5.2.2. Sialagogues

Treatments to stimulate the function of remaining salivary gland tissue have had more success than artificial saliva. Systemic sialagogues stimulate saliva secretion from residual, functional salivary gland acinar cells to compensate somewhat for decreases in saliva flow due to RT and, thus, their effectiveness depends heavily on the number of surviving acinar cells [203]. Both pilocarpine and bethanechol are systemic sialagogues that activate muscarinic-cholinergic receptors. A phase III randomized clinical trial studying the effects of pilocarpine therapy after RT in HNC patients demonstrated that unstimulated saliva flow in the patients who received pilocarpine therapy was significantly higher than in those receiving a placebo [204]. The authors reported that this increase in saliva flow did not correlate with improved QoL scores and also concluded that pilocarpine therapy had no significant effect on the incidence of mucositis. These observations support previous clinical studies [205–207]. Cevimeline, a quinuclidine derivative of acetylcholine that selectively activates M3 muscarinic receptors, has obtained FDA approval for xerostomia treatment in Sjögren's syndrome patients, although its use for RT-induced xerostomia remains off-label [21,208]. In a prospective, single-arm study with 255 participants, cevimeline taken orally for 52 weeks improved symptoms in 59.2% of HNC patients who received RT [209]. The benefit of cevimeline over pilocarpine is that its half-life is much longer [210], offering prolonged benefit to patients. Similarly, bethanechol is a stable analogue of acetylcholine and, thus, its effects last longer, as it undergoes slower degradation by cholinesterases. Similar to pilocarpine, bethanechol stimulates the parasympathetic nervous system by activating muscarinic

receptors. Although still only indicated for post-operative or postnatal urinary retention, studies by Epstein et al. and Gorsky et al. demonstrate that post-RT bethanechol therapy is just as effective as pilocarpine therapy [211,212]. Patients receiving either bethanechol or pilocarpine reported a 39% or 33% subjective increase in unstimulated saliva production, respectively [212]. Patients receiving a combination therapy of bethanechol and pilocarpine did not show statistically significant improvements over either monotherapy. The authors postulate that this is due to "parenchymal fatigue", hinting at a saturation limit of the remaining healthy tissues [212]. Jham et al. was one of the first studies to evaluate bethanechol therapy concomitant with receiving RT in regards to preventing rather than ameliorating xerostomia [213]. They observed that the use of bethanechol throughout the duration of RT led to a statistically significant increase in whole resting saliva secretion at the culmination of RT, compared to a control group receiving artificial saliva. Similarly, a double-blind randomized clinical study [214] evaluating the utility of bethanechol therapy concomitantly with or after RT demonstrated that patients receiving bethanechol reported improved xerostomia symptoms and had statistically significant increases in unstimulated and stimulated whole saliva flow [214]. Despite many promising studies with a diverse cohort of HNC patients, there is still a lack of longitudinal studies. A systemic meta-analysis assessing the effect of pharmacological interventions for RT-induced xerostomia found that there was insufficient data to support any effect of pilocarpine therapy on salivary gland function or QoL [215]. The authors noted that what data were available were of very low quality, supporting the need for additional studies. As the time of writing this review, there have been no clinical studies evaluating treatment outcomes utilizing muscarinic receptor agonists beyond a few months post-RT. Given the lifelong presentation of post-RT xerostomia, therapies need to be effective over an extended period of time. Additionally, because of the transient effect of artificial saliva and sialagogues, these treatment options present a significant financial burden [12].
