Benefits and limitations of the use of glucose for the treatment of pain in neonates: a literature review

REVIEW ARTICLE

Benefits and limitations of the use of glucose for the treatment of pain in neonates: a literature review

Juliana de Oliveira Marcatto^I,II; Eduardo Carlos Tavares^II; Yerkes Pereira e Silva^II,III

^IHospital Dia e Maternidade UNIMED – Belo Horizonte (MG), Brazil

^II Department of Pediatrics – Faculdade de Medicina da Universidade Federal de Minas Gerais – UFMG – Belo Horizonte (MG), Brazil

^IIIHospital Lifecenter – Belo Horizonte (MG), Brazil

Corresponding author

ABSTRACT

This article aims to review the main studies evaluating glucose as a therapeutic alternative during mildly to moderately painful procedures in neonatology, highlighting its benefits and limitations.

During their stay in neonatal intensive care units, neonates are constantly subjected to a number of painful procedures without proper therapeutic management, although the medical literature emphatically recommends this type of management, highlighting the deleterious neurological consequences of pain. Most of these interventions are frequently necessary in neonatal intensive care units to maintain clinical stability in these children; the use of systemic analgesia, however, is not considered to be a good option.

The administration of oral glucose solution is apparently effective and safe for pain control during procedures causing mild-to-moderate pain in neonate intensive care units, with rare adverse effects; however, its mode of action has not yet been described clearly in the literature.

The administration of oral glucose solution is well described for use in venous punctures; it is apparently effective also for heel punctures, especially when associated with nonnutritive sucking, with most studies showing favorable results.

Keywords: Pain/therapy; Infant, newborn; Glucose/therapeutic use

RESUMO

Esta revisão se propõe analisar os estudos que utilizaram a glicose como recurso terapêutico em neonatologia durante procedimentos que resultam em dor de intensidade leve a moderada apontando os benefícios e limitações de sua utilização.

Os recém-nascidos internados em unidades neonatais são submetidos a inúmeros procedimentos dolorosos sem abordagem terapêutica adequada, apesar de a literatura recomendar de maneira enfática a necessidade de tratamento e ressaltar as repercussões neurológicas deletérias para esses pacientes. A maior parte destas intervenções constitui procedimentos frequentemente realizados nas unidades e necessários à manutenção da estabilidade clínica, nos quais a analgesia sistêmica não está indicada.

A administração de solução oral de glicose parece ser eficaz e segura no controle da dor durante procedimentos que geram dor de intensidade leve a moderada nas unidades de terapia intensiva neonatais, os efeitos adversos são raros e o mecanismo de ação ainda não está descrito de maneira consistente na literatura. A indicação da solução oral de glicose durante punções venosas é bem descrita e durante punções de calcanhar parece ser o método mais eficaz de controle da dor especialmente quando associado à sucção não nutritiva, com resultados favoráveis na maior parte dos estudos.

Descritores: Dor/terapia; Recém-nascido; Glucose/ uso terapêutico

INTRODUCTION

Prematurely delivered children often require therapeutic interventions to maintain their clinical stability. Because of the plasticity and immaturity of their central nervous systems, some interventions, including tactile stimuli, are perceived as painful.⁽¹⁾

It is estimated that a preterm newborn is exposed to between two and 14 painful procedures daily within the first two weeks of life and may be exposed to more than 100 procedures before hospital discharge.⁽²⁾ It is also known that from as early as 24 weeks of pregnancy, the neuroanatomical and neurochemical structures necessary for pain recognition are already developed. Therefore, untreated painful interventions during this time may change the brain architecture with both immediate and late effects that may affect the individual's biopsychosocial development.⁽³⁾

Painful experiences in newborns have to be evaluated indirectly, by observing changes to physiological and behavioral parameters during the interventions.⁽⁴⁾ These physiological changes include the following: heart rate, respiratory rate, blood pressure, saturation of oxygen and hormonal changes. Pain behavioral parameters include facial mimicry, motor patterns and crying.

Several pharmacological and non-pharmacological therapeutic strategies have been developed and proposed to prevent or reduce pain in the neonate. Restricted and gentle handling, appropriate positioning, music therapy, acupuncture, massage, nonnutritive sucking, sweet solutions and drug therapy are the most often discussed therapeutic alternatives.^(5-8)

Oral glucose solution (OGS) has been used for the treatment of pain with favorable results during procedures causing mild-to-moderate pain, or as adjuvant therapy for severe pain.^(9-29) The adverse effects of systemic analgesics discourage their routine use in pain control.^(30,31) However, in the long term, these untreated painful experiences may result in both physiological and behavioral changes.

The need for neonatal pain control is well described in the literature. Most of the neonatal intensive care units (NICUs) use pain control strategies for procedures causing severe pain. However, procedures causing mild-to-moderate pain are more frequent in NICUs, requiring interventions appropriate for the level of pain intensity. Clinical practice suggests that these procedures are often performed with no analgesic considerations. The use of OGS during procedures causing mild-to-moderate pain is a pain control strategy worthy of consideration.

This article aims to present a literature review concerning the use of oral glucose solution in clinical practice, highlighting the different opinions regarding dosage, concentration, safety and possible induction of tolerance following consecutive administrations. It also aims to point out both the benefits and limitations of this treatment strategy.

Mode of action of oral glucose as an analgesic and potential tolerance induction

The mode of action of oral glucose solution for pain control is not fully understood; however, its effectiveness is well accepted by the scientific community. Two mechanisms are apparently involved in this process, and their combination is believed to provide the analgesia described in the literature.

The first of these mechanisms is the sweet sense stimulation of taste- and pleasure-differentiated cortical areas, a process which promotes both physiologic and sensorial effects.⁽³²⁾ Endogenous opioids are apparently released acting through their receptors (mainly µ receptors), modulating the painful experience.^(33,34) The benefits are increased when some type of oral stimulation is provided just before the intervention, such as sucking a pacifier.^(9,28) The administration should be made over the tongue, where the sweet sensation receptors are located. By comparison, administration at the lateral portion of the mouth or by nasogastric tube failed to show benefit.⁽³⁵⁾ Beneficial effects are more frequently observed in newborns and infants less than 12 months of age.⁽³⁶⁾

The binding of endogenous opioids to nociceptors thereby modulating neuronal transmission of painful stimuli has been the central hypothesis for the mode of action of oral glucose. This mechanism has been detailed in animal models, where antagonist administration has inhibited this effect.⁽³⁷⁾ However, Gradin and Schollin⁽²¹⁾ conducted a trial in neonates in which naloxone (an antagonist opioid) was given intravenously before OGS administration; the results showed that the analgesic effects were not reduced for the group receiving the antagonist as compared with the control group. These results illustrate that the mode of action of glucose for pain control is not yet fully understood.

Regarding the question of tolerance, this process is known to occur rapidly with opioids, commonly after 72 hours of continuous or intermittent therapy.⁽³⁸⁾ Because the hypothesized mode of action of oral glucose would be the release of endorphins (endogenous opioids), successive glucose administrations could be thought to result in tolerance and consequent reduction of the anticipated analgesic effects. Therefore, the benefits would be clearer during the early days of hospitalization. The role of tolerance is relevant because glucose has been used intensively in neonatal units, with no relevant considerations regarding concentration, dosage and indications.

The hypothesis of tolerance has been tested only in animal models, not in human studies.^(19,37) Four studies evaluated recurrent sucrose dosing, with analgesic effects identified consistently in each study.^(39-42)

OGS concentration and dose

Oral glucose dosage and concentration for painful procedures in routine neonatal units care have not been defined. In the available studies, the concentrations have ranged between 10% and 30%, with an administered volume between 0.05 and 2 mL. A 2010 Cochrane review concluded that the data on appropriate glucose doses are inconclusive, and consequently, an optimized dose could not be suggested.^(24,43)

Clinical conditions in which OGS is recommended

Despite the advances in neonatal pain control in recent years, procedures causing mild-to-moderate pain tend to be disregarded and consequently, undertreated. Glucose is one of the primary indicated resources for these conditions. Procedures in which OGS has been used include the following: venous and arterial puncture, heel puncture, lumbar puncture, percutaneous catheter installation, venous dissections, subcutaneous and intramuscular injections, removal of skin patches and tapes and removal of drains. When associated with nonnutritive sucking, the paired interventions may result in more effective control of indirect signs of pain.^(44,45)

This intervention can be used in association with a pacifier as long as the oral route is not contraindicated, as it is in intubated patients. Continued positive airway pressure (nasal CPAP) does not contraindicate the use of OGS because the volume given is usually not above 2 mL. OGS limitations include oral route contraindications and procedures which require severe pain control measures.

Complications related to analgesic oral glucose are rare and include nausea, vomiting, abdominal distension and sporadic oxygen saturation drops. No study has shown significant contraindications to OGS, except for necrotizing enterocolitis.⁽⁴⁵⁾ For this condition, other alternative pain therapies should be considered, both because of the severe pain associated with the procedure (for which glucose therapy would be insufficient) and the absolute oral route contraindication. Wills et al.⁽⁴⁶⁾ suggest an association between the frequency of sucrose administration and necrotizing enterocolitis; this association, however, has not been confirmed in clinical practice.

Johnston et al.⁽³⁹⁾ have indicated that excessive doses of sucrose (≥ 10) as analgesia in newborns at less than 31 weeks of gestacional age could result in impairments in motor development, energy, alertness and orientation at 36 weeks. These are not clinically significant findings, but were additionally investigated. These preliminary finds however need more investigation.

Charts 1, 2 and 3 describe the available clinical trials using oral glucose as pain control therapy in neonates, categorized according to the procedures evaluated: venous puncture, heel puncture and other procedures, respectively.

COMMENTS

The first study proposed to evaluate the effectiveness of glucose for pain control was published in 1991⁽⁴⁷⁾, and 298 articles were published through 2010. After the first Cochrane review in 2010, 50 studies have investigated the use of oral glucose as a pain control strategy;⁽³⁶⁾ from these, only 3 were conducted in Brazil. The most studied procedures were heel puncture and venous puncture, followed by intramuscular injection.

The results of these studies indicate that oral glucose is effective for pain control during venous puncture in neonates, along with the recommended complementary interventions of nonnutritive sucking and kangaroo care.

The use of OGS during heel puncture apparently mitigates pain as compared to placebo or topical analgesics. However, heel puncture is comparatively more painful than venous puncture, and mild-to-moderate pain control strategies are apparently less effective for this procedure.

For other procedures causing mild-to-moderate pain, more studies are necessary to confirm OGS effectiveness for pain control; however, some studies suggest that this intervention is effective during subcutaneous and intramuscular injections and pharyngeal suction.

The data is insufficient to describe the effects of oral glucose solution for prolonged procedures, such as ophthalmologic examinations and urinary bladder catheterization, as well as during the immunization of children older than 12 months.

A study by Slater et al.⁽²⁷⁾ used infrared spectroscopy (NIRS) to evaluate the correlation between behavioral changes and cortical activation during painful interventions when oral glucose solution was used as a therapeutic strategy; the results showed that even with a statistically significant reduction of the behavioral score (premature infant pain profile - PIPP), cortical activation was observed even in the group receiving oral glucose solution, suggesting that it was ineffective for pain control. However, more studies are necessary to confirm this conclusion.

CLOSING REMARKS

OGS administration is apparently effective and safe for pain control during mildly to moderately painful procedures in neonatal intensive care units. Adverse effects are rare, and the mode of action is still incompletely described in the literature. The indication for OGS during venous punctures is well described; for heel punctures, it is apparently the most effective method of pain control, especially when associated with nonnutritive sucking, showing favorable results in most studies. Both the 2001 consensus on pain management in newborns and the 2009 guideline for painful procedures in newborns recommended using sucrose as adjuvant therapy during arterial punctures, lumbar punctures and the insertion of percutaneous catheters in association with other methods such as topical and systemic analgesics.

The use of infrared spectroscopy will assist in the confirmation of behavioral strategies for the evaluation of pain and in the development of appropriate therapeutic strategies for each painful procedure.

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Publication Dates

• Publication in this collection
  01 Aug 2011
• Date of issue
  June 2011

History

• Received
  20 Oct 2009
• Accepted
  17 May 2011