Description of underlying health problem
Hyperhidrosis is characterised by uncontrollable, excessive and unpredictable sweating that occurs at rest, regardless of temperature, and has a major impact on quality of life. It is caused by hyperfunction of the exocrine sweat glands, which are controlled by the sympathetic nervous system via postsynaptic cholinergic fibres.
Hyperhidrosis is a common condition that can be primary or secondary. Primary hyperhidrosis is excessive sweating without any discernible cause. It most commonly involves the axillae, palms and soles, but may also involve the face, groin or any area of the body. Secondary hyperhidrosis has an underlying cause, such as an endocrine disorder (e.g. hyperthyroidism), secretory tumour (e.g. phaeochromocytoma), sympathetic nervous system disorder, primary neurological condition (e.g. neuropathy), spinal disease or injury, or a psychiatric disorder. It is usually generalised over the entire body (i.e. not restricted to any specific areas of the body).
Primary hyperhidrosis is thought to affect approximately 1% of the UK population.1 Firm estimates of prevalence for the UK or England, or England and Wales, are not available. Estimates of prevalence from a large US study2 reported a figure of 2.1%, although a recent much smaller study reported a much higher estimate of 4.8%.3 A recent study of prevalence in Sweden reported a figure of 1.4% for primary hyperhidrosis [Hyperhidrosis Disease Severity Scale (HDSS) 3–4], whereas a study from Germany reported a figure of 6.1% with frequent or continuous disturbing sweating.4,5 A study of two ethnically different cities reported prevalence rates of 14.5% in Shanghai and 12.3% in Vancouver.6 It is unclear why the estimates are so varied, but reasons may include differences in study design and definition of primary hyperhidrosis. Primary hyperhidrosis normally develops in childhood and adolescence. In a few instances, it may improve with age, but it usually persists for the majority of life, although it may resolve spontaneously in the elderly. Although the cause of primary hyperhidrosis is unknown, it is likely that there is a genetic link, with one study reporting 65% of patients having a positive family history.7
The symptoms of hyperhidrosis can significantly affect quality of life and can lead to social embarrassment, loneliness, anxiety and depression. Functional problems may arise from skin maceration and soreness. Severely affected patients also may have secondary microbial infections. Teenagers may be referred for treatment because problems holding a pen and sweating ruining paperwork lead to an inability to do schoolwork and examinations. Adults may find the condition affects employability and it may prevent individuals having personal relationships. The unpredictable and uncontrollable nature of the condition can make it very distressing for sufferers.
Description of current NHS service provision
Patients suffering from hyperhidrosis often have anxiety disorders or depression, which may exacerbate or can in some instances be the cause of their hyperhidrosis.8 It is important to distinguish between primary and secondary hyperhidrosis as the treatment options are different. Treatment for secondary hyperhidrosis should be directed towards the underlying cause, rather than the hyperhidrosis itself.
The management of primary hyperhidrosis has been summarised in two non-systematic evidence reviews.9,10 Therapy for primary hyperhidrosis differs depending on the site of the condition. The generally accepted treatment pathway with the various treatment options is summarised as follows.
Primary care
Patients have often tried various over-the-counter remedies before presenting to their general practitioner (GP). In primary care, an assessment of patients’ symptoms will include an assessment of the psychological and social effects of the condition to the patient.
As hyperhidrosis can be exacerbated by foods containing stimulants, especially caffeine and theobromine, dietary restriction of coffee, tea, caffeinated soft drinks and chocolate may improve mild cases of hyperhidrosis. Other lifestyle changes that may reduce symptoms include avoiding clothing that can make sweating worse, such as tight-fitting garments or man-made fibres, wearing clothing that absorbs sweat or disguises its appearance, or using devices such as armpit guards.11 Hyperhidrosis can be associated with weight gain, and overweight people may benefit from advice about weight reduction. Drugs and physiological or disease-driven hormonal abnormalities may lead to secondary hyperhidrosis and should be excluded.
The first line of treatment for primary hyperhidrosis is topical pharmacological agents.8 Most patients try a variety of topical antiperspirants and deodorants, but find no relief until they use 10% or 20% aluminium chloride applied daily to dry skin. This dose of aluminium chloride has been shown to be effective in clinical trials for mild to moderate hyperhidrosis.10 It is hypothesised that the metallic antiperspirants enter the sweat gland duct and form an occlusive plug by combining with ductal keratin. Unfortunately, skin irritation is very common with these antiperspirants and often forces discontinuation of the treatment.9 In UK clinical practice, for axillary hyperhidrosis, a 1-month trial of 20% aluminium chloride is the initial treatment. Treatment is similar for plantar hyperhidrosis except that a month’s trial of 3% formaldehyde solution to be applied to the soles can be offered. Failure of these treatments over the specified period may be followed by referral to a secondary care dermatologist.
The evidence base for the use of aluminium chloride in primary care is weak. The National Institute for Health and Care Excellence (NICE) Clinical Knowledge Summary found no placebo-controlled randomised controlled trials (RCTs) and identified a limited evidence base comprising two small poor-quality RCTs, an open-label trial, four small case series and expert opinion.8 However, this low-cost therapy is used mainly as a first step, helping GPs discriminate between those who do and do not require referral for more specialised care. Patients whose apparent primary hyperhidrosis is actually secondary to an anxiety disorder, medication or a hormonal abnormality may also be identified in primary care and are referred for relevant treatments or investigation, rather than treatments specific to hyperhidrosis. Consequently, there is little decision uncertainty in relation to the treatment of hyperhidrosis in primary care, unlike the situation in secondary care.
Dermatology
Dermatologists may prescribe any of a number of treatments: iontophoresis, botulinum toxin (BTX) injections or systemic agents, such as anticholinergic (antimuscarinic) medications, depending on local prescribing policies.8,10,12
Tap water iontophoresis is a process in which an electrical field drives the flow of ions in a medium and enables drug delivery through the near impenetrable barrier of the skin.13 The technique involves immersion of the palms of the hands or soles of the feet in a shallow tray of water through which a weak electrical current is run. Sponges soaked in water can be used to treat the axillae. Iontophoresis can also be used with solutions of anticholinergics, although there is little evidence this these are any more effective than tap water.9 The exact mechanism of action behind the therapeutic effect in hyperhidrosis is unknown and efficacy has been demonstrated only in small studies.9 Adverse effects are minor, including a tingling ‘pins and needles’ sensation at the treatment site and dryness of the skin, although bruising or blisters can occur if the intensity of the current is too high.
Over the last few years, BTX injections have become an established licensed treatment for axillary hyperhidrosis. BTX blocks neuronal acetylcholine release at the neuromuscular junction and in cholinergic autonomic neurons, blocking the postganglionic sympathetic cholinergic nerve fibres to the sweat glands.9 There is clinical trial evidence demonstrating the efficacy of BTX in hyperhidrosis, although this varies with site of hyperhidrosis, is only temporary (only 3–6 months) and may be technique dependent.14 Potential drawbacks are the expense of the toxin, the discomfort associated with the injections and the need for repeated treatments.9
Administration of anticholinergic (antimuscarinic) agents and beta-blockers may address symptoms in mild cases of hyperhidrosis. Oral propantheline (Pro-Banthine®, Kyowa Kirin Ltd) is licensed for this indication, but the unlicensed drug oral glycopyrronium bromide is often used. Occasionally other anticholinergics are used, such as oxybutynin and also methantheline bromide.10 The doses of oral anticholinergic medication required to truly control abnormal sweating may cause significant adverse effects, including drowsiness, dry mouth, dilated pupils, photophobia, blurred vision, acute glaucoma, impaired micturition, reduced bronchial secretions, constipation, confusion, nausea, vomiting, giddiness, tachycardia, palpitations and arrhythmias. Thus, some patients are forced to discontinue this avenue of treatment, or titrate the dose up or down in accordance with tolerability in order to achieve a positive effect with minimal adverse effects.
The available medical treatments for primary hyperhidrosis are of uncertain efficacy and even when effective are not curative. Current recommendations are not underpinned by robust evidence and there are many areas of uncertainty. Importantly, the NICE Clinical Knowledge Summary on hyperhidrosis, updated in July 2013, was limited by poor-quality evidence: recommendations were often based on expert opinion in the absence of trial evidence.8 In particular, the relative effectiveness of treatments prescribed by a dermatologist is uncertain.
Surgery
Thoracic sympathectomy involves interruption or ablation of the high thoracic sympathetic chain to decrease sympathetic tone to the upper extremity and/or face.10 Open thoracic or cervical sympathectomy is now rarely performed and the less invasive technique of endoscopic thoracic sympathectomy (ETS) is preferred.10 ETS is carried out under general anaesthesia through one or more small insertion incisions between the ribs. It is used for axillary, palmar, or facial hyperhidrosis. ETS can be performed at different levels of the thoracic sympathetic chain with varying efficacy and safety.15 Adverse effects of thoracic sympathectomy can be serious, such as pneumothorax. A common adverse effect of thoracic sympathectomy is compensatory hyperhidrosis, whereby excessive sweating occurs in other parts of the body after treatment; reported in 80% of patients in one large survey.16
Lower limb sympathectomy can also be performed as an open surgical procedure under general anaesthesia, but more minimally invasive procedures are now usually preferred. An alternative is endoscopic lumbar sympathectomy, which is less widely available but has been proposed to produce a more reliable interruption of the sympathetic chain.17 Lower limb hyperhidrosis can be treated by chemical sympathectomy, which involves injecting the lumbar sympathetic chain with a chemical (phenol) to damage the nerve;18 however, it is rarely performed in the UK.
Guidance from NICE does specifically recommend ETS for primary hyperhidrosis of the upper limb (NICE interventional procedures guidance 487),19 but only for those ‘suffering from severe and debilitating primary hyperhidrosis that has been refractory to other treatments’. However, as for the dermatology treatment options, this recommendation for ETS was based on limited quality evidence: a non-systematic literature review, non-randomised comparative studies and case series; and focused on efficacy and safety more than quality of life.
Given the reluctance of patients to undergo ETS and its apparently limited effectiveness in terms of quality of life, alternative surgical options are required. Such procedures, for which guidance has not been issued, include removal of sweat glands. Traditionally, this was achieved through excision of sweat gland-containing skin (such as axillary skin), but now sweat gland clearance is more often done by subcutaneous curettage by open techniques or superficial liposuction, rather than skin resection:20 the inside layer of the skin (which contains the sweat glands) is scraped (curetted) and/or suctioned under general anaesthesia to remove the sweat glands but preserve skin integrity.21–23 Adverse effects are not as serious as for thoracic sympathectomy, but can include wound breakdown or infection. These less invasive procedures are undertaken by only a few dermatology surgeons in the UK and are rarely available through the NHS.
Other emerging treatments for hyperhidrosis of the axilla include energy-based technologies that damage the sweat gland: laser, microwave, fractionated microneedle radiofrequency and ultrasound therapy. Laser treatment involves using a long-pulsed diode-powered laser, under local anaesthesia, to apply energy directly to the underside of the dermis to act on the hair follicle and surrounding sebaceous gland epithelium, causing necrosis and subsequent disruption of the exocrine gland.24–26 The microwave device has been developed to heat target tissue at the interface between the skin and subcutaneous tissue, under local anaesthesia, causing irreversible thermolysis of apocrine and eccrine sweat glands that reside at that interface.27 Fractionated microneedle radiofrequency uses energy to heat the tissue below the surface of the skin at a depth of 2–3 mm.28 The microfocused ultrasound device uses high-intensity ultrasound to produce small (approximately 1 mm3) lesions or thermal coagulation points within the subcutaneous soft tissue layer of the dermis. At a depth of 4.5 mm within the subcutaneous tissue, the sweat glands can be treated without surface effects and once damaged the sweat glands are unable to regenerate.29
Description of technologies under assessment
The technologies under assessment are those that are considered second-line treatments: iontophoresis, BTX, anticholinergic (antimuscarinic) agents and minor surgery (such as curettage, laser, microwave, fractionated microneedle radiofrequency and ultrasound).
As discussed in Description of current NHS service provision, topical aluminium chloride is a low-cost therapy, used mainly as a first step, helping GPs discriminate between those who do and do not require referral for more specialised care. Therefore, aluminium chloride has not been included in this assessment.
Sympathectomy is end-of-line treatment and NICE recommends ETS only for upper limb hyperhidrosis patients ‘suffering from severe and debilitating primary hyperhidrosis that has been refractory to other treatments’ (© NICE 2017, reproduced with permisison from NICE interventional procedures guidance 487).19 As sympathectomy is unlikely to be considered at the same point in the treatment pathway as second-line treatments, it is not a comparator to the other treatments considered in this assessment.
Decision problem
Other than ETS, which is recognised as effective but to be reserved as a treatment of last resort, there is significant variation in the treatment for primary hyperhidrosis available in secondary care and the order in which they are prescribed. Current recommendations are not underpinned by robust evidence; there are many areas of uncertainty. In particular, the relative effectiveness of treatments prescribed by a dermatologist is uncertain and further research (both primary studies and evidence synthesis) may be required to resolve this. With regard to the minor surgical treatments available, guidance on which are the best alternative surgical options is needed, but the relative effectiveness of subcutaneous curettage and targeted sweat gland removal has not been researched or reviewed comprehensively.
Given the lack of clear research evidence to guide clinical practice, new RCTs may be warranted. However, RCTs can be difficult to conduct and extremely expensive to run. They are also demanding of both clinicians and patients and should not be undertaken without careful consideration. The need for further research is informed by both the clinical evidence and the cost-effectiveness of different treatments. The value of any future research is related to the cost of making suboptimal treatment decisions. Furthermore, in clinical practice a suite of interventions is available to patients; therefore, the decision problem also includes which treatment should be given to patients in the event that a treatment is not effective or a patient withdraws due to adverse effects. Therefore, the decision problem includes a comparison of treatment sequences.
This assessment included a systematic review to determine the relative clinical effectiveness and safety of interventions used in the management of refractory primary hyperhidrosis in secondary care (iontophoresis, BTX, anticholinergic agents and minor surgery), followed by a decision model to determine the most cost-effective treatment sequence and a value-of-information (VOI) analysis.
