Plain language summary
Non-drug treatments for dry mouth symptoms
This review, carried out by authors of the Cochrane Oral Health Group, has been produced to assess the effects of non-drug treatments used to stimulate saliva production for the relief of dry mouth (xerostomia) symptoms.
Dry mouth is a common problem with an estimated incidence of between 10% and 26% in men and between 10% and 33% in women, which may or may not be due to reduced saliva secretion. Common causes of dry mouth include the side effects of many commonly prescribed medications, diseases (such as Sjögren's syndrome where the immune system destroys tissues in the glands which produce saliva) and radiotherapy treatments for head and neck cancers.
Saliva moistens the skin in the mouth and helps to maintain oral health. The presence of saliva facilitates speech, acts to wash away food residue from around the teeth, neutralises potentially damaging food and bacterial acids, enhances a person's ability to taste the food, and generally lubricates the mouth. Saliva also acts to soften food, making it easier to chew and swallow. Enzymes in saliva start the digestion of starch and fats, and other substances in saliva, such as epidermal growth factors, promote tissue growth, differentiation and wound healing. The antibacterial, antifungal and antiviral agents in saliva balance the oral flora and help to prevent oral infections, while the minerals in saliva help to maintain tooth enamel.
Non-drug treatments such as acupuncture, mild electrical stimulation, lasers, tooth brushing and other stimulation techniques are used to improve dry mouth symptoms.
The evidence on which this review is based was up-to-date as of 16 April 2013.
Nine studies were included in this review. A total of 366 adult participants took part in these trials, with an average of 40 participants per trial, and an age range from 12 to 77 years. The causes of dry mouth were radiotherapy for oral cancers in four trials, Sjögren's syndrome in three trials, medication-related in one trial, and in the remaining trial participants had a range of causes of dry mouth.
The included studies were divided into three groups, according the interventions evaluated.
1. Five small studies with a total 153 participants evaluated acupuncture.
2. Three studies evaluated electrostimulation devices.
3. One study evaluated a power toothbrush.
The five studies evaluating the effects of acupuncture in people who had dry mouth were generally of poor quality. There was no evidence of a difference in dry mouth symptoms, but there was some evidence of a small increase in saliva production which persisted for a year after the end of the acupuncture treatment. There may not have been enough people included in the trials to show a difference in dry mouth, or it may have been that both the real acupuncture and the 'placebo' acupuncture had some beneficial effect. Acupuncture was associated with more adverse effects (tiny bruises and tiredness which were mild and temporary).
The studies evaluating the effects of electrostimulation devices were poorly conducted and reported, and provided insufficient evidence to determine the effects of these devices on either dry mouth or saliva production.
The single small study of a powered versus a manual toothbrush also found no difference for either dry mouth or saliva production.
None of the included studies reported the outcomes of duration of effectiveness, quality of life, patient satisfaction, or oral health assessment.
Quality of the evidence
These studies were generally of poor quality (low and very low).
Liječenje suhih usta bez lijekova
Ovaj sustavni pregled, koji su napravili autori Cochrane uredničke skupine za oralno zdravlje, proveden je za procjenu učinka različitih terapija koje ne uključuju lijekove, a koje se koriste za poticanje proizvodnje sline za ublažavanje simptoma suhoće usta (kserostomije) .
Suha usta su čest problem. Procjenjuje se da je učestalost tog stanja između 10% i 26% u muškaraca i između 10% i 33% u žena, što može i ne mora biti posljedica smanjenog izlučivanja sline. Česti uzroci suhih usta uključuju nuspojave mnogih lijekova koji se često propisuju, određene bolesti (kao što je Sjögrenov sindrom u kojem imunološki sustav uništava tkiva u žlijezdama koje stvaraju slinu) i liječenje zračenjem (radioterapijom) kod raka glave i vrata.
Slina vlaži usta i pomaže u održavanju zdravlja usne šupljine. Prisutnost sline olakšava govor, ispire ostatke hrane oko zuba, neutralizira potencijalno štetnu hranu i kiselinu bakterija, poboljšava sposobnost osobe da osjeti okus hrane, i općenito podmazuje usta. Slina također omekšava hranu koju je tako lakše žvakati i progutati. Enzimi u slini počinju probavu škroba i masti, i drugih tvari u slini, kao što je epidermalni čimbenik rasta, promiču rast tkiva, diferencijaciju i zacjeljivanje rana. Antibakterijski (protiv bakterija), antifungalni (protiv gljiva) i antivirusni (protiv virusa) čimbenici u slini uravnotežuju mikrorganizme koji se nalaze u ustima i pomažu spriječiti infekcije u usnoj šupljini, dok minerali u slini pomažu održati zubnu caklinu.
Terapije koje ne uključuju lijekove, kao što su akupunktura, blaga električna stimulacije, laseri, četkanje zubi i druge tehnike stimulacije koriste se za ublažavanje simptoma suhih usta.
Analizirani su dokazi objavljeni do 16. travnja 2013. godine.
U ovaj Cochrane sustavni pregled je uključeno devet pokusa. Ukupno 366 odraslih sudionika sudjelovalo je u ovim ispitivanjima, s prosjekom od 40 sudionika po pokusu. Raspon njihove dobi bio je od 12 do 77 godina. Uzroci suhoće usta u pronađenim studijama bili su radioterapija kod karcinoma usne šupljine u četiri pokusa, Sjögrenov sindrom u tri pokusa, nuspojava lijeka u jednom pokusu, a u ostalim pokusima sudionici su imali niz različitih uzroka suhoće usta.
Uključene su studije bile podijeljene u tri skupine, u skladu s intervencijama koje su ispitale.
1. Pet malih studija s ukupno 153 sudionika procijenilo je akupunkturu.
2. Tri studije procijenile su uređaje za elektrostimulaciju.
3. Jedna studija procijenila je električne zubne četkice.
Pet studija koje su procijenile učinke akupunkture kod ljudi koji su imali suha usta uglavnom su bile loše kvalitete. Nije bilo dokaza o razlici u simptomima suhih usta, ali bilo je nekih dokaza o malom povećanju proizvodnje sline koji je trajao godinu dana nakon završetka terapije akupunkturom. Budući se radilo o malim studijama, moguće je da nije uključeno dovoljno pacijenata da bi se pokazala razlika za simptome suhih usta, ili je moguće da su i stvarna akupunktura i "placebo" akupunktura imale neki blagotvoran učinak. Akupunktura je povezana s više negativnih učinaka (sitnih modrica i umorom, koji su bili blagi i privremeni).
Pokusi koji su procijenili učinke uređaja za elektrostimulaciju bili su loše provedeni i opisani u znanstvenim radovima te nisu dali dovoljno dokaza kako bi se utvrdili učinci tih uređaja bilo na suha usta ili proizvodnju sline.
Jedan mali pokus u kojem je uspoređena električna u odnosu na običnu četkicu za zube također nije našao razliku bilo za suha usta ili proizvodnju sline.
Nijedan od uključenih pokusa nije opisao kao rezultat trajanje učinka terapije, kvalitetu života, zadovoljstva pacijenata, ili procjenu zdravlja usne šupljine.
Ovi pokusi su općenito bili loše kvalitete (niska i vrlo niska kvaliteta).
Prevela: Božena Armanda
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: firstname.lastname@example.org
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版（英語版）の内容をご確認ください。
Description of the condition
Xerostomia is the subjective sensation of a dry mouth (Napenas 2009; Visvanathan 2010), which can have a number of different causes. Dry mouth may be an objective finding with a reduction in the quantity of saliva produced, or a change in the composition of the saliva (Napenas 2009; Visvanathan 2010), or it may be a subjective sensation of dry mouth, found in patients with normal salivary gland function.
In a healthy individual, saliva production ranges from 0.5 to 1.5 litres per day (Mese 2007; Porter 2004). Approximately 90% of this saliva is produced by three pairs of major glands (the parotid, submandibular and sublingual salivary glands), with the remaining 10% of saliva produced by the minor salivary glands which are distributed around the mouth (in the labial, buccal, lingual and palatal mucosa) (Mese 2007; Napenas 2009). Secretion of saliva from the salivary glands is controlled by the brain via the saliva reflex arch. The taste, smell and/or chewing of food stimulates the salivary centre in the medulla of the brain, which then stimulates the nerves to the salivary glands which produce saliva (Proctor 2007). Saliva moistens the oral mucosa and helps to maintain oral health. The presence of saliva facilitates speech, acts to wash away food residue from around the teeth, neutralises potentially damaging food and bacterial acids, enhances a person's ability to taste the food, and generally lubricates the mouth (Hopcraft 2010; Mese 2007). Saliva also acts to soften food, making it easier to chew and swallow. Enzymes in saliva start the digestion of starch and fats, and other substances in saliva, such as epidermal growth factors, promote tissue growth, differentiation and wound healing. The antibacterial, antifungal and antiviral agents in saliva balance the oral flora and help to prevent oral infections, while the minerals in saliva help to maintain tooth enamel.
Dry mouth is a very common symptom, with an estimated incidence of between 10% and 26% in men and between 10% and 33% in women (Hopcraft 2010). Sufferers may complain of their mouth feeling dry or sticky in texture, report difficulty with chewing and swallowing food, and describe a decreased sensation of taste. Irritation when wearing dentures has also been reported (Visvanathan 2010).
The causes of xerostomia can be separated into two groups: salivary and non-salivary (Napenas 2009). Non-salivary causes of dry mouth include: mouth breathing, anxiety, neurological dysfunction and dehydration (Napenas 2009). Salivary causes of dry mouth symptoms can be further subdivided into those associated with salivary gland pathology such as Sjögren's Syndrome, sarcoidosis, diabetes mellitus and hepatitis C virus . There is some potential overlap between these groups as Sjögren's Syndrome is not only associated with direct salivary gland damage but is also associated with neuropathy (Tobón 2012) which could result in neurologically mediated salivary dysfunction. In addition, there are over 500 medications reported to cause oral dryness through various proposed mechanisms (Femiano 2008; Porter 2004). It is reported that drugs can inhibit salivation via effects on central and peripheral receptors (Proctor 2007; Scully 2004). The medications known to cause oral dryness are wide ranging and often very commonly prescribed preparations such as those used to treat depression, epilepsy and hypertension. Moreover, xerostomia is a recognised side effect of both radiotherapy (Shiboski 2007) and chemotherapy (Porter 2004) used to treat cancer.
Xerostomia is especially common among the elderly. While salivary glands certainly undergo changes due to age, the impact of changes due to aging on salivary gland function is contentious (Mese 2007). It has been suggested that subjective complaints of dry mouth in the elderly population can mostly be attributed to causes other than age-related changes to the tissues in the salivary glands (Mese 2007); notably the increased prevalence of chronic conditions in this population, and resultant 'polypharmacy' (Femiano 2008; Porter 2004).
The experience of having a dry mouth can have a detrimental effect on a sufferer's quality of life, and can force them to modify their daily behaviour in order to cope with their symptoms (Hopcraft 2010). Dry mouth can be associated with a number of negative consequences which include: difficulty with speaking, chewing, swallowing and tasting food; soreness of the gums and oral mucosa, making the wearing of dentures uncomfortable or impossible; impaired sleep; psychological and social disability; increased risk of caries; oral candidiasis and salivary gland infections (Enger 2011; Fedele 2008; Hackett 2012; Porter 2010; Visvanathan 2010; Wolff 2012). Effective management of this condition is therefore important to improve the quality of life of sufferers. In addition, from both a public health and patient perspective it is important to manage dry mouth symptoms in order to minimise possible sequelae such as dental decay and oral infections.
Because dry mouth is a subjective symptom it is assessed by questioning individuals. A series of questions targeting different aspects of dry mouth may provide more information regarding the aspects which have greatest impact on an individual's quality of life. There are numerous such tools used to assess dry mouth symptoms, including various quality of life scales and some specific tools such as the Xerostomia Questionnaire (XQ) and the Xerostomia Inventory (XI). The Xerostomia Inventory is an 11-item summated rating scale which has been validated as both a discriminative measure of the severity of dry mouth symptoms, and as a responsive measure of the effects of interventions for dry mouth (Thomson 2007). The range of possible XI scores is from 11 to 55 (Appendix 1) and a change in XI score of six points is likely to be clinically meaningful (Thomson 2007).
In some patients it may be possible to manage the problems associated with a dry mouth through optimal management of the underlying condition(s); for example through better management of diabetes. Smoking cessation and a reduction in alcohol consumption may also be of some benefit, as both these factors may exacerbate symptoms of dry mouth (Mese 2007). For individuals with mild symptoms, sucking ice chips or frequent sips of cold water may provide sufficient relief (Hopcraft 2010).
Topical application of salivary substitutes may provide short-term relief during waking hours (Femiano 2008). Salivary stimulation by means of either systemic or topical medications, or chewing gum, may be appropriate for use by patients with some degree of salivary gland function (Porter 2004). However, while the use of some systemic pharmacotherapies, such as pilocarpine, to stimulate saliva production are effective (Davies 2007), these drugs have associated adverse effects and may be contraindicated in patients with existing chronic respiratory, cardiovascular and renal disease (Fedele 2008).
Description of the intervention
Non-pharmacological interventions, such as electrostimulation of the salivary glands, acupuncture or the application of low level laser therapy, have the potential to increase saliva production. In electrostimulation, a hand-held battery-operated device may be used to administer an electrical stimulus to the tongue or hard palate. Alternatively, a transcutaneous electrical nerve stimulation (TENS) machine may be used and electrodes connected to the skin. Electrostimulation may be administered in the patient's home or at a medical facility. In acupuncture, needles are inserted by a professional into pre-determined acupuncture points on the body. In low level laser therapy, a laser beam is applied by a professional to the salivary glands of patients with xerostomia. For patients with some residual salivary gland function, and co-morbidities or contraindications to pharmacological therapies, identifying effective alternative means for stimulating saliva production, could provide a useful management strategy.
How the intervention might work
Acupuncture and electrostimulation have been reported to have both biological and clinical plausibility with regards to the treatment of dry mouth (O'Sullivan 2010; Wolff 2012; Zhuang 2013). It is proposed that application of electrical impulses to one or more arms of the salivary reflex arch may increase salivation (Fedele 2008). Electrostimulation of the efferent trigeminal fibres of the lingual nerve may promote the submandibular and sublingual glands to increase saliva secretion (Wolff 2012). Acupuncture is suggested to produce physiological effects such as stimulation of the autonomic nervous system and increased peripheral blood flow which may in turn stimulate saliva production (O'Sullivan 2010). The mechanism of action for low level laser therapy is complex and is also poorly understood, however laser therapy is thought to increase salivary secretion through the stimulation of mitotic activity in salivary gland epithelial tissue (Lončar 2011).
Why it is important to do this review
The number of people living with dry mouth symptoms is expected to rise as life expectancy increases, and treatment for chronic diseases becomes more effective (Mese 2007; Porter 2004). Dry mouth conditions can have considerable negative impact on the quality of life of patients (Enger 2011; Hackett 2012; Porter 2010). Effective treatments for patients unable to use systemic pharmacotherapies would not only improve the quality of life for these patients, but would also help maintain oral health, avoiding further potentially painful, debilitating and costly oral disease and tooth loss.
This review complements other existing Cochrane reviews of treatments for dry mouth.
Pharmacological interventions for preventing salivary gland dysfunction following radiotherapy (Tavender 2004).
Parasympathomimetic drugs for the treatment of salivary gland dysfunction due to radiotherapy (Davies 2007).
Amifostine for salivary glands in high dose radioactive iodine treated differentiated thyroid cancer (Ma 2009).
Interventions for the management of dry mouth: topical therapies (Furness 2011) which includes the use of saliva substitutes and saliva stimulants such as pastilles and chewing gum.
To assess the effects of non-pharmacological interventions administered to stimulate saliva production for the relief of dry mouth.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) comparing techniques designed or used to stimulate saliva production (such as acupuncture, laser or electrostimulation) with either placebo or with another treatment. Trials were included irrespective of language or publication status.
We excluded cross-over studies from this review due to the potential for non-pharmacological therapies, such as acupuncture, laser therapy and electrostimulation, to exert a prolonged effect that could carry-over to subsequent periods of the trial (Higgins 2011).
Types of participants
Trials where participants were seeking treatment for the symptoms of dry mouth (xerostomia) due to any cause. Participants must have had xerostomia at baseline. Causes of xerostomia may have included haemodialysis, hormonal disorders (diabetes), autoimmune conditions (Sjögren's Syndrome, systemic lupus erythematosus and rheumatoid arthritis) and immune disorders (such as AIDS and graft versus host disease). This review also included patients currently undergoing, or who have previously received, radiotherapy; and patients seeking treatment for xerostomia due to current use of medications to control chronic or neoplastic conditions.
Types of interventions
Non-pharmacological interventions, such as acupuncture, electrostimulation or low level laser therapy, for the management of xerostomia. Active interventions were compared with either placebo, no treatment or another active non-systemic treatment, such as topical salivary stimulants. Trials which compared a non-pharmacological intervention with systemic treatments such as oral pilocarpine or oral cevimeline were excluded. Systemic pharmacological treatments are effective, but may be contraindicated in some patients with co-morbidities or concomitant medications and it is this group who may benefit from non-pharmacological interventions. Trials which compared different frequencies of treatment were included.
Types of outcome measures
Xerostomia both short term (4 weeks after start of treatment) and longer term (3 months after end of treatment). Dry mouth may have been measured using a visual analogue scale (VAS) or been subjectively assessed as improved, no change or worse compared to baseline. Dry mouth symptoms may also have been measured using a validated questionnaire such as the Xerostomia Questionnaire (XQ).
Duration of effectiveness.
Quality of life: assessed using a standard quality of life instrument, or a specific instrument such as head and neck quality of life (HNQOL), or similar.
Patient satisfaction with the treatment(s).
Salivary flow: a clinically measured objective outcome such as unstimulated whole saliva (UWS) or stimulated whole saliva (SWS).
Oral health assessment.
Search methods for identification of studies
For the identification of studies included or considered for this review, detailed search strategies were developed for each database searched. These were based on the search strategy developed for MEDLINE (Appendix 2) but appropriately revised for each database to take account of differences in syntax rules and controlled vocabulary. This subject strategy was combined with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE (as published in box 6.4.c in the Cochrane Handbook for Systematic Reviews of Interventions, Higgins 2011).
We searched the following databases:
The Cochrane Oral Health Group's Trials Register (to 16th April 2013) (Appendix 3)
The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 3) (Appendix 4)
MEDLINE via OVID (1948 to 16th April 2013) (Appendix 2)
EMBASE via OVID (1980 to 16th April 2013) (Appendix 5)
AMED via OVID (1985 to 16th April 2013) (Appendix 6)
CINAHL via EBSCO (1981 to 16th April 2013) (Appendix 7)
CANCERLIT via PubMed (1950 to 16th April 2013) (Appendix 8).
Only handsearching carried out as part of The Cochrane Collaboration's handsearching programme was included in the search, where these references have been incorporated into the CENTRAL database (see the Cochrane Master List of journals which have been handsearched).
The metaRegister of Controlled Clinical Trials (www.controlled-trials.com) and ClinicalTrials.gov (www.clinicaltrials.gov) were also searched to identify ongoing and completed trials and to contact trialists for further information. There were no restrictions on the language of publication or publication status.
Searching other resources
The reference lists of related review articles and all articles obtained were checked for further trials.
Data collection and analysis
Selection of studies
At least two review authors screened the results of the searches to identify possible included studies. Paper copies were obtained of all trials which appeared to meet the inclusion criteria or where there was insufficient information in the title or abstract or both to make a clear decision about eligibility. At least two review authors assessed each of these papers to determine which met the inclusion criteria for this review. Any disagreements were resolved by discussion. Papers not in English were translated by members of The Cochrane Collaboration as required.
Data extraction and management
All randomised controlled trials which appeared to meet the inclusion criteria for this review were assessed by at least two review authors to confirm eligibility, assess risk of bias and extract data using a piloted data extraction form. Disagreements were resolved by discussion. The following data were recorded.
Study design, location, funding, number of centres.
Inclusion and exclusion criteria, number of patients recruited, number of patients randomised to each group, number of patients withdrawn, numbers evaluated.
Intervention(s), comparator, dose, frequency, duration of treatment, concomitant medications.
Primary and secondary outcomes, times measured, numbers of patients included in the outcome evaluation.
Whether a sample size calculation was performed.
Information was entered into the table of characteristics of included studies and additionally into an Excel spreadsheet from which a summary of the characteristics of the studies was made. Where the published paper was unclear concerning aspects of trial design, attempts were made to contact the study authors for clarification or more information or both.
Assessment of risk of bias in included studies
This was conducted using the recommended approach for assessing the risk of bias in studies included in Cochrane reviews (Higgins 2011). We used the two-part tool, addressing the six specific domains (namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and 'other bias'). Each domain included one or more specific entries in a 'Risk of bias' table. Within each study, the first part of the tool involved describing what was reported to have happened in the study. The second part of the tool involved assigning a judgement relating to the risk of bias for that entry. This was achieved by answering a pre-specified question about the adequacy of the study in relation to the entry, such that a judgement of 'low' indicated low risk of bias, 'high' indicated high risk of bias, and 'unclear' indicated unclear or unknown risk of bias.
The domains of sequence generation, allocation concealment, incomplete outcome data and selective outcome reporting are each addressed in the tool by a single entry for each study. For blinding two entries were used because assessments needed to be made separately for a) patients and b) outcome assessor. Where the patients self assessed the outcomes to the trial, this was noted. The final domain ('other sources of bias') was assessed as a single entry for studies as a whole.
The risk of bias assessment was undertaken independently and in duplicate by two review authors as part of the data extraction process.
After taking into account the additional information provided by the authors of the trials, studies were grouped into the following categories.
Low risk of bias (plausible bias unlikely to seriously alter the results) for all key domains.
Unclear risk of bias (plausible bias that raises some doubt about the results) if one or more key domains were assessed as unclear.
High risk of bias (plausible bias that seriously weakens confidence in the results) if one or more key domains were assessed to be at high risk of bias.
A 'Risk of bias' table was completed for each included study. The results were also presented graphically.
Measures of treatment effect
For dichotomous outcomes (e.g. xerostomia improved or not), the estimate of treatment effect of an intervention would have been expressed as risk ratios (RR) (xerostomia improved/not) together with 95% confidence intervals (CIs). For continuous outcomes (such as mean VAS scores), mean differences and standard deviation were used to summarise the data for each trial.
Dealing with missing data
Where data were missing from the published report of a trial, we attempted to contact the author(s) to obtain the data and clarify any uncertainty. The analysis generally included only the available data (ignoring missing data), however, methods for estimating missing standard deviations in section 7.7.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) would have been used if appropriate. Otherwise we did not undertake any imputations or use any statistical methods to impute missing data.
Assessment of heterogeneity
Heterogeneity was assessed by inspection of the point estimates and confidence intervals on the forest plots. The variation in treatment effects was assessed by means of Cochran's test for heterogeneity and quantified by the I2 statistic. Heterogeneity was considered statistically significant if P value was < 0.1. A rough guide to the interpretation of the I2 statistic given in the Cochrane Handbook for Systematic Reviews of Interventions is: 0% to 40% might not be important, 30% to 60% may represent moderate heterogeneity, 50% to 90% may represent substantial heterogeneity, and 75% to 100% considerable heterogeneity (Higgins 2011).
Assessment of reporting biases
If there had been sufficient numbers of trials (more than 10) in any meta-analysis, publication bias would have been assessed according to the recommendations on testing for funnel plot asymmetry (Egger 1997) as described in section 10.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If asymmetry were identified we would have examined possible causes.
A meta-analysis was only conducted if there were studies of similar comparisons reporting the same outcome measures. We would have combined risk ratios for dichotomous data, and we combined mean differences for continuous data, using fixed-effect models. If there were more than three studies included in any meta-analysis, we would have used random-effects models.
Subgroup analysis and investigation of heterogeneity
We planned to investigate clinical heterogeneity by examining the different causes of xerostomia. If there had been sufficient studies of each intervention and outcome, we planned, a priori, to conduct subgroup analyses for different causes of xerostomia (type of drug or type of condition causing xerostomia).
If there had been sufficient studies for each outcome and intervention, we would have undertaken sensitivity analysis based on the overall risk of bias.
Presentation of main results
A summary of findings table was developed for the main outcomes of this review using GRADEPro software. The quality of the body of evidence was assessed with reference to the overall risk of bias of the included studies, the directness of the evidence, the inconsistency of the results, the precision of the estimates, the risk of publication bias and the magnitude of the effect. The quality of the body of evidence of each of the main outcomes was categorised as high, moderate, low or very low.
Summary of main results
The nine studies included in this review of non-pharmacological interventions for dry mouth were divided into three comparisons.
Five small studies (total 153 participants, with dry mouth following radiotherapy treatment) compared acupuncture with placebo and two trials reported outcome data for dry mouth in a form suitable for meta-analysis. The pooled estimate for dry mouth showed no difference between acupuncture and control in these two trials (SMD -0.34, 95% CI -0.81 to 0.14, P value 0.17, I2 = 39%) with the confidence intervals including both 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 treatment (three trials) (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 (UWS, MD 0.06 ml/minute, 95% CI 0.01 to 0.11, P value 0.03, I2 = 10%). For stimulated whole saliva (SWS) there was a benefit favouring acupuncture (MD 0.19 ml/minute, 95% CI 0.07 to 0.31, P value 0.002, I2 = 1%) an effect which also remained 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%) (Summary of findings for the main comparison). It is unclear whether this small increase in saliva production is associated with a clinically important benefit because dry mouth symptoms were not assessed in all of the studies that measured saliva production.
Two small studies compared the use of an electrostimulation device with a placebo device (total 101 patients with Sjögren's Syndrome). A further study compared acupuncture-like electrostimulation 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 electrostimulation and placebo in the outcomes of UWS or SWS at the end of the 4-week treatment period in the one study that provided data for these outcomes. No adverse effects were reported (Summary of findings 2).
A single study compared the stimulatory effect of powered versus manual toothbrushing and found no difference for the outcomes of UWS or SWS.
Overall completeness and applicability of evidence
We have included nine trials which randomised a total of 366 participants. However, the total number included in the outcome assessment is unclear as this information was not stated in one study (Talal 1992) and our attempts to contact the authors were not successful. Only two of the nine trials included in this review reported the primary outcome of this review: dry mouth. We pooled the data using standardised mean difference because each of the trials used a different scale to measure dry mouth. The confidence intervals of the pooled estimate cross the line of no effect, suggesting that there is no difference between acupuncture and placebo, although the point estimate SMD 0.34 could be interpreted as showing a small benefit in favour of acupuncture. It could be that the number of participants included in this meta-analysis is too small to detect a statistically significant effect, and further RCTs evaluating acupuncture are required to determine whether this is the case. There is also a suggestion from the authors of these trials that the placebo ('sham' acupuncture) may actually have a beneficial effect on dry mouth. If there is a beneficial effect from the placebo treatment this would make it less likely to show a difference between the two arms of these trials. Consideration should be given to designing a different control intervention.
In the published protocol, we decided a priori to exclude trials with cross-over designs from this review. The reason for this decision is that there is some suggestion that acupuncture may have a sustained effect on dry mouth. With regard to electrostimulation and laser therapies, there is little information available concerning the duration of effects.
Electrostimulation devices have undergone development over recent years and it is likely that the trials included in this review which were published between 1988 and 2003 evaluate 'first-generation' devices which may be considered obsolete. Newer 'second generation' devices which employ electrodes embedded within a removable oral splint are now available (Fedele 2008). A recent trial of a 'second generation' electrostimulation device (Strietzel 2011) has been excluded from this review due to the use of a cross-over design in this study. This trial reported a "cumulative positive effect" from the electrostimulation device. It is hoped that further research with this or similar electrostimulation devices will be undertaken using a double-blind parallel-group design.
Another consideration is the variation between the participants in these trials. Three trials included participants with Sjögren's Syndrome, four included patients who had previously undergone radiotherapy for head and neck cancer and two trials included participants with a range of cause of dry mouth symptoms. The nature and extent of salivary gland disease is likely to vary between these participants with resultant variations in residual gland function, disease natural history and prognosis amongst participants. Meta-analysis of the acupuncture trials showed some evidence of a benefit due to acupuncture on the outcomes of both unstimulated and stimulated saliva production. It is not known whether or not this small average benefit, translated to an improvement in the symptoms of dry mouth or the (oral health related) quality of life for these trial participants because this information was not reported. From the literature we know that increased saliva production may or may not reduce dry mouth symptoms.
However, while there is little effect as measured by the mean differences between the randomised groups in these four trials, in both trials some individuals did appear to benefit from the active intervention.
Quality of the evidence
None of the trials included in this review are at low risk of bias. All are small (range of 12 to 77 participants per trial), none reported sample size calculations and all are likely to lack statistical power to detect a difference between the arms of the trial should such a difference exist. Few reported important outcomes such as dry mouth symptoms, quantifiable adverse effects or (oral health related) quality of life. There is evidence of reporting bias, whereby important patient-centred outcomes are either not measured and/or not reported, and this is a major limitation on the findings of this review. The quality of the body of evidence for all the main outcomes of this review has been assessed as low or very low.
Potential biases in the review process
We conducted a broad search of several databases and placed no restrictions on the language of publication when searching the electronic databases or reviewing reference lists of included studies. However, it is likely that there are other studies, which may or may not be RCTs, published in the Chinese language literature which we have not identified for this review. However a similar published review prepared by a team of authors based in China (Zhuang 2013) identified the same three RCTs for treatment of radiotherapy-induced xerostomia that we included in this review.
We decided to exclude cross-over studies from this review because we were unable to determine empirically the duration of any potential effect of either acupuncture or electrostimulation techniques on dry mouth symptoms. It seemed likely that the potential effects of these interventions could extend for weeks or months after the end of the treatment phase. In this case the use of a cross-over study design to evaluate these interventions would be inappropriate.
Agreements and disagreements with other studies or reviews
Our findings are broadly in agreement with those of other published systematic reviews (Garcia 2013; O'Sullivan 2010; Zhuang 2013) which focused on participants with post-radiotherapy xerostomia and found evidence of some increase in saliva production but no difference in dry mouth symptoms. A review of treatment approaches for patients with xerostomia due to Sjögren's Syndrome (Wolff 2012) refers to one of the studies included in our Cochrane review (Talal 1992) and reports that electrostimulation is effective in stimulating saliva secretion. This review goes on to describe initial testing in a cross-over trial of a small intraoral electrostimulation device, which is activated by a remote control. Early results appear promising for patients and further research is ongoing and may be included in future updates of this Cochrane review.
Our thanks to Phil Riley (Deputy Managing Editor of the Cochrane Oral Health Group) for his help with the administration of this review, and to Anne Littlewood for undertaking the searches for this review. Our thanks to the referees who provided comments on this review.
Appendix 1. Xerostomia Inventory
Individuals are asked to choose a response to the following 11 questions. Each response is assigned a score between 1 and 5 and the combined total score (a number between 11 and 55) is calculated, which represents the severity of the underlying xerostomia (score of 11 represents very mild xerostomia and 55 represents severe xerostomia) (Thomson 2005).
My mouth feels dry
I have difficulty in eating dry foods
I get up at night to drink
My mouth feels dry when eating a meal
I sip liquids to aid in swallowing food
I suck sweets or cough lollies to relieve dry mouth
I have difficulties swallowing certain foods
The skin of my face feels dry
My eyes feel dry
My lips feel dry
The inside of my nose feels dry
|Response to each question||Score|
Appendix 2. MEDLINE via OVID search strategy
3. (dry$ adj2 (oral or mouth$)).mp.
4. (asialia or "salivary gland hypofunction" or hyposalivat$).mp.
5. (radioxerostomia or radio-xerostomia).mp.
7. Electrical Stimulation/
8. ((electric$ adj3 stimulat$) or neuroelectrostimulation or "masticatory stimulation").mp.
11. "intra-oral device$".mp.
15. (hypnosis or hypnotism or "autogenic train$" or autosuggestion or auto-suggestion).mp.
17. 6 and 16
Appendix 3. Cochrane Oral Health Group's Trials Register search strategy
((xerostomia or "dry mouth*" or asialia or "salivary gland hypofunction" or hyposaliva*) AND (neuroelectrostimulation or "masticatory stimulation" or (electro and stimulat*) or "intra-oral device*" or acupuncture* or hypnosis or hypnotism or "autogenic* train*" or autosuggest* or auto-suggest* or laser*))
Appendix 4. CENTRAL search strategy
#1 MeSH descriptor Xerostomia this term only
#2 xerostomia in All Text
#3 ((dry* in All Text near/2 oral in All Text) or (dry in All Text near/2 mouth* in All Text))
#4 (asialia in All Text or "salivary gland hypofunction" in All Text or hyposalivat* in All Text)
#5 (radioxerostomia in All Text or radio-xerostomia in All Text)
#6 (#1 or #2 or #3 or #4 or #5)
#7 MeSH descriptor Electric Stimulation this term only
#8 ((electric* in All Text near/3 stimulat* in All Text) or neuroelectrostimulation in All Text or "masticatory stimulation" in All Text)
#9 MeSH descriptor Lasers this term only
#10 laser* in All Text
#11 "intra-oral device*" in All Text
#12 MeSH descriptor Acupuncture this term only
#13 acupuncture in All Text
#14 MeSH descriptor hypnosis this term only
#15 (hypnosis in All Text or hypnotism in All Text or "autogenic train*" in All Text or autosuggestion in All Text or auto-suggestion in All Text)
#16 (#7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15)
#17 (#6 and #16)
Appendix 5. EMBASE via OVID search strategy
3. (dry$ adj2 (oral or mouth$)).mp.
4. (asialia or "salivary gland hypofunction" or hyposalivat$).mp.
5. (radioxerostomia or radio-xerostomia).mp.
8. ((electric$ adj3 stimulat$) or neuroelectrostimulation or "masticatory stimulation").mp.
11. "intra-oral device$".mp.
15. (hypnosis or hypnotism or "autogenic train$" or autosuggestion or auto-suggestion).mp.
17. 6 and 16
The above subject search was linked to the following Filter for EMBASE via OVID:
3. (crossover$ or cross over$ or cross-over$).ti,ab.
5. (doubl$ adj blind$).ti,ab.
6. (singl$ adj blind$).ti,ab.
10. CROSSOVER PROCEDURE.sh.
11. DOUBLE-BLIND PROCEDURE.sh.
12. RANDOMIZED CONTROLLED TRIAL.sh.
13. SINGLE BLIND PROCEDURE.sh.
15. ANIMAL/ or NONHUMAN/ or ANIMAL EXPERIMENT/
17. 16 and 15
18. 15 not 17
19. 14 not 18
Appendix 6. AMED via OVID search strategy
2. (dry$ adj2 (oral or mouth$)).mp.
3. (asialia or "salivary gland hypofunction" or hyposalivat$).mp.
4. (radioxerostomia or radio-xerostomia).mp.
7. ((electric$ adj3 stimulat$) or neuroelectrostimulation or "masticatory stimulation").mp.
8. "intra-oral device$".mp.
10.(hypnosis or hypnotism or "autogenic train$" or autosuggestion or auto-suggestion).mp.
12. 5 and 11
Appendix 7. CINAHL via EBSCO search strategy
S1 MH Xerostomia
S3 ((dry* N2 oral) or (dry* N2 mouth*))
S4 (asialia or "salivary gland hypofunction" or hyposalivat*)
S5 (radioxerostomia or radio-xerostomia)
S6 S1 or S2 or S3 or S4 or S5
S7 MH "Electric Stimulation"
S8 ((electric* N3 stimulat*) or neuroelectrostimulation or "masticatory stimulation")
S9 "intra-oral device*"
S10 MH Acupuncture
S12 MH Hypnosis
S13 (hypnosis or hypnotism or "autogenic train*" or autosuggestion or auto-suggestion)
S14 MH Lasers
S16 S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15
S17 S6 and S16
Appendix 8. CANCERLIT via PubMed search strategy
#1 Search Xerostomia [mh:noexp]
#2 Search xerostomia
#3 Search (dry* and (oral or mouth*))
#4 Search (asialia or "salivary gland hypofunction" or hyposalivat*)
#5 Search radioxerostomia or radio-xerostomia
#6 Search #1 or #2 or #3 or #4 or #5
#7 Search Electrical Stimulation [mh:noexp]
#8 Search ((electric* and stimulat*) or neuroelectrostimulation or "masticatory stimulation")
#9 Search "intra-oral device*"
#10 Search Acupuncture [mh:noexp]
#11 Search acupuncture
#12 Search Hypnosis [mh:noexp]
#13 Search hypnosis or hypnotism or "autogenic train*" or autosuggestion or auto-suggestion
#14 Laser [mh:noexp]
#16 #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15
#17 #6 and #16
Appendix 9. Search strategy for Clinicaltrials.gov
1. xerostomia and laser
2. xerostomia and acupuncture
3. xerostomia and electrostimulation
Contributions of authors
Gemma Bryan (GB), Sue Furness (SF) and Helen Worthington (HW) wrote the protocol. Roddy McMillan (RM) and Sarah Birchenough (SB) provided a clinical perspective on xerostomia and treatments for dry mouth.
The search results were screened against the inclusion criteria for this review by GB and SF. Full-text copies of papers appearing to meet the inclusion criteria were then evaluated by at least two authors (GB, SF or HW) independently, and any disagreements were resolved by discussion, following clinical input as required from RM.
Risk of bias assessment and data extraction were conducted by GB, SF and HW, with at least two authors independently evaluating each included study. Data entry and analysis were conducted by SF.
The text of the review was drafted by SF and reviewed by all the other authors.
Declarations of interest
Gemma Bryan: no interests to declare.
Sue Furness: no interests to declare.
Helen Worthington: no interests to declare.
Roddy McMillan: no interests to declare.
Sarah Birchenough: no interests to declare.
Differences between protocol and review
The review was amended to clarify that participants in included studies must have dry mouth symptoms at baseline.