Side Effects of Pain Medications (Part 2)
By Larry C. Driver, MD
(Reprinted with permission from the Chronic Pain Report,
Volume I, Issue 4)
The first installment of this article dealt with the side
effects of opioids such as codeine, hydrocodone, morphine,
oxycodone, hydromorphone, fentanyl, and meperidine, among
others. In many patients, opioids provide the foundation of
a chronic pain medication regimen; however, that foundation
must sometimes be reinforced. This is done by the addition
of adjuvant medications, which serve to enhance analgesic
activity by bolstering the opioid effect, or by providing
another effect that is complementary to the opioid.
Commonly used adjuvants include nonsteroidal antiinflammatory
drugs (NSAIDs), tricyclic antidepressants (TCAs), and anti-epileptic
drugs (AEDs). These classes of medications have side effects
common to most members of the group, and individual drugs
may have side effects unique to the specific agent. An overview
of the general side effects of commonly used adjuvant medications
follows.
NSAIDs
These aspirin-like medications are commonly used as a primary
or adjuvant approach to treat mild-to-moderate pain that includes
an inflammatory component, including various chronic musculoskeletal
disorders such as rheumatoid arthritis, osteoarthritis, gout,
fibromyalgia, and other muscle or joint inflammation. Though
a diverse group of chemicals, these drugs share common mechanisms
of action and side effects.
NSAIDs work by inhibiting one or both subtypes of the enzyme
cyclooxygenase (COX-1 or COX-2) whose chemical pathways are
integral to various systemic protective mechanisms as well
as the production of inflammation and pain mediated by prostaglandins.The
traditional NSAIDs (the most commonly prescribed are ibuprofen,
indomethacin, and naproxen) inhibit both enzyme pathways.
The increasingly popular “COX-2 inhibitors” selectively impede
inflammation and pain while leaving some of the protective
mechanisms intact and hence may have a “safer” side effect
profile. These include celecoxib, rofecoxib, and the recently
approved valdecoxib. Other secondgeneration COX-2 agents are
on the horizon as well.
Side effects of NSAIDs are variable and widespread throughout
many organ systems and a complete review is beyond the scope
of this article. However, you can find complete information
in publications such as The PDR Pocket Guide to Prescription
Drugs and you can consult with your physician or pharmacist.
The predominant sequelae of frequent concern are in gastrointestinal
(GI), renal, cardiovascular, and blood-clotting effects, and
asthma patients should be aware of potential problems as well.
GI effects are numerous, ranging from mild nausea
or indigestion to frank gastritis with bleeding, or ulceration
with hemorrhage or perforation.To counter these potential
problems, anti-acid medications are often prescribed along
with the NSAIDs. The COX-2 agents appear to offer a significant
advantage in their GI safety profile, with a lower incidence
of adverse events, especially ulcers and their sequelae.
Renal effects may include water retention and edema,
with subsequent fluid volume and blood chemistry disturbances.
Renal insufficiency or even failure may occur, but is fortunately
usually temporary and resolves with stopping the NSAID.
Cardiovascular problems may include hypertension,
edema, or even increased risk for heart attack. A recent article
indicting rofecoxib as a cause of myocardial infarction has
generated some discussion, though further evidence is needed
to reach a conclusion.
Blood-clotting effects related to NSAIDs with increased
risk of excessive bleeding are due to inhibition of platelet
aggregation and clot formation. This may be especially serious
for patients also taking anticoagulation drugs. The COX-2
agents do not impair platelet function, and hence coagulation,
and appear to be relatively safe in this area.
Asthma and other respiratory disorders may be aggravated
by NSAIDs and patients with those problems should be careful
in using these medications.
Though not a member of the NSAID group, acetaminophen deserves
a comment regarding potential toxicity. Widely available in
numerous compounds, acetaminophen is used as a weak analgesic
or co-analgesic. It is available alone, but is commonly mixed
with other agents such as opioids. Potential hepatic toxicity
and even liver failure are of concern, especially with daily
doses above 4 grams total. This fact limits the recommended
daily intake of medications containing acetaminophen, especially
in patients with existing liver disease or with excessive
alcohol use.
TCAs
Medications in this group are frequently prescribed to treat
burning or tingling neuropathic (nerve) pain. Commonly used
drugs include amitriptylene, nortriptilene, and desipramine.
Bothersome side effects may include sedation, fatigue, dry
mouth, constipation, urinary retention, or blurred vision.
Acute glaucoma is possible in at-risk patients. Weight gain
is a common side effect of TCAs.
Cardiovascular side effects may be potentially serious, especially
in patients with existing disease or taking high doses of
TCAs. These include hypotension or hypertension, tachycardia,
arrhythmias, or even congestive heart failure.
Liver enzymes are often elevated by TCAs, and hepatitis is
a rare but potentially serious possible problem. Allergic
skin rashes are occasionally seen in patients taking TCAs.
Because withdrawal symptoms can be problematic, TCAs should
be tapered gradually rather than abruptly discontinued.
AEDs
These medications are frequently prescribed to treat shooting,
stabbing, neuropathic pain, various chronic headaches, and
other types of pain. The traditional agents in this category
have been largely replaced by newer drugs, especially gabapentin,
and the newer drugs show promise for the future. Some of the
AEDs used for treating pain are: carbamazepine, oxcarbazepine,
valproic acid, gabapentin, lamotrigine, and clonazepam.
Carbamazepine is used to treat trigeminal neuralgia (Tic
douloureux) and its side effects include GI disturbances,
drowsiness, unsteadiness, double vision, and rare severe anemias.
Oxcarbazepine is a chemical analog of carbamazepine, which
should be as effective, but with lesser side effects.
Valproic acid may be used in migraine headache treatment.
Among the known side effects are GI disturbances, tremor,
hair loss, weight gain, bruising and bleeding. Elevated liver
enzymes are common, and hepatitis is rare but potentially
serious.
Gabapentin is known to be helpful in painful diabetic neuropathy,
postherpetic neuralgia, and various cancerrelated neuropathic
conditions. Bothersome side effects include drowsiness, dizziness,
unsteadiness, fatigue, and nausea.
Lamotrigine is sometimes used in trigeminal neuralgia, and
may be useful in other situations as well. Drowsiness, dizziness,
and rashes are not uncommon; severe skin reactions are rare
but serious. Clonazepam is sometimes used to treat painful
muscle spasms. Side effects include sedation and lethargy,
or a noticeable personality change.
Summary
This review of medications frequently used as adjuvant pain
therapy and their common side effects is by no means exhaustive.
Discovery of new drugs and new uses for old drugs is an ongoing
process. Hopefully the desired beneficial effects of these
medications and any pain management regimen greatly outweigh
their side effects.
GLOSSARY
Adjuvant Medication: medications used to enhance the
pain relieving effects of opioids, treat other symptoms that
exacerbate pain, and provide independent pain relief for specific
types of pain.
Anticoagulation: medications used to thin the blood
Arrhythmia: abnormal heart rhythm
Edema: swelling
Hepatic Toxicity: negatively affecting the liver,
may be reversible but can progress to liver failure.
Hypertension: high blood pressure
Hypotension: low blood pressure
Myocardial Infarction: heart attack
Neuropathic/Neuropathy: pain which results when some
part of the nervous system is damaged.
Postherpetic Neuralgia: pain persisting 6 months after
an outbreak of shingles, which involves actual permanent damage
to the nervous system
Psychostimulant: medications used to prevent the sleepiness
or decreased alertness sometimes seen with opioids. Sequelae:
symptoms which result from a medical condition.
Tachycardia: fast heart rate
Tic douloureaux: disorder of the Trigeminal Nerve
in the face, causing pain and spasm, also known as Trigiminal
Neuralgia.
Larry C. Driver, MD is Associate Professor at The University
of Texas, M. D. Anderson Cancer Center, Houston, Texas.
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