Pain is an unpleasant, subjective sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.
- Nociceptive (acute) pain is either somatic (arising from skin, bone, joint, muscle, or connective tissue) or visceral (arising from internal organs such as the large intestine or pancreas).
- Stimulation of free nerve endings known as nociceptors is the first step leading to the sensation of pain. These receptors are found in both somatic and visceral structures and are activated by mechanical, thermal, and chemical impulses. Release of bradykinins, K+, prostaglandins, histamine, leukotrienes, serotonin, and substance P may sensitize and/or activate nociceptors. Receptor activation leads to action potentials that are transmitted along afferent nerve fibers to the spinal cord.
- Action potentials continue from the site of noxious stimuli to the dorsal horn of the spinal cord and then ascend to higher centers. The thalamus acts as a relay station and passes the impulses to central structures where pain is processed further.
- The body modulates pain through several processes. The endogenous opiate system consists of neurotransmitters (e.g., enkephalins, dynorphins, and Î²-endorphins) and receptors (e.g., Âµ, Î´, Îº) that are found throughout the central nervous system (CNS). Endogenous opioids bind to opioid receptors and inhibit the transmission of pain impulses.
- The CNS also contains a descending system for control of pain transmission. This system originates in the brain and can inhibit synaptic pain transmission at the dorsal horn. Important neurotransmitters here include endogenous opioids, serotonin, norepinephrine, Î³-aminobutyric acid (GABA), and neurotensin.
- Neuropathic (chronic) pain is sustained by abnormal processing of sensory input by the peripheral or central nervous system. There are a large number of neuropathic pain syndromes that are often difficult to treat (e.g., low back pain, diabetic neuropathy, postherpetic neuralgia, cancer-related pain, spinal cord injury).
- Nerve damage or persistent stimulation may cause pain circuits to produce spontaneous nerve stimulation, autonomic neuronal pain stimulation, and a progressive increase in discharge of dorsal horn neurons.
Patients may be in obvious acute distress (trauma pain) or appear to have no noticeable suffering (chronic/persistent).
- Pain can be described as sharp, dull, burning, shocklike, tingling, shooting, radiating, fluctuating in intensity, and varying in location.
- Over time, the same pain stimulus may cause symptoms that completely change (e.g., sharp to dull, obvious to vague).
- Nonspecific symptoms include anxiety, depression, fatigue, insomnia, anger, and fear.
- Acute pain can cause hypertension, tachycardia, diaphoresis, mydriasis, and pallor, but these signs are not diagnostic.
- In some acute cases and in most chronic/persistent pain, there may be no obvious signs.
- Pain is always subjective; thus pain is best diagnosed based on patient description and history.
- There are no laboratory tests that can diagnose pain.
- A comprehensive history and physical examination are required to evaluate underlying diseases and possible contributing factors. A baseline description of pain can be obtained by assessing PQRST characteristics (palliative and provocative factors, quality, radiation, severity, and temporal factors). Attention should be given to mental factors that may lower the pain threshold (anxiety, depression, fatigue, anger, fear). Behavioral, cognitive, social, and cultural factors may also affect the pain experience.
- Nociceptive pain is often acute, localized, well described, and relieved with conventional analgesics. Somatic pain usually presents as throbbing and well-localized discomfort, but visceral pain can feel as if it were coming from other structures (referred) or present as a well-localized phenomenon.
- Neuropathic pain is often chronic, not well described, and not easily treated with conventional analgesics. Patients commonly present with pain described as burning, tingling, shock-like, or shooting; exaggerated painful responses to normally noxious stimuli (hyperalgesia); or painful responses to normally nonnoxious stimuli (allodynia).
- Ineffective pain treatment may result in hypoxia, hypercapnea, hypertension, excessive cardiac activity, and emotional difficulties.
- Chronic pain can be divided into four subtypes: (1) pain that persists beyond the normal healing time for an acute injury, (2) pain related to a chronic disease, (3) pain without an identifiable organic cause, and (4) pain involving both the chronic and acute pain associated with cancer.
- Patients with chronic pain may develop psychological problems, dependence on and tolerance to analgesics, trouble sleeping, and sensitivity to environmental changes that intensify pain.
The goals of therapy are to minimize pain and provide reasonable comfort at the lowest effective analgesic dose. With chronic pain, goals may include rehabilitation and resolution of psychosocial issues.
- The elderly and the young are at a higher risk for undertreatment of pain because of misunderstanding about the pathophysiology of their pain.
- Nonopioid Agents
- Analgesia should be initiated with the most effective analgesic with the fewest side effects. Dosage, pharmacokinetic, pharmacodynamic, and side-effect profiles of Food and Drug Administration (FDA)-approved nonopioid analgesics.
- These drugs (except acetaminophen) reduce prostaglandins produced by the arachidonic acid cascade, thereby decreasing the number of pain impulses received by the CNS.
- Aspirin given concurrently with other nonsteroidal anti-inflammatory drugs (NSAIDs) is more likely to cause gastrointestinal (GI) side effects. The salicylate salts cause fewer GI side effects than aspirin and do not inhibit platelet aggregation.
- Aspirin-like compounds should not be given to children or teenagers with influenza or chickenpox, as Reye’s syndrome may result.
- Acetaminophen has analgesic and antipyretic activity but little anti-inflammatory action. It is highly hepatotoxic on overdose.
- With oral analgesics, the onset of action usually takes about 45 minutes, and peak effect usually is seen in about 1 to 2 hours.
- Equianalgesic doses, dosing guidelines, major adverse effects, and pharmacokinetics of opioids are shown in Tables 52-4,52-5,52-6 and 52-7. The equianalgesic doses are only a guide, and doses must be individualized.
- Partial agonists and antagonists compete with agonists for opiate receptor sites and exhibit mixed agonist-antagonist activity. They may have selectivity for analgesic receptor sites and cause fewer side effects.
- In the initial stages of acute pain treatment, analgesics should be given around the clock. As the painful state subsides, as-needed schedules can be used.
- With patient-controlled analgesia (PCA), patients self-administer preset amounts of intravenous opioids via a syringe pump electronically interfaced with a timing device; thus, patients can balance pain control with sedat- ion.
- Administration of opioids directly into the CNS (epidural and intrathecal/subarachnoid routes) is becoming prominent for acute pain. These methods require careful monitoring because of reports of marked sedation, respiratory depression, pruritus, nausea, vomiting, urinary retention, and hypotension. Naloxone is used to reverse respiratory depression, but continual infusion may be required. The analgesic effects of single doses of epidural opioids are given below:
- Morphine, 1 to 6 mg (onset 30 minutes, duration 6 to 24 hours)
- Hydromorphone, 1 to 2 mg (onset 15 minutes, duration 6 to 16 hours)
- Fentanyl, 0.025 to 0.1 mg (onset 5 minutes, duration 1 to 4 hours)
- Intrathecal and epidural opioids are often administered by continuous infusion or PCA. They are safe and effective when given simultaneously with intrathecal or epidural local anesthetics such as bupivacaine. All agents administered directly into the CNS should be preservative free.
- Subarachnoid doses are smaller than epidural doses (e.g., morphine 0.1 to 0.3 mg, fentanyl 0.005 to 0.025 mg).
Morphine and Congeners
- Morphine is considered by many clinicians to be the first-line agent for moderate to severe pain. It can be given orally, parenterally, or rectally.
- Nausea and vomiting are more likely in ambulatory patients and with the initial dose.
- Respiratory depression increases progressively as doses are increased. It often manifests as a decrease in respiratory rate, and the cough reflex is also depressed. Patients with underlying pulmonary dysfunction are at risk for increased respiratory compromise. Respiratory depression can be reversed by naloxone.
- The combination of opioid analgesics with alcohol or other CNS depressants amplifies CNS depression and is potentially harmful and possibly lethal.
- Morphine produces venous and arteriolar dilatation, which may result in orthostatic hypotension. Hypovolemic patients are more susceptible to morphine-induced hypotension. Morphine is often considered the opioid of choice when using opioids to treat pain associated with myocardial infarction, as it decreases myocardial oxygen demand.
- Morphine can cause constipation, spasms of the sphincter of Oddi, urinary retention, and pruritus (secondary to histamine release) (see Table 52-6). In head trauma patients who are not ventilated, morphine-induced respiratory depression can increase intracranial pressure and cloud the neurologic examination results.
Meperidine and Congeners (Phenylpiperidines)
- Meperidine is less potent and has a shorter duration of action than morphine. In most settings, it offers no advantages over morphine.
- With high doses or in patients with renal failure, the metabolite normeperidine accumulates, causing tremor, muscle twitching, and possibly seizures.
- Meperidine should not be combined with monoamine oxidase inhibitors because of the possibility of severe respiratory depression or excitation, delirium, hyperpyrexia, and convulsions.
- Fentanyl is a synthetic opioid structurally related to meperidine. It is often used in anesthesiology as an adjunct to general anesthesia. It is more potent and shorter acting than meperidine. Transdermal fentanyl can be used for treatment of chronic pain requiring opioid analgesics. After a patch is applied, it takes 12 to 24 hours to obtain optimal analgesic effect, and analgesic support may last 72 hours. It may take 6 days after increasing a dose before new steady-state levels are achieved. Thus, the fentanyl patch should not be used for acute pain. A fentanyl lozenge on a stick is available for treatment of breakthrough cancer pain.
Methadone and Congeners
Methadone has oral efficacy, extended duration of action, and ability to suppress withdrawal symptoms in heroin addicts. With repeated doses, the analgesic duration of action of methadone is prolonged, but excessive sedation may also result. Although effective for acute pain, it is usually used for chronic pain.
Opioid Agonist-Antagonist Derivatives
This class produces analgesia and has a ceiling effect on respiratory depression and lower abuse potential than morphine. However, psychotomimetic responses (e.g., hallucinations and dysphoria with pentazocine), a ceiling analgesic effect, and the propensity to initiate withdrawal in opioid-dependent patients have limited their widespread use.
Naloxone is a pure opioid antagonist that binds competitively to opioid receptors but does not produce an analgesic response. It is used to reverse the toxic effects of agonist and agonist-antagonist opioids.
- Tramadol, a centrally acting analgesic for moderate to moderately severe pain, binds to Âµ opiate receptors and weakly inhibits norepinephrine and serotonin reuptake.
- Although associated with less respiratory depression than morphine at recommended doses, tramadol has a side-effect profile similar to that of other opioid analgesics. It may also enhance the risk of seizures. It may be useful for treating chronic pain, especially that of neuropathic origin, but it has little advantage over other opioid analgesics for acute pain.
The combination of an opioid and nonopioid oral analgesic often results in analgesia superior to monotherapy and may allow for lower doses of each agent. An NSAID with a scheduled opioid dose is often effective for painful bone metastases.
- Regional analgesia with local anesthetics can provide relief of both acute and chronic pain. Anesthetics can be positioned by injection (i.e., in joints, in the epidural or intrathecal space, along nerve roots) or topically.
- High plasma concentrations can cause CNS excitation and depression (dizziness, tinnitus, drowsiness, disorientation, muscle twitching, seizures, respiratory arrest). Cardiovascular effects include myocardial depression and other effects. Skillful technical application, frequent administration, and specialized follow-up procedures are required.
- An algorithm for pain management in oncology patients is shown in Figure 52-1.
- NSAIDs are especially effective for bone pain. Strontium-89 and samarium SM 153 lexidronam are also effective.
- For cancer pain, round-the-clock schedules in conjunction with as-needed doses are employed when patients experience breakthrough pain.
- Methadone has regained prominence in treating cancer pain. It has a prolonged mechanism of action, N-methyl-d-aspartate (NMDA) receptor antagonist activity (d-isomer), and is inexpensive. However, it can be hard to titrate. Epidural clonidine is also effective with epidurally administered opioid analgesics for treatment of refractory pain.
- The choice of opioid is controversial, but many clinicians prefer morphine for chronic cancer pain. The fentanyl patch may provide a more convenient dosing alternative in patients on stable regimens.
- Tricyclic antidepressants and anticonvulsants (e.g., gabapentin) can be effective for neuropathic pain.
- Meperidine is not recommended for long-term use because of its relatively short duration of action and CNS hyperirritability of normeperidine.
EVALUATION OF THERAPEUTIC OUTCOMES
- Pain intensity, pain relief, and medication side effects must be assessed on a regular basis. The timing and regularity of assessment depend on the type of pain and the medications administered.
- Postoperative pain and acute exacerbations of cancer pain may require hourly assessment, whereas chronic nonmalignant pain may need only daily (or less frequent) monitoring.
- Quality of life must also be assessed on a regular basis in all patients.
- The best management of opioid-induced constipation is prevention. Patients should be counseled on proper intake of fluids and fiber, and a laxative may be added if needed.
- If acute pain does not subside within the anticipated time frame (usually 1 to 2 weeks), further investigation of the cause is warranted.