Opioid Analgesics

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Morphine

Morphine, the mainstay of pain therapy in the pediatric population, is the standard |x opioid analgesic to which all other opioids are compared (Table 30.3). Derived from the opium poppy, Papaver somniferum, morphine, along with codeine, is considered a naturally occurring opiate and is often the first-line agent for management of moderate to severe pain in the emergency room, operating room, ICU, and pediatric floor. Morphine can be given orally, intravenously, intramuscularly, neuraxially (via caudal, epidural, or intrathecal routes) but is often administered via intravenous patient-controlled analgesia (PCA) when used for hospitalized patients requiring acute or chronic pain management. Oral morphine is available in both immediate release and sustained release forms.

The hydrophilic nature of morphine allows a longer duration of analgesia when compared to more lipid soluble counterparts (e.g., fentanyl). Administration of intrathecal morphine may provide 12-24 h of analgesic effect due to the tendency to remain sequestered in the cerebrospinal fluid (CSF) with sustained interaction at the |i receptor in the sub-stantia gelatinosa. Patients receiving neuraxial morphine (intrathecal or epidural) should be monitored for hypoxemia given the potential biphasic ventilatory depression caused by morphine (early respiratory depression at 1-2 h after neuraxial morphine administration and late depression up to 12 h after opioid injection).

The majority of morphine is metabolized by the liver to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), with the latter being an active metabolite. Both M3G and M6G are water soluble and renally excreted. The ability to metabolize by glucuronida-tion, although immature, is present at birth and develops with age as morphine total body clearance may reach 80% of adult values by 6 months and 96% by 1 year of age (Bouweester 2004). In a review pooling the results of multiple pharmacological studies of pediatric patients receiving an intravenous (IV) morphine bolus and/or continuous IV infusions, Kart et al. (1997) noted the pooled half-life estimate for preterm neonates to be 9.0+ 3.4 h, 6.5+2.8 h for term neonates, and 2.0+1.8 h for infants and children and clearance to be 2.2+0.7 ml/min-1/kg-1 for preterm neonates, 8.1+3.2 ml/min-1/kg-1 for term neonates, and 23.6+8.5 ml/min-1/kg-1 for infants and children. As compared with adults,

Table 30.2 Pain assessment scales.

Pain assessment tool

Type of scale

Directions for use/scoring

Comments

Numeric Rating

• Self-report

• Ask to give a verbal rating of pain using

• Quick, simple, and easy to score

Scale (NRS)a-b

• Administered

"0 = no pain to 10 = worst pain

• Easily translated to other languages

either verbally

imaginable"

• Decreased reliability with visual, auditory,

or visually

or cognitive impairments and extremes

• Two scales:

in age

numbers or

words

Visual Analog

• Self-report

• Rate pain by making a mark on a 10-cm

• Must understand concept of number and

Scale (VAS)c

• Administered

line

order

visually

• Quick and simple

• Easily translated and available in multiple

languages

• Difficult for extremes in patient ages

• High degree of sensitivity

• Reliable tool for research

WongBaker FACES

• Self-report

• Ask the child to choose from the six

• Validated in children > 3 years of age

Rating Scaled

• Administered

cartoon faces the face that best

• Simple, quick, and no gender influence

visually

describes your own pain

• Emotion displayed on faces may reflect

• Three scales:

• Smiling face represents "no hurt" to

mood instead of pain

faces, words,

tearful face representing "hurts worst"

• Available in multiple languages

and numbers

• Do not use affected words

Ouchere

• Self-report

• Photographic scale

• Ages 3-13 years

• Administered

• Child must seriate six geometric shapes;

• Quick and simple

visually

scored 0-5

• Available in three ethnic groups

• Three scales:

• Ask the child to choose from the six the

• May reflect mood instead of pain

faces, words,

pictures "how much hurt you have right

and numbers

now"

• Numeric scale if child can count to 100

by ones and identify the larger of two

numbers. "no hurt" to the "biggest hurt

you could ever have"

Poker Chipf

• Self-report

• Four poker chips represent pieces of

• Ages 3-7 years

hurt

• Easy

• Ask how many pieces of hurt do you

• Need some verbal skills

have right now

FLACCg

• Observational

• Five categories of pain behaviors: facial

• Validated for scoring postoperative pain

tool

expression, leg movement, activity, cry,

in infants and children

• Postoperative

and consolability

• 2 months-7 years

pain tool

• Each scored 0-2

• (has been used 0-18 years)

• Good evidence of reliability and validity

CHEOPSh

• Observational

• Six behavioral items: cry, facial, child

• ages 1-17 years (has been used 4

tool

verbal, torso, touch, and legs

months-17 years)

• Procedural pain

• Scored 0-3; maximum score 13

• Good evidence of reliability and validity

Premature Infant

• Observational

Scored <6 = minimal to no pain,

• <36 weeks of gestation

Pain Profile (PIPP)i

tool

6-12 = mild to moderate pain, and

>12 = moderate to severe pain

Neonatal Infant

• Observational

• Six categories: facial expression, cry,

• Use for children less than 1 year of age

Pain Scale (NIPS)i

tool

breathing pattern, arms, legs, and state

• Greater than 3 indicates pain

of arousal

Table 30.2 Continued

Pain assessment tool

Type of scale

Directions for use/scoring

Comments

CRIES Pain Scalek

• Observational

• Five categories: crying, increased vital

• Validated for neonates from 32 weeks of

tool

signs, expression (facial), and sleepless

gestation to 6 months

• Each scored 0-2

• Crying requires supplemental O2 for

saturation below 95%

• Increased vital signs (arterial pressure

and heart rate)

COMFORT Scale1

• Observational

• Eight items: alertness,

• Newborn to 17 years

tool

calmness/agitation, respiratory

• Requires unobtrusive observation for

• Measures

response, physical movement, muscle

2 min

distress in

tone, facial tension, blood pressure,

unconscious or

and heart rate

ventilated

• Scored 1-5

infants,

• Scores range from 9 to 45; 17-26

children, and

generally indicate adequate sedation

adolescents

and pain control

aDownieetal. (1978). bJensen et al. (1986). cHuskisson (1974). dWong et al. (2009). eBeyeretal. (1992). fHester (1979). gMerkel et al. (1997). hMcGrathetal. (1985). iStevens et al. (1996). jLawrence et al. (1993). kKrechel and Bildner (1995). lAmbueletal. (1992).

aDownieetal. (1978). bJensen et al. (1986). cHuskisson (1974). dWong et al. (2009). eBeyeretal. (1992). fHester (1979). gMerkel et al. (1997). hMcGrathetal. (1985). iStevens et al. (1996). jLawrence et al. (1993). kKrechel and Bildner (1995). lAmbueletal. (1992).

these results showed age-related differences in half-life and clearance with half-life decreasing and clearance increasing with age.

Side effects of morphine include nausea/vomiting, pruritus, urinary retention, constipation, sedation, and confusion. Concomitant use of low-dose naloxone, an opioid receptor antagonist, has been shown in pediatric patients to decrease the untoward side effects of morphine without impacting its analgesic effect (Maxwell et al. 2005). Nevertheless, patients exhibiting side effects of morphine, other opioid analgesics, or epidural mixtures containing opioids should be thoroughly evaluated and treated appropriately (Table 30.4).

Fentanyl

Along with morphine, the synthetic opioid fentanyl is the most commonly used |x receptor agonist administered to pediatric patients by the anesthesiologist. The widespread use of fentanyl is marked by the multiple routes of administration (oral, intravenous, intramuscular, subcutaneous, transdermal, intranasal, epidural, and intrathecal). Pediatric uses of fentanyl include analgesia for intubated patients requiring mechanical ventilation, acute and chronic

Table 30.3 Systemic opioid analgesics.

Drug

Recommended dose

Interval

Comments

Codeine

Oxycodone Morphine PCA dosing

Morphine Fentanyl

Remifentanil

Hydromorphone PCA dosing

Methadone

1 mg/kg/dose Common elixir form: 12 mg codeine mixed w/ 120 mg acetaminophen 0.1-0.15 mg/kg dose 50-100 mcg/kg 30-50 mcg/kg 15-20 mcg/kg 15-20 mcg/kg/hr 0.2-0.5 mg/kg 1 mcg/kg/dose 1-4 mcg/kg/h 0.05-0.5 mcg/kg/min

10-15 mcg/kg 6-10 mcg/kg/dose 3-4 mcg/kg/h 75-100 mcg/kg/dose 0.1-0.4 mg/kg/dose

Q4 h PO

Q4h PO tab/elixir Q2-3 h IV Load

Bolus 6-10 min Per hour infusion Q4-6 PO Q1-2 h IV Per hour infusion Per hour infusion

Q3-4 h IV Load

Per h infusion Q3-4 h PO Q8-12h PO

Ceiling effect with higher doses May show inter-individual variability

Commonly used for postoperative analgesia Histamine-related side effects

Immediate release

Development of tolerance may occur with extended use Highly titratable

Not suitable for patients requiring prolonged analgesia Minimal histamine-related side

Prolonged half-life

Multiple drug-drug interactions

Unpredictable rates of metabolism pain management, treatment of emergence delirium from general anesthesia, and preoper-ative anxiety. Compared with morphine, fentanyl is lipid soluble (accounting for its rapid onset and increased context sensitive half-life with prolonged infusion), 20-100 times more potent, has minimal histamine release even with high doses, and is more likely to cause opi-oid tolerance with extended use (Franck et al. 1998). Fentanyl is metabolized by the liver via the cytochrome P450 system with a small amount excreted unchanged by the kidneys. Age differences in fentanyl pharmacokinetics have been described with beta elimination halflife prolonged and clearance decreased the most in the preterm infant and neonate (Collins et al. 1985, Saarenmaa et al. 2000). However, results in pharmacokinetic studies with fentanyl have been largely variable making it difficult to demonstrate clear assessments in the pediatric population.

Additional side effects seen with fentanyl include chest wall rigidity, bradycardia, and laryngospasm (Baraka 1995), which may occur even with low doses.

Remifentanil

The high titratability and rapid metabolism of remifentanil distinguish it from other members of the opioid family and make remifentanil an analgesic alternative for patients undergoing both invasive and non-invasive procedures. Pediatric uses of remifentanil include sedation and analgesia for patients undergoing spinal surgery, plastic surgery procedures, magnetic

Table 30.4 Complications of opioid analgesia/postoperative epidural anesthesia and recommended intervention (Yaster et al. 1997, Dalens 1989).

Complication

Recommended intervention

Cardiovascular instability

i.

Support airway, breathing, and circulation

2.

Fluid bolus 10-20 ml/kg

a.

Epinephrine 5-10 mcg/kg and then 0.1 mcg/kg/min titrated to effect

4

Discontinue epidural infusion if present

Severe respiratory depression

i.

Support airway, supplemental o2

(apnea, obtunded)

2.

Naloxone 5-10 mcg/kg IV + infusion 5 mcg/kg/h

a.

Stop all opioid containing infusions and boluses

Mild respiratory depression

i.

Supplemental o2

(slow respiratory rate, sedated)

2.

Naloxone 0.5 mcg/kg IV titrated to effect

a.

Decrease epidural infusion rate 20-25%

Seizures

i.

Support airway, breathing, and circulation

2.

Discontinue infusion

a.

Thiopental 2-3 mg/kg IV and midazolam 0.05-0.1 mg/kg IV

Motor blockade

i.

Decrease concentration of local anesthetic in epidural mixture

2.

Decrease epidural infusion rate

a.

Withdraw epidural catheter 1 cm if one-sided block is present and reassess level

Pruritus

i.

Nalbuphine 0.05-0.1 mg/kg q4-6

2.

Naloxone 0.5-1.0 mcg/kg/IV + infusion 0.25-1 mcg/kg/h

a.

Diphenydramine 0.5 mg/kg/dose IV/PO q4-6

4.

Decrease epidural rate by 10-20% if present; decrease/remove opioid

Nausea/vomiting

i.

Ondansetron 0.05-0.1 mg/kg IV

2.

Naloxone: see pruritus

a.

Metoclopromide 0.1 mg/kg IV/PO q6

Urinary retention

i.

Warm compresses and gentle bladder massage

2.

Straight catheterization (q6 x 2); followed by indwelling catheter if necessary

a.

Naloxone 0.5 mcg/kg IV

Signs of local infection

i.

Remove catheter

2.

Culture catheter tip

a.

Careful follow-up

Leaking catheter

i.

Carefully dry and redress catheter

2.

Application of external pressure dressing

The authors' stress that these are only recommended interventions. Intervention should be based on and tailored to the needs of the patient and clinical situation.

resonance imaging (MRI), congenital heart surgery, cardiac catheterization, short oncological procedures (e.g., bone marrow aspiration), and short-term mechanical ventilation. Unlike other opioid analgesics, remifentanil is rapidly metabolized in the plasma by nonspecific esterases in the tissue and erythrocytes and does not accumulate with prolonged infusion. In looking at the pharmacokinetics of remifentanil in anesthetized pediatric patients, Ross et al. noted that age-related differences in clearance and volume of distribution were seen but not in half-life (3.4-5.7 min), with largest volume of distribution and rapid clearance noted in infants <2 months (Ross et al. 2001). As with other opioids, bradycardia and hypotension may occur, especially when giving boluses and large doses. Given its short duration of action, remifentanil is not a suitable option for patients requiring longer acting opioid therapy particularly in the postoperative period or for chronic pain management.

Codeine

Codeine, a naturally occurring opiate and weak |x opioid agonist, is typically given for the treatment of mild to moderate pain. It has one-tenth the potency of morphine and may be administered by oral, rectal, and intramuscular routes. Intravenous codeine is not a recommended route of delivery due to reports of profound hypotension seen in pediatric patients (Shanahan et al. 1983). Often given in combination with acetaminophen, codeine is a popular oral analgesic agent for children presenting for ambulatory surgery.

Following oral administration, codeine is quickly absorbed with peak plasma concentrations occurring within 1-2 h after ingestion. Codeine is metabolized in the liver in three ways, primarily by glucuronidation (75%), N-demethylation to norcodeine (15%), and 0-demethylation to morphine (10%) by the hepatic enzyme cytochrome P450 ED6 (CYP2DG6), a pathway that is hypothesized to be the major source of codeine's analgesic activity. Genetic polymorphism of CYP2DG6 is thought to account for the inter-individual variability in drug efficacy seen with codeine with 7% of Caucasians considered poor metab-olizers of codeine (Alvan et al. 1990). Poor metabolizers will therefore generate little or no morphine from 0-demethylation, whereas extensive metabolizers may generate excessive amounts.

Side effects of codeine include nausea and vomiting, sedation, decreased gastric motility, pruritus/itching, and miosis, which may account for its ceiling effect when given in high doses (Williams et al. 2001).

Oxycodone

Oxycodone is an oral semi-synthetic |i opioid agonist that is 1.5-2 times more potent than oral morphine and typically used for moderate to severe pain. It may be given alone (available in immediate or sustained release form) or in combination with acetaminophen or acetylsali-cylic acid. Oxycodone is metabolized by the liver to noroxycodone (major) and oxymorphone (minor). When given in immediate release form, peak plasma concentrations occur 1-2 h after oral administration with duration of action of approximately 4 h.

The pharmacokinetics of oxycodone has been described in the pediatric population. In a study looking at 18 children (2-10 years of age) who received intravenous oxycodone, terminal elimination half-life was approximately 100 min (less than observed adult values) and clearance was almost 50% higher in the pediatric population compared to adults (Olkkola et al. 1994). In infants less than 6 months who were given intravenous oxycodone, values for clearance and elimination half-life (riy showed inter-individual variability (especially in patients <2 months) despite an overall assessment of clearance increasing and f1/ decreasing with age (Pokela et al. 2005).

Hydromorphone

Due to its lack ofassociated active metabolite and histamine release, hydromorphone, a semi-synthetic morphine derivative, is a popular analgesic alternative to morphine for acute and chronic pediatric pain patients. It is commonly administered by intravenous, oral, and epidural routes and has a potency 5-7 times that of morphine. In addition, hydromorphone has similar drug onset to morphine and provides approximately 4-5 h of analgesia to the nontolerant patient when given intravenously. The majority of hydromorphone is metabolized by the liver to the inactive metabolite hydromorphone-3-glucuronide which is then renally eliminated.

Methadone

Methadone is largely considered a second-line opioid for acute pain management due to its potential for drug to drug interactions, long half-life (18-24 h), and cases of serious side effects when patients were given large and frequent doses leading to gradual accumulation and toxic levels. However, methadone has been used safely in pediatric patients requiring relief for cancer pain (Miser and Miser 1985, Shir et al. 1998, Davies et al. 2008), burns (Williams et al. 1998), trauma (Shir et al. 1998), postoperative pain (Berde et al. 1991), and tapering for opioid dependency and withdrawal prevention (Tobias et al. 1990, Robertson et al. 2000, Siddappa et al. 2003). Methadone is a racemic mixture of L and D isomers, which acts both as a |i opioid agonist and as a N-methyl-D-aspartic acid (NMDA) antagonist. This latter property of methadone is of particular interest as the activation of NMDA receptors is noted to increase spinal neuron sensitivity to pain and reduce the activity of opioid agonists on neural opioid receptors. Methadone is metabolized by the hepatic cytochrome system which may show inter-individual variability. Therefore, patients who have received methadone should be closely monitored for potential drug-drug interactions and side effects of sedation and respiratory depression given its long half-life and potential unpredictable rates of metabolism.

Tramadol

A synthetic analog of codeine, tramadol has been increasingly used in the pediatric population. It has one-tenth the potency of morphine, is a weak |i opioid agonist, and a monoaminergic (serotonin and norepinephrine) reuptake inhibitor in the central nervous system (Bozkurt 2005). This latter activity of tramadol is thought to synergize with its | opioid agonist property, thereby potentiating analgesia and perhaps minimizing side effects such as respiratory depression, nausea/vomiting, sedation, and constipation associated with the conventional |i opioid analgesics (Bosenberg and Ratcliffe 1998, Finkel et al. 2002, Chu 2006). To date, tramadol has been used for both acute and chronic pain management in the pediatric population and may be given by oral, intramuscular, intravenous, caudal/epidural routes or by local infiltration.

Patient-Controlled Analgesia

The patient-controlled analgesia (PCA) is the most common means of delivering intravenous opioids to the hospitalized pediatric patient for acute or chronic pain management. Long-acting analgesics such as morphine or hydromorphone are typically selected. PCA settings consist of a demand dose (drug delivered by pressing the PCA button when desired), basal hourly rate (drug dose delivered continuously during an hourly period), and lockout interval (time in minutes in which a patient is unable to have drug delivered). The use of PCA in younger patients less than 2 years of age is controversial. In younger pediatric patients who are unable to control the PCA, the demand dose may be given by nursing-controlled analgesia (NCA) or parent-controlled analgesia (PARCA). Pain management teams should always tailor the PCA settings to the needs of the patient either increasing the demand or basal dose if current settings are not adequately providing enough pain control or decreasing the demand or basal dose if the patient shows signs of being overdosed with opioids.

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