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