Introduction

Health professionals interpret the information gained from measuring and assessing the pain for the purpose of implementing a pain-management plan. A number of analgesic therapies can be a part of the management plan for pain that is nociceptive, neuropathic, or a combination of these two types of pain.

In 1986, the World Health Organization118 proposed that health professionals use analgesic medications via a systematic plan. Click here to see the plan. The systematic plan is a three-step ladder approach relevant to pain management for all types of pain, including pain at end of life. For mild, chronic, nonmalignant, and cancer pain, drug use is recommended from the bottom of the ladder to the top, i.e., up the ladder from step 1 to step 2 to step 3. For severe, acute pain or other types of pain experienced by people with life-limiting illness, the steps are ordered from the top step to the bottom step, i.e., down the ladder from step 3 to step 2 to step 1.111 The following sections provide specific information about the mechanism of action, routes of administration, dosages, dose intervals, side effects, toxicity, and implications for using these drugs to relieve pain.


Step One: Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs are powerful analgesics, especially for nociceptive pain. NSAIDs also are effective in some neuropathic pain syndromes when used with other analgesics.121 The prototype drug for the NSAIDs is aspirin. Indomethacin (Indocin™) and ibuprofen (Motrin™) are two NSAIDs other than aspirin specifically approved for use in children. Aspirin or another nonsteroidal anti-inflammatory drug (NSAIDs) is used with or without adjuvant drugs to control mild pain. Step-1 drugs can be very effective for many types of pain; they provide adequate analgesia until death for 27% of patients with mild to moderate cancer pain.107

Mechanism of desired actions
Aspirin and NSAIDs provide analgesia by blocking chemicals (prostaglandins), that sensitize the peripheral pain receptors to send a pain signal to the central nervous system (CNS). These drugs have anti-inflammatory, analgesic, and antipyretic actions. The anti-inflammatory and analgesic actions are both CNS and peripheral nervous system (PNS) effects, whereas the antipyretic actions are CNS effects. Click on the following files to see a demonstration of the specific anti-inflammatory and analgesic actions of the NSAIDs.

When tissue is traumatized and cells are damaged, a number of chemicals are released near the pain fiber (Figure 3, pain mechanisms section). Some chemicals (bradykinin, serotonin, histamine, potassium ions, norepinephrine) stimulate while others (leukotrienes, prostaglandins, substance P) sensitize the pain fiber to be excitable and to fire an action potential toward the spinal cord. Several details help to explain this process and how NSAID analgesics affect it.

All human cells have a two-layer lipid membrane. When a cell is damaged, phospholipids and other substances are liberated from the cell into the intracellular space. The release of phospholipids initiates the arachidonic acid cascade through which 5-lipo-oxygenase and cyclo-oxygenase synthesize leukotrienes and prostaglandins, respectively.121 These events are displayed in the previous animation. Leukotrienes and prostaglandins sensitize the pain fiber to be activated by a smaller stimulus than when these chemicals are not near the pain fiber. For example, light pressure is not perceived as painful in normal conditions, but sometimes is sensed as pain (allodynia) if leukotrienes or prostaglandins surround the pain fiber.

Routes of administration
Parenteral formulation is available in the U.S. for only one NSAID, Toradol (ketorolac). Oral formulations are available for many different NSAIDs available over the counter (OTC) and by prescription. Rectal formulations are available for several different NSAIDs available over the counter (OTC) and by prescription. Click here to see examples of NSAIDs.

Dosages and dose intervals differ for each NSAID. The NSAIDs have a ceiling analgesic effect, meaning that above maximum doses increased toxicity rather than increased analgesia is observed.

Side effects and toxicity are mainly related to gastrointestinal (bloating, dyspepsia, nausea, vomiting, bleeding, diarrhea, and peptic ulceration) and renal (decreased blood flow, interstitial nephritis, papillary necrosis) effects. Renal failure has been observed in people consuming large amounts of NSAIDs to achieve pain relief. Although aspirin and many other NSAIDs are available OTC, the danger of excessive doses of these drugs should be emphasized to patients and providers unaware of their potential harm. Although the Cox2 NSAID agents are an important pain management breakthrough and are believed to have less GI and renal effects than other NSAIDs, the long-term safety of the Cox2 drugs is uncertain. Cox2 specific agents include celecoxib and rofecoxib. NSAIDs that appear to be partial Cox2 agents include choline magnesium trisalicylate, nabumetone and etodolac. Hypersensitivity occurs with increased incidence in middle-aged people, women, and people with nasal polyps. Hypersensitivity manifests as rhinitis, edema, urticaria, bronchial asthma, and laryngeal edema.

Implications include ongoing assessment of pain and other symptoms as well as being aware of drug interactions. NSAIDs have important interactions with alcohol, antirheumatic agents, antacids, anticoagulants, diuretics, antidiabetic agents, lithium, beta-blockers, phenytoin, and methotrexate. Antacids are often suggested to treat the dyspepsia, but they interfere with absorption of the NSAIDs. Aspirin should not be used in children with viral infections because of possible adverse consequences associated with Reyes syndrome. Instead of aspirin as an antipyretic for viral illnesses, acetaminophen is indicated.



Step One: Acetaminophen

Acetaminophen is a well-known drug and commonly used in children and the elderly. It is available OTC and is inexpensive.

Mechanism of desired actions
Acetaminophen (Tylenol™) is another step-1 drug that is used with or without adjuvant drugs to control mild pain. Acetaminophen does not block the prostaglandin synthesis in the peripheral tissues but instead produces pain relief through central mechanisms not clearly understood. The small anti-prostaglandin effects of acetaminophen appear to occur via CNS actions. Acetaminophen has both analgesic and antipyretic actions. Acetaminophen is equipotent to aspirin 650 mg or 2 mg IM morphine.

Routes of administration include oral and rectal formulations, but no parenteral form is available in the U.S. Oral formulations include liquids, tablets, and capsules.

Dosages and dose intervals
Typical and maximum doses for acetaminophen are listed in the WHO Step 1 Analgesic Table. New evidence indicates that adults should not take more than 4,000 of acetaminophen per day. The maximum daily dose for elderly patients is 2,700. People who also consume alcohol should not take acetaminophen because of the additive toxicity effects on the liver. The dose for children and small individuals (less than 50 kg or 110 lbs) is 6 mg/kg to 12 mg/kg every 4 hours. As with the NSAIDs, acetaminophen has a ceiling effect. Doses above 1,000 mg every 6 hours do not provide significantly greater analgesia than 650 mg every 4 hours. The duration of analgesia is greater with 1,000 mg, but the amount of analgesia is not increased.

Side effects and toxicity of acetaminophen are thought to be less than aspirin. Acetaminophen does not cause gastric irritation or affect platelet function. However, serious hepatic toxicity is possible with chronic use or acute overdose. Within the first 24 hours of an acute overdose, nausea and vomiting, anorexia, and abdominal pain are experienced, and then the intoxication leads to liver enzyme changes, encephalopathy, coma and death.

Implications include ongoing assessment of pain and being aware of risk factors for toxicity. Since many OTC products (cold remedies such as Nyquil™) and prescription drugs (Percocet™, Tylox™, Vidodin™) contain acetaminophen, acetaminophen toxicity is an important issue, especially in people with a history of alcohol use or other conditions often associated with hepatic damage.

Assessment is important to identify people at risk for acetaminophen toxicity.



Step One: Overview of Adjuvant Analgesics

Many drugs not often thought of as analgesics have been shown to provide pain relief and are known as adjuvant analgesics or as co-analgesics. Adjuvant drugs act in many different ways, some have CNS and some have PNS actions, but adjuvant drugs work differently from acetaminophen, aspirin, NSAIDs, or opioids. Therefore, it is a rational approach to combine selected adjuvants (e.g., tricyclic antidepressants and anxiolytics) with Step 1 drugs and to continue the adjuvants when moving to step-2 or step-3 drugs. Many of the adjuvant drugs are effective for neuropathic types of pain.



Copyright © 2002-2003 D.J. Wilkie & TNEEL Investigators