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SIDE EFFECTS OF PAIN MEDICATIONS
BY LARRY C. DRIVER, MD

Associate Professor at the University of Texas
M.D. Anderson Cancer Center, Houston, TX

The intended effect of pain medications is obvious, to relieve pain.  However, desired effects are sometimes accompanied by side effects that may be bothersome or even problematic themselves, and may involve various organ systems.  In Part 1 and Part 2, we will review some common side effects of the classes of medications used as primary and adjuvant treatments for chronic pain.  This article will discuss opioid side effects.  We will also address steroids and non-steroidal anti-inflammatory drugs (NSAIDs), medications used to treat neuropathic pain including tricyclic anti-depressants (TCAs) and anti-epileptic drugs (AEDs), skeletal muscle relaxants, and drugs used for anxiety and depression.

Opioid Side Effects

Opioids, often the foundation of a chronic pain medication regimen, share common mechanisms of action, and also common side effect profiles.  Their impact on the central nervous system (CNS), gastro-intestinal (GI) function, and respiration may be clear, with less obvious effects on other systems including cardiovascular, urinary, skin and others.  Side effects may be related to a specific drug or combination of drugs, the total daily opioid dose, to starting a drug or increasing the amount taken, to drug by-products, and to the patient’s age and concurrent medical conditions.

CNS effects may be inhibitory or excitatory, include alterations in consciousness and cognition, and range from mild drowsiness to profound sedation, euphoria to delirium with hallucinations.   Patients may have mild lightheadedness or sickening dizziness.  Excitatory effects include exaggerated sensitivity to pain, muscle twitching or jerking, or seizures, all of which may be related to excessive accumulation of the opioid or its

by-products.  Combining opioids with other substances such as alcohol or benodiazepine medications may aggravate CNS effects.  Older adults may be especially sensitive to both the effects and side effects of opioids and other medications.  Treatment may include decreasing the opioid dose, changing to another opioid, or adding another drug to address specific problems, e.g. a psychostimulant for drowsiness.

GI effects of nausea and constipation are predictable issues.  Acute nausea may complicate recovery following surgery, while chronic nausea may be bothersome or even debilitating.  Patients may avoid taking pain medications because of fear of nausea.  Nausea and vomiting may lead to dehydration which then worsens nausea.  Nausea is due to opioid-induced slowed gastric emptying and decreased gut motility, opioid activity in the brain’s nausea centers, and perhaps increased sensitivity in the inner ear causing vertigo-like symptoms.  Patients often develop tolerance to this problem within a few days, but may need anti-emetics in the meantime, especially when starting a new opioid or increasing dosage.  Metoclopramide is an anti-emetic that enhances gut motility and can be quite useful in these situations.

Nausea may also be caused or aggravated by another GI side effect – constipation.  Opioid-induced constipation is due to impaired bowel motility and diminished intestinal secretions.  Unlike most other side effects, tolerance does not develop over time and constipation remains an ongoing issue.  The best approach to treatment is proactive use of stool softeners and stimulant laxatives.  For refractory constipation, suppositories or enemas may be necessary.

Respiratory depression is a potentially dangerous situation, but fortunately infrequent in the chronic pain patient taking opioids on a long-term basis.  Tolerance to this side effect is generally protective.  However, older patients and those with underlying lung disease should nevertheless be cautious in their use of opioids.

Cardiovascular effects of opioids are usually drug-specific and not problematic for most chronic pain patients.  Depression of the heart and vascular dilation may be due to direct effects of opioids, or medicated by histamine.  Care of choice and dose of the opioid should be exercised.

Urinary retention, urgency, and bladder spasm may be problems, particularly in older patients who usually develop tolerance but may require a change in dose or drug or other intervention.

Itching as a side effect is poorly understood but may be related to histamine.  Thus, typical treatment includes using antihistamines, but novel approaches may be useful.

Loss of body heat may occur due to opioid effects in the brain’s temperature-regulatory centers, impairing the ability to maintain constant body temperature.

Endocrine hormonal effects of opioids on brain centers may result in diminished libido.

Allergy to opioids is uncommon.  People may describe a “bad experience” or side effects of opioids as an allergy, or they may have some histamine type symptoms that are perceived as “allergy.”  Along with reassurance of the patient, careful prescription of opioids can usually proceed.

Careful patient assessment and rational prescribing of appropriate medications can successfully address most opioid side effects.  Dose adjustment or switching to an alternate opioid, or adding another drug to treat the side effect is usually effective.  Proactive consideration of likely side effect along with the pain treatment is the best approach. 

Part 2

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. 

Whereas, in many patients, opioids provide the foundation of a chronic pain medication regimen, that foundation must sometimes be reinforced.  This is done by the addition of adjuvant medications.  These adjuvant medications 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 anti-inflammatory 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.  Following is an overview of the general side effects of commonly used adjuvant medications. 

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. 

They 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 (ibuprofen, indomethacin, and naproxen among those commonly prescribed) 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 second-generation 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.  The reader is referred to a publication such as The PDR Pocket Guide to Prescription Drugs and to 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 coanalgesic.  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.  The list of AEDs useful for treating pain includes carbamazepine, oxcarbazepine, valproic acid, gabapentin, lamotrigine, and clonazepam, among several proving to have benefit in chronic pain conditions.

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 cancer-related 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 evolution. 

Hopefully the desired beneficial effects of these medications and any pain management regimen greatly outweigh the side effects that occur. 

Other useful adjuvant medications include drugs used to treat anxiety and depression, skeletal muscle relaxants, agents to help sleep, and psychostimulants.  Review of these drugs and side effects may be done in a future article. 

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.

Adjuvant Treatments – treatment other than the primary treatment of a condition or disease which compliments the primary treatment.

Anticoagulation - medications used to thin the blood.

Anti-emetics – something, usually a medication, to reduce nausea and/or vomiting.

Arrhythmia - abnormal heart rhythm.

Benzodiazepine – a class of medications most often used to treat anxiety or sleep on a short term basis but occasionally used to treat pain.

Edema - swelling.

Excitatory – increases activity in the central nervous system.

Hepatic Toxicity - negatively affecting the liver; may be reversible but can progress to liver failure.

Hypertension – high blood pressure.

Hypotension - low blood pressure.

Inhibitory – decreases activity in the central nervous system.

Libido – sex drive.

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 involve actual permanent damage to the nervous system.

Psychostimulant - medications used to prevent the sleepiness or decreased alertness sometimes seen with opioids.

Refractory constipation – constipation not responsive to standard treatment.

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 trigeminal neuralgia.        

Tricyclic anti-depressants – older class of antidepressants most often used in low doses to control pain from neuropathic or myofascial conditions by increasing levels of seratonin and norepinephrine.

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