Pain control in very young infants: An update

Pain control for very young infants:An update

By Anne M. Lynn, MD, George A. Ulma, Jr., MD, and Martha Spieker, MD

Pain in infants is often undertreated. A new synthetic opiate, a parenteral NSAID now approved for use in patients as young as 1 year, and improvements in the use of local anesthetics have expanded physicians' options.

Pain is perhaps the most feared symptom of disease. Advances in scientific knowledge have enabled us to treat severely ill infants and children, including those with severe congenital abnormalities requiring surgical repair in infancy, with increasing success. Until recently, however, alleviating pain and suffering received very little attention. In fact, the prevalent view for most of the 20th century has been that children experience less pain than adults and that infants and neonates do not feel pain.

The 1960s brought an explosion of knowledge in developmental physiology and pharmacology, revolutionizing medical care for newborns, infants, and children. With refinement of surgical techniques and improved perioperative monitoring, more neonates had surgery. Although postoperative medical care and clinical outcome improved for preterm and term infants, their postoperative morbidity and mortality remained disproportionately high compared to older children and adults.¹ In 1977, Eland and Anderson reported nearly universal undertreatment of postoperative pain in infants and children.

Untreated pain is an important component of postoperative morbidity. If we are to ensure the best possible outcomes for such infants, we must acknowledge, recognize, and relieve their suffering as well as treat their diseases. This article reviews methods and agents available to treat pain in neonates and young infants, updating our article from 1995.

How pain affects newborns

Twentieth century ideas about childhood pain arose primarily from the assumption that complete myelinization was necessary for mature nerve tract function and pain perception. Since neonates have incompletely myelinized nerve fibers, painful stimuli were believed to be inadequately transmitted and thus have little or no effect.

The work of Anand and of Fitzgerald in the 1980s challenged this assumption, particularly with regard to newborns, by revealing that infants clearly have the neural and biochemical pathways to perceive and respond to pain.^2,3 Neonates exposed to painful procedures exhibit enormous hormonal responses (increased corticosterone, aldosterone, epinephrine, norepinephrine, and glucagon) and metabolic changes. These changes are a measure of the stress response, which is also associated with metabolic, cardiovascular, infectious, and hematologic complications. Anand's widely discussed study suggests that maintaining deep levels of opiate infusion postoperatively in neonates undergoing cardiac surgery reduced the stress response, decreased postoperative complications, and improved clinical outcome.

Data concerning neonatal hormonal responses to less invasive procedures are limited. In neonates undergoing circumcision without anesthesia, plasma cortisol levels increased. Studies by Taddio suggest that infants circumcised without anesthesia display more pain behaviors even six months later during immunizations.⁴

Chest physiotherapy and endotracheal suctioning in unsedated, ventilated, preterm neonates significantly increased plasma catecholamines. This response decreased in sedated ventilated infants. Significant norepinephrine responses are also associated with infant handling and the many nursing procedures required in neonatal intensive care.⁵

Assessing the pain

Of course, one cannot use self-report to measure pain in neonates as one does in children and adults. An objective assessment tool is needed. To date, however, no reliable physiologic or biochemical measures that can be done easily in the clinical setting allow rapid, specific confirmation of pain.

Hormonal and metabolite blood levels as direct indices of pain are nonspecific, resulting from many simultaneous physiologic and psychologic events. Physiologic parameters such as heart and respiratory rate, blood pressure, and transcutaneous PO₂ (TCPO₂) are likewise ambiguous, and in the case of palmar sweating, which seems more specific, difficult to obtain.

Recent systematic clinical observations of neonates have increased awareness of their ability to experience and respond to painful events. Newborns have a limited capacity to communicate distress because they have a limited repertoire of responses to stimuli. As caregivers we need to decipher the subtle cues they give.

Behavioral assessment of pain in the newborn includes evaluation of the baby's cry, facial expression, and bodily activity. Acoustical analyses of pain cries have limited potential as an assessment measure because not all crying is specific to pain and acoustical analysis is not easily accomplished at the bedside.

Investigations of facial expression have led to detailed, objective, anatomically based descriptions of the newborn's reaction to potentially painful events. A well-defined facial grimace can be identified and used to assess severity of pain, as with the Neonatal Facial Coding System (NFCS). Bodily movements and posture-particularly reflex limb withdrawal and torso activity (whether the newborn is at rest, rigid, or thrashing) are also used to assess response to pain. The complexity of the neonate's behavioral responses to pain are influenced by changes in wakefulness, activity, and sleep. These factors are in turn affected by external events and biological states such as fatigue, hunger, and need for stimulation.

Commonly used neonatal pain scoring systems include the scale described by Attia, the NFCS scale, and the Neonatal Infant Pain Scale (NIPS).⁶ They help both to identify the distressed neonate and to serially assess the efficacy of interventions. At Children's Hospital and Medical Center in Seattle, we use a modified pain scoring system, the Infant Pain Score (Table 1), which is based on the Attia scale and NFCS. It is reliable and easy to use and takes about five minutes to complete.⁶

Analgesic agents

Analgesic drugs approved and available for the neonate are quite limited. Because controlled trials are lacking, many drugs that are widely used in neonates, infants, and young children still have not been approved for use in these age groups by the Food and Drug Administration. For ethical reasons, studies assessing drug concentrations and clinical effects of analgesics in healthy infants (the equivalent of healthy adult volunteers) are scarce. As a result, neonates have become "therapeutic orphans." Even a drug as old as morphine has undergone fewer than desirable well-controlled trials that would allow practitioners to use it comfortably in neonates.

All medications used for pain relief are potentially toxic. The goal of pain management is to keep the patient within the "therapeutic window" by providing enough analgesia to prevent or reduce pain and distress without causing adverse side effects. The following sections focus on analgesics for neonates and infants in the first months of life.

Nonopioid analgesics

Nonopioid analgesics may be used alone to treat mild pain or as adjuvants with opioid, regional, or topical analgesia. They can be safely administered without potentiating the ventilatory depressant effects that can occur with opioids or sedatives. Table 2 discusses routes of administration, dosages, and age approved for use by the FDA for some nonopioid analgesics.

Acetaminophen  (APAP) is the most commonly used antipyretic and analgesic in all age groups. Unlike nonsteroidal anti-inflammatory drugs (NSAIDs), APAP does not cause gastric irritation or platelet dysfunction. Given in recommended amounts, APAP has a wide margin of safety and minimal risk of chronic toxicity.⁷ Because it can be administered rectally it is particularly useful for neonates, avoiding the need for an IV when medication cannot be given by mouth. Recently, the rectal dose of APAP has changed. The old dose of 10 to 20 mg/kg rectally every 4 to 6 hours has been found to deliver subtherapeutic levels of APAP (based on antipyretic plasma concentrations).^8,9 A dose of rectal APAP of 45 mg/kg was found to result in peak plasma concentrations comparable with those resulting from 10 to 15 mg/kg of oral APAP at three hours after suppository insertion. A loading dose of 50 mg/kg followed by a dose of 30 mg/kg every 6 hours has been shown to achieve an APAP level satisfactory for temperature control in the presence of fever. These rectal doses add up to between 170 mg/kg/day to 270 mg/kg/day. Reversible liver toxicity has been reported with oral doses greater than 150 mg/kg/day after 2 to 8 days in patients with previously normal liver function.¹⁰ APAP toxicity is usually seen in patients with normal livers when doses exceed 250 mg/kg/day. A daily dose of 170 to 180 mg/kg/day is higher than the current recommended 90 mg/kg/day by the oral route. However, rectal delivery has a lower bioavailability and higher absorption variability than oral administration. The higher rectal doses are considered clinically safe for short-term use.

It is important to note that the peak concentration of APAP occurs 2.3 to 3 hours after rectal administration, that is, it is delayed and can be erratic. It is also useful to know that there is a lag time between peak plasma APAP concentration and maximum analgesia of one hour.

When the pain is expected to last, APAP should be given around the clock rather than prn for better pain control. Long-term effects of daily administration are not known, so it is prudent to restrict the drug's use to periods less than two weeks.

Salicylates. Several decades ago aspirin was commonly given to children for fever and pain control, but its association with Reye syndrome, as well as platelet dysfunction and gastritis, has greatly limited its use in neonates and children.

Nonsteroidal anti-inflammatory drugs  are a diverse group of drugs with anti-inflammatory and antipyretic properties. They are widely used in children and adults alike to treat inflammatory diseases, acute pain, fever, visceral pain, and bone pain. Data on their safe use in neonates is limited.

The toxicity of NSAIDs limits their usefulness. Potential adverse reactions include gastrointestinal injury as well as hepatotoxicity, decreased renal and splanchnic perfusion, blood dycrasias, and, more rarely, skin reactions. They have many advantages over opioid analgesia, including long duration of action without respiratory depression or tolerance.

Ibuprofen is an NSAID that is being widely used in the pediatric population as an antipyretic analgesic and an anti-inflammatory drug. Clinical trials in older infants (weighing more than 8 kg) document ibuprofen's efficacy as an antipyretic and anti-inflammatory agent. Researchers saw a low incidence of adverse reactions but did not look at its analgesic effects.¹¹ Ibuprofen and indomethacin have been used for many years to treat and prevent patent ductus arteriosus (PDA) in premature infants. Ibuprofen causes less gastritis and skin reaction than aspirin and indomethacin, and reports of renal and hepatic toxicity are rare. The therapeutic ratio of ibuprofen is high, which supports its use in children, and it has been approved for children as young as 6 months of age. Studies still need to be performed to prove its efficacy and safety as a treatment for pain in newborns and infants.

The NSAID indomethacin is most commonly given to newborns to facilitate closure of PDA. Because it may cause renal dysfunction and thrombocytopenia, it is contraindicated in patients with renal failure or coagulopathy. Although some data on its use in children exist, lack of studies in neonates and concerns about the drug's potential risks limit its usefulness as an analgesic.

Ketorolac is the first parenteral NSAID approved in the United States. It has been approved for IM and IV use in patients as young as 1 year. It is a potent analgesic with a relatively low incidence of side effects. The dosage of ketorolac is slightly higher in children than adults based on a twofold higher volume of distribution. The dosing schedule is the same because of a similar half-life as in adults. Loading doses of 1 mg/kg (maximum 60 mg) of ketorolac followed by 0.5 mg/kg (maximum 30 mg) every 6 hours IV are suggested.¹² Hypovolemia should be corrected before administration. The manufacturer recommends that ketorolac not be administered for more than five days. No studies have been conducted regarding the use of ketorolac in infants. Some practitioners are using ketorolac in infants as young as 1 month old when they feel that using opioids for pain management is riskier in an infant this age.

Other NSAIDS used in children are colchicine, naproxen (Naprosyn), diclofenac, and ketoprofen, but there is no reported information on use of these drugs in neonates.

Topical anesthesia

Topical anesthetics are now available to alleviate pain and distress associated with needle insertion and other minor, simple procedures. Lidocaine-prilocaine 5% cream (EMLA) is a topical anesthetic that has been extensively used in adults and older children to diminish procedural pain. The cream is applied to intact skin and covered with an occlusive dressing. It penetrates the skin and provides satisfactory analgesia for venipuncture after 45 minutes in children under 5 years and after 60 minutes in older children. Drug absorption varies depending on the site and integrity of the skin. The neonate's epidermal layer allows for greater and faster transdermal absorption than adult skin; this creates concerns about potential toxicity.¹³ Plasma concentration of lidocaine and prilocaine after application of 5% EMLA (2 mL over a 16 cm² area for less than four hours) in 22 infants 3 to 12 months of age were below toxic levels. Initially, there was some apprehension about its use in neonates because of the potential for methemoglobinemia secondary to prilocaine metabolites. A review of nine randomized controlled studies found that methemoglobin concentrations did not differ between EMLA-treated infants and placebo-treated infants.¹⁴ There is still insufficient data to assess the risk of methemoglobinemia after multiple doses of EMLA. EMLA should be used with caution in infants receiving methemoglobin-inducing medications (sulfonamides, benzocaine, nitrates, and aniline dye), as there has been one documented report of a problem.

EMLA was found to decrease crying, average heart rate, and grimacing during circumcision. Lower heart rate and cry duration after venipuncture and lower behavioral pain scores during arterial puncture, after EMLA application, has also been documented. EMLA did not show any benefit in decreasing pain during heel lancing and lumbar puncture. Squeezing the heel prior to lancing, particularly with the vasoconstriction caused by the EMLA, and positioning the infant for lumbar puncture add discomfort that cannot be diminished by the application of an anesthetic cream.

Analgesia for venipuncture occurs 45 minutes after the application of EMLA in children under 5 years of age (60 minutes in older children). Analgesia lasts approximately two hours after the removal of the cream. It should not be applied to damaged skin, open wounds, mucous membranes, eyes, or tympanic membrane.

Another topical anesthetic solution, TAC (a mixture of 5% tetracaine, adrenaline 1:2000, and cocaine 12%) has been used successfully in children during repair of lacerations, especially of the face and scalp. Since no data exist on its effect on infants, TAC is best avoided when treating them.

Infiltration analgesia

Adult studies have demonstrated that incisional pain and tenderness can be alleviated by subcutaneous infiltration of a local anesthetic into the wound. Similarly, infiltration of local anesthesia into herniorrhaphy incisions in children produces effective analgesia. Buffered lidocaine containing one part sodium bicarbonate (1 mEq/mL) to 10 parts 1% lidocaine injected slowly with a 30-gauge needle appears to lessen the discomfort of venous cannulations. Bupivacaine can also be buffered in order to help decrease the amount of stinging with infiltration. The same degree of buffering is achieved by 0.1 mL of 1 mEq/mL sodium bicarbonate added to 10 mL of bupivacaine 0.25%.

Ropivacaine is the most recent local anesthetic to come onto the market, but data on its use in children or infants are limited. It has not been approved for use by the FDA in this age group in the United States.

Absorption of local anesthetics after subcutaneous infiltration is relatively slow. Plasma levels measured after administering 0.5 mL/kg of 0.25% bupivacaine were far below the toxic range. The technique is quite simple, safe, and effective for newborns and young infants.

Infants and neonates have lower levels of *₁-acid glycoprotein in their circulating plasma than older children. Since most local anesthetics absorbed in the bloodstream adhere to this protein, local anesthetic may be less protein-bound in the blood stream of infants. More free local anesthetic will be in the blood of an infant than in the blood of an older child.¹⁵ Direct intravascular injection of the local anesthetic allows rapid increase in concentration and may also increase the drug's availability by eliminating the first-pass effect of liver metabolism.

There are two ways to minimize the likelihood of local anesthetic reaching the bloodstream in toxic amounts. The first is frequent aspiration with the syringe during injection of the local anesthetic to be sure that the needle hasn't entered a blood vessel. However, small gauge needles (27 to 30) may not allow the withdrawal of blood even when placed into a large vein. Because of this drawback and the increased stress on the patient caused by more maneuvering with the needles and longer times injecting the drug, it may be better to use the second method, with strict volume limitations, as outlined in Table 3. The second method is continual movement of the needle so that if a vessel is entered, only a minute amount of local anesthetic is injected intravenously before the needle moves on.

More concentrated solutions of local anesthetic have a longer duration of action and more profound analgesic effect than do less concentrated solutions; however, the maximum dose that can be administered without reaching toxic levels is lower in volume. Concentrated doses may not be suitable for neonates and infants simply because enough volume cannot be injected to anesthetize the nerves of the area needed. The major systems affected by toxicity of local anesthetics are the central nervous system and cardiovascular system, and signs of impending problems—irritability, restlessness, hypertension—are hard to interpret in pre-verbal patients. Therefore, strictly adhering to dosing guidelines and constantly moving the needle tip may be the safest ways to avoid intravascular injections of toxic amounts of local anesthetics.¹⁶

Regional anesthesia

Regional analgesia has gained recent popularity in managing intraoperative, postoperative, and cancer- related pain in infants and children. Regional methods of pain relief include central neuraxial analgesia (epidural via the caudal, lumbar, or thoracic approach), peripheral nerve blocks (most commonly digital, penile, intercostal, ilioinguinal, and iliohypogastric nerves), and plexus analgesia (most commonly brachial plexus via the interscalene or axillary approach).

Central neuraxial analgesia is most often performed by anesthesiologists and monitored by professionals with expertise in pain management. Regional analgesia offers many advantages for infants and neonates. A growing body of evidence supports the fact that newborn infants require effective analgesia and shows that appropriate use of analgesia may improve outcomes. A study that compared 155 Nissen fundoplication patients demonstrated that the need for postoperative ventilation was less and the rate of complications lower for the patients who had epidurals for pain management than for those managed with IV morphine.¹⁷ Preemptive analgesia has also been shown to decrease the amount of postoperative pain experienced by children. Another advantage of epidurals is that opiate-based analgesics can be avoided, which may prevent the need to mechanically ventilate certain postoperative patients.

Recent reports with large numbers of patients support the safety and efficacy of the regional anesthetic techniques. Murrel and colleagues have shown that using epidural catheters infusing 0.1% bupivacaine and fentanyl 1 mg/mL relieves pain in premature infants, neonates, and older infants postoperatively.¹⁸ Others have used regional techniques out of necessity, in countries where ventilators are not always available for postoperative care. Good postoperative analgesia is essential when performing major abdominal or thoracic surgery. Epidural analgesia may be the only option when postoperative ventilation is not feasible.

The anesthesiologist places the epidural catheter, usually in a sleeping patient, using a lumbar or thoracic approach or threading the catheter up from the caudal space. To support these techniques, many pediatric hospitals have developed specific pain management services available to patients.

Brachial plexus blocks are employed for procedures on the upper arm, and may include the use of catheters to infuse medications continuously. Indications for their use include the relief of cancer pain, relief of postoperative pain, and relief of chronic pain by deliberate sympathectomy. Vasodilation after microvascular surgery of the hand is another indication for the use of brachial plexus catheter infusions.

While surgeons commonly perform peripheral nerve blocks such as ilioinguinal and iliohypogastric nerve blocks for herniorrhaphy, pediatricians can easily perform some of them. Chief among the latter is the dorsal penile nerve block (DPNB) for circumcision.

DPNB: The choice for circumcision

Circumcision is the most common neonatal surgery performed in the world; yet it continues to be one of the procedures that doctors perform without anesthesia or analgesia. The dorsal penile nerve block is easy to administer, and recent studies have proven its efficacy and safety. A recent statement from the American Academy of Pediatrics supports newborn male circumcision as having potential medical benefits.¹⁹ However, the AAP urges that analgesia be used during the procedure. The statement briefly discusses EMLA cream, dorsal penile nerve block, and subcutaneous ring block of the penis, and provides a good reference list of articles.

Because the dorsal penile arteries are end arteries, only local anesthetic without epinephrine is used. Local anesthetic (1% lidocaine) is injected 3 to 4 mm beneath the skin at the junction of the penile base and the suprapubic skin. The needle should remain freely mobile after piercing the skin and encounter no further resistance as it is advanced and the local anesthetic injected. Care should be taken to avoid perforating visible cutaneous vessels, although local bruising is common (11%) and uniformly resolves within several days. For detailed instructions, see a box entitled "Three ways to perform newborn circumcision," in "What to tell parents about circumcision," Contemporary Pediatrics, February 1999.

Recent studies have investigated other methods of reducing the pain of circumcision. A sucrose-flavored pacifier decreased crying in infants during the procedure,²⁰ but the technique has been challenged on the basis that absence of crying may not necessarily denote analgesia. Sucrose pacifiers, topical agents (EMLA, topical 30% lidocaine), and parenteral analgesics such an acetaminophen may be useful adjuncts to DPNB, but have not yet proved as effective in relieving the pain of circumcision. The efficacy and excellent safety record of DPNB, combined with its ease of administration, make it the standard against which future pain control techniques for newborn circumcision should be measured.

Opioid analgesics

Opioids are the strongest agents used in neonatal pain management, primarily for pain associated with invasive procedures or surgery. Their most important, and feared, side effect is ventilatory depression, and infants have been classified as at increased risk for this specific side effect.²¹

Only a few studies have attempted to evaluate the general opinion that neonates are more "sensitive" than older children to the respiratory depressant effects of opioid analgesics. Table 4 compares what is known about clearance, elimination half-life, and volume of distribution of opioids in neonates and adults. Table 5 lists dosages and routes of administration for newborns and young infants. Changes in metabolism of opiates in infants, compared to adults, may help explain this "sensitivity."

Morphine  is the gold standard to which most analgesics are compared. It is inexpensive and widely available. Studies dating back to 1963 and 1965 suggested that a more permeable blood brain barrier accounted for the "increased sensitivity" of the neonate to morphine.²¹ Another study using neonatal primates suggested that morphine's central nervous system effects from increased drug penetration are a very transient phenomenon. A more recent pharmacokinetic study demonstrated decreased clearance of morphine in neonates, most likely a result of immature hepatic metabolic pathways. This may explain its prolonged effects in newborns.^22,23

Morphine's low clearance and prolonged elimination half-life in neonates extends to premature infants. A step-wise increase in clearance occurs over the first few months of life, corresponding to increasing levels of urinary glucuronide metabolites.²³ In infants without heart disease, clearance of morphine increases rapidly, reaching adult values by three months of age,²² while in infants with congenital heart disease, adult clearance of morphine is reached at six months of age.^22,23 The metabolites, morphine-3-glucuronide and morphine-6-glucuronide, which also have CNS activity, are excreted by the kidney and can accumulate in patients with renal failure.

Morphine is more commonly used postoperatively than intraoperatively to allow titration of the drug in the awake infant. In nonventilated infants under 6 months of age, the recommended initial doses are one fourth to one third the adult doses (that is, 0.025 to 0.033 mg/kg); administration should be followed by serial pain assessments using the Infant Pain Score.

For infants undergoing surgery in whom moderate to severe postoperative pain is expected, continuous morphine infusions may be useful. A British study found that several nonventilated infants developed ventilatory problems requiring intervention after receiving bolus doses of opiates.²⁴

Our study of infants following cardiac surgery showed ventilatory depression when serum morphine concentrations at steady state exceeded 20 ng/mL, or 0.02 mg/mL. Depression was rare with levels under this "threshold."²⁵ If this holds true for all postoperative infants, it should be possible to determine infusion rates that achieve target blood levels at or below the threshold. We recently completed a study suggesting that morphine infusions dosed for infant age and surgery to reach this threshold concentration could be used with a low risk of respiratory depression occurring (seen in less than 4% of the 83 infants studied).

Meperidine. The kinetics of meperidine in neonates show the pattern encountered with most opiates—lower clearance and longer half-life.²⁶ Meperidine is rarely used intraoperatively, and its postoperative use is less common now than 20 years ago. It is best reserved for short-term use (less than three days) since a metabolite, normeperidine, can accumulate with long-term use and may cause excitation resulting in dysphoria, twitching, or rarely, seizures.

The usual infant dose of 0.5 mg/kg IV is extrapolated from information on children and adults. There is no information about oral use of meperidine in infants and neonates.

Fentanyl  is a synthetic opioid commonly used as the analgesic component of a general anesthesic. Several authors have reported that neonates maintain hemodynamic stability during general anesthesia with fentanyl. A dose of 12 mg/kg provided stable heart rate, blood pressure, and oxygen saturation for 75 minutes in neonates undergoing surgery.²⁷

The pharmacokinetics of fentanyl seem similar in infants, children, and adults, with prolonged clearance reported only in premature infants. Since neonatal surgery often demands assisted mechanical ventilation during the initial postoperative period, a change in postoperative care is not necessarily required if the ventilatory effects of fentanyl (or other opiates) extend beyond surgery.

Information about the ventilatory effects of fentanyl in nonventilated neonates and infants is limited. Hertzka reported no difference in transcutaneous pCO₂ or apneic events among infants over 3 months of age, children, and adults given a general anesthetic that included 12 to 30 mg/kg of fentanyl. Koehntop reported that among neonates 1 to 7 days of age who received fentanyl 25 to 50 mg/kg intraoperatively, several required postoperative assisted ventilation and had tenfold lower fentanyl levels at extubation than adults. These findings suggest neonates are more sensitive to fentanyl's ventilatory depressant effects.

Fentanyl is commonly used postoperatively in neonates and infants to maintain sedation and analgesia in intensive care settings or to prevent pulmonary hypertensive crises. Infusion doses start at 2 to 3 mg/kg/h. Frequent increases in dosage to maintain a stable level of sedation have been reported in neonates and seem related to rapid development of tolerance. Infants who need fentanyl for more than seven days will develop opiate withdrawal symptoms unless weaned slowly from the drug over seven to 10 days.

In older children, fentanyl 1 to 2 mg/kg has been used to provide short-term analgesia for painful procedures. Kinetics studies suggest that this also might be done safely in infants, but clinical studies are lacking. Fentanyl's short duration of action after a single small dose results from redistribution (decreasing brain drug concentrations as the drug moves into muscle and fat tissues). When repeated doses or high initial doses (greater than 25 mg/kg) are given, duration becomes dependent on elimination, a much slower process.

Monitoring for drug side effects is mandatory for two hours after a dose of 1 to 2 mg/kg and up to 24 hours for higher doses. Fentanyl patches and oral dosing (Oralet) have not been evaluated in neonates or infants.

Sufentanil  is another synthetic opioid about 10 times as potent as fentanyl. Its kinetics follow the usual infant pattern—lower clearance and longer half-life than seen in adults. Its use as a major component of the anesthetic for cardiac surgery in neonates has confirmed that it provides the same hemodynamic stability as fentanyl.

Postoperative use of sufentanil in infants has been limited. A study by Anand suggests that maintaining relatively high doses of 2 mg /kg/h in critically ill cardiac surgical infants can suppress stress responses and improve outcome.

Alfentanil  is a newer synthetic opiate. Although its pharmacokinetics in adults make it even shorter acting than fentanyl, information in infants is sparse. Alfentanil has caused chest wall rigidity, requiring muscle relaxants when given to neonates prior to chest tube insertion. Pharmacokinetic studies show the typical opiate pattern of decreased clearance and longer elimination half-life in neonates compared to adults.

Remifentanil, the newest synthetic opiate, offers some pharmacokinetic properties that are unique and potentially useful in neonatal surgery and intensive care. Remifentanil has an ester linkage and is metabolized by multiple blood and tissue esterases to by-products with less than1% the potency of remifentanil. These esterases are not affected by liver or renal disease in adults and are present in neonates. This means the half-life for remifentanil is very short, less than 5 min, and does not change if the drug is given for long durations. With fentanyl, sufentanil, or alfentanil, the longer the drug is given by infusion, the longer it takes for its effects to wear off after the drug is stopped.

Remifentanil must be given as a continuous IV infusion, at doses of 0.2 to 1 mg/kg/min. during surgery and at doses of 0.05 to 0.2 mg/kg/min for postoperative analgesia in adults. Boluses given rapidly can cause chest wall rigidity, as has been seen with alfentanil. Limited information in children and infants²⁸ suggests that doses similar to adult doses are appropriate. The analgesic action is totally gone within 15 to 30 minutes of stopping this drug so other agents or therapies may be needed if pain is still present. This agent may offer the opportunity to use an opiate and "turn off" its effect quickly. As the newest opiate, it is expensive compared to fentanyl or morphine, but titrating it may offset this initial cost, allowing the tailoring of opiate need and effect and minimizing the "wait time" for drug effects to wear off.

Codeine  is an orally administered, naturally occurring opiate. Some adult studies report that one of its metabolites, morphine, accounts for all of the drug's analgesic effect. Information on codeine's kinetics in children and infants is lacking, but a recent study reported measurable codeine and morphine blood levels in infants who breastfed one hour after their mothers ingested 60 mg of codeine.²⁹ All infants showed morphine levels well under the ventilatory threshold value suggested in our work of 20 ng/mL (0.02 mg/mL). Codeine's active metabolites (morphine and glucuronide metabolites) may accumulate in renal failure and cause delayed toxicity.³⁰

Methadone  is another synthetic opioid that has been used for many years. While its kinetics have been studied in children, information on infants is less complete. It is well absorbed after oral administration in children and adults. An elimination half-life of up to 53 hours has been reported in infants exposed to methadone prenatally, and ventilatory depression may occur.³¹ The prolonged half-life makes its use in infants problematic since overdosage causes prolonged effects and may require sustained ventilatory support.

Methadone may be used to wean opioid-tolerant infants after opiates are no longer necessary. The total dose per day of opiate is converted to the equivalent dose of methadone, which may be given in divided doses every eight to 12 hours and then decreased by 5% to 10% daily. Symptoms of withdrawal include irritability, poor feeding, diarrhea, nasal discharge, and mydriasis.

Reversing opioid effects

Naloxone is a pure opioid antagonist that reverses all opiate effects, desired (analgesia) and undesired (ventilatory depression, urinary retention, pruritis, and constipation). The neonatal resuscitation dose is 0.01 mg/kg. If the aim is to maintain as much analgesia as possible while reversing ventilatory depression, titration of 0.001 mg/kg/min IV may be done.

Naloxone is rapidly metabolized and has an elimination half-life of only 60 minutes in adults. A continuous IV infusion at 0.001 to 0.003 mg/kg/h (the same dose hourly as was needed initially) or repeat IV doses may be necessary for 12 to 24 hours so that the drug's opiate antagonist effects do not wane before the opiate effects it is reversing. Naloxone can precipitate acute withdrawal in opiate-tolerant infants, so titrated doses are important in this population.

A question of tolerance

Fear of causing "addiction" can be a stumbling block to treating infants with opiates. It is true that the body develops tolerance to opiates. Over time, increasing doses are needed to maintain the same effect. This occurs in adults, children, and infants treated for longer than seven days (the exact duration of opiate use needed to develop tolerance has not been well studied). It is important to identify infants who are tolerant to opiates (tolerance is assumed if opiates are needed for over a week) so that these infants can be weaned slowly from the drug (5% to 10% per day) to avoid withdrawal symptoms.

Tolerance is a physiologic process. Addiction is a personality disorder in which all actions focus on the procurement and use of psychotropic agents. No information suggests that an infant treated with opiates is at any increased risk for developing an addictive personality disorder as an adult.

Nonpharmacologic interventions

Although a painful event causes distress, not all distress results from a painful stimulus. Much neonatal stress and discomfort can be alleviated by modifying environmental conditions to reduce noxious stimuli such as bright lighting, noise, and excessive handling. Rocking, swaddling, and nonnutritive sucking also help soothe infants. All these techniques have the advantage of no toxicity!

Side-to-side rocking has been shown to have beneficial effects on neuromuscular and neurobehavioral development in premature infants. Swaddling and blanket rolls provide a secure nest, which may calm the distressed neonate by providing a low level of tactile stimulation and help to contain disorganized gross motor behaviors.

Recent European literature indicates that skin-to-skin contact between low birth-weight infants and their mothers is safe and may have physiologic and psychosocial advantages for both. Using pacifiers for non-nutritive sucking has been correlated with more regular sleep patterns and decreased restlessness and may promote behavioral stability.

Administration of oral sucrose and oral glucose has been shown— with and without non-nutritive sucking (pacifiers)—to decrease crying in response to painful stimuli. Stevens and colleagues32 performed a systematic review and meta-analysis of five studies looking at the efficacy and optimal dose of sucrose for relieving procedural pain in neonates. They found that 2 mL of 12% sucrose (0.24 g) given by syringe or pacifier approximately two minutes prior to painful stimuli was effective in diminishing cries and, in some cases, heart rate in neonates. Larger doses of sucrose, 2 mL of 24% sucrose (0.5 g), gave no additional benefit. Skogsdal³³ found that 1 mL of 30% glucose given orally by syringe significantly alleviated pain, but breast milk or 12% glucose did not. Although benign in full-term infants, the safety and efficacy of repeated doses of oral sucrose or glucose has yet to be established in less healthy low birth-weight infants. Hyperosmolarity of undiluted solutions carrying the sucrose or glucose could damage the upper intestinal wall, leading to necrotizing enterocolitis. The mechanism by which oral sugar reduces pain and anxiety remains unclear. Is it just calming the infants or is it truly reducing the pain? It is interesting to note the oral sucrose elevates the pain threshold in rats, an effect that is reversed by naloxone. Also, saccharine intake can induce morphine tolerance in rats. More research needs to be done to elicit the mechanism of action of oral glucose and sucrose.

What's ahead

While effective analgesia is known to reduce postoperative morbidity, little is known about the long- term impact of unrelieved pain on the neonate. Given the remarkable plasticity of the newborn's developing brain, it follows that sensory experiences, especially painful events, may have permanent effects on the neuronal architecture and memory (that is, memory not accessible to conscious recall). Tentative evidence and theory support the hypothesis that painful experiences have psychological and behavioral sequelae. Studies in the field of neonatal pain research that address the clinical significance of these sequelae are emerging. As guardians of children's physical, mental, and emotional maturation, it is our responsibility to make every effort to alleviate the pain and suffering infants undergo while we treat their diseases.

DR. LYNN is Professor, Departments of Anesthesiology and Pediatrics, University of Washington School of Medicine, and Associate Director, Department of Anesthesia and Critical Care, Children's Hospital and Regional Medical Center, Seattle, WA. She has a research grant from Glaxo Wellcome, Inc.

DR. ULMA is Assistant Professor of Anesthesiology, Department of Anesthesiology, University of Washington School of Medicine, and Director, Pain Management Service, Children's Hospital and Regional Medical Center, Seattle, WA.

DR. SPIEKER is Acting Assistant Professor, Department of Anesthesiology, University of Washington School of Medicine.

SELECTED REFERENCES

1. Kiely E: Surgery in very low birth-weight infants. Arch Dis Child 1984;59:707

2. Anand KJS, Hickey PR: Pain and its effects in the human neonate and fetus. N Engl J Med 1987;317:1321

3. Fitzgerald M, Millard C, MacIntosh N, et al: Hyperalgesia in premature infants. Lancet 1988;8530:292

4. Taddio A, Katz J, Ileisich AL, et al: Effect of neonatal circumcision on pain response during vaccination in boys. Lancet 1997;349:599

5. Lagercrantz H, Nilsson E, Redham I, et al: Plasma catecholamines following nursing procedures in a neonatal ward. Early Hum Dev 1986;14:61

6. Buchholz M, Karl HW, Pomietto M, et al: Pain scores in infants: a modified infant pain scale vs. visual analogue. J Pain Symptom Manage 1998;15:117

7. Sutton E, Soyka LF: How safe is acetaminophen? Clin Pediatr 1973;12:692

8. Lin Yuan-Chi, Sussman H, Benitz WE, et al: Plasma concentrations after rectal administration of acetaminophen in preterm neonates. Pediatric Anesthesiology 1997;7:457

9. Birmingham PK, Tobin MN, Henthorn TK, et al: Twenty-four hour pharmacokinetics of rectal acetaminophen in children. Anesthesiology 1997;87:244

10. Penna A, Buchanan N: Paracetamol poisoning in children and hepatotoxicity. Br J Clin Pharmacol 1991;32:143

11. Marriott SC, Stephenson TJ, Hull D: A dose ranging study of ibuprofen suspension as an antipyretic. Arch Dis Child 1991;66;1037

12. Forrest JB, Heitlinger EL, Revell S, et al: Ketorolac for postoperative pain management in children. Drug Safety 1997;16:309

13. Rutter N: Drug absorption through the skin: A mixed blessing. Arch Dis Child 1987;62:220

14. Taddio A, Ohlsson A, Einarson TR, et al: A systematic review of lidocaine-prilocaine cream (EMLA) in the treatment of acute pain in neonates. Pediatrics 1998;101:E1

15. Mazoit JX, Denson DD, Samii K, et al: Pharmacokinetics of bupivacaine following caudal anesthesia in infants. Anesthesiology 1988;68:387

16. Berde CB: Toxicity of local anesthetics in infants and children. J Pediatr 1993;122:S14

17. McNeely JK, Farber NE, Rusy LM, et al: Epidural analgesia improves outcome following pediatric fundoplication. A retrospective analysis. Reg Anesth 1997;22:16

18. Murrell D, Gibson PR, Cohen RC, et al: Continuous epidural analgesia in newborn infants undergoing major surgery. J Pediatr Surg 1993;28:548

19. American Academy of Pediatrics. Task Force on Circumcision: Circumcision Policy Statement. Pediatrics 1999;103:686

20. Blass EM, Hoffmeyer LB: Sucrose as an analgesic for newborn infants. Pediatrics 1991;87:215

21. Way WL, Costley EC, Way EL, et al: Respiratory sensitivity in the newborn to meperidine and morphine. Clin Pharmacol Ther 1965;6:454

22. Lynn A, Nespeca MK, Bratton SL, et al: Clearance of morphine in postoperative infants during intravenous infusion: The influence of age and surgery. Anesth Analg 1998;86:958

23. McRorie TL, Lynn AM, Nespeca MK, et al: The maturation of morphine clearance and metabolism. Am J Dis Child 1992;146:972

24. Purcell-Jones G, Dorman F, Sumner E, et al: The use of opioids in neonates: A retrospective study of 933 cases. Anesthesia 1987;42:1316

25. Lynn AM, Nespeca MK Opheim KE, et al: Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery. Anesth Analg 1993;77:675

26. Pokela ML, Olkkola KT, Korvisto M, et al: Pharmacokinetics and pharmacodynamics of intravenous meperidine in neonates and infants. Clin Pharmacol Ther 1992;52:342

27. Yaster M: The dose responses of fentanyl in neonatal anesthesia. Anesthesiology 1987;66:433

28. Eck JB, Lynn AM: Case report: Use of remifentanil in infants. Paediatr Anaes 1998;8:437

29. Meny RG, Naumburg EG, Alger LS, et al: Codeine and the breastfed neonate. J Hum Lact 1993;9:237

30. Talbott GA, Lynn AM, Levy FH, et al: Respiratory arrest precipitated by codeine in a child with chronic renal failure. Clin Pediatr 1997;36:171

31. Olsen GD, Lees MH: Ventilatory response to C0₂ of infants following chronic prenatal methadone exposure. Pediatrics 1980;96:983

32. Stevens B, Taddio A, Ohlsson A, et al: The efficacy of sucrose for relieving procedural pain in neonates—a systematic review and meta-analysis. Acta Paediatr 1997;86:837

33. Skogsdal Y, Eriksson M, Schollin J, et al: Analgesia in newborns given oral glucose. Acta Paediatr 1997;86:217

Anne Lynn,George Ulma,Martha Spieker. Pain control in very young infants: An update. Contemporary Pediatrics 1999;11:39.