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Susan
Shatter. Mono Lake II (detail), 1990.
Watercolor on paper, 25-1/4" X 53-1/2".
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The Efficacy of Nonsteroidal Anti-inflammatory Drugs for Acute Pain
Donald R. Mehlisch, MD, DDS, Joseph Markenson, MD, FACP, FACR,
and Thomas J. Schnitzer, MD, PhD
Introduction
The modern science of drug testing began to mature in the 1960s, when scientific methodology developed the capability to provide demonstrable safety and efficacy data on new drugs, such as those used for the pharmacotherapy of pain. In subsequent decades, standardized models have been developed that constitute a key component of a sophisticated methodology permitting the objective investigation of analgesics.
Various major models of acute pain are now accepted as important areas of investigation for clinical trials. The postoperative pain model is among the most important and has been explored in clinical trials in a wide range of surgeries, such as postorthopedic, postgeneral, and postgynecologic surgery.
The oral surgery model, which focuses on the extraction of impacted third molars, is important because it is associated with several distinct advantages of experimental approach. Major advantages include the following: the patients in whom the evaluation of pain management is studied are young and healthy, and they can be rapidly enrolled; the degree of interpatient variation is less than is characteristic of other pain models; and these patients are generally naive of previous pain experiences.
Dysmenorrhea provides another important model for pain management because this
self-repeating condition is suitable to investigation by means of crossover
design. More than one treatment may be administered to each patient over the
course of several months. Such an experimental strategy addresses interpatient
variations through the study design itself.
Analgesic research methodology has been enhanced since the 1960s through the use of categorical and visual analog scales. These scales are tools that permit the standardization of pain scores, thus a rationalization of the results of analgesic trials. Decades of scientific study have shown that they provide the best indication available for the evaluation of the efficacy of analgesics. One frequently used categorical scale is a four-point measure of pain intensity (0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain) and a five-point measure of relief (0 = no relief, 1 = a little relief, 2 = some relief, 3 = a lot of relief, 4 = complete relief). Visual analogue scales are also used to measure pain. The validity and reliability of both categorical and visual analogue scales have been confirmed in numerous trials, although the visual analogue scale appears to be slightly more sensitive for the measurement of both acute and chronic pain.1
Additional advances in the study of nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat acute pain include methods to approach the definition of differing characteristics that affect the relative efficacy of various analgesics. For example, a variety of variables have been employed to ascertain how the benefits conferred by a drug with a rapid onset, but a short duration of action differentiate from the benefits conferred by another drug with a longer onset, and an extended duration. Results of clinical studies are analyzed so that data are produced that measure, for example, the sum of pain intensity differences (the difference between baseline pain compared to subsequent pain assessments summed over time) and the total pain relief achieved over time. In addition, a measurement of the percentage of patients requiring rescue analgesia in placebo-controlled studies, after one or more hours, has become an important endpoint for clinical analgesic trials. Furthermore, patients’ global assessment of a drug, ie, how they feel about it overall, can be an important measure of the clinical effectiveness of an analgesic. The quantitative measurement of the safety and tolerability of pain medications has also been developed.
Analgesic Properties of NSAIDs —Mechanism of Action
NSAIDs are known to have analgesic and anti-inflammatory effects albeit sometimes at different doses, depending on the particular drug. Initially, the analgesic effect was thought to be peripheral in nature by modulating the response of the nociceptor. More recent data have suggested a dual action, both peripheral and central.2-4
Peripheral Mechanism
With cellular damage, there is release of products of both the cyclooxygenase
and lipoxygenase pathways resulting in prostaglandins and leukotrienes. Prostaglandins
sensitize afference neurons (nociceptors) to noxious stimuli such as chemical,
heat, and mechanical pressure.5,6 Prostaglandins and leukotrienes
probably do not activate the nociceptors directly, but work through activation
of cyclic adenosine monophosphate (cAMP),7,8 and/or activation of
products of polymorphonuclear cells. Inhibition of prostaglandins or leukotrienes
by NSAIDs results in analgesia.
Central Mechanism
Evidence now indicates that NSAIDs are antihyperalgesic through a direct action
on the spinal cord (central mechanism).9 This effect can be dissociated
from the peripheral action of NSAIDs and may be dissociated from their anti-inflammatory
mechanism.
As a painful stimulus activates the peripheral
nociceptor, stimuli are sent along the afferent C fibers into the dorsal horn
where they synapse with second-order neurons for transmission to higher centers.
One of these mechanisms, known as windup,
allows for amplification of an incoming signal in both intensity and duration
to create a state of hyperalgesia. With repetitive C-fiber nociceptor stimulation
from the periphery, excitatory amino acids (neurotransmitters) such as glutamate
and aspartate, as well as several peptides (including substance P) are thought
to increase. These cause activation of NMDA (N-methyl D-aspartate) receptors
of the postsynaptic second neuron in the dorsal horn. Activation of these receptors
is not thought to function to transmit nociceptive information evoked by a peripheral
stimulus, but rather to facilitate the processing of such incoming signals to
create a state of hyperalgesia (windup in the dorsal horn). Experiments utilizing
intrathecal NSAIDs in the rat model,9 as well as antagonists to the
NMDA receptor, suppressed the hyperalgesic component but not the acute pain
behavior of the pain stimulus. In addition, intrathecal injection of several
cyclooxygenase products such as PGE2, PGD2, and Pg also
functioned in this model to induce a hyperalgesic state. NSAIDs are thought
to block activation of the NMDA receptor induced by excitatory amino acids released
by repetitive C-nociceptor firing. This is thought to occur through calcium-induced
release of prostaglandins in the dorsal horn. By blocking this activation in
the experimental model, NSAIDs are thought to be antihyperalgesic. Lastly, NSAIDs
block windup at doses much lower than doses required for systemic effects.
Thus, NSAIDs work in the periphery by decreasing the sensitivity of the nociceptor
to painful stimuli induced by heat, trauma, or inflammation. In the central
nervous system, they are thought to function as antihyperalgesics and block
the increased transmission of repetitive incoming signals to higher centers.
In effect, they modulate perception of pain (which is enhanced through windup
in the dorsal horn) caused by repetitive stimulation from the periphery. Since
they function by modulation of the perception of pain, they may be useful when
given in the preoperative period and may reduce the need for postoperative analgesia.
Efficacy of NSAIDs
A considerable number of NSAIDs with proven efficacy and safety are currently
available for prescription and nonprescription use. Many patients with acute
pain obtain good pain relief with these drugs. Pharmacotherapy may be an important
component of a multimodal or balanced approach to the management of pain.10
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The
"analgesic ladder" developed by the Cancer Pain Relief and Palliative
Care Program of the World Health Organization.
Reproduced by permission of WHO.
Cancer Pain Relief. 2nd ed. Geneva: WHO: 1996.
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"Drug therapy is the mainstay of treatment for the management of acute pain,"
according to the American Pain Society. Three facts relative to the efficacy
of non-opioid analgesics for acute pain management need mention: (1) NSAIDs
possess proven efficacy for mild to moderate acute pain. (2) The potency of
some NSAIDs is greater than that of others. Several of the newer NSAIDs have
demonstrated potency comparable to or greater than that of opioid agents and
are indicated for postoperative pain management.11 (3) Since individual
patient response varies considerably,11-13 therapeutic failure with
one agent does not preclude success with another. Analgesics may require adjustment
until the patient reports adequate pain relief. Such an adjustment can be guided
by the "analgesic ladder" promulgated by the Cancer Pain Relief and Palliative
Care Program of the World Health Organization (Figure).14
Potency of Nonnarcotic Analgesics
Nonnarcotic analgesics have been differentiated into two broad levels of potency:
(1) low or moderate potency and (2) potency comparable to that of opioids.15
NSAIDs of Moderate Potency
A considerable number of nonnarcotic analgesics can provide effective pain
relief. However, clinically important differences have been shown among agents
of moderate potency. Therefore, it is useful to differentiate between those
NSAIDs with a half-life of less than 6 hours and those with a half-life of more
than 10 hours.13 As a rule, agents with long half-lives will have
a slower onset of action. The use of a medication with a rapid onset is helpful
to patients with acute conditions.12 Selected individual agents include
the following:
Acetaminophen
is comparable to the potency of aspirin in its analgesic and antipyretic effects.
It has no known antiplatelet and little anti-inflammatory activity. Clinicians
should be aware of the total amount of acetaminophen being taken by a patient
per day.16-18
Etodolac may be used to provide relief for postoperative pain and pain
associated with gouty conditions and traumatic injury.19 Etodolac,
nabumetone, and COX-2 selective agents are associated with less gastric injury
when prescribed at doses commonly used to treat osteoarthritis.20,21
Mefenamic acid is approved for analgesia of moderate pain. It is determined
to possess efficacy for pain of dysmenorrhea.22,23
Naproxen has a half-life of 12 to 14 hours, and twice-a-day dosing may
be employed. Peak plasma levels are attained 2 to 4 hours following administration.24
It provides effective relief in acute traumatic injury and for acute pain associated
with migraine, tension headache, postoperative pain, postpartum pain, pain consequent
to various gynecologic procedures, and the pain of dysmenorrhea.25
Sulindac is specifically indicated for acute painful shoulder (acute
subacromial bursitis/supraspinatus tendinitis).23 The slow accumulation
of sulindac sulfide has led some authorities to conclude that other NSAIDs should
be preferred for the management of acute pain.26
NSAIDs of Efficacy Approximately Equal to That of Opioids
The potency of the following drugs is comparable to that of certain opioids.
Moderate postoperative pain, for example, may be managed using these agents.
These drugs should not be used to treat mild pain. The major NSAIDs of potency
comparable to opioids are diclofenac and ketorolac.
The selection of a specific formulation
of diclofenac is important because only one of the available formulations (sodium
or potassium salts) of diclofenac provides prompt relief (potassium formulation),
a characteristic essential in the management of acute pain. Efficacy has been
demonstrated with postoperative pain including gynecologic, oral, and orthopedic
surgery models, as well as dysmenorrhea.27,28
The overall analgesic effect of 30 mg
of ketorolac is equivalent to that of 6 to 12 mg of morphine,11,23
and efficacy has been demonstrated for postsurgical pain including oral, orthopedic,
gynecologic, and abdominal procedures.29,30
Efficacy for acute musculoskeletal pain has also been shown.23,31
Its antipyretic activity is significant. Anti-inflammatory activity is achieved
only at doses higher than those needed for analgesia.12
Clinical Guidelines
The following recommendations may facilitate clinical decisions relative to
the efficacy of NSAIDs:
· Combinations of NSAIDs with opioids should be favored because synergy
has been demonstrated.12 Administration of more than one NSAID should
be avoided because superior efficacy has not been proven, while risks associated
with NSAID toxicity may be increased.12 NSAIDs are characterized
by dose ceilings; thus, administration of increasingly greater doses provides
no more analgesia than does the maximum effective dose.
· The use of corticosteroids, anticonvulsants, antidepressants, muscle
relaxants, and antispasmodics may increase pain relief. Some patients may benefit
from antidepressants, anxiolytics, and antipsychotics to address anxiety and
psychiatric symptoms that frequently accompany pain.32 For the anxiety
that often accompanies pain, benzodiazepines or hydroxyzine may be prescribed.11
· Placebos should rarely be used to assess the severity or genesis of pain,
except as part of a clinical trial that has received adequate investigational
review board approval. Placebos may correctly be used to supplement a course
of drugs in an attempt to gain added benefit.11
· For patients with such conditions as dysmenorrhea who need management
over long periods of time, failure to achieve adequate pain relief with the
NSAID first recommended may be followed by a trial of an analgesic of the same
or another class. Good management of pain may be achieved with such a "second
choice" agent.12 If two NSAIDs of two different classes have been
tried individually, further attempts to obtain benefit from NSAIDs are unlikely
to succeed.33
· Doses of NSAIDs should be modified over time to maximize benefits and
minimize risks.12
· Elderly patients may obtain great benefit from NSAIDs. Dosing should be
addressed carefully, and reevaluation of the therapy should be performed regularly.12
Conclusions
The investigation of analgesics has grown in sophistication, and clinical studies
have demonstrated the efficacy of NSAIDs in the management of acute pain. The
potency of NSAIDs is founded on a mechanism of action that appears to affect
both peripheral and central activity. A number of nonnarcotic agents provide
effective pain relief for mild to moderate acute pain.
In recent years, progress in the area of pain management has been enhanced
by the development of NSAIDs whose potency is equal to or greater than that
of opioids. Because synergy has been demonstrated, the combinations of NSAIDs
with opioids may demonstrate a number of advantages. The development of highly
selective COX-2 agents, which may offer increased safety margins, is progressing.
References
1. Sunshine A. Methodology of analgesic
clinical trials. Am J Orthoped.
1998;27:S12-S16.
2. McCormack K, Brune K. Dissociation between the antinociceptive and anti-inflammatory
effects of the nonsteroidal anti-inflammatory drugs: a survey of their analgesic
efficacy. Drugs. 1991;41: 533-547.
3. Brune K, Beck WS, Geisslinger G, et al. Aspirin-like drugs may block
pain independently of prostaglandin synthesis inhibition. Experientia.
1991;47:257-261.
4. Bannwarth B, Demotes-Mainard F, Schaeverbeke T, et al. Where are peripheral
analgesics acting? Ann Rheum Dis. 1993;52-1-4.
5. Chahl LA, Iggo A. The effects of bradykinin and prostaglandin E1 on rat
cutaneous afferent nerve activity. Br J Pharmacol. 1977;59:343-347.
6. Birrell GJ, McQueen DS, Iggo A, et al. PGI2-induced activation
and sensitization of articular mechanonociceptors. Neurosci Lett. 1991;124:5-8.
7. Taiwo YO, Levine JD. Further confirmation of the role of adenyl cyclase
and of cAMP-dependent protein kinase in primary afferent hyperalgesia. Neuroscience.
1991;44:131-135.
8. Martin HA. Leukotriene B4 induced decrease in mechanical and thermal
thresholds of C-fiber mechanonociceptors in rat hairy skin. Brain Res.
1990;509:273-279.
9. Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance
P receptor blocked by spinal cyclooxygenase inhibition. Science. 1992;257:1276-1278.
10. Ashburn MA. The role of non-opioid analgesics for the management of
post-operative pain. Cancer Control. 1999;6(suppl):10-13.
11. American Pain Society. Principles of Analgesic Use in the Treatment
of Acute Pain and Cancer Pain. 3rd ed. Glenview, Ill: American Pain Society;
1992.
12. Zuckerman LA, Ferante FM. Nonopioid and opioid analgesics. In: Ashburn
MA, Rice LJ, eds. The Management of Pain. New York, NY: Churchill Livingstone;
1998.
13. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs: differences
and similarities. N Engl J Med. 1991;324:1716-1725.
14. Cancer Pain Relief and Palliative Care: Report of a WHO Expert Committee.
Geneva, Switzerland: World Health Organization: 1990.
15. Bushnell TG, Justins DM. Choosing the right analgesic: a guide to selection.
Drugs. 1993;46:394-408.
16. Mehlisch DR. Review of the comparative analgesic efficacy of salicylates,
acetaminophen, and pyrazolones. Am J Med. 1983;75:47-52.
17. Mehlisch DR, Isaacs W, Brown P, et al. Double-blind, single-dose evaluation
of acetaminophen 500 mg, 1000 mg, 1500 mg, 2000 mg, and placebo in the treatment
of pain following oral or periodontal surgery. Presented at IV World Conference
on Clinical Pharmacology & Therapeutics; 1989. Mannheim-Heidelberg, Germany.
18. Mehlisch DR, Frakes LA. A controlled comparative evaluation of acetaminophen
and aspirin in the treatment of postoperative pain. Clin Ther. 1984;7:89-97.
19. Balfour JA, Buckley MM. Etodolac: a reappraisal of its pharmacology
and therapeutic use in rheumatic diseases and pain states. Drugs. 1991;42:274-299.
20. Simon LS. Nonsteroidal antiinflammatory drugs and their effects: the
importance of COX "selectivity." J Clin Rheumatol. 1996;2:135-140.
21. Laine L, Sloane R, Ferretti M, et al. A randomized double-blind comparison
of placebo, etodolac, and naproxen on gastrointestinal injury and prostaglandin
production. Gastrointest Endosc. 1995;42:428-433.
22. Conroy MC, Randinitis EJ, Turner JL. Pharmacology, pharmacokinetics,
and therapeutic use of meclofenamate sodium. Clin J Pain. 1991;7:S44-S48.
23. Physician’s Desk Reference, 1998. 52nd ed. Montvale, NJ: Medical
Economics Co; 1998.
24. Honig SM. Nonsteroidal anti-inflammatory drugs. In: Tollison CD, ed.
Handbook of Pain Management. 2nd ed. Baltimore, Md: Williams & Wilkins;
1994.
25. Todd PA, Clissold SP. Naproxen: a reappraisal of its pharmacology, and
therapeutic use in rheumatic diseases and pain states. Drugs. 1990;40:91-137.
26. Denson DD, Katz JA. Nonsteroidal anti-inflammatory agents. In: Sinatra
RS, Hord A, Ginsberg B, et al., eds. Acute Pain: Mechanisms & Management.
St. Louis, Mo: Mosby-Year Book; 1992.
27. Mehlisch DR, Brown P. Single-dose therapy with diclofenac potassium,
aspirin, or placebo following dental impaction surgery. Today’s Therapeutic
Trends. 1995;12:15-31.
28. Adair SF, Mehlisch DR, Brandes S, et al. Analgesic efficacy of diclofenac
potassium in dental pain trial. Presented at the American Society for Clinical
Pharmacology and Therapeutics Annual Session, Nashville, Tenn. March 10, 1989.
29. Spindler JS, Mehlisch DR, Brown CR. Intramuscular ketorolac and morphine
in the treatment of moderate to severe pain after major surgery. Pharmacotherapy.
1990;10:51S-58S.
30. Gwirtz KH, Kim HC, Nagy DJ, et al. Intravenous ketorolac and subarachnoid
opioid analgesia in the management of acute postoperative pain. Reg Anesth.
1995;20:395-401.
31. Buckley MM, Brogden RN. Ketorolac: a review of its pharmacodynamic and
pharmacokinetic properties, and therapeutic potential. Drugs. 1990;39:86-109.
32. Rummans TA. Nonopioid agents for treatment of acute and subacute pain.
Mayo Clin Proc 1994;69:481-490.
33. Irving GA, Wallace MS, eds. Pain Management for the Practicing Physician.
New York, NY: Churchill Livingstone; 1997.
Dr Mehlisch is Senior Clinical Advisor and Chairman
of the Analgesic Advisory Committee at SCIREX Corp, Austin, Tex. Dr Markenson
is Professor of Clinical Medicine at the Cornell Medical College, Hospital for
Special Surgery, New York, NY. Dr Schnitzer is Professor and Director of the Office
of Clinical Research and Training at Northwestern University, Chicago, Ill.
No significant relationship exists between the authors and the companies whose products
are referenced in this article. Dr Markenson and Dr Schnitzer are on the speaker’s
bureau for Wyeth-Ayerst who provided an educational grant to support this supplement.
Dr Mehlisch has no significant relationship with Wyeth-Ayerst.
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