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. Also, opioid therapy
has not been associated with major organ toxicity even in 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.14
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, so 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 is not given unless overt impairment is observed.15
Although respiratory depression may occur and can be life-threatening,
it is rare in patients who have been receiving long-term opioid
therapy, even at high doses. Opioid antagonists (ie, naloxone) should
be available for patients initiating opioid therapy.
Weak opioids are often used when stronger opioids are 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 nonopioid 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.16,17
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
Hydromorphone is a strong opioid that can be used instead of
morphine for patients who do not tolerate morphine or if 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 long-term administration
because of the accumulation of toxic metabolites associated with
central nervous system excitation and seizures. Combination agonist-antagonist
opioids such as buprenorphine, butorphanol, and nalbuphine may interfere
with the effects of pure agonist opioids and are not recommended
for treatment of chronic pain.
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.
Long-acting morphine, which is indicated for use for 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.18 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) (Fig. 48-1 and Fig. 48-2).
Serum fentanyl concentration over 3 days after application
of a single 100-μg/hour patch.
Serum fentanyl concentration over 30 days during multiple
applications of 125-μg/hour patches followed
by tapering. (From Miser AW, et al. Transdermal fentanyl for pain
control in patients with cancer. Pain. 1989;37:18.)
A depot of drug concentrates in the viable epidermis under the
transdermal fentanyl patch, and this depot is slowly introduced
into the systemic circulation in the subdermal tissue through the cutaneous
microcirculation in the dermis (Fig. 48-3).
Pathway for fentanyl absorption through the layers of
the skin. (From Varvel JR, et al. Absorption characteristics of
transdermally administered fentanyl. Anesthesiology. 1989;70:928.)
In patients with fever, not uncommon in patients with HIV disease,
fentanyl release may be faster since there is increased cutaneous
circulation. Therefore, 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.
Because of the slow onset, analgesia using the 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 breakthough 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 to 22 hours).
Transdermal administration, which is convenient in most patients,
is particularly desirable in those patients with GI problems such
as nausea, vomiting, or diarrhea, where malabsorption of oral medications
is likely. Many patients with HIV have periods during which swallowing
is difficult because of opportunistic complications of 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 depends on the pain syndrome,
the patient, and the physician’s judgment.
The patch must be applied to an area of intact normal skin. Significant
dermatolgoic 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
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.21 Patients received one
treatment for 15 days, followed immediately by the other treatment.
Immediate-release morphine was used freely to titrate patient’s
pain control at the start of the study, 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.
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.