Vertebral Augmentation: The Comprehensive Guide to Vertebroplasty, Kyphoplasty, and Implant Augmentation

5 Medical Pain Management in Patients with Vertebral Compression Fractures

Young Hoon Kim and Yong-Chul Kim

Summary

Vertebral compression fractures (VCFs) can result from osteoporosis, trauma, or neoplasm. Among these causes, the osteoporotic compression fracture is the most commonly encountered. Patients with compression fractures manifest a wide range of symptoms from being asymptomatic to having excruciating pain. In general, if VCFs heal, the symptoms will improve in approximately 6 to 12 weeks; however, during this time, the health-related quality of life can deteriorate. Therefore, management of the patient’s symptoms including adequate pain control is needed. Nonsurgical treatment is the traditional first-line management for VCFs and medications may also be prescribed to maximize patient comfort along with other procedures such as vertebroplasty or kyphoplasty. Although relatively little data on the medical management of nonoperative management of osteoporotic VCF have been reported, experts recommend that the pain management should initially begin with acetaminophen and/or nonsteroidal anti-inflammatory drugs. Analgesics (including narcotics and tramadol), muscle relaxants, and transdermal lidocaine can also be used for pain control. Additionally, medications to control neuropathic pain can be used in patients with VCFs and accompanying foraminal stenosis or tumor invasion. Finally, VCFs occur predominantly in older patients, and physicians must be aware of the pharmacological properties of the medications and their effects on elderly patients.

Keywords: acetaminophen, analgesics, medical management, nonsteroidal anti-inflammatory drug, nonsurgical management, vertebral compression fracture

5.1 Introduction

Osteoporosis, trauma, or neoplasm can all lead to vertebral compression fractures (VCFs). The osteoporotic compression fracture is the most commonly encountered type of fracture and the spectrum of symptoms vary widely from being asymptomatic to having excruciating pain. Nonsurgical management is the traditional first-line management for VCFs. The goals of nonsurgical management are pain control, early mobilization, prevention of deformity, and functional restoration. In spite of the nonsurgical management of VCFs being fairly common, there are relatively little data on the clinical outcomes of nonoperative management of osteoporotic VCF that have been reported.¹^–³ Additionally, the studies related to the cost-effectiveness of nonsurgical management have also been sparse. In a retrospective, propensity score-matched study of vertebroplasty, kyphoplasty, and nonsurgical management for the treatment of VCFs in 2,740 patients, vertebroplasty and kyphoplasty were identified to be significantly costlier at 1-year follow-up, but at 2- and 4-year follow-ups, no significant difference in cost was found.⁴ Moreover, the American Academy of Orthopaedic Surgeons determined that the strength of recommendation of the opioids/analgesics for patients who have VCFs is inconclusive due to a lack of data.¹ In practice, however, the medical management with or without bracing is usually recommended as the initial conventional treatment of VCFs.² Although medications are often used with other therapies for the treatment of back pain, they remain the mainstay in the management of moderate to severe fracture pain.

Table 5.1 Commonly used medications for the management of the vertebral compression fracture

Medication	Acute stage	Subacute to chronic stage
Acetaminophen	+	+
NSAID	+	–
Muscle relaxant	+	–
Tramadol	+	+
Transdermal lidocaine	+	+
Opioid	–	+
Anticonvulsant	–	+
Abbreviations: NSAID, nonsteroidal anti-inflammatory drug; +, available; –, not available.

VCFs usually manifest with nociceptive pain. However, when there is concomitant foraminal stenosis, severe spinal canal stenosis, or tumor invasion, they may present with accompanying neuropathic pain. Neuropathic pain is a direct consequence of a lesion or a compressive irritation affecting the nervous system.⁵ It is not easy to treat and the information available from randomized controlled trials upon which to base treatment in this matter is scarce. The management decisions may therefore be based on the individual physician’s perspectives and experience with this condition. The medications to manage pain include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics (including narcotics and tramadol), muscle relaxants, transdermal lidocaine, and adjuvant agents used to relieve neuropathic pain.⁶ Although the acute pain due to VCF is generally tolerable or gone within 6 to 12 weeks, it is recommended that the pharmacological management be started with acetaminophen and/or NSAIDs. If pain does not decrease with the first-line medications, opioids can then be used (▶Table 5.1). Finally, VCFs are more frequently found in elderly patients, and physicians should be aware of the pharmacological characteristics of these medications along with the possible adverse effects associated with the them in this particular patient population.

5.2 Nonsteroidal Anti-Inflammatory Drugs

NSAIDs are the most commonly prescribed medications for the treatment of pain. They have antipyretic, anti-inflammatory, and analgesic effects; the latter two explain their use in patients needing treatment for pain. The mechanism of action of NSAIDs is the inhibition of the prostaglandin synthesis through the inhibition of the cyclooxygenase (COX) enzymes (COX-1 and COX-2), which cause anti-inflammatory and analgesic effects. The COX-2 enzyme can be induced in some stressful conditions, such as nerve injury. Several organs such as the central nervous system and the kidney express COX-1 constitutively.⁷ NSAIDs that inhibit both COX-1 and COX-2 include aspirin, indomethacin, sulindac, diclofenac, ibuprofen, naproxen, and piroxicam. Those that selectively inhibit COX-2 include celecoxib, etoricoxib, and nimesulide.⁷ Although few studies have been published on the use of NSAIDs in patients with VCFs, there is some low-quality evidence that demonstrates immediate- and short-term effects of NSAID on reducing the pain of VCFs.³ Additionally, in a systematic review of 65 randomized controlled trials of NSAIDs in different types of back pain, NSAIDs were more effective than placebo and acetaminophen. However, there was strong evidence that there were no differences between the effects of various types of NSAIDs including COX-2 NSAIDs.⁸ Additionally, in a systematic review of 13 randomized controlled trials of NSAIDs in chronic low back pain, authors identified no difference in efficacy between different NSAID types.⁹

NSAIDs have a variety of side effects on various organ systems including the cardiovascular system (cardiovascular thrombosis, myocardial infarction, and stroke), the gastrointestinal tract (hemorrhagic gastric erosion and gastric ulcer), and the kidney (renal insufficiency, sodium and water retention, hypertension, and edema). The risk factors for NSAID-induced gastrointestinal complications include advanced age, history of ulcer, concomitant use of corticosteroids, high doses of NSAIDs, concomitant anticoagulants, serious systemic disorder, smoking, alcohol consumption, and concomitant infection with Helicobacter pylori.¹⁰ The risk of renal toxicity increases with chronic NSAID use, multiple NSAID use, dehydration, volume depletion, congestive heart failure, vascular disease, hyperreninemia, shock, sepsis, systemic lupus erythematosus, hepatic disease, sodium depletion, nephrotic syndrome, diuresis, concomitant drug therapy, and an age of 60 years or older.¹¹

Pharmacologically, COX-1 is involved in the formation of cytoprotective prostanoids and constitutively expressed in platelets and gastrointestinal tracts. Therefore, inhibition of COX-1 increases the risk of gastrointestinal bleeding. Gastric bleeding from preexisting gastric ulcers may also occur due to NSAID suppression of platelet aggregation.¹² Although the exact mechanism is not fully understood, video capsule endoscopy has found that NSAID-induced enteropathy occurs in the small intestine as well as the large intestine.¹³ Moreover, the discovery of COX enzyme, COX-1, and COX-2 led to the production of selective COX-2 inhibitors. Compared with nonselective COX inhibitors, the incidence and complications associated with gastrointestinal tract ulcers are reduced. In a comparative study, the risk of gastrointestinal adverse events was lower in patients treated with a COX-2 selective NSAID (celecoxib) than in those receiving a nonselective NSAID (diclofenac) with omeprazole.¹⁴ Celecoxib was also associated with significantly fewer small bowel mucosal breaks than ibuprofen plus omeprazole.¹⁵^,¹⁶ The preference for COX-2 selective agents to reduce gastrointestinal tract complications, however, has likely given rise to increased cardiovascular side effects. The worrisome complications discovered by various studies resulted in the withdrawal of two of three COX-2 selective agents (rofecoxib and valdecoxib). Only celecoxib remains in the market with warnings regarding its cardiovascular profile.

The mechanism for the increase in cardiovascular risks is believed to result from an imbalance between pro- and antithrombotic prostaglandin. Thromboxane A2 is a platelet activator and vasoconstrictor, whereas prostacyclin (PGI2) is a platelet inhibitor and vasodilator. Platelet activity is maintained by the balance between thromboxane A2 effects on platelets and PGI2 effects on endothelium. Aspirin and nonselective NSAIDs inhibit both COX-1 and COX-2 and decrease both thromboxane A2 and PGI2. Conversely, COX-2 selective NSAIDs reduce PGI2 synthesis without affecting thromboxane A2 synthesis.¹⁷^,¹⁸ The antithrombotic unbalance may thereby cause the increased cardiovascular risk. Nonetheless, the Food and Drug Administration (FDA) announced labeled changes for all NSAIDs, both COX-2 selective and nonselective, that may have a similar cardiovascular risk. Consequently, patients without cardiovascular risk factors and low gastrointestinal tract risk can receive a monotherapy of an NSAID. However, patients with low cardiovascular risk without prophylactic aspirin but who are at high gastrointestinal tract risk should receive COX-2 selective NSAID or a traditional NSAID plus a proton-pump inhibitor.¹⁹

NSAIDs may also result in deterioration of renal function and renal failure. The mechanism of renal dysfunction is a decreased renal prostaglandin production, which leads to a reduction in renal blood flow and medullary ischemia.²⁰ The renal profile of NSAIDs is related to sodium retention and glomerular filtration rate changes. All NSAIDs have been associated with hypertension and edema, but most of these side effects improve with discontinuation of therapy.¹¹

5.3 Acetaminophen

No studies have reported the efficacy of acetaminophen (paracetamol) for the management of VCFs. Its usage is based on tradition, low economic burden, optimal gastrointestinal safety profile, and uncommon side effects. Acetaminophen, known as paracetamol, is a p-aminophenol derivative with analgesic and antipyretic properties. The mechanism of action is not fully understood, but it is thought to act via central and peripheral mechanisms. Its ability to inhibit the central prostaglandin synthesis is similar to aspirin, but its peripheral inhibition of prostaglandin synthesis is not significant. Therefore, it lacks effectiveness for peripheral anti-inflammatory inhibition compared to aspirin for painful, inflammatory conditions.²¹ Doses of 600 to 650 mg are more effective than doses of 300 to 350 mg, but better effects are not reported above 1,000 mg, indicating an analgesic ceiling effect.²² A dose of 2,600 to 3,200 mg per day is adequate as a chronic daily dose, but the overall dose of acetaminophen should not exceed 4 g/d.²³ Nephrotoxicity may occur in relation to acetaminophen but less so than with NSAIDs. Acetaminophen is almost completely metabolized in the liver, and the minor metabolites in overdose are associated with hepatotoxicity.⁷

5.4 Opioid Analgesics

Opioids are the most potent analgesics available and play an important role in the management of acute and chronic pain. Nociceptive pain is more responsive to opioid analgesics than neuropathic pain. In general, there is sufficient evidence to suggest that opioid analgesia is safe and effective in treating patients with chronic low back pain for at least a short duration but should not be used chronically.²⁴^–²⁷ Although there is a lack of data and studies on nonsurgical management of VCFs, in a meta-analysis of study associated with nonsurgical management of osteoporotic compression fractures, the use of opioids (tramadol, oxycodone, and tapentadol) showed a significant improvement in pain compared with the use of placebo or Chinese medicine.³ Opioids may be used in patients with inadequately treated pain that does not respond to the first-line medications. Opioid analgesia is usually continued until the acute pain is reduced, proper mobilization is possible, and no progressive deformity is confirmed.

Opioids function by binding to μ-, κ-, and δ-receptors in the central and peripheral nervous system. They are G protein–coupled receptors that modulate ionic channels and intracellular pathways.²⁸ Opioids are available in combination with NSAIDs, which have significant opioid dose-sparing effects.²⁹ Among the available opioids, meperidine is not appropriate due to its low oral bioavailability, potential metabolite accumulation, and toxicity with prolonged administration. Although opioid has no ceiling effect, high doses increase the occurrence of adverse effects and increase the risk of overdose; thus, a practical ceiling effect should be accounted in the clinical practice. The side effects of opioids include constipation, urinary retention, nausea and vomiting, itching, sedation, decreased libido, cognitive blunting, and respiratory depression. Among those, constipation is the most common side effect. Therefore, a high-fiber diet with a good bowel regimen should be advised, and often a laxative should be prescribed when using opioid therapy. The patients develop tolerance to some side effects of opioids, such as sedation, nausea, and respiratory depression, but not to other side effects including constipation, sweating, and urinary retention.

5.5 Muscle Relaxants

Muscle relaxants are a heterogeneous group of agents that mainly act on the central nervous system. Many patients with VCFs often present with muscle spasms, and muscle relaxants may be helpful in managing painful paravertebral muscle spasms. It is recommended that muscle relaxants be used only during the acute phase, and there is no information on the long-term outcomes in chronic low back pain.³⁰ The side effects of muscle relaxants include drowsiness, dizziness, dependence, and abuse in the long-term period.³¹

5.6 Calcitonin

A systematic review and meta-analysis on the use of calcitonin for the management of patients with recent osteoporotic vertebral fractures identified five randomized double-blind placebo-controlled trials involving a total of 246 patients and suggested that calcitonin appears to provide a significant improvement in pain control.³² Calcitonin may be helpful in facilitating earlier mobilization during the time of hospitalization.³³ A number of mechanisms have been suggested to account for the analgesic action of calcitonin, including increased plasma β-endorphin release in the pituitary gland, decreased synthesis of prostaglandins or other humoral factors, modulation of pain perception through a central mechanism involving calcitonin-binding receptors in the central nervous system, and perhaps an effect on local pain mediators through calcitonin-binding sites in the periphery.³²^,³⁴

5.7 Transdermal Lidocaine

Although no randomized trial has reported that transdermal lidocaine is beneficial for the management of patients with osteoporotic vertebral fractures, it is commonly used in the clinical practice.⁶ The recommended maximum daily dose is three patches applied simultaneously every 12 hours. Transdermal lidocaine is not associated with side effects except for mild skin reactions. However, attention is required in patients who receive oral Class I antiarrhythmic agents (e.g., mexiletine) and in patients with severe hepatic dysfunction to avoid antagonistic cardiac effects or toxicity.³⁵

5.8 Bisphosphonate

Bisphosphonates have been used for reducing back pain related to acute vertebral fracture. In a randomized, double-blind controlled trial comparing intravenous pamidronate (30-mg intravenous pamidronate daily for three consecutive days) and placebo, pamidronate provided rapid and sustained pain relief in patients with acute painful osteoporotic VCFs.³⁶ In a comparison study of the analgesic efficacy of intravenous pamidronate and calcitonin in osteoporotic VCFs, however, calcitonin was recommended because of no difference in analgesic effect between groups and the low cost of calcitonin.³⁷

5.9 Anticonvulsants

Anticonvulsants, including gabapentin, carbamazepine, and pregabalin, have been traditionally used to treat chronic neuropathic pain. Although gabapentin was originally made as a structural analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind to GABA receptors and its mechanism is not fully elucidated. Its analgesic effect is likely to act on the α2δ subunit of voltage-dependent calcium channels for which it has a substantial affinity and which are upregulated in the dorsal root ganglia and spinal cord after peripheral nerve injury.³⁸^,³⁹ Analgesic effects of gabapentin result from binding to and presynaptically inhibiting voltage-dependent calcium channels, preventing calcium influx, then inhibiting the release of excitatory amino acids such as glutamate from the presynaptic terminals.⁴⁰ Gabapentin has been shown to be effective in the treatment of a variety of chronic neuropathic pain. However, there is controversy regarding its therapeutic effect on acute pain and there has been no randomized controlled trial on the effect of gabapentin in acute painful VCFs. The use of gabapentin may be appropriate for the patients who have coexistence of both nociceptive and neuropathic pain, such as foraminal stenosis or tumor invasion. A meta-analysis showed that gabapentin significantly reduced pain and decreased the opioid usage in patients who perioperatively received gabapentin,⁴¹ but there is little evidence in the literature regarding the use of anticonvulsants in painful vertebral compressed fractures, and more research in this matter is needed to formulate evidence-based recommendations.

5.10 Conclusion

VCFs may result in serious pain and deteriorate patients’ health-related quality of life. Although the acute pain due to VCF is often alleviated within 6 to 12 weeks, it may persist and medical management of pain is recommended in both the acute and subacute phases. Pharmacological therapy should be started with acetaminophen and/or NSAIDs. Patients who do not respond to the first-line medications may be prescribed with opioids. Adjuvant medications can be added in patients who show signs of neuropathic pain. Physicians should be aware of the useful role and side effects associated with these medications to achieve the goals of optimal nonsurgical management, such as adequate pain control, early mobilization, prevention of deformity, and functional restoration.