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. 2018 Aug 24;2018(8):CD013104. doi: 10.1002/14651858.CD013104

Clonidine for painful procedures or conditions in infants

Olga Romantsik 1, Maria Grazia Calevo 2, Elisabeth Norman 1, Matteo Bruschettini 1,3,✉
PMCID: PMC6513528

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To determine the efficacy and safety of clonidine for the prevention or treatment of procedural or postoperative pain, or pain associated with clinical conditions in neonates. Clonidine will be compared to placebo, no treatment, dexmedetomidine, paracetamol, and opioids. In addition, the safety of clonidine administration will be assessed for potential harms.

Background

Description of the condition

The importance of pain in the neonate was not recognized until the late 1980s when research describing the developmental physiology of nociception emerged (i.e. the sensory nervous system's response to harmful stimuli, frequently manifested as pain) (Anand 1987a; Anand 1987b). In newborn infants, there is an imbalance between the excitatory neural pathways accountable for nociception and the inhibitory neural pathways responsible for localization and alleviation of noxious stimuli (Fitzgerald 1986). Pain perception develops slowly and advances with postnatal age. In addition, normal brain development is abruptly interrupted by preterm birth, and repetitive painful stimuli may lead to developmental alterations of the nociceptive pathways (Taddio 2009).

Critically ill newborn infants undergo numerous and repeated invasive procedures during their early life in the neonatal intensive care unit (NICU). The "Epidemiology of Procedural Pain in Neonates" (EPIPPAIN) study reported that 430 preterm and term infants experienced a total of 60,969 first‐attempt procedures during the first two weeks in the NICU. They went through a median of 16 stressful procedures per day, of which 10 were considered not only to be stressful, but also painful (Carbajal 2008). Other investigators have reported a similar number of painful procedures: Barker 1995 reported an average of 60 painful procures per patient in 54 preterm infants, while Benis 2001 described a total of 5663 procedures in a cohort of 15 preterm infants. In the Johnston 1997 study, a mean of two procedures per patient per day were performed, and some neonates had as many as eight procedures per day during the first week of NICU care. Additionally, in a Dutch cohort of 151 neonates admitted to the NICU, neonates experienced a mean of 14 procedures each day during the first two weeks (Simons 2003).

Despite the growing knowledge about long‐term consequences of neonatal pain and discomfort, a safe and effective strategy to minimize these complications remains a challenge in everyday clinical care (McPherson 2012). Non‐pharmacologic support and interventions, such as non‐nutritive sucking and wrapping, are well accepted first‐hand strategies, but are insufficient to provide comfort for moderate and severe pain (Brummelte 2012; Golianu 2007).

Oral sucrose and glucose are commonly used in the NICUs to provide analgesia or comfort infants, or both, during mild to moderately painful procedures (Lim 2017). Both have been extensively studied as possible analgesic agents in newborns, however many gaps of knowledge still remain, including appropriate dosing and long‐term consequences (Bueno 2013; Stevens 2016). Nevertheless, neither glucose nor sucrose may be effective for longer or more painful procedures (Costa 2013).

Opioids are the pharmacological agents most commonly administered to treat pain in newborn infants, with fentanyl and morphine most commonly used. The dosage of these drugs varies between studies and the reports of long‐term effects of opioids given during the neonatal period are conflicting (de Graaf 2013; Roze 2008). Rodent models have demonstrated that early opiate exposure diminishes neuronal density and dendritic length (i.e. density and length of brain cells), as well as to increase apoptosis (natural death of cells that occurs during growth or development) (Hammer 1989; Ricalde 1990; Seatriz 1993). Furthermore, rodents exposed to postnatal morphine exhibited reduced brain growth (Zagon 1977), persistently decreased motor activity and impaired learning ability (Handelmann 1985; McPherson 2007; Ma 2007). Several other pharmacological agents, such as methadone, ketamine and propofol have been suggested, and used, for analgesia during neonatal intensive care, but data regarding appropriate dosage and short‐ and long‐term safety in this vulnerable population are currently insufficient, and further research is needed before these drugs are introduced to clinical practice (Allegaert 2007; Anand 2004; Chana 2001; Cravero 2011; Simons 2003).

It has been shown that co‐administration of morphine and paracetamol (acetaminophen) in the management of neonatal postoperative pain may reduce the final amount of opioid needed (Ceelie 2013). However, concerns have been raised about the safety of paracetamol (Bauer 2013; Viberg 2014). The use of nonsteroidal anti‐inflammatory agents, such as ibuprofen and indomethacin, is restricted to the pharmacological management of patent ductus arteriosus (i.e. a neonatal heart problem) because of possible adverse effects, e.g. renal insufficiency, platelet dysfunction and pulmonary hypertension (Ohlsson 2016).

Description of the intervention

A limited experience with alpha2‐agonists (α2‐agonists), chiefly clonidine and dexmedetomidine, in term and preterm infants, suggests that they may provide an analgesic and sedative effect. Alpha2‐agonists may induce sedation, provide analgesia and ameliorate anxiety (Chen 2015; Mantz 2011; Pichot 2012). These effects are mediated through α2‐adrenergic receptor subtype agonism located in the locus coeruleus, which is a nucleus in the pons of the brainstem and the main site for brain synthesis of norepinephrine (noradrenaline). Both clonidine and dexmedetomidine reduce the neuronal activity in the locus coeruleus without affecting the respiratory drive (Hoy 2011). Moreover, it has been suggested that α2‐agonists might have a neuroprotective and anti‐inflammatory effect (Mantz 2011). In animal models of endotoxic shock, both drugs preserve neutrophil function and inhibit the cytokine response (i.e. in cells that regulate the immune response) (Nishina 1999; Taniguchi 2004; Taniguchi 2008). Furthermore, both α2‐agonists protect neurons from damage in vitro and diminish brain lesion size in animal models (Laudenbach 2002; Paris 2006). The two main side effects of α2‐agonists are bradycardia (slow heart beat) and hypotension (low blood pressure). These are mediated through the α2‐adenoreceptors in the medullary dorsal motor nucleus and motor complex and have been shown to be independent of the sedative effect (Gregoretti 2009; Pichot 2012).

Traditionally, clonidine has been used in management of attention deficit hyperactivity disorder (ADHD) (Hazell 2003), opioid withdrawal (Gold 1978), and as an anaesthetic adjuvant (i.e. added to the anaesthetic to improve performance) (Gregoretti 2009; Lambert 2014). Its use as sedative agent persists 'off label' in many countries. In the critically ill paediatric and neonatal population, clonidine is routinely prescribed as an adjunct to opioids or benzodiazepines, or both, aiming to reduce the doses of these drugs that are required for analgesia or sedation, or to facilitate weaning from mechanical ventilation (Duffett 2012). Furthermore, clonidine has been shown to reduce pain, discomfort and agitation in a paediatric population following sevoflurane anaesthesia (Tesoro 2005). A Cochrane Review showed that clonidine premedication might have a positive effect on postoperative pain in the paediatric population (neonates not included) (Lambert 2014). Moreover, the addition of clonidine to bupivacaine for spinal anaesthesia in newborns may double the duration of the block (Rochette 2004). It is worth noting that a study in newborn rats showed that intrathecal administration (via the spine) of clonidine did not induce signs of spinal histopathology (Walker 2012).

The current literature on practices for procedural and postoperative pain in critically ill newborn infants lacks a comprehensive data summary about the efficacy and safety of clonidine as a potential agent. In 2016, a systematic review was published on clonidine for sedation, analgesia and iatrogenic drug withdrawal in critically ill infants and children (Capino 2016). However, this review by Capino and colleagues included only mechanically ventilated infants and children.

Cochrane Reviews have also focused on pain management with other interventions, e.g. paracetamol (Ohlsson 2016); breastfeeding or breast milk (Shah 2012); and non‐pharmacological management, which included 4905 infants from 63 studies (Pillai Riddell 2015).

How the intervention might work

Clonidine is a centrally acting α2‐selective adrenergic agonist. It has been suggested that clonidine mediates its sedative effects through the stimulation of the presynaptic α2‐ adrenoceptors of the locus coeruleus, leading to a decrease in the release of norepinephrine (Jamadarkhana 2010). As well as exerting a sedative effect, clonidine also acts on the cholinergic, purinergic and serotonergic pathways, to produce analgesia (Jamadarkhana 2010). This analgesic action is thought to be optimal when combined with other agents. Moreover the administration of clonidine may exert neuroprotective effects by preventing apoptosis induced by agents such as ketamine (Pontén 2012). The ability of α2‐agonists to protect the neuronal culture from damage in vitro and to reduce the brain lesion size in animal models is promising in the view of neuroprotection (Laudenbach 2002). An expanded description of how clonidine might work in the newborn is provided in a separate review (Romantsik 2017).

Why it is important to do this review

Despite the theoretical advantages of α2‐agonists, the safety and efficacy of their short‐term and long‐term use remain unclear. It is important to note that clonidine is not licensed for use in infants and its effectiveness and safety for pain management in non‐ventilated newborns has not been systematically reviewed.

Clonidine is an alfa2‐agonist with sedative and analgesic characteristics. In contrast to other analgo‐sedatives, clonidine does not reduce respiratory drive. Clonidine has been shown to be neuroprotective in animal research. For serious painful conditions (e.g. necrotizing enterocolitis and postoperative care) the additive use of clonidine might reduce the dose of opioid treatment and subsequent negative effects. However, clonidine pharmacokinetics (PK), pharmacodynamics (PD), pharmacogenetics (PG) or the PK/PD/PG relation has not been tested in this population. It has been used for adults and older children, and the newborn population is treated accordingly. Clonidine was introduced for treatment of hypertension in adults; hypotension and bradycardia are well known side effects in that population. The PK, PD, PG or the PK/PD/PG relation needs to be studied in the newborn term and preterm population. Both general vital parameters and specific effects of cerebral activity (EEG) and cerebral hemodynamics (NIRS) are of major interest for the evaluation of the drug effects and side effects in this vulnerable population.

Pain and stress are still a problem in the NICU and evidence‐based consensus and clear guidelines are lacking. Clonidine is increasingly used because of the side effects of opioids, however more knowledge about the drug is needed in order to make safe recommendations.

Objectives

To determine the efficacy and safety of clonidine for the prevention or treatment of procedural or postoperative pain, or pain associated with clinical conditions in neonates. Clonidine will be compared to placebo, no treatment, dexmedetomidine, paracetamol, and opioids. In addition, the safety of clonidine administration will be assessed for potential harms.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials, quasi‐randomised controlled trials, and cluster‐randomised trials. We will exclude cross‐over trials.

Types of participants

Full term and preterm (gestational age < 37 weeks) infants less than 44 weeks' postmenstrual age (PMA) requiring pain management for one or more of the following procedures or clinical conditions during their hospital stay or as outpatients:

  • painful procedures: heel lance, venipuncture, lumbar puncture, bladder tap, insertion of nasogastric tube, insertion of venous or arterial catheter/line or chest drain, or surgery (including neonatal circumcision, any surgery performed in the operating room); or

  • painful clinical conditions: including a fractured long bone, necrotizing enterocolitis, open skin lesions from an inherited skin disorder, or pain from an assisted vaginal birth.

We will exclude studies where clonidine infusion is administered in ventilated newborns, as this has been addressed in another Cochrane Review (Romantsik 2017). However, we will include studies where clonidine infusion is administered in ventilated newborns if the intervention specifically aims to treat procedural or postoperative pain, or pain associated with clinical conditions.

Types of interventions

Clonidine administered at any dose for the prevention or treatment of pain. Clonidine may be delivered intravenously, orally (or via nasogastric tube), or transdermally. We will include studies that report on single administration of clonidine or multiple (repeated) doses of clonidine over a prolonged period during the initial hospital stay. We will exclude studies that compare clonidine with local or regional anaesthesia.

Procedural pain, postoperative pain, and pain associated with clinical conditions will be assessed in separate comparisons.

Clonidine will be compared with placebo or no intervention; opioids; paracetamol; dexmedetomidine; or non‐pharmacological pain‐reducing intervention, e.g. sucrose, glucose, other sweet‐tasting solutions, breast milk, breastfeeding, non‐nutritive sucking, skin‐to‐skin care, or other intervention.

Comparison 1: Clonidine compared to placebo or no treatment for the prevention or treatment of procedural, postoperative pain or pain associated with clinical conditions in neonates.

Comparison 2: Clonidine compared to opioids for the prevention or treatment of procedural, postoperative pain or pain associated with clinical conditions in neonates.

Comparison 3: Clonidine compared to paracetamol for the prevention or treatment of procedural, postoperative pain or pain associated with clinical conditions in neonates.

Comparison 4: Clonidine compared to dexmedetomidine for the prevention or treatment of procedural, postoperative pain or pain associated with clinical conditions in neonates.

Comparison 5: Clonidine compared to non‐pharmacologic pain‐reducing interventions (e.g. sucrose, glucose, other sweet‐tasting solution, breast milk, breastfeeding, non‐nutritive sucking, skin‐to‐skin care) for the prevention or treatment of procedural, postoperative pain or pain associated with clinical conditions in neonates.

We plan to perform subgroup analyses according to gestational age (term; preterm; extreme preterm infants), birth weight (normal; low; very low), type of pain, dose, duration and route of clonidine administration, and pharmacologic sedation as a co‐intervention (see Subgroup analysis and investigation of heterogeneity).

Types of outcome measures

Primary outcomes

Analgesia assessed using the pain scales listed in Table 1.

Table 1.

Pain scales

Pain scale Population Type of pain
ABC pain scale (Bellieni 2005)a Preterm and term infants Procedural pain
Astrid Lindgren and Lund Children’s Hospitals Pain and Stress Assessment Scale for Preterm and sick Newborn Infants (ALPS‐Neo) (Lundqvist 2014) Preterm and term infants Prolonged pain/stress
Behavioral Indicators of Infant Pain (BIIP) (Holsti 2008) Preterm infants Procedural pain
Comfort Neo (van Dijk 2009) Preterm and term infants Postoperative and prolonged pain/stress
CRIES (Krechel 1995) Preterm and term infants Procedural and postoperative pain
Douleur Aiguë du Nouveau‐né (DAN) (Acute pain in newborn infants, APN, English version) (Carbajal 1997) Preterm and term infants Procedural pain
Echelle Douleur Incomfort Nouveau‐né (EDIN) (Debillon 2001) Preterm infants Prolonged pain
’Faceless’ Acute Neonatal pain Scale (FANS) (Milesi 2010) Preterm and term infants Procedural pain
Neonatal Facial Coding System (NFCS) (Grunau 1986; Peters 2003) Preterm and term infants Procedural, postoperative and prolonged pain/stress
Neonatal Infant Pain Scale (NIPS) (Lawrence 1993) Preterm and term infants Procedural pain
Neonatal Pain, Agitation, and Sedation Scale (N‐PASS) (Hummel 2008; Hummel 2010) Preterm and term infants Procedural, postoperative and prolonged pain/stress

Pain Assessment Tool (PAT) (Hodgkinson 1994; Spence 2005) Preterm and term infants Postoperative and prolonged pain/discomfort
Premature Infant Pain Profile (PIPP and PIPP‐R) (Gibbins 2014; Stevens 1996) Preterm and term infants Procedural and postoperative pain
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aPublication of development or validation, or both, within parentheses

For procedural pain, we will report the mean values of each analgesia scale assessed during the procedure and at one to two hours after the procedure.

For postoperative pain and for pain associated with clinical conditions, we will report the mean values of each analgesia scale assessed: at 30 minutes, three hours, and 12 hours after the administration of the intervention.

Secondary outcomes

  • Neonatal mortality: during initial hospitalisation

  • Completion of the targeted objective (relief of either procedural or postoperative pain, or pain associated with clinical conditions) without use of any other agent.

  • Any intraventricular hemorrhage (IVH) (yes/no): any IVH, grades 1 to 4 (according to the Papile 1978 classification); severe IVH (grades 3 and 4)

  • Cystic periventricular leukomalacia at brain ultrasound in the first month of life (yes/no)

  • Retinopathy of prematurity (ICROP 1984; yes/no): any; requiring laser therapy

  • Duration of mechanical ventilation (days)

  • Duration of hospital stay (days)

  • Bronchopulmonary dysplasia/chronic lung disease (yes/no): 28 days; 36 weeks' PMA (Jobe 2001); "physiological definition" (Walsh 2004)

  • Necrotizing enterocolitis (yes/no): any grade; requiring surgery

  • Time to full enteral feeding (days)

  • Episodes of apnoea spells (mean rates of apnoea)

  • Episodes of bradycardia, defined as a fall in heart rate of more than 30% below the baseline or less than 100 beats per minute for 10 seconds or longer, occurring:

    • for procedural pain, during the procedure and at one to two hours after the procedure;

    • for postoperative or pain associated with clinical conditions, at 30 minutes, three hours, and 12 hours after administration of the intervention.

  • Altered reactions to painful stimuli following NICU discharge, as reported by study authors

  • Parent satisfaction with care provided in the NICU (as measured by a validated instrument/tool) (Butt 2013)

  • Major neurodevelopmental disability:

    • cerebral palsy;

    • developmental delay (Bayley Mental Developmental Index (Bayley 1993; Bayley 2006), or Griffiths Mental Development Scale assessment more than two standard deviations (SDs) below the mean (Griffiths 1954));

    • intellectual impairment (intelligence quotient > 2 SD below the mean);

    • blindness (vision < 6/60 in both eyes);

    • or sensorineural deafness requiring amplification (Jacobs 2013).

    • We plan to evaluate each of these components as a separate outcome and to extract data on this long‐term outcome from studies that evaluated children after 18 months of chronological age. Data on children aged 18 to 24 months and those aged three to five years are to be assessed separately.

Search methods for identification of studies

We will use the criteria and standard methods of Cochrane and Cochrane Neonatal (see the Cochrane Neonatal search strategy for specialized register). We will search for errata or retractions from included studies published in full text on PubMed (www.ncbi.nlm.nih.gov/pubmed) and report the date this was done within the review.

Electronic searches

We will conduct a comprehensive search including: the Cochrane Central Register of Controlled Trials (CENTRAL, current issue) in the Cochrane Library; MEDLINE via PubMed (1996 to current); Embase (1980 to current); and CINAHL (1982 to current) using the following search terms: (clonidine OR alpha‐2 agonists), plus database‐specific limiters for RCTs and neonates (see Appendix 1 for the full search strategies for each database). We will not apply language restrictions. We will search clinical trials registries for ongoing or recently completed trials (clinicaltrials.gov; the World Health Organization’s International Trials Registry and Platform, and the ISRCTN Registry).

Searching other resources

Additionally, we will review the reference lists of all identified articles for any relevant articles that were not identified in the primary search.

Data collection and analysis

Selection of studies

Independently, two review authors (OR, MB) will search and identify eligible trials that meet the inclusion criteria. We will screen the titles and abstracts to identify potentially relevant citations, retrieve the full texts of all potentially relevant articles, and assess independently the eligibility of the studies by filling out eligibility forms designed in accordance with the specified inclusion criteria. We will review studies for relevance based on study design, types of participants, interventions and outcome measures. We will resolve any disagreements by discussion and, if necessary, by consulting a third author (MGC). We will provide details of studies excluded from the review in the 'Characteristics of excluded studies' table along with the reasons for exclusion. We will contact the trial authors if the details of the primary trials are not clear to request further information.

Data extraction and management

Independently, two reviewers (OR, MB) will undertake data abstraction using a data extraction form developed and integrated with a modified version of the Cochrane Effective Practice and Organisation of Care Group (EPOC) data collection checklist (Cochrane EPOC 2013).

We will extract the following characteristics from each included study:

  • administrative details: author(s); whether published or unpublished; year of publication; year in which study was conducted; details of other relevant papers cited;

  • details of the study: study design; type, duration and completeness of follow‐up (e.g. > 80%); country and location of study informed consent and ethics approval;

  • details of participants: birth weight, gestational age, and number of participants;

  • details of intervention: modality of administration and dose of clonidine;

  • details of outcomes, as listed in Types of outcome measures.

We will resolve any disagreement by discussion between the reviewers.

We will describe any on‐going studies identified, detailing the primary author, research question(s), methods and outcome measures, together with an estimate of the reporting date.

When queries arise or when additional data are required, we will contact the authors of the trial reports. MGC and MB will use Review Manager 5 software to enter all the data (Review Manager 2014).

Assessment of risk of bias in included studies

Independently, two review authors (OR, MGC) will assess the risk of bias (low, high, or unclear) of all included trials using the Cochrane ‘Risk of bias’ tool (Higgins 2011) for the following domains:

  • sequence generation (selection bias);

  • allocation concealment (selection bias);

  • blinding of participants and personnel (performance bias);

  • blinding of outcome assessment (detection bias);

  • incomplete outcome data (attrition bias);

  • selective reporting (reporting bias);

  • any other bias.

We will resolve any disagreements by discussion or through a third assessor (MB).

We will use the standard methods of Cochrane and Cochrane Neonatal to assess the methodological quality (to meet the validity criteria) of the trials. For each trial, we will seek information regarding the method of randomisation, and the blinding and reporting of all outcomes of all the infants enrolled in the trial. We will assess each criterion as being at low, high, or unclear risk. Separately, two review authors will assess each study. We will resolve any disagreement by discussion. We will add this information to the Characteristics of included studies table. We will evaluate the following issues and enter the findings into the 'Risk of bias' table.

Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

For each included study, we will categorize the method used to generate the allocation sequence as:

  • low risk (any truly random process e.g. random‐number table; computer random‐number generator);

  • high risk (any non‐random process e.g. odd or even date of birth; hospital or clinic record number);

  • unclear risk.

Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we will categorize the method used to conceal the allocation sequence as:

  • low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);

  • unclear risk

Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study?

For each included study, we will categorize the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding will be assessed separately for different outcomes or class of outcomes. We will categorize the methods as:

  • low risk, high risk or unclear risk for participants; and

  • low risk, high risk or unclear risk for personnel.

Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?

For each included study, we will categorize the methods used to blind outcome assessment. Blinding will be assessed separately for different outcomes or class of outcomes. We will categorize the methods as:

  • low risk for outcome assessors;

  • high risk for outcome assessors;

  • unclear risk for outcome assessors.

Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?

For each included study and for each outcome, we will describe the completeness of data including attrition and exclusions from the analysis. We will note whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion, where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported or supplied by the trial authors, we will re‐include missing data in the analyses. We will categorize the methods used to deal with missing data as:

  • low risk (< 20% missing data);

  • high risk (≥ 20% missing data);

  • unclear risk.

Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?

For each included study, we will investigate the possibility of selective outcome reporting bias. For studies in which study protocols were published in advance (clinicaltrials.gov), we will compare prespecified outcomes versus outcomes eventually reported in the published results. If the study protocol was not published in advance, we will contact study authors to gain access to the study protocol. We will assess the likelihood of selective reporting bias as:

  • low risk (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified outcomes of interest and are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk.

Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?

For each included study, we will describe any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data‐dependent process). We will assess the degree to which each study was free of other problems that could put it at risk of bias and categorize them as:

  • low risk;

  • high risk;

  • unclear risk.

If needed, we will explore the impact of the level of bias through undertaking sensitivity analyses.

Measures of treatment effect

We will extract categorical data for each intervention group and calculate risk ratios (RRs) and absolute risk differences (RDs). We will obtain means and standard deviations for continuous data, and perform analyses using mean differences (MDs). We will calculate standardized MDs when combining different pain scales. For each measure of effect we will also calculate the corresponding 95% confidence intervals (CIs). We will present the number needed to treat to benefit and number needed to treat to harm (NNTB and NNTH, respectively) when RDs are found to be statistically significant (P value < 0.05).

Unit of analysis issues

The unit of analysis will be individual infants. For multiple painful procedures we will consider the first procedure performed in the randomised infant. The unit of analysis for cluster‐randomised trials will be the randomising treating centre or cluster. We plan to include cluster‐randomised trials in the analyses, using an estimate of the intracluster correlation coefficient (ICC) derived from the trial (if possible), or from another source, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

We will contact the original study investigators to request additional data where information about critical and important outcomes is missing. We will investigate attrition rates (e.g. dropouts, losses to follow‐up, and withdrawals). We plan to perform a sensitivity analysis to evaluate the overall results with and without the inclusion of studies with significant drop‐out rates. If a study reports outcomes only for participants completing the trial, or only for participants who followed the protocol, we plan to contact the author(s) and ask them to provide additional information to facilitate an intention‐to‐treat analysis; and in instances where this is not possible we will perform a complete case analysis. We will address the potential impact of missing data on the findings of the review in the 'Discussion' section.

Assessment of heterogeneity

We plan to assess clinical heterogeneity by comparing the distribution of important participant factors between trials and trial factors (randomisation concealment, blinding of outcome assessment, loss to follow‐up, treatment type, co‐interventions). We will assess statistical heterogeneity by examining the I2 statistic (Higgins 2011), a quantity that describes the proportion of variation in point estimates that is due to variability across studies rather than sampling error.

We will interpret the I2 statistic as described by Higgins 2003:

  • < 25%: no heterogeneity;

  • 25% to 49%: low heterogeneity;

  • 50% to 74%: moderate heterogeneity;

  • ≥ 75%: high heterogeneity.

In addition, we will employ the Chi2 test of homogeneity to determine the strength of evidence that heterogeneity is genuine. We will explore clinical variation across studies by comparing the distribution of important participant factors among trials and trial factors (randomisation concealment, blinding of outcome assessment, loss to follow‐up, treatment type and co‐interventions). We will consider a threshold P value of < 0.1 as an indicator of whether heterogeneity (genuine variation in effect sizes) is present.

Assessment of reporting biases

We will investigate publication by using funnel plots if at least 10 clinical trials are included in the meta‐analysis (Egger 1997; Higgins 2011)

Data synthesis

We will perform statistical analyses according to the recommendations of the Cochrane Neonatal Review Group (neonatal.cochrane.org/en/index.html). We will analyse all infants randomised on an intention‐to‐treat basis. For any meta‐analyses we will synthesize data using RR, RD, NNTB, NNTH, MD, and 95% confidence intervals (CI). We plan to analyse and interpret individual trials separately when we judge meta‐analysis to be inappropriate.

Quality of evidence

We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the quality of evidence for the following (clinically relevant) outcomes:

  • pain scale measure (the two scales which are reported more often across the included trials);

  • neonatal mortality;

  • completion of the targeted objective without use of any other agent;

  • intraventricular hemorrhage;

  • episodes of bradycardia; and

  • parent satisfaction with care provided in the NICU.

Two authors will independently assess the quality of the evidence for each of the outcomes above. We will consider evidence from randomised controlled trials as high quality but downgrade the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias. We will use the GRADEpro GDT Guideline Development Tool to create a ‘Summary of findings’ table to report the quality of the evidence.

The GRADE approach results in an assessment of the quality of a body of evidence as being one of the following four grades:

  • high: we are very confident that the true effect lies close to that of the estimate of the effect;

  • moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different;

  • low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect;

  • very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Subgroup analysis and investigation of heterogeneity

We plan to present data from the following subgroups:

  • gestational age: term infants (≥ 37 weeks); preterm infants (≥ 28 but < 37 weeks); extreme preterm (< 28 weeks);

  • birth weight: under 1500 grams; 1500 grams or more;

  • type of pain: 1) painful procedures: heel lance, venipuncture, lumbar puncture, bladder tap, insertion of nasogastric tube, insertion of venous or arterial catheter/line or chest drain, or surgery (including neonatal circumcision, any surgery performed in the operating room); 2) painful clinical conditions: including a fractured long bone, necrotizing enterocolitis, open skin lesions from an inherited skin disorder, or pain from an assisted vaginal birth.

  • dose of clonidine. For infusion administration: < 0.3 µg/kg/hour) versus 0.3 µg to 1 µg/kg/hour versus > 1 µg/kg/hour. For bolus administration: < 2 µg/kg versus 2 µg to 4 µg/kg versus > 4 µg/kg;

  • duration of treatment (< 24 hours; one to five days; ≥ five days);

  • route of administration: parenteral; enteral; transdermal;

  • with versus without pharmacologic sedation and pain management as co‐interventions;

  • within studies that included co‐interventions: studies in which the protocol allowed co‐interventions for sedation and pain management for one or both of the intervention groups; studies in which the protocol mandated sedation with co‐interventions.

Sensitivity analysis

We will conduct sensitivity analyses to explore the effect of the methodological quality of the trials, checking to ascertain if studies with a high risk of bias over‐estimate the effect of treatment.

Acknowledgements

We thank Colleen Ovelman and Roger Soll for editorial support.

The methods section of this protocol is based on a standard template used by Cochrane Neonatal.

Appendices

Appendix 1. Standard search methodology

PubMed: ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh]))

Embase: (infant, newborn or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW or Newborn or infan* or neonat*) AND (human not animal) AND (randomized controlled trial or controlled clinical trial or randomized or placebo or clinical trials as topic or randomly or trial or clinical trial)

CINAHL: (infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or Newborn or infan* or neonat*) AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

Cochrane Library: (infant or newborn or neonate or neonatal or premature or preterm or very low birth weight or low birth weight or VLBW or LBW)

Contributions of authors

OR and MB reviewed the literature and wrote the protocol.

MGC assisted in the review of literature and in writing of the protocol.

EN commented on and reviewed the protocol.

Sources of support

Internal sources

  • Institute for Clinical Sciences, Lund University, Lund, Sweden.

    to OR, EN and MB

  • Istituto Giannina Gaslini, Genoa, Italy.

    to MGC

External sources

  • Vermont Oxford Network, USA.

    Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence‐based care of the highest quality for newborn infants and their families.

Declarations of interest

OR: none known

MGC: none known

EN: none known

MB: none known.

New

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