Pain is an unpleasant, subjective experience that is often a significant issue for patients who require physical and rehabilitative care. Pain can be classified as acute or chronic. Acute pain is associated with tissue damage, increased autonomic nervous activity, and resolution with healing of injury. Chronic pain extends beyond the expected period of healing, has no protective function, degrades health and function, and contributes to depressed mood. Pain can be further separated into nociceptive pain (which arises from a stimulus outside the nervous system and is proportionate to receptor stimulation) or neuropathic pain (which arises from a primary lesion or dysfunction in the nervous system, requires no nociceptive stimulation, and is disproportionate to receptor stimulation), or a mix of nociceptive and neuropathic pain.
Pain can be managed pharmacologically at different levels of the pain pathway (Figure 10–1) using multiple pharmacologic agents. Several of these agents are described here. For additional discussion of pain management, see also Chapter 21.
Multimodal analgesic approach to pain management. ASA, aspirin; LAs, local anesthetics; NSAIDs, nonsteroidal antiinflammatory drugs; SNRIs, serotonin-norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.
Acetaminophen is a commonly used pain medication that acts peripherally on pain and does not inhibit nociception or change the perception of pain. Its analgesic mechanism of action is unclear but involves weak inhibition of cyclooxygenase (COX), possibly selective to COX-2. Due to its action on COX, acetaminophen has weak antiinflammatory activity. Acetaminophen is rapidly absorbed in the gastrointestinal tract. The onset of analgesia is approximately 11 minutes, peaking in 30–60 minutes, with a half-life of 1–4 hours and duration of 1–4 hours. Studies of its benefits for pain relief have reported mixed results compared with aspirin or ibuprofen. Although, the safety profile of acetaminophen is superior to that of nonsteroidal antiinflammatory drugs (NSAIDs), in that gastrointestinal and coagulation effects with acetaminophen are minimized, high doses can lead to liver, kidney, and brain damage. The common side effects include nausea, rash, and headache. Chronic use may lead to anemia, thrombocytopenia, and hematologic malignancies.
Nonsteroidal Antiinflammatory Drugs
NSAIDs are frequently used in the treatment of various pain manifestations and are classified as mild analgesics. The pain-reducing mechanism derives from their effect on antiinflammatory and analgesic pathways. The antiinflammatory effects occur through inhibition of the enzyme COX, resulting in reduction of arachidonic acid to prostaglandin H2. Depending on the NSAID, inhibition may be nonselective (COX-1 and -2) or selective for COX-2. The antiinflammatory action leads to an analgesic effect by interfering with prostaglandin sensitization of nociceptors. Patients are generally more tolerant to NSAIDs than to opioids, experiencing fewer side effects, lack of psychological or physical dependence, and no development of tolerance. Side effects of NSAIDs include gastrointestinal ulceration and bleeding, renal insufficiency, hepatic inflammation, and hypertension. Because of the gastrointestinal side effects, certain NSAIDs are enteric-coated. Taking NSAIDs with meals or coadministration of an H2 blocker or proton pump inhibitor has also been shown to be effective in reducing gastrointestinal side effects. Selective COX-2 inhibitor NSAIDs have fewer gastrointestinal side effects; however, the selective COX-2 inhibitors increase the risk of cardiovascular toxicity.
NSAIDs are most often administered orally. Currently, one NSAID, diclofenac, is FDA approved for topical use. Diclofenac can be prescribed as a pill, gel, jelly, solution, or a patch. Topical administration aims to restrict NSAID action to the pain location and to decrease blood concentrations, resulting in fewer systemic side effects. Topical diclofenac has an increased risk for hepatotoxicity; therefore, it is important to monitor liver enzymes before and after administration. Table 10–3 contrasts pharmacologic properties of commonly prescribed NSAIDs.
Table 10–3Nonsteroidal antiinflammatory drugs. |Favorite Table|Download (.pdf) Table 10–3 Nonsteroidal antiinflammatory drugs.
|Medication ||Half-Life (h) ||Peak Effect (h) ||Duration (h) ||Comments |
|Aspirin ||4–16 ||1–2 ||4–6 ||Irreversible effect on platelet aggregation |
|Diclofenac ||6–8 ||2–4 ||10–12 ||Decreased gastrointestinal (GI) toxicity |
|Indomethacin ||4–5 ||1–2 ||4 ||Greater GI toxicity and central nervous system side effects |
|Ibuprofen ||2–4 ||1–2 ||4–6 ||Rapid onset |
|Naproxen ||12–17 ||2–3 ||8–12 ||Longer duration |
|Sulindac ||14–16 ||3–4 ||8–12 ||Decreased renal toxicity |
|Meloxicam ||15–20 ||5–12 ||8–12 ||Lesser GI toxicity |
|Celecoxib ||11–13 ||2–9 ||8–12 || |
Selective cyclooxygenase-2 (COX-2) inhibitor
Increased cardiovascular toxicity
|Ketorolac ||3.5–9 ||2–3 ||4–6 ||Short-term use |
K: Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. FASEB J 2008;22:383–390.
E: Long-term use of acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs and risk of hematologic malignancies: Results from the prospective Vitamins and Lifestyle (VITAL) study. J Clin Oncol 2011;29:2424–2431.
Opioid analgesics are narcotics used to treat moderate to severe pain. Opiates can be divided into three classes: those that are naturally occurring (eg, morphine), those that are semisynthetic (eg, oxycodone, hydrocodone), and those that are synthetic (eg, methadone, fentanyl). The mechanism of action involves binding of opioid receptors (μ, κ, δ, OFQ/N) on neurons, peripheral nerves, and joints. Binding of these receptors leads to pain relief by decreasing pain perception, decreasing pain reaction, and increasing pain tolerance. Opioid receptor binding also results in the wide range of side effects, which include respiratory depression, decreased gastrointestinal motility, nausea, vomiting, pruritus, orthostatic hypotension, and mood alteration. Most opiates are metabolized in the liver and eliminated in the kidney. Continued administration of opiates can lead to the development of tolerance and physical dependence on the opiate. Severe adverse effects of opiates are reversed by naloxone, an opiate antagonist. Table 10–4 contrasts features of several commonly prescribed opioid analgesics.
Table 10–4Opioid analgesics. |Favorite Table|Download (.pdf) Table 10–4 Opioid analgesics.
|Medication ||Route and Dosage (mg) ||Half-Life (h) ||Duration (h) ||Peak Effect (h) ||Comments |
|Morphine || |
|2–3 ||2–4 ||0.5–1.5 ||Multiple routes: PO, IM, IV, rectal, intrathecal |
|Morphine CR || |
|2–3 ||8–12 ||— || |
|Oxycodone ||PO: 20 ||2–3 ||3–4 ||0.5–1 ||Fast-acting |
|Oxycodone CR ||PO: 20 ||2–3 ||8–12 ||— || |
|Hydromorphone || |
|2–3 ||2–4 ||0.5–1.5 ||Fast-acting |
|Methadone ||IM: 10 ||12–190 ||4–12 ||1–2 ||Avoid in patients with significant respiratory, hepatic, or renal failure |
|Hydrocodone ||PO: 30 ||2–4 ||3–6 ||1–2 ||Combined with acetaminophen or NSAID |
|Codeine || |
|2–3 ||3–6 ||1–2 ||Weak, short-acting |
|Fentanyl transdermal ||25 mcg ||16–24 ||58–72 ||12 ||Avoid heat application directly on patch |
|Oxymorphone || |
|2–3 ||2–4 ||0.5–1.5 ||Rectal suppository |
Tramadol is a synthetic dual-mechanism analgesic agent used in the treatment of moderate to severe pain. The dual mechanism of action produces analgesia by enabling the drug to bind to opioid receptors with codeine-like affinity as well as serotonin and norepinephrine receptors; however, the drug is not classified as a controlled substance. Tramadol has been effective in treating nociceptive and neuropathic pain. The onset of action is within 1 hour and peaks within 1.5–2 hours. Tramadol has a half-life of 6 hours and duration of 4–6 hours. Side effects include nausea, dizziness, sedation, pruritus, dry mouth, and sweating. There is a risk of physical dependence, but this is not as severe as with opiates. Caution is advised in patients concurrently taking medications affecting seizure threshold, tricyclic antidepressants, carbamazepine, and monoamine oxidase inhibitors.
Tapentadol is another synthetic dual-mechanism analgesic agent for moderate to severe pain. The dual mechanism of action produces analgesia by acting as an agonist to opioid receptors as well as a norepinephrine reuptake inhibitor. The potency of tapentadol is between that of tramadol and morphine. Its onset of action is within 30 minutes and peaks within 1–1.5 hours. Tapentadol has a half-life of 4 hours and duration of 3–4 hours. The drug has fewer gastrointestinal side effects and produces less tolerance compared with opiates. However, patients can develop nausea, dizziness, and sedation. Patients who concurrently take antiseizure medications and antidepressants have an increased risk of hallucinations and potential risk of serotonin syndrome; thus, cautious use in advised.
Gabapentin is a structional analog to GABA that was initially developed for treatment of epilepsy. The drug is now widely used to treat neuropathic pain owing to its combination of antihyperalgesic and antiallodynic, but not antinociceptive, properties. The mechanism of action is unknown and seems to involve a complex synergy of GABA synthesis, calcium channel binding, and non-NMDA receptor antagonism. The onset of drug action is within 1–3 hours, peaking within 2–4 hours. The half-life is 5–7 hours and duration is 8–12 hours. Although the drug begins to act within hours, studies have demonstrated that onset of pain relief generally begins at 1–3 weeks. Side effects include loss of coordination, lightheadedness, sedation, thirst, dizziness, peripheral edema, and weight gain. Renal function is an important factor in dosing as gabapentin is renally eliminated.
Pregabalin has similar effects to gabapentin but it also has anticonvulsant, antihyperalgesic, and anxiolytic properties. It is FDA approved for treatment of neuropathic pain resulting from diabetes, spinal cord injury, and fibromyalgia. Pregabalin is structurally similar to the inhibitory neurotransmitter (GABA) and binds to voltage-gated calcium channels, leading to a reduction of calcium influx and excitatory neurotransmitters; however, it does not directly bind to GABAA, GABAB, or benzodiazepine receptors. Pregabalin, like gabapentin, reduces the hyperexcitability of dorsal horn neurons caused by tissue damage. The onset of action is within 30 minutes to 3 hours and peaks within 1.5 hours. The half-life is 6.3 hours. In marked contrast to gabapentin, onset of pain relief occurs generally within 24–48 hours. Side effects include loss of coordination, lightheadedness, sedation, thirst, dizziness, peripheral edema, and thrombocytopenia. Pregabalin can also potentiate the effects of benzodiazepines due to the increase in GABA. Because its mechanism of action differs from that of gabapentin, both medications can be combined, which can have the benefit of lowering the dosage required and number of side effects. Moreover, pregabalin has been shown to be synergistic with opioids by having opioid-sparing effects and decreasing opioid consumption.
et al.: Pregabalin for postherpetic neuralgia: Placebo-controlled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief. J Pain. 2008;9:1006–1017.