CHAPTER 105 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 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 young people younger than 45 years of age and the second leading cause for doctor visits and absenteeism from work. The lower back is the primary site of pain in 85% of the sufferers. It also has a major economic impact in the form of direct costs (costs incurred for physician services, medical devices, medications, hospital services, diagnostic testing, etc.) and indirect costs (cost incurred from absenteeism and decreased productivity). The cost of treating low back pain has been increasing, and 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.1–4
It is important to distinguish between nociceptive pain and neuropathic pain. Nociceptive pain results from tissue injury and subsequent activation of peripheral nociceptors, whereas neuropathic pain arises from the nerve injury or dysfunction. Radicular pain or pain in the distribution of the spinal nerve is a form of neuropathic pain. It is frequently referred to as sciatica when it involves the lower extremities. Radiculopathy is objective loss of sensory or motor function due to conduction block in the axons of a spinal nerve or its roots as a result of irritation of the outer layers of the nerve by compression or inflammatory mediators. It is important to avoid the indiscriminate use of adjunctive analgesics for nociceptive pain because they have a much stronger theoretical basis for use in neuropathic pain. Neuropathic pain is notoriously difficult to treat, and 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.5–9
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 anti-inflammatory drugs.10–11 The mechanism of action is not fully understood but is thought to have central and peripheral mechanism. Acetaminophen is a weak inhibitor of cyclooxygenase enzyme (COX-1 and COX-2) and may be cloned COX-3 enzyme.12 It has few side effects and is entirely metabolized in liver. The usual dosage range of 2600 to 3200 mg/day is safe, and the recommended adult dose is up to 4 g/day. Chronic administration of higher doses is associated with hepatotoxicity (especially in chronic ethanol users, malnutrition, and fasting patients).13
Nonsteroidal Anti-inflammatory Drugs
NSAIDs are the most frequently prescribed medications worldwide and are commonly used for treating back pain. They possess antipyretic, anti-inflammatory, and analgesic effects, the latter two accounting for their use in arthritic and painful disorders. The mechanism of action of NSAIDs includes cyclooxygenase enzyme (COX-1 and COX-2) inhibition, resulting in decreased tissue levels of prostaglandins. NSAIDs also have a central action. Those that inhibit both COX-1 and COX-2 include aspirin, ibuprofen, diclofenac, indomethacin, naproxen, and piroxicam. NSAIDs that selectively inhibit COX-2 include celecoxib, etodolac, meloxicam, and nimesulide.14 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.15
NSAIDs can have serious side effects on various organ systems including the gastrointestinal tract (gastroduodenal ulceration and bleeding); kidneys (renal insufficiency, salt and water retention, edema, and hypertension); cardiovascular system (peripheral edema, hypertension, and congestive heart failure); and reproductive system (adverse pregnancy outcomes).16–19 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 anticoagulants. 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.20–21
The toxicity associated with chronic NSAID administration limits NSAIDs’ benefit-to-risk ratio. The discovery of isoenzymes of cyclooxygenase, COX-1 (constitutive), 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.19,21 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 incidence and complications related to gastroduodenal ulceration, provided patients are not taking aspirin concomitantly.18,21,22,23 Nonetheless, COX-2 inhibitors were just as effective analgesics as nonselective NSAIDs.15 Misoprostol, a synthetic analogue of prostaglandin E1 (PGE1), exerts a gastrointestinal mucosal protective effect by increasing mucous, bicarbonate ion secretion, and increasing mucosal blood flow. Concomitant use of Misoprostol or proton pump inhibitors with NSAIDs reduces the risk of gastrointestinal complications.24 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-1 and 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.17,22,23
The cardiovascular effects of NSAIDs have caused a major stir since the introduction of COX-2 selective inhibitors (coxibs). There has been increased risk of cardiovascular events with patients using selective COX-2 inhibitors.25–27 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 pro and antithrombotic prostaglandins. Thromboxane A2 is a platelet activator and aggregator that is mediated by prostaglandin products of the COX-1 isomer pathway. Prostaglandin PGI2 vasodilates and inhibits platelet aggregation when the COX-2 isomer is activated. Thrombotic cardiovascular events may follow when thromboxane A2 predominates over PGI2.28 Coxibs use should be avoided in patients with increased cardiovascular risk including patients with recent cardiovascular events, unstable angina, acute myocardial infarction, and ischemic cerebrovascular events. If coxibs are indicated, the smallest effective dose for the shortest duration should be used. Naproxen may be a better alternative to coxibs.29 Physicians should weigh the risk-to-benefit ratio when prescribing NSAIDs in all patients.
Medicated 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.30
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.31 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.28 Commonly used drugs include cyclobenzaprine, methocarbamol, metaxalone, carisoprodol, diazepam, tizanidine, baclofen, orphenadrine, and chlorzoxazone. The most common adverse effect includes drowsiness and dizziness. Physicians should be aware of possible dependence and abuse of some of the muscle relaxants like diazepam and carisoprodol.32
Antidepressants
Antidepressants have been used widely for managing various painful conditions, mainly neuropathic pain. Antidepressants differ in their effectiveness in pain control depending on whether they inhibit reuptake of serotonin (serotonergic antidepressants like paroxetine, fluoxetine sertraline, and citalopram); norepinephrine (noradrenergic antidepressants like desipramine, nortriptyline, and maprotiline); or both (serotonergic-noradrenergic antidepressants like amitriptyline, doxepin, imipramine, clomipramine, venlafaxine, and duloxetine). Serotonergic-noradrenergic antidepressants were found to be more effective than placebo in chronic low back pain.33–35 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.9 In addition to chronic back pain, antidepressants exhibit an apparent antinociceptive effect in other musculoskeletal conditions including osteoarthritis, rheumatoid arthritis, and fibromyalgia.33,34 Antidepressants are associated with significant adverse events, namely drowsiness, dizziness, dry mouth, constipation, urinary retention, and weight gain.36
Duloxetine, a serotonin-norepinephrine reuptake inhibitor, has been approved for use in fibromyalgia and diabetic peripheral neuropathic pain.37–42 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. Adverse effects tend to be mild.
Opioids
Opioids remain the most potent analgesic and are a mainstay in the treatment of acute and chronic painful conditions of moderate to severe intensity. Although their analgesic efficacy is well established, their effect on functional improvement is controversial.43–47 Nociceptive pain is more responsive to opioid therapy than is neuropathic pain. Opioids have been widely used for non–cancer pain including chronic low back pain and radiculopathy. But some important issues need to be addressed with regard to opioid prescription for non–cancer pain, namely the framework in which opioids are prescribed, when to initiate opioid therapy, who the appropriate candidates for opioid therapy are, and what the end point of treatment is.48 In general there is sufficient evidence to suggest that opioid analgesia is safe and effective for the treatment of patients with chronic low back pain, at least for the short duration. The evidence for functional improvement with opioids, however, is limited. Opioids appear to be a reasonable treatment option for patients with moderate to severe chronic low back pain that is refractory to general rehabilitation, injections, and nonopioid analgesic medications; for patients with pain that is not directly treatable because of the structural disorder; or because of patient preference.49
