US Pharm. 2008;33(5):HS-4-HS-9.

Seldom do patients in the acute-care setting present with the sole issue of pain management. By definition, pain is an indicator of disease, and its function is to detect and localize tissue-damaging processes.1 Pain may present as a function of an underlying disease or as a process separate from the primary diagnosis.

The purpose of this article is to review acute illnesses that interact with the management of pain, where misuse of analgesic agents would be detrimental to the patient. Two broad etiologies can be applied to most of the discussion: increased drug toxicity due to acute illness and worsened acute illness due to improper analgesic selection.

Managing Pain in Liver Disease
Because the liver is responsible for the metabolism of many drugs, concerns about pain management in liver disease are similar regardless of the cause of compromise, whether alcoholic liver disease, hepatitis, cirrhosis, or carcinoma. The elevation of liver biomarkers such as total and direct bilirubin, alanine aminotransferase, and aspartate aminotransferase is a red flag for the alteration of drug therapy.2

Acetaminophen may come to mind in this setting. The acetaminophen content of several opioid combination products (e.g., Vicodin, Percocet) must be considered with regard to the following discussion.

A 50% to 75% dose reduction from the recommended 4-g maximum daily dose is warranted in hepatic insufficiency or alcohol use, where the potential for liver damage is already present.3 In chronic alcohol users, however, the data conflict with clinical wisdom and what is known about the metabolism of acetaminophen.4

Acetaminophen is metabolized via several pathways, the most common one being glucuronide and sulfate conjugation to inactive metabolites. A small portion of the acetaminophen is eliminated unchanged in the urine; another portion is metabolized by the CYP450 system--one being isoenzyme 2E1 (CYP2E1)--to a toxic metabolite, N -acetyl-p-benzoquinone imine (NAPQI). In therapeutic doses, NAPQI is conjugated with glutathione and rendered nontoxic. When increased NAPQI concentrations are present, however, glutathione stores are depleted, and the unconjugated NAPQI causes oxidative hepatocellular injury, liver failure, and death.5

With acute ingestion, even in chronic alcohol use, ethanol inhibits CYP2E1 activity, theoretically minimizing the formation of NAPQI. Chronic use of alcohol induces CYP2E1 activity, theoretically increasing the formation of NAPQI. It has been suggested that this induction is modest and short-lived, and therefore clinically insignificant. Acetaminophen should be used with extreme discretion in these situations.4

Principles of pharmacokinetics such as first-pass effect and bioavailability account for the necessity of adjusting the doses of analgesic agents in moderate-to-severe liver disease (TABLE 1).6 First-pass effect occurs when an oral agent is absorbed from the gastrointestinal (GI) tract and enters the hepatic circulation, where an amount of the drug may be metabolized before reaching the systemic circulation. The ratio of the amount entering the circulation to the total dose is the drug's bioavailability. When liver disease is present, the lack of hepatic blood flow results in increased bioavailability and the need to lower the dose. Opioids with increased bioavailability due to this phenomenon are morphine and hydromorphone to a large degree, and oxycodone and fentanyl to a lesser degree.6

The principle of hepatic clearance mirrors that of first-pass effect, but here the concern is removal of an agent from the blood rather than the agent's introduction to the body. In a fashion similar to that of first-pass effect, when hepatic blood flow is compromised because of disease, clearance is decreased. This occurs with oral and parenteral administration of the drug. Extending the drug interval may help overcome the accumulation associated with decreased clearance. Several of the opioids are dependent on hepatic clearance: morphine, hydromorphone, and methadone to a small degree, and tramadol, codeine, oxycodone, and fentanyl to a greater degree.6

Codeine and tramadol are unique agents because of their hepatic conversion to their active forms. Codeine is metabolized to morphine and tramadol to O-desmethyltramadol, both by CYP2D6; in advanced liver disease, analgesia with these agents can be unpredictable due to decreased enzyme activity and therefore should not be used. Transdermal fentanyl also can be unpredictably absorbed due to altered skin blood flow and should be avoided.6 The other aforementioned opioids should be used cautiously (TABLE 1).6

Managing Pain in Kidney Disease
As with the liver, the kidneys are responsible for clearing many drugs from the body. Insult to the kidney warrants an examination of drug therapy regardless of etiology. 7,8 With an acute kidney injury, the choice of analgesic drug and dose becomes extremely important due to the potential for accumulation of certain analgesics and their metabolites as well as the potential for increased damage to the kidney. Markers of organ function such as serum creatinine and urine protein play a major role in signaling a damaging event; however, acute changes in mental status may be the first indicator of acute kidney failure in patients receiving chronic opioid therapy for the management of malignant or nonmalignant pain secondary to decreased drug elimination.9

Due to their lack of active metabolites and lack of formation of metabolites with weak opioid activity, the ideal opioids for use in the presence of kidney disease are fentanyl, hydromorphone, methadone, and oxycodone. Caution is advised when these agents are used in severe kidney dysfunction, however, as a portion of the parent drug may be eliminated renally without hepatic deactivation. Opioids that should be avoided or used with much caution are morphine and codeine (which is hepatically metabolized to morphine), due to the formation of the active metabolite morphine-6-glucuronide from both parent drugs. Propoxyphene forms norpropoxyphene, which accumulates in the presence of kidney failure and can cause profound central nervous system (CNS) and respiratory depression.9 Meperidine should be avoided at all costs due to the formation of the active metabolite normeperidine, which accumulates in the presence of kidney disease and causes seizures.9 Normeperidine has been shown to cause seizures even in the absence of kidney failure.10

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely discouraged in both acute and chronic kidney failure due to blocking of the prostaglandin-mediated effect of renal vasodilation and the altering of renal blood flow, along with sodium retention and volume overload.11 While it was formerly hypothesized that cyclooxygenase-2 (COX-2) inhibitors would circumvent this problem, it has been shown that COX-2 inhibitors also adversely affect renal blood flow and vascular tone.12

Adverse Effects of Analgesic Agents

Cardiovascular (CV) System: Patients with atherosclerotic disease, recent coronary-artery bypass (CAB) graft, unstable angina, myocardial infarction (MI), or ischemic stroke may be at greater risk for increased CV risk.13 In a meta-analysis, the CV risk of selective and nonselective COX inhibitors was reviewed.14 Rofecoxib, which was associated with the highest relative risk, has been removed from the U.S. market; valdecoxib, which was contraindicated in patients undergoing CAB surgery, was removed from the U.S. market as well. 14,15 Diclofenac was associated with the highest risk of CV events. Naproxen and celecoxib at doses <= 200 mg per day were not associated with an increased risk of CV events.14

In the management of acute pain, acetaminophen should be tried initially unless it is contraindicated. An opioid-acetaminophen combination or an opioid alone should be considered if acetaminophen alone is insufficient. The decision to use a selective COX-2 inhibitor or nonselective NSAID must be carefully weighed against the potential harm associated with its use. Patients undergoing cardiac-bypass surgery or those at risk for CV events should avoid these medications.13 The use of ibuprofen has been shown to decrease the effectiveness of concurrent aspirin therapy and thus should be avoided.13 It is unclear whether the increased risk of CV effects could be attenuated with the use of daily aspirin. The use of naproxen with a proton-pump inhibitor may be safer and more cost-effective for the treatment of pain in patients at high risk for CV events who are at greater risk for GI bleeding.16 Both selective and nonselective NSAIDs can worsen blood pressure control through sodium retention, with resultant decreased kidney perfusion.

GI System: One of the most common side effects of opioid analgesics is constipation. In acute illness, constipation can contribute to or worsen urinary retention; it also can lead to nausea, which can further weaken the patient or delay accurate differential diagnosis of the nausea or vomiting. Tolerance is the body's reaction to decreased response after continued exposure to a medication. In most patients taking opioids, tolerance usually develops to the side effects of nausea, vomiting, and fatigue within five to seven days. Opioids and NSAIDs can cause anorexia, and NSAIDs can aggravate peptic ulcer disease or gastroesophageal reflux disease. The NSAID ketorolac is frequently overlooked as the cause of GI bleeding or renal impairment. Another complication seen in acute illness is diarrhea. Severe diarrhea can cause electrolyte disturbances and dehydration, possibly leading to acute renal insufficiency. Postoperative paralytic ileus, particularly after abdominal surgery, can be associated with the use of opioid analgesics.17

The choice of opioid analgesic is usually based on patient-specific factors. Transdermal fentanyl is an option in nonopioid-naive patients who are unable to swallow oral formulations.

CNS: NSAIDs and opioids can contribute to an increased risk of falls, possibly due to centrally mediated dizziness.18 Propoxyphene has been associated with an increased risk of falls and hip fractures and is not recommended for routine use in elderly patients.19 Falls in older patients can lead to an increased risk of hip fracture and the accelerated downward spiral of morbidity and mortality.20,21 In older patients with delirium or dementia, worsened cognition may decrease functional status. The use of fentanyl, sufentanil, or alfentanil in critically ill patients with baseline increased intracranial pressure (ICP) can cause a transient increase in ICP. 22

Hematologic System: Several types of hematologic events can arise in the acute-care setting. Rates of deep venous thrombosis (DVT) and resulting complications such as pulmonary embolism, MI, and stroke are important measures of quality in most health care institutions. In an immobilized patient receiving pain control for chronic or acute conditions, masking of pain caused by DVT can occur, leading to one of the sequelae described above.23

Particularly in the postoperative setting, acute blood loss is quite common among inpatients. 24,25 The use of NSAIDs should be avoided in these instances, particularly when a patient's hemoglobin is below values considered to be adequate (e.g., 10 mg/dL).24,25 Nonselective NSAIDs have been shown to decrease platelet function and increase the propensity for bleeding; meloxicam and nabumetone have less of an impact on platelet activity, however. 26 COX-2 inhibitors have not been shown to decrease platelet function. 26 Patients predisposed to bleeding, such as those with thrombocytopenia, or patients on warfarin should avoid the use of NSAIDs. 27,28 Acetaminophen at doses of 2 to 4 g per day has been shown to increase the international normalized ratio in patients on warfarin.29

Integumentary System: Transdermal fentanyl is a good option for pain control when oral formulations are inappropriate or cannot be tolerated in nonopioid-naive patients. Medication absorption can be less than optimal in patients with increased body temperature, however.30 Increases in body temperature can occur through direct application of heat, fever, physical exertion, or application of the patch to warm skin immediately after a shower or bath.30 Few cases exist of fentanyl toxicity secondary to an increase in body temperature; none have been secondary to fever.31-33 Serum fentanyl concentration can vary in patients for reasons not well understood; one possibility is that this is due to pharmacogenomic or pharmacokinetic variability in the population.

Psychiatric Conditions: While depression is not an acute illness, it is prevalent in patients experiencing pain, and vice versa; pain coexisting with depression is harder to manage.34 Treatment of the depression before analgesic therapy is introduced greatly improves the patient's response to the analgesic.34 Antidepressants have consistently shown benefits in patients with various types of pain and pain syndromes with or without depression.34 The preferred agent for neuropathic pain with or without depression is a serotonin norepinephrine reuptake inhibitor.35 Tricyclic antidepressants are an option, but they have fallen out of favor due to their adverse-effects profile and the availability of safer agents.35

One of the fears concerning the use of opioid analgesics is the potential for dependence and addiction. 36 Dependence and addiction are distinctly different states. Dependence is a physical reliance on an agent without which a withdrawal syndrome would be present. For opioids, the withdrawal syndrome includes agitation, insomnia, increased pain, nausea, vomiting, and palpitations, among other things.37 Addiction is psychological; it combines a craving for opioids with the existence of impaired control over use, compulsive use, or continued use despite harm. In the treatment of an opioid-dependent patient in an acute-pain situation, it is important to keep in mind that the opioid requirement will be higher.37 A scheduled maintenance dose should be given to prevent withdrawal, with breakthrough doses given in addition.37 If increasing the doses of an opioid does not control pain, opioid rotation is recommended.37 Tramadol appears to have a lower risk of dependence and addiction; however, in patients previously dependent, it may cause reemergence of the addiction.38

In pseudoaddiction, a patient whose pain is inadequately managed engages in drug-seeking behavior to acquire more drugs for the pain. Superficially, it is nearly impossible to distinguish pseudoaddiction and true addiction; however, Lusher et al found that behaviors associated with pseudoaddiction were disputes between patients and staff over analgesia and the use of OTC analgesics, and behaviors associated with true addiction were illicit drug use and physiologic dependence.39

Opioids should be prescribed cautiously in depressed patients with suicidal ideation, particularly on an outpatient basis.40 The quantity dispensed should be limited, as intentional overdose can lead to respiratory depression and death.40 Multiple organ failure and subsequent death have been noted in cases of tramadol overdose.41


The selection of analgesics in the acute-care setting requires a careful consideration of the coexisting disease states and the potential for interaction between drug and disease. Care should be taken to ensure that the changes occurring during an acute illness do not compromise the safety of the selected analgesic and that the selected analgesic does not promote the severity of the illness.

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