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thermal and chemical stimuli but conduct impulses at a much

slower rate compared with Aδ fibers. Transmission of electrical

impulses via C fibers results in pain that is dull, aching, burning, and diffuse (called “second pain”). Prolonged stimulation of

C fibers causes an additive effect on the perceived intensity of

second pain, called wind-up.

At the level of the dorsal horn of the spinal cord, the primary

afferents cause calcium release into the presynaptic terminal.

This leads to release of excitatory amino acids (EAAs) like glutamate into the synapse (Fig. 7-3). C fibers also release peptides

such as substance P, neurokinins, and calcitonin gene-related peptide (CGRP). The EAAs then stimulate the postsynaptic receptors and the electrical signals stimulate second-order neurons

in the CNS. The postsynaptic α-amino-3-hydroxy-5-methyl-4-

isoxazoleproprionate (AMPA) receptors are sodium channel–

mediated, and are responsible for the first pain mentioned previously. N-methyl-d-aspartate (NMDA) receptor channels allow

both sodium and calcium passage. Usually a magnesium ion

holds the channels closed; however, when there is sustained firing from the primary afferents, the magnesium ion is displaced

NMDA AMPA NK1

Secondary

spinothalamic

neurons

Dorsal horn cell

(post synaptic)

Presynaptic primary

afferent fiber

Ca2+ Ca2+ Ca2+

Substance

P

Glutamate

FIGURE 7-3 Synaptic activity at the dorsal horn. AMPA, α-amino3-hydroxy-5-methyl-4-isoxazoleproprionate; NK1, neurokinin 1;

NMDA, N-methyl-D-aspartate.

Calcium, total, 9.0 mg/dL

CBC With Differential:

White blood cell count, 7.1 × 109/μL

Red blood cell count, 3.25 × 106/μL

Hemoglobin, 14 g/dL

Hematocrit, 43%

Mean cell volume, 91 × 106/μL

Mean cell hemoglobin, 30 pg/cell

Mean cell hemoglobin concentration, 33 g/dL

Platelet, 369 × 103/μL

Absolute neutrophils, 5 × 109/L

Absolute lymphocytes, 1.2 × 109/L

Absolute monocytes, 0.2 × 109/L

Absolute eosinophils, 0 × 109/L

Absolute basophils, 0 × 109/L

The radiation oncologist decides to admit L.V. to the hospital for dehydration and pain management. What are the

possible etiologies of L.V.’s pain?

L.V. is presenting with a new complaint of a severe sore throat

and persistent neck and shoulder pain. Laboratory data rule out

infection and myelosuppression. His kidney function may be

impaired by dehydration and cisplatin therapy. The most likely

causes of L.V.’s pain are the recent surgical neck resection and

mucositis from external beam radiation.

L.V. also has postoperative peripheral neuropathy characterized by shocklike sensation in the neck and shoulders after

the resection of the tumor. The physical examination of L.V.’s

neck and shoulders is remarkable for allodynia, which can be

present with neuropathy. The cervical lymph node resection

may have caused neuropathy due to nerve damage via crushing, pressure, incision, or inflammation. This results in ectopic

firing and changes in the receptive field, causing nerve excitability

and spontaneous activity (wind-up). Neuronal hyperexcitability

may be related to overexpression of sodium channels and activation of the NMDA receptor.154 Cervical plexopathy may also be

contributing to the discomfort.

Mucositis occurs in up to 45% of individuals treated for

head and neck cancer with the chemoradiation regimen L.V.

is receiving.154,155 Chemotherapy and radiation directly affect

the proliferation of epithelial cells and connective tissue, causing

damage to and loss of the mucosal barrier. On physical examination, the oropharynx is red and ulcerated, which is indicative of

mucositis. Chapter 90, Adverse Effects of Chemotherapy and Targeted Agents, provides information on the signs and symptoms

of mucositis. Pain associated with mucositis is dependent on the

degree of tissue damage, sensitization of nociceptors, and activation of inflammatory and pain mediators. L.V.’s complaint of sore

throat pain limiting his ability to swallow is a common presentation of mucositis. In head and neck cancer patients treated with

radiation, pain intensity scores directly correspond to mucositis

and increase at week 3, often peak at week 5, and persist for

weeks after the end of treatment.153

In addition, L.V. may have cisplatin-related neurotoxicity.

Approximately 30% to 40% of patients may experience sensory

loss as a result of direct neuronal DNA damage and apoptotic cell

death caused by cisplatin. Neurotoxicity is a dose-limiting side

effect for all the platinum agents. Cisplatin peripheral toxicity can

occur in patients who receive a cumulative dose of more than

400 to 500 mg/m2.

156 All sensory modalities are involved, but loss

of large fiber function is often prominent. Persistent dysesthetic

pain (e.g., an unpleasant abnormal sensation, whether spontaneous or evoked) is a late phenomenon that may continue to

progress for several months after cessation of cisplatin.

TRANSDERMAL FENTANYL DOSE CALCULATION

CASE 7-7, QUESTION 2: L.V. was started on IV hydromorphone using patient-controlled analgesia (PCA) with an

average usage of 14 mg/day. He now rates his pain as 4 of

10. Owing to difficulty swallowing secondary to the mucositis and xerostomia, he had a gastric feeding tube placed

for nutrition. The plan is to convert the IV hydromorphone

to a transdermal fentanyl patch. What transdermal fentanyl

patch dose should L.V. be started on, and what are the

instructions for use?

For more than two decades, the World Health Organization’s

(WHO) analgesic ladder has been used to guide cancer pain

management.157 The ladder progresses in a stepwise manner

starting with acetaminophen, NSAIDs, and adjuvant medications

(e.g., coanalgesics such as anticonvulsants and antidepressants

for neuropathic pain) as initial therapy. If the pain intensity is

greater than 4 of 10 but not severe, weak opioid analgesics may

be added to the pain regimen. For severe pain, strong opioids such

as morphine, hydromorphone, fentanyl, and oxycodone are recommended in step 3 of the WHO analgesic ladder. The downside

to using this algorithm is that cancer pain rarely progresses in the

stepwise fashion that the WHO ladder implies. Therefore, several organizations including the APS, National Comprehensive

Cancer Network, and American Cancer Society have proposed

different strategies for managing cancer pain based on the assessment of the patient, development of an individualized care plan

for pain, and symptom management.152,158,159

Before starting IV hydromorphone, L.V. has severe throat pain

rated 10 of 10 and moderate-severe neck and shoulder pain rated

6 of 10. Because of the severity of pain and inability to swallow,

IV opioid therapy using PCA is appropriate. Chapter 8, Perioperative Care, provides a discussion of PCA. Hydromorphone is a

good choice for IV opioid therapy because it does not have active

metabolites that could accumulate with renal insufficiency. The

transdermal fentanyl patch is an excellent choice for L.V.’s eventual outpatient pain management because it will provide continuous release of opioid and is convenient to use.160 Kadian, an

extended-release morphine capsule, can be administered via the

gastric feeding tube because the capsule is opened and contents

flushed through the gastric feeding tube with water. Limitations

to Kadian include patient manipulation of the gastric feeding tube

with self-administration and potential for morphine side effects

secondary to metabolite accumulation if renal insufficiency

persists.

Transdermal fentanyl patches are intended for opioid-tolerant

patients with stable chronic pain. Opioid-tolerant patients are

those who have been taking daily, for a week or longer, at least

60 mg of oral morphine, 30 mg of oral oxycodone, or at least 8

mg of oral hydromorphone or an equianalgesic dose of another

opioid. Respiratory depression associated with opioids is more

likely to occur in opioid-na¨ıve patients, patients with postoperative pain, and those with intermittent or mild pain that is

managed with PRN opioid administration.159,161 Before the current hospital admission, L.V. was taking 120 mg of long-acting

oral morphine per day with additional oral morphine for breakthrough pain. L.V. is a good candidate for a transdermal fentanyl

patch.

L.V.’s transdermal fentanyl regimen will need to be determined by converting IV hydromorphone using an equianalgesic

dose approximation. Doses of two different opioids (or two different routes of administration of the same opioid) are considered to be equianalgesic if they provide the same degree of pain

relief. Table 7-21162 gives equianalgesic opioid doses. The calculations to convert L.V. from IV hydromorphone to transdermal

141Pain and Its Management Chapter 7

TABLE 7-21

Equianalgesic Opioid Dosing

Equianalgesic Dose (mg)

Opioid Oral Parenteral Comments

Morphine 30 10 Standard for comparison of opioid analgesics.

Frequency for controlled release preparations:

8 or 12 hours for MS Contin or Oramorph.

12 or 24 hours for Kadian.

24 hours for Avinza.

Embeda (morphine sulfate and naltrexone) is a diversion-deterrent

formulation.

Morphine not recommended in patients with severe renal impairment.

Hydromorphone (Dilaudid,

Exalgo)

7.5 1.5 Exalgo (extended release) dosed every 24 hours.

Can be used in patients with renal or liver impairment.

Fentanyl — 0.1 Refer to Table 7-22 for transdermal fentanyl.

Equianalgesic conversion ratios have not been established for transmucosal

and transbuccal fentanyl formulations.

Can be used in patients with renal or liver impairment.

Oxycodone 20 — OxyContin (controlled release) is dosed every 8 or 12 hours.

Can be used in patients with renal impairment.

Levorphanol (Levo-Dromoran) 4 acute

1 chronic

1 chronic Long plasma half-life (12–16 hours but may be as long as 90–120 hours).

Use with caution in older adults.

Buprenorphine (Buprenex,

Butrans)161,162

0.3 0.4 (SL) Available as sublingual tablets and injection.

Analgesic ceiling of 32 mg/d SL.

Butrans (transdermal buprenorphine) available.

Suboxone (buprenorphine and naloxone) restricted to treatment of opioid

dependence.

Partial agonists not recommended for cancer pain management.

Meperidine (Demerol)159,161 100 300 Not recommended for routine clinical use.

Normeperidine is a toxic metabolite that produces anxiety, tremors,

myoclonus and generalized seizures.

SL, sublingual.

fentanyl (Duragesic) are shown in Figure 7-7. There are several

published tables for converting morphine to transdermal fentanyl by researchers and manufacturers of transdermal fentanyl

products. They provide slightly different dose conversion recommendations. Duragesic has wide morphine dose ranges, which

may result in underdosing the transdermal fentanyl patch in cancer patients (Table 7-22).161,163 Breitbart et al. recommend a 2:1

ratio of oral morphine to transdermal fentanyl (i.e., 2 mg oral

morphine is equivalent to 1 mcg/hour transdermal fentanyl),

TABLE 7-22

Conversion from Oral Morphine to Duragesic163

Oral 24-Hour Morphine (mg/d) Duragesic Dose (mcg/h)

60–134 25

135–224 50

225–314 75

315–404 100

405–494 125

495–584 150

585–674 175

675–764 200

765–854 225

855–944 250

945–1034 275

1035–1124 300

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resulting in higher transdermal fentanyl doses, which may be

excessive for elderly patients.164 A study by Donner et al. suggested a dose ratio of 60 mg/day oral morphine is equal to 25

mcg/hour transdermal fentanyl, which falls between the manufacturer’s table and the study recommendations by Breitbart et

al.163–165 The Donner conversion ratio is used in most references

because it is less likely to cause underdosing or overdosing.165

L.V.’s transdermal fentanyl patch dose is 116 mcg/hour

(Fig. 7-7) using the dose ratio 60 mg/day oral morphine to

25 mcg/hour transdermal fentanyl. Because L.V.’s pain is well

controlled based on the intensity rating of 4 of 10, the dose of

transdermal fentanyl should be rounded down to the nearest

available patch size, which is 100 mcg/hour. If L.V.’s pain was

not controlled, the transdermal patch dose should be rounded

up to the nearest available patch size.161

Patients who have been on opioid therapy for a prolonged

time are likely to exhibit tolerance to the therapeutic effect.

However, when switched to a different opioid, the level of tolerance may change (i.e., diminished tolerance to the new opioid)

owing to the pharmacokinetic properties of the new opioid. This

change in sensitivity to the new opioid is called incomplete cross

tolerance.161 Most opioid doses need to be reduced by 25% to

50% after the conversion calculation to account for the incomplete cross tolerance.159 The exception to this is methadone and

fentanyl. Conversion ratios for methadone and fentanyl have

already accounted for incomplete cross tolerance, so no further

reductions are generally needed. Therefore, L.V.’s transdermal

fentanyl patch dose should not be reduced for incomplete cross

tolerance.

After the initial transdermal patch is applied, it will take 12

hours to reach the minimal effective blood concentration and up

142 Section 1 General Care

Step 1:

Determine the 24-hour total of the opioid that will be converted. For L.V., the 24-hour total of intravenous hydromorphone is 14

mg.

Step 2:

Select the equianalgesic dose ratio that corresponds to the opioid and route that will be converted from Table 7-21. Ratio

calculations should be set up to correlate the actual dose with the equianalgesic equivalent as shown below:

For conversion of L.V.’s hydromorphone dose, 1.5 mg intravenous hydromorphone is equianalgesic to 30 mg oral morphine:

“X” mg total daily dose of new opioid

mg total daily dose of current opioid = equianalgesic factor of new opioid

equianalgesic factor of current opioid

“X” mg total daily dose of new opioid

14 mg intravenous hydromorphone =

Step 3:

Cross multiply the ratio to determine the total daily dose of oral morphine.

30 mg oral morphine

1.5 mg intravenous hydromorphone

Step 4:

Determine L.V.’s transdermal fentanyl patch dose equivalent to 280 mg oral morphine.

(1.5)(X) = (14)(30)

1.5X = 420

X = 280 mg of oral morphine

Manufacturer’s Conversion Ratio163

225–314 mg oral morphine/day = 75 mcg/hour transdermal fentanyl

Donner Study Ratio165

The conversion ratio of 60 mg/day oral morphine to 25 mcg/hour transdermal fentanyl will be used for the calculation.

(60)(X) = (280)(25)

X = 116 mcg/hour transdermal fentanyl

Breitbart Study Ratio164

The conversion ratio of 2 mg oral morphine to 1 mcg/hour transdermal fentanyl will be used for the calculation.

(2)(X) = (280)(1)

X = 140 mcg/hour transdermal fentanyl

“X” mg total daily dose of new opioid

280 mg oral morphine/day = 25 mcg/hour transdermal fentanyl

60 mg oral morphine/day

“X” mg total daily dose of new opioid

280 mg oral morphine/day = 1 mcg/hour transdermal fentanyl

2 mg oral morphine

FIGURE 7-7 Conversion of L.V. from intravenous hydromorphone to transdermal fentanyl.

to 36 hours to achieve the maximal concentration. The transdermal fentanyl patch must be changed every 72 hours to maintain

the steady-state blood concentration. Elderly, cachectic, or debilitated patients may have altered pharmacokinetics (i.e., more

rapid rate of release) as a result of poor subcutaneous fat stores,

thus requiring the transdermal fentanyl patch be changed every

48 hours.163

L.V. should be instructed that the transdermal fentanyl patch

should be applied to an intact, nonirritated and nonirradiated

flat skin surface such as the chest, back, flank, or upper arm.161

He should be warned about the risk of elevated body temperature (e.g., 40◦C or 104◦F) resulting in a faster release of fentanyl

from the patch. The increased fentanyl level could cause serious

respiratory depression. L.V. should be cautioned about avoiding

external heating sources such as electric blankets, heating pads,

tanning beds, sunbathing, hot baths, hot tubs, saunas, and heated

water beds.161 Fentanyl transdermal skin patches should not be

used if damaged or cut as this may increase the absorption of

the medication. L.V. should be told to wash his hands immediately if contact is made with the fentanyl gel that was inside the

transdermal patch.

TRANSITION TO TRANSDERMAL FENTANYL

CASE 7-7, QUESTION 3: How should L.V. be transitioned

from IV hydromorphone to the transdermal fentanyl patch?

Reducing the IV hydromorphone continuous infusion by 50%

should occur 6 hours after the initial transdermal fentanyl patch

is placed. Discontinuation of the IV hydromorphone continuous

infusion and PCA dose should occur 12 hours after the initial

transdermal fentanyl patch placement.161 L.V. may need to use

a short-acting (i.e., immediate-release) opioid until the maximal

fentanyl blood concentration is achieved. Additional short-acting

opioid may be needed for pain that occurs near the end of the

72-hour dose interval.

143Pain and Its Management Chapter 7

TABLE 7-23

Equianalgesic Doses for Actiq (Transmucosal Fentanyl) and

Fentora (Buccal Fentanyl)166

Current Actiq Dose (mcg) Initial Fentora Dose (mcg)

200 100

400 100

600 200

800 200

1,200 400

1,600 400

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