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CHAPTER OUTLINE
Medications can provide effective pain management in most patients. Choosing the appropriate medication requires that the pain state being treated is correctly diagnosed and classified as somatic, visceral, or neuropathic. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the principal medications for somatic pain, whereas adjuvant medications such as antidepressants, antiepileptics, anesthetics, and adrenergic agents are useful for neuropathic pain. Severe pain, whether somatic or neuropathic, usually requires opioid therapy. For example, in clinical trials, when classic adjuvants (e.g., gabapentin, amitriptyline) failed for moderate to severe neuropathic pain, a good response was demonstrated with tramadol, low-dose methadone, and, of course, morphine (1–4). After the appropriate class of medication has been selected, the choice of a specific drug is determined by its side effects, route of administration, and individual patient characteristics. Balancing the benefits of a drug with the patient’s ability to take it is the art of drug therapy. Other treatment modalities include interventional techniques and physical modalities. In the management of chronic pain, these are adjuncts to primary therapy and are not substitutes for pharmacotherapy. This chapter provides an overview of these methods and their indications. (Psychological approaches, which are integral to a multidisciplinary approach to pain management, are reviewed in Chapters 94 and 95. Use of opioid medications is discussed in Chapter 97.)
NONOPIOID PHARMACOLOGIC AGENTS
Many of the medications used to treat pain are not primary analgesics, but have analgesic efficacy under certain conditions. Such medications are classified as adjuvant analgesics. They include antiepileptic drugs (AEDs), antidepressants, adrenergic agonists, local anesthetics, and muscle relaxants. Other medications are primary analgesics, but are not opioids. Appropriate use of both types of medications can greatly improve analgesia as well as overall pain management.
NONOPIOID ANALGESICS
Nonsteroidal Anti-Inflammatory Drugs
NSAIDs, which are the most widely used analgesics, are indicated for somatic pain of mild to moderate intensity. They are most useful in bone and joint pain, but can be used in conjunction with opioids for all forms of pain. The first NSAID, aspirin, remains the model for all others. Newer compounds have the same presumed mode of action but offer advantages in side effect profiles and ease of use. Although the exact mechanism of NSAID analgesia is unclear, it is thought to be related to the inhibition of cyclooxygenase activity (COX), which in turn inhibits prostaglandin production (5). Prostaglandins sensitize peripheral nerve endings to noxious stimuli and are the key to the inflammatory cascade. There also is evidence that NSAIDs have a role in modulating pain in the central nervous system, particularly at the spinal cord level (5), independent of their anti-inflammatory action (6). It is not clear which mechanism is more important clinically.
All NSAIDs are well absorbed in the gastrointestinal (GI) tract. Most undergo some hepatic conjugation or oxidation and are excreted in urine. For this reason, hepatic and renal impairment can lead to drug accumulation. Generally, NSAIDs that are conjugated require further renal metabolism to be excreted, whereas NSAIDs that predominantly undergo oxidative metabolism in the liver are simply excreted and appear safer in renal failure (tenoxicam and piroxicam) (7). It should be noted that the aforementioned NSAIDs, those requiring hepatic oxidation, are dangerous in patients with liver failure. Overall, most NSAIDs require hepatic and renal clearance; therefore, dose adjustment in these settings is required.
There is a ceiling level to the analgesic effect of NSAIDs, beyond which increasing the dose does not improve analgesia. Unfortunately, this ceiling varies from patient to patient, requiring individualized titration of dose. Patients have variable responses to the different classes of NSAIDs: some do not respond at all to one class, but have excellent results with a different class.
The toxicity of NSAIDs is well recognized. In elderly persons and patients with renal, hepatic, and hematologic disease, associated side effects are enhanced. For this reason, the usual guidelines regarding dosing need to be adjusted and often cannot be used. Several studies suggest that the rate of significant GI problems is about 10% (8). Nausea and diarrhea are common GI side effects of NSAIDs. Gastric and duodenal ulceration, although less common, are clinically more important. The effects of NSAIDs on the GI tract are thought to be due to prostaglandin inhibition and loss of their protective effect on the gastric mucosa. NSAIDs do not produce ulceration by a local effect alone, as is shown by the ulcerogenic effect of parenteral NSAIDs and by the fact that prostaglandin decrease is seen throughout the entire GI tract. It is difficult to predict which patient will develop GI ulceration. Nausea and abdominal pain are poor warning symptoms of toxicity. Proton pump inhibitors (PPIs) are clinically accepted and suggested by both the American College of Rheumatology and the American Pain Society for patients with GI risk factors when such alternatives as acetaminophen or COX-1 alternatives cannot be employed (9,10). Prophylaxis with misoprostol can also be useful (11), but it is expensive and its long-term effects are unknown. Consequently, it should be reserved for patients who have a known sensitivity to NSAIDs and after PPI failure. Renal damage is another major toxic effect of NSAIDs, particularly for patients with compromised renal function (12). NSAIDs should be used very cautiously in these patients. A useful rule of thumb is to avoid the use of NSAIDs in any patient with proteinuria and decreased glomerular filtration rate. Hematologic toxicity, primarily platelet inhibition, can be particularly problematic. Most NSAIDs inhibit platelet aggregation and prolong bleeding time; these effects usually last for about 1 week. The nonacetylated salicylates choline magnesium trisalicylate and salsalate have minimal anti-platelet effects and can be used in patients with platelet dysfunction (13). Since NSAIDs compete with aspirin (ASA) for platelet binding sites, they have the potential to reverse the protective effect of ASA on strokes and myocardial infarction. For this reason, the Food and Drug Administration has recommended that, when patients are taking immediate-release ASA for anticoagulation, the NSAID should be taken 8 hours before the ASA or 30 minutes after (14).
Significant interactions between NSAIDs and other medications are common. The most important of these involve the potentiation of renal and hepatic toxicity of coadministered drugs and the changes NSAIDs can produce in anticonvulsant levels. Dramatic and dangerous increases in serum levels of lithium, widely used in psychiatric therapy, can result from coadministered NSAIDs resulting from decreased renal clearance (15). There is no known interaction between NSAIDs and antiretroviral medications. Although the major indication for NSAIDs is the treatment of mild to moderate somatic pain, these drugs often are used in conjunction with low-potency opiates for more severe pain. Bone and joint pains are very responsive to NSAIDs, but neuropathic pain usually is not (16). In the author’s experience, diffuse myalgias also are generally resistant to these medications, except in the setting of fever. Patients with advanced disease and pain sufficiently severe to interfere with their activities of daily living will require additional medications.
COX-2 Selective NSAIDs
In an attempt to decrease the toxicity of traditional NSAIDs, COX-2 selective inhibitors have been developed. Whereas traditional NSAIDs inhibit both COX-1 (which is protective to the gut and important in other constitutive processes) and COX-2 (which is predominantly involved in inflammation and pain), COX-2 selective NSAIDs were thought to affect only the inflammatory pathway. After their introduction, COX-2 inhibitors, celecoxib, valdecoxib, and rofecoxib, were heavily employed because of their therapeutic equality to traditional NSAIDs, but decreased GI side effects. Questions about the importance of COX-2 constitutive expression in vascular endothelium were subsequently raised. Clinical trials and retrospective meta-analysis demonstrated increased myocardial infarctions and strokes in recipients of COX-2 inhibitors compared to traditional NSAIDs (17,18). Rofecoxib and valdecoxib have been withdrawn from the market. Celecoxib is still available, but with a black box warning for cardiovascular risk. COX-2 inhibitors still have use in specific populations, but considering their cost, absence of analgesic superiority, and the ubiquity of cardiovascular disease, their use over traditional NSAIDs or COX-2 “preferred” NSAIDs (such as meloxicam and nabumetone) should be carefully considered.
Adjuvant Analgesics
Medications that have a primary indication other than analgesia, but which have analgesic properties under certain conditions, are termed adjuvant analgesics. Most of these medications enhance the body’s own pain-modulating mechanisms or the effectiveness of other analgesics. Several different classes of medications are used as adjuvants, including antidepressants, antiepileptics, oral local anesthetics, and adrenergic agonists.
Antidepressants
The tricyclic antidepressants (TCAs) have been used for many years for the management of neuropathic pain. Their analgesic effect appears to be independent of their antidepressant actions (19). There is evidence to suggest that their mode of action is to enhance the body’s own pain-modulating pathways and to enhance opioid effect at the opioid receptors (20). Their onset of action is slow, requiring several weeks for the full drug effect to be achieved. They are most effective for continuous, burning, or dysesthetic pain (21). Although TCAs are a first-line therapy for many forms of neuropathy, they appear to have poor efficacy in HIV neuropathy (22,23). This may be due to the rapid degeneration of nerve fibers in HIV. The greatest analgesic effect is seen with the older, tertiary amine antidepressants, such as amitriptyline, imipramine, and doxepin. Secondary amine tricyclics, such as desipramine and nortriptyline, also are effective and have less sedation and anticholinergic side effects (24). The selective serotonin reuptake inhibitor class does not seem to be as effective for neuropathic pain (25,26). Nevertheless, they can be helpful in managing associated depression and insomnia. Tricyclics are well absorbed from the GI tract and have few interactions with antiretroviral agents. However, they do have a significant number of side effects, the most common of which is sedation. In many cases, this can be avoided by starting at a low dose and instructing the patient to take the medication 10 to 12 hours before rising, rather than at bedtime. The usual starting dose for amitriptyline is between 10 and 25 mg, and most patients find benefit at ranges between 50 and 150 mg. Some patients do well with doses above and below this range as well. Many of the other side effects seen with TCAs are related to their anticholinergic properties. These include dry mouth, visual blurring, urinary retention, hypotension, and cardiac arrhythmias. Patients often become tolerant to these after some time. Starting at a low dose of 10 mg and escalating at weekly intervals reduce the likelihood of significant discomfort. TCAs are contraindicated in patients with glaucoma, cardiac arrhythmias, and prolonged QTc (i.e., >440 ms) and should be used with caution in patients with urinary outlet obstruction. QT prolongation is especially hazardous if tricyclics are combined with methadone, which both increases blood level of the tricyclic and independently prolongs QT. Therefore, this combination is best avoided.
Some patients are not able to tolerate TCAs and may benefit from some of the newer antidepressants. In general, serotonin–norepinephrine uptake inhibitors are superior for pain reduction to selective serotonin uptake inhibitors, and typically, the more selective the antidepressant is for serotonin, the less analgesic effect it has. In fact, the tricyclics are serotonin–norepinephrine uptake inhibitors. Nevertheless, some studies have shown benefit, for example, of paroxetine in certain forms of painful peripheral neuropathy and escitalopram in chronic low back pain (27,28). Similar evidence does not exist for other selective serotonin reuptake inhibitors. Venlafaxine and duloxetine (SNRIs) have shown efficacy in peripheral neuropathy and other pain therapy (29–31). In a well-designed crossover study, venlafaxine (225 mg/d) and imipramine (150 mg/d) similarly improved symptoms of painful polyneuropathy where patients rated pain paroxysms, constant pain, and pressure-evoked pain. The number needed to treat was lower in the imipramine group than in those given venlafaxine (2.7 vs. 5.2) (29–31). Venlafaxine has also been shown to be effective in postmastectomy pain syndrome, fibromyalgia, migraine and tension headache, and painful diabetic neuropathy. It lacks the anticholinergic effects associated with classic TCAs (32,33). Multiple clinical trials with duloxetine have demonstrated efficacy in restoring functional status and decreasing pain scores in diabetic peripheral neuropathy when given in doses of 60 mg daily or twice daily (34,35). A recent randomized blinded trial of diabetic neuropathy demonstrated that duloxetine is comparable to amitriptyline in efficacy, but overall participants preferred duloxetine (35). Duloxetine, at the same dose, has also improved global pain scores in fibromyalgia, for which it has an FDA indication (with and without comorbid depression) (36). Duloxetine and venlafaxine may be the preferred drugs for the treatment of depression with comorbid pain syndromes, regardless of whether these pain syndromes have classic etiologies (e.g., diabetic peripheral neuropathy, radicular pain) or nonspecific pain associated with depression (37). Advantages over classic TCAs include fewer anticholinergic effects, less alpha blockade (fewer falls), and absence of QTc prolongation.
Anticonvulsants
Carbamazepine, phenytoin, gabapentin, and several other anticonvulsant/AEDs have efficacy in neuropathic pain (38). Modes of action vary, but generally relate to sodium channel blockade, GABA-ergic action, or modulation of calcium channels. AEDs may reduce pain by reducing neuronal excitability and local neuronal discharges. They appear to be helpful in pain syndromes that are characterized by paroxysmal or lancinating pain, as well as burning pain and allodynia (39). Phenytoin was the first AED used for pain and was found to be effective in trigeminal neuralgia in 1942. It has been used for the management of a variety of neuropathic pain syndromes, including trigeminal neuralgia and postherpetic neuralgia (40); however, it is no longer in common use, as it has been supplanted by newer drugs that are less toxic, have fewer interactions, and have more approved indications. That being said, carbamazepine remains first-line therapy for tic douloureux (40). The average dose of phenytoin is 300 mg/d. A loading dose of 1 g can be used for acute pain management. Phenytoin has significant interactions with a variety of protein-bound medications, including rifampin, methadone, and several antifungal agents. Both phenytoin and carbamazepine induce many cytochrome P450s and glucuronyl transferase enzymes and can reduce the serum concentration of drugs that are substrates of these enzymes, including other AEDs, steroids, cyclosporin A, warfarin, and cardiovascular, antineoplastic, and psychotropic drugs (41). Dizziness and somnolence are common with phenytoin and usually are dose related. Serious skin reactions such as Stevens-Johnson syndrome can occur, necessitating discontinuation of the drug. Leukopenia and thrombocytopenia can occur as idiosyncratic reactions. Elevation of liver enzymes is common. Carbamazepine has been well studied and used successfully in a variety of neuropathic pain states (39,42). It appears to be more effective than phenytoin. Important side effects include dizziness, somnolence, and significant leukopenia. Hyponatremia also can occur as an idiosyncratic reaction. Starting at a dose of 100 mg and gradually escalating in 100 mg increments every 3 to 7 days can minimize the dizziness. Close monitoring of the blood count is necessary and limits the utility of this drug in HIV patients. Carbamazepine has significant autoinduction of metabolism and may require escalating doses over time to achieve the same plasma levels and clinical effect. Oxcarbazepine has similar issues clinically, but there is some evidence that it may be useful in pain of spinal cord injury (SCI), radiculopathy, and diabetic neuropathy, as well as carbamazepine nonresponsive trigeminal neuralgia (43). Its toxicity is less than that of carbamazepine, and drug interactions, other than additive sedation and dizziness, are not a major concern. Hyponatremia is a frequent problem, particularly when combined with a number of psychotropic drugs. Valproic acid has been used for the management of lancinating pain, with mixed results, and for pain of diabetic neuropathy (44). There are no large studies demonstrating long-term effectiveness, and a recent Cochrane Review found support to be poor for its use in neuropathic pain (45). The large number of drug interactions and significant hepatic dysfunction that can occur with this drug make it a second-line choice. There is, however, extensive evidence of its usefulness for migraine, both as an abortive and as a prophylactic agent (46,47).
Several newer AEDs, released in the last 10 to 15 years, have been found to be useful in treating neuropathic pain, and the gabapentinoids have become first-line agents for several of them. Gabapentin is well established, and multiple studies have demonstrated efficacy in both lancinating and continuous dysesthetic pain (48–52). A recent clinical trial compared gabapentin with nortriptyline in 56 people with neuropathic pain. It found that combination of these two medications resulted in a significantly greater pain reduction (52.8%) than did gabapentin alone (31.1%) or nortriptyline alone (38.8%) (53). Gabapentin is a remarkably well-tolerated drug with few interactions and a good side effect profile. Treatment usually is started at 100 mg three times per day and then escalated in increments of 100 to 300 mg every 3 to 5 days. Most patients have a response at 300 mg three times per day, but may require dosing up to 3,600 mg/d (52). There is some evidence that doses higher than 3,600 to 4,800 mg are not well absorbed, so doses above this range are of questionable utility (54
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