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Pharmacologic Strategies in Back Pain and Radiculopathy
Back pain is a major health problem in the United States. About 70% to 85% of the population experiences back pain at some point in their lives, with the annual prevalence ranging from 15% to 45%. Usually, the clinical course is benign, with 95% recovering within a few weeks to months of onset. It is most common in middle-aged adults, with equal distribution in men and women. Back pain is the most frequent reason for activity limitation in people younger than 45 years and the second leading cause for doctor visits and absenteeism from work. The lower back is the primary site of pain in 85% of patients. It also has a major economic impact in the form of direct costs (costs incurred for physician services, surgery, medical devices, medications, hospital services, and diagnostic testing) and indirect costs (cost incurred from absenteeism and decreased productivity). The cost of treating low back pain has been increasing; total cost in the United States is estimated to exceed $100 to $200 billion per year. Two-thirds of the cost is indirect, due to lost wages and reduced productivity. The rate of back surgery in the United States has increased dramatically, especially for spinal fusion. From 1979–1981 to 1988–1990, the rate of hospitalizations with cervical spine surgery increased more than 45%, with the rates for cervical fusion surgery increasing more than 70%. The rate of hospitalizations with lumbar spine surgery increased more than 33%, with the rate for lumbar fusion surgery increasing more than 60%.
Although often used in conjunction with other means of managing back pain, drug therapy remains a mainstay in the treatment of back pain. The ultimate endpoint of any therapeutic intervention is to overcome the pathophysiologic process responsible for pain generation. However, pharmacologic treatment of low back pain often aims to provide symptomatic relief.
It is important to recognize the nature and basic mechanisms of back pain before attempting to use pharmacologic agents. Nociceptive pain results from tissue injury and subsequent activation of peripheral nociceptors, whereas neuropathic pain arises from the nerve injury or dysfunction of central or peripheral nervous system elements. Radicular pain , or pain in the distribution of specific spinal nerve(s), is a form of neuropathic pain. It is frequently referred to as sciatica when it involves the lower extremities. Radiculopathy is the objective change of sensory or motor function due to conduction block in the axons of the spinal nerve or its roots as a result of irritation of the nerve by compression or inflammatory mediators. Neuropathic pain is notoriously difficult to treat. The paucity of well-designed, large, randomized, double-blind, and prospective placebo-controlled trials results in management decisions based on individual physician perspectives and experiences. Most common drug therapies for back pain with or without radiculopathy include acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), muscle relaxants, tramadol, antidepressants, opioids, and membrane-stabilizing medications. This chapter reviews the literature using an evidence-based approach whenever possible.
Acetaminophen
Acetaminophen, also known as paracetamol, is a p -aminophenol derivative with antipyretic and analgesic properties. It is frequently used as a first-line agent in acute low back pain and osteoarthritis due to its favorable gastrointestinal safety profile over aspirin and other antiinflammatory drugs. No trial has evaluated acetaminophen versus placebo for chronic low back pain, and the only trial that compared paracetamol to no treatment did not show any favorable effects in acute low back pain. In five trials, no significant difference was demonstrated between paracetamol at dosages up to 4 g/day and different NSAIDs for back pain of variable duration. However, several systematic reviews of patients with osteoarthritis reliably showed acetaminophen to be slightly less effective in pain relief than NSAIDs. The mechanism of action is not fully understood but is thought to have central and peripheral mechanisms. Acetaminophen is a weak inhibitor of cyclooxygenase enzymes (COX-l and COX-2) and may be a cloned COX-3 enzyme. It has few side effects and is entirely metabolized in the liver. The maximum daily allowed dose of acetaminophen has been the subject of controversy. The pharmaceutical producer of the Tylenol brand of acetaminophen decreased the maximum daily dose of acetaminophen from 4000 mg/day to either 3000 mg/day or 3250 mg/day for consumers taking the 500-mg or 325-mg tablet preparations, respectively, which was not followed by many other manufacturers. In order to diminish acetaminophen hepatotoxicity, the U.S. Food and Drug Administration (FDA) established regulations to limit prescription combination drug products to contain no more than 325 mg of acetaminophen per dosage unit. Chronic administration f higher doses is associated with hepatotoxicity (especially in chronic ethanol users, malnourished, and fasting patients).
Nonsteroidal Antiinflammatory Drugs
NSAIDs are the most frequently prescribed medications worldwide and are commonly used for treating back pain. They possess antipyretic, antiinflammatory, and analgesic effects, the latter two accounting for their use in arthritic and painful disorders. The mechanism of action of NSAIDs includes COX-l and COX-2 inhibition, resulting in decreased tissue levels of prostaglandins. NSAIDs that inhibit both COX-l and COX-2 include aspirin, ibuprofen, diclofenac, indomethacin, naproxen, and piroxicam. NSAIDs that selectively inhibit COX-2 include celecoxib, etodolac, meloxicam, and nimesulide. In a systematic review of 65 randomized controlled trials of NSAIDs in low back pain, the authors concluded that NSAIDs were more effective compared with placebo but at the cost of significantly more side effects. There was moderate evidence that NSAIDs were more effective than acetaminophen for acute low back pain, but acetaminophen had fewer side effects. There was moderate evidence that NSAIDs were not more effective than other drugs for acute low back pain. There was strong evidence that various types of NSAIDs, including COX-2 NSAIDs, were equally effective for acute low back pain. The data suggested that NSAIDs were effective for short-term symptomatic relief in patients with acute and chronic low back pain without sciatica. A systematic review of 13 trials found that NSAIDs are more beneficial than placebo in pain intensity. NSAIDs were slightly more effective than placebo as regards disability. However, the extent of the efficacy was minimal and the level of evidence was not significant.
NSAIDs can have serious side effects on various organ systems, including the gastrointestinal tract (gastroduodenal ulceration and bleeding), kidneys (renal insufficiency and hypertension), cardiovascular system (peripheral edema, hypertension, and congestive heart failure), and reproductive system (adverse pregnancy outcomes). The risk of serious gastrointestinal complications, such as bleeding or perforation, is increased fourfold to fivefold with continued intake of nonselective NSAIDs, and the risk of developing renal failure is twofold. The risk of gastrointestinal complications is increased with age, history of peptic ulcer disease, concomitant corticosteroids, and anticoagulation therapy. Concomitant NSAIDs and anticoagulation therapy is not recommended, as it increases the risk of bleeding. The risk of acute renal failure increases with age, history of renal insufficiency, heart failure, hypertension, and use of diuretics or angiotensin-converting enzyme inhibitors.
The toxicity associated with chronic NSAID administration limits its benefit-to-risk ratio. The discovery of isoenzymes of cyclooxygenase, COX-1 and COX-2 (predominant role in inflammation) led to the development of selective COX-2 inhibitors. COX-1 is responsible for generation of cytoprotective prostanoids and is constitutively expressed in platelets and gastroduodenal mucosa. Thus, inhibition of COX-1 leads to the increased risk of gastroduodenal bleeding. Compared with nonselective COX inhibitors, the selective COX-2 inhibitors are associated with reduced gastrointestinal complications, provided that patients are not taking aspirin concomitantly. Nonetheless, COX-2 inhibitors are just as effective analgesics as nonselective NSAIDs. Misoprostol, a synthetic analog of prostaglandin E 1 , exerts a gastrointestinal mucosal protective effect by increasing mucus, bicarbonate ion secretion, and increasing mucosal blood flow. Concomitant use of misoprostol or proton pump inhibitors with NSAIDs reduces the risk of gastrointestinal complications. Misoprostol is available in tablet form in combination with diclofenac. Misoprostol should be used with caution in females of child-bearing age because it can initiate uterine contractions and miscarriage.
The kidney constitutively expresses both COX-1and COX-2. This may explain why COX-2 inhibitors seem to exhibit a similar renal side effect profile to nonselective NSAIDs. It appears that renal side effects are consequent to the inhibition of COX-2 by NSAIDs.
The cardiovascular effects of NSAIDs have caused a major stir since the introduction of selective COX-2 inhibitors (coxibs). There has been increased risk of cardiovascular events with patients using selective COX-2 inhibitors. This resulted in withdrawal of rofecoxib and valdecoxib. Only celecoxib remains in the market. The possible mechanism of increase in cardiovascular risk seems to be due to the disruption of the normal balance between prothrombotic and antithrombotic prostaglandins. Thromboxane A 2 is a platelet activator and aggregator that is mediated by prostaglandin products of the COX-l isomer pathway. Prostaglandin I 2 vasodilates and inhibits platelet aggregation when the COX-2 isomer is activated.
Thrombotic cardiovascular events may follow when thromboxane A 2 predominates over prostaglandin I 2 . Coxibs use should be avoided in patients with increased cardiovascular risk, including patients with recent cardiovascular events, unstable angina, acute myocardial infarction, ischemic cerebrovascular events, and high blood pressure. If coxibs are indicated, the smallest effective dose for the shortest duration should be used. Naproxen may be a better alternative to coxibs. Physicians should weigh the risk-to-benefit ratio when prescribing NSAIDs in all patients.
A diclofenac patch is available for topical use in acute musculoskeletal sprains. Use of topical patches for localized pain may reduce the risk of serious adverse events due to low systemic concentration.
Muscle Relaxants
Skeletal muscle relaxants are commonly used for back pain. They are a heterogeneous group of agents that mainly act on the central nervous system (CNS). At therapeutic doses they seem to exert their effect through sedation and subsequent depression of the neuronal transmission. Studies have shown that muscle relaxants are effective when used for short duration in treatment of acute low back pain. There is no evidence for long-term use of muscle relaxants in chronic low back pain. In a systematic review of 30 trials, skeletal muscle relaxants were moderately superior to placebo for short-term pain relief. However, there was inadequate evidence to demonstrate the effectiveness of skeletal muscle relaxants for chronic low back pain and they were associated with more CNS adverse events compared to placebo. Commonly used drugs include cyclobenzaprine, methocarbamol, metaxalone, carisoprodol, diazepam, tizanidine, baclofen, orphenadrine, and chlorzoxazone. The most common adverse effects are drowsiness and dizziness. Physicians should be aware of possible dependence and abuse of some of the muscle relaxants, such as diazepam and carisoprodol.
Antidepressants
Antidepressants have been used widely for managing various painful conditions of neuropathic origin. Antidepressants differ in their effectiveness in pain control depending on whether they inhibit reuptake of serotonin (serotonergic antidepressants, such as paroxetine, fluoxetine, sertraline, and citalopram); norepinephrine (noradrenergic antidepressants, such as desipramine, and maprotiline); or both (serotonergic-noradrenergic antidepressants, such as amitriptyline, doxepin, imipramine, clomipramine, venlafaxine, and duloxetine). Serotonergic-noradrenergic antidepressants were found to be more effective than placebo in chronic low back pain. The symptom reduction of these drugs in chronic low back pain seems to be independent of their effect on depression. There was conflicting evidence as to whether antidepressants improved the functional status of the patients with chronic low back pain. In addition to chronic back pain, antidepressants exhibit an apparent antinociceptive effect in other musculoskeletal conditions, including osteoarthritis, rheumatoid arthritis, and fibromyalgia. Antidepressants are associated with significant adverse events: drowsiness, dizziness, dry mouth, constipation, urinary retention, and weight gain.
Duloxetine, a serotonin-norepinephrine reuptake inhibitor, has been approved for use in fibromyalgia and diabetic peripheral neuropathic pain. A meta-analysis of four randomized, double-blind, placebo-controlled studies of duloxetine in the treatment of fibromyalgia showed it to be significantly superior to placebo in relieving pain. For chronic lower back pain, three trials showed lower pain intensity with duloxetine associated with lower pain intensity and better function versus placebo. Adverse effects tend to be mild. The effectiveness of duloxetine compared to tricyclic antidepressants was not evaluated. The efficiency of antidepressants, particularly for radicular low back pain, has not been studied.
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