++
NSAIDs are a heterogeneous group of weakly acidic, highly protein-bound
drugs that appear to have both peripheral effects, mediated by cyclooxygenase
(COX) inhibition (see later discussion), and central effects that
may be mediated by prostaglandins or by other mechanisms.12–16
++
GI side effects, often moderate (e.g., dyspepsia, erosions, and
ulcers), are frequent in patients; these side effects are sometimes
serious (e.g., bleeding, perforation, and gastric outlet obstruction).17–19 Risk
of peptic ulcers associated with NSAID use increases with age; for
example, the risk has been estimated to be four- to fivefold higher
in patients over 60 years of age and five- to tenfold higher in
patients with a history of ulcer disease. Alcohol consumption and
smoking result in a modest (twofold or less) increase in ulcer risk.20,21 A
number of large studies have found that adjuvants, such as omeprazole,
misoprostol, ranitidine, and other drugs, can reduce but not eliminate
the occurrence of gastric or duodenal ulcers.22
++
It is difficult to overstate the importance of GI toxicity associated
with NSAID therapy. Patients with arthritis who are taking NSAIDs
are much more likely to be hospitalized for GI complications: 2.5% per
year for OA and 5.5% per year for RA, which is 2.5 to 5.5
times higher than for the general population.23 One
estimate is that 107,000 patients are hospitalized for NSAID-related
GI complications each year and that at least 16,500 deaths occur
among patients whose arthritis is treated with NSAIDs.23
++
Aspirin and other NSAIDs may also cause lower GI problems, such
as ulcerations, strictures, colitis, or exacerbation of inflammatory
bowel disease.24–26 Aspirin and other
NSAIDs, especially diclofenac and sulindac, are also associated
with increased risk of hepatotoxicity,24 but hepatotoxicity
of NSAIDs is rare (<0.1%) compared with
that associated with acetaminophen, especially in alcoholic patients.27
++
NSAIDS, which are weak organic acids, cause gastric damage by
a combination of local effects (direct acid damage) and systemic
effects related to impaired prostaglandin synthesis (e.g., decreased
mucous layer thickness, decreased bicarbonate secretion, and decreased
submucosal blood flow).28 Combination of traditional
NSAIDs with misoprostol, a prostaglandin analogue, reduces GI and
renal adverse events.29 Misoprostol reduces both
gastric and duodenal ulcers associated with NSAID treatment. Omeprazole
and H2 antagonists (e.g., ranitidine, famotidine) have
been shown to reduce NSAID-induced duodenal ulcers. Sucralfate has
not been shown to be effective in preventing either type of ulcer.28 Several
adjunctive therapies have been considered to reduce GI side effects
of NSAIDs, including misoprostol, omeprazole, and various H2 blockers.
++
In a 6-month, randomized, double-blind, placebo-controlled trial
(Misoprostol Ulcer Complications Outcome Safety Assessment, or MUCOSA),
overall complications were reduced by 40% (P = .045)
in patients with RA receiving NSAIDs (definite serious GI events
occurred in 25 of 4,404 patients treated with misoprostol compared
with 42 of 4,439 patients receiving placebo).31 In
this study, there were 242 suspected events reported in 8,843 patients;
however, only 95 (about 1%) had definitive or probable
upper GI complications (147 patients had alterative causes for GI complications,
primarily lower GI bleeding).28,31–33
++
A fixed-dose combination of 50 or 75 mg of diclofenac with 200 μg
of misoprostol is available and has been shown to be effective in
treating signs and symptoms of both RA and OA and to be well tolerated
in most patients.34,35
++
In a 6-month, randomized, double-blind, placebo-controlled trial
comparing misoprostol with omeprazole (Omeprazole versus Misoprostol
for NSAID-induced Ulcer Management, or OMNIUM), the efficacy in
treating ulcers, erosions, and other symptoms of NSAID therapy was similar
for the two agents.36 However, during maintenance
treatment more patients remained in remission with omeprazole (61%)
than with misoprostol (48%) or placebo (27%).
Also, omeprazole was better tolerated than misoprostol.36
++
In a sister study to OMNIUM, the Acid Suppression Trial: Ranitidine
versus Omeprazole for NSAID-Associated Ulcer Treatment (ASTRONAUT),
omeprazole at 20 or 40 mg/day (89% and 79%,
respectively) had a higher success rate against NSAID-associated
ulcers than ranitidine at 150 mg twice daily (63%); P < .001.37,38
++
In a report of a substudy of the Arthritis, Rheumatism and Ageing
Medical Information System (ARAMIS),39 the authors
noted that asymptomatic patients who took antacids or H2-receptor
antagonists (30% of the nearly 2,000 subjects) had a higher
risk (OR 2.69; CI 1.36–5.31) of serious GI complications
than patients who did not take these agents. A summary of the entire
ARAMIS data set estimates the mortality rate for NSAID-related GI
complications as much greater than that of cervical cancer, asthma,
or malignant melanoma; comparable to that of leukemia; and one third
to one half that of diabetes or human immunodeficiency virus (HIV)
disease (both about 40,000 deaths per year).40
++
Patients with RA were more willing to accept risks of treatment
with NSAIDs than were patients with OA.41 For example,
RA patients would accept mild indigestion or even indigestion requiring
an antacid (70% and 60%) more willingly than would
patients with OA (45% and 33%); P = .01
and .05, respectively, and were more willing to accept the risk
of developing an ulcer or kidney disease.41 As
with opioids, balancing the risk of side effects of NSAIDs with
the fact that unrelieved arthritis-related pain results in reduced
function and diminished quality of life is important.4
++
Combination of two NSAIDs results in increased toxicity without
increased efficacy.42 Monitoring for GI, renal,
and hepatic toxicity is critical, especially in older patients and
those with abnormalities in these organs.42
++
The risk of an adverse drug reaction has been estimated to be
twice as high in older patients compared with younger patients.43 In
addition, polypharmacy is especially common in older patients; thus,
drug interactions are more common. There is a known potential for
drug interactions between NSAIDs and certain antihypertensive agents
(beta blockers, angiotensin-converting enzyme [ACE] inhibitors,
and diuretics), anticonvulsants (phenytoin, valproic acid), hypoglycemics
(sulfonylureas), anticoagulants (warfarin), and medications for
congestive heart failure (digoxin).43
++
The toxicity of NSAIDs has been ranked using data from a subset
of ARAMIS (see earlier discussion), which has been monitoring approximately
17,000 subjects in the United States and Canada.44 Hospitalizations
for GI disorders were monitored in 2,747 patients followed for a
total of 9,525 years in five centers. Overall, 107 (87% affecting
the upper GI tract) of the 116 hospitalizations for GI disorders
occurred while patients were taking NSAIDs. The overall hospitalization rate
for GI disorders in patients receiving NSAIDs was 1.6% per
year, 5.2 times higher than in the subjects not receiving NSAIDs.
Typically GI toxicity accounted for about 67% of the total
toxicity, with a few exceptions (e.g., sulindac).44 The
rankings of selected NSAIDs by GI and total toxicity indices deduced
from this analysis are listed in Table 31-1. It is important to
consider that individual patients often tolerate different NSAIDs
to varying degrees based on idiosyncratic factors.
++
++
Acetaminophen has analgesic and antipyretic activity comparable
to aspirin, but does not reduce inflammation. Hematologic, renal,
and GI toxicities of acetaminophen at standard doses are rare; however,
when acetaminophen is used at high doses it can cause serious hepatic
(and renal) injury, especially in patients with predisposing factors
(e.g., acute alcohol ingestion, especially in an individual with
chronic alcohol use).45 Although acetaminophen
can relieve mild to moderate pain caused by OA, its efficacy appears
to decrease over time, and patients require additional analgesia.46 In
a meta-analysis of randomized controlled trials for OA of the knee,
acetaminophen was comparable in efficacy to low-dose naproxin and
ibuprofen, 2,400 mg/day.47 In addition,
aspirin and indomethacin were identified as the most toxic NSAIDs.47
++
Aspirin use, especially over long periods and especially in elderly
individuals, results in GI irritation and GI bleeding. When renal
function is compromised, therapy with aspirin can result in accumulation
of salicylate and intoxication.
++
Ibuprofen and other NSAIDs, as appropriate for the patient’s
individual risk factors for toxicity, are alternatives in patients
for whom acetaminophen is not effective. However, for patients whose pain
relief is not adequately relieved by agents in this therapeutic
class, use of long-acting opioid analgesics should be considered
(see later discussion).
++
The mechanism of action of aspirin and other NSAIDs by inhibition
of prostaglandin synthesis was established in 1971.48–51 The
relevant enzyme prostaglandin synthase, also known as cyclooxygenase
(COX), catalyzes two different reactions essential for prostaglandin
synthesis (Fig. 31-1). COX is inhibited by aspirin and other NSAIDs
but not by opioids, acetaminophen, or tramadol.52 Aspirin
irreversibly acetylates a specific serine (530 for COX-1 and 516
for COX-2). The simple competitive inhibition by ibuprofen and naproxen
is rapidly reversible, whereas the time-dependent competitive inhibition
by indomethacin or diclofenac results from a conformational change
and is less easily reversible.52
++
++
A decade ago it was discovered that COX has two isoforms that
share about 75% of their amino acids but have nearly identical
enzyme kinetics.49,50,52–54 The two isoforms
vary in their expression and distribution. COX-1, which is the primary
target of older NSAIDs,55 maintains a variety of
normal physiologic functions in the GI tract, kidneys, and platelets, whereas
COX-2 appears to mediate inflammatory reactions52 (Table
31-2). When inhibited by aspirin or other NSAIDs, COX-1 is completely
inactivated, whereas COX-2 can convert arachidonic acid to the precursor
of leukotrienes,52 which are associated with asthma
and anaphylactic shock.
++
++
Celecoxib (manufacturer: Searle; trade name: Celebrex, formerly
SC-58635),56–60 the first COX-2 specific
inhibitor licensed in the United States, was approved in 1998. In
short-term pain studies, celecoxib was effective in relieving pain
but did not cause typical side effect associated with NSAIDs (i.e.,
GI problems, platelet dysfunction, renal insufficiency, or liver
toxicity).46 A new drug application (NDA) for another
COX-2 specific inhibitor, rofecoxib (manufacturer: Merck; trade
name: Vioxx, formerly MK-0966), has been submitted to the U.S. Food
and Drug Administration (FDA).61
++
The potential role of selective COX-2 inhibitors in various diseases,
including arthritis, cancer, and Alzheimer’s disease has
been reviewed.15,16,53,62,63 However, there are
concerns about new adverse effects on normal physiological processes
(e.g., ovulation, pregnancy, vascular tone, and renal function)
that may emerge over the course of long-term COX-2 inhibition.53 For
example, there has been a report of fulminant liver failure in a
patient taking a COX-2 inhibitor.
++
Two of the newer NSAIDs, nabumetone (a prodrug of the active
metabolite 6-MNA) and etodolac, exhibit some preferential inhibition
of COX-2.64 The preference for COX-2 is approximately
tenfold for etodolac.65 Nabumetone and etodolac
offer equivalent efficacy profiles but often with markedly reduced
GI toxicity compared with older medications.29 In
a head-to-head comparison in treatment of patients with OA, etodolac
was as effective as naproxen, and etodolac and nabumetone were equally
effective; all drugs had comparable rates of adverse events and
drug discontinuation.66 However, whether this is
mediated via COX-2 is not clear for either agent.67 An
NDA for another COX-2 preferential inhibitor, meloxicam,68–71 has been
submitted to the U.S. FDA. These COX-2 preferential NSAIDs appear
to have less GI toxicity than earlier NSAIDs, which typically inhibit
both COX-1 and COX-2 at therapeutic concentrations.72 The
advantages of such COX-2 preferential inhibitors are subtle and
difficult to verify in clinical trials.72,73
++
Note: Interestingly, several lines of evidence suggest a role
for COX-2 in the pathogenesis of malignancy. Increased production
of prostaglandin mediated by increased COX-2 expression may be a
common mechanism for dysregulation of cell proliferation.62,74
++
NSAIDs and acetaminophen are the mainstays of initial therapy
for both RA and for OA.75 In a survey of 176 primary
care physicians using questions about a hypothetical patient,75 most respondents
indicated they would use an NSAID as initial treatment for RA. Ibuprofen
(51%) was the most common choice, followed by naproxen
(22%) and aspirin (12%).75 The
most common management approach if the initial NSAID was not effective
was to change to another NSAID before referring the patient to a
rheumatologist after approximately 3 months of treatment. For OA,
only one third used acetaminophen (the recommended agent) for initial
therapy, and two thirds prescribed an NSAID, most commonly ibuprofen
(65%). Typically OA patients received an average of two
NSAIDs over the course of 5 months before referral, usually to an
orthopedist.75 If their pain was not controlled
by the NSAID or acetaminophen, most patients had to experience uncontrolled
pain for several months. As discussed subsequently, the guidelines
for treatment of cancer pain note that mild to moderate pain not
relieved by NSAIDs or acetaminophen or moderate to severe pain should
be treated with more powerful analgesics, including opioids.
++
These analgesics are underused in patients with pain caused by
arthritis. Use of long-acting opioids (sustained-release oral formulations
of morphine or oxycodone or transdermal fentanyl), initiated at
low doses with an immediate-release opioid (not necessarily the
same drug) as a medication for breakthrough pain, is as appropriate
in these patients as in cancer patients.
++
Tramadol is a non-opioid drug with dual analgesic action and
analgesic power equivalent to codeine.76 Tramadol
binds weakly to the μ-opioid receptor and also
inhibits reuptake of the monoamines norepinephrine and serotonin.77 The
incidence of respiratory depression is low, but side effects such
as dizziness and vertigo, nausea, and constipation are common.77 Because
the addictive potential of tramadol is low, it offers an alternative
to opioids when a pure analgesic (rather than an NSAID) is desired.77 Tramadol,
however, is not a potent analgesic; 200 to 400 mg/day is
equivalent to ibuprofen, 1200 to 2400 mg/day.78
++
Adapting the WHO analgesic ladder for cancer pain8 for
arthritis largely involves more extensive trials of NSAIDs before
treatment with an opioid. If a weak opioid is inadequate, the recommended
approach is to titrate with instant-release morphine, which can
subsequently be used as a rescue medication for occasional breakthrough
pain, followed by a sustained-release formulation after stable pain
control is achieved.3 In a retrospective study
of 644 rheumatology patients, nearly half (45%) had received
a prescription for an opioid during the past 3 years. Of these patients,
more than half (153) were treated with an opioid for less than 3
consecutive months. Approximately one fourth of all these rheumatology
patients received an opioid for pain relief for more than 3 months.
Opioids reduced pain severity scores from 8.2 to 3.6 (10-point scale); P < .001.
Dose escalation occurred in 32 patients and was attributable to
worsening disease severity in all but 4 patients (1.4%),
who exhibited abuse behaviors.79 This study indicates
that opioid analgesia should not be withheld from patients with
pain resulting from arthritis.
++
For patients likely to require low doses of strong opioids, it
is also possible to move from a weak opioid to a long-acting, strong
opioid.3 The opioid analgesics80 and
transdermal fentanyl81 have been the subject of
detailed reviews. One review article discussing chronic pain notes
that all opioids have similar side effects (especially constipation,
which should be managed preemptively) and raise similar concerns
about tolerance and possible addiction. However, unlike NSAIDs which
are associated with GI and renal toxicity, chronic opioid use is
not associated with organ system toxicity.82 A
reasonable approach to initiation of a strong opioid is to set specific
goals that can be measured (e.g., the ability to walk a certain
distance or to go to work each day).82
++
Unfortunately, concerns about patient addiction or regulatory
oversight cause some physicians to be reluctant to prescribe opioids
at all or to prescribe adequate dosages for maintenance and for breakthrough
pain.4 Some patients may resist initiation of opioid
analgesics for a variety of reasons, including risk of addiction.
However, the risk of drug addiction is extremely low when patients
with arthritis are treated for pain. Patients with a history of
substance abuse have a higher, but still quite low, risk of addiction
when opioids are used appropriately for the relief of pain.83 Major
aberrant drug-related behavior (e.g., prescription forgery, multiple
episodes of prescription loss) may be indications to control opioid
treatment for pain relief very closely, including providing weekly
or even daily supplies. Minor aberrant behaviors (e.g., aggressive
complaining about the need for a higher dose, drug hoarding during
a period of reduced symptoms, and unsanctioned dose escalation)
are less predictive of development of drug addiction.83
++
As with NSAIDs, balancing the risk of side effects of opioids
with the fact that unrelieved arthritis-related pain results in
reduced function and diminished quality of life is important.4
++
Morphine is the standard against which other strong opioids are
compared. Morphine and other pure agonist opioids have no ceiling
effect, and greater pain relief can be achieved by higher doses
until toxicity (e.g., sedation, impaired cognition, and nausea)
occurs. For patients receiving opioids for chronic pain, opioid-related
respiratory depression, which is an important side effect in treatment
of acute pain, is usually not a serious problem. Patients experiencing
toxicity may benefit by substitution of another strong opioid, especially
one that is not taken orally, such as transdermal fentanyl.3
++
Opioids are effective against many types of pain, especially
nociceptive pain. There is no ceiling effect for the pure agonist
opioids, such as morphine, hydromorphone, and fentanyl. Furthermore, opioid
therapy has not been associated with major organ toxicity, even
in very long-term use. Patient response to opioids varies, and some
patients require sequential trials of several different opioids
before an effective and well-tolerated regimen is identified.80
++
Opioid dose can be increased until pain is relieved or until
side effects limit therapy. Constipation, sedation, and nausea are
the most common side effects. Opioid side effects are usually manageable.
Many practitioners manage these side effects preemptively. The prevalence
of diarrhea is high among patients with HIV disease; thus, constipation
is usually not a problem. Antiemetics to control nausea may also
cause sedation. Use of caffeine or psychostimulants (dextroamphetamine,
methylphenidate, or pemoline) may be helpful. In most cases, pain
management with opioids, such as methadone maintenance, is fully
compatible with normal function. Instructions to limit driving or
other activities are not given unless overt impairment is observed.84
++
Although respiratory depression may occur and can be life threatening,
it is rare in patients who have been receiving chronic opioid therapy,
even at high doses. Opioid antagonists (e.g., naloxone) should be
available for patients initiating opioid therapy.
++
Weak opioids are often used when stronger opioids are really
necessary, which results in inadequate pain relief. A patient with
moderate to severe pain should receive a strong opioid initially, with
the dose increased until effective pain relief is achieved. Dose
titration is limited by the customary formulations combining a weak
opioid and aspirin, acetaminophen, or ibuprofen. Codeine is relatively
emetogenic and constipating relative to its analgesic potency. Dihydroxycodone
and hydrocodone are stronger than codeine but not as strong as oxycodone.
Tramadol, a non-opioid with dual analgesic action (modest affinity
for the opioid μ receptor and inhibition of uptake
of norepinephrine and serotonin) is generally considered equivalent
in analgesic power to codeine.76,78
++
Morphine is the prototypical strong opioid and is available in
a wide variety of short-acting, immediate-release formulations.
Onset of analgesia begins within 30 minutes of oral administration
and usually persists for 3 to 4 hours. Maintaining effective levels
of morphine with these formulations requires frequent administration,
and these formulations are best used to initiate analgesia and to
treat breakthrough pain in patients maintained on a long-acting,
sustained-release opioid formulation. The usual initial oral dose
of morphine for adults and children weighing more than 50 kg (110
lb) is 30 mg every 3 to 4 hours around the clock, which is three
times the parenteral dose. Oxycodone, which is 1.5 to 2 times as
potent as morphine, should be classed as a strong opioid along with
morphine and hydromorphone. The usual initial oral dose of oxycodone is
5 to 10 mg every 3 to 4 hours. Both morphine and oxycodone are available
in long-acting formulations.
++
Hydromorphone is a strong opioid that can be used instead of
morphine for patients who do not tolerate morphine or those in whom
extremely high doses are needed. The usual initial oral dose of
hydromorphone is 7.5 mg every 3 to 4 hours. No sustained-release
formulation of hydromorphone is available.
++
A number of opioid analgesics are not appropriate for chronic
pain relief. Meperidine is not suitable for chronic administration
because of the accumulation of toxic metabolites associated with CNS
excitation and seizures. Agonist-antagonist opioids, such as buprenorphine,
butorphanol, and nalbuphine, may interfere with the effects of pure
agonist opioids and are not recommended in treatment of chronic
pain.
++
Hydromorphone has been reported to produce excellent analgesia
with reduced side effects, but comparative studies with other strong
opioids are not available.3 Oxycodone, which is
sometimes considered a weak rather than a strong opioid, has a longer
half-life and may have a more favorable side-effect profile than
morphine.3 Oxycodone is now available in both immediate-
and sustained-release formulations.
++
Codeine, hydrocodone, and oxycodone are often formulated with
acetaminophen, aspirin, or, recently, ibuprofen. Because the non-opioid
component is associated with a ceiling effect, the pain relief available
using these agents is limited. These agents, particularly codeine,
are often chosen because their addiction potential is presumed to
be low. However, codeine, which is very frequently prescribed, is
metabolized to morphine and its metabolites, which are responsible
for the pain relief from codeine.
++
Note: The combination of an N-methyl-d-aspartate (NMDA) antagonist
with an opioid may have benefits for pain treatment.85 Good
pain relief has been reported with ketamine alone, although the
therapeutic window is narrow and adverse effects are common (psychotomimetic
syndromes are the most troublesome).85 Low doses
of systemic ketamine reduced the need for opioids for postoperative
pain in some studies; however, combined infusion of low doses of
ketamine and morphine had no beneficial effects compared with morphine
alone in controlling postoperative pain in elderly patients.85 Clinical
studies evaluating the combination of the NMDA antagonist dextromethorphan
and opioids are needed. NMDA antagonists, including the investigational agent
MK-801, may have a role in treatment of neuropathic pain.85
+++
Long-Acting
Oral Opioids
++
Long-acting morphine, which is indicated for use in patients
who will require repeated administration of a strong opioid for
more than a few days, is available in two oral formulations, MS
Contin and Oramorph. A long-acting formulation of oxycodone, OxyContin,
is now available. These formulations are tablets that must be swallowed
whole; tablets must not be broken in half, crushed, or chewed. The
usual dosing interval is 12 hours. The orally administered, sustained-release
morphine results in higher peak levels and lower trough levels than
more frequent administration of immediate-release morphine. The
release of morphine from these controlled-release tablets is not
continuous over the dosing interval.
++
Patients are typically initially treated with immediate-release
morphine and then converted to sustained-release formulations. If
opioid-related side effects occur early in the dosing interval,
the dose should be reduced. If breakthrough pain occurs near the
end of the dosing interval, the dosing interval should be shortened.
To avoid acute toxicity from overdosing, the dosing interval should
never be longer than every 12 hours.
++
Fentanyl is a potent opioid analgesic whose pharmacologic properties
are particularly suitable to transdermal administration.81 Fentanyl
is short acting when administered intravenously, but the transdermal
system (Duragesic) provides a long duration and overall smoothing
of the plasma concentration curve (reduction in height of peaks
and depth of troughs). Most patients change patches every 3 days
(72 hours) (Figs. 31-1 and 31-2). A depot of drug concentrates in
the viable epidermis under the transdermal fentanyl patch, and this
depot is slowly absorbed into the systemic circulation in subdermal
tissue through the cutaneous microcirculation in the dermis (Fig.
31-3).
++
++
++
In a randomized, open-label, crossover study comparing 15-day
treatment with transdermal fentanyl and sustained-release morphine
in patients with cancer, transdermal fentanyl was associated with
less constipation and less daytime drowsiness but with greater sleep
disturbance and shorter sleep duration than sustained-release morphine.86 Of
the 136 of 202 patients in the study who expressed a preference,
54% preferred transdermal fentanyl and 36%, sustained-release
morphine (P = .037).86
++
Sustained-release morphine and transdermal fentanyl were compared
in a randomized, open-label, crossover study of 202 cancer patients
requiring strong opioid analgesia at 38 palliative care centers
in the United Kingdom.86 Patients received one
treatment for 15 days followed immediately by the other treatment.
Immediate-release morphine was used freely to titrate patients’ pain control
at the start of the study and at the crossover and for breakthrough
pain. Pain relief as recorded by patients was comparable; however,
of those who felt able to express an opinion, transdermal fentanyl
was preferred by 54% compared with 36% who preferred
sustained-release morphine tablets (P = .037).
++
Fentanyl release may be faster in patients with fever, because
there is increased cutaneous circulation; thus, lower dose patches
may need to be applied more frequently. Dosing at 2- or 3-day intervals
simplifies the pain relief regimen, reducing mediation errors and
increasing compliance, especially in patients with cognitive impairment.
Patients with reduced body fat may require lower doses of transdermal
fentanyl to achieve pain relief.
++
Because of the slow onset of analgesia, a short-acting opioid
prescribed for breakthrough pain should be provided during the first
12 to 24 hours after application of the first transdermal fentanyl
patch. The short-acting breakthrough medication can be any strong
opioid. The maximum level is typically sustained for 48 hours. After
a transdermal patch is removed, plasma fentanyl levels decline,
with a half-life of approximately 17 hours (range: 13–22
hours).
++
Transdermal administration, which is convenient in most patients,
is particularly desirable in patients with GI problems, such as
nausea and vomiting or diarrhea, in whom malabsorption of oral medications
is likely. Many patients with HIV disease have periods when swallowing
is difficult because of opportunistic complications associated with
HIV infection. Transdermal fentanyl is particularly useful in such
patients, but it is beneficial and effective in all patients with
pain. The choice of analgesic and route of administration depend
on the pain syndrome, the patient, and the physician’s
judgment.
++
The patch must be applied to an area of intact normal skin. Significant
dermatologic or allergic reactions are rare, but some patients experience
erythema at the site of application.
++
In opioid-naive patients the initial dose is typically 25 μg/hour,
supplemented with a short-acting opioid. Based on use of breakthrough
medication, the dose and dosing interval can be adjusted over 1
to 2 weeks to achieve consistent pain relief with minimal use of
breakthrough medication.
+++
Potential for
Abuse of Long-Acting Opioids
++
Although it is possible to abuse almost any psychoactive drug,
it is quite uncommon for patients, even those with a history of
intravenous drug use, to abuse transdermal fentanyl or other long-acting
opioids. The steady blood levels of analgesic provided by these
formulations provide effective pain relief but little euphoria,
which is associated with the peak levels that occur with frequent dosing
of short-acting opioids. Appropriate treatment of moderate to severe
pain with opioids, especially long-acting opioids, in my clinical
experience rarely results in substance abuse or addiction.
++
The development of long-acting opioids, including transdermal
fentanyl, has simplified treatment of acute pain that requires strong
opioids for more than a few days and chronic painful syndromes. In
addition, the less-frequent dosing and flatter and lower peak drug
levels are associated with less risk of drug abuse. In general,
addiction is not a problem in elderly patients treated for arthritis-related
pain, especially when the mainstay of treatment is a long-acting
oral or transdermal opioid.