**4. Sweet solution analgesia in animal studies**

Around the world more and more hospitals and clinics are implementing the use of sweet substances to reduce pain and discomfort among premature and mature infants. Yet important knowledge and research gaps concerning long-term analgesic effects of repeated administration of sweet solutions still exist. One reason could be related to the fact that the mechanism of sweet-taste-induced analgesia is still not precisely understood, which prevented the uptake

Sweet solution as analgesic for painful events performed on premature and full term infants is a true revolutionary, novel and relatively current idea [30, 31]. It took long time for the clinical community to recognize and accept the fact that this special group of people does feel pain and this pain has short- and long-term negative consequences [32]. Moreover, available treatments such as opioids were considered unsafe and fear of their adverse effects lead to under treatment or even no treatment at all even for invasive practices [33]. Another obstacle was the lack of proper pain assessment measures for infants and nonverbal children [34]. Physiological and behavioral responses to pain were observed [34], and this lead to the development of pain assessment tools appropriate for measuring premature and infants pain, one of these tools is the premature infant pain profile (PIPP) that is utilized to assess pain and

Sweet solution analgesia has been used for painful procedures performed in the NICU, for immunization, injections and circumcision. Heel lances performed quite often in the NICU provoked less physiological and behavioral responses of pain when proceeded with 2 mL of oral sucrose solution of 50% [36]. Same had been noticed for other routinely applied procedures such as intravenous or arterial line insertion, lumbar puncture, tape removal and venipuncture [37–39]. This analgesic effect also extends to even older infants; sucrose was also effective in lowering pain scores due to immunization for babies aged between 1 and 12 months [23, 40]. Sucrose was beneficial when paired with other analgesic for pain relief during circumcision, probably since circumcision is a more intensely painful procedure than other routine procedures undertaken at NICU, yet it gave a synergistic effect with other analgesic methods [41]. The concentration of the sweet agent also mattered; a more concentrated sugar solution was found to be a more effective analgesic than less concen-

Sucrose is the most widely used agent for sweet solution-induced analgesia, nevertheless, other sweeteners were also tried and found to be effective. Fructose, lactose, milk and noncaloric sweeteners had been used for analgesia, although less frequently [21]. Glucose 20–30% solution is effective for heel lance and venipuncture in preterm and term infants [42, 43]. Fructose was as effective as sucrose and both were more effective than glucose [31]. In humans, fructose is as sweet as sucrose and sweeter than glucose; this might explain why fructose and sucrose were more effective than glucose [44]. Non-caloric sweeteners were also as effective

of such intervention using research evidence from being used in practice.

**3. Sweet solution analgesia in human studies**

304 Pain Relief - From Analgesics to Alternative Therapies

effectiveness of pain management among premature infants [35].

as sucrose in reducing pain due to procedures such as heel lance [45].

trated ones [21].

Animal studies have shown an analgesic effect of sweet solutions during infancy similar to that of humans [52]. Sweet components of milk including sucrose, glucose or fructose have shown to alleviate neonatal pain [53, 54]. The analgesic effect of sweet solutions is confined to the intraoral route as sucrose reduces pain sensation when administered orally not when applied via gastric gavage [12]. The antinociceptive actions of these solutions are not due to intraoral infusion alone because they are not produced by water or lactose [54, 55].

The most commonly studied is the natural sweetener sucrose. Sucrose has a long history of calming and analgesic effect especially for neonatal pain. The first observation of sucrose pain modulating effects was obtained by Blass et al. 1987 who reported that contact with a small amount of sucrose solution on the tongue of infant rats rapidly increased the paw withdrawal latency (a measure of pain threshold) in a hot-plate test [56]. Sucrose-induced analgesia during infancy develops rapidly and persists for several minutes [57]. In addition, sucrose ingestion for a relatively long period of time produces analgesia [58, 59]. Acute sucrose-induced analgesia is age-dependent that means it occurs mainly during the preweaning period in rats [57].

Artificial sweeteners have also shown analgesic actions when administered orally. Chronic saccharin intake decreases pain sensitivity and increases pain threshold as measured in hotplate test [60]. Furthermore, acute saccharin administration for 5 hours resulted in analgesia that persists for 3 hours [61]. Aspartame, another sweetener, decreases pain sensitivity, and has shown to produce analgesic effects comparable with sucrose [62, 63].

Although the mechanisms behind sweet substances-induced analgesia are still not clearly defined; endogenous opioid system is implicated. Sweet palatable solutions augment morphine-induced analgesia [64–67], this has suggested that sweet solutions ingestion is associated with the release of endogenous opioids, a mechanism which involves stimulation of gustatory sweet receptors [68]. This mechanism was supported by the observation that sucrose reduces pain sensation when administered orally not when applied via gastric gavage [12, 69]. Furthermore, naltrexone and naloxone, opioid antagonists, were shown to abolish the analgesic effect of sweet-tasting solutions [56, 70–72] In addition, consuming palatable sweet substances increases endogenous β-endorphin activity in rat brain and in human plasma [69, 73–75]. Besides, endogenous opioid system, other neurotransmitters and receptors are probably involved. One study revealed a major involvement of nicotinic cholinergic receptors in the sweet substanceinduced analgesia as atropine (cholinergic antagonist) diminished sucrose-induced analgesia [76]. Other studies have shown the involvement of noradrenaline, serotonin and their receptors in the central modulation sweet substance-induced analgesia [71, 77, 78].

Likewise, sweet solutions ability to prevent, decrease or reverse unfavorable long-term effects of neonatal pain had been explored. Unpublished data and a previous study from our lab indicate that early pain experience increases pain sensitivity and impairs spatial memory during adulthood in rats; the interventions using sucrose or saccharin solution prevented these long-term consequences of neonatal pain [75].
