spinal actions, efficacy, and adverse effects of opioids and local

anesthetics administered by the epidural route.114,121,122,124

As previously mentioned, opioids and local anesthetics are

combined in the same solution because these two classes of

drugs act synergistically at two different sites to produce analgesia, allowing the administration of lower doses of each drug

to reduce the risk of adverse effects while providing effective

analgesia. Table 8-14 lists the drugs, concentrations, and typical

infusion rates for epidural administration.115,122,123,125 Bupivacaine is commonly chosen as the local anesthetic agent. Because

pain fibers are on the outer aspect of the nerve and are not heavily

myelinated, a low concentration of bupivacaine (≤0.125%) can

be administered to block these fibers without significantly blocking motor fibers. The choice of opioid is based on pharmacokinetic differences among the available agents. Onset, duration,

spread of agent in the spinal fluid (dermatomal spread), and systemic absorption are affected by the lipophilicity of the drug.124

Highly lipophilic opioids such as fentanyl and sufentanil have

a faster onset of action, a shorter duration of action (from a

TABLE 8-13

A Comparison of the Spinal Actions, Efficacy, and Adverse Effects of Opioids and Local Anestheticsa,114,121,122,124

Opioids Local Anesthetics

Actions

Site of action Substantia gelatinosa of dorsal horn of spinal cordb Spinal nerve roots

Modalities blocked “Selective” block of pain conduction Blockade of pain nerve fibers; can block sensory or motor fibers

Efficacy

Surgical pain Partial relief Complete relief possible

Labor pain Partial relief Complete relief

Postoperative pain Fair or good relief Complete relief

Adverse effects Nausea, vomiting, sedation, pruritus, constipation or

ileus, urinary retention, respiratory depression

Hypotension, urinary retention, loss of sensation, loss of motor

function (patient may not be able to bear weight and ambulate)

a Epidurally administered morphine and local anesthetics exert their effects mainly by a spinal mechanism of action; lipophilic opioids such as fentanyl and sufentanil achieve

therapeutic plasma concentrations when administered epidurally and therefore exert their effects by a systemic mechanism of action.

b Other sites where opioid receptor binding sites are present.

171Perioperative Care Chapter 8

TABLE 8-14

Adult Analgesic Dosing Recommendations for Epidural Infusion115,122,123,125

Drug Combinationa Infusion Concentrationb Usual Infusion Rateb

Morphine + bupivacaine 12.5–25 mcg/mL (M) 4–10 mL/h

0.5–1.25 mg/mL (B)

Hydromorphone + bupivacaine 3–10 mcg/mL (H) 4–10 mL/h

0.5–1.25 mg/mL (B)

Fentanyl + bupivacaine 2–5 mcg/mL (F) 4–10 mL/h

0.5–1.25 mg/mL (B)

Sufentanil + bupivacaine 1 mcg/mL (S) 4–10 mL/h

0.5–1.25 mg/mL (B)

aUse only preservative free products and preservative free 0.9% sodium chloride as the admixture solution.

b Exact concentrations and rates are institution specific. Initial concentration and rate often depend on the age and general condition

of the patient and the location of the catheter.

B, bupivacaine; F, fentanyl; H, hydromorphone; M, morphine; S, sufentanil.

single dose), less dermatomal spread, and much greater systemic absorption. After several hours of epidural infusion, the

dermatomal (regional) effect of fentanyl is lost, and analgesia

is achieved because of a therapeutic plasma concentration. Morphine, which is relatively hydrophilic, has a slower onset of action,

longer duration of action, greater dermatomal spread and migration to the brain, and less systemic absorption.122,124 Morphine,

unlike fentanyl, retains its spinal site of action.122 The lipophilicity

of hydromorphone is intermediate between fentanyl and morphine. Clinically, hydromorphone has a faster onset and shorter

duration than morphine. Its site of action is likely in the spinal

cord.126 A comparison of the pharmacokinetic properties important to epidural opioids is found in Table 8-15.115,116,124,125 T.M.

should receive a combination of opioid and local anesthetic, such

as hydromorphone and bupivacaine, as an epidural infusion for

postoperative pain management.

CASE 8-15, QUESTION 3: Hydromorphone–bupivacaine is

chosen for T.M. How should this be prepared, and what infusion rate should be chosen?

Hydromorphone and bupivacaine are commonly admixed

in 0.9% sodium chloride (usual concentration ranges are found

in Table 8-14). Concentrations are often institution-specific and

depend on the rate of administration. Preservative free preparations of each drug should be used because neurologic effects

are possible with inadvertent subdural administration of large

amounts of benzyl alcohol or other preservatives. Strict aseptic

technique should be used when admixing and administering an

epidural solution.

The rate of administration is chosen empirically based on the

anticipated analgesic response, the concentration of opioid in the

admixture, and the potential for adverse effects. Usually, a rate of

4 to 10 mL/hour is adequate; the epidural space can safely handle

up to approximately 20 mL/hour of fluid. An initial infusion rate

of 8 mL/hour would be reasonable for T.M., with titration based

on efficacy and adverse effects.

ADVERSE EFFECTS

CASE 8-15, QUESTION 4: Two hours after initiation of his

hydromorphone–bupivacaine epidural infusion, T.M. experiences discomfort in the form of an itchy feeling on his nose,

torso, and limbs. Is this related to his epidural infusion?

Adverse effects of the epidural infusion may be caused by

the opioid or the local anesthetic. Pruritus has been associated

with almost all opioids, with a significantly greater frequency

when the opioid is administered as an epidural infusion rather

than by IV administration.127 This effect is usually seen within

2 hours and is probably dose-related. It generally subsides as the

opioid effect wears off and can be more of a problem with continuous epidural administration of opioids or when opioids are

administered via PCA. Although pruritus from opioids is probably mu-receptor mediated and not histamine mediated, antihistamines (e.g., diphenhydramine) are commonly used with equivocal effectiveness. A better approach is to administer very small

doses of a mu-antagonist (e.g., naloxone 0.04 mg or nalbuphine

2.5 mg) to effectively reverse opioid adverse effects, such as pruritus, but not analgesia. Because of naloxone’s short duration

of action, nalbuphine is often preferred. Ondansetron has also

shown some efficacy for managing itching from an intrathecal

or epidural opioid.128

Other adverse effects possible with epidural opioids include

nausea, vomiting, constipation, ileus, urinary retention, sedation, and respiratory depression. Although rare, respiratory

depression from epidural opioids is the most dangerous adverse

effect. Respiratory depression can occur as long as 12 to

24 hours after a single bolus of morphine122,124 or within hours

after beginning a continuous infusion of fentanyl–bupivacaine

TABLE 8-15

Pharmacokinetic Comparison of Common Epidural Opioid Analgesics115,116,124,125

Agent Partition Coefficienta

Onset of Action of

Bolus (minutes)

Duration of Action

of Bolus (hours) Dermatomal Spread

Fentanyl 955 5 2–4 Narrow

Hydromorphone 525 15 6–12 Intermediate

Morphine sulfate (Duramorph) 1 30 12–24 Wide

Sufentanil 1,737 5 2–4 Narrow

aOctanol–water partition coefficient; used to assess lipophilicity; higher numbers indicate greater lipophilicity.

172 Section 1 General Care

or hydromorphone–bupivacaine. Sedation level, as well as respiratory rate and effort, must be assessed every hour for the first

12 hours, then every 2 hours for the next 12 hours, then if stable,

every 4 hours until removal of the catheter.129 As with parenteral

opioids, particular attention must be paid to patients at high

risk for respiratory depression from an opioid. These risk factors include age older than 65 years, obesity, pulmonary disease

or other conditions that reduce ventilatory capacity, and known

or suspected history of sleep apnea.114 In a patient with known

obstructive sleep apnea, for example, the anesthesia provider may

prescribe an epidural analgesic solution containing bupivacaine

only (no opioid).

Adverse effects of epidural local anesthetics include hypotension, urinary retention, lower limb paresthesias or numbness,

and lower limb motor weakness. Depending on the degree of

numbness and motor weakness, the patient may have difficulty

ambulating. In a patient prone to hypotension or in whom motor

weakness would be detrimental, for example, the anesthesia care

provider may prescribe an epidural analgesic solution containing

an opioid only (no local anesthetic). Monitoring for efficacy and

adverse effects of epidural analgesia should include pain intensity and quality, response to treatment, number of on-demand

requests (if epidural PCA is being used), analgesic consumption,

BP, heart rate, respiratory rate and effort, level of sedation, urinary output, sensory and motor assessment (e.g., presence of

numbness or tingling, inability to raise legs or flex knees or

ankles), and a site and dressing check.

ADJUNCTIVE KETOROLAC USE

CASE 8-15, QUESTION 5: On the second postoperative

day, T.M. is able to rest comfortably when undisturbed

while receiving treatment with a lumbar epidural infusion

of hydromorphone 10 mcg/mL and bupivacaine 1.25 mg/mL

at a rate of 8 mL/hour. However, when he is moved at the

change of each nursing shift, he complains of significant

pain. Increasing the rate of his epidural infusion was tried,

but caused unacceptable pruritus and sedation. How can

T.M.’s intermittent pain needs be addressed?

The use of additional analgesics for breakthrough pain may

be necessary in patients receiving continuous epidural infusion.

T.M.’s intermittent pain could be managed by epidural PCA.

Like IV PCA, patient-activated epidural boluses can be administered to control pain during movement. Alternatively, injectable

ketorolac or acetaminophen may be considered for T.M.; these

agents do not contribute to respiratory depression, sedation, or

pruritus and can effectively treat moderate pain. The analgesic

effects of acetaminophen and NSAIDs are additive with the opioids and can lower postoperative pain scores. Patient selection

for ketorolac therapy should consider renal function, plasma

volume and electrolyte status, GI disease, risk of bleeding, and

concomitant drugs such as LMWH (which increases the risk

for bleeding and epidural hematoma). Acetaminophen is contraindicated in patients with severe hepatic impairment, severe

active liver disease, or known hypersensitivity to acetaminophen

or any excipient in the formulation. Acetaminophen should be

used with caution in patients with severe hypovolemia or severe

renal impairment.130

ADJUNCTIVE ANTICOAGULANT ADMINISTRATION

CASE 8-15, QUESTION 6: The surgeon has determined that

T.M. is at risk for developing postoperative venous thromboembolism. Enoxaparin 40 mg subcutaneously every day

has been ordered postoperatively. What are the risks of

enoxaparin in this situation? What are reasonable precautions?

Administration of an anticoagulant can increase the risk of

epidural or spinal hematoma formation, which can lead to longterm or permanent paralysis. Administration of antiplatelet or

anticoagulant drugs in combination with an anticoagulant (such

as an LMWH) results in an even greater risk of hemorrhagic

complications, including spinal hematoma. These findings have

led to concern for the safety of epidural analgesia in patients

receiving an LMWH. Important considerations for managing

a patient being administered an LMWH and receiving continuous epidural analgesia are (a) the time of catheter placement

and removal relative to the timing (and peak effect) of LMWH

administration and (b) whether the anticoagulant dose is low

(prophylactic dose) or high (treatment dose).131 For T.M., the

epidural catheter is already in place, and the LMWH is started

postoperatively as a single daily low (prophylactic) dose. It is safe

to leave the epidural catheter in place as long as the first dose of

LMWH is administered 6 to 8 hours postoperatively. The second

LMWH dose should be administered no sooner than 24 hours

after the first dose. The timing of the catheter removal is of the

utmost importance; it should be delayed for at least 12 hours after

the last dose of LMWH, with subsequent LMWH dosing to occur

a minimum of 2 hours after the catheter has been removed. The

risk of spinal hematoma is even greater when treatment doses

of LMWH are administered or if fondaparinux is selected as

the anticoagulant for deep vein thrombosis prophylaxis. In these

instances, the epidural catheter should be removed before the first

dose of LMWH or fondaparinux, and the first dose given at least

2 hours after catheter removal. Because T.M. is receiving prophylactic daily enoxaparin, his catheter should be removed no earlier

than 12 hours after his last dose of enoxaparin, with his next dose

administered no earlier than 2 hours after catheter removal.

MULTIMODAL PAIN MANAGEMENT

CASE 8-16

QUESTION 1: W.W., a 36-year-old man, arrives at the ambulatory surgery center for an inguinal hernia repair. This procedure will be performed under local anesthesia, with sedation as needed, and is expected to be completed within

TABLE 8-16

Comparison of Select Opioids for Perioperative Pain Management3,132–136

Property

Intravenous

Morphine

Intravenous

Hydromorphone

Intravenous

Fentanyl

Oral

Hydrocodone

Oral

Oxycodone

Onset 5 minutes ≤5 minutes ≤2 minutes 30–60 minutes 30–60 minutes

Peak effect 15–20 minutes 10–20 minutes 5–7 minutes 1–2 hours 1.5–2 hours

Duration 3–4 hours 2–3 hours 30–60 minutes 4–6 hours 3–4 hours

Approximate equianalgesic dose 2 mg 0.4 mg 25 mcg 5 mg 4 mg

173Perioperative Care Chapter 8

TABLE 8-17

Commonly Used Analgesic Drugs and Nonpharmacologic Techniques for Postoperative Pain Management105,106,132–136

Type of Agent Examples Potential Adverse Effects

Local anesthetics Tissue infiltration, wound instillation, peripheral

nerve block, epidural

Tingling, numbness, motor weakness,

hypotension, CNS and cardiac effects from

systemic absorption

NSAIDs Ketorolac (IV, IM, oral), ibuprofen (oral), naproxen

(oral), celecoxib (oral)

GI upset, edema, hypertension, dizziness,

drowsiness, GI bleeding, operative site bleeding

(not celecoxib)

Other nonopioids Acetaminophen (oral, intravenous, rectal) GI upset, hepatotoxicity, hypotension (IV

formulation)

Nonpharmacologic Ice or cold therapy Excessive vasoconstriction, skin irritation

Distraction, music, deep breathing for relaxation

Opioid combination products (oral) Hydrocodone + acetaminophen, oxycodone +

acetaminophen

Nausea, vomiting, pruritus, constipation, rash,

sedation, respiratory depression

Opioids Morphine (IV, epidural), hydromorphone (IV,

epidural), fentanyl (IV, epidural), oxycodone (oral)

Nausea, vomiting, pruritus, constipation, rash,

sedation, respiratory depression

CNS, central nervous system; GI, gastrointestinal; IM, intramuscular; IV, intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs.

30 minutes. His medical and surgical histories are unremarkable. He is not currently taking any medication and

reports no drug allergies. After discharge from the ambulatory surgery center, how should W.W.’s postoperative pain

be managed?

In general, one expects that the greater the magnitude of the

surgical trauma, the greater the patient’s postoperative pain. For

minor surgical procedures (e.g., inguinal hernia repair, breast

biopsy), there is minimal surgical trauma, and the patient goes

home shortly after surgery. For intermediate surgical procedures

(e.g., total abdominal hysterectomy, laparoscopic cholecystectomy), short-term hospitalization is often necessary to observe

the patient’s recovery and to manage any pain. Patients undergoing major surgery (e.g., bowel resection, thoracotomy) experience a significant surgical stress response that can significantly

increase postoperative morbidity. Effective pain management is

essential, particularly in these patients.

If pain is mild in intensity, a nonopioid analgesic such as

acetaminophen or an NSAID is appropriate. If pain is moderate or severe in intensity or not controlled with acetaminophen

or an NSAID, an opioid is indicated. As previously discussed, the

agent, dose, and route are determined by the clinical scenario. If

the patient cannot take oral medications or a fast onset of action

is required to control pain, an IV opioid is indicated. Administration of an oral opioid and nonopioid combination product

will require a longer time before the patient will feel its analgesic effect. However, depending on the dose administered, the

anticipated degree of analgesia it will produce can be greater

than a lower dose of an IV opioid. One tablet of hydrocodone

10 mg plus acetaminophen 325 mg would be expected to provide greater and more long-lasting analgesia than one dose of

morphine 2 mg IV (Table 8-16).3,132–136 If a fixed combination of

opioid and nonopioid is used, the total daily dose administered

to the patient is limited by the maximum allowable daily dose of

the nonopioid (e.g., acetaminophen, ibuprofen).

Multimodal or balanced analgesia is often used to provide

postoperative analgesia. It can be difficult to optimize postoperative pain relief, to the point of achieving normal function, by

using one drug or route of administration. By using two or more

drugs that work at different points in the pain pathway, additive or

synergistic analgesia can be achieved and adverse effects reduced

because doses are lower and side effect profiles are different.

For an illustration that shows the sites of

action of the major drug classes used for pain

management, go to http://thepoint.

lwwcom/AT10e.

For perioperative pain management, combining acetaminophen with an NSAID provides superior analgesia than either

agent alone.137 Opioids are a mainstay of analgesic therapy for

moderate to severe pain. However, opioids are often associated

with intolerable adverse effects (e.g., nausea, vomiting, constipation, itching, sedation). Maximizing the use of nonopioid analgesics can result in less need for opioids and improved analgesia

(Table 8-17).105,106,136 When compared with morphine alone, the

addition of an NSAID after major surgery reduces pain intensity

and 24-hour morphine consumption, with a reduction in the incidence of morphine-related adverse effects of nausea, vomiting,

and sedation.133

For W.W., the anticipated surgical trauma is minor, and he will

recover at home. The surgeon will inject a long-acting local anesthetic (e.g., bupivacaine) into the tissues surrounding the surgical

incision. This will provide intraoperative anesthesia at the surgical site and postoperative analgesia until the effects of the bupivacaine wear off. Then, W.W. will likely require acetaminophen or

an NSAID for pain management. If his pain is not controlled, a

less potent opioid (e.g., hydrocodone) plus acetaminophen may

be used as a rescue analgesic.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT10e. Below are the key references

and websites for this chapter, with the corresponding reference