Industrial Medicine and Acute Musculoskeletal Rehabilitation. 2. Medications for the Treatment of Acute Musculoskeletal Pain

Article (PDF Available)inArchives of Physical Medicine and Rehabilitation 88(3 Suppl 1):S10-3 · April 2007with76 Reads
DOI: 10.1016/j.apmr.2006.12.009 · Source: PubMed
Unlabelled: This self-directed learning module highlights medications used in the treatment of acute musculoskeletal pain in the context of industrial rehabilitation. It is part of the study guide on industrial rehabilitation medicine and acute musculoskeletal rehabilitation in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article compares various skeletal muscle relaxants, addresses issues related to nonsteroidal anti-inflammatory medications, provides an algorithm for acute pain management in an injured worker, and discusses topical medications for the treatment of pain. Overall article objective: To summarize medication options in the treatment of acute musculoskeletal pain in the setting of injured workers.
Industrial Medicine and Acute Musculoskeletal Rehabilitation.
2. Medications for the Treatment of Acute Musculoskeletal
William J. Sullivan, MD, Andre Panagos, MD, Patrick M. Foye, MD, Aaron W. Sable, MD,
Robert W. Irwin, MD, Joseph P. Zuhosky, MD
ABSTRACT. Sullivan WJ, Panagos A, Foye PM, Sable
AW, Irwin RW, Zuhosky JP. Industrial medicine and acute
musculoskeletal rehabilitation. 2. Medications for the treatment
of acute musculoskeletal pain. Arch Phys Med Rehabil 2007;
88(3 Suppl 1):S10-3.
This self-directed learning module highlights medications
used in the treatment of acute musculoskeletal pain in the
context of industrial rehabilitation. It is part of the study guide
on industrial rehabilitation medicine and acute musculoskeletal
rehabilitation in the Self-Directed Physiatric Education Pro-
gram for practitioners and trainees in physical medicine and
rehabilitation. This article compares various skeletal muscle
relaxants, addresses issues related to nonsteroidal anti-inflam-
matory medications, provides an algorithm for acute pain man-
agement in an injured worker, and discusses topical medica-
tions for the treatment of pain.
Overall Article Objective: To summarize medication op-
tions in the treatment of acute musculoskeletal pain in the
setting of injured workers.
Key Words: Administration, topical; Analgesics; Anti-
inflammatory agents; Muscle relaxants, central; Rehabilitation.
© 2007 by the American Academy of Physical Medicine and
Case Presentation: A 45-year-old Department of Transpor-
tation employee was working on a highway project when
the vehicle she was driving was hit from behind. She expe-
rienced neck pain immediately after the collision but had
no focal neurologic problems. Since the collision, she has
had some difficulty with neck motions and is experiencing
increased pain on the job. Her duties include driving a
pickup truck loaded with barricades, setting up barricades
and cones, and working as a flagperson. She was referred to
you from her nurse case manager with a diagnosis of
2.1 Educational Activity: To differentiate the mechanisms
of action and side effects of commonly prescribed
“muscle relaxants” to consider in treating this work-
er’s neck pain.
prescribed for the treatment of acute musculoskeletal pain.
The term “muscle relaxant” is a misnomer, because most
medications in this class have little or no direct action on the
contractile mechanisms of striated skeletal muscle. Because
many of these medications were initially used as treatment for
nonspecific back pain typically labeled as a strain, sprain, or
mechanical back pain, these drugs were considered muscle
relaxants. It is unclear whether these medications actually
decrease painful muscle spasm or if they exert other effects.
This finding is in contrast to agents used to decrease spasticity
associated with upper motoneuron lesions. Agents used in the
treatment of both neurogenic spasticity and local muscle
“spasm,” such include medications as tizanidine (Zanaflex),
baclofen (Lioresal), and diazepam (Valium).
agents, which are generally classified as muscle relaxants, are
listed in table 1.
These medications have various primary sites of action, and
consequently they differ in their drug actions and side effects.
However, all can cause significant drowsiness. The drug man-
ufacturers warn patients that activities such as driving or op-
erating machinery may be impaired while they are taking these
medications. This is an important consideration in the case of
the injured Department of Transportation worker, who must be
able to drive and/or function on the job in heavy, high-speed
traffic. Also, these drugs are hepatically metabolized and re-
nally excreted and must be used cautiously in patients with
liver or kidney disease.
Three commonly prescribed agents used as SMRs include
metaxalone, cyclobenzaprine, and carisoprodol. Each SMR has
different mechanisms of action and side-effect profiles, al-
though older studies have not shown any particular SMR to
have superior efficacy. Medications that are approved for treat-
ment of spasticity and are sometimes used to treat musculo-
skeletal pain include baclofen and tizanidine.
Metaxalone was initially introduced in 1962. Its exact mech-
anism of action is unknown; it is thought to act by depressing
polysynaptic spinal reflexes. Studies
have shown a low rate of
side effects with no reports of sedation. Double-blind placebo
from the 1960s and 1970s showed positive effects in
reducing back pain with no reports in the literature of danger-
ous side effects or safety concerns.
Cyclobenzaprine is structurally similar to tricyclic antide-
pressants (TCAs) and was first studied as an antidepressant
with regard to efficacy and safety.
The exact mechanism of
action is unknown, but it is presumed to work at the level of the
brainstem or higher with a generalized sedative effect.
have repeatedly shown its superiority over placebo
and effi-
cacy at least comparable to diazepam.
It is also more effective
From the Department of Physical Medicine and Rehabilitation, University of
Colorado at Denver and Health Sciences Center, Denver, CO (Sullivan); Department
of Rehabilitation Medicine, Weill Cornell Medical Center, New York–Presbyterian
Hospital, New York, NY (Panagos); Department of Physical Medicine and Rehabil-
itation, University of Medicine and Dentistry of New Jersey: New Jersey Medical
School, Newark, NJ (Foye); St. John’s Macomb Hospital, Warren, MI (Sable);
Department of Rehabilitation Medicine, University of Miami, Miller School of
Medicine, Miami, FL (Irwin); and Total Spine Specialists, Department of Physical
Medicine and Rehabilitation, Carolinas Medical Center, Charlotte, NC (Zuhosky).
No commercial party having a direct financial interest in the results of the research
supporting this article has or will confer a benefit upon the author(s) or upon any
organization with which the author(s) is/are associated.
Correspondence to William J. Sullivan, MD, PO Box 6508, Mailstop F-493,
Aurora, CO 80045, e-mail: Reprints are not available
from the author.
Arch Phys Med Rehabil Vol 88, Suppl 1, March 2007
when used in combination with nonsteroidal anti-inflammatory
drugs (NSAIDs) than are NSAIDs alone.
Its chemical simi
larity to TCAs explains its main side effects of sedation,
lethargy, and other anticholinergic effects. There are case re-
ports of adverse reaction of cyclobenzaprine in combination
with alcohol, tramadol, droperidol, and other multiple drug
Carisoprodol has been in use for decades. Although its exact
mechanism is not clear, it may be related to its sedative effects.
Some studies
suggest blockage of interneuronal activity in the
descending reticular formation and spinal cord. Although car-
isoprodol has been shown to be more effective than placebo,
comparison with other SMRs has not shown any reproducible
differences. More importantly, there are serious safety con-
cerns related to its active metabolite, meprobamate, which is a
schedule IV controlled substance. There are multiple reports
of abuse and cases of impaired driving associated with cariso-
prodol. Interestingly, a questionnaire probing prescribing prac-
tices showed that a low percentage of physicians recognized
the abuse potential and had an understanding of the active
metabolite, despite this being a heavily prescribed drug.
Baclofen is a chemical analog of
-aminobutyric acid that
acts by inhibiting synaptic transmission in the spinal cord.
It is
mainly used in the treatment of neurogenic spasticity with
efficacy similar to diazepam, dantrolene, and tizanidine. It
generally causes less sedation but may lead to increased weak-
ness. Baclofen is not generally used as therapy for acute
paravertebral muscle spasm.
Tizanidine is approved for the treatment of spasticity and is
also used to treat pain and “spasm” from musculoskeletal
conditions. It is an agonist at
-adrenergic receptor sites and
presumably reduces spasticity by increased presynaptic inhibi-
tion of motoneurons.
Several studies
have shown its efficacy
for patients with musculoskeletal back pain with side effects
similar to those of other SMRs and drowsiness as the primary
reason for discontinuing the medication. There is a case report
of hypotension when used in combination with an antihyper-
tensive medication, possibly due to its chemical similarity to
In the case of the highway worker with presumed “muscle
spasm” and pain, the choice of SMR for pain relief is impor-
tant. Side effects and abuse potential should be considered
before prescribing this class of medication. Shorter duration of
treatment is generally recommended to limit potential of side
effects and/or abuse.
2.2 Educational Activity: To discuss the use of NSAIDs in
the treatment of neck pain in this highway worker.
NSAIDs are commonly prescribed medications. Since 1991,
7 new NSAIDs have entered the U.S. market. These are listed
in table 2.
Drug manufacturers are required to show analgesic efficacy
for each of the agents. The models most commonly used to
obtain approval from the U.S. Food and Drug Administration
(FDA) are dental pain, postsurgical pain, dysmenorrheal, and
postpartum cramps. Although some of these agents have FDA
approval for the treatment of rheumatoid arthritis and osteoar-
thritis, some are also approved for the treatment of acute pain.
Note that several of these medications have been pulled from
the market because of the postmarketing identification of side
effects. Bromfenac was withdrawn because of liver toxicity.
Rofecoxib and valdecoxib were withdrawn because of cardio-
vascular events. The FDA also recommended stronger warn-
ings for all NSAIDs because of gastrointestinal (GI) toxicity
and increased risk of cardiovascular events. This recommen-
dation included conventional NSAIDs, because little informa-
tion existed regarding their cardiovascular risks.
Although there is no evidence to suggest superior efficacy of
one NSAID over another, individual patients may respond
differently to different medications. Conventional NSAIDs act
by inhibiting cyclooxygenase (COX)–2 and the pathologic
responses to pain and inflammation. In the GI tract, they also
inhibit COX-1 activity, decrease prostaglandins, and increase
the risk of GI side effects such as life-threatening bleeding.
Conventional NSAIDs show dose-dependent side effects,
which may limit their use in elderly people or other patients at
high risk. Additional side effects include renal dysfunction and
platelet inhibition. The COX-2–specific agents (celecoxib)
have a decreased incidence of GI toxicity,
but increased costs
and cardiovascular risks may limit their utility in the elderly
and in those with cardiovascular risk factors. COX-2–selective
agents (etodolac, meloxicam) have a decreased risk of clini-
Table 1: Antispasmotic Medications
Category Medication (Product) Manufacturer
Antihistamines Orphenadrine (Norflex) 3M
Central nervous system
Chlorzoxazone (Parafon, Forte
DSC; Paraflex) Ortho-McNeil
Metaxalone (Skelaxin) King
Methacarbamol (Robaxin) Schwarz
Carisoprodol (Soma) Wallace
Central alpha
Tizanidine (Zanaflex) Elan
Tricyclic antidepressant
Cyclobenzaprine (Flexeril) McNeil
-aminobutyric acid agonists Diazepam (Valium) Roche
Baclofen (Lioresal) Novartis
Other benzodiazepines
Table 2: Recently Approved NSAIDs
Medication (trade name) Manufacturer Year FDA Approved
Ketorolac (Toradol) Syntex 1991
Diclofenac potassium (Cataflam) Novartis 1993
Bromfenac (Duract) Wyeth-Ayerst 1997 (withdrawn 1998)
Celecoxib (Celebrex) Searle 1998
Refecoxib (Vioxx) Merck 1999 (withdrawn 2004)
Meloxicam (Mobic) Boehringer Ingleheim/Abbott 2000
Valdecoxib (Bextra) Searle 2001 (withdrawn 2005)
NOTE. Data from Ridgway.
Arch Phys Med Rehabil Vol 88, Suppl 1, March 2007
cally significant GI side effects compared with other
Etodolac has increased COX-2 selectivity com
pared with celecoxib and meloxicam, but the cardiovascular
risks are unknown. Whether a patient is on a COX-2–selective
or –specific agent, those agents’ GI protectivity may be com-
promised by concomitant use of even low-dose aspirin, and
renal side effects are not decreased.
A medication recently approved by the FDA for the treat-
ment of osteoarthritis is flavocoxid (Limbrel). This product is a
blend of natural ingredients from phytochemical food source
materials. It is presumed to have action on COX and lipoxy-
genase pathways, limiting prostaglandins and leukotrienes. It is
not a COX-2–specific or –selective agent, and its ingredients
are generally regarded as safe according to the FDA. To our
knowledge, there is no literature available at the time of this
writing to suggest efficacy in the treatment of acute musculo-
skeletal pain.
2.3 Educational Activity: To outline a treatment algo-
rithm for the medication management of acute pain in
a 40-year-old home improvement warehouse store
worker who fell off a ladder, injuring his foot and
Physicians most often recommend or prescribe oral medica-
tions for the treatment of acute musculoskeletal pain. Acute
pain generally does not require long-term use of analgesics.
Much of the literature on oral analgesics defines the efficacy of
a specific medication as the proportion of patients who need to
take that particular drug to experience a least a 50% reduction
in pain when compared with placebo. The number needed to
treat (NNT) is a concept that refers to the number of patients
who have to use the treatment for 1 patient to have a benefit. A
lower NNT is better. Other measures of pain relief include a
visual analog scale, with a meaningful analgesia effect of
13mm on a 100-mm scale.
Acetaminophen is a unique medication without a clearly
defined mechanism of action related to analgesia. It has little or
no anti-inflammatory effects. It also has an excellent safety
profile with the exception of liver toxicity at doses exceeding
4000mg daily. An increased GI ulceration risk is not supported
by the current literature. Direct comparison studies between
acetaminophen (1000-mg dose) and NSAIDs show equivalent
analgesia in some settings (orthopedic surgery, tension head-
ache) and NSAID superiority in others (dental and menstrual
Acetaminophen remains a good initial choice for most
mild to moderate acute pain, with equivalent analgesia to
aspirin but a better safety profile.
NSAIDs remain excellent analgesics for the treatment of
acute pain. As noted above, some study models have shown
NSAIDs’ superiority to acetaminophen and equality to narcot-
ics for certain types of pain. Whether this means they are
superior for acute pain treatment in all people, such as the
patient discussed, has yet to be proven. It is often the dose-
dependent side effects that limit their usefulness. Epidemio-
logic studies support the use of ibuprofen at 400mg per dose
when first choosing NSAIDs.
At 800 to 1200mg a day,
ibuprofen has an excellent safety profile that is not significantly
different from placebo. Higher doses are used for anti-inflam-
matory effects and may provide better analgesia, but they are
associated with increased risk of side effects.
blockers, proton pump inhibitors, and misoprostol have been
shown to reduce the risk of duodenal ulcers with daily NSAID
use, but only misoprostol has been shown to reduce the risk of
GI perforation and bleeding.
However, because the NNT is
relatively high (264 patients), it is likely that misoprostol
would only be necessary in high-risk patients.
A meta-anal
ysis of the COX-2 inhibitor celecoxib showed fair to good
efficacy for postsurgical pain but overall inconsistent evidence
to warrant its routine use in those without a history of GI
Opioids are potent and appropriate analgesics for acute mod-
erate to severe pain, although their use in chronic nonmalignant
pain conditions does not have universal consensus. There is no
substantial evidence to support the claim that any particular
opioid has greater efficacy or fewer side effects than equipotent
doses of morphine. The usual treatment of acute pain is with
codeine, propoxyphene, hydrocodone, and oxycodone. Studies
have indicated that combination therapy with acetaminophen or
ibuprofen is highly effective for treatment of acute pain.
Codeine is a prodrug that depends on cytochrome P450 me-
tabolism to convert to morphine for its analgesic effect. Up to
10% of the white population lacks this enzyme, and this may
explain its poor efficacy in meta-analyses addressing acute
postsurgical and dental pain. Propoxyphene provides little ad-
ditional analgesia to acetaminophen alone and is associated
with significant adverse side effects.
For this reason, it cannot
be recommended for routine use for the treatment of acute pain
such as for the patient discussed.
Tramadol (Ultram) is a synthetic analog of codeine. It is a
central analgesic with a low affinity for opioid receptors; how-
ever, its primary metabolite shows a higher affinity for opioid
receptors than the parent drug. Moreover, the analgesic action
of tramadol is only partially inhibited by the opioid antagonist
naloxone, which suggests the existence of another mechanism
of action. This hypothesis was confirmed by the discovery of
monoaminergic activity that inhibits norepinephrine and sero-
tonin reuptake, contributing to the analgesic action. Tramadol
should not be administered to patients receiving monoamine
oxidase inhibitors, and cotreatment with TCAs and selective
serotonin reuptake inhibitors should be undertaken with cau-
tion to avoid serotonin syndrome and increased risk of seizure.
Tramadol has pharmacologic properties that may make it less
likely to lead to dependence. It may be of value in treating pain
conditions where treatment with stronger opioids is not re-
quired. Others
report side effects and a lack of efficacy, both
of which limit its usefulness. Additional preparations are
325mg of acetaminophen with 37.5mg of tramadol (Ultracet)
and an extended-release preparation (Ultram ER).
Options for the treatment of acute ankle pain after a fall off
a ladder thus can be summarized as shown in table 3.
2.4 Educational Activity: To identify the rationale for the
use of topical analgesics in the treatment of lateral
epicondylitis in a 50-year-old secretary.
Alternative delivery systems such as topical preparations
have been developed to try to minimize the adverse effects of
Table 3: Treatment Options for Acute Ankle Pain
Treatment Comment
Acetaminophen 1000mg up to 4 times daily
Acetaminophen plus
Ibuprofen 400mg every 4–6h
Opioid or tramadol with acetaminophen
and/or ibuprofen
Prescription NSAID For anti-inflammatory effects as needed
GI protectant As needed for higher-risk patients
COX-2 NSAID Reserved for elderly or high-risk
Arch Phys Med Rehabil Vol 88, Suppl 1, March 2007
NSAIDs. When NSAIDs are applied topically, there is a high
concentration in the dermis and muscle levels at least equiva-
lent to systemic administration. There is penetration into syno-
vial fluid, but it is unclear if this is facilitated by systemic
circulation. Several studies
have addressed the efficacy of
topical analgesics, including a study on musculoskeletal and
soft-tissue injuries. Each study reported efficacy of topical
NSAIDs, whether it was by gel, spray, or patch. Most drug
reactions were local cutaneous reactions. GI effects were less
common but were found to be more likely to occur in those
who had GI side effects from oral NSAIDs.
Topical opioid administration has recently been used for the
local treatment of painful ulcers and skin lesions. Factors
determining bioavailability after application and the potential
for cutaneous side effects associated with histamine release
need to be evaluated.
To our knowledge, there are no studies
addressing the use of topical opioids for acute musculoskeletal
pain. Delivery systems that minimize systemic uptake would
also be beneficial to minimize central nervous system side
Capsaicin—a natural constituent in red chili peppers—may
induce analgesia via desensitization from substance P and
calcitonin gene–related peptide release. Capsaicin has been
found to activate a family of thermosensitive vanilloid recep-
tors. Several studies have reported benefit in postherpetic neu-
ralgia, postmastectomy pain, trigeminal neuralgia, cluster
headache, osteoarthritis, and other conditions. Whereas pain
relief is widely observed, the degree is often modest, and
capsaicin is usually reserved for use as an adjunct treatment.
Further, side effects, such as burning pain in the initial treat-
ment period, are often difficult for patients to tolerate; such
pain has been reported in clinical studies as a common reason
for patient drop-out.
Compliance may also be an issue be
cause of the delay between onset of treatment and observation
of therapeutic benefit. For acute musculoskeletal pain, capsa-
icin likely is not a good treatment option.
Topical formulations of local anesthetics such as the 5%
lidocaine patch (Lidoderm) may be an effective alternative to
systemic treatment, but most studies have focused on chronic
pain conditions. Studies
on postherpetic neuralgia showed
efficacy for treatment of pain with no systemic side effects.
Although the use of the 5% lidocaine patch in professional
athletes with soft-tissue pain has been reported,
there is a
paucity of published evidence regarding its use in the treatment
of acute musculoskeletal pain.
Multiple other classes of medication have been developed,
including topical doxepin, glutamate receptor antagonists,
-adrenergic agonists, adenosine, cannabinoids, neostigmine
(cholinesterase inhibitor), and gabapentin. These have been
studied in animal models and various chronic pain models
have not gained acceptance in the treatment of acute pain.
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4. Borenstein DG, Lacks S, Wiesel SW. Cyclobenzaprine and
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Arch Phys Med Rehabil Vol 88, Suppl 1, March 2007
    • "The exact mechanism of action is unknown, but it is presumed to work at the brainstem level of the central nervous system rather than the spinal cord level [5, 6]. Its chemical similarity to TCAs explains its anticholinergic activity and main adverse effects567. Tolerability of cyclobenzaprine hydrochloride 5 mg and 10 mg is similar, but the 5 mg dose is associated with lower incidence of somnolence (29% versus 38%) and dry mouth (21% versus 32%). "
    [Show abstract] [Hide abstract] ABSTRACT: The purpose of this study was to investigate cyclobenzaprine pharmacokinetics and to evaluate bioequivalence between two different tablet formulations containing the drug. An open, randomized, crossover, single-dose, two-period, and two-sequence design was employed. Tablets were administered to 23 healthy subjects after an overnight fasting and blood samples were collected up to 240 hours after drug administration. Plasma cyclobenzaprine was quantified by means of an LC-MS/MS method. Pharmacokinetic parameters related to absorption, distribution, and elimination were calculated. Cyclobenzaprine plasma profiles for the reference and test products were similar, as well as absorption pharmacokinetic parameters AUC (reference: 199.4 ng ∗ h/mL; test: 201.6 ng ∗ h/mL), Cmax (reference: 7.0 ng/mL; test: 7.2 ng/mL), and T max (reference: 4.5 h; test: 4.6 h). Bioequivalence was evaluated by means of 90% confidence intervals for the ratio of AUC (93%-111%) and C max (93%-112%) values for test and reference products, which were within the 80%-125% interval proposed by FDA. Cyclobenzaprine pharmacokinetics can be described by a multicompartment open model with an average rapid elimination half-life (t (1/2)β ) of 3.1 hours and an average terminal elimination half-life (t (1/2)γ ) of 31.9 hours.
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  • [Show abstract] [Hide abstract] ABSTRACT: This article provides a review for current practice. Strict guidelines are not available on some topics, and they may never be drafted because pain is such a unique individual experience. It is recommended to coordinate care with other medical specialties when patients present with organ dysfunctions or are at the extremes of age. More data are required in the field of pain management, particularly with regard to renal and hepatic dysfunction. In turn, these data serve as a foundation for physicians making practice decisions based on current evidence. Until this is achieved, clinicians must rely on anecdotal evidence and the experiences of others to treat a complex issue: pain.
    Article · Aug 2008
  • [Show abstract] [Hide abstract] ABSTRACT: Topical formulations of non-steroidal anti-inflammatory drugs (NSAIDs), in particular diclofenac (DI), have become popular for treating various acute and chronic painful inflammatory conditions. To perform a literature review of (1) the use of topical NSAIDs; (2) the pharmaceutical, pharmacokinetic and pharmacodynamic properties of a medicated plaster (patch) containing diclofenac epolamine (DI-EP, Flector Tissugel, Flector patch) compared with other formulations of topical NSAIDs; and (3) evaluation of the clinical findings from studies with this novel DI-EP patch. (1) Pharmacokinetic studies involved determination of DI from DI-EP and separately epolamine (EP) and the epoxide metabolite (N-oxide-EP) in laboratory animals and humans; the latter being the major metabolite in humans. About 2% of DI is absorbed by the skin in humans and is excreted in the urine. Maximum plasma concentrations of 17.4 ng/mL DI are reached at 5.4 hours (approximate steady state conditions); the plasma elimination half-time (t(1/2)) being 26.4 hours. Low systemic levels of DI and EP are produced from DI-EP. Pronounced accumulation of DI occurs in the muscle layers and in synovial fluids of arthritic patients; (2) No significant toxicity occurs from EP nor N-oxide-EP, while that of oral DI-EP was similar to that from DI; and (3) In acute musculoskeletal conditions (sprains, tendonitis and sports injuries) and osteoarthritis DI-EP patches control pain and signs of joint or physical injury compared with placebo controls by 3-5 days with almost complete pain relief at 14 days. DI-EP was shown to have equivalent therapeutic effect to another DI diethylammonium gel formulation (Voltaren Emulgel). There were no reports of serious adverse events in the gastro-intestinal (GI) tract, kidneys or liver from DI-EP. Mild GI symptoms and skin reactions occur in 2 and 10% of patients, respectively. The patch delivery of DI in DI-EP affords controlled delivery of the active drug in contrast to that from application of gels or ointments of NSAIDs.
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