, APRN, NP-C, is a nurse practitioner at Memorial Sloan Kettering Cancer Center in New York, NY; Joanne Itano, RN, PhD, APRN,
is the associate vice president for Academic Affairs and an associate professor in the School of Nursing and Dental Hygiene at the University of Hawaii in Manoa;
and Pinaki R. Dutta, MD, PhD, is an assistant attending physician at Memorial Sloan Kettering Cancer Center. The authors take full responsibility for the content
of the article. The authors were participants in the Clinical Journal of Oncology Nursing (CJON) Writing Mentorship Program. The content of this article has been
reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content
of this article have been disclosed by the authors, independent peer reviewers, or editorial staff. Mention of specific products and opinions related to those products
do not indicate or imply endorsement by CJON or the Oncology Nursing Society. Milazzo-Kiedaisch can be reached at milazzoc@mskcc.org, with copy to editor at
CJONEditor@ons.org. (Submitted December 2015. Revision submitted February 2016. Accepted for publication March 10, 2016.)
Key words: neuropathic pain; head and neck cancer; radiation therapy; radiation-induced oral mucositis; gabapentin; pain
Digital Object Identifier: 10.1188/16.CJON.623-628

C
ancers of the head and neck involve several site-
specific anatomic areas. These areas include the
oral cavity, pharynx (including the nasopharynx,
oropharynx, and hypopharynx), larynx, nasal
cavity, paranasal sinuses, and salivary glands
(National Cancer Institute, 2015) (see Figure 1). Primary
management of head and neck cancer may include surgery,
radiation therapy (RT), chemotherapy, or a combination.
Treatment plans are based on several factors, including the
stage of the cancer at diagnosis, location of the tumor, gen-
eral health status, and presence of comorbidities. RT alone
or in combination with chemotherapy or targeted therapies
has become accepted standard care for locally advanced
head and neck cancer (Pignon, le Maître, & Bourhis, 2007;
Takes et al., 2012). Chemotherapy and targeted therapies,
like cetuximab (Erbitux®), act as radiosensitizers to cancer-
ous cells and achieve increased cell kill and ideally improve
local tumor control (Lambertz et al., 2010; Takes et al., 2012).
Patients with locally advanced head and neck cancer treated
with chemotherapy and RT have been found to have an ab-
solute survival benefit of 7% at five years when compared to
patients who received RT alone (Takes et al., 2012). However,
concurrent treatment with chemotherapy and RT increases
the incidence and severity of oral mucositis (OM) as much
as 100% (Eilers, Harris, Henry, & Johnson, 2014). OM in
patients with head and neck cancer undergoing RT with or
without chemotherapy has been reported by patients as the
most distressing symptom in the treatment course (Eilers &

Clinical Journal of Oncology Nursing • Volume 20, Number 6 • Use of Gabapentin for Mucositis Pain 623

Paranasal
sinuses
Nasal cavity
Nasopharynx
Oral cavity
Pharynx Oropharynx Tongue
Salivary
glands
Hypopharynx
Larynx
FIGURE 1. Head and Neck Cancer Regions
Note. For the National Cancer Institute © Terese Winslow LLC, U.S.
Govt. has certain rights.
Million, 2011). High-grade OM (grade 3 or 4) is associated
with significant patient morbidity (e.g., pain; inability to
chew, swallow, or maintain caloric intake; unplanned hos-
pitalizations; worse quality of life) (Eilers et al., 2014; Trotti
et al., 2003).
Mucositis is one of the most common complications in
patients undergoing cancer treatment (Silverman, 2007; So-
nis, 2004a). The term mucositis refers to the inflammation
along the epithelial cells lining the gastrointestinal tract from
mouth to rectum. Oral mucositis (OM) is an inflammation of
the mucous membranes along the oral cavity, including the
gingiva, buccal mucosa, tongue, and lips. OM affects from
80%–100% of patients undergoing RT to the head and neck
(Sonis, 2004a). It is often the starting point for a cascade of
complications that leads to pain, infection, decreased nutri-
tional intake, diminished quality of life, and unplanned treat-
ment breaks, potentially leading to decreased locoregional
disease control and patient survival (Mallick, Benson, &
Rath, 2016; Trotti et al., 2003).
The presentation and course of RT-induced OM follows a
clinically predictable course. Radiation is typically given in
daily doses, referred to as fractions. A common course of RT
for treatment of head and neck cancer is about 200 cGy given
daily five days per week for an average of five to seven weeks
(Kumar, Balan, Sankar, & Bose, 2009; Sonis, 2012). OM is usu-
ally clinically evident by the third week of RT or after about
25–30 Gy of radiation have been delivered. Symptoms may
persist for more than four weeks after treatment is completed
(Sonis, 2012). Early-stage OM often presents as erythema
of the oral cavity and is commonly described by patients
as a burning or tingling sensation. The lesions can become
confluent and friable, with subsequent bacterial and fungal
colonization and overgrowth that can worsen pain and lead
to systemic infections requiring treatment breaks, hospitaliza-
tions for supportive care, and sepsis (Sonis, 2012).
With the breach in the oral mucosal membrane, secondary
infections may occur, resulting in potentially life-threatening
624 December 2016 • Volume 20, Number 6 • Clinical Journal of Oncology Nursing
systemic infections and hospitalizations (Eilers et al., 2014).
Patients with head and neck cancer who develop severe OM
from combined RT and chemotherapy are reported to incur
52% higher costs during treatment when compared to patients
who do not develop high-grade OM (Mason, DeRubeis, Foster,
Taylor, & Worden, 2013). This finding illustrates the overall
financial impact and potential burden of OM on the individual
and community.
Unplanned treatment breaks in patients with head and neck
cancer are associated with a reduction in local and regional
disease control. Clinical studies have demonstrated that ma-
lignant tumors accelerate the repopulation process during un-
planned radiation treatment breaks (Russo, Haddad, Posner, &
Machtay, 2008). OM has been identified as a dose-limiting side
effect requiring modification and interruption of the radiation
regimen, potentially leading to suboptimal disease control and
treatment outcomes (Eilers et al., 2014; Mallick et al., 2016).
This article (a) describes the presentation, pathophysiol-
ogy, and grading of OM in patients undergoing RT to the
head and neck region, as well as the types of pain these
patients experience; (b) reviews the novel role of gabapentin
(Neurontin®) as a co-analgesic to improve pain management
and possibly prevent escalating doses of opioids; and (c) de-
scribes the treatment of OM in patients with head and neck
cancers receiving RT.
Pathophysiology of Oral Mucositis
The pathophysiology of OM has historically been de-
scribed as a linear “outside-in” process, beginning with
damage of the superficial epithelial layer of the oral mucosa.
However, research has supported a more complex process.
Sonis (2004b) postulated a model that describes the dynamic
and complex process of OM where the process actually be-
gins in the submucosal endothelium and connective tissue.
This deeper damage results in a cascade of biologic pathways
that causes damage to the oral epithelium, ulceration, and
the potential for microorganisms to enter the bloodstream,
which could lead to systemic infections. The five stages con-
sist of initiation, primary damage response, signal amplifica-
tion, ulceration, and healing (see Figure 2).
Grading of Oral Mucositis
Consistent and uniform reporting of OM is important to
compare outcomes of prevention and therapeutic interven-
tions. The use of multiple grading scales made head-to-head
comparison of trials unreliable. A variety of grading systems
are used worldwide to grade the severity of mucositis, includ-
ing systems by the Radiation Therapy Oncology Group, the
World Health Organization, and the National Cancer Institute
(NCI). The NCI (2010) has developed criteria to describe
a variety of toxicities, including mucositis. The use of the
Common Terminology Criteria for Adverse Events provides a
standardized grading system used to describe and document
OM (Liu, Zhu, & Guan, 2012) (see Table 1). The use of a uni-
form standardized system allows for comparisons of multiple
studies and can assist in comparing studies and drug trials
(Trotti et al., 2003).
 Compelling evidence exists that oral hygiene and standard
oral care protocols are effective in decreasing severity and
delaying onset of OM (Kartin, Tasci, Soyuer, & Elmali, 2014).
Professional organizations, including the Oncology Nursing
Society, Multinational Association of Supportive Care, and
the International Society for Oral Oncology, recommend
that patients receive instruction on oral hygiene using a soft-
bristle toothbrush, flossing, and use of bland rinses, such as
sodium bicarbonate or saline (Kumar et al., 2009). Regular
oral assessment before, during, and for several weeks follow-
ing RT is generally recommended. Symptom management,
including pain control, remains a pivotal part of care because
no gold-standard evidence exists to reliably prevent the de-
velopment of OM in this population (Armstrong & McCaffrey,
2006; Eilers et al., 2014).
system. This can be from the direct result of tumor invasion,
such as with leptomeningeal disease, nerve plexus invasion,
or epidural metastases. Neuropathic pain is often described
as aching or burning and is usually poorly relieved with
opioids. Evidence supports that a significant percentage of
patients with head and neck cancer experience neuropathic
pain (Aiello-Laws et al., 2009; Dy, 2010).
Literature on the specific recommendations for the use
of systemic analgesics to treat pain from OM is sparse (Ling
& Larsson, 2011). The mainstay of OM pain management
has been opioid therapy, often leaving the patient open for
additional life-altering side effects, including depression,
sedation, nausea, vomiting, constipation, pruritus, and re-
spiratory depression. Opioid pain medications have been
found to be less effective in neuropathic pain, even with dose
escalation (Bar Ad, Weinstein, Dutta, Dosoretz, et al., 2010).

Pain Associated With Oral Mucositis
Pain is a common and often undertreated symptom in
patients with cancer and is a nursing-sensitive outcome. A
nursing-sensitive outcome is within the scope of nursing
practice and can be greatly affected by nursing interventions
(Aiello-Laws et al., 2009). Pain is reported in as many as 85%
of patients with head and neck cancer on presentation and
may be the first symptom of head and neck cancer in 20%–
50% of patients. Pain in the head and neck region is thought
to be multifactorial. Infiltration by the tumor into adjacent
tissue and nerves can cause pain. Surgery, chemotherapy, or
RT can cause tissue and neural destruction (Epstein, Wilkie,
Fischer, Kim, & Villines, 2009). Evidence exists in the litera-
ture that patients with head and neck cancer experience a
combination of nociceptive and neuropathic pain (Bar Ad,
Weinstein, Dutta, Chalian, et al., 2010; Epstein et al., 2009).
Nociceptive pain occurs when somatic or visceral tissue
injury results in stimulation of the nociceptive receptors in
the skin, connective tissue, viscera, or muscle. The tissue
damage can be a result of thermal, chemical, or mechanical
injury. This type of pain is typically described as dull, tender,
or throbbing. Mild to moderate nociceptive pain may re-
spond to nonsteroidal anti-inflammatory drugs, with opioids
being recommended for moderate to severe cancer-related
pain (Aiello-Laws et al., 2009; Dy, 2010; Vardy & Agar, 2014).
Neuropathic pain is estimated to be as high as 40% in
the general oncology population (Jongen et al., 2013) and
is caused by damage to the central or peripheral nervous
Co-analgesics can play an important role in improving pain
management, along with the use of narcotic pain medications
(Aiello-Laws et al., 2009). They can assist in preventing dose es-
calations of opioids and address the often untreated neuropath-
ic components of certain pain syndromes (Bar Ad, Weinstein,
Dutta, Dosoretz, et al., 2010). Co-analgesics (also referred to as
adjuvants) encompass a category of medications that were not
initially developed or officially indicated for pain management.
These co-analgesic agents were found to be particularly useful
when combined with other categories of pain medications and
include medications like antidepressants, topical anesthetics,
and anticonvulsants. With many of these agents, the onset of
pain relief is delayed, and analgesia may take weeks and re-
quire dose escalations until acceptable pain relief is achieved
(Aiello-Laws et al., 2009; Ling & Larsson, 2011).
Gabapentin, a co-analgesic agent initially developed as
an antiseizure medication, is currently recommended for
non–cancer-related pain syndromes, including diabetic neu-
ropathy and generalized anxiety disorders (Dworkin et al.,
2007). The exact pharmacologic mechanism is unclear; how-
ever, gabapentin has been shown to inhibit calcium influx
through voltage-gated ion channels found in the membranes
of neurons (Brant, 2010). Gabapentin is not protein-bound
in the bloodstream and is excreted though the renal system
(Dooley, Taylor, Donevan, & Feltner, 2007). Generally, patients
are started on gabapentin with one dose of 100–300 mg at
bedtime or daily and are gradually titrated to increasing doses
every two to three days until an acceptable level of pain relief
is achieved (Dworkin et al., 2007). Patients with impaired

Initiation phase: Message generation Signaling and Ulceration phase: Healing phase:
DNA strands break phase: Activation of amplification phase: Breach in the mucosa Cells regenerate and
and damage transcription factors and Tumor necrosis factor and secondary bacterial normal microbial flora
increased production alpha activates ceramide and fungal infections establishes
of pro-inflammatory and caspase pathways
cytokines

FIGURE 2. A Five-Phase Model Proposed to Characterize Major Steps in Development and Resolution of Oral Mucositis
Note. With permission from Springer Science+Business Media: European Archives of Oto-Rhino-Laryngology, Radiation induced oral mucositis: A review
of current literature on prevention and management, 27, 2016, p. 2,286, S. Mallick, R. Benson, & G.K. Rath, Figure 1.

Clinical Journal of Oncology Nursing • Volume 20, Number 6 • Use of Gabapentin for Mucositis Pain 625

TABLE 1. Common Terminology Criteria for Adverse
Events for Oral Mucositis
Grade Description
0 No oral lesions or discomfort
1 Asymptomatic or mild symptoms
2 Moderate pain; not interfering with oral intake; modified diet
indicated
3 Severe pain; interfering with oral intake
4 Life-threatening consequences; urgent intervention indicated
Note. From Common Terminology Criteria for Adverse Events [v.4.0], by
National Cancer Institute Cancer Therapy Evaluation Program, 2009. Re-
trieved from https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_
QuickReference_5x7.pdf
renal function or older adults may require slower titration
and a lower total daily dose. The most common side effects
include somnolence, dizziness, ataxia, edema, weight gain,
dyspepsia, and leukopenia. Older adults may require lower
overall dosing or slower titration because they are more likely
to have a variety of physiologic changes that can alter absorp-
tion and pharmacokinetics. Older adult patients also require
particular attention to other medications they may be taking
concomitantly with similar side effects because polypharmacy
is common in this age group. Patients with renal impairment
also require slower titration and lower total daily doses.
Several weeks may be required to reach therapeutic levels,
and, therefore, patients must have an understanding of the
importance of adherence with recommended daily gabapen-
tin dosage and should be encouraged to report side effects to
clinicians (Brandt, 2010; Dworkin et al., 2007).
Literature Review
A literature search using CINAHL® and PubMed databases
was conducted by a senior reference librarian with search
terms gabapentin and oral mucositis in articles published
from January 2010 to October 2015. The selected articles
and abstracts were briefly screened for relevance. Inclusion
criteria were published research studies. Abstracts, posters,
and review articles were not included. Other exclusion criteria
were nonsystemic use, topical application, or swish or swal-
low formulations of gabapentin. No systematic reviews were
found on the specific use of gabapentin for neuropathic pain
in radiation-induced OM. A total of 10 articles met the criteria,
and three retrospective studies were included in this review.
Oral Mucositis in Intensity-Modulated Radiation Therapy
A study by Bar Ad, Weinstein, Dutta, Chalian, et al. (2010)
examined the role of gabapentin to treat the neuropathic
pain syndrome in radiation-induced OM. This retrospec-
tive study evaluated the effectiveness of gabapentin as a
co-analgesic in patients undergoing intensity-modulated RT
to the head and neck. A total of 29 patients were included
626 December 2016 • Volume 20, Number 6 • Clinical Journal of Oncology Nursing
in the data analysis, but the N value was 30 because one
patient underwent two courses of radiation, and both were
included in the analysis. All of the patients had undergone
surgery for primary or recurrent disease and were treated
with radiation postoperatively from 2004–2006. No patients
received concurrent or induction chemotherapy. Two pa-
tients who received concurrent cetuximab were included in
this sample. The patients were started on gabapentin during
the second week of treatment at a dose of 600 mg at bedtime
and gradually titrated over one week to three daily doses
of 900 mg, with a total daily dose of 2,700 mg. Oxycodone
(Roxicodone®) was prescribed in addition to the gabapentin
in response to patients’ subjective pain scores, and additional
narcotic pain medications were added as clinically indicated.
The study found that, despite having grade 2 or higher OM
during the third (56%) and fourth (73%) weeks of radiation,
only 10% required additional narcotic pain medications
(15–30 mg oxycodone per day). During the final fifth and
sixth weeks of treatment, 35% required additional narcotic
pain medications despite the presence of grade 2 or higher
OM in 80% of cases. During both of these time periods, 93%
of patients were treated with a median dose of 2,700 mg/day
of gabapentin. Two patients had interruptions in treatment of
greater than three days; however, these interruptions were
unrelated to RT toxicity.
Oral Mucositis in Patients Undergoing Concurrent
Chemotherapy and Radiation Therapy
In another retrospective study conducted by Bar Ad,
Weinstein, Dutta, Dosoretz, et al. (2010), patients were
followed for seven weeks during concurrent intensity-
modulated RT and chemotherapy for head and neck can-
cers. The sample consisted of 42 patients with head and
neck cancer undergoing concurrent chemotherapy and RT
from December 2003 to November 2006. Eighteen patients
had undergone surgical resection of the primary tumor,
with the rest undergoing definitive concurrent chemother-
apy and RT. The patients were started on gabapentin with
the same titration schedule, with a median dose of 2,700 mg
daily in the second week of radiation. Opioid pain medica-
tions were added in response to patients’ subjective pain
scores and if additional pain medication was clinically indi-
cated. For the purposes of statistical data analysis, specific
opioid doses were converted to an oxycodone-equivalent
dose. During the fourth week of treatment, a total of 38 pa-
tients were maintained on gabapentin 2,700 mg daily, with
only 23 patients requiring additional opioid pain medica-
tion despite grade 2 or higher OM occurring in 86% of these
patients. During the final weeks (weeks six and seven) of
treatment, 38 patients were maintained on gabapentin at
a median dose of 2,700 mg daily. At this time, 30 patients
required opioids for adequate pain control (median dose
of 60 mg per day of oxycodone, ranging from 10–180 mg
per day) despite the presence of grade 2 or higher OM in
95% (week five) and 100% (week six) of patients. During
the study, one patient required a treatment break of greater
than three days during treatment because of aspiration
pneumonia caused by concurrent chemotherapy and RT.
Based on these studies, many cancer centers have adopted
the use of gabapentin to treat radiation-induced OM pain
syndrome in patients with head and neck cancer.
Effect of Gabapentin on Swallowing and Feeding Tube Use
A study by Starmer et al. (2014) retrospectively examined
the impact of gabapentin on swallowing and feeding tube use
in patients during concurrent chemotherapy and RT for oro-
pharyngeal squamous cell carcinoma. This was a retrospective
study of 23 patients using historic controls matched for cancer
stage. The patients underwent prophylactic percutaneous
endoscopic gastrostomy (PEG) tube placement as standard
of care. Patients were started on gabapentin prophylactically
during the first week of RT. Patients treated with gabapentin
began using the PEG tubes at a later date (3.7 weeks versus
2.29 weeks) and had the PEG tubes removed earlier (7.29
weeks versus 32.56 weeks). This difference was attributed to
improved pain control, allowing patients to maintain normal
physiologic swallowing mechanisms for a greater amount of
time during and after RT (Starmer et al., 2014).
Implications for Nursing Practice
OM and pain are nursing-sensitive outcomes. The use of
evidence-based management of symptoms in the population
of patients with cancer may improve patient outcomes over-
all, promote patient and clinician satisfaction, and reduce
costs to the healthcare system (Schulmeister & Gobel, 2008).
The identification of mixed neuropathic and nociceptive
pain in patients with head and neck cancers and treatment-
induced OM has provided additional direction for pain
management with the use of co-analgesics. The use of ga-
bapentin shows promise in managing the neuropathic pain
component of OM. Further research, including randomized,
controlled trials, are warranted to determine the potential
role of gabapentin in managing OM neuropathic pain. In par-
ticular, nursing research studies may be beneficial because
pain and OM are nursing-sensitive outcomes.
Nursing considerations in the use of gabapentin include
patient education regarding the titration and side effects,
including dizziness, somnolence, ataxia, and leukopenia.
Patients with compromised renal function and older adults
may require starting gabapentin at lower doses and with
slower titration to higher doses. Older adults are particularly
at increased risk of polypharmacy and require careful moni-
toring of all medications.
Conclusion
Radiation-induced OM occurs in the majority of patients
undergoing radiation to the head and neck region. This dose-
limiting side effect can lead to diminished quality of life,
disruption in treatment, and potential for suboptimal disease
control and patient outcome. Pain from radiation-induced OM
appears to be caused by somatic and neuropathic pathways.
The use of gabapentin in the early treatment phase appears to
be a promising co-analgesic that can address the neuropathic
component that otherwise may be left untreated, resulting in
Clinical Journal of Oncology Nursing • Volume 20, Number 6 • Use of Gabapentin for Mucositis Pain 627
Implications for Practice
u Assess and manage the nociceptive and neuropathic compo-
nents of oral mucositis pain.
u Suggest the use of gabapentin (Neurontin®), a co-analgesic
that has shown promise in preventing escalating doses of
opioids for oral mucositis pain.
u Educate patients about gabapentin, a generally well-tolerated
drug with few drug–drug interactions, and monitor for side
effects, particularly in older adults who are at increased risk
for polypharmacy.
escalating opioid doses, which are not as effective for neuro-
pathic pain management. Special attention should be paid to
the patient’s renal function and risk for side effects, including
sedation, ataxia, and interactions with other medications; in
these cases, dose reduction may be needed.
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