Topical Analgesics
Charles E. Argoff
In contrast to the use of a systemic analgesic, use of a topical
analgesic may result in relief of pain without the require-
ment for notable systemic absorption. A topical analgesic is
not a transdermal analgesic. For example, the mechanism
of action of transdermal nitroglycerin or fentanyl and cloni-
dine patches is systemic, which requires systemic absorption
through the skin, as well as a systemic concentration of the
specific drug. A topical analgesic requires neither systemic
absorption nor a significant systemic concentration to be
clinically effective. A topical analgesic is an analgesic that is
applied locally and directly to the painful areas, with the pri-
mary site of action being local to the site of application. As
noted previously, it is not a “transdermal analgesic,” which
unlike a topical analgesic, requires a systemic analgesic con-
centration for its analgesic action. This is not a trivial dis-
tinction; analgesics have been inappropriately considered
“topical” agents even when formal pharmacologic studies to
demonstrate a lack of systemic activity or systemic drug con-
centration (or both) had not been completed, and at other
times, true topical agents have been incorrectly described
as transdermal agents. As discussed in this chapter, topical
analgesics have been studied and are used for acute pain,
as well as for a variety of types of chronic neuropathic and
non-neuropathic pain. Different topical analgesics are asso-
ciated with different mechanisms of action, a point to be
considered when choosing a topical analgesic for a patient
with chronic pain. Of great interest is the recent observa-
tion (described in greater detail later in this chapter) that
although a topical analgesic’s primary mechanism of action
may occur locally and within the peripheral nervous system
(PNS), the effect of a topical analgesic can be detected in the
central nervous system (CNS) by functional neuroimaging.
BACKGROUND
Undoubtedly, pain cannot be ultimately experienced in
the absence of relevant brain activity; however, we have also
appreciated for many years the importance of PNS activity,
including provision of input to the CNS, in initiating and
maintaining acute and some chronic painful conditions.
There are specific painful conditions, such as central post-
stroke pain and spinal cord injury pain, in which the pain
mechanisms lie within the CNS and do not respond to
topical analgesics. Many common chronic pain syndromes,
including post-herpetic neuralgia (PHN), chronic low back
pain (CLBP), and osteoarthritis (OA), probably result from
mechanisms involving both the PNS and CNS.
If pain cannot be experienced without brain activation,
how can a topical analgesic whose primary mechanism of
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action is largely within the PNS be helpful? A topical anal-
gesic may interrupt, depending on the specific analgesic,
certain mechanisms of pain transmission and by doing so
may actually lead to a reduction in central pain mechanisms
and thus pain as well. In other words, acknowledging that
the experience of pain cannot occur without the brain, less
pain may be experienced if use of a topical analgesic leads
to reduced activation of PNS mechanisms, which if activated
would facilitate transmission of pain signals to the CNS for
central processing. This chapter reviews the use of topical
analgesics for the treatment of various painful conditions
and provides an update of previously published similar
reviews.1-3
The potential clinical benefit of any analgesic—or for that
matter any medical treatment—is diminished by its adverse
effect profile, toxicities, and drug-drug interactions. When
considering the use of a topical analgesic, the risk for and
severity of significant adverse effects and drug-drug interac-
tions are often less than those for the same analgesic admin-
istered systemically.4 Consider, for example, the treatment of
OA with a nonsteroidal anti-inflammatory drug (NSAID). If
one can successfully treat someone with a topical NSAID ver-
sus a systemic NSAID, this may be helpful in reducing the
risk for systemic side effects typically associated with NSAIDs.
Rash and unpleasant skin sensations may occur with the use
of a topical analgesic, but neither is typically experienced.5
Among the topical analgesics currently approved by the
Food and Drug Administration (FDA) (see Box 42.1), the
5% lidocaine patch (Lidoderm) has been studied widely. Sev-
eral studies of the 5% lidocaine patch have been designed to
evaluate its safety and tolerability. For example, the outcome
of one study assessing the tolerability and safety of 24-hr/day
use of four 5% lidocaine patches demonstrated that there
were no significant systemic side effects and that plasma lido-
caine levels remained below those known to be associated
with cardiac abnormalities. In this study, the safety and toler-
ability were similar if the subject used the patch for 12 or for
24 hr/day.6 In a multicenter open-label study, patients with
a history of CLBP from a variety of causes were treated safely
with four 5% lidocaine patches every 24 hours for extended
periods.5 In each of these reports, no significant dermal reac-
tions were experienced.6,7
Dermal sensitivity is a potential side effect of all topical
analgesics; however, other adverse effects may be experi-
enced as a result of the use of a specific topical analgesic
that may be more related to the specific medication in the
specific topical analgesic. An example is capsaicin. After
the topical application of capsaicin, severe burning at the
site of application commonly occurs. This particular side
effect may in fact not infrequently lead to reduced clinical
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