Download Pharmacologic therapy of cancer pain

Pharmacologic therapy of cancer pain
Stuart W Hough, MD
Zahid H Bajwa, MD
Carol A Warfield, MD
UpToDate performs a continuous review of over 270 journals and other resources.
Updates are added as important new information is published. The literature review
for version 9.3 is current through August 2001; this topic was last changed on
August 31, 2001. The next version of UpToDate (10.1) will be released in February
2002.
The majority of pain in patients with advanced cancer is caused by the cancer itself
[1,2]. As an example, in a study of 200 patients referred to a specialized cancer pain
clinic, pain caused by tumor growth was found in 158 patients (79 percent) [2].
Visceral involvement (74 cases), bone metastases (68 cases), soft tissue invasion
(56 cases) and nerve/plexus pressure or infiltration (39 cases) were the most
frequent causes of pain due to tumor growth. Determining the cause of pain is
important since it may signal advancing disease [3] and can assist in selecting the
most appropriate analgesic approach. (See "Cancer pain syndromes").
This card will review the systemic pharmacologic therapy of cancer pain.
Nonpharmacologic therapy is discussed separately. (See "Nonpharmacologic therapy
of cancer pain").
GENERAL PRINCIPLES OF THERAPY — Pain treatment is usually best
accomplished with antitumor therapy. Radiation, chemotherapy, and palliative
surgery should be applied in appropriate cases to debulk or shrink the tumor. When
therapy directed at the tumor is not feasible or ineffective, efforts are turned to
symptomatic relief. These efforts are usually pharmacologic, but also include
anesthetic, surgical, psychiatric, and physical modalities.
The World Health Organization proposed a three-step approach to the pharmacologic
treatment of cancer pain [4]. The first step, for mild pain, utilizes non-opioids and
adjuvant drugs. For increasing pain, an opioid is added. For severe pain, more potent
opioids are added. This approach is designed to be simple to understand and usable
around the world.
Uncontrolled field testing has found the WHO guidelines effective for 70 to 100
percent of patients with cancer [5]. In developed countries, a fourth step is added
for patients who have not responded well to systemic administration of strong
opioids and appropriate adjuvants. (See "Nonpharmacologic therapy of cancer
pain").
Measuring pain — Pain is often underrecognized in cancer patients. One study, for
example, surveyed physicians and 1308 outpatients with metastatic cancer from 54
treatment centers: 42 percent of 597 patients with pain were not receiving adequate
analgesia by the WHO guidelines [1]. Insufficient pain relief was particularly common
among minorities, women, and the aged. The principal barrier to effective pain
management was a discrepancy between the patient's and physician's assessments
of the extent to which pain was interfering with daily activities. Efficient and
objective means of pain assessment are therefore essential to providing adequate
cancer pain relief.
In addition to diagnosing the pain mechanism or syndrome (see "Cancer pain
syndromes"), the treating clinician must assess pain quality and intensity, its
functional impact, and psychologic comorbidity. The emotional response to pain and
dying is often called suffering, and may not be easily separated from the rest of the
pain experience. It is essential to accept the patient's report of pain at face value,
realizing that anxiety and depression may exacerbate, rather than exaggerate, the
pain.
Pain should be assessed frequently and systematically, especially when a new pain is
reported or a new analgesic treatment is initiated. The pain's location, intensity,
quality (neuropathic, visceral, somatic), associated symptoms, aggravating and
relieving factors, and the patient's emotional and cognitive response to pain should
be noted. (See "Epidemiology and pathogenesis of cancer pain").
Pain measurement tools — Although there is no quantitative biochemical or
neurophysiologic test for pain, tools have been devised to assess pain intensity. The
verbal numerical scale, rating pain from zero for "no pain," to 10 for "the worst
imaginable pain" is easily implemented and recorded during frequent assessments.
Similarly, a 100-centimeter visual analog scale may be used, with or without
intensity descriptors. These instruments are useful for tracking pain intensity, but
unidimensional in that they do not reflect the complexity of the pain experience.
A visual analog pain score for one patient may not mean the same thing to another,
but it is reliable on repeated use in the same patient [6], allowing serial assessments
by different clinicians over the course of treatment. Pain scores should be recorded,
like the vital signs [7], with intervention performed when the score exceeds an
acceptable level.
When the patient cannot communicate, pain intensity must be evaluated by other
means. Next of kin are usually able to verify the existence of pain, but are not
accurate when describing its intensity, location, and treatment [8]. Non-English
speakers will need a translator or a pain scale with instructions in their language.
The faces pain scale, originally designed for use in children, may be useful in some
cognitively impaired patients [9]. Attention to nonverbal pain manifestations is also
important. These include:

Autonomic changes such as hypertension, tachycardia, and diaphoresis.

Agitation or confusion in patients with organic brain disease.

Apathy, inactivity, or irritability in patients with cognitive impairment; these
patients may also refuse to eat without explanation, protect the painful part,
and show facial grimacing. Although these manifestations are not specific for
pain, empiric analgesic treatment in such situations, after ruling out more
serious acute illness, will often confirm the assessment.
Several assessment instruments incorporate pain quality, intensity, location,
emotional and functional impact, and effectiveness of coping skills [10]. The best
known of these is the McGill Pain Questionnaire (MPQ) [11]. The patient chooses
among 16 groups of descriptive words to characterize the sensory, affective, and
evaluative qualities of his pain. Four additional word groups are specific to certain
pain conditions. A pain intensity scale, a questionnaire on the use of analgesics and
prior pain experience, and a human figure drawing on which the patient indicates his
pain location are also included in the MPQ. The disadvantage of the MPQ is that it is
not self-administered, and takes up to 20 minutes to complete.
A shorter instrument, the Memorial Pain Assessment Card, is designed to allow rapid
assessment of cancer pain intensity, effectiveness of analgesics, and general
psychological distress. It uses three visual analog scales and a set of eight pain
intensity descriptors [12]. It may be self-administered and is more appropriate for
cancer patients who are too fatigued or sedated to complete the MPQ. It appears to
correlate with some of the more complicated instruments, yet it can be administered
repeatedly without the evaluator's assistance.
NONOPIOID ANALGESICS — Nonsteroidal antiinflammatory drugs (NSAIDs) and
acetaminophen are routinely used in the treatment of cancer pain. In general, they
should be used on an around-the-clock schedule before advancing to step two of the
pain ladder. At that step and beyond, they should be continued in addition to opioids.
Some physicians feel that NSAIDs are especially effective for bone pain [13], but
they are probably useful in all types of pain. They act synergistically with opioids in
the spinal cord [14], allowing a reduction in the opioid dose and possibly forestalling
the development of opioid tolerance.
There are many NSAIDs from which to choose (show table 1). There is little
literature substantiating improved efficacy of one NSAID over another [15].
Nevertheless, a patient who does not tolerate a particular NSAID may do well on
another. Compliance can be improved by switching to a BID or QD preparation. (See
"NSAID: Therapeutic use and variability of response"). When the oral route is not
available, as in the patient with unremitting nausea, some NSAIDs and
acetaminophen can be given rectally, and ketorolac is available for intramuscular and
intravenous use.
NSAID side effects — The reluctance of many patients and physicians to use
NSAIDs to their full benefit stems in part from the many side effects that may be
associated with these drugs. (See "NSAID: Overview of adverse effects"):

Most NSAIDs interfere with platelet aggregation; two exceptions are choline
magnesium trisalicylate[16], and the selective COX-2 inhibitors. (See
"Overview of selective COX-2 inhibitors"). Despite its short half-life, aspirin
irreversibly inhibits platelet aggregation for the lifetime of the platelet (four to
seven days); the inhibitory effect of other NSAIDs lasts about two days.

NSAIDs produce adverse gastrointestinal side effects, including dyspepsia and
gastric ulceration. The likelihood varies with the type of NSAID (eg, relative
protection, at least over the short-term, with COX-2 inhibitors). (See "NSAID:
Pathogenesis of gastroduodenal toxicity").
Food and antacids may help patients tolerate NSAIDs with less dyspepsia. In
addition, protection against gastroduodenal toxicity can be achieved with
misoprostol, high doses of some H2 blockers, and a proton pump inhibitor. (See
"NSAID: Prevention and treatment of gastroduodenal toxicity").

There are a variety of forms of nephrotoxicity associated with NSAID use,
including reversible renal insufficiency due to renal vasoconstriction, acute
interstitial nephritis, and a predisposition to acute tubular necrosis in the
patient with low renal perfusion. In addition, NSAIDs should be prescribed
with caution in patients with hypertension, renal insufficiency, or heart failure.
(See "NSAID: Acute renal failure and nephrotic syndrome").

Other side effects of NSAIDS include hepatic toxicity, even at normally
recommended doses; confusion and an inability to concentrate; allergic
reactions in some patients who are allergic to aspirin may also be allergic to
other NSAIDs. The elevations in liver enzymes are generally mild and
reversible with discontinuation of the NSAID. Acetaminophen can produce a
more severe form of hepatotoxicity, particularly in chronic alcoholics. (See
"Pathophysiology and diagnosis of acetaminophen (paracetamol)
intoxication").
Patients who are predisposed to NSAID or acetaminophen toxicity should not receive
these medications, or should be monitored closely for adverse effects.
OPIOID THERAPY — Steps two and three of the WHO analgesic ladder advocate
the addition of opioids for moderate to severe pain, with or without an adjuvant
analgesic. Opioids are indicated for the treatment of cancer pain because of their
reliability, safety, multiple routes of administration, and ease of titration. Although
neuropathic pain may be more difficult to treat with opioids, its presence does not
preclude a favorable response to opioid-based analgesia [17].
"Weak" and "strong" opioids are not inherently different in their ability to control
pain, but are customarily used and dispensed in amounts appropriate for milder and
stronger pain, respectively. The "weak" opioids (codeine, hydrocodone, oxycodone)
are commonly prepared in combination with nonopioid analgesics (acetaminophen,
aspirin, NSAIDs). The coanalgesic prevents unfettered dose escalation, necessitating
a change to another opioid or preparation as pain increases.
Dependence — Opioids predictably induce tolerance to and physical dependence on
their effects. Despite the development of tolerance to opioid analgesia, disease
progression is usually to blame for increasing analgesic requirements [3].
Increasingly manipulative demands for opioids and dramatic pain behavior are
commonly interpreted as markers of addiction. However, addiction (ie, psychologic
dependence) is rare and unpredictable in the cancer patient [18]. Thus,
undertreatment of pain is more likely to result in this behavior ("pseudoaddiction")
than is true addiction. Adequate analgesia results in prompt cessation of "drug
seeking" in the nonaddicted patient [19]. When considering the initiation of opioid
analgesia for cancer pain, it is important to realize that their benefits usually far
outweigh their side effects and addictiveness [20].
Choice of opioid — Opioids are selected according to the route of administration
and duration of action. Any pure opioid agonist, given in sufficient quantity, is the
analgesic equivalent of any other. However, some opioids may produce more side
effects than others when given at equianalgesic doses [21,22]. As a result, certain
opioids may have higher therapeutic indices than others for a particular type of pain
or a particular patient.
Initial agent — The first preparation chosen typically has a short half-life and is
taken as needed, since initial pain is often episodic and predictable. As pain becomes
constant, a sustained-release preparation (available orally for morphine and
oxycodone (OxyContin) and transdermally for fentanyl), methadone, or levorphanol
is added on a regular dosing schedule.
Methadone and levorphanol have long half-lives (22 and 16 hours, respectively), and
may be used in place of sustained-release preparations for baseline opioid
requirements. However, they are difficult to titrate, because the initial duration of
action (4 to 6 hours) is shorter than the half-life, leading to drug accumulation with
repeated dosing over two to five days. Furthermore, methadone pharmacokinetics
are highly variable among patients, due to differences in protein binding, urinary
excretion, and induction of metabolism by methadone and other drugs [23,24].
For these reasons, it is wise to use methadone and levorphanol on an as-needed
basis initially, permitting an adjustment for drug accumulation by titrating to the
analgesic effect and to the degree of sedation [25]. One advantage of these drugs is
that they are absorbed easily by the gut; as a result, they are equally effective in
patients with short bowel conditions, while sustained release preparations may pass
through the small intestine incompletely absorbed. Another advantage is that they
can be given rectally, sublingually, and parenterally, permitting a more continuous
action with intermittent dosing than is achievable with morphine by these routes
[23].
Use of tramadol — Tramadol is a selective mu-opioid receptor agonist which, like
tricyclic antidepressants, also inhibits neuronal reuptake of serotonin and
norepinephrine[26]. It has been used in Europe since the late 1970s, where it is
available in oral and parenteral forms. In the United States, tramadol is only
available as a immediate-release, 50 mg tablet. Fifty to 100 mg of tramadol is an
effective dose for moderate pain.
The daily dose of tramadol should not exceed 400 mg because, like tricyclic
antidepressants, it lowers seizure threshold [26]. It is prudent to avoid tramadol in
patients predisposed to epileptic activity, such as those with brain tumors. Tramadol
is less likely to cause respiratory depression and constipation than equianalgesic
doses of pure opioids, but does cause dizziness, nausea, dry mouth, and sedation
[26]. It is not known whether combining typical opioids and tricyclic antidepressants
can achieve similar effects to tramadol.
The efficacy of tramadol was assessed in a double-blind, randomized, crossover
comparison of tramadol and morphine in 20 patients with "strong" cancer pain [27].
By titrating doses over four days, equivalent pain ratings were achieved with both
drugs. More patients and nurses preferred morphine, although constipation and
nausea were less severe and total side effects were fewer with tramadol.
Another study compared tramadol to buprenorphine in 131 patients with moderate
cancer pain [28]. The trial was planned to last six months, but the average patient
withdrew within two months because of inadequate analgesia. Efficacy, tolerability,
and quality of life were better in the tramadol group. In summary, because of its cost
and potential to cause seizures at high doses, tramadol probably should be used only
for mild to moderate pain in cancer patients who do not tolerate typical opioids.
Use in renal failure — Certain opioids should be used cautiously in patients with
renal failure [29].

Meperidine (Demerol) is particularly dangerous, since its active metabolite,
normeperidine, accumulates with renal dysfunction or prolonged use at high
doses. Normeperidine has a long half-life and causes central nervous system
(CNS) excitability.

Morphine is metabolized in part to a potent sedative/analgesic compound,
morphine-6-glucuronide. It does not tend to cause problems in patients with
normal renal function, but can lead to prolonged narcosis in those with renal
failure.

Codeine and tramadol can accumulate in patients with renal failure, extending
their effects. Increased serum concentrations of tramadol might add to the
risk of seizure [26].
Inappropriate drugs for chronic use or combination therapy — Certain
opioids are inappropriate for chronic use or in combination with other opioids.

Partial opioid receptor agonists (buprenorphine and dezocine) and
agonist/antagonists (pentazocine, nalbuphine, and butorphanol) should be
avoided in patients tolerant to opioids or in those likely to need high doses.
These opioids may precipitate withdrawal and pain in patients already
physically dependent on opioids. When used alone, increasing amounts
provide less incremental analgesia, a phenomenon known as the ceiling
effect. Finally, because of their activity at sigma opioid receptors, pentazocine
(Talwin) and butorphanol (Stadol) may cause delirium [30].

Combination analgesics, which often contain acetaminophen, are also
inappropriate for chronic use in cancer patients because of the possibility of
acetaminophen hepatotoxicity. Daily acetaminophen intake should be limited
to 4 grams. Alcohol use and starvation (which may be present in debilitated
cancer patients) predispose to acetaminophen hepatotoxicity at low doses
[31]. (See "Pathophysiology and diagnosis of acetaminophen (paracetamol)
intoxication" and see "Treatment of acetaminophen (paracetamol)
intoxication").
Opioid dosing — Use of the appropriate opioid dose and interval controls pain
without unacceptable side effects. The required dose varies with the severity of pain,
the type of pain, preexisting opioid tolerance, psychological distress, and perhaps
genetic factors [17]. The elderly are more susceptible to opioid-induced analgesia,
but may also be more susceptible to side effects [32].
Large doses may be necessary as the disease progresses. Although there is no
theoretical limit to the dose, a practical limit may be reached. A large injectate
volume, numerous pills or suppositories, or excessive skin surface required for
fentanyl patches may necessitate switching to another drug or route. Until a limit is
reached with several opioids and routes, more invasive analgesic modalities should
not be employed.
Initiation of therapy — When initiating opioids, a short-acting drug is given as
needed every two or three hours (show table 2). After five or six half-lives (one day
for morphine), the basal daily opioid requirement is determined and a long-acting
opioid preparation is substituted. This should be provided regularly to prevent most
pain. An additional short-acting opioid (5 to 15 percent of the basal daily
requirement) is made available for breakthrough pain every 1 to 3 hours [25]. If the
short-acting opioid is needed more than three times per day, the amount of longacting opioid is increased.
Changing the dose — It is inconvenient and unnecessary to increase the dosing
frequency of long-acting oral preparations when increasing the total daily dose. Dose
changes should be in increments of one-third to one-half of the preceding dose, or
according to the patient's usage of breakthrough opioid. If side effects prevent dose
escalation, another opioid should be tried before changing to another route of
administration or abandoning opioids [33].
Cessation or reduction of opioid use may be appropriate when the patient is painfree following antitumor therapy or anesthetic or neuroablative procedures.
Reduction of the daily dose by less than 75 percent will prevent symptomatic
withdrawal, which is marked by yawning, nausea, vomiting, abdominal cramps,
diarrhea, insomnia, anxiety, irritability, temperature instability, diaphoresis, and
salivation.
Route of administration — The usual route of systemic opioid administration is
oral. Peak effect typically occurs 20 to 90 minutes and lasts three to six hours
[34,35]. Sustained-release oral preparations (morphine and oxycodone) are
available for maintenance of steady analgesia, with peak effect at two to three
hours, and a duration of 8 to 24 hours [36,37]. The clear advantages of oral
administration are the numerous drugs available and their ease of use. However,
most cancer patients require alternative routes of analgesic administration at some
time during the course of their illness [38]. Reasons include oral mucositis,
dysphagia, bowel obstruction, and severe nausea.
Alternatives to oral therapy — Rectal, oral transmucosal, and transdermal
routes are alternative delivery routes. Morphine, oxymorphone (Numorphan), and
hydromorphone (Dilaudid) are manufactured for rectal use [38,39]; injectable
methadone and sustained-release morphine are also available.

An advantage of rectal administration is the ability to remove the drug if too
much is given.

Disadvantages are the interpatient variability in absorption and the degree of
first-pass metabolism. Partial avoidance of the portal circulation can result in
slightly increased bioavailability compared with oral opioids. The particular
preparation affects the absorption and spread (thus, bioavailability) of the
drug. Morphine suppositories are slowly absorbed [38], while morphine
microenema (10 mg in 1 mL) has a more rapid onset and longer duration
than the same dose given orally [40]. Mucositis or transmucosal lesions,
diarrhea, severe thrombocytopenia, and neutropenia are contraindications to
rectal therapy.
Fentanyl is available in the form of a "lollipop" ("Actiq") for breakthrough pain, which
may be impractical in the presence of oral mucositis. An interested pharmacist can
compound concentrated solutions of morphine, oxycodone, and hydromorphone (up
to 50 mg/mL) for sublingual use. These may be easier to use than the lollipop. The
injectable preparation of methadone is particularly well absorbed sublingually, and
may have a faster onset of action than when given orally [41].
Fentanyl is the only opioid prepared for transdermal use, which is especially
important when the oral route is unavailable [42]. The onset of analgesia is 12 to 14
hours from patch application, and continues for 16 to 24 hours after removal.
Transdermal fentanyl alone cannot provide adequate analgesia for fluctuating pain.
Injected opioids reliably deliver analgesia with a rapid onset. They are indicated for
part or all of the opioid requirement in patients who cannot take opioids by the oral,
sublingual, or rectal routes, who need rapid dose titration, or whose high opioid
needs cannot be easily met by other routes. Subcutaneous injection is preferred over
intramuscular, since the latter is more painful. Intravenous injection of most opioids
provides peak effect in 5 to 15 minutes, with a similarly shortened effect duration.
Continuous infusion (subcutaneous or intravenous) or frequent redosing is usually
necessary to maintain analgesia with injected opioids. Subcutaneous infusions should
generally be limited to about 3 mL/h [43]. Subcutaneous and intravenous
hydromorphone infusions were compared in a double-blind, randomized, crossover
trial of 15 patients with cancer pain [44]. The pain scores and need for breakthrough
medication were not different in the two groups.
Patient-controlled analgesia — Patient-controlled analgesia (PCA) is indicated
for initiation of parenteral opioid therapy, rapid opioid titration with changing pain
intensity, and treatment of incident pain [45]. Since the patient controls the delivery
of opioid, individual differences in pain intensity, drug clearance, and effectiveness
are taken into account. Psychological drug dependence is no more likely, total opioid
consumption and side effects are less, and analgesia is the same or better with PCA
when compared with nurse-administered opioids [46].
PCA devices are individually programmed for the size of the dose, the minimum time
between doses (lockout interval), and the cumulative dose allowed in one or four
hours (several times higher than the anticipated need). Continuous infusion can be
programmed as well as the PCA doses to allow sleep and to cover baseline pain. An
important safety feature of PCA is that the patient will not request additional
medication when overly sedated. Those attending to the patient must not circumvent
this safety feature by pressing the demand button.
Recommended PCA settings for morphine, hydromorphone, and fentanyl are shown
in Table 3 (show table 3). Much larger doses may be needed for the opioid-tolerant
patient. In order to limit the total volume of injectate, hydromorphone may be
chosen over fentanyl and morphine because of its potency and solubility. Fentanyl is
available only at 50 µg/mL, whereas morphine, oxycodone, and hydromorphone can
be compounded to 50 mg/mL for injection.
PCA is an efficient means of determining a patient's opioid requirement when
initiating or changing opioids. The pump records the amount of drug used, which is
then converted to continuous infusion, transdermal fentanyl, or a sustained-release
oral preparation. PCA is available for use in the home as well as the hospital,
obviating the need for injections by untrained persons. Patients without intravenous
access can use subcutaneous PCA [45].
Changing opioids or routes — Dose-limiting side effects, loss of the previous route
of administration, and rapidly developing tolerance are the usual reasons for
changing drugs or routes. Three or more opioids should be tried before abandoning
systemic opioids for treatment of cancer pain, since patients may respond differently
to different drugs. Incomplete cross-tolerance between opioids may account for the
apparent decrease in required dose and side effects when changing analgesic drugs
[33,47]. When changing a long-acting opioid to another drug or route of
administration, conversion is made with the assistance of opioid conversion charts
(show table 2).
All opioid doses can be expressed in parenteral morphine equivalents. Typically, 10
mg of parenteral morphine is considered the unit dose, and doses of other drugs for
oral or parenteral administration are listed in equianalgesic amounts. The conversion
tables contain approximations based largely upon short-term use of smaller opioid
doses (show table 2). However, the calculated dose equivalents using such tables
may not be accurate among patients tolerant to opioids, and an unanticipated
potency may result from a new agent incomplete cross resistance [48]. The following
general principles should be observed:

When converting large opioid doses, caution dictates at least a one-half dose
reduction to account for incomplete cross-tolerance [47]. If, however,
inadequate analgesia necessitates the conversion, the new drug may be
started at or near an equianalgesic dose [25].

Additional short-acting opioid is made available while titrating the new drug to
achieve stable analgesia. Converting from a drug with a short half-life to one
with a long half-life (methadone, levorphanol) requires dose reduction over
several days to allow for drug accumulation [23]. Conversely, increasing
amounts of a short half-life drug are needed to replace a long half-life drug
while the first drug is eliminated.

When any change in opioid or route is made, frequent assessments are
needed to keep pain controlled and to prevent excessive narcosis.
Many nomograms provide a dose equivalent of methadone that is inadequate in
patients switching from oral morphine[49]. One report evaluated the following dose
ratios for conversion of oral morphine equivalents to methadone: 1:4 (1 mg
methadone = 4 mg oral morphine) for patients receiving less than 90 mg morphine
daily; 1:8 for patients receiving 90 to 300 mg per day; 1:12 for patients receiving
>300 mg per day, and methadone was dosed every 8 hours. Although methadone
doses had to be increased by an average of 33 percent over those predicted by the
algorithm, adequate analgesia was achieved by 80 percent within 3.65 days.
ANALGESIC ADJUVANTS — Analgesic adjuvants, such as antidepressants,
anticonvulsants, and local anesthetics, are rarely adequate analgesics when used
alone for cancer pain. They are primarily used to relieve neuropathic pain and to
provide an opioid-sparing effect, thereby lessening opioid-related side effects and
possibly slowing the development of opioid tolerance. Neuropathic pain is often
difficult to treat with opioids alone [17,50,51].
Antidepressants — Tricyclic antidepressants are the most commonly used
adjuvants in our practice [52,53]. The mechanism of their analgesic action is not
certain, but probably includes enhancement of monoamine concentrations in the
dorsal horn [54], leading to stimulation of alpha-2 receptors [55]. They are useful in
treating neuropathic pain, and have been proven analgesic activity in well-designed
trials for postherpetic neuralgia, diabetic neuropathy, atypical facial pain, migraine
headache, fibrositis, and central post-stroke pain [52,53].
There are few controlled trials of tricyclic antidepressants in cancer pain, perhaps
because cancer pain encompasses so many entities: somatic, visceral, and
neuropathic. (See "Cancer pain syndromes"). In a small placebo-controlled trial of
twenty patients with neuropathic postmastectomy pain, amitriptyline provided
effective pain relief [56]. The analgesic activity of the tricyclics on neuropathic pain
seems to be separate from their antidepressant or sedative effects [56-60].
We use tricyclic antidepressants for cancer patients whose pain seems neuropathic
as with burning, searing, aching, or dysesthetic pain in the setting of known or
probable neural compression or infiltration. The choice of drug is empiric; there is no
clearly superior drug. A patient having difficulty with sleep may benefit from a more
sedating drug, such as amitriptyline, imipramine, or doxepin; in comparison,
nortriptyline is less sedating, and desipramine has the fewest side effects [57,61].
Only 30 percent of patients with neuropathic pain achieve greater than 50 percent
pain relief with an antidepressant [53]; thus, lack of complete relief should not be
interpreted as treatment failure.
In our experience and that of others, trazodone and the selective serotonin reuptake
inhibitors are not as effective analgesics for neuropathic pain [53,60,61]. They may,
however, be indicated in the cancer pain patient with coexisting clinical depression.
Suggested dosing for the antidepressants is shown in Table 1 (show table 4).
Because these drugs are usually sedating, they are best given in the evening. If the
initial low dose is not effective, it should be increased every few days until an effect
is seen or side effects become intolerable. As with opioids, greater analgesia is seen
with higher doses [58].
Side effects — Tricyclic antidepressants are frequently associated with side effects
[53]. They are primarily anticholinergic, including sedation, constipation, urinary
retention and overflow incontinence, tachycardia, dry mouth, blurred vision,
dysphoria, and agitation. Antihistaminergic effects include sedation and weight gain,
while alpha-1 and alpha-2 adrenergic blockade contribute to orthostatic hypotension
and tachycardia. Most of these side effects are not life-threatening and diminish with
time, except for dry mouth which tends to persist. However, they often prevent the
continued use of tricyclics.
Cardiac conduction abnormalities and seizures are of greater concern [62,63]. An
electrocardiogram should be obtained prior to the initiation of therapy. Bundle
branch block and bifascicular block are relative contraindications to tricyclic use, as is
a history of seizures. Dose adjustment according to drug levels may help to prevent
these adverse effects [62].
When a patient experiences side effects that are serious or interfere with the quality
of life, it is wise to switch to another antidepressant since patient responses are
variable and often idiosyncratic. Persistent treatment is essential, since an analgesic
response may take four weeks to achieve [52].
Anticonvulsants — Carbamazepine has long been used for the treatment of
trigeminal neuralgia, and it and other anticonvulsants are commonly employed to
treat neuropathic pain [64]. One mechanism of anticonvulsant analgesia may be
through suppression of ectopic firing at sites of neural compression and axonal
sprouting (neuromas) [65].
The data supporting the use of anticonvulsants for pain relief were assessed in a
systematic review of 20 randomized, controlled anticonvulsant trials [66]. Trigeminal
neuralgia responded to carbamazepine, and diabetic neuropathy responded to
carbamazepine and phenytoin.
There are few prospective, controlled trials of anticonvulsants in cancer pain. One
study compared phenytoin, buprenorphine, and both drugs in combination in three
groups of 25 patients with cancer pain of various etiologies [67]. A low dose of
phenytoin (100 mg BID) provided greater than 50 percent pain relief in most
patients, and enhanced the effect of buprenorphine without increasing side effects.
However, individual patients may respond dramatically, and these medications
should not be withheld from patients in pain, pending definitive evidence of their
efficacy. (See "Pharmacology of antiepileptic drugs").
Carbamazepine — Carbamazepine is started at 100 mg BID, and is escalated until
toxicity occurs, pain is relieved, or the safe serum concentration is exceeded (12
µg/mL). Among the side effects that can be encountered are sedation, vertigo,
ataxia, hyponatremia, nausea, and cutaneous reactions (show table 5) [64].
Reversible hepatotoxicity, resembling viral hepatitis, is a rare complication [68].
Bone marrow suppression often manifests as mild leukopenia or thrombocytopenia,
and rarely aplastic anemia. Patients receiving carbamazepine should have their
complete blood counts and serum aminotransferases monitored.
Phenytoin — Phenytoin has the advantage of being injectable. A loading dose (up
to the lesser of 20 mg/kg up or 1000 mg) is given intravenously to rapidly achieve a
therapeutic plasma concentration, and to test the hypothesis that phenytoin will be
an effective analgesic for the particular patient. Subsequent treatment may begin
with 100 mg TID given orally or intravenously. The dose is increased if pain recurs
and the serum concentration is less than 20 µg/mL; the dose is decreased if
significant side effects occur (anemia, anorexia, nausea, somnolence, and ataxia)
(show table 5). The potential for hepatotoxicity and bone marrow suppression
mandates periodic monitoring of liver function tests and blood counts [64].
Hypersensitivity to phenytoin is uncommon and potentially fatal, and manifests with
rash, fever, and hepatitis. Up to 19 percent of patients on phenytoin develop
cutaneous reactions, usually without hypersensitivity [69].
Clonazepam — Clonazepam is available for oral or parenteral use; the starting
dose is 0.25 mg TID. It is the most sedating anticonvulsant, and may be useful for
patients with anxiety and insomnia. The dose is increased as needed. Serum
concentrations are not measured and toxicities are not significant.
Valproate — Valproate is available for oral administration, starting at a dose of
125 mg BID. The most common side effects are nausea and epigastric pain, which
are reduced by taking it with food, and with enteric coated tablets (show table 5).
Hepatotoxicity is rare [64].
Gabapentin — Gabapentin is receiving considerable attention in pain
management, but few published clinical trials support its use [70]. It has not been
studied in cancer pain, but we occasionally use it because it has few side effects and
no apparent drug interactions. A randomized, double-blind, placebo-controlled trial
involving 229 subjects found gabapentin an effective analgesic for postherpetic
neuralgia, a frequent condition among cancer patients [71]. The usual starting dose
is 300 mg QHS, which may be increased to as much as 800 mg Q6 hours. The dose
should be reduced in patients with renal failure. Side effects (somnolence, ataxia,
dizziness) are not life-threatening (show table 5) and serum concentrations are not
monitored, making this an easy anticonvulsant to use [72].
Local anesthetics — Topical and systemic local anesthetics are often used in the
treatment of mucocutaneous and neuropathic pain states. Topical lidocaine and
capsaicin provide temporary relief of pain from oral mucositis, which may permit oral
intake and oral hygiene [73]. Among patients with postherpetic neuralgia, the effect
is greatest when lidocaine is applied in the painful dermatome [74]. Intravenous
lidocaine (5 mg/kg over 30 minutes) [75,76] and oral mexiletine (10 mg/kg per day)
also may relieve neuropathic pain [77,78].
Sedatives and tranquilizers — Sedation is usually considered an undesirable
consequence of opioid analgesia. Benzodiazepines and barbiturates have no
significant primary analgesic effect, but may reduce anxiety associated with
uncontrolled pain and cancer. Clonazepam (0.25 mg TID), when used for lancinating
neuropathic pain and myoclonus, may be an effective coanalgesic (see above).
Benzodiazepines may also reduce muscle spasm, which may accompany pain and
spinal cord injury, and have a coanalgesic role in these conditions.
Occasionally, patients will present just prior to death with rapidly increasing pain,
dyspnea, nausea, or other distressing symptoms. They and their family members
may desire terminal sedation when these symptoms cannot be controlled with more
specific measures. The use of benzodiazepines or barbiturates in these situations is
often helpful [79,80]. (See "Use of sedative medications in critically ill patients").
Phenothiazines have been used commonly in conjunction with opioids for acute pain
management. While they have a tranquilizing effect, only methotrimeprazine (10 to
15 mg IM) is analgesic when used alone [81]. Extrapyramidal side effects, sedation,
and hypotension make chronic phenothiazine use impractical for the treatment of
cancer pain. They are more often indicated in the treatment of nausea and anxiety.
Most antihistamines are mild analgesics. The mechanism of analgesic activity is
unknown. Hydroxyzine (50 to 100 mg IM) is commonly used in conjunction with
opioids for acute pain and for cancer pain [82]. These drugs are most useful for their
sedative, muscle relaxing, antipruritic, and antiemetic properties.
Bisphosphonates and calcitonin — Pain from osteolytic metastases may be
caused by bony destruction alone or by neural or soft tissue compression by
pathologic fracture. Bisphosphonates (pamidronate and etidronate) and calcitonin
inhibit osteoclast activity and are often used for the management of hypercalcemia
of malignancy. (See "Hypercalcemia of malignancy").
Pamidronate (as little as 60 mg/month IV) reduces pain from bone metastases and
may induce healing of lytic lesions [83,84]. The bisphosphonates also appear to
reduce bone fractures in patients with multiple myeloma and to delay the
appearance of bone metastases in patients with breast cancer [85]. (See
"Bisphosphonates in multiple myeloma, breast cancer, and prostate cancer").
In comparison, calcitonin (100 µg/day for three months) was not effective for bone
pain when compared with placebo in patients with breast cancer [86]. It may,
however, reduce pain intensity and frequency in patients with neuropathic pain [87].
The mechanism of analgesia is uncertain, but binding of calcitonin in the
hypothalamus and limbic system, areas rich in serotonin, may play a role.
Corticosteroids — Corticosteroids are used as coanalgesics when inflammation or
the mass effect of vasogenic edema causes pain [88]. Acute neural compression,
intracranial hypertension, bony and soft tissue infiltration, and visceral distention
cause pain that may respond to steroids. Corticosteroids reduce inflammation by
inhibiting prostaglandin synthesis and they may reduce axonal sprouting and
neurokinin concentrations in sensory fibers near injured tissue [89]. Regenerating
axons in neuromas discharge spontaneously or with minimal tactile stimulation due
to high sodium channel expression [90]. Locally injected corticosteroids decrease
neuroma discharge in animal models, and appear to be effective in humans as well.
Common drugs and daily doses are dexamethasone (4 to 8 mg), methylprednisolone
(8 to 40 mg), and prednisone (10 to 50 mg). Multiple daily doses are not needed,
except for hydrocortisone[88]. High initial doses are continued until a response is
seen, then tapered to the minimum effective dose. Concurrent use of enzyme
inducers such as phenytoin or carbamazepine increases the hepatic metabolism of
corticosteroids, thereby increasing the required dose. Dexamethasone may be given
in very high doses (40 to 100 mg IV) for the initial treatment of spinal cord
compression and intracranial hypertension.
Corticosteroids have numerous, well described toxicities when taken chronically [88].
(See "Major side effects of corticosteroids").
Capsaicin — Capsaicin is the chemical in chili peppers that makes them taste "hot."
When it is applied to the skin or a mucus membrane, it produces a burning sensation
due to C fiber activation, but repeated application causes substance P depletion and
C-fiber toxicity [91]. Topical capsaicin has been found useful for treatment of
mucocutaneous neuropathic pain [91,92]. Oral mucositis [73], postmastectomy pain,
and postherpetic neuralgia, are the cancer pain syndromes that may respond to
capsaicin. Studies have been complicated by difficulty in blinding because only the
active preparation causes a burning sensation.
At best, topical capsaicin provides partial analgesia and is best used in conjunction
with other analgesics. Capsaicin is available over-the-counter in 0.25 and 0.75
percent concentrations in a cream vehicle and a "roll-on," and can be prepared as a
candy for mucositis [73]. The cream should be used four to five times daily. Many
patients do not persist in applying the cream after the first few treatments because
of the uncomfortable burning [92].
Clonidine — Clonidine, an alpha-2 receptor agonist, may contribute to analgesia by
stimulating presynaptic or postsynaptic receptors in the superficial dorsal horn,
decreasing sympathetic outflow, and enhancing noradrenergic inhibitory fibers from
the brainstem [93]. These mechanisms may make clonidine a useful analgesic
adjuvant for opioids, especially in the setting of neuropathic pain [94,95]. The
epidural route appears to be more effective than the systemic route for clonidine
[95].
Side effects associated with clonidine are significant. Orthostatic hypotension,
sedation, dry mouth, and constipation are the most bothersome. Clonidine does not
appear to aggravate opioid-induced respiratory depression.
MANAGEMENT OF OPIOID SIDE EFFECTS — Many of the analgesics described
produce dose-limiting side effects. Unfortunately, patients and their families are
often asked to accept a compromise between pain and these other symptoms. As the
use of opioids and other analgesics becomes more widespread for cancer pain,
control of side effects is receiving increased attention [96].
There is striking interindividual variability in the sensitivity to adverse effects from
opioids. Some of this variability may be due to genetic background, age,
comorbidity, or interactions with other drugs [96].
In general, there are four approaches to treating adverse effects from opioids:




Dose reduction
Opioid rotation or substitution
Changing the route of administration
Symptomatic management
Opioid side effects may be successfully reduced by changing to an alternative opioid
or a different route of administration [97]. This approach requires familiarity with a
range of opioid antagonists and with the use of opioid conversion tables when
switching between opioids. (show table 6). (See "Changing opioids or routes" above)
Management of specific adverse events—
Nausea and vomiting — Opioids have three emetogenic mechanisms: a direct
effect on the chemoreceptor trigger zone, an enhancing effect on vestibular
sensitivity and a slowing effect on gastric emptying. While nausea is common with
opioids, tolerance to this effect occurs quickly. Treatment is given as needed [25].
(See "Characteristics of antiemetic drugs").
When evaluating opioid-induced nausea, refractory constipation and impaction of
stool must be considered and treated first. If nausea follows meals or is accompanied
by postprandial vomiting, metoclopramide is an appropriate choice. If it occurs with
movement, meclizine may be more effective. In the absence of these associations,
we treat empirically with a phenothiazine, butyrophenone, antihistamine, or
serotonin antagonist (show table 7). Corticosteroids [88] and benzodiazepines may
also be useful. Changing from the oral to the subcutaneous may be helpful; in
contrast, the value of switching to the rectal route is controversial [96,98].
Constipation — Opioids bind to specific receptors in the gastrointestinal tract and
central nervous system to produce constipation by direct and anticholinergic effects
[99]. Increased gastrointestinal transit time causes excessive water and electrolyte
reabsorption from the feces, while decreased biliary and pancreatic secretion further
dehydrates the stool. Tricyclic antidepressants, clonidine, dehydration, surgical
procedures, and bowel obstruction by tumor also may contribute. Elderly patients are
particularly susceptible to constipation and impaction of stool [100].
Opioid-induced constipation is so common that cathartic and stool softening
medications should be routinely initiated with around-the-clock opioid orders.
Adequate hydration, physical activity, and regular toileting are also helpful. We
prefer the coadministration of docusate (100 mg PO BID) and senna (2 to 8 tablets
QHS) for prophylaxis (show table 8). After ruling out impaction, we treat
uncontrolled constipation with an osmotic laxative, such as lactulose (15 to 30 mL)
or magnesium citrate (200 mL). A bisacodyl suppository or sodium
phosphate/biphosphate enema is used for patients who are too nauseated to take
oral cathartics. Disimpaction may be facilitated with oral mineral oil, glycerine
suppositories, or saline enemas.
Refractory constipation may respond to oral naloxone (1 to 12 mg), which acts at
enteric opioid receptors. Because naloxone is only about 3 percent bioavailable,
systemic opioid withdrawal and recrudescence of pain can be minimized with low
doses. Oral naloxone should be avoided in patients with bowel obstruction
[101,102]. Methylnaltrexone, a peripherally acting opioid antagonist, also shows
promise as a treatment for opioid-induced constipation [103,104]. Since it does not
cross the blood-brain barrier, it has no anti-analgesic effect. But it has only been
tested parenterally and is not available for clinical use. At least three studies suggest
a reduction in constipation by switching from morphine to transdermal
fentanyl[22,105,106].
Sedation — Somnolence and mental clouding are common complaints when
opioids are initiated or escalated. Some patients continue to have these problems,
especially when others coanalgesics (antidepressants, anticonvulsants,
benzodiazepines, antihistamines, and phenothiazines) are being used.
After ruling out primary central nervous system pathology and metabolic
abnormalities, unnecessary contributors are gradually eliminated. If symptoms
persist, and analgesia is adequate, the opioid dose may be reduced. If analgesia is
unsatisfactory, coanalgesics may be initiated or increased in order to achieve an
opioid-sparing effect. Psychostimulants, such as caffeine (100 to 200 mg PO per
day), dextroamphetamine (2.5 to 10 mg PO BID), or methylphenidate (5 to 10 mg
PO BID), may be added to offset the sedative effects of opioids [107]. However,
these drugs may produce adverse effects such as hallucinations, delirium or
psychosis, decreased appetite, tremor, and tachycardia. In one small study, a switch
from the oral to the subcutaneous route produced significantly less drowsiness
[108]. Finally, a different opioid or an anesthetic or neuroablative procedure may be
necessary if the patient finds sedation particularly troubling [25].
Respiratory depression — Respiratory depression occurs with sedation when
opioids are given systemically, but tolerance to this effect occurs quickly. All opioids
affect the medullary respiratory center directly, and no pure opioid agonist is less
likely to cause respiratory depression than any other when given at an equianalgesic
dose.
Most patients are able to tolerate mild respiratory depression (respiratory rate of 8 to
12 per minute). However, problems can occur in those with limited ventilatory or
respiratory reserve. If hypoventilation and moderate sedation occur near the
expected peak of opioid activity, it is best to withhold further opioids until the
respiratory rate rises or pain returns. If respiratory depression or sedation is severe
or seen at other times or if the patient is unarousable, a concurrent acute process
(eg, pulmonary embolism, cerebral edema) should be suspected. Ventilatory support
and a small dose of naloxone (20 to 80 µg IV) may be given and repeated as
necessary. Since naloxone's effects are shorter than those of most opioids, continued
close monitoring for recurrence of respiratory depression is necessary [25].
Myoclonus and hyperalgesia — Myoclonus (uncontrollable spasms of certain
muscle groups) and hyperalgesia (excessive sensitivity to mildly noxious stimuli) are
sometimes seen at very high doses of opioids. Their occurrence, separately or
together, may limit the ability of opioids to control pain at the end of life [80]. The
mechanisms of these conditions are not certain, but may include the inhibition of
nonopioid CNS inhibitory systems [109], and the potentiation of glutamate activity at
NMDA receptors [110]. Morphine-3-glucuronide and morphine-6-glucuronide
accumulate with chronic morphine administration, and may play a role in these
hyperexcitability conditions by stimulating nonopioid receptors in the CNS [111].
A change to another opioid and the addition of coanalgesics and adjuvants may
permit a reduction in the opioid dose, relieving either condition [47]. There are no
prospective studies on the treatment of opioid-induced myoclonus. However,
clonazepam (0.5 to 2 mg PO TID) and perhaps other anticonvulsants also can be
used to suppress myoclonus [47,112]. Finally, an anesthetic or neuroablative
procedure may be indicated in the rare patient with a more favorable prognosis.
Dyspepsia and peptic ulcer disease — Gastroduodenal distress and ulceration
are common with chronic NSAID use, and active peptic ulcer disease contraindicates
their use. Dyspepsia is best managed prophylactically by taking the drugs with food.
If this is insufficient, addition of an H2 receptor blocker (cimetidine, ranitidine),
misoprostol, omeprazole, sucralfate, or an oral antacid may be necessary. (See
"NSAID: Prevention and treatment of gastroduodenal toxicity"). Newer,
cyclooxygenase-2-selective NSAIDS appear to have less gastrointestinal toxicity
[113,114]. (See "Overview of selective COX-2 inhibitors").
Pruritus — Pruritus due to histamine release is observed in 2 to 10 percent of
patients receiving chronic opioids [96]. Antihistamines are commonly recommended
but there are no prospective studies on the treatment of opioid-induced pruritus.
Anecdotal experience suggests benefit from paroxetine[115]; there are conflicting
data on whether fentanyl or oxymorphone are less likely to produce histamine
release [116,117].
The Association of Cancer Online Resources, the largest online community of cancer
patients has created a website about cancer pain: www.cancer-pain.org. The site
provides information on the causes of pain, pain treatment options, and
complementary and alternative therapies for pain control. Although primarily
directed at patients, the site plans to develop professional-level content in the future.
REFERENCES
1. Cleeland, AS, Gonin, R, Hatfield, AK, et al. Pain and its treatment in outpatients
with metastatic cancer. N Engl J Med 1994; 330:592.
2. Banning, A, Sjogren, P, Henriksen, H. Pain causes in 200 patients referred to a
multidisciplinary cancer pain clinic. Pain 1991; 45:45.
3. Gonzales, GR, Elliott, KJ, Portenoy, RK, et al. The impact of a comprehensive
evaluation in the management of cancer pain. Pain 1991; 47:141.
4. World Health Organization. Cancer pain relief and palliative care. (WHO Technical
Report Series, 804). World Health Organization, Geneva, 1990.
5. Jadad, AR, Browman, GP. The WHO analgesic ladder for cancer pain
management. Stepping up the quality of its evaluation. JAMA 1995; 274:1870.
6. Revill, SI, Robinson, JO, Rosen, M, Hogg, MI. The reliability of a linear analogue
for evaluating pain. Anaesthesia 1976; 31:1191.
7. McCaffery, M, Pasero, CL. Pain ratings: The fifth vital sign. Am J Nurs 1997;
97:15.
8. O'Brien, J, Francis, A. The use of next-of-kin to estimate pain in cancer patients.
Pain 1988; 35:171.
9. Bieri, D, Reeve, RA, Champion, GD, et al. The faces pain scale for the selfassessment of the severity of pain experienced by children: Development, initial
validation, and preliminary investigation for ratio scale properties. Pain 1990;
41:139.
10. Bruera, E, Watanabe, S. New developments in the assessment of pain in cancer
patients. Support Care Cancer 1994; 2:312.
11. Melzack, R. The McGill pain questionnaire: Major properties and scoring
methods. Pain 1975; 1:277.
12. Fishman, B, Pasternak, S, Wallenstein, SL, et al. The Memorial Pain Assessment
Card: A valid instrument for the evaluation of cancer pain. Cancer 1987; 60:1151.
13. Stambaugh, JE, Drew, J. The combination of ibuprofen and
oxycodone/acetaminophen in the management of chronic cancer pain. Clin
Pharmacol Ther 1989; 44:665.
14. McCormack, K. Non-steroidal anti-inflammatory drugs and spinal nociceptive
processing. Pain 1994; 59:9.
15. Amadio, P, Cummings, DM, Amadio, PB. NSAIDs revisited: Selection,
monitoring, and safe use. Postgrad Med 1997; 101:257.
16. Stuart, JJ, Pisko, EJ. Choline magnesium trisalicylate does not impair platelet
aggregation. Pharmatherapeutica 1981; 2:547.
17. Portenoy, RK, Foley, KM, Inturrisi, CE. The nature of opioid responsiveness and
its implications for neuropathic pain: New hypotheses derived from studies of opioid
infusions. Pain 1990; 43:273.
18. Kanner, RM, Foley, KM. Patterns of narcotic drug use in a cancer pain clinic. Ann
N Y Acad Sci 1981; 362:161.
19. Weissman, DE, Burchman, SL, Dinndorf, PA, Dahl, JL. Handbook of cancer pain
management, 2nd ed, Wisconsin Cancer Pain Initiative, Milwaukee 1990.
20. Joranson, DE, Ryan, KM, Gilson, AM, Dahl, JL. Trends in medical use and abuse
of opioid analgesics. JAMA 2000; 283:1710.
21. Turturro, MA, Paris, P, Yealy, DM, Menegazzi, JJ. Hydrocodone versus codeine in
acute musculoskeletal pain. Ann Emerg Med 1991; 20:1100.
22. Ahmedzai, S, Brooks, D. Transdermal fentanyl versus sustained-release oral
morphine in cancer pain: Preference, efficacy, and quality of life. The TTS-Fentanyl
Comparative Trial Group. J Pain Symptom Manage 1997; 13:254.
23. Fainsinger, R, Schoeller, T, Bruera, E. Methadone in the management of cancer
pain: A review. Pain 1993; 52:137.
24. Plummer, JL, Gourlay, GK, Cherry, DA, Cousins, MJ. Estimation of methadone
clearance: Applications in the management of cancer pain. Pain 1988; 33:313.
25. Cherny, NI, Portenoy, RK. The management of cancer pain. CA Cancer J Clin
1994; 44:262.
26. Lewis, KS, Han, NH. Tramadol: A new centrally acting analgesic. Am J Health
Syst Pharm 1997; 54:643.
27. Wilder-Smith, CH, Schimke, J, Osterwalder, B, Senn, HJ. Oral tramadol, a muopioid agonist and monoamine reuptake-blocker, and morphine for strong cancerrelated pain. Ann Oncol 1994; 5:141.
28. Brema, F, Pastorino, G, Martini, MC, et al. Oral tramadol and buprenorphine in
tumour pain. An Italian multicentre trial. Int J Clin Pharmacol Res 1996; 16:109.
29. Chan, GL, Matzke, GR. Effects of renal insufficiency on the pharmacokinetics and
pharmacodynamics of opioid analgesics. Drug Intell Clin Pharm 1987; 21:773.
30. Houde, RW. Analgesic effectiveness of the narcotic agonist-antagonists. Br J Clin
Pharmacol 1979; 7 Suppl 3:297S.
31. Schiodt, FV, Rochling, FA, Casey, DL, et al. Acetaminophen toxicity in an urban
county hospital. N Engl J Med 1997; 337:1112.
32. Kaiko, RF, Wallenstein, SK, Rogers, AG, et al. Narcotics in the elderly. Med Clin
North Am 1982; 66:1079.
33. Galer, BS, Coyle, N, Pasternak, BW, Portenoy, RK. Individual variability in the
response to different opioids: report of five cases. Pain 1992; 49:87.
34. Sawe, J, Dahlstrom, B, Rane, A. Steady-state kinetics and analgesic effect of
oral morphine in cancer patients. Eur J Clin Pharmacol 1983; 24:537.
35. Ellison, NM, Lewis, GO. Plasma concentrations following single doses of
morphine sulfate in oral solution and rectal suppository. Clin Pharmacol Ther 1984;
3:614.
36. Broomhead, A, Kerr, R, Tester, W, et al. Comparison of a once-a-day sustainedrelease morphine formulation with standard oral morphine for cancer pain. J Pain
Symptom Manage 1997; 14:63.
37. Kaiko, RF, Benziger, DP, Fitzmartin, RD, et al. Pharmacokineticpharmacodynamic relationships of controlled-release oxycodone. Clin Pharmacol Ther
1996; 59:52.
38. Ripamonti, C, Zecca, E, Brunelli, C, et al. Rectal methadone in cancer patients
with pain. A preliminary clinical and pharmacokinetic study. Ann Oncol 1995; 6:841.
39. Campbell, WI. Rectal controlled-release morphine: plasma levels of morphine
and its metabolites following the rectal administration of MST Continu 100mg. J Clin
Pharm Ther 1996; 21:65.
40. De Conno, F, Ripamonti, C, Saita, L, et al. Role of rectal route in treating cancer
pain: a randomized crossover clinical trial of oral versus rectal morphine
administration in opioid-naive cancer patients with pain. J Clin Oncol 1995; 13:1004.
41. Weinberg, DS, Inturrisi, CE, Reidenberg, B, et al. Sublingual absorption of
selected opioid analgesics. Clin Pharmacol Ther 1988; 44:335.
42. Grond, S, Zech, D, Lehmann, KA, et al. Transdermal fentanyl in the long-term
treatment of cancer pain: a prospective study of 50 patients with advanced cancer of
the gastrointestinal tract or the head and neck region. Pain 1997; 69:191.
43. Bruera, E, Brenneis, C, Michaud, M, et al. Continuous SC infusion of narcotics
using a portable disposable device in patients with advanced cancer. Cancer Treat
Rep 1987; 71:635.
44. Moulin, DE, Kreft, JH, Murray-Parsons, NM, et al. Comparison of continuous
subcutaneous and intravenous hydromorphone infusions for management of cancer
pain. Lancet 1991; 337:465.
45. Ripamonti, C, Bruera, E. Current status of patient-controlled analgesia in cancer
patients. Oncology 1997; 11:373.
46. Chapman, CR, Hill, HF. Prolonged morphine self-administration and addiction
liability: Evaluation of two theories in a bone marrow transplant unit. Cancer 1989;
63:1636.
47. MacDonald, N, Der, L, Allan, S, Champion, P. Opioid hyperexcitability: the
application of alternate opioid therapy. Pain 1993; 53:353.
48. Cherny, N, Ripamonti, C, Pereira, J, et al. Strategies to manage the adverse
effects of oral morphine: an evidence-based report. J Clin Oncol 2001; 19:2542.
49. Mercadante, S, Casuccio, A, Fulfaro, F, et al. Switching from morphine to
methadone to improve analgesia and tolerability in cancer patients: a prospective
study. J Clin Oncol 2001; 19:2898.
50. Arner, S, Myerson, BA. Lack of analgesic effect of opioids on neuropathic and
idiopathic forms of pain. Pain 1988; 33:11.
51. Yoshioka, H, Tsuneto, S, Kashiwagi, T. Pain control with morphine for vertebral
metastases and sciatica in advanced cancer patients. J Palliat Care 1994; 10:10.
52. Magni, G. The use of antidepressants in the treatment of chronic pain. A review
of the current evidence. Drugs 1991; 42:730.
53. McQuay, HJ, Tramer, M, Nye, BA, et al. A systematic review of antidepressants
in neuropathic pain. Pain 1996; 68:217.
54. Spiegel, K, Kalb, R, Pasternak, GW. Analgesic activity of tricyclic
antidepressants. Ann Neurol 1983; 13:462.
55. Yaksh, TL. Pharmacology of spinal adrenergic systems which modulate spinal
nociceptive processing. Pharmacol Biochem Behav 1985; 22:845.
56. Eija, K, Tiina, T, Pertti, NJ. Amitriptyline effectively relieves neuropathic pain
following treatment of breast cancer. Pain 1996; 64:293.
57. Kishore-Kumar, R, Max, MB, Schafer, SC, et al. Desipramine relieves
postherpetic neuralgia. Clin Pharmacol Ther 1990; 47:305.
58. Max, MB, Schafer, SC, Culnane, M, et al. Amitriptyline, but not lorazepam,
relieves postherpetic neuralgia. Neurology 1988; 38:1427.
59. Max, MB, Culnane, M, Schafer, SC, et al. Amitriptyline relieves diabetic
neuropathy pain in patients with normal or depressed mood. Neurology 1987;
37:589.
60. Watson, CPN, Evans, RJ. A comparative trial of amitriptyline and zimelidine in
postherpetic neuralgia. Pain 1985; 23:387.
61. Max, MB, Lynch, SA, Muir, J, et al. Effects of desipramine, amitriptyline, and
fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992; 326:1250.
62. Preskorn, SH, Fast, GA. Tricyclic antidepressant-induced seizures and plasma
drug concentration. J Clin Psychiatry 1992; 53:5.
63. Dietch, JT, Fine, M. The effect of nortriptyline in elderly patients with cardiac
conduction disease. J Clin Psychiatry 1990; 51:2.
64. Swerdlow, M. Anticonvulsant drugs and chronic pain. Clin Neuropharmacol
1984; 7:51.
65. Yaari, Y, Devor, M. Phenytoin suppresses spontaneous ectopic discharge in rat
sciatic nerve neuromas. Neurosci Lett 1985; 58:117.
66. McQuay, H, Carroll, D, Jadad, AR, et al. Anticonvulsant drugs for management
of pain: A systematic review. Br Med J 1995; 311:1047.
67. Yajnik, S, Singh, GP, Singh, G, Kumar, M. Phenytoin as a coanalgesic in cancer
pain. J Pain Symptom Manage 1992; 7:209.
68. Horowitz, S, Patwardham, R, Marcus, E. Hepatotoxic reactions associated with
carbamazepine therapy. Epilepsia 1988; 29:149.
69. Conger, LA, Grabski, WJ. Dilantin hypersensitivity reaction. Cutis 1996; 57:223.
70. Wetzel, CH, Connelly, JF. Use of gabapentin in pain management. Ann
Pharmacother 1997; 31:1082.
71. Rowbotham, M, Harden, N, Stacey, B, et al. Gabapentin for the treatment of
postherpetic neuralgia: A randomized controlled trial. JAMA 1998; 280:1837.
72. Ramsay, RE. Clinical efficacy and safety of gabapentin. Neurology 1994;
44:S23.
73. Berger, AM, Bartoshuk, LM, Duffy, VB, Nadoolman, W. Capsaicin for the
treatment of oral mucositis pain. PPO Updates 1995; 9:1.
74. Rowbotham, MC, Davies, PS, Fields, HL. Topical lidocaine gel relieves
postherpetic neuralgia. Ann Neurol 1995; 37:246.
75. Rowbotham, MC, Reisner-Keller, LA, Fields, HL. Both intravenous lidocaine and
morphine reduce the pain of postherpetic neuralgia. Neurology 1991; 41:1024.
76. Kastrup, J, Angelo, H, Petersen, P, et al. Treatment of chronic painful diabetic
neuropathy with intravenous lidocaine infusion. Br Med J (Clin Res Ed) 1986;
292:173.
77. Chabal, C, Jacobson, L, Mariano, A, et al. The use of oral mexiletine for the
treatment of pain after peripheral nerve injury. Anesthesiology 1992; 76:513.
78. Dejgard, A, Petersen, P, Kastrup, J. Mexiletine for treatment of chronic painful
diabetic neuropathy. Lancet 1988; 29:9.
79. Greene, WR, Davis, WH. Titrated intravenous barbiturates in the control of
symptoms in patients with terminal cancer. South Med J 1991; 84:332.
80. Truog, RD, Berde, CB, Mitchell, C, Grier, HE. Barbiturates in the care of the
terminally ill. N Engl J Med 1992; 327:1678.
81. McGee, JL, Alexander, MR. Phenothiazine analgesia fact or fantasy? Am J Hosp
Pharm 1979; 36:633.
82. Stambaugh, JE, Lane, C. Analgesic efficacy and pharmacokinetic evaluation of
meperidine and hydroxyzine, alone and in combination. Cancer Invest 1983; 1:111.
83. Kanis, JA. Bone and cancer: pathophysiology and treatment of metastases. Bone
1995; 17(Suppl 2):101.
84. Vinholes, JJ, Purohit, OP, Abbey, ME, et al. Relationships between biochemical
and symptomatic response in a double-blind randomised trial of pamidronate for
metastatic bone disease. Ann Oncol 1997; 8:1243.
85. Mundy, GR, Yoneda, TY. Bisphosphonates as anticancer drugs. N Engl J Med
1998; 339:398.
86. Blomqvist, C, Elomaa, I, Porkaa, L, et al. Evaluation of salmon calcitonin
treatment in bone metastases from breast cancer a controlled trial. Bone 1988;
9:45.
87. Jaeger, H, Maier, C. Calcitonin in phantom limb pain: a double-blind study. Pain
1992; 48:21.
88. Twycross, R. The risks and benefits of corticosteroids in advanced cancer. Drug
Saf 1994; 11:163.
89. Hong, D, Byers, MR, Oswald, RJ. Dexamethasone treatment reduces sensory
neuropeptides and nerve sprouting reactions in injured teeth. Pain 1993; 263:830.
90. Devor, M, Govrin-Lippmann, R, Raber, P. Corticosteroids suppress ectopic neural
discharge originating in experimental neuromas. Pain 1985; 22:127.
91. Lynn, B. Capsaicin: actions on nociceptive C-fibres and therapeutic potential.
Pain 1990; 40:61.
92. Watson, CP. Topical capsaicin as an adjuvant analgesic. J Pain Symptom Manage
1994; 9:425.
93. Max, MB, Schafer, SC, Culnane, et al. Association of pain relief with drug side
effects in post-herpetic neuralgia: A single-dose study of clonidine, codeine,
ibuprofen, and placebo. Clin Pharmacol Ther 1988; 43:363.
94. Ossipov, MH, Lopez, Y, Bian, D, et al. Synergistic antinociceptive interactions of
morphine and clonidine in rats with nerve-ligation injury. Anesthesiology 1997;
86:196.
95. Eisenach, JC, DeKock, M, Klimscha, W. Alpha-2-adrenergic agonists for regional
anesthesia: A clinical review of clonidine (1984-1995). Anesthesiology 1996; 85:655.
96. Cherny, N, Ripamonti, C, Pereira, J, et al. Strategies to manage the adverse
effects of oral morphine- an evidence-based report. J Clin Oncol 2001; 19:2542.
97. Bruera, E, Pereira, J, Watanabe, S, et al. Opioid rotation in patients with cancer
pain. A retrospective comparison of dose ratios between methadone,
hydromorphone, and morphine. Cancer 1996; 78:852.
98. De Conno, F, Ripamonti, C, Saita, L, et al. Role of rectal route. J Clin Oncol
1995; 13:1004.
99. Canty, SL. Constipation as a side effect of opioids. Oncol Nurs Forum 1994;
21:739.
100. Portenoy, RK. Pain management in the older cancer patient. Oncology
(Huntingt) 1992; 6(Suppl 2):86.
101. Culpepper-Morgan, JA, Inturrisi, CE, Portenoy, RK, et al. Treatment of opioidinduced constipation with oral naloxone: A pilot study. Clin Pharmacol Ther 1992;
52:90.
102. Sykes, NP. An investigation of the ability of oral naloxone to correct opioidrelated constipation in patients with advanced cancer. Palliat Med 1996; 10:135.
103. Murphy, DB, Sutton, JA, Prescott, LF, Murphy, MB. Opioid induced delay in
gastric emptying: A peripheral mechanism in man. Anesthesiology 1997; 87:765.
104. Yuan, CS, Foss, JF, O'Connor, M, et al. Methylnaltrexone for reversal of
constipation due to chronic methadone use: a randomized controlled trial. JAMA
2000; 283:367.
105. Donner, B, Zenz, M, Tryba, M, Strumpf, M. Direct conversion from oral
morphine to transdermal fentanyl: a multicenter study in patients with cancer pain.
Pain 1996; 64:527.
106. Payne, R, Mathias, SD, Pasta, DJ, et al. Quality of life and cancer pain:
satisfaction and side effects with transdermal fentanyl versus oral morphine. J Clin
Oncol 1998; 16:1588.
107. Wilwerding, MB, Loprinzi, CL, Mailliard, JA, et al. A randomized, crossover
evaluation of methylphenidate in cancer patients receiving strong narcotics. Support
Care Cancer 1995; 3:135.
108. Drexel, H, Dzien, A, Spiegel, RW, et al. Treatment of severe cancer pain by
low-dose continuous subcutaneous morphine. Pain 1989; 36:169.
109. Dickenson, AH. Mechanisms of the analgesic actions of opiates and opioids. Br
Med Bull 1991; 47:690.
110. Chen, L, Huang, L-Y. Sustained potentiation of NMDA receptor-mediated
glutamate responses through activation of protein kinase C by a my opioid. Neuron
1991; 7:319.
111. Sjogren, P, Jonsson, T, Jensen, NH, et al. Hyperalgesia and myoclonus in
terminal cancer patients treated with continuous intravenous morphine. Pain 1993;
55:93.
112. Eisele, JH, Grigsby, EJ, Dea, G. Clonazepam treatment of myoclonic
contractions associated with high-dose opioids: case report. Pain 1992; 49:231.
113. Simon, LS, Weaver, AL, Graham, DY, et al. Anti-inflammatory and upper
gastrointestinal effects of celecoxib in rhematoid arthritis: A randomized controlled
trial. JAMA 1999; 282:1921.
114. Langman, MJ, Jensen, DM, Watson, DJ, et al. Adverse upper gastrointestinal
effects of rofecoxib compared with NSAIDS. JAMA 1999; 282:1929.
115. Zylicz, Z, Smits, C, Krajnik, M. Paroxetine for pruritus in advanced cancer. J
Pain Symptom Manage 1998; 16:121.
116. Hermens, JM, Ebertz, JM, Hanifin, JM, Hirshman, CA. Comparison of histamine
release in human skin mast cells induced by morphine, fentanyl, and oxymorphone.
Anesthesiology 1985; 62:124.
117. Warner, MA, Hosking, MP, Gray, JR, et al. Narcotic-induced histamine release:
a comparison of morphine, oxymorphone, and fentanyl infusions. J Cardiothorac Vasc
Anesth 1991; 5:481.