Nakayama M, Okizaki A, Takahashi K. A randomized controlled trial for the effectiveness of aromatherapy in decreasing salivary gland damage following radioactive iodine therapy for differentiated thyroid cancer. Biomed Res Int. 2016;2016:95098.
Randomized controlled trial
To investigate the effects of aromatherapy in decreasing salivary gland damage for patients undergoing radioactive iodine (RAI) therapy with differentiated thyroid cancer (DTC)
Seventy-one patients with differentiated thyroid cancer were divided into either group A, an aromatherapy group (n=35) or group B, a control group (n=36). All participants had primarily undergone a total thyroidectomy followed by RAI (with a mean activity of 5.31 GBq). Any hormonal therapy was discontinued 2 weeks before RAI therapy. Patients who had a history of salivary gland disease or autoimmune disease, were taking drugs to manage xerostomia, or who had received or were currently receiving external radiotherapy to the head and neck or additional sites were excluded from the study.
Study Medication and Dosage
Patients were randomized to undergo treatment with an essential oil mixture of 1.0 mL Citrus limon (primary constituents were monoterpene hydrocarbons, D-limonene and B-pinene) and 0.5 mL Zingiber officinale (primary constituents were sesquiterpene hydrocarbons, zingiberene and B-sesquiphellandrene) or distilled water (placebo). The aromatic oil blend and the distilled water were placed in bottles of the same shape and size. All bottles were numbered and recorded. All participants received a treatment in the form of an aromatic bath for 10 minutes before each meal for a total of 2 weeks while they were hospitalized. The inhalation method was demonstrated and inhalation confirmed for all patients by a board-certified lecturer from the Japan Clinical Aromatherapy Society. The timing of treatment in relation to RAI therapy was not reported.
To assess the functional outcome of aromatherapy, patients underwent salivary gland scintigraphy before RAI therapy and 4 days post I-131 administration. Imaging of the anterior head using a dual-head gamma camera and medium-sensitivity collimator was performed after an intravenous injection of 185 MBq 99mTc-pertechnetate. Sequential images were then obtained at 1 minute per frame for 30 minutes. Twenty minutes after this injection, 3 mL of lemon juice of 100% concentration was instilled into each patient’s mouth, via syringe, to stimulate salivary function/secretion. Regions of interest were drawn around the bilateral parotid and submandibular glands on the summation images. For quantitative analysis, a time-activity curve was created for each patient, per individual salivary gland. The defined measurements on the time-activity curve consisted of (1) maximum count before stimulation; (2) minimum count post-stimulation; (3) background count (ie, areas outside of the 4 glands) at the time of peak activity; and (4) injected counts. The glandular functional parameters were then calculated with the use of the time-activity curves. The maximum accumulation ratio, as an index of salivary uptake, and washout ratio, as an index of salivary excretion, were measured.
Compared to the placebo group (group B), participants assigned to the aromatherapy group (group A) demonstrated a significantly higher rate of salivary gland secretion in the parotid and submandibular glands (P<0.05). Group A also showed a significantly increased rate of change of the washout ratio before and after the therapy in the bilateral parotid glands (P<0.05). An increasing trend was observed for the submandibular glands in group A; however, the differences were not significant between groups. These findings suggest that aromatherapy may help prevent treatment-related salivary gland disorder.
The prevalence of thyroid cancer is increasing, with an estimated 56,870 new cases of thyroid cancer expected to be diagnosed in the United States in the year 2017.1 It is the most rapidly increasing cancer diagnosis in the United States, and the fifth most common cancer in women.2 The increasing rate of diagnosis is likely attributable to increased detection of smaller cancers, due to the advent of highly sensitive diagnostic tests.
Radioactive iodine can be used to ablate thyroid tissue not completely removed post-thyroidectomy and is the most common treatment for thyroid cancer that has spread to lymph nodes or other parts of the body.3
Given the limited efficacy of current xerostomia treatment options, the use of aromatherapy in salivary gland hypofunction is intriguing.
Sialadenitis (ie, inflammation of the salivary glands) is the most common complication of RAI therapy post-thyroidectomy.4 The presence of sodium/iodine transporters within salivary glands make them one of the tissues, outside the thyroid, with the highest iodine accumulation.5 The prevalence of radiation-induced sialadenitis ranges from 11% to 67% and has the ability to cause not only pain, swelling, and overall oral discomfort but also increased risk for oral disease such as dental caries and candidiasis.6
Unfortunately, the standard recommendations for the management of sialadenitis are of limited efficacy. The most common of these include gum chewing, sucking on hard candy (most typically lemon), massage of the salivary glands and oral mucosa, and exercise of the tongue, jaw, and lips.7 Xerostomia, as a result of sialadenitis, remains the largest obstacle despite these therapies.
The American Dental Association (ADA) Council on Scientific Affairs lists 4 options as the “standards” in the management of xerostomia and salivary gland dysfunction: pharmacotherapeutics that stimulate salivary function (sialagogues), topical dry-mouth formulations (salivary substitutes), sugar-free gum, and acupuncture.8 However, the council acknowledges the limited efficacy of any one of these therapies in the management of dry mouth.
Sialagogues in the form of pilocarpine and cevimeline are approved by the US Food and Drug Administration (FDA) for the management of salivary gland hypofunction due to either radiation or Sjogren’s syndrome. These drugs not only have numerous side effects (visual blurring, sweating, nausea, rhinitis, sinusitis, and diarrhea),9 they also depend on the presence of healthy acinar cells within salivary glands, which makes their utility limited. The latter is especially true with glandular damage due to radiation ablation.
While a wide array of topical dry-mouth formulations does exist, there remains no clear consensus as to what the efficacious ingredients may be. In fact, a 2011 Cochrane review states that there is “no strong evidence from this review that any topical therapy is effective for relieving the symptom of dry mouth.”10 Most importantly, salivary substitutes do not provide the functions of saliva.
Sugar-free gum is an option and patients with residual salivary function found it to be more helpful than a salivary substitute.11 However, insufficient evidence exists to promote its superiority over other given interventions in the alleviation of dry mouth symptoms.10
Finally, acupuncture, as noted, is also recognized as a potential therapy in the management of xerostomia. While the ADA acknowledges that the use of acupuncture has limited scientific backing, there are some studies that suggest it has therapeutic benefits.
A 2015 randomized, placebo-controlled study evaluated the use of laser acupuncture on salivary flow rates in 26 patients with Sjogren’s syndrome.12 The use of specific acupuncture points with laser therapy resulted in a significantly higher amount of saliva production. Obviously, a larger sample and further protocol evaluation are needed.
A 2016 literature review of 22 full-text articles on the use of acupuncture treatment for radiation-induced xerostomia sought to assess the relative standardization of acupuncture protocols.13 The authors concluded that despite heterogeneities in acupuncture treatment protocols, a general recommendation for the use of acupuncture in the treatment of radiation-induced xerostomia exists and that greater research was warranted. This review was followed by a 2016 multisite randomized clinical trial that compared the use of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) to pilocarpine.14 While there were no significant treatment differences, patients who received ALTENS had consistently lower scores, which seemed to indicate better salivary gland function compared to the pilocarpine group. Acupuncture is clinically promising, but additional studies are needed to scientifically verify its efficacy in the management of xerostomia.
Given the limited efficacy of current xerostomia treatment options, the use of aromatherapy in salivary gland hypofunction is intriguing.
The sense of smell is intimately tied to our physiology and has played a large role in our survival. It is the oldest and one of the most powerful senses and aids in the discovery of food, the identification of threats, and human communication—human pheromones serve to relay information (of which we are often unaware).15 From a molecular standpoint, smell is the meeting of odorous air molecules with olfactory epithelial receptors. These receptors are essentially neurons, transmitting sensory information along the olfactory conduction pathway via the hippocampus. These receptors only bind to certain molecules, functioning like a “lock and key” mechanism. Because these molecules have many different shapes and multiple receptors are used, the human nose is able to discern many different scents.16 Thanks to the 2004 Nobel Prize-winning work of Richard Axel and Linda Buck, we now know the human nose is capable of smelling 1 trillion of them.17
The present study by Nakayama et al highlights the association between the sense of smell and the autonomic nervous system. Saliva is the only digestive juice regulated by the autonomic nervous system without the help of hormones.17 As exhibited by the patients in the aromatherapy group, the autonomic nervous system was activated, as displayed by increased salivation. This is likely because the memory of specific aromas, in this case, Citrus limon (lemon) and Zingiber officinale (ginger), stimulated the transmission of information to the thalamus and hypothalamus, 2 epicenters closely linked with eating behavior. This in turn positively influenced the secretion of saliva.
Whether this was sympathetic or parasympathetic activity remains to be determined. Theoretically, the latter could be assessed in future studies, as greater quantities of serous saliva are secreted by the parasympathetic nervous system. In fact, when past studies are taken into account, one could hypothesize that the parasympathetic nervous system may play a greater role here.
A 2014 randomized controlled crossover study investigated the effects of Yuzu, a Japanese citrus fruit, on salivary chromogranin A (CgA), a stress hormone that reflects sympathetic nervous system activity.18 After 10 minutes of inhaling the Yuzu aroma, levels of salivary CgA significantly decreased, and after 30 minutes they decreased even more. In addition, subjective measurements of mood disturbance significantly decreased as well as 4 subscores of emotional symptoms, including tension/anxiety, depression-dejection, anger-hostility, and confusion. A similar 2015 study assessed the use of Bergamot essential oil inhalation on salivary cortisol levels. Again, those in the intervention group did exhibit a significant decrease in salivary cortisol levels, reflecting an overall decrease in sympathetic nervous system activity.19
This effect was also noted with use of lavender and rosemary aromatherapy in a 2007 study.20 In this case, 22 healthy volunteers sniffed either lavender or rosemary aromas. Instead of only measuring salivary cortisol, salivary free radical scavenging activity (FRSA) was also assessed. Notably, inhalation of both scents resulted in a significant decrease in salivary cortisol levels and inversely, a significant increase in free radical scavenging activity. This study illustrates the potential role aromas may play in not only the decrease in stress hormones (sympathetic activity) but also the functional composition of saliva and, potentially, the overall ability to manage oxidative stress.
Finally, a notable 2014 crossover intervention study evaluated the use of orange essential oil in children during dental treatment.21 Again, anxiety was measured via salivary cortisol measurement and, in this case, pulse rate. The decrease in salivary cortisol levels were again significant, as was pulse rate, between the control and therapeutic intervention groups.
These studies highlight the role aroma may play on overall parasympathetic activity. The heterogeneity of the aromas selected is notable. And because overall digestive function is regulated largely by the parasympathetic nervous system, one could hypothesize that aromatherapy may incite it over the sympathetic nervous system, its counterpart. Furthermore, decreased stress may certainly play a larger overall role for patients undergoing any form of conventional therapy, in this case radiation iodine ablation, as it is well-known that elevated stress hormones adversely affect immune function, increase surgical recovery time, and increase susceptibility to disease.22,23 Although the types of aromas used in previous studies are varied, it behooves clinicians to evaluate which aromas have the largest positive impact in the maintenance of important physiological functions and overall well-being.
As noted above, the 2 aromas used in the present study were lemon and ginger. The use of these for stimulation of digestive functions makes sense. In fact, when orally injected, lemon juice is used to stimulate salivary secretion. The memory of its scent would seem to play a large role in salivation. In addition, previous studies have demonstrated the ability of its aroma to stimulate the autonomic nervous system by way of increasing gastric mucus secretions.24 Ginger has also been studied and is widely used to assist in digestion. It is mostly commonly known for its antinausea effects. Because it regulates digestion and absorption of nutrients and so helps activate digestive organs and stimulate appetite, ginger is often sold in teas and candies to assist those with chemotherapy-induced anorexia. Of note, ginger has also been shown to exhibit gastrointestinal mucosal protective mechanisms and promote salivary gland secretion.25,26 Its use, along with lemon, makes sense for the management of salivary gland secretion.
Black pepper may be a warranted addition to the use of lemon and ginger in the induction of salivary gland function. A 2006 randomized trial evaluated the olfactory stimulation of volatile black pepper oil on 105 post-stroke patients.27 Results revealed that inhalation of black pepper oil increased serum substance P and significantly improved the swallowing reflex. Although salivary excretion was not measured, it is known that serum substance P is reported to have saliva-secretion-promoting effects.28 This study was followed by a 2008 study which assessed the use of volatile black pepper oil in a pediatric population who had been on chronic enteral nutrition for 10 months or more due to neurological disorders.29 Again, black pepper oil was found to increase serum substance P and its inhalation did facilitate oral feeding, as noted per improvement in swallowing movements and function. In these cases, an aroma could help facilitate digestion at the neurological level. Which, given olfaction is one of our oldest neurological functions and our oldest sense, makes sense.
Given the limited research regarding the use of aromatherapy for salivary gland hypofunction, the present study by Nakayama et al serves as an intriguing starting point. Lemon, ginger, and potentially black pepper oils seem to hold the greatest promise, at this point, in the induction of salivation, feeding functions, and, potentially, stress reduction and immune function. Additional studies are certainly warranted and the identification of additional aromas assessed.
Salivary gland hypofunction is a significant issue greatly affecting quality of life for those it afflicts. Because scents have few to no side effects, are a reusable source, and are highly accessible, aromatherapy serves as a safe, cost-effective intervention with the potential for use across patient populations in the management of salivary gland compromise.