CHAPTER 8: PAIN: PATHOPHYSIOLOGY AND MANAGEMENT

TREATMENT: Acute Pain

The ideal treatment for any pain is to remove the cause; thus, while treatment can be initiated immediately, efforts to establish the underlying etiology should always proceed as treatment begins. Sometimes, treating the underlying condition does not immediately relieve pain. Furthermore, some conditions are so painful that rapid and effective analgesia is essential (e.g., the postoperative state, burns, trauma, cancer, or sickle cell crisis). Analgesic medications are a first line of treatment in these cases, and all practitioners should be familiar with their use.

These drugs are considered together because they are used for similar problems and may have a similar mechanism of action (Table 8-1). All these compounds inhibit cyclooxygenase (COX), and, except for acetaminophen, all have anti-inflammatory actions, especially at higher dosages. They are particularly effective for mild to moderate headache and for pain of musculoskeletal origin.

Because they are effective for these common types of pain and are available without prescription, COX inhibitors are by far the most commonly used analgesics. They are absorbed well from the gastrointestinal tract and, with occasional use, have only minimal side effects. With chronic use, gastric irritation is a common side effect of aspirin and NSAIDs and is the problem that most frequently limits the dose that can be given. Gastric irritation is most severe with aspirin, which may cause erosion and ulceration of the gastric mucosa leading to bleeding or perforation. Because aspirin irreversibly acetylates platelet cyclooxygenase and thereby interferes with coagulation of the blood, gastrointestinal bleeding is a particular risk. Older age and history of gastrointestinal disease increase the risks of aspirin and NSAIDs. In addition to the well-known gastrointestinal toxicity of NSAIDs, nephrotoxicity is a significant problem for patients using these drugs on a chronic basis. Patients at risk for renal insufficiency, particularly those with significant contraction of their intravascular volume as occurs with chronic diuretic use or acute hypovolemia, should be monitored closely. NSAIDs can also increase blood pressure in some individuals. Long-term treatment with NSAIDs requires regular blood pressure monitoring and treatment if necessary. Although toxic to the liver when taken in high doses, acetaminophen rarely produces gastric irritation and does not interfere with platelet function.

The introduction of parenteral forms of NSAIDs, ketorolac and diclofenac, extends the usefulness of this class of compounds in the management of acute severe pain. Both agents are sufficiently potent and rapid in onset to supplant opioids for many patients with acute severe headache and musculoskeletal pain.

There are two major classes of COX: COX-1 is constitutively expressed, and COX-2 is induced in the inflammatory state. COX-2–selective drugs have similar analgesic potency and produce less gastric irritation than the nonselective COX inhibitors. The use of COX-2–selective drugs does not appear to lower the risk of nephrotoxicity compared to nonselective NSAIDs. On the other hand, COX-2–selective drugs offer a significant benefit in the management of acute postoperative pain because they do not affect blood coagulation. Nonselective COX inhibitors are usually contraindicated postoperatively because they impair platelet-mediated blood clotting and are thus associated with increased bleeding at the operative site. COX-2 inhibitors, including celecoxib (Celebrex), are associated with increased cardiovascular risk. It appears that this is a class effect of NSAIDs, excluding aspirin. These drugs are contraindicated in patients in the immediate period after coronary artery bypass surgery and should be used with caution in elderly patients and those with a history of or significant risk factors for cardiovascular disease.

Opioids are the most potent pain-relieving drugs currently available. Of all analgesics, they have the broadest range of efficacy and provide the most reliable and effective method for rapid pain relief. Although side effects are common, most are reversible: nausea, vomiting, pruritus, and constipation are the most frequent and bothersome side effects. Respiratory depression is uncommon at standard analgesic doses, but can be life-threatening. Opioid-related side effects can be reversed rapidly with the narcotic antagonist naloxone. Many physicians, nurses, and patients have a certain trepidation about using opioids that is based on an exaggerated fear of addiction. In fact, there is a vanishingly small chance of patients becoming addicted to narcotics as a result of their appropriate medical use. The physician should not hesitate to use opioid analgesics in patients with acute severe pain. Table 8-1 lists the most commonly used opioid analgesics.

Opioids produce analgesia by actions in the CNS. They activate pain-inhibitory neurons and directly inhibit pain-transmission neurons. Most of the commercially available opioid analgesics act at the same opioid receptor (μ-receptor), differing mainly in potency, speed of onset, duration of action, and optimal route of administration. Some side effects are due to accumulation of nonopioid metabolites that are unique to individual drugs. One striking example of this is normeperidine, a metabolite of meperidine. At higher doses of meperidine, typically greater than 1 g/d, accumulation of normeperidine can produce hyperexcitability and seizures that are not reversible with naloxone. Normeperidine accumulation is increased in patients with renal failure.

The most rapid pain relief is obtained by intravenous administration of opioids; relief with oral administration is significantly slower. Because of the potential for respiratory depression, patients with any form of respiratory compromise must be kept under close observation following opioid administration; an oxygen-saturation monitor may be useful, but only in a setting where the monitor is under constant surveillance. Opioid-induced respiratory depression is typically accompanied by sedation and a reduction in respiratory rate. A fall in oxygen saturation represents a critical level of respiratory depression and the need for immediate intervention to prevent life-threatening hypoxemia. Ventilatory assistance should be maintained until the opioid-induced respiratory depression has resolved. The opioid antagonist naloxone should be readily available whenever opioids are used at high doses or in patients with compromised pulmonary function. Opioid effects are dose-related, and there is great variability among patients in the doses that relieve pain and produce side effects. Synergistic respiratory depression is common when opioids are administered with other CNS depressants, most commonly the benzodiazepines. Because of this, initiation of therapy requires titration to optimal dose and interval. The most important principle is to provide adequate pain relief. This requires determining whether the drug has adequately relieved the pain and frequent reassessment to determine the optimal interval for dosing. The most common error made by physicians in managing severe pain with opioids is to prescribe an inadequate dose. Because many patients are reluctant to complain, this practice leads to needless suffering. In the absence of sedation at the expected time of peak effect, a physician should not hesitate to repeat the initial dose to achieve satisfactory pain relief.

An innovative approach to the problem of achieving adequate pain relief is the use of patient-controlled analgesia (PCA). PCA uses a microprocessor-controlled infusion device that can deliver a baseline continuous dose of an opioid drug as well as preprogrammed additional doses whenever the patient pushes a button. The patient can then titrate the dose to the optimal level. This approach is used most extensively for the management of postoperative pain, but there is no reason why it should not be used for any hospitalized patient with persistent severe pain. PCA is also used for short-term home care of patients with intractable pain, such as that caused by metastatic cancer.

It is important to understand that the PCA device delivers small, repeated doses to maintain pain relief; in patients with severe pain, the pain must first be brought under control with a loading dose before transitioning to the PCA device. The bolus dose of the drug (typically 1 mg of morphine, 0.2 mg of hydromorphone, or 10 μg of fentanyl) can then be delivered repeatedly as needed. To prevent overdosing, PCA devices are programmed with a lockout period after each demand dose is delivered (5–10 min) and a limit on the total dose delivered per hour. Although some have advocated the use of a simultaneous continuous or basal infusion of the PCA drug, this increases the risk of respiratory depression and has not been shown to increase the overall efficacy of the technique.

The availability of new routes of administration has extended the usefulness of opioid analgesics. Most important is the availability of spinal administration. Opioids can be infused through a spinal catheter placed either intrathecally or epidurally. By applying opioids directly to the spinal or epidural space adjacent to the spinal cord, regional analgesia can be obtained using relatively low total doses. Indeed, the dose required to produce effective localized analgesia when using morphine intrathecally (0.1–0.3 mg) is a fraction of that required to produce similar analgesia when administered intravenously (5–10 mg). In this way, side effects such as sedation, nausea, and respiratory depression can be minimized. This approach has been used extensively during labor and delivery and for postoperative pain relief following surgical procedures. Continuous intrathecal delivery via implanted spinal drug-delivery systems is now commonly used, particularly for the treatment of cancer-related pain that would require sedating doses for adequate pain control if given systemically. Opioids can also be given intranasally (butorphanol), rectally, and transdermally (fentanyl and buprenorphine), or through the oral mucosa (fentanyl), thus avoiding the discomfort of frequent injections in patients who cannot be given oral medication. The fentanyl and buprenorphine transdermal patches have the advantage of providing fairly steady plasma levels, which maximizes patient comfort.

Recent additions to the armamentarium for treating opioid-induced side effects are the peripherally acting opioid antagonists alvimopan (Entereg) and methylnaltrexone (Rellistor). Alvimopan is available as an orally administered agent that is restricted to the intestinal lumen by limited absorption; methylnaltrexone is available in a subcutaneously administered form that has virtually no penetration into the CNS. Both agents act by binding to peripheral μ-receptors, thereby inhibiting or reversing the effects of opioids at these peripheral sites. The action of both agents is restricted to receptor sites outside of the CNS; thus, these drugs can reverse the adverse effects of opioid analgesics that are mediated through their peripheral receptors without reversing their analgesic effects. Alvimopan has proven effective in lowering the duration of persistent ileus following abdominal surgery in patients receiving opioid analgesics for postoperative pain control. Methylnaltrexone has proven effective for relief of opioid-induced constipation in patients taking opioid analgesics on a chronic basis.

When used in combination, opioids and COX inhibitors have additive effects. Because a lower dose of each can be used to achieve the same degree of pain relief and their side effects are nonadditive, such combinations are used to lower the severity of dose-related side effects. However, fixed-ratio combinations of an opioid with acetaminophen carry an important risk. Dose escalation as a result of increased severity of pain or decreased opioid effect as a result of tolerance may lead to ingestion of levels of acetaminophen that are toxic to the liver. Although acetaminophen-related hepatotoxicity is uncommon, it remains a significant cause for liver failure. Thus, many practitioners have moved away from the use of opioid-acetaminophen combination analgesics to avoid the risk of excessive acetaminophen exposure as the dose of the analgesic is escalated.

TREATMENT: Chronic Pain

Once the evaluation process has been completed and the likely causative and exacerbating factors identified, an explicit treatment plan should be developed. An important part of this process is to identify specific and realistic functional goals for therapy, such as getting a good night’s sleep, being able to go shopping, or returning to work. A multidisciplinary approach that uses medications, counseling, physical therapy, nerve blocks, and even surgery may be required to improve the patient’s quality of life. There are also some newer, relatively invasive procedures that can be helpful for some patients with intractable pain. These include image-guided interventions such as epidural injection of glucocorticoids for acute radicular pain and radiofrequency treatment of the facet joints for chronic facet-related back and neck pain. For patients with severe and persistent pain that is unresponsive to more conservative treatment, placement of electrodes within the spinal canal overlying the dorsal columns of the spinal cord (spinal cord stimulation) or implantation of intrathecal drug-delivery systems has shown significant benefit. The criteria for predicting which patients will respond to these procedures continue to evolve. They are generally reserved for patients who have not responded to conventional pharmacologic approaches. Referral to a multidisciplinary pain clinic for a full evaluation should precede any invasive procedure. Such referrals are clearly not necessary for all chronic pain patients. For some, pharmacologic management alone can provide adequate relief.

The tricyclic antidepressants (TCAs), particularly nortriptyline and desipramine (Table 8-1), are useful for the management of chronic pain. Although developed for the treatment of depression, the TCAs have a spectrum of dose-related biologic activities that include analgesia in a variety of chronic clinical conditions. Although the mechanism is unknown, the analgesic effect of TCAs has a more rapid onset and occurs at a lower dose than is typically required for the treatment of depression. Furthermore, patients with chronic pain who are not depressed obtain pain relief with antidepressants. There is evidence that TCAs potentiate opioid analgesia, so they may be useful adjuncts for the treatment of severe persistent pain such as occurs with malignant tumors. Table 8-2 lists some of the painful conditions that respond to TCAs. TCAs are of particular value in the management of neuropathic pain such as occurs in diabetic neuropathy and postherpetic neuralgia, for which there are few other therapeutic options.

The TCAs that have been shown to relieve pain have significant side effects (Table 8-1; Chap. 61). Some of these side effects, such as orthostatic hypotension, drowsiness, cardiac conduction delay, memory impairment, constipation, and urinary retention, are particularly problematic in elderly patients, and several are additive to the side effects of opioid analgesics. The selective serotonin reuptake inhibitors such as fluoxetine (Prozac) have fewer and less serious side effects than TCAs, but they are much less effective for relieving pain. It is of interest that venlafaxine (Effexor) and duloxetine (Cymbalta), which are nontricyclic antidepressants that block both serotonin and norepinephrine reuptake, appear to retain most of the pain-relieving effect of TCAs with a side effect profile more like that of the selective serotonin reuptake inhibitors. These drugs may be particularly useful in patients who cannot tolerate the side effects of TCAs.

These drugs are useful primarily for patients with neuropathic pain. Phenytoin (Dilantin) and carbamazepine (Tegretol) were first shown to relieve the pain of trigeminal neuralgia. This pain has a characteristic brief, shooting, electric shock–like quality. In fact, anticonvulsants seem to be particularly helpful for pains that have such a lancinating quality. Newer anticonvulsants, gabapentin (Neurontin) and pregabalin (Lyrica), are effective for a broad range of neuropathic pains. Furthermore, because of their favorable side effect profile, these newer anticonvulsants are often used as first-line agents.

The long-term use of opioids is accepted for patients with pain due to malignant disease. Although opioid use for chronic pain of nonmalignant origin is controversial, it is clear that, for many patients, opioids are the only option that produces meaningful pain relief. This is understandable because opioids are the most potent and have the broadest range of efficacy of any analgesic medications. Although addiction is rare in patients who first use opioids for pain relief, some degree of tolerance and physical dependence is likely with long-term use. Furthermore, animal studies suggest that long-term opioid therapy may worsen pain in some individuals. Therefore, before embarking on opioid therapy, other options should be explored, and the limitations and risks of opioids should be explained to the patient. It is also important to point out that some opioid analgesic medications have mixed agonist-antagonist properties (e.g., butorphanol and buprenorphine). From a practical standpoint, this means that they may worsen pain by inducing an abstinence syndrome in patients who are physically dependent on other opioid analgesics.

With long-term outpatient use of orally administered opioids, it is desirable to use long-acting compounds such as levorphanol, methadone, sustained-release morphine, or transdermal fentanyl (Table 8-1). The pharmacokinetic profiles of these drug preparations enable the maintenance of sustained analgesic blood levels, potentially minimizing side effects such as sedation that are associated with high peak plasma levels, and reducing the likelihood of rebound pain associated with a rapid fall in plasma opioid concentration. Although long-acting opioid preparations may provide superior pain relief in patients with a continuous pattern of ongoing pain, others suffer from intermittent severe episodic pain and experience superior pain control and fewer side effects with the periodic use of short-acting opioid analgesics. Constipation is a virtually universal side effect of opioid use and should be treated expectantly. As noted above in the discussion of acute pain treatment, a recent advance for patients is the development of peripherally acting opioid antagonists that can reverse the constipation associated with opioid use without interfering with analgesia.

Soon after the introduction of a controlled-release oxycodone formulation (OxyContin) in the late 1990s, a dramatic rise in emergency department visits and deaths associated with oxycodone ingestion appeared, focusing public attention on misuse of prescription pain medications. The magnitude of prescription opioid abuse has grown over the last decade, leading the Centers for Disease Control and Prevention to classify prescription opioid analgesic abuse as an epidemic. This appears to be due in large part to individuals using a prescription drug nonmedically, most often an opioid analgesic. Drug-induced deaths have rapidly risen and are now the second leading cause of death in Americans, just behind motor vehicle fatalities. In 2011, the Office of National Drug Control Policy established a multifaceted approach to address prescription drug abuse, including Prescription Drug Monitoring Programs that allow practitioners to determine if patients are receiving prescriptions from multiple providers and use of law enforcement to eliminate improper prescribing practices. This increased scrutiny leaves many practitioners hesitant to prescribe opioid analgesics, other than for brief periods to control pain associated with illness or injury. For now, the choice to begin chronic opioid therapy for a given patient is left to the individual practitioner. Pragmatic guidelines for properly selecting and monitoring patients receiving chronic opioid therapy are shown in Table 8-3.

It is important to individualize treatment for patients with neuropathic pain. Several general principles should guide therapy: the first is to move quickly to provide relief, and the second is to minimize drug side effects. For example, in patients with postherpetic neuralgia and significant cutaneous hypersensitivity, topical lidocaine (Lidoderm patches) can provide immediate relief without side effects. Anticonvulsants (gabapentin or pregabalin; see above) or antidepressants (nortriptyline, desipramine, duloxetine, or venlafaxine) can be used as first-line drugs for patients with neuropathic pain. Systemically administered antiarrhythmic drugs such as lidocaine and mexiletine are less likely to be effective; although intravenous infusion of lidocaine can provide analgesia for patients with different types of neuropathic pain, the relief is usually transient, typically lasting just hours after the cessation of the infusion. The oral lidocaine congener mexiletine is poorly tolerated, producing frequent gastrointestinal adverse effects. There is no consensus on which class of drug should be used as a first-line treatment for any chronically painful condition. However, because relatively high doses of anticonvulsants are required for pain relief, sedation is very common. Sedation is also a problem with TCAs but is much less of a problem with serotonin/norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine and duloxetine). Thus, in the elderly or in patients whose daily activities require high-level mental activity, these drugs should be considered the first line. In contrast, opioid medications should be used as a second- or third-line drug class. Although highly effective for many painful conditions, opioids are sedating, and their effect tends to lessen over time, leading to dose escalation and, occasionally, a worsening of pain due to physical dependence. Drugs of different classes can be used in combination to optimize pain control. Repeated injections of botulinum toxin is an emerging approach to focal neuropathic pain based on recent studies.

It is worth emphasizing that many patients, especially those with chronic pain, seek medical attention primarily because they are suffering and because only physicians can provide the medications required for pain relief. A primary responsibility of all physicians is to minimize the physical and emotional discomfort of their patients. Familiarity with pain mechanisms and analgesic medications is an important step toward accomplishing this aim.