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

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 effectiveness of pain management among premature infants [35].

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 concentrated ones [21].

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

The effect of sweet solution in reducing pain and calming crying infants is restricted to oral administration [12], providing evidence that it is the taste of sweetness what causes analgesia and not the sugar itself. Further evidence comes from the observation that different sugars and even artificial sweeteners produce the same effect when given orally into the oral cavity. Activating sensory afferents in the oral cavity leads to pleasurable sensation or effect. This positive hedonic effect of sweet tasting substances induced analgesia further supports the theory that it is the taste of sweetness not the caloric value of the food [46].

The mechanism of this sweet-induced analgesia is not fully elucidated. While animal studies provided more convincing evidence for the involvement of the endogenous opioid system, human studies were equivocal [42, 47, 48]. Tolerance to repeated doses of glucose did not develop, and an opioid antagonist, naloxone, given before glucose did not diminish its analgesic effects. On the other hand, babies born to methadone-addict mothers did not respond to the calming effects of sucrose. Thus, so far the evidence support the idea that the mechanism of analgesia induction might be mediated via opioid and non-opioid pathways [8, 47].

This analgesic effect is short lived and repeat administration is needed for repeated procedures. Furthermore, this effect of sweet tasting solutions does not persist beyond infancy [21]. This sweet taste–induced analgesia does not extend to adults, and it seems to be related to the degree of sweetness; thus higher sucrose concentration were preferred by children compared to adults [49]. One explanation is that as we grow, the positive hedonic value of sweet tasting substances decreases thus evoking less pleasure and less analgesia.

Other non-pharmacological methods were also studied, kangaroo mother care KMC was found to be mildly effective at lowering pain responses to heel lance in full and preterm neonates [50]. Skin-to-skin contact between infant and mother alleviated pain occurrence during heel lance as well [51].
