Evidence-based review and assessment of botulinum neurotoxin for the treatment of secretory disorders

Abstract

Botulinum neurotoxin (BoNT) can be injected to achieve therapeutic benefit across a large range of clinical conditions. To assess the efficacy and safety of BoNT injections for the treatment of certain hypersecretory disorders, including hyperhidrosis, sialorrhea, and chronic rhinorrhea, an expert panel reviewed evidence from the published literature. Data sources included English-language studies identified via MEDLINE, EMBASE, CINAHL, Current Contents, and the Cochrane Central Register of Controlled Trials. Evidence tables generated in the 2008 Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) review of the use of BoNT for autonomic disorders were also reviewed and updated. The panel evaluated evidence at several levels, supporting BoNT as a class, the serotypes BoNT-A and BoNT-B, as well as the four individual commercially available formulations: abobotulinumtoxinA (A/Abo), onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), and rimabotulinumtoxinB (B/Rima). The panel ultimately made recommendations for each therapeutic indication, based upon the strength of clinical evidence and following the AAN classification scale. For the treatment of axillary hyperhidrosis in a total of 923 patients, the evidence supported a Level A recommendation for BoNT-A, with a Level B recommendation for A/Abo and A/Ona and a Level U recommendation (insufficient data) for A/Inco and B/Rima. Five trials in 82 patients supported the use of BoNT in palmar hyperhidrosis, with a Level B recommendation for BoNT-A and a Level C recommendation for BoNT-B; individual formulations received a Level U rating due to insufficient data. BoNT (and all individual formulations) received a Level U recommendation for the treatment of gustatory sweating. Support for use of BoNT in sialorrhea was derived from eight trials in a total of 222 adults and children. Evidence supported a Level B recommendation for A/Abo, A/Ona, and B/Rima and a Level U recommendation for A/Inco. Evidence supported a Level B recommendation for A/Ona for the treatment of allergic rhinitis, based on two Class II studies in 73 patients. A lack of published studies for A/Abo, A/Inco, or B/Rima supported a Level U recommendation for those formulations. Further clarity on the optimal mode of administration and additional studies using other BoNT formulations are needed to fill current evidence gaps.

Introduction

The use of botinulinum neurotoxin (BoNT) within the broad category of autonomic indications includes hypersecretory disorders, such as hyperhidrosis, sialorrhea, and chronic rhinorrhea, and a variety of urologic disorders, which are discussed elsewhere.

Hyperhidrosis is excessive sweating due to overactivity of the sweat glands beyond what is physiologically appropriate for temperature regulation. Primary hyperhidrosis is generally idiopathic but may be exacerbated under conditions of stress and the associated sympathetic stimulation; it affects about 1%–3% of the population (Atkins and Butler, 2002; Cohen et al., 2007). Hyperhidrosis usually affects the axillae, palms, and soles of the feet, but it may also occur in the face and head (craniofacial hyperhidrosis) or it may be generalized throughout the body. The burden of hyperhidrosis is mainly due to the significant social stigma and a reduced quality of life (QoL) rather than medical consequences (Cohen et al., 2007).

Gustatory sweating is a unique entity characterized by profuse sweating of the face, scalp, and neck during or immediately after ingestion of food or drink (Naumann et al., 1997). Gustatory sweating is the main feature of Frey's syndrome, which most often occurs as a complication of surgery to the area of the face near the parotid glands (Eckardt and Kuettner, 2003).

Currently approved treatments for hyperhidrosis include pharmacologic approaches (systemic and topical agents), surgical procedures in extreme cases (sweat gland resection/curettage and endoscopic transthoracic sympathectomy), and BoNT (Cohen et al., 2007). Systemic medications, including anticholinergic agents and beta blockers, have limited efficacy and substantial side effects. Surgical approaches are irreversible and may be associated with increased compensatory sweating in other body areas (Cohen et al., 2007).

The severity of hyperhidrosis and the efficacy of treatment can be assessed objectively using gravimetric techniques, by measuring the rate of sweating over a period of time, or by semi-quantitative methods such as the iodine-starch test or other staining procedures (Heckmann et al., 2001). A detailed description of established quantitative and subjective assessments for evaluating the efficacy of interventions for hyperhidrosis is provided in a review by Bhidayasiri and Truong (Bhidayasiri and Truong, 2008).

Sialorrhea is a socially disabling disorder that affects patients with Parkinson's disease (PD), cerebral palsy (CP), amyotrophic lateral sclerosis (ALS), motor-neuron disease, and other neurologic conditions. Approximately 70%–80% of patients with PD and up to 38% of children with cerebral palsy (CP) are affected (Benson and Daugherty, 2007). While the burden of sialorrhea is largely related to the social and quality-of-life consequences, medical sequelae include skin irritation and infection, and aspiration of saliva. Generally, drooling is not a disorder of hypersalivation alone but, rather, results from failure to swallow saliva due to compromised motor control and coordination of facial muscles and/or difficulty swallowing due to the underlying disease. Although hypersalivation is not the root cause of sialorrhea, treatment is generally aimed at decreasing saliva production. Management options include radiotherapy, surgery in severe cases, and drug therapy, commonly with anticholinergic medications, which are effective but limited due to their side effects (Truong and Bhidayasiri, 2008). Injection with BoNT is also a treatment option.

The mechanism of action underlying the use of BoNT in sialorrhea is related to inhibition of acetylcholine release at the neurosecretory junction of the salivary glands, which reduces saliva production (Ellies et al., 2000).

Allergic rhinitis (AR) is a common disorder affecting about 10%–35% of the population (Cingi et al., 2009; Weber, 2008). Although AR itself is not a disabling disorder, it imposes a substantial burden in medical costs and indirect costs due to loss of productivity (Simoens and Laekeman, 2009). The evidence supporting a wide variety of approved treatments for AR has recently been reviewed and indicates that intranasal steroids produce the greatest improvements in nasal symptoms of seasonal AR, and intranasal steroids and oral antihistamines may be equally effective in patients with perennial AR (Benninger et al., 2010).

Of the available classes of medications for AR, leukotriene receptor antagonists and cromolyn sodium are somewhat less effective in reducing rhinorrhea than are intranasal steroids and oral or intranasal antihistamines (Benninger et al., 2010). Despite the availability of these medications, a large proportion of AR patients report limited satisfaction with current therapies (Nathan, 2007). There has been some clinical research on the use of BoNT for the treatment of AR (Unal et al., 2003; Yang et al., 2008).

The aim of this review of evidence is to assess the effectiveness of interventions involving injections of BoNT for hypersecretory disorders. Two BoNT serotypes (A and B) are approved by the Food and Drug Administration for clinical use in the United States. Approved BoNT-A formulations are onabotulinumtoxinA (A/Ona; Allergan, Inc.), abobotulinumtoxinA (A/Abo; Ipsen Limited), and incobotulinumtoxinA (A/Inco; Merz Pharmaceuticals); the only approved BoNT-B formulation is rimabotulinumtoxinB (B/Rima; Solstice Neurosciences, Inc.). These agents are marketed under the brand names Botox^®, Dysport^®, Xeomin^®, and Myobloc^®/Neurobloc^®, respectively.