Xerostomia: Selected Treatments - Aetna

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Xerostomia: Selected Treatments

Clinical Policy Bulletins Medical Clinical Policy Bulletins

Number: 0302

Policy History

Last

Review

05/20/2019

Effective: 02/06/200

Next Review:

03/13/2020

Review

History

Definitions

Additional Information

Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

Aetna considers electrical stimulation (e.g., the Salitron System and the Saliwell

Crown device) experimental and investigational for the prevention or treatment of

xerostomia (dry mouth) or for any other indications because its effectiveness has

not been established.

Aetna considers the following interventions experimental and investigational for the

treatment of xerostomia because their effectiveness for this indication has not been

established (not an all-inclusive list):

Acupuncture

Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS)

Adipose tissue-derived mesenchymal stem cell therapy

Fat grafting to salivary glands

Hyperbaric oxygen,

Low-level laser therapy

Transcutaneous electrical nerve stimulation (TENS)

Venalot Depot (coumarin plus troxerutin).

http://www.aetna.com/cpb/medical/data/300_399/0302.html 05/31/2019

http://www.aetna.com/cpb/medical/data/300_399/0302.html

http://www.aetna.com/)

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Background

Chronic xerostomia can be caused by Sjogren's syndrome, certain medications or

therapeutic irradiation. It can cause difficulty in eating dry foods, swallowing and

wearing dentures; and susceptibility to dental caries, oral pain and frequent

infections. Proponents of electrostimulation as a treatment option postulate that

stimulating the tongue and the roof of the mouth simultaneously will result in

impulses to all residual salivary tissues, major and minor, in the oral and

pharyngeal regions, thus causing salivation.

Electrical Stimulation

Although the Food and Drug Administration (FDA) approved the Salitron System in

1988 to treat xerostomia secondary to Sjogren's syndrome, the Agency for Health

Care Policy and Research (AHCPR) advised in a 1991 assessment that there were

“insufficient data to determine the clinical effectiveness of this modality of salivary

production, or to identify those xerostomic patients who would benefit from the

procedure” (Erlichman, 1991). One published study (Weiss et al, 1986) reported

some degree of response after 3 stimulation sessions of 3 minutes each in 24

patients with xerostomia related to Sjogren's, radiation therapy, drugs or unknown

etiology. However, there was no control group, information on the duration of

response, quantitative assessment of salivary response, or intermediate or long

term assessment of effectiveness.

Another report, a double-blind study (Steller et al, 1988) noted a statistically

significant mean increase in post-stimulation whole saliva flow between subjects (n

= 29) using active and placebo stimulators. However, this was due mainly to the

responses of 3 subjects who showed marked increases in their whole saliva flow

rate during the study. Of the active study arm, only 1 subject showed evidence of a

cumulative response over the 4 weeks of the study. Further research of electrical

stimulation of salivary flow is needed to ascertain its role in the treatment of

Sjogren's patients with xerostomia.

Talal and colleagues (1992) reported that electrical stimulation improves salivary

function of patients with Sjogren's syndrome. In this placebo controlled study,

patients received three treatments (2 weeks apart, over a 4-week period) with an

active device (n = 34) or a placebo device (n = 37). Patients using active devices

showed a statistically greater increase in salivary production than patients using

placebo devices. Moreover, patients demonstrated significant improvement in



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other symptoms such as difficulty in swallowing as well as burning tongue. The

major shortcomings of this study were (i) it is unclear whether the control group

was age-matched, (ii) lack of long-term assessment of effectiveness, and (iii) the

number of patients in the active device group who did not respond to

treatment was not disclosed, and the range or standard deviation for pre- and

post-stimulation whole salivary flow rates was not given.

The role of electrical stimulation in the management of patients with xerostomia

awaits the outcomes of randomized, double-blind, controlled clinical studies with

large sample sizes and long-term follow-up. In many reviews on the management

of patients with xerostomia (Cooke, 1996; Fox, 1997; Davies, 1997; Mariette, 2002;

Fox, 2003), salivary electrostimulation was not mentioned as a method to manage

patients with this condition.

Strietzel et al (2007) evaluated the safety and effectiveness of a recently developed

electro-stimulating device mounted on an individualized intra-oral removable

appliance. The device, containing electrodes, a wetness sensor, an electronic

circuit and a power source, was tested on patients with xerostomia in a cross-over,

randomized, sham-controlled, double-blinded, multi-center study (n = 23; 10 with

primary Sjogren's syndrome, 7 with medication-induced xerostomia, and 6 with

idiopathic xerostomia). Electrical stimulation and also sham were delivered for 10

mins to the oral mucosa, in the mandibular third molar region. Oral dryness was

measured by the sensor. As the primary outcome, sensor dryness and xerostomia

symptom changes as a result of device wearing were assessed, and compared

between active and sham modes. In addition, side-effects were recorded. Electro-

stimulation resulted in a significant decrease in sensor dryness, leading to a

beneficial effect on patients' subjective condition. No significant adverse events

were observed. However, 30.4 % patients reported the sham mode to be more

effective than the active mode. The authors stated that these findings are

encouraging enough to continue developing and investigating the miniature

electrostimulating device mounted on a dental implant.

In a preliminary study, Ami and Wolff (2010) evaluated the effect on xerostomia of

the Saliwell Crown (Saliwell Ltd., Harutzim, Israel), an innovative saliva

electrostimulation device fixed on an implant, placed in the lower third molar area.

A Saliwell Crown was placed in the lower third molar area of an 81-year old female

patient with complaints of dry and burning mouth. Salivary secretion was

measured, and the patient was asked to fill in written satisfaction questionnaires.



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The patient was monitored for 1 year, comparing her salivary secretion rates and

the written questionnaires. The results showed a constant slight but significant

increase in the salivary secretion and in the patient's personal feelings as

presented in the questionnaires. The authors concluded that the saliva stimulation

device Saliwell Crown, placed on an implant in an 81-year old patient with dry and

burning mouth complaints, presented promising results when both the salivary

secretion tests and the self-assessment questionnaires were examined and

compared. The findings of this case study need to be validated by well-designed

studies.

Strietzel and colleagues (2011) evaluated the safety and effectiveness of an intra-

oral electrostimulation device, consisting of stimulating electrodes, an electronic

circuit, and a power source, in treating xerostomia. The device delivers

electrostimulation through the oral mucosa to the lingual nerve in order to enhance

the salivary reflex. The device was tested on a sample of patients with xerostomia

due to Sjogren's syndrome and other sicca conditions in a 2-stage prospective,

randomized, multi-center trial. Stage I was a double-blind, cross-over stage

designed to compare the effects of the electrically active device with the sham

device, each used for 1 month, and stage II was a 3-month open-label stage

designed to assess the long-term effects of the active device. Improvement in

xerostomia severity from baseline was the primary outcome measure. A total of

114 patients were randomized. In stage I, the active device performed better than

the sham device for patient-reported xerostomia severity (p < 0.002), xerostomia

frequency (p < 0.05), quality of life impairment (p < 0.01), and swallowing difficulty

(p < 0.02). At the end of stage II, statistically significant improvements were verified

for patient-reported xerostomia severity (p < 0.0001), xerostomia frequency (p <

0.0001), oral discomfort (p < 0.001), speech difficulty (p < 0.02), sleeping difficulty

(p < 0.001), and resting salivary flow rate (p < 0.01). The authors concluded that

the results indicated that daily use of the device alleviated oral dryness, discomfort,

and some complications of xerostomia, such as speech and sleeping difficulties,

and increased salivary output. These findings need to be verified by additional

research.

Fedele et al (2010) noted that xerostomia is a very common condition, which not

only involves dry mouth feeling, but can also lead to psychosocial distress, impaired

quality of life, and complications, such as dental caries and oral candidiasis. It is

generally induced by hypofunction of salivary glands, which has a wide variety of

etiologies, such as Sjogren's syndrome, radiotherapy to the head and neck and



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side effects of medications. Current therapies rely on saliva substitutes and

pharmacological stimulation of the parasympathetic system. These treatment

modalities are somewhat limited by their short-term efficacy, high cost and drug

interactions or other adverse effects. Local transcutaneous or per-mucosal

electrostimulation in areas close to the nerves participating in the salivary

autonomic reflex has been found to increase salivary secretion in animal and

clinical experiments and to relieve symptoms of dry mouth in patients with salivary

gland hypofunction. These investigators reviewed the current status and potential

of intra-oral miniature electrostimulating devices. The authors stated that these

intra-oral electrostimulating devices offer promise as an optional safe and non-

chemical treatment of xerostomia.

In a phase II randomized, controlled study, Wong et al (2010) examined the

potential effectiveness of xerostomia prevention using acupuncture-like

transcutaneous electrical nerve stimulation (ALTENS) delivered concomitantly with

radiotherapy administered to head and neck cancer patients. A total of 60 patients

were randomized to either the treatment group (n = 30) that received ALTENS daily

with radiotherapy or the control group (n = 26) that had standard mouth care only.

Stimulated and basal unstimulated whole saliva production (WSP) plus radiation-

induced xerostomia (RIX) symptoms visual analog score (RIXVAS) were assessed

at specific time points. Generalized linear models and generalized estimating

equations were used for analysis. RIXVAS at 3 months follow-up after therapy

completion was used as the primary study endpoint. The mean RIXVAS for the

ALTENS intervention at 3 months was 39.8, which was not significantly different

from the control arm value of 40.5. There were no statistically significant

differences between the 2 groups for their mean RIXVAS and WSP at all

assessment time points. The authors concluded that there was no significant

difference in mean WSP and RIXVAS between the 2 groups, so ALTENS is not

recommended as a prophylactic intervention.

In a phase II component of a multi-institutional, phase II/III, randomized trial, Wong

et al (2012) evaluated the feasibility and preliminary effectiveness of ALTENS in

reducing radiation-induced xerostomia. Patients with cancer of the head and neck

who were 3 to 24 months from completing radiotherapy with or without

chemotherapy (RT +/- C) and who were experiencing xerostomia symptoms with

basal whole saliva production greater than or equal to 0.1 ml/min and were without

recurrence were eligible. Patients received twice-weekly ALTENS sessions (24

sessions over 12 weeks) using a proprietary electrical stimulation unit. The primary



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study objective was to assess the feasibility of ALTENS treatment. Patients were

considered compliant if 19 of 24 ALTENS sessions were delivered, and the

targeted compliance rate was 85 %. Secondary objectives measured treatment-

related toxicities and the effect of ALTENS on overall radiation-induced xerostomia

burden using the University of Michigan Xerostomia-Related Quality of Life Scale

(XeQOLS). Of 48 accrued patients, 47 were evaluable. The median age was 60

years, 84 % of patients were men, 70 % completed RT +/- C for greater than 12

months, and 21 % had previously received pilocarpine. Thirty-four patients

completed all 24 ALTENS sessions, 9 patients completed 20 to 23 sessions, and 1

patient completed 19 sessions, representing a 94 % total compliance rate. Six-

month XeQOLS scores were available for 35 patients and indicated that 30 patients

(86 %) achieved a positive treatment response with a mean +/- standard deviation

reduction of 35.9 % +/- 36.1 %. Five patients developed grade 1 or 2 gastro

intestinal toxicity, and 1 had a grade 1 pain event. The authors concluded that the

current results indicated that ALTENS treatment for radiation-induced xerostomia

can be delivered uniformly in a cooperative, multi-center setting and produced

possible beneficial treatment response. They noted that given these results, the

phase III component of this study was initiated.

In a Cochrane review, Furness et al (2013) evaluated the effects of non-

pharmacological interventions administered to stimulate saliva production for the

relief of dry mouth/xerostomia. These investigators searched the Cochrane Oral

Health Group's Trials Register (to April 16, 2013), the Cochrane Central Register of

Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 3), MEDLINE via

OVID (1948 to April 16, 2013), EMBASE via OVID (1980 to April 16, 2013), AMED

via OVID (1985 to April 16, 2013), CINAHL via EBSCO (1981 to April 16, 2013),

and CANCERLIT via PubMed (1950 to April 16, 2013). The metaRegister of

Controlled Clinical Trials and ClinicalTrials.gov were also searched to identify

ongoing and completed trials. References lists of included studies and relevant

reviews were also searched. There were no restrictions on the language of

publication or publication status. These researchers included parallel group

randomized controlled trials of non-pharmacological interventions to treat dry

mouth, where participants had dry mouth symptoms at baseline. At least 2 review

authors assessed each of the included studies to confirm eligibility, assess risk of

bias and extract data using a piloted data extraction form. They calculated mean

difference (MD) and 95 % confidence intervals (CI) for continuous outcomes or

where different scales were used to assess outcome, they calculated standardized

mean differences (SMD) together with 95 % CIs. These investigators attempted to



http://ClinicalTrials.gov

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extract data on adverse effects of interventions. Where data were missing or

unclear, they attempted to contact study authors to obtain further information.

There were 9 studies (total 366 participants randomized) included in this review of

non-pharmacological interventions for dry mouth, which were divided into 3

comparisons: (i) 8 studies were assessed at high-risk of bias in at least one

domain and the remaining study was at unclear risk of bias, (ii) 5 small studies

(total 153 participants, with dry mouth following radiotherapy treatment)

compared acupuncture with placebo, and 4 were assessed at high-risk and 1 at

unclear risk of bias, (iii) 2 trials reported outcome data for dry mouth in a form

suitable for meta-analysis. The pooled estimate of these 2 trials (70 participants,

low-quality evidence) showed no difference between acupuncture and control in dry

mouth symptoms (SMD -0.34, 95 % CI: -0.81 to 0.14, p value 0.17, I(2) = 39 %)

with the CIs including both a possible reduction or a possible increase in dry mouth

symptoms. Acupuncture was associated with more adverse effects (tiny bruises

and tiredness that were mild and temporary). There was a very small increase in

unstimulated whole saliva (UWS) at the end of 4 to 6 weeks of treatment (3 trials,

71 participants, low-quality evidence) (MD 0.02 ml/min, 95 % CI: 0 to 0.04, p value

0.04, I(2) = 57 %), and this benefit persisted at the 12-month follow-up evaluation (2

trials, 54 participants, low-quality evidence) (UWS, MD 0.06 ml/min, 95 % CI: 0.01

to 0.11, p value 0.03, I(2) = 10 %). For the outcome of stimulated whole saliva

(SWS, 3 trials, 71 participants, low-quality evidence) there was a benefit favoring

acupuncture (MD 0.19 ml/min, 95 % CI: 0.07 to 0.31, p value 0.002, I(2) = 1 %) an

effect which also persisted at the 12-month follow-up evaluation (SWS MD 0.28

ml/min, 95 % CI: 0.09 to 0.47, p value 0.004, I(2) = 0 %) (2 trials, 54 participants, low-

quality evidence). Two small studies, both at high-risk of bias, compared the use of

an electro-stimulation device with a placebo device in participants with Sjogren's

syndrome (total 101 participants). A further study, also at high-risk of bias,

compared acupuncture-like electro-stimulation of different sets of points in

participants who had previously been treated with radiotherapy. None of these

studies reported the outcome of dry mouth. There was no difference between electro-

stimulation and placebo in the outcomes of UWS or SWS at the end of the

4-week treatment period in the 1 study (very low that provided data for these

outcomes). No adverse effects were reported. A single study at high-risk of bias,

compared the stimulatory effect of powered versus manual tooth-brushing and

found no difference for the outcomes of UWS or SWS. The authors concluded that

there is low-quality evidence that acupuncture is no different from placebo

acupuncture with regard to dry mouth symptoms, which is the most important

outcome. This may be because there were insufficient participants included in the



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2 trials to show a possible effect or it may be that there was some benefit due to

“placebo” acupuncture that could have biased the effect to the null. There is

insufficient evidence to determine the effects of electro-stimulation devices on dry

mouth symptoms. It is well-known that dry mouth symptoms may be problematic

even when saliva production is increased, yet only 2 of the trials that evaluated

acupuncture reported dry mouth symptoms, a worrying reporting bias. There is

some low-quality evidence that acupuncture results in a small increase in saliva

production in patients with dry mouth following radiotherapy. There is insufficient

evidence to determine the effects of electro-stimulation devices on dry mouth

symptoms or saliva production in patients with Sjogren's syndrome. Reported

adverse effects of acupuncture are mild and of short duration, and there were no

reported adverse effects from electro-stimulation.

In a phase II clinical trial, Vijayan et al (2014) evaluated the effectiveness of TENS

delivered using an extra-oral device in patients with radiation-induced xerostomia.

A total of 30 oral cavity and oropharyngeal cancer patients post-adjuvant (n = 26) or

definitive radiotherapy (n = 4) were enrolled in this study. The TENS electrode

pads were placed externally on the skin overlying the parotid glands. Un-stimulated

whole saliva was collected for 5 mins into graduated tubes using the low forced

spitting method. The TENS unit was then activated and stimulated saliva was

collected for an additional 5 mins. The difference between un-stimulated and

stimulated saliva output was measured using the paired t-test. Linear regression

was used to determine factors significantly influencing the improvement in salivary

output. Twenty-nine (96.7 %) of 30 patients showed increased saliva flow during

stimulation. A statistically significant improvement in saliva production (p < 0.05)

during stimulation was noted. The mean un-stimulated saliva flow was 0.056

ml/min and the mean stimulated saliva flow was 0.12 ml/min with a median

increase of 0.06 ml/min. The interval to the application of TENS after radiotherapy

significantly influenced the improvement in salivary flow. The authors concluded

that extra-oral application of TENS is effective in increasing the whole salivary flow

in most of the post-radiated oral cavity/oropharyngeal cancer patients with

xerostomia. They stated that TENS therapy may be useful as an effective

supportive treatment modality in post-radiated oral cancer patients. These

preliminary findings from a small (n = 30) phase II study need to be validated by well-

designed studies.



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In a case-series study, Zadik et al (2014) investigated the safety of an intra-oral

electrostimulator (GenNarino) in symptomatic chronic graft-versus-host disease

(cGVHD) patients. The secondary objective was to study the impact on the salivary

gland involvement of cGVHD patients. The study included patients treated for 4

weeks, randomly assigned to the active device and then crossed-over to a sham-

device or vice versa. The patients and clinicians were blind to the treatment

delivered. Data regarding oral mucosal and salivary gland involvement were

collected. A total of 6 patients were included in this study. Most of the intra-oral

areas with manifestations of cGVHD were not in contact with the GenNarino

device. Two patients developed mild mucosal lesions in areas in contact with the

GenNarino during the study. However, only 1 of them had a change in the National

Institutes of Health (NIH) score for oral cGVHD. The un-stimulated and stimulated

salivary flow rate increased in 4 out of the 5 patients included in this analysis.

Symptoms of dry mouth and general oral comfort improved. The authors

concluded that the findings of this study suggested that GenNarino is safe in

cGVHD patients with respect to oral tissues. Furthermore the use of GenNarino

resulted in subjective and objective improvements in dry mouth symptoms.

Moreover, they stated that a large scale study is needed to confirm the impact and

safety of GenNarino on systemic cGVHD.

Bakarman and Keenan (2014) examined the evidence of non-pharmacological

treatments for patients with dry mouth. Study assessment and data extraction were

carried out independently by at least 2 reviewers. Mean difference and SMD

together with 95 % CIs were calculated where appropriate. A total of 9 studies (366

participants) were included in this review, 8 were assessed at high risk of bias and

1 at unclear risk of bias. Five small studies (153 participants), with dry mouth

following radiotherapy treatment compared acupuncture with placebo. Four were at

high risk and 1 at unclear risk of bias. Two trials reported outcome data for dry

mouth in a form suitable for meta- analysis. The pooled estimate of these 2 trials

(70 participants, low quality evidence) showed no difference between acupuncture

and control in dry mouth symptoms (SMD -0.34, 95 % CI: -0.81 to 0.14, p value

0.17, I2 = 39 %) with the CIs including a possible reduction or a possible increase

in dry mouth symptoms. Acupuncture was associated with more adverse effects

(tiny bruises and tiredness which were mild and temporary). There was a very

small increase in unstimulated whole saliva (UWS) at the end of 4 to 6 weeks of

treatment (3 trials, 71 participants, low quality evidence) (MD 0.02 ml/minute, 95 %

CI: 0 to 0.04, p value 0.04, I2 = 57 %), and this benefit persisted at the 12-month

follow-up evaluation (2 trials, 54 participants, low quality evidence) (UWS, MD 0.06



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ml/minute, 95 % CI: 0.01 to 0.11, p value 0.03, I2 = 10 %). For the outcome of

stimulated whole saliva (SWS, 3 trials, 71 participants, low quality evidence) there

was a benefit favoring acupuncture (MD 0.19 ml/minute, 95 % CI: 0.07 to 0.31, p

value 0.002, I2 = 1 %) an effect which also persisted at the 12-month follow-up

evaluation (SWS MD 0.28 ml/minute, 95 % CI: 0.09 to 0.47, p value 0.004, I2 = 0

%) (2 trials, 54 participants, low quality evidence). Two small studies, both at high

risk of bias, compared the use of an electrostimulation device with a placebo device

in participants with Sjogren's syndrome (total 101 participants). A further study,

also at high risk of bias, compared acupuncture-like electrostimulation. None of

these studies reported the outcome of dry mouth. A single study at high risk of bias

compared the stimulatory effect of powered versus manual tooth-brushing and

found no difference for the outcomes of UWS or SWS. The authors concluded that

there is low quality evidence that acupuncture is no different from placebo

acupuncture with regard to dry mouth symptoms, which is the most important

outcome. This may be because there were insufficient participants included in the

2 trials to show a possible effect or it may be that there was some benefit due to

“placebo” acupuncture, which could have biased the effect to the null. There is

insufficient evidence to determine the effects of electrostimulation devices on dry

mouth symptoms. It is well-known that dry mouth symptoms may be problematic

even when saliva production is increased, yet only 2 of the trials that evaluated

acupuncture reported dry mouth symptoms, a worrying reporting bias. There is

some low quality evidence that acupuncture results in a small increase in saliva

production in patients with dry mouth following radiotherapy. There is insufficient

evidence to determine the effects of electrostimulation devices on dry mouth

symptoms or saliva production in patients with Sjogren's syndrome. Reported

adverse effects of acupuncture are mild and of short duration, and there were no

reported adverse effects from electrostimulation.

In a pilot study, Lakshman et al (2015) evaluated the effectiveness of a TENS unit

in stimulating the whole salivary flow rate in radiation-induced xerostomia patients.

A total of 40 subjects were included in the study. The study group consisted of 30

individuals and was divided into Group S1 (n = 20), which was further subdivided

into Group S1A (n = 10) subjects complaining of dry mouth who were undergoing

head and neck radiotherapy with TENS stimulation during the commencement of

radiotherapy, on the 3rd , 6th week and after a month of completion of radiotherapy

and Group S1B (n = 10) with TENS stimulation daily during the full course of

radiotherapy and Group S2 (n = 10) subjects complaining of dry mouth who had

undergone head and neck radiotherapy that ended 1 month prior to their entry into



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the study. The control group (n = 10) consisted of healthy individuals not

complaining of dry mouth and who have not undergone head and neck

radiotherapy. Whole saliva was collected without stimulation for 10 mins and after

electrostimulation with TENS unit for additional 10 mins in a graduated test tube.

The results were statistically analyzed using Mann-Whitney U-test and Kruskal

Wallis's test. The data analysis revealed that control and S1B group showed

increased salivary flow rate after stimulation by TENS therapy compared with the

unstimulated salivary flow, whereas in S1A and S2 group it was found to be

statistically non-significant. The authors concluded that the findings of this study

provided an insight about the effectiveness of TENS therapy in stimulating salivary

flow in healthy subjects and it is very effective when used in conjunction with

radiation therapy by reducing the side-effects of radiation therapy. They stated that

TENS therapy can be used as an adjunctive method for the treatment of xerostomia

along with other treatment modalities. These preliminary findings need to be

validated by well-designed studies.

Wong et al (2015) presented the results of the phase III clinical trial, RTOG 0537,

which compared ALTENS with pilocarpine (PC) for relieving radiation-induced

xerostomia. Eligible patients were randomized to twice-weekly 20-min ALTENS

sessions for 24 sessions during 12 weeks or PC (5 mg 3 times daily for 12 weeks).

The primary end-point was the change in the University of Michigan Xerostomia-

Related Quality of Life Scale (XeQOLS) scores from baseline to 9 months from

randomization (MFR). Secondary end-points included basal and citric acid primed

whole salivary production (WSP), ratios of positive responders (defined as patients

with greater than or equal to 20 % reduction in overall radiation-induced

xerostomia symptom burden), and the presence of adverse events based on the

Common Terminology Criteria for Adverse Events version 3. An intention-to-treat

analysis was conducted. A total of 148 patients were randomized. Only 96

patients completed the required XeQOLS and were evaluable at 9 MFR

(representing merely 68.6 % statistical power); 76 patients were evaluable at 15

MFR. The median change in the overall XeQOLS in ALTENS and PC groups at 9

and 15 MFR were -0.53 and -0.27 (p = 0.45) and -0.6 and -0.47 (p = 0.21). The

corresponding percentages of positive responders were 81 % and 72 % (p = 0.34)

and 83 % and 63 % (p = 0.04). Changes in WSP were not significantly different

between the groups. Grade 3 or less adverse events, mostly consisting of grade 1,

developed in 20.8 % of patients in the ALTENS group and in 61.6 % of the PC

group. The authors concluded that the observed effect size was smaller than

hypothesized, and statistical power was limited because only 64.8 % (96 of 148) of



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the recruited were evaluable. The primary end-point -- the change in radiation-

induced xerostomia symptom burden at 9 MFR-was not significantly different

between the ALTENS and PC groups. There was significantly less toxicity in

patients receiving ALTENS.

Patient (a medical information and support organization from England and Wales)’s

webpage on “Dry Mouth (Xerostomia)” (last updated 12/23/2015) stated that “A

technique called acupuncture-like transelectrical nerve stimulation is currently being

investigated”.

Furthermore, an UpToDate review on “Management of late complications of head

and neck cancer and its treatment” (Galloway and Amdur, 2016) states that

“Neuromuscular electrical stimulation (NMSE) is a potentially promising

improvement to traditional therapy (for dysphagia)”. It does not mention electrical

stimulation as a therapeutic option for xerostomia.

Fat Grafting to Salivary Glands

Kawakami and colleagues (2016) stated that atrophy or hypo-function of the

salivary gland because of aging or disease leads to hypo-salivation that affects

patient quality of life by causing dry mouth, deterioration of mastication/deglutition,

and poor oral hygiene status. Current therapy for atrophy or hypo-function of the

salivary gland in clinical practice focuses on symptom relief using drugs and

artificial saliva; therefore, there is still a need to develop new therapies. To

investigate potential novel therapeutic targets, these researchers induced the

differentiation of salivary gland cells by co-culturing human adipose-derived stem

cells isolated from buccal fat pads (hBFP-ASCs) with human salivary-gland-derived

fibroblasts (hSG-fibros). They examined their potential for transplantation and

tissue neogenesis. Following the culture of hBFP-ASCs and hSG-fibros,

differentiated cells were transplanted into the submandibular glands of SCID mice,

and their degree of differentiation in tissues was determined. These investigators

also examined their potential for functional tissue reconstitution using a three-

dimensional (3D) culture system. Co-cultured cells expressed salivary gland-

related markers and generated new tissues following transplantation in-vivo.

Moreover, cell reconstituted glandular structures in the 3D culture system. The

authors concluded that co-culture of hSG-fibros with hBFP-ASCs led to successful

differentiation into salivary gland cells that could be transplanted to generate new

tissues.



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Furthermore, a systematic review on “Treatment of xerostomia and hyposalivation

in the elderly” (Gil-Montoya et al, 2016) and an UpToDate review on “Treatment of

dry mouth and other non-ocular sicca symptoms in Sjogren's syndrome” (Baer,

2016) does not mention fat grafting as a therapeutic option.

Acupuncture

Assy and Brand (2018) noted that several studies have suggested a positive effect

of acupuncture on oral dryness. These investigators carried out a systematic

review of the effects of acupuncture on xerostomia and hypo-salivation. PubMed

and Web of Science were electronically searched. Reference lists of the included

studies and relevant reviews were manually searched. Studies that met the

inclusion criteria were systematically evaluated; 2 reviewers assessed each of the

included studies to confirm eligibility and assessing the risk of bias. A total of 10

randomized controlled trials (RCTs) investigating the effect of acupuncture were

included; 5 trials compared acupuncture to sham/placebo acupuncture; 4 trials

compared acupuncture to oral hygiene/usual care. Only 1 clinical trial used oral

care sessions as control group. For all the included studies, the quality for all the

main outcomes had been rated as low. Although some publications suggested a

positive effect of acupuncture on either salivary flow rate or subjective dry mouth

feeling, the studies were inconclusive about the potential effects of acupuncture.

The authors concluded that insufficient evidence was available to conclude

whether acupuncture is an evidence-based therapeutic option for xerostomia/hypo

salivation. They stated that further well-designed, larger, double-blinded trials are

needed to determine the potential benefit of acupuncture. Sample size calculations

should be performed before initiating these studies.

Artificial Saliva

Apperley and co-workers (2017) noted that researchers have recently developed a

novel oily formulation for potential use as a saliva substitute for the treatment of dry

mouth. In a randomized, cross-over study, these researchers compared this new

formulation to a currently available saliva substitute and a control of water on

measures of mastication, subjective feeling of oral dryness and product

acceptability. A total of 40 participants treated with radiotherapy to the head and

neck and experiencing xerostomia were invited to participate in the trial. Each

participant tried all 3 products in a randomized order. The effect of each product

was measured using the Test of Masticating and Swallowing Solids (TOMASS), the



Page 14 of 26

Shortened Xerostomia Inventory (SXI) and a questionnaire designed to test patient

acceptability of each product. Outcome data were gathered in a single session

after the 1st administration of each product to evaluate immediate effects and after

7 days of use to evaluate longer-term effects. Statistical analyses consisted of

repeated-measures analysis of variance and mixed models. There was no

evidence that application of the 3 formulations had an effect on any of the TOMASS

measures, either immediately or after 1 week of use (p > 0·05). There was a

significant main effect of formulation on the SXI score (p = 0·02). Application of the

novel emulsion resulted in a clinically small but significant improvement in SXI

score (p < 0·01); however, application of methylcellulose (p = 0·21) and water (p =

0·81) resulted in no significant difference. There was no difference in participant

acceptability between the 3 products (p = 0·32). The novel oily emulsion showed

no clinically significant benefit over 2 existing products for relief of xerostomia; in

fact, none of the 3e products demonstrated significant change in patient outcomes.

In a double-blind, randomized, controlled study, Cifuentes and colleagues (2018)

compared the efficacy of pilocarpine and artificial saliva as symptomatic treatments

for xerostomia and xerophthalmia in patients with Sjogren's Syndrome (SS). A total

of 72 patients with SS were assigned randomly to receive 10 drops of pilocarpine (5

mg) or 10 drops of artificial saliva, orally, t.i.d. for 12 weeks. Patients were

evaluated at baseline and periodically throughout the study by whole saliva and

tear flow for global assessment of their dryness as well as for any adverse effects.

Patients receiving pilocarpine had a statistically significant improvement in their

salivary flow (p < 0.0001), lachrymal flow (p < 0.0001), and their subjective global

assessment (p < 0.0001), compared with patients on artificial saliva. The most

common side effects were sialorrhea and nausea. The authors concluded that

pilocarpine was more effective than artificial saliva for enhancing salivary and

lachrymal secretion in patients with SS. They noted that this was the first study

comparing the efficacy of pilocarpine and artificial saliva as treatments for

xerostomia and xerophthalmia in SS.

Low-Level Laser Therapy

In a randomized trial, Fidelix and associates (2018) evaluated the effectiveness of

low-level laser therapy (LLLT) in the treatment of xerostomia in primary SS.

Patients with dry mouth symptoms associated with primary SS receiving care at a

university hospital were eligible for enrollment in the study. A total of 66 patients

were randomly assigned with a 1:1 allocation ratio to receive LLLT (laser group, n =



Page 15 of 26

33) or placebo treatment (placebo group, n = 33). Patients in the laser group

received LLLT twice-weekly for 6 weeks, for a total of 12 treatment sessions. Laser

irradiation was performed with an aluminum-gallium-arsenide laser diode at a

wavelength of 808 nm, 100-mW output power, and energy density of 4.0 J/cm2 per

irradiation point per session. Placebo treatment was performed following the same

protocol used for irradiated patients and using the same laser device to mimic a

real irradiation, but with no active laser emission and the tip of the laser probe

covered with aluminum foil. The outcomes of interest were xerostomia inventory

scores, salivary flow rate, salivary beta-2 microglobulin levels, and salivary sodium

and chlorine concentrations. Patients in both groups showed no improvement in

xerostomia. Likewise, there was no significant improvement in xerostomia

inventory scores (p = 0.301) or salivary flow rate (p = 0.643) in either group. There

was no difference in salivary beta-2 microglobulin levels, sodium concentration, and

chlorine concentration before and after intervention or between the 2 groups. The

authors concluded that the LLLT protocol used in this study effected no

improvement in xerostomia or salivary flow rate in patients with primary SS.

Transcutaneous Electrical Nerve Stimulation (TENS)

Sivaramakrishnan and Sridharan (2017) stated that the use of transcutaneous

electrical nerve stimulation (TENS) has been contemplated on by various

researchers for treatment of xerostomia. These researchers performed a

systematic compilation and quantitative synthesis of the existing evidence related to

the utility of TENS in patients with xerostomia. A total of 6 RCTs were identified

from databases for inclusion and analyzed using non-Cochrane mode in RevMan

5.0 software. The heterogeneity between the studies were assessed using Forest

plot, I2 statistics wherein more than 50 % was considered to have moderate-to

severe heterogeneity and Chi-square test with a statistical p-value of less than 0.10

to indicate statistical significance. Results show that the effect of TENS on salivary

flow rate in 369 participants with SMD [95 % CI] was 0.63 [-0.03 to 1.29] and was

not statistically significant. The authors concluded that the available evidence did

not support the use of TENS in patients with xerostomia and may be considered as

a salivary substitute for symptomatic improvement. However the type, frequency

and amplitude of current used needs to be studied in detail. They stated that high

quality RCTs with adequate power are needed, either to support or refute the use of

TENS in xerostomia.



Page 16 of 26

Experimental and Investigational Interventions for the Treatment of Xerostomia

Ferraiolo and Veitz-Keenan (2018) reviewed the evidence regarding various

interventions to prevent dry mouth and salivary gland dysfunction following head

and neck radiotherapy. Data sources included Cochrane Oral Health's Trials

Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline,

Embase, CINAHL, EBSCO (Cumulative Index to Nursing and Allied Health

Literature, LILACS, BIREME, Virtual Health Library (Latin American and Caribbean

Health Science Information database), Zetoc Conference Proceedings, the US

National Institutes of Health (NIH) Ongoing Trials Register, (ClinicalTrials.gov) and

the World Health Organization (WHO) International Clinical Trials Registry Platform

for ongoing trials. No restrictions were placed on the language or date of

publication when searching the electronic databases. The review included RCTs,

irrespective of their language of publication or publication status. Subjects could be

out-patients or in-patients. The review included trials comparing any

pharmacological agent regimen, prescribed prophylactically for salivary gland

dysfunction before or during radiotherapy, with placebo, no intervention or an

alternative pharmacological intervention. Comparisons of radiation techniques

were excluded. Standard Cochrane methodological processes were followed. A

total of 39 studies that randomized 3,520 participants were included; the number of

participants analyzed varied by outcome and time-point. The studies were ordered

into 14 separate comparisons with meta-analysis only being possible in 3 of these.

These investigators found low-quality evidence to show that amifostine, when

compared to a placebo or no treatment control, might reduce the risk of moderate- to

severe xerostomia (grade 2 or higher on a 0 to 4 scale) at the end of radiotherapy

(risk ratio (RR) 0.35, 95 % CI: 0.19 to 0.67; p = 0.001, 3 studies, 119 participants),

and up to 3 months after radiotherapy (RR 0.66, 95 % CI: 0.48 to 0.92; p = 0.01, 5

studies, 687 participants), but there was insufficient evidence that the effect was

sustained up to 12 months following radiotherapy (RR 0.70, 95 % CI:

0.40 to 1.23; p = 0.21, 7 studies, 682 participants). These researchers found very

low-quality evidence that amifostine increased unstimulated salivary flow rate up to

12 months after radiotherapy, both in terms of mg of saliva/5 mins (MD 0.32, 95 %

CI: 0.09 to 0.55; p = 0.006, 1 study, 27 participants), and incidence of producing

greater than 0.1 g of saliva over 5 mins (RR 1.45, 95 % CI: 1.13 to 1.86; p = 0.004,

1 study, 175 participants). However, there was insufficient evidence to show a

difference when looking at stimulated salivary flow rates. There was insufficient

(very low-quality) evidence to show that amifostine compromised the effects of



http://ClinicalTrials.gov

Page 17 of 26

cancer treatment when looking at survival measures. There was some very low-

quality evidence of a small benefit for amifostine in terms of QOL (10-point scale) at

12 months after radiotherapy (MD 0.70, 95 % CI: 0.20 to 1.20; p = 0.006, 1 study,

180 participants), but insufficient evidence at the end of and up to 3-month post-

radiotherapy. A further study showed no evidence of a difference at 6-, 12-, 18

and 24-month post-radiotherapy. There was low-quality evidence that amifostine

was associated with increases in: vomiting (RR 4.90, 95 % CI: 2.87 to 8.38; p <

0.00001, 5 studies, 601 participants); hypotension (RR 9.20, 95 % CI: 2.84 to

29.83; p = 0.0002, 3 studies, 376 participants); nausea (RR 2.60, 95 % CI: 1.81 to

3.74; p < 0.00001, 4 studies, 556 participants); and allergic response (RR 7.51, 95

% CI: 1.40 to 40.39; p = 0.02, 3 studies, 524 participants). The authors founded

insufficient evidence (that was of very low-quality) to determine whether or not

pilocarpine performed better or worse than a placebo or no treatment control for the

outcomes: xerostomia, salivary flow rate, survival and QOL. There was some low-

quality evidence that pilocarpine was associated with an increase in sweating (RR

2.98, 95 % CI: 1.43 to 6.22; p = 0.004, 5 studies, 389 participants). The authors

found insufficient evidence to determine whether or not palifermin performed better

or worse than placebo for: xerostomia (low-quality); survival (moderate-quality); and

any adverse events (AEs). There was also insufficient evidence to determine the

effects of the following interventions: biperiden plus pilocarpine, Chinese medicines,

bethanechol, artificial saliva, selenium, antiseptic mouth rinse, anti-microbial

lozenge, polaprezinc, azulene rinse and Venalot Depot (coumarin plus troxerutin).

The authors concluded that there was some low-quality evidence to suggest that

amifostine prevented the feeling of dry mouth in individuals receiving radiotherapy

to the head and neck (with or without chemotherapy) in the short- (end of

radiotherapy) to medium-term (3-month post-radiotherapy). However, it was less

clear whether or not this effect is sustained to 12-month post-radiotherapy. The

benefits of amifostine should be weighed against its high cost and side effects.

There was insufficient evidence to show that any other intervention is beneficial.

In a randomized, placebo-controlled, phase-I/Ii clinical trial, Gronhoj and co-workers

(2018) examined the safety and efficacy of adipose tissue-derived mesenchymal

stem cell (ASC) therapy for radiation-induced xerostomia. This trial included 30

patients, randomized in a 1:1 ratio to receive ultrasound (US)-guided

transplantation of ASCs or placebo to the submandibular glands. Patients had

previously received radiotherapy for a T1-2, N0-2A, human papillomavirus (HPV)

-positive, oropharyngeal squamous cell carcinoma (SCC). The primary outcome

was the change in unstimulated whole salivary flow rate, measured before and after



Page 18 of 26

the intervention. All assessments were performed 1 month prior (baseline) and 1

and 4 months following ASC or placebo administration. No AEs were detected.

Unstimulated whole salivary flow rates significantly increased in the ASC-arm at 1

month (33 %; p = 0.048) and 4 months (50 %; p = 0.003), but not in the placebo-

arm (p = 0.6, and p = 0.8), compared to baseline. The ASC-arm symptom scores

significantly decreased on the xerostomia and VAS questionnaires, in the domains

of thirst (-22 %, p = 0.035) and difficulties in eating solid foods (-2 %, p = 0.008)

after 4 months compared to baseline. The ASC-arm showed significantly improved

salivary gland functions of inorganic element secretion and absorption, at baseline

and 4 months, compared to the placebo-arm. Core-needle biopsies showed

increases in serous gland tissue and decreases in adipose and connective tissues

in the ASC-arm compared to the placebo-arm (p = 0.04 and p = 0.02, respectively);

MRIs showed no significant differences between groups in gland size or intensity (p

< 0.05). The authors concluded that ASC therapy for radiation-induced

hypofunction and xerostomia was safe and significantly improved salivary gland

functions and patient-reported outcomes. They stated that these findings should

encourage further exploratory and confirmatory trials.

In a randomized, double-blind, clinical trial, Lee and associates (2018) examined if

pre-treatment with amifostine reduced the incidence of RTOG grade greater than or

equal to 2 acute and late xerostomia in patients receiving definitive or adjuvant

radiotherapy for head and neck squamous cell carcinoma (HNSCC), without

reducing tumor control or survival. Between September 14, 2001 and November 8,

2004, a total of 44 Royal Adelaide Hospital patients were randomized to receive

amifostine (200 mg/m2 IV) or placebo (normal saline IV) for 5 days/week, prior to

standard radiotherapy (60 to 70 Gy), each having greater than or equal to 75 % of

the parotids treated to greater than or equal to 40 Gy. Side effects were assessed

weekly during treatment, at 3 and 5 months after radiotherapy, then every 6 months

until disease progression or death. The accrual target was 200 patients over 4 to 5

years, but the trial closed prematurely when only 44 patients had been randomized

after 3 years. Of 41 evaluable patients, 80 % (16/20) in the amifostine arm had

grade greater than or equal to 2 acute radiation salivary toxicity versus 76 %

(16/21) in the placebo arm (p = 1.00). The rate of grade greater than or equal to 2

late radiation salivary toxicity at 12 months was 66 % in the amifostine arm and 82

% in the placebo arm (estimated hazard ratio [HR] 1.61, 95 % CI: 0.74 to 3.49, p =

0.22). Other toxicities tended to be worse in the amifostine arm: acute grade 3 to 4

skin 35 % versus 5 % and mucous membrane 40 % versus 5 %; grade greater than

or equal to 2 vomiting 35 % versus 5 %, hypocalcaemia 25 % versus 5 % and



Page 19 of 26

fatigue 85 % versus 33 %, with only the latter retaining statistical significance after

adjusting for multiple comparisons. There were no significant differences in failure-

free (p = 0.70) or overall survival (OS) (p = 0.86), with estimated 4-year rates of 48

% versus 54 % and 49 % versus 59 % for the amifostine versus placebo arms,

respectively. The authors concluded that there was no clear evidence that pre

treatment with amifostine made any difference to the incidence of grade greater

than or equal to 2 acute or late xerostomia. Other toxicity tended to be more

severe with amifostine. There was no effect on failure-free or OS. These

researchers noted that acknowledging the low statistical power, these results did

not support the use of intravenous amifostine pre-radiotherapy in HNSCC.

M and colleagues (2019) noted that xerostomia is a significant problem affecting

QOL in patients treated with radiation therapy for head and neck cancer. Strategies

for reduction of xerostomia burden vary widely, with options including: sialagogue

medications, saliva substitutes, acupuncture, vitamins, hyperbaric oxygen,

submandibular gland transfer, and acupuncture or associated treatments. These

investigators evaluated long-term outcomes of patients treated with various

interventions for radiation-induced xerostomia. They carried out a literature search

using the terms "xerostomia" and "radiation" or "radiotherapy"; all prospective

clinical trials were evaluated, and only studies that reported 1 year follow-up were

included. The search results yielded 2,193 studies, 1,977 of which were in English.

Of those, 304 were clinical trials or clinical studies. After abstract review, a total of

23 trials were included in the review evaluating the following treatment modalities:

pilocarpine (n = 3); cevimeline (n= 1); amifostine (n = 11); submandibular gland

transfer (n = 5); acupuncture like transcutaneous electrical nerve stimulation

(ALTENS) (n = 1); hyperbaric oxygen (n = 1); and acupuncture (n = 1). Pilocarpine,

cevimeline, and amifostine had been shown in some studies to improve xerostomia

outcomes, at the cost of toxicity; ALTENS had similar efficacy with fewer side

effects. Submandibular gland transfer was effective but needed an elective

surgery, and thus may not always be appropriate or practical. The authors stated

that the use of intensity-modulated radiation therapy (OMRT), in addition to dose

de-escalation in select patients, may result in fewer patients with late xerostomia,

reducing the need for additional interventions.

An UpToDate review on “Management and prevention of complications during initial

treatment of head and neck cancer” (Galloway and Amdur, 2019a) states that

“Amifostine is an organic thiophosphate that is thought to act by donating a

protective thiol group that is a scavenger of free radicals generated in tissues



Page 20 of 26

exposed to radiation. Amifostine is the only pharmacologic agent with established

efficacy in the prevention of xerostomia. Its role in patient management is

uncertain ... Currently, the routine use of amifostine in patients receiving modern

combined modality chemoradiation is not justified … Surgical transfer of the

submandibular salivary gland from an uninvolved hemi-neck to the submental

space prior to radiation can be useful to maintain saliva production in carefully

selected patients. Although a small prospective multi-institutional trial has

demonstrated the reproducibility of this technique, it is currently practiced only at

select centers. The reasons for the limited use of this technique seem to be 3-fold:

It requires an elective operation on the contralateral neck that includes a level I-III

dissection that could be construed as an intensification of therapy. It has never

been tested against modern (i.e., submandibular and oral cavity sparing) IMRT, an

intervention that does not require an additional operation. There is no billing code

for the procedure, potentially discouraging head and neck surgeons".

Furthermore, an UpToDate review on “Management of late complications of head

and neck cancer and its treatment” (Galloway and Amdur, 2019b) states that

“Commercially available salivary substitutes or artificial saliva (oral rinses

containing hyetellose, hyprolose, or carmellose) relieve the discomfort of

xerostomia by wetting the oral mucosa. Although these agents may provide

temporary relief, many patients need frequent sips of water to remain comfortable.

In addition to being inconvenient, this can lead to secondary problems, such as

nocturia from late night fluid intake in men with prostatic hypertrophy and in men

and women with small bladder capacity … Preliminary evidence suggests that

hyperbaric oxygen may have a beneficial effect on xerostomia, but these results

must be confirmed on a larger scale before such therapy can be recommended. As

an example, a pilot study evaluated the salivary effects of hyperbaric oxygen in a

group of 80 patients, 45 of whom had hypo-salivation. Patient self-assessment of

xerostomia, and unstimulated and stimulated whole saliva flow rates all increased

after 30 sessions of hyperbaric oxygen”.

CPT Codes / HCPCS Codes / ICD-10 Codes

Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

Code Code Description

CPT codes not covered for indications listed in the CPB:



Page 21 of 26

Code Code Description

20926 Tissue grafts, other (eg, paratenon, fat, dermis)

64550 Application of surface (transcutaneous) neurostimulator (eg, TENS unit)

97810 - 97814 Acupuncture

99183 Physician or other qualified health care professional attendance and

supervision of hyperbaric oxygen therapy, per session

HCPCS codes not covered for indications listed in the CPB:

E0755 Electronic salivary reflex stimulator (intraoral/noninvasive)

G0277 Hyperbaric oxygen under pressure, full body chamber, per 30 minute

interval

S8948 Application of a modality (requiring constant provider attendance) to one

or more areas; low-level laser; each 15 minutes

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

K02.3 - K02.9

K03.89

Dental caries and other specified diseases of hard tissues of teeth

K11.7 Disturbance of salivary secretion (xerostomia)

K12.1

K13.1

K13.4

K13.6 - K13.79

Other and unspecified diseases of oral soft tissues

M35.00 -

M35.09

Sicca syndrome [Sjögren]

R13.10 - R13.19 Dysphagia

R68.2 Dry mouth, unspecified

T66.xx+ Effects of radiation, unspecified [radiation-induced xerostomia]

Z92.3 Personal history of irradiation

The above policy is based on the following references:

1. Weiss WW Jr, Brenman HS, Katz P, Bennett JA. Use of electronic stimulation

for the treatment of dry mouth. J Oral Maxillofacial Surg. 1986;44(11):845

850.



Page 22 of 26

2. Steller M, Chou L, Daniels TE. Electrical stimulation of salivary flow in

patients with Sjogren's syndrome. J Dental Res. 1988;67(10):1334-1337.

3. Erlichman M. Salivary electrostimulation in Sjogren's syndrome. AHCPR

Health Technology Assessment Report No. 8. AHCPR Pub. No. 91-0009.

Rockville, MD: Agency for Health Care Policy and Research (AHCPR); March

1991.

4. Talal N, Quinn JH, Daniels TE. The clinical effects of electrostimulation on

salivary function of Sjogren's syndrome patients. Rheumatol Int. 1992;12

(2):43-45.

5. Cooke C. Xerostomia -- A review. Palliative Med. 1996;10(4):284-292.

6. Fox PC. Management of dry mouth. Dent Clin North Am. 1997;41(4):863

875.

7. Davies AN. The management of xerostomia: A review. Eur J Cancer Care.

1997;6(3):209-214.

8. Mariette X. Current and potential treatments for primary Sjogren's

syndrome. Joint Bone Spine. 2002;69(4):363-366.

9. Fox RI. Sjogren's syndrome: Evolving therapies. Expert Opin Investig

Drugs. 2003;12(2):247-254.

10. Strietzel FP, Martín-Granizo R, Fedele S, et al. Electrostimulating device in

the management of xerostomia. Oral Dis. 2007;13(2):206-213.

11. Ami S, Wolff A. Implant-supported electrostimulating device to treat

xerostomia: A preliminary study. Clin Implant Dent Relat Res. 2010;12

(1):62-71.

12. Wong RK, Sagar SM, Chen BJ, et al. Phase II randomized trial of

acupuncture-like transcutaneous electrical nerve stimulation to prevent

radiation-induced xerostomia in head and neck cancer patients. J Soc

Integr Oncol. 2010;8(2):35-42.

13. Fedele S, Wolff A, Strietzel FP, et al. Electrostimulation for the treatment of

dry mouth. Harefuah. 2010;149(2):99-103, 123.

14. Strietzel FP, Lafaurie GI, Mendoza GR, et al. Efficacy and safety of an

intraoral electrostimulation device for xerostomia relief: A multicenter,

randomized trial. Arthritis Rheum. 2011;63(1):180-190.

15. Wong RK, James JL, Sagar S, et al. Phase 2 results from Radiation Therapy

Oncology Group Study 0537: A phase 2/3 study comparing acupuncture-

like transcutaneous electrical nerve stimulation versus pilocarpine in

treating early radiation-induced xerostomia. Cancer. 2012;118(17):4244

4252.



Page 23 of 26

16. Furness S, Bryan G, McMillan R, et al. Interventions for the management of

dry mouth: Non-pharmacological interventions. Cochrane Database Syst

Rev. 2013;9:CD009603.

17. Vijayan A, Asha ML, Babu S, Chakraborty S. Prospective phase II study of

the efficacy of transcutaneous electrical nerve stimulation in post-

radiation patients. Clin Oncol (R Coll Radiol). 2014;26(12):743-747.

18. Zadik Y, Zeevi I, Luboshitz-Shon N, et al. Safety and efficacy of an intra-oral

electrostimulator for the relief of dry mouth in patients with chronic graft

versus host disease: Case series. Med Oral Patol Oral Cir Bucal. 2014;19

(3):e212-e219.

19. Bakarman EO, Keenan AV. Limited evidence for non-pharmacological

interventions for the relief of dry mouth. Evid Based Dent. 2014;15(1):25

26.

20. Wu X, Chung VCh, Hui EP, et al. Effectiveness of acupuncture and related

therapies for palliative care of cancer: Overview of systematic reviews. Sci

Rep. 2015;5:16776.

21. Lakshman AR, Babu GS, Rao S. Evaluation of effect of transcutaneous

electrical nerve stimulation on salivary flow rate in radiation induced

xerostomia patients: A pilot study. J Cancer Res Ther. 2015;11(1):229-233.

22. Wong RK, Deshmukh S, Wyatt G, et al. Acupuncture-like transcutaneous

electrical nerve stimulation versus pilocarpine in treating radiation-

induced xerostomia: Results of RTOG 0537 Phase 3 Study. Int J Radiat

Oncol Biol Phys. 2015;92(2):220-227.

23. Galloway T, Amdur RJ. Management of late complications of head and

neck cancer and its treatment. UpToDate [online serial]. Waltham, MA:

UpToDate; reviewed January 2016.

24. Kawakami M, Ishikawa H, Tanaka A, Mataga I. Induction and differentiation

of adipose-derived stem cells from human buccal fat pads into salivary

gland cells. Hum Cell. 2016;29(3):101-110.

25. Gil-Montoya JA, Silvestre FJ, Barrios R, Silvestre-Rangil J. Treatment of

xerostomia and hyposalivation in the elderly: A systematic review. Med

Oral Patol Oral Cir Bucal. 2016;21(3):e355-e366.

26. Baer AN. Treatment of dry mouth and other non-ocular sicca symptoms in

Sjögren's syndrome. UpToDate [online serial]. Waltham, MA:

UpToDate; reviewed December 2016.



Page 24 of 26

27. Apperley O, Medlicott N, Rich A, et al. A clinical trial of a novel emulsion for

potential use as a saliva substitute in patients with radiation-induced

xerostomia. J Oral Rehabil. 2017;44(11):889-895.

28. Sivaramakrishnan G, Sridharan K. Electrical nerve stimulation for

xerostomia: A meta-analysis of randomised controlled trials. J Tradit

Complement Med. 2017;7(4):409-413.

29. Fidelix T, Czapkowski A, Azjen S, et al. Low-level laser therapy for

xerostomia in primary Sjögren's syndrome: A randomized trial. Clin

Rheumatol. 2018;37(3):729-736.

30. Assy Z, Brand HS. A systematic review of the effects of acupuncture on

xerostomia and hyposalivation. BMC Complement Altern Med. 2018;18

(1):57.

31. Cifuentes M, Del Barrio-Díaz P, Vera-Kellet C. Pilocarpine and artificial

saliva for the treatment of xerostomia and xerophthalmia of Sjogren's

syndrome: A double blind control trial. Br J Dermatol. 2018;179(5):1056

1061.

32. Riley P, Glenny AM, Hua F, Worthington HV. Pharmacological interventions

for preventing dry mouth and salivary gland dysfunction following

radiotherapy. Cochrane Database Syst Rev. 2017;7:CD012744.

33. Ferraiolo DM, Veitz-Keenan A. Insufficient evidence for interventions to

prevent dry mouth and salivary gland dysfunction post head and neck

radiotherapy. Evid Based Dent. 2018;19(1):30-31.

34. Gronhoj C, Jensen DH, Vester-Glowinski P, et al. Safety and efficacy of

mesenchymal stem cells for radiation-induced xerostomia: A randomized,

placebo-controlled phase 1/2 trial (MESRIX). Int J Radiat Oncol Biol Phys.

2018;101(3):581-592.

35. Lopez-Pintor RM, Ramírez L, Serrano J, et al. Effects of Xerostom®

products on xerostomia in primary Sjögren's syndrome: A randomized

clinical trial. Oral Dis. 2018 Dec 17 [Epub ahead of print].

36. Lee MG, Freeman AR, Roos DE, et al. Randomized double-blind trial of

amifostine versus placebo for radiation-induced xerostomia in patients

with head and neck cancer. J Med Imaging Radiat Oncol. 2018 Nov 21

[Epub ahead of print].

37. Management of late complications of head and neck cancer and its

treatmentMa SJ, Rivers CI, Serra LM, Singh AK. Long-term outcomes of

interventions for radiation-induced xerostomia: A review. World J Clin

Oncol. 2019;10(1):1-13.



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38. Galloway T, Amdur RJ. Management and prevention of complications

during initial treatment of head and neck cancer. UpToDate [online

serial]. Waltham, MA: UpToDate; reviewed January 2019a.

39. Galloway T, Amdur RJ. Management of late complications of head and

neck cancer and its treatment. UpToDate [online serial]. Waltham, MA:

UpToDate; reviewed January 2019b.



Page 26 of 26

Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in

private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible

for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to

change.

Copyright © 2001-2019 Aetna Inc.



AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0302 Xerostomia

Selected Treatments

There are no amendments for Medicaid.

www.aetnabetterhealth.com/pennsylvania revised 05/20/2019

http://www.aetnabetterhealth.com/pennsylvania

Documents

Xerostomia: Selected Treatments - Aetna