Key points
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Analgesics, including opioids, steroidal and nonsteroidal anti-inflammatory drugs, aspirin, acetaminophen, antiepileptics, and serotonin-norepinephrine reuptake inhibitors are medications commonly used to treat many forms of pain.
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All of these medications may have significant adverse side effects.
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Adverse effects may occasionally be inseparable from desired effects. Side effects are often dose dependent and time dependent.
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It is critical that the prescribing practitioner and the dispensing pharmacist provide a thorough, understandable review of the potential side effects to all patients before these drugs are administered.
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Proper monitoring and follow-up during therapy are crucial.
Introduction
Pain is classified by duration as either acute or chronic, with chronic pain usually lasting longer than 3 months. Chronic pain typically is associated with longer-term medication exposure, thus increasing the likelihood of adverse events. Complex regimens with multiple medications, particularly when there are several prescribers, often result in a lack of continuity of care and proper monitoring; this can also be associated with inadequate patient education. Many drugs have names that sound alike or look alike, and drug names are sometimes miswritten, misheard, and misread. All of these factors contribute to the likelihood of adverse drug events (ADEs). Counseling with patient communication is an important way to avoid medication errors, and to help patients understand the intended effects as well as the side effects of their drugs. Proper patient counseling by both physicians and pharmacists will help prevent ADEs. Studies have shown that appropriate medication counseling for patients can save money, unnecessary hospitalization, and possibly prevent harm or even death in patients. Patients’ understanding of their medication regimen assists in the identification of drug-related problems. Early identification of drug-related problems has also been shown to be associated with a lower rate of preventable ADEs.
Introduction
Pain is classified by duration as either acute or chronic, with chronic pain usually lasting longer than 3 months. Chronic pain typically is associated with longer-term medication exposure, thus increasing the likelihood of adverse events. Complex regimens with multiple medications, particularly when there are several prescribers, often result in a lack of continuity of care and proper monitoring; this can also be associated with inadequate patient education. Many drugs have names that sound alike or look alike, and drug names are sometimes miswritten, misheard, and misread. All of these factors contribute to the likelihood of adverse drug events (ADEs). Counseling with patient communication is an important way to avoid medication errors, and to help patients understand the intended effects as well as the side effects of their drugs. Proper patient counseling by both physicians and pharmacists will help prevent ADEs. Studies have shown that appropriate medication counseling for patients can save money, unnecessary hospitalization, and possibly prevent harm or even death in patients. Patients’ understanding of their medication regimen assists in the identification of drug-related problems. Early identification of drug-related problems has also been shown to be associated with a lower rate of preventable ADEs.
Gender considerations
Women and men feel pain differently and respond to treatment differently. Women report more severe and longer-lasting pain than men, and there are gender differences in pharmacokinetics. Notable reasons for these differences include the lower body weight in women. Women also have a higher percentage of body fat, which can also affect the volume of distribution. Adults are often given the same dose of drug regardless of body weight, so women tend to have higher serum concentrations of drugs. Other gender differences in bioavailability, metabolism, and renal elimination may also be involved in medication effects. Drug metabolism and distribution differ between women and men. The menstrual cycle can affect drug blood levels as a result of fluctuating body fluid mass, which can result in differing renal drug clearance in women caused by changes in glomerular filtration. These factors need to be taken into consideration during patient counseling.
Treating chronic pain can be seen as layered with available first-line, second-line, and third-line pharmacologic treatments. Historically many drugs used to treat chronic pain are considered adjuvant analgesics. These medications are, by definition, agents whose primary indication is not analgesia. For example, tricyclic antidepressants and antiepileptic drugs (AEDs) have been the mainstay in the treatment of neuropathic pain. Even today these drugs are still used primarily as pain medications, although neither is approved by the Food and Drug Administration (FDA) for this use. Newer drugs such as the serotonin-norepinephrine reuptake inhibitor duloxetine (Cymbalta) and the AED pregabalin (Lyrica) are approved by the FDA for analgesic use.
Tables 1–7 review the common adverse side effects and the percentages associated with use of the particular drug classes. In general, side effects are fairly class specific.
| Classification | Drugs | Adverse Effects and Relative Risks |
|---|---|---|
| Phenanthrenes | Morphine | Dermatologic: Pruritus (≤80%) Gastrointestinal: Constipation (≥9%), nausea (oral, 7% and >10%; epidural or intrathecal, 15%–70%), vomiting (>10%) Neurologic: Dizziness (6%), headache (>10%), lightheadedness, somnolence (≥9%) Renal: Urinary retention (oral, <5%; epidural/intrathecal, 15%–70%) |
| Codeine | Cardiovascular: Hypotension (1%–10%), tachycardia or bradycardia (1%–10%) Dermatologic (1%–10%): Pruritus (1%–10%), rash (1%–10%), urticaria (1%–10%) Gastrointestinal: Constipation (>10%), nausea (1%–10%), vomiting (1%–10%), anorexia (1%–10%), xerostomia (1%–10%) Neurologic: Drowsiness (>10%), dizziness (1%–10%), lightheadedness (1%–10%), sedated, somnolence Renal: Urinary retention Respiratory: Dyspnea (1%–10%) Ophthalmic: Blurred vision (1%–10%), visual disturbances | |
| Hydromorphone | Dermatologic: Flushing (extended-release, <2%), pruritus (extended-release, 1%–8%), sweating Gastrointestinal: Constipation (extended-release, 7%–31%), nausea (extended-release, 9%–28%), vomiting (extended-release, 6%–14%) Neurologic: Asthenia (extended-release, 1%–11%), dizziness (extended-release, 2%–11%), headache (extended-release, 5%–12%), lightheadedness, sedated (extended-release, <2%), somnolence (extended-release, 1%–15%) | |
| Oxycodone | Dermatologic: Pruritus (controlled-release, 13%; immediate-release, ≥3%), Sweating (controlled-release, 5%; immediate-release, <3%) Gastrointestinal: Abdominal pain (≤5%), constipation (controlled-release, 23%; immediate-release, ≥3%), nausea (controlled-release, 23%; immediate-release, ≥3%), vomiting (controlled-release, 12%; immediate-release, ≥3%), xerostomia (controlled-release, 6%; immediate-release, <3%) Neurologic: Asthenia (controlled-release, 6%; immediate-release, ≥3%), dizziness (controlled-release, 13%; immediate-release, ≥3%), headache (controlled-release, 7%; immediate-release, ≥3%), somnolence (controlled-release, 23%; immediate-release, ≥3%) | |
| Levorphanol | Cardiovascular: Hypotension (1%–10%) Dermatologic: Pruritus (>10%) Gastrointestinal: Constipation (1%–10%), nausea (>10%), vomiting (1%–10%) Psychiatric: Altered mental status (1%–10%), disturbance in mood (1%–10%) | |
| Hydrocodone a | Dermatologic: Pruritus, rash Gastrointestinal: Constipation, bowel obstruction, nausea, vomiting, pharyngeal dryness, xerostomia Neurologic: Confusion, dizziness, impaired cognition, lethargy, sedated, somnolence Psychiatric: Anxiety, dysphoric mood, euphoria, fear, mood swings Renal: Urinary retention, spasm of bladder, urethral spasm Respiratory: Depression, tight chest | |
| Oxymorphone | Cardiovascular: Hypotension (<10%) Dermatologic: Pruritus (≤15.2%), sweating symptom (1% to <10%) Gastrointestinal: Abdominal pain (1% to <10%), constipation (4.1%–27.6%), nausea (2.9%–33.1%), vomiting (≤15.6%), xerostomia (1% to <10%) Neurologic: Confusion (≤10%), dizziness (≤17.8%), headache (2.9%–12.2%), somnolence (1.9%–19.1%) Respiratory: Dyspnea (1% to <10%), hypoxia (1% to <10%) Other: Fever (1%–14.2%) | |
| Buprenorphine | Dermatologic: Application-site erythema (5%–10%), application-site irritation (3%–5%), application-site rash (6%–9%), pruritus, application site (4%–15%) Gastrointestinal: Constipation (14%), nausea (23%), vomiting (11%), xerostomia (≥5%) Neurologic: Dizziness (16%), headache (16%), somnolence (14%)—does have ceiling dose for analgesia. Not recommended above 30 mg total daily dose. Buprenorphine is associated with less QTc prolongation than methadone, but this can occur at higher doses | |
| Butorphanol | Gastrointestinal: Nausea and vomiting (13%) Neurologic: Dizziness (19%–54%), insomnia (11%), sedated (30%–40%), somnolence (43%–88%) Respiratory: Nasal congestion (13%), long-term use of intranasal product (13%) | |
| Phenylpiperidines | Fentanyl | Dermatologic: Application-site reaction (adults, ≥1%; pediatrics, 3%–10%), diaphoresis (adults: transdermal ≥10%, sublingual ≥1%; pediatrics: transdermal ≥1%), pruritus (transdermal, 3%–10%; sublingual, ≥1%) Gastrointestinal: Abdominal pain (transdermal, 3%–10%; sublingual, ≥1%), constipation (adults, ≥10%; pediatrics, 3%–10%), diarrhea (adults: transdermal 3%–10%, sublingual ≥1%; pediatrics: transdermal ≥1%), indigestion (transdermal, 3%–10%; sublingual, ≥1%), loss of appetite (transdermal, 3%–10%; sublingual, ≥1%), nausea (≥10%), vomiting (≥10%), xerostomia (adults: transdermal ≥10%, sublingual ≥1%; pediatrics: transdermal ≥1%) Neurologic: Asthenia (adults, ≥9.7%; pediatrics, 3%–10%), confusion (adults: transdermal ≥10%, sublingual ≥1%; pediatrics: transdermal ≥1%), dizziness (adults, 3%–10%; pediatrics, ≥1%), feeling nervous (3%–10%), headache (transdermal, 3%–10%; sublingual, ≥1%), insomnia (adults, ≥1%; pediatrics, 3%–10%), somnolence (adults, ≥9.5%; pediatrics, 3%–10%) Psychiatric: Anxiety (adults, 3%–10%; pediatrics, ≥1%), depression (adults: transdermal 3%–10%, sublingual ≥1%; pediatrics: transdermal ≥1%), euphoria (3%–10%), hallucinations (adults: transdermal 3%–10%, sublingual ≥1%; pediatrics: transdermal ≥1%) Renal: Urinary retention (adults: transdermal 3%–10%, sublingual <1%; pediatrics: transdermal ≥1%) Respiratory: Dyspnea (adults: transdermal 3%–10%, sublingual 10.4%; pediatrics: transdermal ≥1%), upper respiratory infection (3%–10%) Other: Fatigue (transdermal, 3%–10%; sublingual, ≥1%), influenza-like symptoms (3%–10%) |
| Alfentanil | Cardiovascular: Bradyarrhythmia (14%), hypertension (18%), hypotension (10%), tachycardia (12%) Gastrointestinal: Nausea (28%), vomiting (18%) | |
| Sufentanil | Cardiovascular: Bradyarrhythmia (3%–9%), Hypotension (3%–9%) Dermatologic: Pruritus (25%) Gastrointestinal: Nausea (3%–9%), vomiting (3%–9%) Musculoskeletal: Muscle rigidity, chest wall (3%–9%) Neurologic: Somnolence (3%–9%) | |
| Meperidine a | Dermatologic: Sweating, pruritus, rash, urticaria Gastrointestinal: Abdominal cramps, anorexia, biliary spasm, constipation, nausea, paralytic ileus, sphincter of Oddi spasm, vomiting, xerostomia Neurologic: Agitation, confusion, delirium, disorientation, dizziness, lightheadedness, sedation Neuromuscular and skeletal: Muscle twitching, myoclonus, tremor, weakness Ocular: Visual disturbances | |
| Methadone a | Cardiovascular: Cardiac dysrhythmia, hypotension Endocrine metabolic: Diaphoresis Gastrointestinal: Constipation, nausea, vomiting Neurologic: Asthenia, dizziness, lightheadedness, sedated | |
| Other | Tapentadol | Gastrointestinal: Constipation (8%–17%), nausea (21%–30%), vomiting (8%–18%) Neurologic: Dizziness (17%–24%), headache (extended-release tablets, 10%–15%), somnolence (12%–15%); avoid combining with SNRI or SSRI |
| Tramadol | Dermatologic: Flushing (8%–16%), pruritus (3%–11.9%) Gastrointestinal: Constipation (9%–46%), nausea (15%–40%), vomiting (5%–17%), dyspepsia (1%–13) Neurologic: Dizziness (7%–28.2%), headache (3%–15.8%), insomnia (1%–10.9%), somnolence (4%–20.3%) Neuromuscular and skeletal: Weakness (4%–12%); avoid combining with SNRI or SSRI |
| Oral NSAIDs | |
|---|---|
| Cardiovascular | Edema (<9%), palpitation, hypertension. A recent meta-analysis looking at the cardiovascular effects of NSAIDs (including selective COX-2 inhibitors) shows that the risks are similar. Naproxen is associated with less cardiovascular risk than other NSAIDs a |
| Dermatologic | Rash (3%–9%), itching (<9%) |
| Central nervous system | Dizziness (3%–9%), headache (1%–3%), nervousness (1%–3%) Indomethacin: Headache (12%) Ketorolac: Headache (17%) |
| Endocrine and metabolic | Fluid retention (≤9%) |
| Gastrointestinal | Epigastric pain (3%–9%), heartburn (3%–9%), nausea (3%–9%), abdominal pain/cramps/distress (1%–3%), appetite decreased (1%–3%), constipation (1%–3%), diarrhea (1%–3%), dyspepsia (1%–3%), flatulence (1%–3%), vomiting (1%–3%), stomatitis |
| General | Dyspnea (3%–9%), thirst |
| Hepatic | Ketoprofen: Liver function test abnormality (<15%) |
| Otic | Tinnitus (3%–9%) |
| Renal | Ketorolac: Renal function abnormal |
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